2-aminopyrimidine compound derivative and application thereof

Abstract

The invention relates to a 2-aminopyrimidine compound derivative as shown in a formula (I) and application thereof, and the compound has adenosine A2BR inhibitory activity and is expected to be used for preparing drugs for preventing or treating diseases related to A2BR. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to a 2-aminopyrimidine compound derivative and a 2-aminopyrimidine compound derivative as adenosine A 2B Receptor (A 2B R) antagonists, such compounds have adenosine A 2B R inhibitory activity, and is expected to be used in the preparation of prevention or treatment of A 2B Drugs for R-related diseases. Background Art

[0002] Adenosine signaling plays a key role in the physiological and pathological functions of the human body. Adenosine receptors are a class A G protein-coupled receptor, including A1R, A 2A R.A. 2B There are four subtypes, A3R and A4R, which 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 subtype has a unique function, among which A 2B R has attracted the attention of many scholars and companies and has become a potential drug target for a variety of diseases, including inflammation, central nervous system and immune system diseases.

[0003] A 2B Adenosine R is widely expressed in tissues except the cecum, large intestine, mast cells and hematopoietic cells, but usually at low levels. It has the lowest affinity for adenosine of the four isoforms (30-300 nM) and remains silent under healthy conditions. There is now ample evidence that under certain pathological conditions, such as hypoxia, inflammation, infection and cancer, extracellular adenosine levels can reach micromolar concentrations, and Adenosine R is expressed in tissues except the cecum, large intestine, mast cells and hematopoietic cells, but usually at low levels. It has the lowest affinity for adenosine of the four isoforms (30-300 nM) and remains silent under healthy conditions. 2B R is activated at this time. Therefore, people pay more and more attention to A 2B The therapeutic potential of R as a drug target.

[0004] A 2B A R antagonists are considered as potential drugs for the treatment of inflammation, diabetes, pain, asthma, pulmonary fibrosis and anti-aging. 2B R is considered to be an important 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). Recent studies have shown that adenosine can activate A 2B R stimulation polarizes tumor-associated macrophages into immunosuppressive M2 macrophages, which further inhibits 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), and has become a new mechanism for promoting tumor growth (Sorrentino C, Oncotarget, 2015, 6, 27478). Blocking A with PSB1115 in a mouse melanoma model 2B R may limit tumor growth by reducing the accumulation of MDSCs and restoring effective anti-tumor T cell responses (Iannone R, et al. Neoplasia, 2013, 15, 1400). These results confirm that A 2B R is an important player in tumor growth and immunosuppression. Inhibition of this target not only has a direct anti-proliferative effect but also activates the immune system.

[0005] So far, there have been a large number of A 2B R selective antagonists are reported, and these antagonists are mainly divided into two categories, xanthines and non-xanthines. Xanthines are mainly xanthine derivatives related to natural products caffeine and theophylline (WO2023039125Al). Non-xanthines mainly include 2-aminopyrazines (WO2007017096 A1), thienopyrimidinediones (WO2018054846 A1), pyrazolotriazole pyrimidines (Pastorin, G, et al. J Med Chem, 2003, 46, 4287-4296.), pyrimidine benzimidazoles (El Maatougui, A, et al. J Med Chem, 2016, 59, 1967-1983).

[0006] Among the many reported A 2B Among the selective antagonists of Aβ, three compounds have entered clinical research. Among them, PBF1129 has been launched into Phase 1 clinical research (clinical trial number: NCT03274479) for the treatment of non-small cell lung cancer. 2B Solid tumors with overexpression of R and A 2A R / A 2B Solid tumors that overexpress R are also undergoing phase 1 clinical studies (clinical trial number: NCT04976660). Recently, TEON's TT-702 has also entered phase 1 / 2 clinical trials (clinical trial number: NCT05272709) for the treatment of a range of difficult-to-treat cancer patients, including metastatic castration-resistant prostate cancer, triple-negative breast cancer, and microsatellite instability / gene mismatch repair function-related tumors. This shows that A 2BR-selective antagonists have practical application prospects in the treatment of cancer.

[0007] Since xanthine skeletons generally have poor water solubility, poor physicochemical and pharmacokinetic properties, it is therefore necessary to find new non-xanthine A with good drugability. 2B R antagonists have great potential and market value for the development of cancer immunotherapy drugs. Summary of the invention

[0008] The present invention aims to provide a class of compounds as novel adenosine A 2B Receptor (A 2B R) inhibitors with adenosine A 2B R inhibitory activity, and is expected to be used in the preparation of prevention or treatment of A 2B Drugs for R-related diseases.

[0009] In the first aspect, the present invention provides a compound of the following chemical structure general formula (I) or a pharmaceutically acceptable salt thereof:

[0010] Among them, Ar is or X is NH, S or O; when in the connecting position, Y, Z, W, U, V are C; when not in the connecting position, U is N or CR1, W is N or CR2, Y, Z, V are independently N or CR3, R1, R2 are independently selected from H, C 1-3 Alkyl, halogen (preferably Cl, F), C 1-3 Alkyl, C 1-3 Alkoxy, C having one or more fluorine-substituted 1-3 Alkoxy, C 3-6 Cycloalkyloxy, C 1-3 Alkylsulfone, C 1-3 Alkoxyacyl, aminoacyl or cyano, R3 is H, Cl or F.

[0011] That is, Ar can be selected from

[0012] Preferably, at most one of Y, Z, W, U, and V is N, more preferably, Z and V are C, and at most one of Y, W, and U is N.

[0013] Preferably, at least one of R1 and R2 is H, and R3 is H.

[0014] Preferably, Ar is or Even The selected place, Ar is or

[0015] Preferably, Ar is selected from

[0016] Preferably, R1 is selected from H, C 1-3 Alkyl, Cl, F, C 1-3 Alkoxy, C 3-6 Cycloalkyloxy, C 1-3 Alkylsulfone, C 1-3 Alkoxy acyl or cyano, R2 is selected from H, C 1-3 Alkyl, Cl, F, C 1-3 Alkoxy, C 3-6 Cycloalkyloxy, C 1-3 Alkylsulfone, C 1-3 an alkoxyacyl group, an aminoacyl group or a cyano group.

[0017] More preferably, Ar is selected from

[0018] The above-mentioned compound of the present invention (Ar is indole or indole-like structure) shows an A superior to AB928 (WO2018136700A1). 2B R antagonist activity and has A 2B The indole ring or indole-like ring exhibits excellent selectivity for the antagonism of R when it is connected to the triazole through a methylene group at the 3-, 5- or 6-position. 2B R inhibits activity and selectivity, especially when the indole ring or indole-like ring is connected to the triazole through a methylene group at the 3-position or the 5-position. When the indole-3-methylene group is connected to the triazole, it is preferred that the pyrrole ring has no substituent (especially no substituent at N), and the benzene ring has no substituent or has one substituent (especially a substituent at the 5-position or the 6-position). If there is a substituent at the 5-position of the indole, the compound is effective for A 2A R and A 2B R have good inhibitory activity, showing A 2A R and A 2B R dual-target inhibitor; if there is a substituent at the 6-position of indole, the compound still maintains a high A 2B R inhibitory activity, 2A The inhibitory activity of R was weakened, showing a high selectivity for A 2B R inhibitor. When N on the indole ring is replaced by S, the compound still has A 2B R inhibitory activity was slightly weakened, and the 2AThe inhibitory activity of R is enhanced. It is also advantageous that one of the carbon atoms at positions 2, 4, 5, 6, and 7 on the indole ring can be changed to a nitrogen atom. In particular, when one of the carbon atoms at positions 5 and 6 is changed to a nitrogen atom, A exhibits particularly excellent 2B R inhibitory activity with high selectivity.

