Tricyclic pyrimidine compound derivative and use thereof

Abstract

The present invention relates to the field of medicinal chemistry, and specifically relates to a tricyclic pyrimidine compound derivative and a use thereof. Specifically, the present invention provides a tricyclic pyrimidine compound derivative as represented by formula I, or a pharmaceutically acceptable salt or solvent thereof. The compound, as a novel adenosine A2A and / or A2B receptor antagonist, has adenosine A2AR and / or A2BR inhibitory activity, and is expected to be used for preparing a drug for preventing or treating diseases related to A2AR and / or A2BR.

Description

A tricyclic pyrimidine derivative and its application Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a tricyclic pyrimidine compound derivative and its applications, particularly a tricyclic pyrimidine compound derivative and its use as adenosine A. 2A and / or A 2B Uses of receptor antagonists. Background Technology

[0002] Adenosine signaling plays a crucial role in physiological and pathological processes in the human body. Adenosine receptors are class A G protein-coupled receptors, including A1R and A... 2A R, A 2B The four adenosine receptor subtypes, R and A3R, are regulated by endogenous ligands and directly affect the level of 3′,5′-cyclic adenosine monophosphate (cAMP). Due to their unique tissue distribution, sequence homology, and specific signaling pathways, each adenosine receptor subtype has a unique function, among which A... 2A R / A 2B R has attracted the attention of many scholars and companies, becoming a potential drug target for a variety of diseases, including inflammation, tumors, central nervous system and immune system diseases.

[0003] A 2A R has a high affinity for adenosine and is widely expressed on the surface of many immune cells, such as regulatory T (Treg) cells, cytotoxic T cells, and NK cells. Activation of A 2A R works by limiting Treg cell function, NK cell toxicity, and tumor-specific CD4. + / CD8 + It inhibits tumor immunity by suppressing cell activity and the production of cytokines such as IL-2 and IFN-γ (Kjaergaard J, et al. J Immunol, 2018, 201, 782-791). Furthermore, it blocks A with the antagonist SCH58261. 2A R can also enhance the efficacy of anti-PD1 therapy by strengthening anti-tumor T-cell responses (Beavis PA, et al. Cancer Immunol Res, 2015, 3, 506-517). Therefore, blocking A with specific antagonists... 2A R is considered an effective cancer immunotherapy strategy.

[0004] A 2BR is widely expressed in tissues other than the cecum, colon, mast cells, and hematopoietic cells, but usually at low levels. It has the lowest affinity for adenosine among the four isoforms (30-300 nM) and remains silent under healthy conditions. There is now strong evidence that extracellular adenosine levels can reach micromolar concentrations under specific pathological conditions such as hypoxia, inflammation, infection, and cancer. 2B R is activated at this time. Therefore, A 2B The therapeutic potential of R as a drug target is receiving increasing attention. 2B R-antagonists are considered potential drugs for treating inflammation, diabetes, pain, asthma, pulmonary fibrosis, and anti-aging. Recently, A... 2B R is considered a key player in cancer progression, such as tumor growth, metastasis, and angiogenesis (Effendi WI, et al. Cells, 2020, 9, 785; Jain S, et al. Biochem Pharmacol, 2021, 187, 114393). Previous studies have shown that adenosine, through A... 2B R stimulation polarizes tumor-associated macrophages into immunosuppressive M2 macrophages, thereby further inhibiting CD4. + T cell activity (Vijayan D, et al. Nat Rev Cancer, 2017, 17, 709-724). In addition, A 2B R has also been shown to increase the secretion of angiogenic factors (such as VEGF) and angiogenesis of myeloid-derived suppressor cells (MDSCs), becoming a novel mechanism for promoting tumor growth (Sorrentino C, Oncotarget, 2015, 6, 27478). In a mouse melanoma model, blocking A with PSB1115 2B R may inhibit tumor growth by reducing the accumulation of MDSCs and restoring an effective anti-tumor T cell response (Iannone R, et al. Neoplasia, 2013, 15, 1400). These results confirm that A 2B R plays an important role in tumor growth and immunosuppression. Inhibiting this target not only has a direct anti-proliferative effect, but also activates the body's anti-tumor immune response.

[0005] It is worth noting that A 2A R and A 2B R is often co-expressed on immune cells in the tumor microenvironment, A 2B R can affect A by directly regulating tumor cell survival or activating MDSCs. 2A R plays a compensatory role. In addition, anti-tumor CD8... + T cells express A, which has cAMP-promoting function. 2A R and A 2BR, leading to T cell dysfunction (Ohta A, et al. Proc Natl Acad Sci USA, 2006, 103, 13132-13137). In adoptive cell therapy, A 2A R / A 2B Co-targeting of R can promote T cell activation and effector function (Seifert M, et al. Br J Cancer. 2022, 127, 2175-2185). Therefore, simultaneous inhibition of A 2A R / A 2B Using R to relieve adenosine-mediated tumor immunosuppression may be more effective. Currently, A... 2A R / A 2B A1R dual antagonists have entered the clinical stage, with AB928 already in Phase II clinical trials for the treatment of lung cancer, prostate cancer, and colorectal cancer. However, AB928 exhibits high A1R antagonistic activity (Commun Chem, 2023, 6(1), 106), indicating a deficiency in selectivity. 2A R / A 2B The dual antagonists YZJ-5053 and INCB106385 are currently undergoing Phase I clinical trials. Therefore, the development of novel A... 2A R / A 2B R-antagonists have enormous market potential and value as cancer immunotherapy drugs. Summary of the Invention

[0006] The purpose of this invention is to provide a class of compounds as novel adenosine A. 2A and / or A 2B Receptor antagonists, containing adenosine A 2A R and / or A 2B R-inhibitory activity, promising applications in the preparation of drugs for the prevention or treatment of A 2A R and / or A 2B Medications for diseases related to R.

[0007] In a first aspect, the present invention provides a tricyclic pyrimidine compound derivative of general formula I or a pharmaceutically acceptable salt or solvate thereof: Where X is CH2, O, or S; Y is CR 2 , N or S; R 1 R 2 R 3 and R 4 Independently selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkyl, halogen, and cyano groups; m is 0 or 1; n is 0, 1, or 2; The R 5 for The ring atoms are connected by double or single bonds, a is 0 or 1, and W is CH or CR. 15 N, NH or S, Z is N, C=O, CR 6 or NR 16 V represents N and CR 7 or NR 8 R 6 R 7 R 8 R 15 and R 16 Independently selected from hydrogen, hydroxyl group, having 0-3 ions selected from hydroxyl group, halogen, C 1-3 C1-C6 alkyl groups with alkoxy or cyano substituents, having 0-3 hydroxyl groups, halogens, or C6 groups. 1-3 C of alkoxy and cyano substituents 3-8 Cycloalkyl groups, having 0-3 hydroxyl groups, halogens, C 1-3 C2-C4 alkenyl groups with alkoxy or cyano substituents, or 3- to 6-membered heterocyclic alkyl groups having 1-2 heteroatoms selected from N and / or O; or R 6 and R 7 They are connected to form a 5- to 6-element ring. In some implementations, R 6 and R 7 Linked to form 0-3 ions selected from hydroxyl, halogen, C 1-3 A 5- to 6-membered ring with alkoxy or cyano substituents.

[0008] Preferably, the present invention provides a tricyclic pyrimidine compound derivative of general formula II or a pharmaceutically acceptable salt or solvate thereof: Where X is CH2 or O; R 1 R 2 R 3 and R 4 Independently selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, halogen, and cyano groups; The R 5 for The ring atoms are connected by double or single bonds, a is 0 or 1, and W is CH or CR. 15 N, NH or S, Z is N, C=O, CR 6 or NR 16 V represents N and CR 7 or NR 8 R 6 R 7 R 8 R 15 and R 16 Independently selected from hydrogen, hydroxyl group, having 0-3 ions selected from hydroxyl group, halogen, C 1-3C1-C6 alkyl groups with alkoxy or cyano substituents, having 0-3 hydroxyl groups, halogens, or C6 groups. 1-3 C of alkoxy and cyano substituents 3-8 Cycloalkyl groups, having 0-3 hydroxyl groups, halogens, C 1-3 C2-C4 alkenyl groups with alkoxy or cyano substituents, or 3- to 6-membered heterocyclic alkyl groups having 1-2 heteroatoms selected from N and / or O; or R 6 and R 7 They are connected to form a 5- to 6-element ring. In some implementations, R 6 and R 7 Linked to form 0-3 ions selected from hydroxyl, halogen, C 1-3 A 5- to 6-membered ring with alkoxy or cyano substituents.

[0009] Ideally, R 1 R 2 R 3 and R 4 It is independently selected from hydrogen, methoxy, halogen, and cyano groups. For example, R 1 Preferably, it is hydrogen, methoxy, chlorine, or fluorine. For example, R 2 Preferably, it is hydrogen, chlorine, fluorine, or methoxy. For example, R 3 Preferably, it contains hydrogen, chlorine, fluorine, methoxy, or cyano groups.

[0010] Ideally, R 15 and R 16 Selected independently from methyl.

[0011] Preferably, the R 5 Selected from the following structures: Among them, R 9 R 10 R 11 and R 13 Independently selected from hydrogen, hydroxyl group, having 0-3 ions selected from hydroxyl group, halogen, C 1-3 C1-C6 alkyl groups with alkoxy or cyano substituents, having 0-3 hydroxyl groups, halogens, or C6 groups. 1-3 C of alkoxy and cyano substituents 3-8 Cycloalkyl groups, 3- to 6-membered heterocyclic alkyl groups having 1-2 heteroatoms selected from N and / or O; R 12 and R 14 It is independently selected from hydrogen and C1-C3 alkyl groups.

[0012] Ideally, R 5 for R 9Selected from hydrogen- or hydroxy-substituted C1-C3 alkyl groups, methoxy-substituted C1-C3 alkyl groups, and 3- to 6-membered heterocyclic alkyl groups having 1-2 heteroatoms selected from N and / or O, such as, but not limited to, hydrogen, methyl, ethyl, isopropyl, hydroxymethyl, hydroxy-substituted isopropyl, morpholino, tetrahydrofuran, methoxy-substituted methyl, etc.

[0013] Ideally, R 5 for R 10 It is selected from hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, such as but not limited to hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, etc.

[0014] Ideally, R 5 for R 11 and R 13 Independently selected from hydrogen, C1-C6 alkyl groups having 0-3 substituents selected from halogens or cyano groups, C 3-6 Cycloalkyl groups, 3- to 5-membered heterocycloalkyl groups having 1-2 heteroatoms selected from N and / or O, such as, but not limited to, hydrogen, methyl, ethyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetyl, 2,2,2-trifluoroethyl, cyano-substituted ethyl, etc.

[0015] Preferably, the R 5 Selected from the following structures:

[0016] Preferably, the tricyclic pyrimidine derivative is selected from the following compounds:

[0017] In a second aspect, the present invention provides a pharmaceutical composition comprising the aforementioned tricyclic pyrimidine compound derivative or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0018] Thirdly, the present invention provides the aforementioned tricyclic pyrimidine compound derivatives or their pharmaceutically acceptable salts or solvates, or the aforementioned pharmaceutical compositions in the preparation of adenosine A. 2A R and / or A 2B Uses of R antagonists.

[0019] Fourthly, the present invention provides the aforementioned tricyclic pyrimidine compound derivatives or their pharmaceutically acceptable salts or solvates, or the aforementioned pharmaceutical compositions in the preparation of drugs for the prevention and / or treatment of A. 2A R and / or A 2B Application in drugs for diseases related to R.

[0020] Preferably, the disease is selected from at least one of cancer and immune-related diseases; more preferably, the cancer is selected from prostate cancer, colorectal cancer, gastric cancer, pancreatic cancer, melanoma, breast cancer, small cell lung cancer, non-small cell lung cancer, leukemia, brain tumor, lymphoma, myeloma, kidney cancer, liver cancer, bile duct cancer, bladder cancer, cervical cancer, testicular cancer, uterine cancer, fallopian tube cancer, thyroid cancer, skin cancer, sweat gland cancer, sebaceous gland cancer, head and neck cancer, esophageal cancer, and ovarian cancer; the immune-related disease is selected from rheumatoid arthritis, renal failure, asthma, psoriasis, colitis, lupus, allergy, fibrosis, anemic fibromyalgia, Alzheimer's disease, Parkinson's disease, Crohn's disease, arteriosclerosis, osteoporosis, eczema, systemic sclerosis, and multiple sclerosis. Beneficial effects

[0021] The compounds provided by this invention contain adenosine A. 2A R and / or A 2B R-inhibitory activity, promising applications in the preparation of drugs for the prevention or treatment of A 2A R and / or A 2B Medications for diseases related to R. Attached Figure Description

[0022] Figure 1 shows the in vivo efficacy of compound 41 in a mouse MC38 colorectal cancer model. (A) Tumor volume change trend during administration; (B) Mouse body weight change during administration; (C) Comparison of tumor weight between the model group and the compound 41 30 mg / kg administration group; (D) Tumor profiles after sampling from the model group and the compound 41 30 mg / kg administration group.

