CN111018858B - Heterocyclic derivative and preparation method and application thereof - Google Patents
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Abstract
The invention belongs to the technical field of pharmaceutical chemistry and medicine, and relates to heterocyclic derivatives, and a preparation method and application thereof. The invention provides heterocyclic derivatives as shown in formula (1), wherein R represents substituted or unsubstituted five-membered or six-membered heterocyclic ring. The invention also provides a preparation method of the heterocyclic derivative and adenosine A 2A Receptor antagonistic activity and use as antitumor drug.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry and medicine, and particularly relates to heterocyclic derivatives, and a preparation method and application thereof.
Background
The prior art discloses that the tumor immunotherapy is the fourth major tumor treatment method following surgical treatment, radiotherapy and chemotherapy drug treatment, and has made rapid progress in recent years, leading to a major breakthrough in the field of tumor therapy. The american clinical oncology society of 2016 and 2017 has rated "immunotherapy" as an annual advance in antitumor research for two consecutive years. It is reported that the tumor immunotherapy is a therapeutic strategy for stimulating and enhancing the immune function of the body by various means, and finally achieving the purpose of controlling and killing tumor cells through the body's own immune system. According to Lerink Partners' prediction, the global tumor immunotherapy drug market size will reach $ 167 billion by 2020, and the tumor immunotherapy drug market size will achieve more than 2-fold increase to $ 361 billion by 2025. Currently, the focus of the field and research in which tumor immunotherapy is successful is mainly on immune checkpoint inhibitors.
Since 2011 Ipilimumab (CTLA-4 inhibitor, bristol, precious) was approved by the FDA in the united states for marketing as the first immunotherapeutic agent for melanoma, research in this area has progressed at a surprising rate. Nivolumab (PD-1 inhibitor, bosch, zu-miyao, 2014), pembrolizumab (PD-1 inhibitor, merck, 2014), and Atezolizumab (PD-L1 inhibitor, roche, 2016) were all successively approved by the FDA in the united states for marketing. In addition to novel immune checkpoints such asIndole amine 2, 3-dioxygenase-1 (IDO 1), adenosine A 2A Receptor (A) 2A R), T cell immunoglobulin, mucin-3 (TIM-3), and the like have also been the focus of research.
Adenosine A 2A R antagonists have been studied previously as therapeutic parkinson agents: istradefylline, although approved in Japan, is terminated by the United states FDA; the clinical phase III of Preladenant is terminated; vipadenant phase II was terminated. In recent years, the research on tumor immunotherapy discovers A 2A The R antagonist SCH58261 significantly inhibits the metastatic spread of CD73 positive tumors (B16F 10 melanoma) by improving NK cell function, and SCH58261 or ZM241365 was found to improve the activity of anti-PD 1 monoclonal antibody or anti-CTLA 4 monoclonal antibody when used in combination. Gov website discloses the clinical phase I/Ib trial by nova and Palobiofarma on PBF-509 alone or in combination with the PD-1 inhibitor PDR001 for the treatment of non-small cell lung cancer, and the clinical phase I/Ib trial by gortex and Corvus on CPI-444 alone or in combination with the PD-1 inhibitor Atezolizumab for the treatment of solid tumors. Also, the company Asricon and Heaptare Therapeutics was also prepared to initiate a clinical phase I trial of HTL-1071 alone or in combination with the PD-L1 inhibitor Durvalumab for the treatment of non-small cell lung cancer. Redox therapeutics was purchased by CAR-T Juno corporation 2016 to obtain its small molecule drug Vipadenant ready for combination therapy with CAR-T therapy.
Based on the current state of the art, the inventors of the present application intend to provide heterocyclic derivatives, and preparation methods and uses thereof.
Disclosure of Invention
The present invention aims to provide a heterocyclic derivative based on the current state of the art.
The invention also aims to provide a preparation method and application of the heterocyclic derivative.
The invention provides a heterocyclic derivative shown as the following formula (1):
in the formula, R represents a substituted or unsubstituted five-membered or six-membered heterocyclic ring.