[0019] In a second aspect, the present invention provides a pharmaceutical composition comprising the compound as described above or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0020] In a third aspect, the present invention provides a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use in the preparation of a compound for treating or preventing 2B Application of drugs in R-related diseases.

[0021] Preferably, the 2B The disease associated with R is selected from cancer, inflammation, diabetes, pain, asthma, and Alzheimer's disease.

[0022] In a fourth aspect, the present invention provides an adenosine A 2B R inhibitors include the compounds described above or pharmaceutically acceptable salts thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 The experimental results of the effect of compound 34 prepared in Example 34 on the expression of the immunosuppressive molecule PD-1 are shown.

[0024] Figure 2 The experimental results showing the effect of compound 34 prepared in Example 34 on the expression of the immunosuppressive molecule TIM-3.

[0025] Figure 3 and Figure 4 The experimental results showing the effect of compound 34 prepared in Example 34 on the T cell-mediated cancer cell killing ability. DETAILED DESCRIPTION

[0026] The present invention is further described below in conjunction with the accompanying drawings and the following embodiments. It should be understood that the accompanying drawings and the following embodiments are only used to illustrate the present invention, rather than to limit the present invention. The same or corresponding reference numerals in the various figures represent the same components, and repeated descriptions are omitted.

[0027] As mentioned above, the present invention provides a 2-aminopyrimidine compound derivative:

[0028]

[0029] When Ar is The compound can be prepared by the following method:

[0030] X, Y, Z, W, U, and V are defined as above. Reagents and conditions: (a) triisopropylsilyl acetylene, bis(triphenylphosphine)palladium(II) dichloride, cuprous iodide, dioxane / triethylamine, 100°C, 4 hours, 61-92%; (b) tetrabutylammonium fluoride, 0°C, 15 minutes, 80-95%; (c) anhydrous copper sulfate, sodium ascorbyl acetate, tert-butyl alcohol / water = 2 / 1, 6 hours, 25%-64%. That is, the starting material 1.1 is coupled with triisopropylsilyl acetylene to obtain the intermediate 1.2, which is then reacted with tetrabutylammonium fluoride to obtain the intermediate 1.3, which is then reacted with the corresponding azide derivative to obtain the final product 1.4 by azide-alkyne cycloaddition reaction.

[0031] For other compounds, the synthesis scheme can be determined by referring to the following specific examples and the existing knowledge in the art.

[0032] The “compound” described in the present invention includes all stereoisomers, geometric isomers, tautomers and isotopes.

[0033] The "compounds" of the present invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the present invention containing asymmetric carbon atoms may be isolated in optically pure form or in racemic form; optically pure forms may be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0034] The “compound” described in the present invention also includes tautomeric forms; tautomeric forms are derived from the exchange of a single bond with an adjacent double bond accompanied by the migration of a proton.

[0035] The present invention also includes all isotopic atoms, whether in the intermediates or the final compounds; isotopic atoms include atoms having the same atomic number but different mass numbers, for example, isotopes of hydrogen include deuterium and tritium. Again, if necessary, for example for a particular therapeutic or diagnostic treatment, the compounds of the present invention may be introduced with isotopes or radioisotopes known in the art, such as 3 H. 15 O. 13 C or 13 N isotope.

[0036] "Pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt that maintains the pharmacological activity of its parent compound while improving the physicochemical properties or metabolic properties. Such salts include acid addition salts and base addition salts prepared from pharmaceutically acceptable acids or bases (including organic acids, inorganic acids, organic bases, inorganic bases), or mixtures thereof. In the present invention, suitable inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or similar acids; suitable organic acids include 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, muconic acid, or the like.

[0037] The compounds according to the present invention may also exist in the form of their solvates, such as hydrates (hemihydrate, monohydrate, dihydrate, trihydrate, etc.).

[0038] "Treatment" means any treatment of a disease in a mammal, including: (1) preventing the disease, i.e., causing clinical symptoms of the disease not to develop; (2) inhibiting the disease, i.e., preventing the development of clinical symptoms; (3) alleviating the disease, i.e., causing the regression of clinical symptoms.

[0039] The "pharmaceutical composition" of the present invention refers to a preparation of one or more compounds of the present invention or their salts and a carrier generally accepted in the art for delivering biologically active compounds to an organism (e.g., human). The purpose of a pharmaceutical composition is to facilitate administration and delivery to an organism.

[0040] The term "pharmaceutically acceptable carrier" refers to a substance that is co-administered with an active ingredient and is conducive to the administration of the active ingredient, including but not limited to any glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that is acceptable for human or animal (e.g. livestock) and approved by the State Food and Drug Administration. For example, it includes but is not limited to calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycol.

[0041] The pharmaceutical composition of the present 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, inhalants, gels, microspheres and aerosols, etc.

[0042] The pharmaceutical composition of the present invention can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making sugar-coated pills methods, grinding methods, emulsifying methods, freeze-drying methods, etc.

[0043] The administration routes of the compounds of the present invention or their pharmaceutically acceptable salts or their pharmaceutical compositions include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration. The preferred administration route is oral administration.

[0044] For oral administration, the pharmaceutical composition can be prepared 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, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients. For example, a pharmaceutical composition for oral administration can be obtained in the following manner: the active ingredient is combined with one or more solid carriers, the resulting mixture is granulated if necessary, and a small amount of excipients is added if necessary to process the mixture or granules to form tablets or tablet cores. The tablet core can be combined with an optional enteric coating material to be processed into a coated preparation form that is more conducive to absorption by an organism (e.g., a human).

[0045] The pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts formed by reacting an alkali with an inorganic acid or an organic acid. That is, the free base of the compound is reacted with an inorganic or organic acid to form a salt. The inorganic or organic acid can 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, and the like.

[0046] If the inventive compound is acidic, then suitable "pharmaceutically acceptable salts" refer to salts prepared by pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. They can be selected from aluminum salts, ammonium salts, lithium salts, magnesium salts, sodium salts, etc. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred. Salts obtained from pharmaceutically acceptable organic non-toxic bases, including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine and caffeine, etc.

[0047] In summary, the present invention provides a class of compounds having a general formula (I) structure, and studies have found that the compounds can effectively inhibit adenosine A 2B Receptors regulate the body's immune physiological response and can be used as a treatment or prevention 2B RMedications for related diseases.