[0023] Figure 2 shows the effect of compound 41 on immune cells (CD4). + T cells, CD8 + The effects of infiltration by T cells, NK cells, macrophages, regulatory T cells, and bone marrow-derived suppressor cells. Detailed Implementation

[0024] The present invention will be further described below with reference to the accompanying drawings and the following embodiments. It should be understood that the drawings and the following embodiments are for illustrative purposes only and are not intended to limit the present invention.

[0025] The preparation method of the above-mentioned tricyclic pyrimidine compound derivatives or their pharmaceutically acceptable salts provided by the present invention may include the following two synthetic schemes:

[0026] Scheme 1:

[0027] Reagents and conditions: (a) Diethyl carbonate, sodium hydride, tetrahydrofuran, 70℃, 3h, 65-85%; (b) Guanidine carbonate, potassium tert-butoxide, ethanol, 80℃, overnight, 40-57%; (c) Phosphorus oxychloride, dioxane, 100℃, 12h; (d) Triisopropylsilylacetylene, bis(triphenylphosphine)palladium dichloride, dioxane / water = 1:1, 90℃, 60-75%; (e) Tetrabutylammonium fluoride (TBAF), tetrahydrofuran, 0℃, 15min, 80-90%; (f) Corresponding azide compounds, anhydrous copper sulfate, sodium vitamin C, tert-butanol / water = 2:1, 60℃, 6-35%.

[0028] Scheme 1 represents a general synthetic route for some compounds having general chemical formulas (I) or (II). Starting material 1a-1l reacts with diethyl carbonate via a Claisen condensation to generate 2a-2l. 2a-2l then reacts with guanidine carbonate under basic conditions to construct the key tricyclic pyrimidinone structure 3a-3l. Subsequently, chlorination with phosphorus oxychloride, a Sonogashira reaction, and deprotection with TBAF yields terminal alkynyl compounds 6a-6l. Finally, these compounds are reacted with their respective azide derivatives via azido-alkynyl cycloaddition reactions to generate compounds 1, 3-14, and 16-41.

[0029] Scheme 2:

[0030] Reagents and conditions: (a) Cuprous bromide, N,N-dimethylformamide, 100°C, 1 h, 66%; (b) Sodium hydroxide, ethanol, room temperature, overnight, 15%-16%; (c) Guanidine carbonate, sodium hydroxide, ethanol, 80°C, overnight, 2%.

[0031] Scheme 2 represents a general synthetic route for some compounds having general chemical formulas (I) or (II). Starting materials 7a and 8a undergo an azide-alkyne cycloaddition reaction to generate 9a, which then reacts with the corresponding chromones to generate intermediates 10a-10b. 10a-10b react with guanidine carbonate to give compounds 2 and 15, respectively.

[0032] The above synthesis schemes only illustrate some of the preparation methods of the compounds in this invention. Based on the above synthesis schemes, those skilled in the art can use similar methods to synthesize the compounds of this invention, referring to commonly used techniques and existing technologies in the field.

[0033] In addition to standard methods known in the literature or illustrated in experimental procedures, the compounds of the present invention can be prepared by reactions shown in the following schemes. Therefore, the following illustrative schemes are for illustrative purposes and not limited to the listed compounds or any particular substituents. The number of substituents shown in the schemes does not necessarily need to conform to the number used in the claims, and for clarity, the definition of showing a single substituent connected to the structure of this patent allows for compounds with multiple substituents.

[0034] The "compounds" described in this invention include all stereoisomers, geometric isomers, tautomers, and isotopes.

[0035] The "compound" described in this invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers. Compounds containing asymmetric carbon atoms in this invention may be isolated in optically active pure form or in racemic form; the optically active pure form may be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0036] The "compound" described in this invention also includes a tautomer form; the tautomer form is derived from the exchange of a single bond with an adjacent double bond and the migration of a proton.

[0037] This invention also includes atoms of all isotopes, whether in intermediates or the final compound; isotopic atoms include those having the same number of atoms but different mass numbers, for example, hydrogen isotopes include deuterium and tritium. Furthermore, if desired, for example for specific therapeutic or diagnostic purposes, the compounds of this invention may incorporate isotopes or radioactive isotopes known in the art, such as… 3 H, 15 O、 13 C or 13 Nitrogen isotopes.

[0038] "Pharmaceutically acceptable salts" refer to salts that are pharmaceutically acceptable in maintaining the pharmacological activity of their parent compounds while improving their physicochemical or metabolic properties. These salts include acid addition salts and base addition salts, or mixtures thereof, prepared from pharmaceutically acceptable acids or bases (including organic acids, inorganic acids, organic bases, and inorganic bases). In this invention, suitable inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or similar acids; suitable organic acids include, for example, acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, mandelic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, salicylic acid, stearic acid, mucoconic acid, or their analogues.

[0039] The compounds according to the present invention can also exist in their solvated forms, such as hydrates (hemihydrates, monohydrates, dihydrates, trihydrates, etc.).

[0040] The present invention also provides a pharmaceutical composition comprising the compound as described above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0041] The term "pharmaceutical composition" as used in this invention refers to a formulation comprising one or more compounds of the invention or salts thereof, and a carrier commonly accepted in the art for delivering a bioactive compound to an organism (e.g., a human). The purpose of the pharmaceutical composition is to facilitate drug delivery to the organism.

[0042] The term "pharmaceutically acceptable carrier" refers to a substance that is co-administered with the active ingredient and facilitates the administration of the active ingredient. This includes, but is not limited to, any flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, disintegrants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that are permitted by the State Food and Drug Administration for use in humans or animals (e.g., livestock). Examples include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol.

[0043] The pharmaceutical compositions described in this invention can be formulated into solid, semi-solid, liquid, or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalers, gels, microspheres, and aerosols, etc.

[0044] The pharmaceutical composition described in this invention can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc.

[0045] The routes of administration for the compounds or pharmaceutically acceptable salts thereof or pharmaceutical compositions described in this invention include, but are not limited to, oral, rectal, transmucosal, enteral, or local, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration. The preferred route of administration is oral administration.

[0046] For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with a pharmaceutically acceptable carrier well known in the art. These carriers enable the compounds of the present invention to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, liquids, gels, pastes, suspensions, etc., for oral administration to patients. For example, a pharmaceutical composition for oral administration can be obtained as a tablet by combining the active ingredient with one or more solid carriers, granulating the resulting mixture if necessary, and adding a small amount of excipients to process it into a mixture or granules to form a tablet or tablet core. The tablet core can be combined with a coating material optionally suitable for enteric coating to process it into a coated formulation more favorable for absorption by the organism (e.g., human).

[0047] The present invention also provides adenosine A 2A R and / or A 2B R antagonists, including compounds as described above or pharmaceutically acceptable salts thereof.

[0048] Pharmaceutically acceptable salts of the compounds of this invention include conventional non-toxic salts formed by the reaction of a base with an inorganic or organic acid. Specifically, the reaction is carried out using the free base of the compound, reacting with an inorganic or organic acid to form a salt. The inorganic or organic acid may be selected from hydrochloric acid, sulfuric acid, nitric acid, hydrofluoric acid, hydrobromic acid, formic acid, acetic acid, picric acid, citric acid, maleic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, etc.

[0049] If the inventive compound is acidic, then a suitable "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic alkali, including inorganic and organic bases. Options include aluminum salts, ammonium salts, lithium salts, magnesium salts, sodium salts, etc. Particularly preferred are ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts. Salts derived from pharmaceutically acceptable non-toxic organic alkalis, including salts of primary, secondary, and tertiary amines, with substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as arginine, betaine, and caffeine, are also acceptable.

[0050] The present invention also provides a tricyclic pyrimidine compound derivative as described above, or a pharmaceutically acceptable salt thereof, for the preparation of a treatment or prevention of A 2A R and / or A 2B Application in drugs for diseases related to R.

[0051] “Treatment” means any treatment of disease in a mammal, including: (1) preventing disease, i.e. causing the symptoms of clinical disease to not develop; (2) suppressing disease, i.e. preventing the development of clinical symptoms; and (3) alleviating disease, i.e. causing the clinical symptoms to subside.

[0052] The disease is selected from at least one of cancer and immune-related diseases.

[0053] For example, the cancers mentioned are selected from prostate cancer, colorectal cancer, stomach cancer, pancreatic cancer, melanoma, breast cancer, small cell lung cancer, non-small cell lung cancer, leukemia, brain tumor, lymphoma, myeloma, kidney cancer, liver cancer, bile duct cancer, bladder cancer, cervical cancer, testicular cancer, uterine cancer, fallopian tube cancer, thyroid cancer, skin cancer, sweat gland cancer, sebaceous gland cancer, head and neck cancer, esophageal cancer, and ovarian cancer.

[0054] For example, the immune-related diseases are selected from rheumatoid arthritis, kidney failure, asthma, psoriasis, colitis, lupus, allergies, fibrosis, anemic fibromyalgia, Alzheimer's disease, Parkinson's disease, Crohn's disease, arteriosclerosis, osteoporosis, eczema, systemic sclerosis, and multiple sclerosis.

[0055] In summary, this invention provides a class of compounds having the general formula (I) structure or their pharmaceutically acceptable salts or solvates, which have been found to effectively inhibit adenosine A. 2A and / or A 2B Receptors regulate the body's immune physiological responses and can be used for treatment or prevention in relation to A. 2A R and / or A 2B Drugs related to R-related diseases. Therefore, the present invention provides a novel adenosine A derivative of a tricyclic pyrimidine compound. 2A R and / or A 2B R antagonists, containing adenosine A 2A R and / or A 2B R inhibitory activity, which can be used to prepare preparations for prevention or treatment of A 2A R and / or A 2B Medications for diseases related to R.

[0056] The present invention will be further described in detail below with reference to specific embodiments. It should also be understood that the following embodiments are only for further illustration of the present invention and should not be construed as limiting the scope of protection of the present invention. Any non-essential improvements and adjustments made by those skilled in the art based on the above description of the present invention are within the scope of protection of the present invention. The specific process parameters, etc., in the following examples are merely examples within a suitable range; that is, those skilled in the art can make appropriate selections within the appropriate range based on the description herein, and are not intended to be limited to the specific values ​​in the examples below.

[0057] In the method for preparing the target compound provided by this invention, column chromatography uses silica gel (300-400 mesh) produced by Rushan Taiyang Desiccant Co., Ltd.; thin-layer chromatography uses GF254 (0.25 mm); nuclear magnetic resonance chromatography (NMR) is performed using a Varian-400 NMR spectrometer; and liquid chromatography-mass spectrometry (LC / MS) is performed using an Agilent Technologies 6120 LC / MS system.

[0058] Furthermore, all operations involving easily oxidized or hydrolyzed raw materials are performed under nitrogen protection. Unless otherwise stated, the raw materials used in this invention are commercially available and can be used directly without further purification, although it should be understood that purification may be necessary before use.

[0059] PE: petroleum ether; EA: ethyl acetate; DCM: dichloromethane; CH3CN: acetonitrile; MeOH: methanol; EtOH: ethanol; DMF: N,N'-dimethylformamide; PdCl2(PPh3)2: bis(triphenylphosphine)palladium(II) dichloride; CuBr: cuprous bromide; TLC: thin-layer silica gel plate analysis (G254); P-TLC: preparation of thin-layer silica gel plate.

[0060] Unless otherwise specified in this invention, the eluent ratio refers to the volume ratio.