The invention also provides a preparation method of the heterocyclic derivative, which comprises the following specific steps:
a, step a: carrying out reflux reaction on 5-bromo-4-chloropyrimidine-2-amine (2) and heterocycle substituted carbohydrazide compounds (3) in the absence of a solvent or in a solvent to generate 5-bromo-pyrimidine-2-amine derivatives (4);
step b: 5-bromo-pyrimidine-2-amine derivative (4), and N, O-bis-trimethylsilylacetamide (cas: 10416-59-8), hexamethyldisilazane (cas: 999-97-3), in the absence of solvent or in solvent, refluxing to form ring, 8-bromo- [1,2,4] triazolo [1,5-c ] pyrimidine-5-amine compound (5);
step c: the 8-bromo- [1,2,4] triazolo [1,5-c ] pyrimidine-5-amine compound (5) and 1-methyl-6-oxo-1, 6-dihydropyridine-3-boronic acid pinacol ester are subjected to reflux reaction in a solvent under the action of a catalyst under alkaline conditions to generate the corresponding heterocyclic compound (1).
In the present invention, the solvent used in step a may be any solvent as long as the solvent itself is inert in the reaction and does not inhibit the reaction; the solvent includes halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1, 2-dichloroethane, etc.; aromatic hydrocarbon solvents such as benzene and toluene, etc.; aprotic solvents such as acetone, acetonitrile, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, sulfolane, cyclobutanesulfoxide, and hexamethylenephosphoric triamide; ester solvents such as ethyl acetate and methyl acetate, etc.; ether solvents such as tetrahydrofuran, diethyl ether and 1, 4-dioxane; organic base solvents such as pyridine, picoline, etc.; protic solvents such as methanol, n-butanol, etc.; or mixtures of these solvents. The reaction temperature can be between 80 ℃ and 120 ℃, and 100 ℃ to 120 ℃ is preferably adopted; the molar ratio of the starting materials may be any, but it is preferred to use a ratio of 2: 1.
In the present invention, the solvent used in step b may be any solvent as long as the solvent itself is inert in the reaction and does not inhibit the reaction; the solvent includes halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1, 2-dichloroethane and the like; aromatic hydrocarbon solvents such as benzene and toluene, etc.; aprotic solvents such as acetone, acetonitrile, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, sulfolane, cyclobutanesulfoxide, and hexamethylenephosphoric triamide; ester solvents such as ethyl acetate and methyl acetate, etc.; ether solvents such as tetrahydrofuran, diethyl ether and 1, 4-dioxane; organic base solvents such as pyridine, picoline, etc.; protic solvents such as methanol, n-butanol, etc.; or mixtures of these solvents. The reaction temperature can be between 80 ℃ and 120 ℃, and preferably 100 ℃ to 120 ℃; the molar ratio of the starting materials may be any, and 1: 1 is preferably used.
In the present invention, the base in step c may be an organic base such as triethylamine, pyridine, N-diisopropylethylamine, 4-dimethylaminopyridine, 1, 8-diazabicyclo [5.4.0] -7-undecene, 1,2, 6-pentamethylpiperidine and the like, or an inorganic base such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate and the like; the solvent used in the preparation method may be any solvent as long as the solvent itself is inert in the reaction and does not inhibit the reaction; the solvent includes halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1, 2-dichloroethane, etc.; aromatic hydrocarbon solvents such as benzene and toluene, etc.; aprotic solvents such as acetone, acetonitrile, N-dimethylformamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, sulfolane, cyclobutanesulfoxide, and hexamethylenephosphoric triamide; ester solvents such as ethyl acetate, methyl acetate and the like; ether solvents such as tetrahydrofuran, diethyl ether and 1, 4-dioxane; organic base solvents such as pyridine, picoline, etc.; or a mixture of these solvents, the preferred solvent being water, 1, 4-dioxane. The reaction temperature can be between 80 ℃ and 120 ℃, and preferably between 80 ℃ and 100 ℃; the molar ratio of the starting materials may be any, and 1: 1 is preferably used. The catalyst may be a palladium-based catalyst, and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium is preferably used.
The heterocyclic compound can be used for preparing medicines, in particular to tumor immunotherapy medicines.