[0048] In addition to standard methods known in the literature or exemplified in the experimental procedures, the compounds of the present invention may be prepared by reactions as shown in the following schemes. Therefore, the following illustrative schemes are for illustrative purposes and are 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 showing a single substituent attached to the patent formula allows for compounds with multiple substituents.

[0049] The present invention is further described in detail below in conjunction with specific examples. It should also be understood that the following examples are only used to further illustrate the present invention and cannot be understood as limiting the scope of protection of the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the above content of the present invention belong to the scope of protection of the present invention. The specific process parameters and the like in the following examples are also only examples within a suitable range, that is, those skilled in the art can make a selection within a suitable range through the description herein, and are not limited to the specific values ​​​​exemplified below.

[0050] In the preparation method of the target compound provided by the present invention, the column chromatography uses silica gel (300-400 mesh) produced by Rushan Sun Desiccant Co., Ltd.; the thin layer chromatography uses GF254 (0.25 mm); the nuclear magnetic resonance chromatography (NMR) uses a Varian-400 nuclear magnetic resonance instrument for determination; and the liquid chromatography-mass spectrometry (LC / MS) uses an Agilent Technologies 6120 liquid chromatography-mass spectrometer.

[0051] In addition, all operations involving easily oxidized or hydrolyzed raw materials were performed under nitrogen protection. Unless otherwise specified, the raw materials used in the present invention are commercially available raw materials and can be used directly without further purification, but it should be understood that they can be used after purification.

[0052] PE: petroleum ether; EA: ethyl acetate; DCM: dichloromethane; CH3CN: acetonitrile; MeOH: methanol; EtOH: ethanol; DMF: N,N'-dimethylformamide; HOAc: glacial acetic acid; KHCO3: potassium bicarbonate; K2CO3: potassium carbonate; Cs2CO3: cesium carbonate; Pd(PPh3)4: tetrakis(triphenylphosphine)palladium; PdCl2(PPh3)2: bis(triphenylphosphine)palladium(II) dichloride; NIS: N-iodosuccinimide; TLC: thin layer silica gel plate (G254) analysis; P-TLC: preparative thin layer silica gel plate.

[0053] Example 1: Preparation of Compound 1

[0054] 3-(6-(1-((1H-indol-5-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-aminopyrimidin-4-yl)2-methylbenzonitrile

[0055]

[0056] Step 1: Preparation of 3-(2-amino-6-((triisopropylsilyl)ethynyl)pyrimidin-4-yl)-2-methylbenzonitrile

[0057] Take 3-(2-amino-6-chloropyrimidin-4-yl)-2-methylbenzonitrile (1.22g, 5mmol), triisopropylsilyl acetylene, bistriphenylphosphine palladium dichloride (175mg, 0.25mmol) and cuprous iodide (95mg, 0.5mmol) in a 50mL flask, add 10mL dioxane and 10mL triethylamine, and fully replace with nitrogen. Then place in a 100℃ oil bath and react for 4h. Monitor the reaction by TLC. After the reaction is completed, cool to room temperature. Dilute with ethyl acetate, then wash with water and saturated brine in turn. Take the organic phase and dry it over anhydrous sodium sulfate. After concentration, separate it by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1 to 5 / 1) to obtain a light yellow solid product (1.40g, 71.8%).

[0058] Step 2: Preparation of 3-(2-amino-6-ethynylpyrimidin-4-yl)-2-methylbenzonitrile

[0059] Separately take the product of step 1, 3-(2-amino-6-((triisopropylsilyl)ethynyl)pyrimidin-4-yl)-2-methylbenzonitrile (1.40 g, 3.6 mmol) in a 50 mL flask, add 30 mL of tetrahydrofuran, and dropwise add tetrabutylammonium fluoride (940 mg, 3.6 mmol) in tetrahydrofuran solvent at 0°C, and react for 15 minutes. Monitor the reaction by TLC. After the reaction is completed, dilute with ethyl acetate, and then wash with water and saturated brine in sequence. Take the organic phase and dry it over anhydrous sodium sulfate. After concentration, separate it by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to obtain a white solid product (700 mg, 83%).

[0060] Step 3: Preparation of 3-(6-(1-((1H-indol-5-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-aminopyrimidin-4-yl)2-methylbenzonitrile

[0061] Take the product of step 2, 3-(2-amino-6-ethynylpyrimidin-4-yl)-2-methylbenzonitrile (100 mg, 0.42 mmol), 5-(azidomethyl)-1H-indole (110 mg, 0.64 mmol) and place them in a 50 mL flask, add 6 mL of tert-butyl alcohol, and then add 3 mL of ultrapure water. Then add anhydrous copper sulfate (27 mg, 0.17 mmol) and sodium vitamin C (68 mg, 0.34 mol), place it in a 60 ° C oil bath, and react for 4 hours. TLC monitors the reaction. After the reaction is completed, cool to room temperature, dilute with ethyl acetate, and then wash with water and saturated brine in turn. Take the organic phase and dry it over anhydrous sodium sulfate. After concentration, separate it by silica gel column chromatography (dichloromethane / methanol=50 / 1~30 / 1) to obtain a white solid product (51 mg, 29.5%).

[0062] 1 H NMR (400MHz, DMSO-d6) δ11.24(s,0.5H),8.55(s,1H),7.92(d,J=7.1Hz,1H),7.77(d,J=7.5Hz,1H),7.68(s,1H),7.53(t, J=7.8Hz,1H),7.47–7.39(m,2H),7.27(s,1H),7.19(dd,J=8.4,1.2Hz,1H),6.90(s,1H),6.48(d,J=3.0Hz,1H),5.75(s,2H ),2.56(s,3H).13CNMR(101MHz,DMSO-d6)δ167.07,163.98,158.63,146.33,140.42,139.54,136.04,134.08,133.71,12 8.12,127.40,126.60,126.34,124.64,121.95,120.85,118.47,113.64,112.28,105.36,101.65,54.46,18.71.HRMS(ESI + )m / s calcd for C 23 H 18 N8[M+H] + :407.1727; found,407.1733.

[0063] Example 2: Preparation of Compound 2

[0064] Preparation of 3-(6-(1-((1H-indol-4-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-aminopyrimidin-4-yl)-2-methylbenzonitrile

[0065]

[0066] Refer to the synthetic route of Example 1. The azide derivative is selected from 4-(azidomethyl)-1H-indole. A white solid product (60 mg, 35%) is obtained by separation through silica gel column chromatography (dichloromethane / methanol=50 / 1-30 / 1).