[0061] Example 1: Preparation of Compound 1

[0062] 2-(6-((4-(2-amino-5,6-dihydrobenzo[h]quinazolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2-yl)prop-2-ol

[0063] Step 1: Ethyl 1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate

[0064] 3,4-Dihydronaphthyl-1(2H)-one (7.3 g, 50 mmol) and diethyl carbonate (11.8 g, 100 mmol) were dissolved in tetrahydrofuran (200 mL), stirred until homogeneous, and then sodium hydride (2.4 g, 100 mmol) was added. The mixture was then placed in an oil bath at 70 °C and reacted for 3 h. After the reaction, the solution was cooled to room temperature. The reaction mixture was diluted with water, extracted with EA, washed with saturated brine, and the organic phase was concentrated. The solution was then separated by column chromatography (PE / EA = 7 / 1) to obtain a yellow oily liquid (8.7 g, yield: 79.8%).

[0065] Step 2: 2-Amino-5,6-dihydrobenzo[h]quinazolin-4-ol

[0066] Ethyl 1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (8.7 g, 40 mmol), guanidine carbonate (7.2 g, 80 mmol), and potassium tert-butoxide (11 g, 80 mmol) were dissolved in ethanol (150 mL) and stirred overnight in an oil bath at 80 °C. After stirring, the mixture was cooled to room temperature. The ethanol was concentrated and diluted with water, filtered, and the solid was washed with ethyl acetate. The product was dried to obtain a gray crude product, which was directly added to the next step without further purification.

[0067] Step 3: 4-Chloro-5,6-dihydrobenzo[h]quinazolin-2-amine

[0068] 2-Amino-5,6-dihydrobenzo[h]quinazoline-4-ol (4 g, 18.8 mmol) and phosphorus oxychloride (10 mL) were placed in a dioxane solution (30 mL), and then stirred in an oil bath at 100 °C for 12 h. After the reaction was completed, the mixture was cooled to room temperature, and the reaction solution was slowly poured into crushed ice. The mixture was filtered, and the solid was collected to obtain the crude product. No purification was required. After drying, the product was directly added to the next step.

[0069] Step 4: 4-((triisopropylsilyl)ethynyl)-5,6-dihydrobenzo[h]quinazolin-2-amine

[0070] 4-Chloro-5,6-dihydrobenzo[h]quinazoline-2-amine (2.31 g, 10 mmol), triisopropylsilylacetylene (3.65 g, 20 mmol), bis(triphenylphosphine)palladium dichloride (702 mg, 1 mmol), and cuprous iodide (190 mg, 1 mmol) were dissolved in dioxane / triethylamine (25 mL / 25 mL), purged with nitrogen, and stirred in an oil bath at 100 °C for 4 h. After the reaction, the mixture was cooled to room temperature, diluted with EA, and then washed successively with water and saturated brine. The organic phase was concentrated and separated by column chromatography (PE / EA = 2 / 1) to give a pale yellow solid (2.7 g, yield: 72%).

[0071] Step 5: 4-ethynyl-5,6-dihydrobenzo[h]quinazolin-2-amine

[0072] 4-((triisopropylsilyl)ethynyl)-5,6-dihydrobenzo[h]quinazolin-2-amine (2.7 g, 7.35 mmol) was dissolved in 30 mL of tetrahydrofuran, and a tetrahydrofuran solution of tetrabutylammonium fluoride (960 mg, 3.67 mmol) was added dropwise under an ice-water bath. The reaction was carried out under an ice bath for 15 minutes. After the reaction was completed, the solution was diluted with EA and then washed successively with water and saturated brine. The organic phase was concentrated and separated by column chromatography (PE / EA = 2 / 1) to give a yellow solid (1.46 g, 90%).

[0073] Step 6: 2-(6-((4-(2-amino-5,6-dihydrobenzo[h]quinazolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2-yl)prop-2-ol

[0074] 4-Ethynyl-5,6-dihydrobenzo[h]quinazolin-2-amine (100 mg, 0.45 mmol) and 2-(6-(azidomethyl)pyridin-2-yl)prop-2-ol (104 mg, 0.54 mmol) were dissolved in a mixture of 8 mL tert-butanol and 4 mL water. Anhydrous copper sulfate (27 mg, 0.17 mmol) and sodium vitamin C (68 mg, 0.34 mol) were then added, and the reaction mixture was reacted at 60 °C for 4 h. After the reaction, the mixture was cooled to room temperature, diluted with EA, and then washed successively with water and saturated brine. The organic phase was concentrated and separated by silica gel column chromatography (DCM / MeOH = 30 / 1) to give a white solid (32 mg, yield: 16%). 1 H NMR (600MHz, DMSO-d6) δ8.61 (s, 1H), 8.18 (dd, J = 7.7, 1.4Hz, 1H), 7.81 (t, J = 7. 8Hz, 1H), 7.62 (dd, J=7.9, 0.9Hz, 1H), 7.42 (td, J=7.3, 1.5Hz, 1H), 7.37 (td, J= 7.5,1.4Hz,1H),7.34–7.27(m,1H),7.11(dd,J=7.6,0.9Hz,1H),6.46(s,2H),5 .81(s,2H),5.22(s,1H),3.29–3.22(m,2H),2.87(t,J=7.3Hz,2H),1.40(s,6H). 13 C NMR(151MHz,DMSO-d6)δ168.62,162.57,160.98,155.13,153.63,147.30,140.07,138.24,133.28,130.92,128.3 2,127.17,127.11,125.46,119.92,118.47,114.54,72.75,55.00,31.03,27.83,23.20.MS(ESI)m / z:414.9[M+H] + .

[0075] Example 2: Preparation of Compound 2

[0076] 2-(6-((4-(2-amino-5H-chromeno[4,3-d]pyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2-yl)prop-2-ol

[0077] Step 1: 1-((6-(2-hydroxypropyl-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-carboxaldehyde

[0078] 2-(6-(azidomethyl)pyridin-2-yl)prop-2-ol (960 mg, 5 mmol) and 3-(trimethylsilyl)propynylpentanal (630 mg, 5 mmol) were dissolved in 10 mL of DMF and stirred until homogeneous. Triethylamine (500 mg, 5 mmol) was then added, followed by cuprous bromide (28 mg, 5 mmol). The reaction mixture was reacted in an oil bath at 100 °C for 1 h. After reaction, the mixture was cooled to room temperature. The mixture was diluted with EA and then washed successively with water and saturated brine. The organic phase was concentrated and separated by column chromatography (PE / EA = 1 / 1) to obtain a yellow oily liquid (810 mg, yield: 66%).

[0079] Step 2: (E)-3-((1-((6-(2-hydroxypropyl-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methylene)chroman-4-one

[0080] 1-((6-(2-hydroxypropyl-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-carboxaldehyde (810 mg, 3.3 mmol) and tropane-4-one (488 mg, 3.3 mmol) were dissolved in 10 mL of ethanol, stirred until homogeneous, and then sodium hydroxide (132 mg, 3.3 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was completed, the reaction system was concentrated and separated by column chromatography (DCM / MeOH = 15 / 1) to obtain a yellow oily liquid (200 mg, yield: 16.3%).

[0081] Step 3: 2-(6-((4-(2-amino-5H-chromeno[4,3-d]pyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2-yl)prop-2-ol

[0082] (E)-3-((1-((6-(2-hydroxypropyl-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methylene)chroman-4-one (200 mg, 0.53 mmol) and guanidine carbonate (180 mg, 1 mmol) were dissolved in 10 mL of ethanol and reacted overnight at 80 °C. After the reaction was completed, the mixture was cooled to room temperature, concentrated, and then separated by column chromatography (DCM / MeOH = 30 / 1) to give a white solid product (8 mg, yield: 2%). 1H NMR (600MHz, DMSO-d6) δ8.67(s,1H),8.07(dd,J=7.8,1.6Hz,1H),7.81(t,J=7.8Hz,1H),7.62(d,J=7.9Hz,1H),7.48–7.4 0(m,1H),7.12(t,J=7.2Hz,2H),7.01(d,J=8.1Hz,1H),6.71(s,2H),5.83(s,2H),5.69(s,2H),5.23(s,1H),1.39(s,6H). 13 C NMR(151MHz,DMSO-d6)δ168.61,163.34,157.77,157.19,153.46,152.78,146.87,138.25,133.33,127.15,12 5.26,122.28,121.82,119.96,118.50,117.41,109.15,72.74,65.47,55.09,31.02.MS(ESI)m / z:416.0[M+H] + .

[0083] Example 3: Preparation of Compound 3

[0084] 2-(6-((4-(2-amino-6,7-dihydro-5H-benzo[6,7]cycloheptano[1,2-d]pyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2-yl)prop-2-ol

[0085] The synthetic route was followed as described in Example 1. The starting material was selected from 6,7,8,9-tetrahydro-5H-benzo[7]cyclohepten-5-one. Column chromatography (DCM / MeOH = 30 / 1) yielded 22 mg of a white solid, with a yield of 13%. 1 H NMR (600MHz, DMSO-d6) δ8.59(s,1H),7.81(t,J=7.8Hz,1H),7.65(dd,J=7.3,1.7Hz,1H),7.61(d,J=7.9Hz,1H),7.46–7.36(m,2H),7.33(dd,J=7.1,1.6 Hz,1H),7.11(d,J=7.4Hz,1H),6.51(s,2H),5.81(s,2H),5.22(s,1H),2.70 (t,J=6.8Hz,2H),2.56(t,J=7.0Hz,2H),2.21(t,J=6.9Hz,2H),1.39(s,6H). 13C NMR(151MHz,DMSO-d6)δ168.72,168.61,162.55,155.35,153.65,147.36,140.28,139.04,138.23,130.11,129.03,1 28.76,127.05,126.87,119.89,118.45,117.55,72.75,55.00,32.40,31.38,31.03,24.68.MS(ESI)m / z:428.2[M+H] + .

[0086] Example 4: Preparation of Compound 4

[0087] 2-(6-((4-(2-amino-5,6-dihydrothieno[2,3-h]quinazolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2-yl)prop-2-ol

[0088] The synthetic route was followed as described in Example 1. The starting material was selected from 6,7-dihydrobenzo[b]thiophene-4(5H)-one. Column chromatography (DCM / MeOH = 30 / 1) yielded 69 mg of a white solid, with a yield of 32.5%. 1 H NMR (600MHz, DMSO-d6) δ8.58(s,1H),7.80(t,J=7.8Hz,1H),7.61(d,J=7.9Hz,1H),7.49(d,J=5.2Hz,1H),7.43(d,J=5.2Hz,1 H),7.10(d,J=7.6Hz,1H),6.40(s,2H),5.80(s,2H),5.22(s,1H),3.43(t,J=7.7Hz,2H),3.00(t,J=7.7Hz,2H),1.40(s,6H). 13 C NMR(151MHz,DMSO-d6)δ168.62,162.54,159.27,154.29,153.65,147.63,145.48,138.24,135.86,127.0 5,124.56,124.29,119.91,118.47,111.82,72.75,55.01,31.03,24.01,23.21.MS(ESI)m / z:420.0[M+H] + .

[0089] Example 5: Preparation of Compound 5

[0090] 2-(6-((4-(2-amino-9-methoxy-5,6-dihydrobenzo[h]quinazolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2-yl)prop-2-ol

[0091] The synthetic route was followed as described in Example 1. The starting material was selected from 7-methoxy-3,4-dihydronaphthyl-1(2H)-one. Column chromatography (DCM / MeOH = 30 / 1) yielded 30 mg of a white solid, with a yield of 17%. 1 H NMR (600MHz, DMSO-d6) δ8.61(s,1H),7.81(t,J=7.8Hz,1H),7.73(d,J=2.8Hz,1H),7.61(dd,J=7.9,0.9Hz,1H),7.24(d,J=8.3Hz,1H),7.11(dd,J=7.7,0 .9Hz,1H),7.00(dd,J=8.3,2.8Hz,1H),6.48(s,2H),5.81(s,2H),5.22(s,1H ),3.81(s,3H),3.27–3.21(m,2H),2.79(dd,J=8.4,6.3Hz,2H),1.40(s,6H). 13 C NMR(151MHz,DMSO-d6)δ168.62,162.52,160.85,158.64,155.22,153.63,147.29,138.24,134.27,132.22,129.38,1 27.18,119.91,118.47,117.27,114.67,109.80,72.75,55.69,55.00,31.03,26.97,23.48.MS(ESI)m / z:444.1[M+H] + .