In the present invention, adenosine A is performed in vitro on the compound represented by the general formula (1) 2A The results of the activity test and the in vivo anti-tumor effect of the receptor show that the compound has adenosine A 2A Receptor antagonistic activity and antitumor action, and thus can be used for preparing medicaments containing the above heterocyclic compounds as active ingredients.
The heterocyclic compound can be prepared into a pharmaceutical composition containing a safe and effective amount of the novel heterocyclic compound and a medicinal carrier and various preparations.
In the present invention, the "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount is determined according to the age, condition, course of treatment, etc. of the subject.
By "pharmaceutically acceptable carrier" is meant: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity.
By "compatible" is meant that the components of the composition are capable of intermixing with and between the compounds of the present invention without significantly diminishing the pharmaceutical effectiveness of the compounds.
Examples of pharmaceutically acceptable carrier moieties are sugars such as glucose, sucrose, lactose and the like; starches, such as corn starch, potato starch, and the like; cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.; gelatin, talc, solid lubricants, such as stearic acid, magnesium stearate; calcium sulfate, vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.; polyhydric alcohols such as propylene glycol, glycerin, mannitol, sorbitol, and the like; emulsifiers, e.g. Tween
(ii) a Wetting agents, such as sodium lauryl sulfate; coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
For the sake of understanding, the present invention will be described in detail below by way of specific examples. It is specifically noted that the specific examples are given for illustrative purposes only, and it will be apparent to those skilled in the art that various modifications and variations can be made in the present invention within the scope of the present invention based on the descriptions herein.
Detailed Description
Example 1: synthesis of heterocyclic Compound (1 a)
A, step a: 5-bromo-4-chloropyrimidin-2-amine (2) (370.27mg, 2.94mmol), 2-furancarbohydrazide (3 a) (300mg, 1.44mmol) in 10mL of n-butanol, refluxing at 120 ℃ under nitrogen for 12 hours, removing the solvent by concentration under reduced pressure, and subjecting to silica gel column Chromatography (CH) 2 Cl 2 MeOH = 10) to give N' - (2-amino-5-bromopincidin-4-yl) furan-2-carbohydrazide (4 a), 1 H NMR(400MHz,DMSO)δ(ppm):8.10(s,1H),7.22(s,1H),7.23-7.22(d,J＝3.6Hz,1H),6.62-6.61(t,J＝1.6Hz,1H)。ESI-MS：298[M+1] + 。
step b: adding hexamethyldisilazane (cas: 999-97-3,1.5 mL) to 5-bromo-pyrimidin-2-amine derivative (4 a) (150mg, 503.19. Mu. Mol) and N, O-bistrimethylsilyl acetamide (cas: 10416-59-8,1.5 mL), reflux-reacting at 120 ℃ for 12 hours under nitrogen protection, concentrating under reduced pressure to remove the solvent, and performing silica gel column Chromatography (CH) 2 Cl 2 MeOH = 10)]triazolo[1,5-c]pyrimidin-5-amine(5a)； 1 H NMR(400MHz,DMSO)δ(ppm):8.16(s,2H),8.04(s,1H),7.98-7.96(d,J＝3.2,1H),7.27-7.26(d,J＝3.2Hz,1H),6.74-6.73(d,J＝1.6Hz,1H)。ESI-MS：280[M+1] + 。
Step c: 8-bromo- [1,2,4]Triazolo [1,5-c ]]Pyrimidin-5-amine compound (5 a) (110mg, 392.74. Mu. Mol), 1-methyl-6-oxo-1, 6-dihydropyridine-3-boronic acid pinacol ester (92.33mg, 392.74. Mu. Mol, 92.33. Mu.L), potassium carbonate (108.56mg, 785.48. Mu. Mol), dissolved in 1, 4-dioxane (3.00 mL) and water (300. Mu.L), nitrogen gasReflux reacting at 90 deg.C for 12 hr under protection, concentrating under reduced pressure to remove solvent, and performing silica gel column Chromatography (CH) 2 Cl 2 MeOH = 10) to give compound 1a (11.80 mg, yield 9.75%).