[0067] 1 H NMR (400MHz, DMSO-d6) δ11.30(s,0.5H),8.45(s,1H),7.88(d,J=7.6Hz,1H),7.73(d,J=7.6Hz,1H),7.50(t,J=7.7Hz,1H),7.42(dd,J=12. 4,5.5Hz,2H),7.24(s,1H),7.12(t,J=7.6Hz,1H),7.05(d,J=7.1Hz,1H),6.84(s,1H),6.54(d,J=2.6Hz,1H),5.93(s,2H),2.53(s,3H).13C NMR(101MHz,DMSO-d6)δ167.10,163.98,158.59,146.25,140.44,139.54,136.50,134.07,133.70,127.40,126 .88,126.72,126.29,124.84,121.45,119.81,118.46,113.65,112.46,105.36,99.45,52.46,18.70.HRMS(ESI + )m / s calcd for C 23 H 18 N8[M+H] + :407.1727; found,407.1734.

[0068] Example 3: Preparation of Compound 3

[0069] Preparation of 3-(6-(1-((1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-aminopyrimidin-4-yl)-2-methylbenzonitrile

[0070]

[0071] Refer to the synthetic route of Example 1. The azide derivative is selected from 6-(azidomethyl)-1H-indole. A white solid product (40 mg, 23%) is obtained by separation through column chromatography (dichloromethane / methanol=50 / 1-30 / 1).

[0072] 1H NMR (400MHz, DMSO-d6) δ11.20(s,1H),8.56(s,1H),7.90(dd,J=7.8,1.4Hz,1H),7.75(dd,J=7.8,1.4Hz,1H),7.56(d,J=8.1Hz,1H),7.51(t,J=7. 8Hz,1H),7.46(s,1H),7.40(t,J=2.8Hz,1H),7.25(s,1H),7.07(dd,J=8. 1,1.6Hz,1H),6.86(s,2H),6.47–6.41(m,1H),5.77(s,2H),2.55(s,3H). 13 C NMR(101MHz,DMSO-d6)δ167.10,164.06,158.66,146.37,140.46,139.54,136.24,134.08,133.71,128.62,127 .99,127.40,126.77,124.78,120.87,119.74,118.49,113.66,111.94,105.38,101.49,54.35,18.71.HRMS(ESI + )m / scalcd for C 23 H 18 N8[M+H] + :407.1727; found,407.1735.

[0073] Example 4: Preparation of Compound 4

[0074] Preparation of 3-(6-(1-((1H-indol-7-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-aminopyrimidin-4-yl)2-methylbenzonitrile

[0075]

[0076] Refer to the synthetic route of Example 1. The azide derivative is selected from 7-(azidomethyl)-1H-indole. A white solid product (43 mg, 25%) is obtained by separation through column chromatography (dichloromethane / methanol=50 / 1-30 / 1).

[0077] 1H NMR (400MHz, DMSO-d6) δ11.44(s,1H),8.50(s,1H),7.89(dd,J=7.8,1.4Hz,1H),7.74(dd,J=7.8,1.4Hz,1H),7.60(d,J=7.6Hz,1H),7.51(t ,J=7.8Hz,1H),7.47(t,J=2.8Hz,1H),7.25(s,1H),7.12–6.99(m,2H),6.86(s,2H),6.54(dd,J=3.2,1.8Hz,1H),5.98(s,2H),2.54(s,3H). 13 C NMR(101MHz,DMSO-d6)δ166.63,163.55,158.08,145.73,139.95,139.03,134.09,133.55,133.21,128.39,126 .91,125.96,124.19,121.74,120.74,119.12,118.18,117.95,113.17,104.85,101.85,49.85,18.19.HRMS(ESI + )m / s calcd for C 23 H 18 N8[M+H] + :407.1727; found,407.1735.

[0078] Example 5: Preparation of Compound 5

[0079] Preparation of 3-(6-(1-((1H-indol-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-aminopyrimidin-4-yl)2-methylbenzonitrile

[0080]

[0081] Refer to the synthetic route of Example 1. The azide derivative is selected from 2-(azidomethyl)-1H-indole. A white solid product (35 mg, 20%) is obtained by column chromatography (dichloromethane / methanol=50 / 1-30 / 1).

[0082] 1H NMR (400MHz, DMSO-d6) δ11.42(s,0.5H),8.58(s,1H),7.93(d,J=7.6Hz,1H),7.78(d,J=7.7Hz,1H),7.62–7.48(m,2H),7.40(d ,J=8.1Hz,1H),7.29(s,1H),7.14(t,J=7.5Hz,1H),7.03(t,J=7.4Hz,1H),6.92(s,1H),6.58(s,1H),5.88(s,2H),2.57(s,3H). 13 CNMR(101MHz,DMSO-d6)δ167.12,164.00,158.53,146.36,140.40,139.54,136.85,134.09,133.74,132.67,127 .91,127.42,124.89,122.26,120.74,119.76,118.47,113.65,111.86,105.35,102.49,47.44,18.71.HRMS(ESI + )m / s calcd for C 23 H 18 N8[M+H] + :407.1727; found,407.1736.

[0083] Example 6: Preparation of Compound 6

[0084] Preparation of 3-(6-(1-((1H-indol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-aminopyrimidin-4-yl)2-methylbenzonitrile

[0085]

[0086] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-1H-indole. A white solid product (40 mg, 23%) is obtained by separation through column chromatography (dichloromethane / methanol=50 / 1-30 / 1).

[0087] 1H NMR (400MHz, DMSO-d6) δ11.31(d,J=2.6Hz,0.6H),8.42(s,1H),7.92(dd,J=7. 8,1.3Hz,1H),7.76(dd,J=7.9,1.3Hz,1H),7.65(d,J=2.3Hz,1H),7.61(d,J=7 .9Hz,1H),7.53(t,J=7.8Hz,1H),7.45(d,J=8.1Hz,1H),7.25(s,1H),7.16(t, J=7.5Hz,1H),7.06(t,J=7.5Hz,1H),6.88(s,0.9H),5.87(s,2H),2.55(s,3H). 13 C NMR(101MHz,DMSO-d6)δ167.05,163.95,158.61,146.15,140.42,139.52,136.56,134.07,133.70,127.40,126 .52,126.37,124.24,122.15,119.79,118.58,118.46,113.62,112.24,108.90,105.29,45.80,18.69.HRMS(ESI + )m / scalcd for C 23 H 18 N8[M+H] + :407.1727; found,407.1731.

[0088] Example 7: Preparation of Compound 7

[0089] Preparation of 3-(2-amino-6-(1-((1-methyl-1H-indol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)2-methylbenzonitrile

[0090]

[0091] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-1-methyl-1H-indole. A white solid product (12 mg, 7%) is obtained by separation through column chromatography (dichloromethane / methanol=90 / 1-50 / 1).

[0092] 1H NMR (400MHz, DMSO-d6) δ8.43(s,1H),7.88(dd,J=7.8,1.3Hz,1H),7.73(dd,J=7.9,1.3Hz,1H),7.62(d,J=7.9Hz,1H),7.58(s,1H),7.49(dd, J=16.7,8.2Hz,2H),7.22(d,J=2.6Hz,1H),7.20(d,J=1.2Hz,1H),7.08(t,J=7.5Hz,1H),6.83(s,1H),5.83(s,2H),3.81(s,3H),2.52(s,3H). 13 C NMR(101MHz,DMSO-d6)δ167.06,163.96,158.64,146.18,140.44,139.52,137.18,134.06,133.70,130.48,127.40 ,126.85,124.31,122.22,119.93,118.82,118.45,113.65,110.58,108.21,105.34,45.57,32.97,18.69.HRMS(ESI + )m / scalcd for C 24 H 20 N8[M+H] + :421.1884; found,421.1892.