[0092] Example 6: Preparation of Compound 6

[0093] 2-(6-((4-(2-amino-8-methoxy-5,6-dihydrobenzo[h]quinazolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2-yl)prop-2-ol

[0094] The synthetic route was followed as described in Example 1. The starting material was selected from 6-methoxy-3,4-dihydronaphthyl-1(2H)-one. Column chromatography (DCM / MeOH = 30 / 1) yielded 37 mg of a white solid, with a yield of 21%. 1H NMR (600MHz, DMSO-d6) δ8.58(s,1H),8.11(d,J=8.6Hz,1H),7.80(t,J=7.8Hz,1H),7.61(d,J=7.9Hz,1H),7.10(d,J=7.6Hz,1H),6.93(dd,J=8.6,2.6H z,1H),6.89(d,J=2.6Hz,1H),6.37(s,2H),5.80(s,2H),5.23–5.21(m,1H) ,3.82(s,3H),3.25(dd,J=8.5,6.2Hz,2H),2.88–2.79(m,2H),1.40(s,6H). 13 C NMR(151MHz,DMSO-d6)δ168.61,162.47,161.59,161.03,154.59,153.65,147.44,142.15,138.24,127.32,127.05,1 26.07,119.91,118.46,113.62,113.13,113.10,72.75,55.73,54.99,31.03,28.19,23.22.MS(ESI)m / z:444.1[M+H] + .

[0095] Example 7: Preparation of Compound 7

[0096] 2-(6-((4-(2-amino-7-methoxy-5,6-dihydrobenzo[h]quinazolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2-yl)prop-2-ol

[0097] The synthetic route was followed as described in Example 1. The starting material was selected from 5-methoxy-3,4-dihydronaphthyl-1(2H)-one. Column chromatography (DCM / MeOH = 30 / 1) yielded 23 mg of a white solid, with a yield of 13%. 1 H NMR (600MHz, DMSO-d6) δ8.60(s,1H),7.91–7.74(m,2H),7.61(d,J=7.8Hz,1H),7.33(t,J=8.0Hz,1H),7.11(d,J=7 .9Hz,2H),6.44(s,2H),5.81(s,2H),5.23(s,1H),3.84(s,3H),3.29–3.17(m,2H),2.83–2.76(m,2H),1.40(s,6H). 13C NMR(151MHz,DMSO-d6)δ168.60,162.50,161.01,156.22,155.05,153.61,147.28,138.24,134.23,128.03,127.40,1 27.15,119.92,118.47,117.78,114.32,113.08,72.75,56.03,55.00,31.02,22.52,20.23.MS(ESI)m / z:444.1[M+H] + .

[0098] Example 8: Preparation of Compound 8

[0099] 2-(6-((4-(2-amino-9-chloro-5,6-dihydrobenzo[h]quinazolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2-yl)prop-2-ol

[0100] The synthetic route was followed as described in Example 1. The starting material was selected from 7-chloro-3,4-dihydronaphthyl-1(2H)-one. Column chromatography (DCM / MeOH = 30 / 1) yielded 38 mg of a white solid, with a yield of 22%. 1 H NMR (600MHz, DMSO-d6) δ8.62(s,1H),8.16(d,J=2.3Hz,1H),7.81(t,J=7.8Hz,1H),7.61(dd,J=7.9,1.0Hz,1H),7.47(dd,J=8.1,2.4Hz,1H),7. 37(d,J=8.1Hz,1H),7.11(dd,J=7.7,0.9Hz,1H),6.57(s,2H),5.81(s,2 H),5.22(s,1H),3.30–3.25(m,2H),2.87(t,J=7.4Hz,2H),1.39(s,6H). 13 C NMR(151MHz,DMSO-d6)δ168.62,162.56,159.56,155.60,153.59,147.18,138.86,138.24,135.16,131.82,130.4 2,130.37,127.28,124.86,119.92,118.47,114.44,72.75,55.01,31.03,27.07,22.91.MS(ESI)m / z:448.1[M+H] + .

[0101] Example 9: Preparation of Compound 9

[0102] 2-(6-((4-(2-amino-8-chloro-5,6-dihydrobenzo[h]quinazolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2-yl)prop-2-ol

[0103] The synthetic route was followed as described in Example 1. The starting material was selected from 6-chloro-3,4-dihydronaphthyl-1(2H)-one. Column chromatography (DCM / MeOH = 30 / 1) yielded 42 mg of a white solid, with a yield of 24%. 1 H NMR (600MHz, DMSO-d6) δ8.61(s,1H),8.20–8.11(m,1H),7.81(t,J=7.8Hz,1H),7.61(dd,J=7.9,0.9Hz,1H),7.44(d,J=6.9Hz ,2H),7.11(dd,J=7.6,0.9Hz,1H),6.52(s,2H),5.81(s,2H),5.22(s,1H),3.30–3.25(m,2H),2.93–2.84(m,2H),1.39(s,6H). 13 C NMR(151MHz,DMSO-d6)δ168.62,162.54,160.00,155.34,153.60,147.19,142.34,138.24,135.43,132.22,128.0 6,127.31,127.24,127.21,119.92,118.47,114.31,72.75,55.01,31.03,27.47,22.94.MS(ESI)m / z:448.1[M+H] + .

[0104] Example 10: Preparation of Compound 10

[0105] 2-(6-((4-(2-amino-7-chloro-5,6-dihydrobenzo[h]quinazolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2-yl)prop-2-ol

[0106] The synthetic route was followed as described in Example 1. The starting material was selected from 5-chloro-3,4-dihydronaphthyl-1(2H)-one. Column chromatography (DCM / MeOH = 30 / 1) yielded 31 mg of a white solid, with a yield of 18%. 1H NMR (400MHz, DMSO-d6) δ8.64(s,1H),8.20(dd,J=7.8,1.2Hz,1H),7.82(t,J=7.8Hz,1H),7.69–7.52(m,2H),7.42(t,J=7.9H z,1H),7.12(d,J=7.7Hz,1H),6.57(s,2H),5.83(s,2H),5.24(s,1H),3.32(d,J=8.2Hz,2H),3.03–2.88(m,2H),1.41(s,6H). 13 C NMR(151MHz,DMSO-d6)δ168.62,162.58,160.04,155.45,153.60,147.17,138.26,137.36,135.53,132.58,131.4 2,128.27,127.28,124.52,119.94,118.48,114.01,72.76,55.01,31.03,24.45,22.37.MS(ESI)m / z:448.1[M+H] + .

[0107] Example 11: Preparation of Compound 11

[0108] 2-(6-((4-(2-amino-9-fluoro-5,6-dihydrobenzo[h]quinazolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2-yl)prop-2-ol

[0109] The synthetic route was followed as described in Example 1. The starting material was selected from 7-fluoro-3,4-dihydronaphthyl-1(2H)-one. Column chromatography (DCM / MeOH = 30 / 1) yielded 24 mg of a white solid, with a yield of 13%. 1 H NMR (600MHz, DMSO-d6) δ8.61(s,1H),8.21(dd,J=9.4,6.0Hz,1H),7.81(t,J=7.8Hz,1H),7.70–7.53(m,1H),7.20(ddd,J=9.1,6. 1,2.7Hz,2H),7.14–7.06(m,1H),6.49(s,2H),5.82(s,2H),5.23(s,1H),3.31–3.22(m,2H),2.89(t,J=7.3Hz,2H),1.40(s,6H). 13C NMR(151MHz,DMSO-d6)δ168.62,164.66,163.02,162.53,160.17,155.17,153.61,147.27,143.20,143.15,138.24,129.88,128.02,1 27.96,127.19,119.92,118.47,115.02,114.88,114.17,114.03,113.98,72.75,55.01,31.03,27.76,22.97.MS(ESI)m / z:432.0[M+H] + .

[0110] Example 12: Preparation of Compound 12

[0111] 2-(6-((4-(2-amino-8-fluoro-5,6-dihydrobenzo[h]quinazolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2-yl)prop-2-ol

[0112] The synthetic route was followed as described in Example 1. The starting material was selected from 6-fluoro-3,4-dihydronaphthyl-1(2H)-one. Column chromatography (DCM / MeOH = 30 / 1) yielded 34 mg of a white solid, with a yield of 19%. 1 H NMR (600MHz, DMSO-d6) δ8.55(s,1H),7.80(dd,J=10.1,2.9Hz,1H),7.73(t,J=7.8Hz,1H),7.54(dd,J=7.9,0.9Hz,1H),7.31(dd,J=8.4,5.6Hz,1H),7. 19(td,J=8.5,2.9Hz,1H),7.04(dd,J=7.7,0.9Hz,1H),6.48(s,2H),5.74( s,2H),5.15(s,1H),3.22–3.19(m,2H),2.79(t,J=7.3Hz,2H),1.32(s,6H). 13C NMR(151MHz,DMSO-d6)δ168.62,162.56,162.49,160.89,159.84,159.83,155.57,153.60,147.19,138.24,136.07,136.06,135.35,135.30,1 30.33,130.28,127.27,119.92,118.48,117.65,117.51,114.46,111.5 4,111.39,72.75,55.01,31.03,26.96,23.14.MS(ESI)m / z:432.0[M+H] + .

[0113] Example 13: Preparation of Compound 13

[0114] 2-(6-((4-(2-amino-7-fluoro-5,6-dihydrobenzo[h]quinazolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2-yl)prop-2-ol

[0115] The synthetic route was followed as described in Example 1. The starting material was selected from 5-fluoro-3,4-dihydronaphthyl-1(2H)-one. Column chromatography (DCM / MeOH = 30 / 1) yielded 12 mg of a white solid, with a yield of 7%. 1 H NMR (600MHz, DMSO-d6) δ8.63(s,1H),8.03(d,J=1.1Hz,1H),7.81(t,J=7.7Hz,1H),7.62(d,J=7.9Hz,1H),7.41(td,J=8.0,5.6Hz,1H),7.32(ddd,J= 9.3,8.2,1.1Hz,1H),7.12(d,J=7.6Hz,1H),6.54(s,2H),5.82(s,2H),5.2 3(s,1H),3.30(dd,J=8.5,6.4Hz,2H),2.88(t,J=7.4Hz,2H),1.40(s,6H). 13C NMR(151MHz,DMSO-d6)δ168.62,162.53,160.26,159.91,158.66,155.50,153.60,147.21,138.24,135.60,135.57,128.17,128.11,127.2 7,126.57,126.45,121.51,121.49,119.92,118.48,117.55,117.41,114.21,72.75,55.01,31.03,22.18,19.59.MS(ESI)m / z:432.0[M+H] + .

[0116] Example 14: Preparation of Compound 14

[0117] 2-Amino-4-(1-((6-(2-hydroxypropyl-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-5,6-dihydrobenzo[h]quinazolin-7-carboxynitrile

[0118] The synthetic route was followed as described in Example 1. The starting material was selected from 5-cyano-3,4-dihydronaphthyl-1(2H)-one. Column chromatography (DCM / MeOH = 30 / 1) yielded 19 mg of a white solid, with a yield of 11%. 1 H NMR (600MHz, DMSO-d6) δ8.64(s,1H),8.46(dd,J=7.9,1.3Hz,1H),7.93(dd,J=7.7,1.3Hz,1H),7.81(t,J=7.8Hz,1H),7.66–7.53(m,2H ),7.12(d,J=7.7Hz,1H),6.61(s,2H),5.82(s,2H),5.23(s,1H),3.37(dd,J=8.6,6.4Hz,2H),3.09(dd,J=8.4,6.4Hz,2H),1.40(s,6H). 13 C NMR(151MHz,DMSO-d6)δ168.63,162.63,159.16,155.70,153.57,147.09,143.41,138.25,134.82,134.48,129.90,1 28.06,127.34,119.94,118.49,117.93,114.12,111.46,72.75,55.03,31.03,26.16,22.29.MS(ESI)m / z:439.1[M+H] + .

[0119] Example 15: Preparation of Compound 15

[0120] 2-Amino-4-(1-((6-(2-hydroxypropyl-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-5H-chromeno[4,3-d]pyrimidin-7-carboxynitrile

[0121] The synthetic route was followed as described in Example 2. The starting material was selected from 4-oxodihydrobenzopyran-8-carboxynitrile. Column chromatography (DCM / MeOH = 30 / 1) yielded 3 mg of a white solid, with a yield of 2%. 1 H NMR (600MHz, DMSO-d6) δ8.71(s,1H),8.32(dd,J=7.8,1.7Hz,1H),7.89(dd,J=7.7,1.7Hz,1H),7.81(t,J=7.8Hz,1H),7.62(d,J=7.9Hz,1H ),7.27(t,J=7.7Hz,1H),7.13(d,J=7.6Hz,1H),6.86(s,2H),5.91(s,2H),5.84(s,2H),5.23(s,1H),1.39(s,6H).MS(ESI)m / z:441.0[M+H] + .