5-(5-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1-methylpyridin-2(1H)-one(1a): 1 H NMR(400MHz,DMSO)δ(ppm):8.43(d,J＝2.3Hz,1H),8.06(dd,J＝8.8,2.6Hz,1H),8.02(s,1H),7.72(s,1H),7.26(d,J＝3.5Hz,1H),6.66–6.61(m,2H),3.66(s,3H). 13 C NMR(400MHz,MeOD)δ(ppm)：160.90,158.18,154.31,152.31,147.05,146.18,139.38,136.86,120.22,113.73,113.02,110.23,101.42,38.55。ESI-MS：309[M+1] + 。
Example 2: synthesis of heterocyclic Compound (1 b-i)
8-bromo- [1,2,4]Triazolo [1,5-c]Pyrimidine-5-amine compounds (5 b-i) (400. Mu. Mol), 1-methyl-6-oxo-1, 6-dihydropyridine-3-boronic acid pinacol ester (400. Mu. Mol), potassium carbonate (800. Mu. Mol), dissolved in 1, 4-dioxane (4.00 mL) and water (400. Mu.L), reacted under reflux at 100 ℃ under nitrogen for 10 hours, concentrated under reduced pressure to remove the solvent, and chromatographed on silica gel Column (CH) with reduced pressure 2 Cl 2 MeOH = 10) to give compounds 1b-i.
5-(5-amino-2-(5-methylfuran-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1-methylpyridin-2(1H)-one(1b). 1 H NMR(400MHz,DMSO)δ(ppm):8.50(s,1H),8.15–7.96(m,4H),7.18(d,J＝1.2Hz,1H),6.53(d,J＝9.7Hz,1H),6.36(d,J＝0.9Hz,1H),3.54(s,3H),2.40(s,3H). 13 C NMR(400MHz,DMSO)δ(ppm)：161.02,156.02,154.42,151.41,146.93,143.91),142.44,138.79,137.40,119.04,113.84,111.56,108.46,107.90,37.29,13.50.ESI-MS：323[M+1] + 。
5-(5-amino-2-(pyridin-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1-methylpyridin-2(1H)-one(1c). 1 H NMR(400MHz,DMSO)δ(ppm):8.77(d,J＝4.2Hz,1H),8.57(d,J＝1.7Hz,1H),8.37(d,J＝7.8Hz,1H),8.21–8.00(m,5H),7.58(dd,J＝7.0,5.2Hz,1H),6.55(d,J＝9.5Hz,1H),3.56(s,3H). 13 C NMR(400MHz,DMSO)δ(ppm)：162.59,161.05,151.65,149.72,148.77,147.10,142.11,138.81,137.46,125.27,123.41,119.06,111.57,108.36,37.34.ESI-MS：320[M+1] + 。
5-(5-amino-2-(thiazol-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1-methylpyridin-2(1H)-one(1d). 1 H NMR(400MHz,DMSO)δ(ppm):δ8.46(d,J＝1.7Hz,1H),8.20–8.09(m,5H),8.04(d,J＝2.9Hz,1H),6.55(d,J＝9.5Hz,1H),3.54(s,3H). 13 C NMR(400MHz,DMSO)δ(ppm)：161.02,158.12,157.84,151.70,147.07,144.65,142.94,138.92,137.46,123.54,119.07,111.39,108.34,37.29.ESI-MS：326[M+1] + 。
5-(5-amino-2-(1-methyl-1H-pyrazol-5-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1-methylpyridin-2(1H)-one(1e). 1 H NMR(400MHz,DMSO)δ(ppm):8.57(d,J＝1.6Hz,1H),8.21–8.05(m,4H),7.59(d,J＝0.6Hz,1H),7.00(d,J＝1.0Hz,1H),6.53(d,J＝9.5Hz,1H),4.32(s,3H),3.54(s,3H)。 13 C NMR(400MHz,DMSO)δ(ppm)：161.00,155.70,151.06,146.84,142.47,138.52,138.19,137.48,133.08,119.14,111.41,108.29,108.03,37.32.ESI-MS：323[M+1] + 。
5-(5-amino-2-(1-methyl-1H-pyrazol-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1-methylpyridin-2(1H)-one(1f). 1 H NMR(400MHz,DMSO)δ(ppm):8.52(d,J＝0.4Hz,1H),8.14(d,J＝12.7Hz,2H),7.99(s,2H),7.87(s,1H),6.89(s,1H),6.53(d,J＝9.4Hz,1H),3.96(s,3H),3.54(s,3H). 13 C NMR(400MHz,DMSO)δ(ppm)：161.05,158.95,151.33,146.94,142.51,142.02,138.88,137.37,132.26,119.02,111.70,108.09,106.26,37.31.ESI-MS：323[M+1] + 。