[0093] Example 8: Preparation of Compound 8

[0094] Preparation of 3-(6-(1-((1H-indazol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-aminopyrimidin-4-yl)2-methylbenzonitrile

[0095]

[0096] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-1H-indazole. A white solid product (55 mg, 32%) is obtained by separation through column chromatography (dichloromethane / methanol=40 / 1-20 / 1).

[0097] 1H NMR (400MHz, DMSO-d6) δ13.26(s,0.4H),8.65(s,1H),7.92(dd,J=7.8,1.3Hz,1H),7.84–7.71(m,2H),7.59(d,J=8.4Hz,1H ),7.53(t,J=7.8Hz,1H),7.42(t,J=7.6Hz,1H),7.28(s,1H),7.18(t,J=7.5Hz,1H),6.93(s,1H),6.13(s,2H),2.56(s,3H). 13 C NMR(101MHz,DMSO-d6)δ167.10,163.95,158.53,146.34,141.40,141.21,140.40,139.54,134.08,133.73, 127.40,126.96,125.17,121.29,121.21,119.98,118.46,113.64,110.92,105.44,46.92,18.71.HRMS(ESI + )m / s calcd for C 22 H 17 N9[M+H] + :408.1680; found,408.1682.

[0098] Example 9: Preparation of Compound 9

[0099] Preparation of 3-(2-amino-6-(1-(imidazo[1,2-a]pyridin-3-ylmethyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)2-methylbenzonitrile

[0100]

[0101] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)imidazo[1,2-a]pyridine. A white solid product (41 mg, 24%) is obtained by column chromatography (dichloromethane / methanol=50 / 1 to=30 / 1).

[0102] 1H NMR (400MHz, DMSO-d6) δ8.60(s,1H),8.57(d,J=6.9Hz,1H),7.88(dd,J=7.7,1.4Hz,2H),7.72(dd,J=7.8,1.3Hz,1H),7.65(d,J= 9.1Hz,1H),7.50(t,J=7.8Hz,1H),7.39–7.29(m,1H),7.22(s,1H),7.04(t,J=6.8Hz,1H),6.87(s,1H),6.18(s,2H),2.52(s,3H). 13 CNMR(101MHz,DMSO-d6)δ167.13,163.99,158.43,146.44,140.40,139.52,135.09,134.05,133.72 ,127.40,125.72,125.21,124.74,118.44,117.74,113.66,113.21,105.46,43.15,18.69.HRMS(ESI + )m / s calcd for C 22 H 17 N9[M+H] + :408.1680; found,408.1689.

[0103] Example 10: Preparation of Compound 10

[0104] Preparation of 3-(2-amino-6-(1-(benzo[b]thiophen-3-ylmethyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0105]

[0106] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)benzo[b]thiophene. A white solid product (59 mg, 34%) is obtained by separation through column chromatography (dichloromethane / methanol=70 / 1-50 / 1).

[0107] 1H NMR (400MHz, DMSO-d6) δ8.60(s,1H),8.07–8.03(m,1H),7.96–7.91(m,2H),7.89(dd,J=7.7,1.3Hz,1H),7.74(dd,J=7. 8,1.3Hz,1H),7.51(t,J=7.8Hz,1H),7.44(tt,J=7.3,5.6Hz,2H),7.25(s,1H),6.86(s,2H),6.01(s,2H),2.54(s,3H). 13 C NMR(151MHz,DMSO-d6)δ167.14,164.04,158.51,146.41,140.43,140.33,139.53,137.64,134.06,133.71,130 .40,128.53,127.41,125.29,125.06,124.90,123.64,122.14,118.45,113.66,105.41,47.48,18.69.HRMS(ESI + )m / s calcd for C 23 H 17 N7S[M+H] + :424.1339; found,424.1345.

[0108] Example 11: Preparation of Compound 11

[0109] Preparation of 3-(2-amino-6-(1-((4-chloro-1H-indol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)2-methylbenzonitrile

[0110]

[0111] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-4-chloro-1H-indole. A white solid product (14 mg, 8%) is obtained by separation through column chromatography (dichloromethane / methanol=60 / 1-40 / 1).

[0112] 1 H NMR (400MHz, DMSO-d6) δ11.72(s,J=2.6Hz,1H),8.14(s,1H),7.89(dd,J=7.8,1.3Hz,1H),7.80–7.7 0(m,2H),7.56–7.40(m,2H),7.25(s,1H),7.19–7.03(m,2H),6.83(s,2H),5.96(s,2H),2.54(s,3H). 13C NMR(101MHz,DMSO-d6)δ166.63,163.52,158.11,145.46,139.99,139.03,138.00,133.56,133.18,129.09, 126.90,124.07,123.27,122.67,120.06,117.96,113.15,111.31,107.04,104.74,45.85,18.19.HRMS(ESI + )m / s calcd for C 23 H 17 ClN8[M+H] + :441.1337; found,441.1343.

[0113] Example 12: Preparation of Compound 12

[0114] Preparation of 3-(2-amino-6-(1-((5-chloro-1H-indol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)2-methylbenzonitrile

[0115]

[0116] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-5-chloro-1H-indole. A white solid product (21 mg, 11%) is obtained by column chromatography (dichloromethane / methanol=60 / 1-40 / 1).

[0117] 1 H NMR (400MHz, DMSO-d6) δ11.50(s,J=2.6Hz,1H),8.51(s,1H),7.92(dd,J=7.8,1.3Hz,1H),7.75(ddd,J=12.6,7.8,1.9Hz,3H), 7.53(t,J=7.8Hz,1H),7.47(d,J=8.6Hz,1H),7.26(s,1H),7.16(dd,J=8.6,2.1Hz,1H),6.89(s,1H),5.86(s,2H),2.56(s,3H). 13CNMR(101MHz,DMSO-d6)δ167.06,163.94,158.60,146.19,140.41,139.53,135.16,134.07,133.71,128.31,127 .74,127.40,124.47,124.35,122.14,118.46,117.99,113.91,113.63,109.07,105.36,45.39,18.70.HRMS(ESI + )m / s calcd for C 23 H 17 ClN8[M+H] + :441.1337; found,441.1348.

[0118] Example 13: Preparation of Compound 13

[0119] Preparation of 3-(2-amino-6-(1-((6-chloro-1H-indol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)2-methylbenzonitrile

[0120]

[0121] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-6-chloro-1H-indole. A white solid product (33 mg, 18%) is obtained by column chromatography (dichloromethane / methanol=60 / 1-40 / 1).