[0122] Example 16: Preparation of Compound 16

[0123] 4-(1-(pyridin-2-methyl)-1H-1,2,3-triazol-4-yl)-5,6-dihydrobenzo[h]quinazolin-2-amine

[0124] The synthetic route was followed as described in Example 1. The azide derivative was selected from 2-(azidomethyl)pyridine. Column chromatography (DCM / MeOH = 30 / 1) yielded 46 mg of a white solid, with a yield of 29%. 1 H NMR (600MHz, DMSO-d6) δ8.60(s,1H),8.57(ddd,J=4.8,1.9,1.0Hz,1H),8.18(dd,J=7.7,1.4Hz,1H),7.86(td,J=7.7,1.8Hz,1H),7.42(td,J= 7.4,1.5Hz,1H),7.37(qd,J=7.5,2.2Hz,3H),7.32(dd,J=7.4,1.3Hz,1H),6.47(s,2H),5.84(s,2H),3.31–3.28(m,2H),2.87(t,J=7.3Hz,2H). 13C NMR(151MHz,DMSO-d6)δ162.55,161.05,155.24,154.95,150.00,147.54,140.11,137.89,133.28,130.92 ,128.31,127.28,127.10,125.47,123.80,122.79,114.50,54.85,27.84,23.15.MS(ESI)m / z:356.1[M+H] + .

[0125] Example 17: Preparation of Compound 17

[0126] 4-(1-((6-(methoxymethyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-5,6-dihydrobenzo[h]quinazolin-2-amine

[0127] The synthetic route was followed as described in Example 1. The azide derivative was selected from 2-(azidomethyl)-6-(methoxymethyl)pyridine. Column chromatography (DCM / MeOH = 30 / 1) yielded 33 mg of a white solid, with a yield of 18%. 1 H NMR (600MHz, DMSO-d6) δ8.60(s,1H),8.18(dd,J=7.8,1.4Hz,1H),7.87(t,J=7.7Hz,1H),7.44–7.35(m,3H),7.32(dd,J=7.6,1. 3Hz,1H),7.23(d,J=7.7Hz,1H),6.47(s,2H),5.82(s,2H),4.48(s,2H),3.36(s,3H),3.31–3.27(m,2H),2.87(t,J=7.3Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ162.55,161.04,158.75,154.96,154.73,147.52,140.10,138.58,133.27,130.93,128.3 1,127.14,127.11,125.47,121.39,121.08,114.53,74.97,58.60,54.87,27.83,23.16.MS(ESI)m / z:400.1[M+H] + .

[0128] Example 18: Preparation of Compound 18

[0129] 4-(1-((6-morpholinylpyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-5,6-dihydrobenzo[h]quinazolin-2-amine

[0130] The synthetic route was followed as described in Example 1. The azide derivative was selected from 4-(6-(azidomethyl)pyridin-2-yl)morpholine. Column chromatography (DCM / MeOH = 30 / 1) yielded 26 mg of a white solid, yield: 13%. 1 H NMR(600MHz,DMSO-d6)δ8.48(s,1H),8.16–7.99(m,1H),7.51(dd,J=8.5,7.3Hz,1H ),7.34(td,J=7.4,1.5Hz,1H),7.30(td,J=7.5,1.3Hz,1H),7.27–7.22(m,1H),6.7 1(d,J=8.6Hz,1H),6.50(d,J=7.3Hz,1H),6.39(s,2H),5.57(s,2H),3.59(t,J=4.8 Hz, 4H), 3.34 (t, J = 4.9Hz, 4H), 3.20 (dd, J = 8.5, 6.2Hz, 2H), 2.80 (t, J = 7.3Hz, 2H). 13 C NMR(151MHz,DMSO-d6)δ162.57,160.97,159.22,155.13,153.17,147.29,140.08,139.16,133.28,130.91,1 28.32,127.11,125.46,114.52,111.45,106.84,66.33,55.02,45.30,27.84,23.18.MS(ESI)m / z:441.1[M+H] + .

[0131] Example 19: Preparation of Compound 19

[0132] 4-(1-((4,5,6,7-tetrahydrobenzo[b]thiophene-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-5,6-dihydrobenzo[h]quinazolin-2-amine

[0133] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene. Column chromatography (DCM / MeOH = 30 / 1) yielded 38 mg of a white solid, with a yield of 21%. 1H NMR (600MHz, DMSO-d6) δ8.40(s,1H),8.17(dd,J=7.7,1.4Hz,1H),7.42(td,J=7.4,1.5Hz,1H),7.37(td,J=7.5,1.4Hz,1H),7.34(s,1H),7.32(dd ,J=7.5,1.3Hz,1H),6.46(s,2H),5.58(s,2H),3.32–3.26(m,2H),2.90–2 .83(m,2H),2.70(t,J=5.7Hz,2H),2.46–2.39(m,2H),1.76–1.67(m,4H). 13 C NMR (151MHz, DMSO-d6) δ162.53,161.06,154.86,147.64,140.11,137.08,134.75,134.26,133.26,130.92,128. 30,127.10,126.04,125.47,122.47,114.49,47.57,27.83,25.10,23.89,23.17,22.34.MS(ESI)m / z:415.1[M+H] + .

[0134] Example 20: Preparation of Compound 20

[0135] 3-((4-(2-amino-5,6-dihydrobenzo[h]quinazolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-5-carboxynitrile

[0136] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-1H-indole-5-carboxynitrile. Column chromatography (DCM / MeOH = 30 / 1) yielded 14 mg of a white solid, with a yield of 8%. 1 H NMR(600MHz,DMSO-d6)δ11.83(s,1H),8.48(s,1H),8.27–8.22(m,1H),8.16(d d,J=7.8,1.4Hz,1H),7.82(s,1H),7.60(d,J=8.5Hz,1H),7.49(dd,J=8.4,1.5 Hz,1H),7.40(dd,J=7.4,1.5Hz,1H),7.38–7.33(m,1H),7.31(d,J=7.4Hz,1H) ,6.42(s,2H),5.89(s,2H),3.27(dd,J=8.4,6.2Hz,2H),2.85(t,J=7.3Hz,2H). 13C NMR (151MHz, DMSO-d6) δ162.50,160.99,154.95,147.50,140.09,138.43,133.25,130.90,129.18,128.28,127.08,126.51 ,125.87,125.45,124.84,124.61,121.02,114.48,113.67,110.52,101.92,44.91,27.82,23.13.MS(ESI)m / z:419.5[M+H] + .

[0137] Example 21: Preparation of Compound 21

[0138] 3-((4-(2-amino-5,6-dihydrobenzo[h]quinazolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)pyridin-2(1H)-one

[0139] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)pyridin-2(1H)-one. Column chromatography (DCM / MeOH = 30 / 1) yielded 22 mg of a white solid, 13% yield. 1 H NMR (600MHz, DMSO-d6) δ11.90(s,1H),8.50(s,1H),8.18(d,J=7.5Hz,1H),7.53(dd,J=6.8,1.8Hz,1H),7.45(dd,J=6.5,1.9Hz,1H),7.42(td,J=7. 4,1.3Hz,1H),7.37(t,J=7.1Hz,1H),7.32(d,J=7.4Hz,1H),6.50(s,2H), 6.25(t,J=6.6Hz,1H),5.45(s,2H),3.33–3.27(m,2H),2.91–2.84(m,2H). 13 C NMR(151MHz,DMSO-d6)δ162.56,162.02,161.03,154.95,147.36,141.08,140.10,136.46,133.28,130.90 ,128.29,127.09,126.72,126.12,125.47,114.45,105.36,49.54,27.84,23.14.MS(ESI)m / z:372.1[M+H] + .

[0140] Example 22: Preparation of Compound 22

[0141] 3-((4-(2-amino-5,6-dihydrobenzo[h]quinazolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1-methylpyridin-2(1H)-one

[0142] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-1-methylpyridin-2(1H)-one. Column chromatography (DCM / MeOH = 30 / 1) yielded 20 mg of a white solid, 11% yield. 1 H NMR (600MHz, DMSO-d6) δ8.51(s,1H),8.20–8.14(m,1H),7.77(dd,J=6.8,2.0Hz,1H),7.52(dd,J=6.9,2.0Hz,1H),7.42(td,J=7.4,1.5Hz,1H),7.37( td,J=7.5,1.3Hz,1H),7.32(d,J=7.4Hz,1H),6.49(s,2H),6.28(t,J=6.8H z,1H),5.48(s,2H),3.48(s,3H),3.32–3.28(m,5H),2.86(t,J=7.3Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ162.54,161.62,161.03,154.93,147.30,140.84,140.10,139.97,133.28,130.90,12 8.28,127.08,126.91,125.46,125.23,114.43,105.21,49.86,37.46,27.84,23.13.MS(ESI)m / z:386.1[M+H] + .

[0143] Example 23: Preparation of Compound 23

[0144] 3-((4-(2-amino-5,6-dihydrobenzo[h]quinazolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1-isopropylpyridine-2(1H)-one

[0145] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-1-isopropylpyridine-2(1H)-one. Column chromatography (DCM / MeOH = 30 / 1) yielded 32 mg of a white solid, with a yield of 17%. 1H NMR (600MHz, DMSO-d6) δ8.53(s,1H),8.18(dd,J=7.7,1.4Hz,1H),7.81(dd,J=7.0,2.0Hz,1H),7.44–7.40(m,2H),7.37(t,J=7.4Hz,1H),7.32(d ,J=7.4Hz,1H),6.49(s,2H),6.34(t,J=6.9Hz,1H),5.49(s,2H),5.20–4 .86(m,1H),3.32–3.28(m,2H),2.91–2.82(m,2H),1.30(d,J=6.8Hz,6H). 13 C NMR (151MHz, DMSO-d6) δ162.54,161.03,160.72,154.96,147.31,140.10,138.88,135.50,133.28,130.91,128. 30,127.10,125.47,125.40,114.46,105.82,50.02,46.84,40.00,27.84,23.15,21.84.MS(ESI)m / z:414.0[M+H] + .

[0146] Example 24: Preparation of Compound 24

[0147] 3-((4-(2-amino-5,6-dihydrobenzo[h]quinazolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1-cyclopropylpyridin-2(1H)-one

[0148] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-1-cyclopropylpyridine-2(1H)-one. Column chromatography (DCM / MeOH = 30 / 1) yielded 17 mg of a white solid, 10% yield. 1H NMR(600MHz,DMSO-d6)δ8.53(s,1H),8.18(dd,J=7.7,1.4Hz,1H),7.61(dd,J=6.9,2.0Hz ,1H),7.47(dd,J=6.9,2.0Hz,1H),7.41(dd,J=7.4,1.5Hz,1H),7.37(td,J=7.5,1.4Hz,1 H),7.33–7.30(m,1H),6.50(s,2H),6.25(t,J=6.9Hz,1H),5.48(s,2H),3.39(tt,J=7.3, 4.1Hz,1H),3.32–3.28(m,2H),2.89–2.83(m,2H),1.02–0.98(m,2H),0.88–0.84(m,2H). 13 C NMR (151MHz, DMSO-d6) δ162.57,162.55,161.03,154.95,147.31,140.10,139.37,138.56,133.29,130.90,128. 29,127.09,127.00,125.46,125.28,114.44,105.14,49.83,32.46,27.84,23.14,6.84.MS(ESI)m / z:412.1[M+H] + .

[0149] Example 25: Preparation of Compound 25

[0150] 3-((4-(2-amino-5,6-dihydrobenzo[h]quinazolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1-cyclobutylpyridin-2(1H)-one

[0151] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-1-cyclobutylpyridin-2(1H)-one. Column chromatography (DCM / MeOH = 30 / 1) yielded 31 mg of a white solid, with a yield of 16%. 1H NMR (600MHz, DMSO-d6) δ8.51(s,1H),8.18(d,J=7.7Hz,1H),7.89(dd,J=7.0,1.9Hz,1H),7.46(d ,J=6.9Hz,1H),7.44–7.40(m,1H),7.37(t,J=7.5Hz,1H),7.32(d,J=7.4Hz,1H),6.49(s,2H),6. 34(t,J=6.9Hz,1H),5.47(s,2H),5.05(ddd,J=17.5,9.7,7.7Hz,1H),3.30(t,J=7.4Hz,2H),2.8 6(t,J=7.3Hz,2H),2.39–2.30(m,2H),2.25(td,J=9.6,2.6Hz,2H),1.78(dq,J=9.9,5.1Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ162.54,161.05,161.03,154.94,147.29,140.10,139.27,136.17,133.28,130.90,128.29,1 27.09,126.94,125.46,125.23,114.45,105.46,51.12,49.85,29.62,27.84,23.14,14.79.MS(ESI)m / z:426.2[M+H] + .