5-(5-amino-2-(6-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1-methylpyridin-2(1H)-one(1g). 1 H NMR(400MHz,DMSO)δ(ppm):8.57(d,J＝1.9Hz,1H),8.20-7.89(m,5H),7.91(t,J＝7.6Hz,1H),7.43(d,J＝7.8Hz,1H),6.55(d,J＝9.5Hz,1H),3.56(s,3H),2.58(s,3H). 13 C NMR(400MHz,DMSO)δ(ppm)：162.84,161.05,158.36,151.55,148.39,147.15,142.21,138.84,137.46,124.67,120.82,119.07,111.60,108.28,37.33,24.06.ESI-MS：334[M+1] + 。
5-(5-amino-2-(5-methylthiazol-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1-methylpyridin-2(1H)-one(1h). 1 H NMR(400 MHz,DMSO)δ(ppm):8.46(d,J＝2.0Hz,1H),8.18(s,1H),8.16–8.09(m,3H),7.79(s,1H),6.55(d,J＝9.6Hz,1H),3.53(s,3H),2.56(s,3H). 13 C NMR(400MHz,DMSO)δ(ppm)：1601.01,155.90,154.56,152.29,1467.03,144.78,142.73,138.88,137.42,129.46,127.24,119.06,108.26,99.53,37.30,11.65.ESI-MS：340[M+1] + 。
5-(5-amino-2-(4-methylthiazol-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1-methylpyridin-2(1H)-one(1i). 1 H NMR(400MHz,DMSO)δ(ppm):δ8.44(d,J＝2.5Hz,1H),8.20–8.08(m,4H),7.58(s,1H),6.55(d,J＝9.4Hz,1H),3.54(s,3H). 13 C NMR(400MHz,DMSO)δ(ppm)：161.04,158.14,156.93,154.21,151.68,147.09,142.95,138.99,137.45,119.07,117.91,111.42,37.30,16.81.ESI-MS：340[M+1] + 。
Example 3: compounds 1a-i adenosine receptor A in vitro 2A R and A 3 Affinity assay for R
Detection of Compound versus A Using radioligand Competition binding assays 2A R and A 3 Affinity of R receptor: a in HeLa cells 2A R and 2 3 H]ZM241385 specific binding, A in HeLa cells 3 R and 2 3 H]-NECA specific binding. A membrane protein solution (60. Mu.g/tube containing ADU 2 mg/mL) and radioactive ligand 1nM 0.2nM [ 2 ], [ 3 H]ZM241385 and the like, adding 10 μ M NECA/R-PIA at the final concentration into a non-specific tube, adding compounds at different concentrations into a compound tube respectively, shaking and uniformly mixing, incubating at 37 ℃ for 30min, terminating the reaction in a water bath, performing negative pressure suction filtration by using GF/C glass fiber filter paper to separate free ligand and bound ligand, and washing 3 times with precooled 50mM Tris-HCl, wherein each time is about 4mL. The film was removed, inverted on a tray (i.e., grid side up), and baked for 3min until dry. The machine is cleaned in the same process. The dried small round filter membranes were placed in an EP tube (which must be pressed to the bottom of the tube) in order, and 540. Mu.L of scintillation fluid was added. Is carried out in a Beckman LS-6500 model multifunctional liquid scintillation counter 3 H]And (6) counting. Two double pipes are made at each joint point, and an average value is taken.
TABLE 1 affinity Ki (nM) of Compounds 1a-i for adenosine receptors
Example 4: compound 1a to A 2A Antagonism of R
A 1 R and A 3 R can inhibit adenylate cyclase and inhibit cyclic adenosine monophosphate (cAMP) generation; and A is 2A R and A 2B R activates adenylate cyclase, inducing an increase in cAMP levels. 5' -N-ethyllcarboxamido-adenosine (NECA) is a stable analog of adenosine and is not readily degraded by natural enzymes and is commonly used in place of adenosine. The experiment shows that the A can be expressed endogenously 2B In HEK293 cells of R, 1 μ M Compound 1a completely inhibited cAMP production in cells stimulated by NECA, indicating that it has A 2A R antagonism.