[0122] 1 H NMR (400MHz, DMSO-d6) δ11.36(s,J=2.5Hz,1H),8.47(s,1H),7.92(dd,J=7.8,1.3Hz,1H),7.81–7.73(m,1H),7.67–7.5 9(m,2H),7.53(t,J=7.7Hz,1H),7.28–7.19(m,2H),6.94(td,J=9.3,2.4Hz,1H),6.88(s,1H),5.86(s,2H),2.55(s,3H). 13C NMR(101MHz,DMSO-d6)δ167.05,163.93,160.68,158.60,158.35,146.18,140.40,139.52,136.56,134.07,133 .71,127.40,124.35,123.31,119.80,118.46,113.63,109.27,108.24,105.32,98.43,45.65,18.69.HRMS(ESI + )m / s calcd for C 23 H 17 ClN8[M+H] + :441.1337; found,441.1341.

[0123] Example 14: Preparation of Compound 14

[0124] Preparation of 3-(2-amino-6-(1-((7-chloro-1H-indol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)2-methylbenzonitrile

[0125]

[0126] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-7-chloro-1H-indole. A white solid product (12 mg, 7%) is obtained by separation through column chromatography (dichloromethane / methanol=60 / 1-40 / 1).

[0127] 1 H NMR (400MHz, DMSO-d6) δ11.67(s,J=2.6Hz,1H),8.45(s,1H),7.89(dd,J=7.8,1.3Hz,1H),7.79–7.68(m,2H),7.59(d, J=7.9Hz,1H),7.51(t,J=7.8Hz,1H),7.27–7.16(m,2H),7.06(t,J=7.8Hz,1H),6.83(s,2H),5.86(s,2H),2.53(s,3H). 13C NMR(101MHz,DMSO-d6)δ166.59,163.53,158.12,145.75,139.96,139.03,133.55,133.19,133.06,128.02,127 .32,126.89,123.87,121.22,120.43,117.95,117.31,116.19,113.16,109.96,104.86,45.11,18.19.HRMS(ESI + )m / s calcd for C 23 H 17 ClN8[M+H] + :441.1337; found,441.1343.

[0128] Example 15: Preparation of Compound 15

[0129] Preparation of 3-(2-amino-6-(1-((5,6-dichloro-1H-indol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)2-methylbenzonitrile

[0130]

[0131] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-5,6-dichloro-1H-indole. A white solid product (33 mg, 16%) is obtained by column chromatography (dichloromethane / methanol=60 / 1-40 / 1).

[0132] 1 H NMR(600MHz,DMSO-d6)δ11.53(s,1H),8.50(s,1H),7.94(s,1H),7.88(dd,J=7.8,1.3Hz,1H),7.80–7 .70(m,2H),7.67(s,1H),7.50(t,J=7.7Hz,1H),7.22(s,1H),6.83(s,2H),5.83(s,2H),2.52(s,3H). 13 C NMR(151MHz,DMSO-d6)δ167.08,164.03,158.63,146.24,140.45,139.53,135.57,134.06,133.70,129.30,127 .40,126.63,124.49,124.42,122.46,119.98,118.45,113.91,113.65,109.33,105.38,45.18,18.69.HRMS(ESI +)m / scalcd for C 23 H 16 Cl2N8[M+H] + :475.0948; found,475.0957.

[0133] Example 16: Preparation of Compound 16

[0134] Preparation of 3-(6-(1-((1H-pyrrolo[3,2-b]pyridin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-aminopyrimidin-4-yl)2-methylbenzonitrile

[0135]

[0136] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-1H-pyrrolo[3,2-b]pyridine. A white solid product (35 mg, 20%) is obtained by column chromatography (dichloromethane / methanol=40 / 1-20 / 1).

[0137] 1 H NMR (400MHz, DMSO-d6) δ11.52(s,J=2.8Hz,0.5H),8.47(s,1H),8.40(d,J=4.6Hz,1H),7.92(d,J=2.6Hz,1H),7.86(ddd,J=16.3,8.0,1 .4Hz,2H),7.76–7.65(m,1H),7.50(t,J=7.7Hz,1H),7.23(s,1H),7.19(dd,J=8.2,4.6Hz,1H),6.85(s,1H),5.86(s,2H),2.52(s,3H). 13 C NMR(101MHz,DMSO-d6)δ167.06,163.98,158.68,146.15,144.34,143.26,140.45,139.53,134.06,133.69, 130.09,129.04,127.39,124.48,119.57,118.46,117.48,113.65,109.00,105.31,44.58,18.69.HRMS(ESI + )m / s calcd for C 22 H 17 N9[M+H] + :408.1680; found,408.1688.ESI(m / z):[M+H] + 408.1688

[0138] Example 17: Preparation of Compound 17

[0139] Preparation of 3-(6-(1-((1H-pyrrolo[3,2-c]pyridin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)2-aminopyrimidin-4-yl)-2-methylbenzonitrile

[0140]

[0141] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-1H-pyrrolo[3,2-c]pyridine. A white solid product (19 mg, 11%) is obtained by separation through column chromatography (dichloromethane / methanol=40 / 1-20 / 1).

[0142] 1 H NMR (400MHz, DMSO-d6) δ11.64(s,1H),8.91(s,1H),8.56(s,1H),8.21(s,1H),7.89(dd,J=7.8,1.3Hz,1H),7.74(dd,J=7.8,1.3H z,1H),7.69(d,J=2.2Hz,1H),7.51(t,J=7.8Hz,1H),7.41(d,J=5.5Hz,1H),7.24(s,1H),6.85(s,2H),5.92(s,2H),2.53(s,3H). 13 CNMR(101MHz,DMSO-d6)δ166.60,163.55,158.13,145.82,141.56,140.61,139.96,139.70,139.04 ,133.56,133.19,127.03,126.89,124.05,117.95,113.16,108.73,104.91,44.90,18.19.HRMS(ESI + )m / s calcd for C 22 H 17 N9[M+H] + :408.1680 found,408.1690.

[0143] Example 18: Preparation of Compound 18

[0144] Preparation of 3-(6-(1-((1H-pyrrolo[2,3-c]pyridin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-aminopyrimidin-4-yl)-2-methylbenzonitrile

[0145]

[0146] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-1H-pyrrolo[2,3-c]pyridine. A white solid product (64 mg, 37%) is obtained by separation through column chromatography (dichloromethane / methanol=40 / 1-20 / 1).

[0147] 1 H NMR (600MHz, DMSO-d6) δ11.76(s,1H),8.77(d,J=1.1Hz,1H),8.48(s,1H),8.13(d,J=5.5Hz,1H),7.88(dd,J=7.8,1.4Hz,1H),7.85(d,J=2.0 Hz,1H),7.72(dd,J=7.8,1.4Hz,1H),7.60(dd,J=5.5,1.1Hz,1H),7.50(t,J=7.7Hz,1H),7.22(s,1H),6.82(s,2H),5.86(s,2H),2.52(s,3H). 13 C NMR(151MHz,DMSO-d6)δ167.07,164.03,158.62,146.27,140.45,139.52,138.57,135.26,134.06,133.86, 133.70,130.89,130.38,127.40,124.41,118.45,113.65,113.40,108.90,105.37,45.26,18.69.HRMS(ESI + )m / s calcd for C 22 H 17 N9[M+H] + :408.1680; found,408.1685.