[0152] Example 26: Preparation of Compound 26

[0153] 3-((4-(2-amino-5,6-dihydrobenzo[h]quinazolin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1-cyclopentylpyridin-2(1H)-one

[0154] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-1-cyclopentylpyridin-2(1H)-one. Column chromatography (DCM / MeOH = 30 / 1) yielded 26 mg of a white solid, 13% yield. 1H NMR (600MHz, DMSO-d6) δ8.52(s,1H),8.18(dd,J=7.7,1.1Hz,1H),7.77(dd,J=7.0,1.9H z,1H),7.42(td,J=7.5,1.5Hz,2H),7.37(td,J=7.5,1.1Hz,1H),7.32(d,J=7.2Hz,1H),6 .49(s,2H),6.33(t,J=6.9Hz,1H),5.48(s,2H),5.13(q,J=8.0Hz,1H),3.31–3.28(m,2H ),2.89–2.84(m,2H),2.05–1.98(m,2H),1.82(dt,J=5.6,3.5Hz,2H),1.70–1.60(m,4H). 13 C NMR(151MHz,DMSO-d6)δ162.54,161.26,161.03,154.95,147.29,140.10,138.92,136.25,133.28,130.91,128.29,1 27.09,126.98,125.47,125.28,114.46,105.89,56.66,50.03,31.98,27.84,24.33,23.15.MS(ESI)m / z:440.2[M+H] + .

[0155] Example 27: Preparation of Compound 27

[0156] 4-(1-((1H-pyrazol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-5,6-dihydrobenzo[h]quinazolin-2-amine

[0157] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-1H-pyrazole. Column chromatography (DCM / MeOH = 30 / 1) yielded 18 mg of a white solid, with a yield of 12%. 1 H NMR (600MHz, DMSO-d6) δ12.93(s,1H),8.44(s,1H),8.17(dd,J=7.7,1.4Hz,1H),7.75(d,J=2.3Hz,1H),7.42(td,J=7.4,1.5Hz,1H),7 .37(td,J=7.5,1.4Hz,1H),7.32(dd,J=7.4,1.3Hz,1H),6.47(s,2H),6.34(s,1H),5.68(s,2H),3.31–3.25(m,2H),2.92–2.81(m,2H).13 C NMR(151MHz,DMSO-d6)δ162.55,161.02,154.95,147.58,146.37,140.10,133.27,130.92,130.22 ,128.30,127.10,126.17,125.46,114.48,104.57,47.66,27.83,23.13.MS(ESI)m / z:345.1[M+H] + .

[0158] Example 28: Preparation of Compound 28

[0159] 4-(1-((1-methyl-1H-pyrazol-5-yl)methyl)-1H-1,2,3-triazol-4-yl)-5,6-dihydrobenzo[h]quinazolin-2-amine

[0160] The synthetic route was followed as described in Example 1. The azide derivative was selected from 5-(azidomethyl)-1-methyl-1H-pyrazole. Column chromatography (DCM / MeOH = 30 / 1) yielded 50 mg of a white solid, with a yield of 31%. 1 H NMR(600MHz, DMSO-d6)δ8.51(s,1H),8.18(dd,J=7.7,1.4Hz,1H),7.46–7.40(m,2H),7.37(td,J=7.5,1.4Hz,1H),7.32(dd, J=7.4,1.4Hz,1H),6.48(s,2H),6.36(d,J=1.9Hz,1H),5.87(s,2H),3.87(s,3H),3.29–3.24(m,2H),2.87(t,J=7.3Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ162.54,161.08,154.78,147.70,140.10,138.32,136.87,133.23,130.95,12 8.31,127.11,126.27,125.47,114.54,107.45,44.05,36.99,27.81,23.12.MS(ESI)m / z:359.1[M+H] + .

[0161] Example 29: Preparation of Compound 29

[0162] 4-(1-((1-methyl-1H-pyrazol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-5,6-dihydrobenzo[h]quinazolin-2-amine

[0163] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-1-methyl-1H-pyrazole. Column chromatography (DCM / MeOH = 30 / 1) yielded 42 mg of a white solid, with a yield of 26%. 1 H NMR (600MHz, DMSO-d6) δ8.45(s,1H),8.17(dd,J=7.7,1.4Hz,1H),7.69(d,J=2.2Hz,1H),7.42(td,J=7.4,1.5Hz,1H),7.37(td,J=7.5,1.4 Hz,1H),7.32(dd,J=7.4,1.3Hz,1H),6.47(s,2H),6.30(d,J=2.2Hz,1H),5.64(s,2H),3.83(s,3H),3.30–3.19(m,2H),2.97–2.80(m,2H). 13 C NMR(151MHz,DMSO-d6)δ162.53,161.02,154.94,147.57,146.25,140.10,133.26,132.57,130.91,12 8.30,127.09,126.20,125.46,114.48,105.39,47.50,38.99,27.83,23.12.MS(ESI)m / z:359.1[M+H] + .

[0164] Example 30: Preparation of Compound 30

[0165] 4-(1-((1,5-dimethyl-1H-pyrazol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-5,6-dihydrobenzo[h]quinazolin-2-amine

[0166] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-1,5-dimethyl-1H-pyrazole. Column chromatography (DCM / MeOH = 30 / 1) yielded 23 mg of a white solid, with a yield of 13%. 1H NMR (600MHz, DMSO-d6) δ8.43(s,1H),8.17(dd,J=7.7,1.4Hz,1H),7.42(td,J=7.4,1.4Hz,1H),7.38–7.35(m,1H),7.32(d, J=7.4Hz,1H),6.46(s,2H),6.08(s,1H),5.56(s,2H),3.70(s,3H),3.30–3.26(m,2H),2.86(t,J=7.3Hz,2H),2.22(s,3H). 13 C NMR(151MHz,DMSO-d6)δ162.53,161.02,154.95,147.56,144.79,140.27,140.10,133.26,130.92,128.3 0,127.10,126.14,125.46,114.48,104.88,47.59,36.35,27.83,23.13,11.10.MS(ESI)m / z:373.1[M+H] + .

[0167] Example 31: Preparation of Compound 31

[0168] 4-(1-((1-isopropyl-1H-pyrazol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-5,6-dihydrobenzo[h]quinazolin-2-amine

[0169] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-1-isopropyl-1H-pyrazole. Column chromatography (DCM / MeOH = 30 / 1) yielded 33 mg of a white solid, with a yield of 19%. 1 H NMR (600MHz, DMSO-d6) δ8.46 (s, 1H), 8.18 (dd, J=7.7, 1.4Hz, 1H), 7.77 (d, J= 2.3Hz,1H),7.42(td,J=7.4,1.5Hz,1H),7.37(td,J=7.5,1.4Hz,1H),7.32(d d,J=7.5,1.3Hz,1H),6.47(s,2H),6.28(d,J=2.3Hz,1H),5.65(s,2H),4.49( p,J=6.7Hz,1H),3.30–3.26(m,2H),2.88–2.84(m,2H),1.41(d,J=6.7Hz,6H). 13C NMR(151MHz,DMSO-d6)δ162.54,161.02,154.97,147.52,145.74,140.09,133.26,130.92,129.37,12 8.30,127.10,126.16,125.46,114.51,104.92,53.52,47.75,27.83,23.15.MS(ESI)m / z:387.2[M+H] + .

[0170] Example 32: Preparation of Compound 32

[0171] 4-(1-((1-(tert-butyl)-1H-pyrazol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-5,6-dihydrobenzo[h]quinazolin-2-amine

[0172] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-1-(tert-butyl)-1H-pyrazole. Column chromatography (DCM / MeOH = 30 / 1) yielded 12 mg of a white solid, 6% yield. 1 H NMR (600MHz, DMSO-d6) δ8.45(s,1H),8.17(dd,J=7.7,1.4Hz,1H),7.82(d,J=2.3Hz,1H),7.41(td,J=7.4,1.5Hz,1H),7.36(td,J=7.5,1.4H z,1H),7.31(dd,J=7.4,1.3Hz,1H),6.46(s,2H),6.26(d,J=2.3Hz,1H),5.66(s,2H),3.29–3.25(m,2H),2.86(t,J=7.3Hz,2H),1.52(s,9H). 13 C NMR(151MHz,DMSO-d6)δ162.54,161.00,154.99,147.49,145.64,140.09,133.27,130.91,128.55,128.3 0,127.10,126.12,125.46,114.51,104.82,58.72,47.88,29.94,27.83,23.15.MS(ESI)m / z:401.2[M+H] + .

[0173] Example 33: Preparation of Compound 33

[0174] 4-(1-((1-isobutyl-1H-pyrazol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-5,6-dihydrobenzo[h]quinazolin-2-amine

[0175] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-1-(isobutyl)-1H-pyrazole. Column chromatography (DCM / MeOH = 30 / 1) yielded 31 mg of a white solid, with a yield of 17%. 1 H NMR (600MHz, DMSO-d6) δ8.44(s,1H),8.18(d,J=7.6Hz,1H),7.71(d,J=2.1Hz,1 H),7.42(t,J=7.3Hz,1H),7.37(t,J=7.4Hz,1H),7.32(d,J=7.4Hz,1H),6.46(s ,2H),6.29(d,J=2.1Hz,1H),5.65(s,2H),3.90(d,J=7.2Hz,2H),3.30–3.23(m, 2H), 2.86 (t, J = 7.3Hz, 2H), 2.09 (dt, J = 13.6, 6.8Hz, 1H), 0.83 (d, J = 6.7Hz, 6H). 13 C NMR(151MHz,DMSO-d6)δ162.54,161.02,154.97,147.51,146.18,140.09,133.26,132.26,130.92,128.30,1 27.10,126.13,125.46,114.50,104.98,58.97,47.64,29.57,27.83,23.14,20.08.MS(ESI)m / z:401.2[M+H] + .

[0176] Example 34: Preparation of Compound 34

[0177] 4-(1-((1-cyclopropyl-1H-pyrazol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-5,6-dihydrobenzo[h]quinazolin-2-amine

[0178] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-1-cyclopropyl-1H-pyrazole. Column chromatography (DCM / MeOH = 30 / 1) yielded 19 mg of a white solid, 11% yield. 1H NMR(600MHz,DMSO-d6)δ8.39(s,1H),8.18–8.07(m,1H),7.70(d,J=2.3Hz,1 H),7.34(td,J=7.4,1.3Hz,1H),7.32–7.27(m,1H),7.24(d,J=7.3Hz,1H),6. 40(s,2H),6.21(d,J=2.3Hz,1H),5.56(s,2H),3.63(tt,J=7.4,3.9Hz,1H), 3.22–3.18(m,2H),2.85–2.73(m,2H),0.97–0.93(m,2H),0.91–0.85(m,2H). 13 C NMR (151MHz, DMSO-d6) δ162.54,161.02,154.96,147.55,146.29,140.10,133.26,131.75,130.92,128. 31,127.10,126.22,125.46,114.50,105.24,47.61,33.15,27.83,23.14,6.72.MS(ESI)m / z:385.1[M+H] + .

[0179] Example 35: Preparation of Compound 35

[0180] 4-(1-((1-cyclobutyl-1H-pyrazol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-5,6-dihydrobenzo[h]quinazolin-2-amine

[0181] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-1-cyclobutyl-1H-pyrazole. Column chromatography (DCM / MeOH = 30 / 1) yielded 26 mg of a white solid, 15% yield. 1 H NMR (400MHz, DMSO-d6) δ8.47 (s, 1H), 8.19 (dd, J=7.7, 1.6Hz, 1H), 7.83 (d, J= 2.3Hz,1H),7.46–7.35(m,2H),7.33(dd,J=7.5,1.5Hz,1H),6.48(s,2H),6.3 1(d,J=2.3Hz,1H),5.67(s,2H),4.90–4.72(m,1H),3.32–3.20(m,2H),2.87( dd,J=8.5,6.2Hz,2H),2.48–2.32(m,4H),1.79(tdd,J=10.3,4.3,3.2Hz,2H). 13C NMR(101MHz,DMSO-d6)δ162.05,160.52,154.48,147.05,145.78,139.60,132.78,130.41,129.82,127.80,1 26.60,125.68,124.97,114.02,104.75,54.69,47.20,30.11,27.34,22.65,14.01.MS(ESI)m / z:399.2[M+H] + .