Example 5: research on antitumor effect of compound 1a in mice
B16 murine melanoma model: b16 murine melanoma cells were suspended in PBS and dilutions (2.0X 10) 5 Cell/cell) were inoculated on the hind sole of six-week-old C57BL/6 male mice, and compound 1a (1 mg/kg) was administered intraperitoneally (i.p) (1 time per week, 4 times in total) and a blank control group of 6 cells each. Tumor volumes were measured every two days for a total of 28 days for efficacy assessment. The experimental result shows that the tumor volume of the blank control group at day 28 is 552 +/-83 mm 3 And the tumor volume of the administration group at day 28 is 281 +/-34 mm 3 (P is less than 0.01), which shows that the compound 1a can obviously delay the growth of the melanoma of the B16 mouse after being treated;
initial anti-tumor growth mechanism study: further detection of CD25 by flow cytometry at day 28 + Foxp3 + Regulatory T cells in CD4 + The ratio in T cells, the ratio of blank control group was 11.3 + -2.1% and the ratio of administered group was 5.2 + -0.9% (P < 0.01), indicating that Compound 1a antagonizes A 2A R, inhibitionT cells differentiate into regulatory T cells, which have the mechanism of promoting anti-tumor immunity.
Claims (3)
1. Heterocyclic derivatives represented by formula (1):
in the formula, R represents a substituted or unsubstituted five-membered or six-membered heterocyclic ring,
the heterocyclic derivative is prepared by the following method, which comprises the following steps:
step a: carrying out reflux reaction on 5-bromo-4-chloropyrimidin-2-amine (2) and a heterocycle substituted carbohydrazide compound (3 a) under the condition of no solvent or in a solvent to generate a 5-bromo-pyrimidine-2-amine derivative (4 a);
step b: 5-bromo-pyrimidine-2-amine derivatives (4 a), N, O-bis (trimethylsilyl) acetamide and hexamethyldisilazane are subjected to a reflux reaction in the absence of a solvent or in a solvent to form 8-bromo- [1,2,4] triazolo [1,5-c ] pyrimidine-5-amine compounds (5 a);
step c: carrying out reflux reaction on 8-bromo- [1,2,4] triazolo [1,5-c ] pyrimidine-5-amine compounds (5 a) and 1-methyl-6-oxo-1, 6-dihydropyridine-3-boronic acid pinacol ester in a solvent under the action of a catalyst under alkaline conditions to generate corresponding heterocyclic compounds (1 a);
or the like, or, alternatively,
the compound (1 b-i) is,
2. use of heterocyclic derivatives according to claim 1 for the preparation of adenosine a 2A Formulations of receptor antagonistic activityThe use of (1).
3. Use of the heterocyclic derivative according to claim 1 for the preparation of an anti-tumor medicament.
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| CN1446202A (en) * | 2000-08-11 | 2003-10-01 | 卫材株式会社 | 2-aminopyridine compounds and use thereof as drugs |
| WO2017100849A1 (en) * | 2015-12-15 | 2017-06-22 | The University Of Queensland | 6-oxopurine phosphoribosyl transferase inhibitors |
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| AR070127A1 (en) * | 2008-01-11 | 2010-03-17 | Novartis Ag | PIRROLO - PIRIMIDINAS AND PIRROLO -PIRIDINAS |
| TWI652014B (en) * | 2013-09-13 | 2019-03-01 | 美商艾佛艾姆希公司 | Heterocyclic substituted bicycloazole insecticide |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1446202A (en) * | 2000-08-11 | 2003-10-01 | 卫材株式会社 | 2-aminopyridine compounds and use thereof as drugs |
| WO2017100849A1 (en) * | 2015-12-15 | 2017-06-22 | The University Of Queensland | 6-oxopurine phosphoribosyl transferase inhibitors |
Non-Patent Citations (1)
| Title |
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| 吡唑类稠环化合物的合成研究进展;陈霄 等;《化工生产与技术》;20101231;第17卷(第3期);第37-45页 * |
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