[0148] Example 19: Preparation of Compound 19

[0149] Preparation of 3-(6-(1-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-1H-1,2,3-triazol-4-yl)2-aminopyrimidin-4-yl)-2-methylbenzonitrile

[0151] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-1H-pyrrolo[2,3-b]pyridine. A white solid product (51 mg, 29%) is obtained by column chromatography (dichloromethane / methanol=40 / 1-20 / 1).

[0152] 1H NMR (400 MHz, DMSO-d6) δ11.82(s,J=2.6 Hz,0.5H),8.48(s,1H),8.25(d,J=4.6Hz,1H),8.02(dd,J=7.9,1.5 Hz,1H),7.88(dd,J=7.7,1.3 Hz,1H),7.80–7.67(m,2H),7.50(t,J=7.7 Hz,1H),7.22(s,1H),7.10(dd,J=7.9,4.7 Hz,1H),6.83(s,1H),5.84(s,2H),2.52(s,3H). 13 C NMR(101 MHz, DMSO-d6)δ167.06,164.02,163.97,158.59,148.95,146.24,143.68,140.41,139.52,134.06,133 .71,127.15,126.96,124.43,118.79,118.46,116.27,113.63,108.05,105.36,45.72,18.69.HRMS(ESI + )m / s calcd for C 22 H 17 N9[M+H] + :408.1680; found,408.1683.

[0153] Example 20: Preparation of Compound 20

[0154] Preparation of 3-(2-amino-6-(1-((5-methyl-1H-indol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)2-methylbenzonitrile

[0155]

[0156] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-5-methyl-1H-indole. A white solid product (11 mg, 6%) is obtained by separation through column chromatography (dichloromethane / methanol=50 / 1-30 / 1).

[0157] 1H NMR (400 MHz, DMS-d6) δ11.14(s,J=2.6 Hz,1H),8.35(s,1H),7.89(dd,J=7.7,1.3 Hz,1H),7.73(dd,J=7.8,1.3 Hz,1H),7.57(d,J=2.5 Hz,1H),7.51(t,J=7.7Hz,1H),7.37(s,1H),7.31(d,J=8.3 Hz,1H),7.24(s,1H),6.96(dd,J=8.4,1.5 Hz,1H),6.82(s,2H),5.80(s,2H),2.53(s,3H),2.36(s,3H). 13 C NMR(101 MHz, DMSO-d6)δ166.61,163.51,158.12,139.98,139.02,134.63,133.54,133.20,127.86,126.90,126.32,126 .15,123.65,123.28,120.34,117.95,117.56,113.17,111.53,107.77,104.90,45.31,21.23,18.19.HRMS(ESI + )m / s calcd for C 24 H 20 N8[M+H] + :421.1884; found,421.1887.

[0158] Example 21: Preparation of Compound 21

[0159] Preparation of 3-(2-amino-6-(1-((6-methyl-1H-indol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)2-methylbenzonitrile

[0160]

[0161] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-6-methyl-1H-indole. A white solid product (17 mg, 10%) is obtained by separation through column chromatography (dichloromethane / methanol=50 / 1-30 / 1).

[0162] 1H NMR (400MHz, DMSO-d6) δ11.10(s,J=2.4Hz,1H),8.35(s,1H),7.89(dd,J=7.8,1.3Hz,1H),7.73(dd,J=7.8,1.3Hz,1H),7.54–7.47(m,2 H),7.45(d,J=8.1Hz,1H),7.23(s,1H),7.21(s,1H),6.87(dd,J=8.2,1.4Hz,1H),6.82(s,2H),5.80(s,2H),2.53(s,3H),2.39(s,3H). 13 C NMR(101MHz,DMSO-d6)δ166.57,163.53,158.17,145.66,139.97,139.03,136.73,133.55,133.19,130.79,126.89 ,125.30,123.98,123.68,121.07,117.95,117.79,113.16,111.54,108.23,104.81,45.42,21.29,18.19.HRMS (ESI + )m / s calcd for C 24 H 20 N8[M+H] + :421.1884; found,421.1890.

[0163] Example 22: Preparation of Compound 22

[0164] Preparation of 3-(2-amino-6-(1-((5-methoxy-1H-indol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)2-methylbenzonitrile

[0165]

[0166] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-5-methoxy-1H-indole. A white solid product (34 mg, 18%) is obtained by separation through column chromatography (dichloromethane / methanol=50 / 1-30 / 1).

[0167] 1H NMR (600MHz, DMSO-d6) δ11.11(d,J=2.6Hz,1H),8.35(s,1H),7.88(dd,J=7.7,1.3Hz,1H),7.72(dd,J=7.8,1.3Hz,1H),7.55(d,J=2.6Hz,1H),7.52–7 .47(m,1H),7.34–7.27(m,1H),7.22(s,1H),7.11(d,J=2.4Hz,1H),6.82(s ,2H),6.78(dd,J=8.8,2.5Hz,1H),5.79(s,2H),3.73(s,3H),2.52(s,3H). 13 C NMR(151MHz,DMSO-d6)δ167.06,164.03,158.67,154.09,146.17,140.46,139.53,134.07,133.70,131.81,127.40 ,127.10,127.07,124.16,118.46,113.65,112.99,112.03,108.61,105.30,100.66,55.88,45.78,18.69.HRMS(ESI + )m / s calcd for C 24 H 20 N8O[M+H] + :437.1833; found,437.1845.

[0168] Example 23: Preparation of Compound 23

[0169] Preparation of 3-(2-amino-6-(1-((6-methoxy-1H-indol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)2-methylbenzonitrile

[0170]

[0171] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-6-methoxy-1H-indole. A white solid product (26 mg, 14%) is obtained by separation through column chromatography (dichloromethane / methanol=50 / 1-30 / 1).

[0172] 1H NMR (600MHz, DMSO-d6) δ11.04(d,J=2.5Hz,1H),8.36(s,1H),7.88(dd,J=7.7,1.4Hz,1H),7.72(dd,J=7.8,1.3Hz,1H),7.52–7.48(m,1H),7.46(d,J=2 .5Hz,1H),7.43(d,J=8.7Hz,1H),7.22(s,1H),6.91(d,J=2.2Hz,1H),6.82( s,2H),6.69(dd,J=8.7,2.3Hz,1H),5.78(s,2H),3.75(s,3H),2.52(s,3H). 13 C NMR(151MHz,DMSO-d6)δ167.07,164.02,158.65,156.38,146.15,140.46,139.53,137.57,134.06,133.69,127.40 ,125.11,124.20,120.82,119.23,118.46,113.65,110.08,108.91,105.30,95.26,55.67,45.91,18.69.HRMS(ESI + )m / s calcd for C 23 H 17 FN8[M+H] + :437.1833; found,427.1842.