[0182] Example 36: Preparation of Compound 36

[0183] 4-(1-((1-(oxecyclobutane-3-yl)-1H-pyrazol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-5,6-dihydrobenzo[h]quinazolin-2-amine

[0184] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-1-(oxecyclobutane-3-yl)-1H-pyrazole. Column chromatography (DCM / MeOH = 30 / 1) yielded 31 mg of a white solid, with a yield of 18%. 1 H NMR (600MHz, DMSO-d6) δ8.51 (s, 1H), 8.18 (d, J = 7.0Hz, 1H), 7.91 (d, J = 2.3Hz, 1H),7.42(td,J=7.4,1.2Hz,1H),7.37(t,J=7.3Hz,1H),7.32(d,J=7.4Hz,1H) ,6.47(s,2H),6.37(d,J=2.3Hz,1H),5.72(s,2H),5.63–5.51(m,1H),4.91(t, J=7.2Hz,2H),4.87(t,J=6.5Hz,2H),3.30–3.23(m,2H),2.86(t,J=7.3Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ162.54,161.02,154.97,147.54,147.33,140.10,133.26,131.67,130.92,128.3 1,127.10,126.28,125.46,114.52,105.81,77.09,54.96,47.62,27.83,23.14.MS(ESI)m / z:401.1[M+H] + .

[0185] Example 37: Preparation of Compound 37

[0186] 4-(1-((1-cyclopentyl-1H-pyrazol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-5,6-dihydrobenzo[h]quinazolin-2-amine

[0187] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-1-cyclopentyl-1H-pyrazole. Column chromatography (DCM / MeOH = 30 / 1) yielded 38 mg of a white solid, with a yield of 21%. 1 H NMR (600MHz, DMSO-d6) δ8.45(s,1H),8.18(d,J=7.4Hz,1H),7.77(d,J=2.2Hz,1H),7.42(td ,J=7.3,1.2Hz,2H),7.37(t,J=7.2Hz,1H),7.32(d,J=7.4Hz,1H),6.47(s,2H),6.27(d,J=2. 2Hz,1H),5.65(s,2H),4.71–4.65(m,1H),3.30–3.26(m,2H),2.90–2.84(m,3H),2.11–2.03( m,3H),1.89(dd,J=12.1,6.5Hz,4H),1.82–1.72(m,4H),1.63(dtt,J=12.9,8.8,3.4Hz,4H). 13 C NMR(151MHz,DMSO-d6)δ162.54,161.01,154.98,147.51,145.97,140.09,133.26,130.92,130.38,128.30,1 27.10,126.15,125.46,114.51,105.01,62.64,47.75,33.05,27.83,24.14,23.14.MS(ESI)m / z:413.5[M+H] + .

[0188] Example 38: Preparation of Compound 38

[0189] 2-Amino-4-(1-((1-isopropyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-5,6-dihydrobenzo[h]quinazolin-7-carboxynitrile

[0190] The synthetic route was followed as described in Example 1. The starting material was selected from 5-oxo-5,6,7,8-tetrahydro-1-naphthonitrile, and the azide derivative was selected from 3-(azidomethyl)-1-isopropylpyridine-2(1H)-one. Column chromatography (DCM / MeOH = 30 / 1) yielded 21 mg of a white solid, in 12% yield. 1 H NMR (600MHz, DMSO-d6) δ8.56 (s, 1H), 8.46 (dd, J=7.9, 1.3Hz, 1H), 7.93 (dd, J=7 .7,1.3Hz,1H),7.82(dd,J=7.0,2.0Hz,1H),7.59(t,J=7.8Hz,1H),7.44(dd,J= 6.9,1.9Hz,1H),6.63(s,2H),6.35(t,J=6.9Hz,1H),5.49(s,2H),5.10(p,J=6. 8Hz,1H),3.46–3.38(m,2H),3.08(dd,J=8.4,6.4Hz,2H),1.30(d,J=6.8Hz,6H). 13 C NMR(151MHz,DMSO-d6)δ162.61,160.73,159.20,155.55,147.06,143.43,138.95,135.54,134.80,134.48,129.90,1 28.04,127.15,125.34,117.93,114.04,111.44,105.82,50.08,46.84,26.17,22.24,21.84.MS(ESI)m / z:439.2[M+H] + .

[0191] Example 39: Preparation of Compound 39

[0192] 2-Amino-4-(1-((1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-5,6-dihydrobenzo[h]quinazolin-7-carboxynitrile

[0193] The synthetic route was followed as described in Example 1. The starting material was selected from 5-oxo-5,6,7,8-tetrahydro-1-naphthonitrile, and the azide derivative was selected from 3-(azidomethyl)-1-cyclopropylpyridine-2(1H)-one. Column chromatography (DCM / MeOH = 30 / 1) yielded 27 mg of a white solid, in 15% yield. 1H NMR(600MHz, DMSO-d6)δ8.56(s,1H),8.46(dd,J=7.9,1.3Hz,1H),7.93(dd,J=7.7,1.3Hz,1H),7.64–7.55(m,2H),7.48(dd,J=6.9,1.9Hz,1H),6.64( s,2H),6.25(t,J=6.9Hz,1H),5.49(s,2H),3.41–3.39(m,2H),3.08(t,J=7 .4Hz,2H),1.23(s,1H),1.00(q,J=7.0Hz,2H),0.86(q,J=6.9,6.2Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ162.61,162.58,159.20,155.54,147.05,143.43,139.45,138.60,134.80,134.47,129.91,1 28.04,127.17,125.21,117.93,114.03,111.44,105.15,49.89,32.46,26.17,22.24,6.84.MS(ESI)m / z:437.2[M+H] + .

[0194] Example 40: Preparation of Compound 40

[0195] 2-Amino-4-(1-((1-ethyl-1H-pyrazol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-5,6-dihydrobenzo[h]quinazolin-7-carboxynitrile

[0196] The synthetic route was followed as described in Example 1. The starting material was selected from 5-oxo-5,6,7,8-tetrahydro-1-naphthonitrile, and the azide derivative was selected from 3-(azidomethyl)-1-ethyl-1H-pyrazole. Column chromatography (DCM / MeOH = 30 / 1) yielded 17 mg of a white solid, in 11% yield. 1 H NMR (600MHz, DMSO-d6) δ8.48(s,1H),8.46(dd,J=7.9,1.3Hz,1H),7.93(dd,J=7.7,1.3Hz,1H),7.74(d,J=2.3Hz,1H),7.59(t,J=7.8Hz,1H ),6.61(s,2H),6.30(d,J=2.2Hz,1H),5.66(s,2H),4.12(q,J=7.3Hz,2H),3.40–3.37(m,2H),3.08(t,J=7.4Hz,2H),1.36(t,J=7.3Hz,3H).13 C NMR(151MHz,DMSO-d6)δ162.60,159.19,155.55,147.31,146.04,143.43,134.81,134.46,131.10,129.90,1 28.05,126.35,117.93,114.08,111.45,105.19,47.66,46.72,26.16,22.23,15.90.MS(ESI)m / z:398.2[M+H] + .

[0197] Example 41: Preparation of Compound 41

[0198] 2-Amino-4-(1-((1-isopropyl-1H-pyrazol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-5,6-dihydrobenzo[h]quinazolin-7-carboxynitrile

[0199] The synthetic route was followed as described in Example 1. The starting material was selected from 5-oxo-5,6,7,8-tetrahydro-1-naphthonitrile, and the azide derivative was selected from 3-(azidomethyl)-1-isopropyl-1H-pyrazole. Column chromatography (DCM / MeOH = 30 / 1) yielded 26 mg of a white solid, with a yield of 35%. 1 H NMR (600MHz, DMSO-d6) δ8.49(s,1H),8.46(dd,J=7.9,1.3Hz,1H),7.93(dd,J=7.7,1.3Hz,1H),7.77(d,J=2.3Hz,1H),7.59(t,J=7.8Hz,1H),6 .61(s,2H),6.28(d,J=2.3Hz,1H),5.66(s,2H),4.49(p,J=6.7Hz,1H),3.41–3.36(m,2H),3.08(dd,J=8.4,6.4Hz,2H),1.41(d,J=6.7Hz,6H). 13 C NMR(151MHz,DMSO-d6)δ162.60,159.19,155.56,147.29,145.69,143.43,134.81,134.46,129.90,129.38,1 28.05,126.33,117.93,114.09,111.45,104.94,53.52,47.78,26.16,23.15,22.24.MS(ESI)m / z:412.2[M+H] + .

[0200] Example 42: Preparation of Compound 42

[0201] 2-Amino-4-(1-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-5,6-dihydrobenzo[h]quinazolin-7-carboxynitrile

[0202] The synthetic route was followed as described in Example 1. The starting material was selected from 5-oxo-5,6,7,8-tetrahydro-1-naphthonitrile, and the azide derivative was selected from 3-(azidomethyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole. Column chromatography (DCM / MeOH = 30 / 1) yielded 23 mg of a white solid product, in 13% yield. 1 H NMR (600MHz, DMSO-d6) δ8.54(s,1H),8.48–8.44(m,1H),7.93(dd,J=7.7,1.3Hz,1H),7.87(d,J=2.4Hz,1H),7.59(t,J=7.8Hz,1H),6.6 1(s,2H),6.43(d,J=2.4Hz,1H),5.72(s,2H),5.15(q,J=9.1Hz,2H),3.39–3.37(m,2H),3.08(t,J=7.4Hz,2H).MS(ESI)m / z:452.4[M+H] + .

[0203] Example 43: Preparation of Compound 43

[0204] 2-Amino-4-(1-((1-(1-(1-cyanoethyl)-1H-pyrazol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-5,6-dihydrobenzo[h]quinazolin-7-carboxynitrile

[0205] The synthetic route was followed as described in Example 1. The starting material was selected from 5-oxo-5,6,7,8-tetrahydro-1-naphthonitrile, and the azide derivative was selected from 2-(3-(azidomethyl)-1H-pyrazol-1-yl)propionitrile. Separation by silica gel column chromatography (DCM / MeOH = 30 / 1) yielded 31 mg of a white solid product, in 18% yield. 1H NMR (600MHz, DMSO-d6) δ8.56(s,1H),8.45(d,J=1.3Hz,1H),7.95–7.91(m,2H),7.59(t,J=7.8Hz,1H),6.61(s,2H),6.41(d,J=2.4Hz ,1H),5.86(q,J=7.1Hz,1H),5.73(s,2H),3.40–3.37(m,2H),3.08(t,J=7.4Hz,2H),1.80(d,J=7.1Hz,3H).MS(ESI)m / z:423.6[M+H] + .

[0206] Example 44: Preparation of Compound 44

[0207] 2-Amino-4-(1-((6-(2-hydroxypropyl-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-5,6-dihydrobenzo[h]quinazolin-9-carboxynitrile

[0208] The synthetic route was followed as described in Example 1. The starting material was 8-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxynitrile. Separation by silica gel column chromatography (DCM / MeOH = 30 / 1) yielded 3 mg of a white solid product, yield: 2%. MS (ESI) m / z: 439.2 [M+H] + .

[0209] Example 45: Compound A in Example 2A R / A 2B cAMP inhibition activity assay of R

[0210] Induced expression of adenosine A 2A R / A 2B The activity of the R receptor antagonist cAMP inhibitor was measured in HEK-293 cells. 3 μg of adenosine receptor (A receptor) was co-transfected with 18 μL of polyethyleneimine (Yeasen, China) in 10 cm cell culture dishes. 2A R, A 2BCells were incubated with 3 μg pGloSensor-22F cAMP plasmid (Promega, USA) for 24 h. After resuspending in CO2-free medium (Gibco, USA) with 1% GloSensor cAMP reagent (Promega, USA), cells were seeded into 384-well plates (Costar, USA). Cells were pre-incubated with different concentrations of the compound for 0.5 h, followed by stimulation with NECA (MCE, USA). Luminescent signals were collected and recorded using a Cytation 5 microplate reader (BioTek, USA). The IC50 of the compounds was analyzed and calculated using GraphPad Prism 8.0. 50 Values. The measurement results are shown in Table 1.

[0211] Table 1. Effects of Compounds in Examples on A 2A R and A 2B cAMP antagonistic activity of R

[0212] a IC 50 Values ​​are expressed as mean ± SEM, n = 3. Where ++++ indicates IC 50 Less than 10nM; +++ indicates IC 50 Greater than or equal to 10 nM and less than 100 nM; ++ indicates IC 50 Greater than or equal to 100 nM and less than 1000 nM; + indicates IC 50 Greater than or equal to 1000 nM. b For the structure of AB928, please refer to WO2018136700A1.

[0213] Table 1, A 2A R / A 2B The results of the R cAMP inhibition activity experiment showed that the compound of the present invention inhibits A 2A R / A 2B R exhibits good inhibitory activity, and most compounds show varying degrees of A inhibition. 2A R / A 2B R dual-target inhibitory activity.

[0214] Example 46: cAMP inhibitory activity test of the compound against A1R and A3R

[0215] Following the method described in Example 45, the activity of the antagonist cAMP inhibitory function was measured in HEK-293 cells induced to express adenosine A1R / A3R receptors.

[0216] Table 2: cAMP antagonistic activity of compound 41 in Example against A1R and A3R

[0217] a IC 50 Values ​​are expressed as mean ± SEM, n = 3. Where ++++ indicates IC 50 Less than 10nM; +++ indicates IC 50 Greater than or equal to 10 nM and less than 100 nM; ++ indicates IC 50 Greater than or equal to 100 nM and less than 1000 nM; + indicates IC 50 Greater than or equal to 1000 nM. b For the structure of AB928, please refer to WO2018136700A1.

[0218] Table 2 shows the A1R / A3R cAMP inhibition activity results, indicating that AB928 exhibits strong A1R antagonistic activity, while compound 41 of this invention does not possess A1R antagonistic activity. 2A R / A 2B R targets are more selective, avoiding the effects of A1R antagonism on A. 2A R / A 2B R antagonizes the opposite effect.

[0219] Example 47: In vivo pharmacokinetic experiment of compound 41

[0220] Compound 41 was administered via both intravenous injection and oral gavage. The intravenous dose was 1 mg / kg, and the oral gavage dose was 5 mg / kg (5% DMSO / 10% Solutol / 85% Saline). Six male Balb / c mice were selected and divided into two groups of three. Sampling was performed before administration and at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. Blood was collected from the orbital sinus of the mice at each time point after administration and centrifuged to obtain plasma. The obtained plasma samples were precipitated with acetonitrile, and the compound concentration was analyzed by LC-MS / MS. Pharmacokinetic parameters were calculated from the plasma concentration-time curve using non-compartmental analysis.

[0221] Table 3. Pharmacokinetic parameters of compound 41 in mice.

[0222] As can be seen from the data in the table above, the compounds of this invention have good oral bioavailability.

[0223] Example 48: In vivo efficacy of compound 41 in a mouse MC38 colorectal cancer model

[0224] MC38 mouse colorectal cancer cells (DMEM + 10% FBS) were cultured. Cells were collected for subcutaneous tumor inoculation in 6-8 week old female C57 / BL6 mice. To establish a xenograft model, MC38 cells (8 × 10⁻⁶ cells) were cultured.5 (Each tumor) was suspended in 50 μL of PBS. Tumors were subcutaneously implanted into the right back of mice, and tumor growth was observed periodically. When the tumor volume reached approximately 100 mm², [the tumor was monitored]. 3 Students were randomly assigned to groups. This experiment used a once-daily oral administration route, with test compound 41 at doses of 30 mg / kg and 100 mg / kg. A single dose of positive control compound AB928 at 100 mg / kg served as a control.

[0225] Figure 1 shows the in vivo activity of compound 41 against mouse MC38 colorectal cancer. The treatment groups were compound 41 (30 mg / kg and 100 mg / kg), and the control group was AB928 (100 mg / kg). As shown in Figure 1, in the in vivo pharmacodynamic experiment in mice, compound 41 at both 30 mg / kg and 100 mg / kg doses exhibited significant antitumor activity against mouse MC38 colorectal cancer, with inhibition rates reaching 83.2% and 84.6%, respectively. In contrast, the positive control group, AB928 at 100 mg / kg, showed an inhibition rate of 74.9%, indicating that compound 41 at 30 mg / kg was superior to AB928 at 100 mg / kg (Figure 1A). During the administration period, the body weight of mice in both the 30 mg / kg and 100 mg / kg groups remained almost unchanged, indicating low in vivo toxicity of compound 41 (Figure 1B). Based on these results, the 30 mg / kg dose group of compound 41 was selected for further analysis. As clearly shown in Figure 1C, the tumor weight in the treatment group was significantly lower than that in the control group. Furthermore, the tumor size comparison in Figure 1D visually demonstrates the excellent antitumor activity of compound 41 against MC38 colorectal cancer. These results indicate that the compounds of this invention possess excellent in vivo antitumor activity.

[0226] Example 49: Regulatory effect of compound 41 on the tumor microenvironment

[0227] The tumor tissue obtained above was placed in a 12-well plate and quickly cut to 1 mm with sterilized scissors. 3 Transfer the cells to 50 mL centrifuge tubes. Rinse the well walls with 2 mL of PBS and transfer to the same tube. Then, shake on a 37°C incubator for 30 minutes, filter through a 40-mesh sieve, and centrifuge. Wash the cells once with Diluent Buffer, resuspend and stain, and finally fix with PFA. Samples were analyzed using a flow cytometer, and data were analyzed using Flowjo software.

[0228] Tumor tissue was selected on the last day of drug administration, minced, and cells from the entire tumor microenvironment were extracted and analyzed for CD45 expression. + Immunocytes were stained with markers. Flow cytometry was used to analyze CD4+. + T cells, CD8 +The levels of T cells, NK cells, macrophages, Treg cells, and MDSCs were analyzed to evaluate the impact of Example 41 on immune cells in the tumor microenvironment (Figure 2).

[0229] Figure 2 shows the effect of compound 41 on immune cells (CD4). + T cells, CD8 + The effects of T cells, NK cells, macrophages, regulatory T cells, and bone marrow-derived suppressor cells (BMS cells) infiltration. Results showed that Example 41 had an effect on intratumoral CD4... + T cells, CD8 + The infiltration of T cells and NK cells was promoted, while the levels of immunosuppressive cells (such as macrophages, Treg cells, and MDSCs) were downregulated. Furthermore, flow cytometry results also showed that CD8+... + Increased secretion of the cytokine granzyme B (GZMB) in T cells and NK cells, and GZMB itself contributes to tumor cell elimination. All of the above results indicate that the highly efficient in vivo antitumor activity of the compounds of this invention is achieved by regulating the tumor microenvironment.

Claims

1. A tricyclic pyrimidine derivative of the general formula I: ###0001### or a pharmaceutically acceptable salt or solvate thereof: ​ wherein X is CH2, O or S; Y is CR 2 , N or S; R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, halogen and cyano; m is 0 or 1 ; n is 0, 1 or 2; The R 5 is The ring atoms are connected by double or single bonds, a is 0 or 1, and W is CH or CR. 15 , N, NH or S, Z is N, C=O, CR 6 or NR 16 V represents N and CR 7 or NR 8 R 6 R 7 R 8 R 15 and R 16 Independently selected from hydrogen, hydroxyl group, having 0-3 ions selected from hydroxyl group, halogen, C 1-3 C1-C6 alkyl groups with alkoxy or cyano substituents, having 0-3 hydroxyl groups, halogens, or C6 groups. 1-3 C of alkoxy and cyano substituents 3-8 Cycloalkyl groups, having 0-3 hydroxyl groups, halogens, C 1-3 C2-C4 alkenyl groups with alkoxy or cyano substituents, or 3- to 6-membered heterocyclic alkyl groups having 1-2 heteroatoms selected from N and / or O; or R 6 and R 7 They connect to form a 5- to 6-element ring.

2. The tricyclic pyrimidine derivative or a pharmaceutically acceptable salt or solvate thereof according to claim 1, characterized in that, The tricyclic pyrimidine compound derivatives of general formula I are tricyclic pyrimidine compound derivatives of general formula II: wherein X is CH2or O; R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, halogen and cyano; The R 5 To The ring atoms are connected by double or single bonds, a is 0 or 1, and W is CH or CR. 15 , N, NH or S, Z is N, C=O, CR 6 or NR 16 V represents N and CR 7 or NR 8 R 6 R 7 R 8 R 15 and R 16 Independently selected from hydrogen, hydroxyl group, having 0-3 ions selected from hydroxyl group, halogen, C 1-3 C1-C6 alkyl groups with alkoxy or cyano substituents, having 0-3 hydroxyl groups, halogens, or C6 groups. 1-3 C of alkoxy and cyano substituents 3-8 Cycloalkyl groups, having 0-3 hydroxyl groups, halogens, C 1-3 C2-C4 alkenyl groups with alkoxy or cyano substituents, or 3- to 6-membered heterocyclic alkyl groups having 1-2 heteroatoms selected from N and / or O; or R 6 and R 7 They connect to form a 5- to 6-element ring.

3. The tricyclic pyrimidine derivative or a pharmaceutically acceptable salt or solvate thereof according to claim 1 or 2, characterized in that, The R 5 selected from the following structures: wherein R 9 , R 10 , R 11 and R 13 are independently selected from the group consisting of hydrogen, hydroxy, C 1-3 -C6alkyl having 0-3 substituents selected from the group consisting of hydroxy, halo, C 1-3 alkoxy, cyano, C 3-8 cycloalkyl, 3 to 6 membered heterocycloalkyl having 1-2 heteroatoms selected from N or / and O; R 12 and R 14 are independently selected from the group consisting of hydrogen and C1-C3alkyl.

4. The tricyclic pyrimidine derivative or pharmaceutically acceptable salt or solvate thereof according to claim 3, wherein R 9 selected from hydrogen, hydroxy substituted C1-C3alkyl, methoxy substituted C1-C3alkyl, 3 to 5 membered heterocycloalkyl having 1-2 heteroatoms selected from N and O; R 10 selected from hydrogen, C1-C3alkyl, C3-C6cycloalkyl; R 11 and R 13 are independently selected from hydrogen, C1-C6alkyl having 0-3 substituents selected from halogen, cyano, C1-C3alkyl, C3-C6cycloalkyl, C1-C3alkoxy, C3-C6cycloalkoxy, C1-C3haloalkyl, C1-C3haloalkoxy; R 3-6 cycloalkyl, 3 to 5 membered heterocycloalkyl having 1-2 heteroatoms selected from N and O.

5. The tricyclic pyrimidine derivative or pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein said R 5 selected from the group consisting of:

6. The tricyclic pyrimidine derivative or a pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein The tricyclic pyrimidine derivative is selected from the following compounds:

7. A pharmaceutical composition comprising the tricyclic pyrimidine derivative of any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

8. A tricyclic pyrimidine derivative, or a pharmaceutically acceptable salt or solvate thereof, according to any one of claims 1 to 6, or a pharmaceutical composition according to claim 7, for use in the preparation of a medicament for the treatment of adenosine A 2A R and / or A 2B use of an R antagonist.

9. Use of a tricyclic pyrimidine derivative or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 6, or a pharmaceutical composition according to claim 7, for the manufacture of a medicament for the prevention and / or treatment of a disease related to A 2A R and / or A 2B R.

10. Use according to claim 9, characterized in that, The disease is selected from at least one of cancer, an immune-related disease; preferably, the cancer is selected from prostate cancer, colorectal cancer, gastric cancer, pancreatic cancer, melanoma, breast cancer, small cell lung cancer, non-small cell lung cancer, leukemia, brain tumor, lymphoma, myeloma, kidney cancer, liver cancer, bile duct cancer, bladder cancer, cervical cancer, testicular cancer, uterine cancer, fallopian tube cancer, thyroid cancer, skin cancer, sweat gland carcinoma, head and neck cancer, esophageal cancer, and ovarian cancer; the immune-related disease is selected from rheumatoid arthritis, renal failure, asthma, psoriasis, colitis, lupus, allergy, fibrosis, anemic fibromyalgia, Alzheimer's disease, Parkinson's disease, Crohn's disease, arteriosclerosis, osteoporosis, eczema, systemic sclerosis, and multiple sclerosis.

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