[0173] Example 24: Preparation of Compound 24

[0174] Preparation of 3-(2-amino-6-(1-((5-isopropoxy-1H-indol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)2-methylbenzonitrile

[0175]

[0176] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-5-isopropoxy-1H-indole. A white solid product (41 mg, 21%) is obtained by separation through column chromatography (dichloromethane / methanol=50 / 1-30 / 1).

[0177] 1H NMR (400MHz, DMSO-d6) δ11.09(s,J=2.6Hz,0.5H),8.39(s,1H),7.88(dd,J=7.7,1.4Hz ,1H),7.73(dd,J=7.8,1.4Hz,1H),7.55(d,J=2.3Hz,1H),7.50(t,J=7.7Hz,1H),7.29(d ,J=8.8Hz,1H),7.22(s,1H),7.08(d,J=2.3Hz,1H),6.82(d,J=1.9Hz,1H),6.76(dd,J=8 .8,2.4Hz,1H),5.79(s,2H),4.49(p,J=6.0Hz,1H),2.52(s,3H),1.23(d,J=6.0Hz,6H). 13 CNMR(101MHz,DMSO-d6)δ166.56,163.54,158.19,151.35,145.67,139.97,139.02,133.55,133.19,131.46,129.75,12 6.90,126.51,123.74,120.03,117.95,113.16,112.41,108.09,104.82,103.48,69.90,45.37,21.95,18.18.HRMS(ESI + )m / s calcd for C 26 H 24 N8O[M+H] + :465.2146; found,465.2158.

[0178] Example 25: Preparation of Compound 25

[0179] Preparation of 3-(2-amino-6-(1-((6-isopropoxy-1H-indol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)2-methylbenzonitrile

[0180]

[0181] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-6-isopropoxy-1H-indole. A white solid product (33 mg, 17%) is obtained by separation through column chromatography (dichloromethane / methanol=50 / 1-30 / 1).

[0182] 1H NMR (400MHz, DMSO-d6) δ11.04(s,J=2.5Hz,0.5H),8.41(s,1H),7.92(dd,J=7.8,1.3 Hz,1H),7.76(dd,J=7.8,1.3Hz,1H),7.53(t,J=7.8Hz,1H),7.49(d,J=2.0Hz,1H),7. 45(d,J=8.6Hz,1H),7.25(s,1H),6.93(d,J=2.1Hz,1H),6.88(s,1H),6.70(dd,J=8.6 ,2.2Hz,1H),5.81(s,2H),4.58(p,J=6.0Hz,1H),2.55(s,3H),1.29(d,J=6.0Hz,6H). 13 C NMR(101MHz,DMSO-d6)δ167.05,163.95,158.63,154.22,146.13,140.42,139.52,137.60,134.07,133.70,127.40,12 5.07,124.23,120.94,119.23,118.47,113.63,111.62,108.88,105.29,98.02,70.10,45.90,22.39,18.70.HRMS(ESI + )m / s calcd for C 26 H 24 N8O[M+H] + :465.2146; found,465.2155.

[0183] Example 26: Preparation of Compound 26

[0184] Preparation of 3-(2-amino-6-(1-((5-(cyclopentyloxy)-1H-indol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0185]

[0186] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-5-(cyclopentyloxy)-1H-indole. A white solid product (40 mg, 19%) is obtained by separation through column chromatography (dichloromethane / methanol=50 / 1-30 / 1).

[0187] 1H NMR (400MHz, DMSO-d6) δ11.08(s,0.5H),8.41(s,1H),7.89(d,J=7.7Hz,1H),7.73(d,J =7.7Hz,1H),7.55(s,1H),7.51(t,J=7.8Hz,1H),7.30(d,J=8.8Hz,1H),7.24(s,1H),7 .02(s,1H),6.82(s,1H),6.75(d,J=8.8Hz,1H),5.80(s,2H),4.73(d,J=5.8Hz,1H),2. 53(s,3H),1.85(dd,J=12.2,5.5Hz,2H),1.69(d,J=6.1Hz,4H),1.57(d,J=11.0Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ166.58,163.46,158.23,151.61,140.04,138.99,133.51,133.19,131.31,131.15,126.90,126.5 6,126.44,126.27,123.85,117.94,113.18,112.88,112.37,108.08,102.72,79.03,45.55,32.20,23.52,18.18.HRMS(ESI + )m / s calcdfor C 28 H 26 N8O[M+H] + :491.2302; found,491.2310.

[0188] Example 27: Preparation of Compound 27

[0189] Preparation of 3-(2-amino-6-(1-((6-(cyclopentyloxy)-1H-indol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0190]

[0191] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-6-(cyclopentyloxy)-1H-indole. A white solid product (49 mg, 23%) is obtained by separation through column chromatography (dichloromethane / methanol=50 / 1-30 / 1).

[0192] 1H NMR (400MHz, DMSO-d6) δ10.99(s,1H),8.37(s,1H),7.89(dd,J=7.8,1.4Hz,1H),7.74(dd,J=7.8,1. 4Hz,1H),7.51(t,J=7.8Hz,1H),7.46(d,J=2.5Hz,1H),7.42(d,J=8.7Hz,1H),7.23(s,1H),6.88(d, J=2.2Hz,1H),6.83(s,2H),6.66(dd,J=8.6,2.2Hz,1H),5.78(s,2H),4.91–4.50(m,1H),2.53(s,3H ),1.89(ddt,J=16.3,10.9,5.9Hz,2H),1.80–1.65(m,4H),1.60(dddd,J=8.4,6.8,5.1,2.2Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ166.57,163.53,158.17,153.99,145.66,139.97,139.03,137.11,133.56,133.19,126.90,124.6 0,123.71,120.25,118.72,117.95,113.16,110.86,108.39,104.81,96.98,78.84,45.43,32.26,23.57,18.19.HRMS(ESI + )m / s calcd for C 28 H 26 N8O[M+H] + :491.2302; found,491.2306.

[0193] Example 28: Preparation of Compound 28

[0194] Preparation of 3-(2-amino-6-(1-((5-fluoro-1H-indol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)2-methylbenzonitrile

[0195]

[0196] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-5-fluoro-1H-indole. A white solid product (28 mg, 13%) is obtained by separation through column chromatography (dichloromethane / methanol=50 / 1-30 / 1).

[0197] 1H NMR (400MHz, DMSO-d6) δ11.41(s,1H),8.50(s,1H),7.92(d,J=7.7Hz,1H),7.76(d,J=7.7Hz,1H),7.72(d,J=2.4Hz,1H),7.5 3(t,J=7.7Hz,1H),7.45(dd,J=8.7,4.1Hz,2H),7.26(s,1H),7.01(d,J=2.4Hz,1H),6.89(s,1H),5.84(s,2H),2.55(s,3H). 13 C NMR(101MHz,DMSO-d6)δ167.06,163.97,158.68,156.37,146.20,140.43,139.52,134.06,133.70,133.34,133 .18,128.36,127.40,124.33,118.46,113.63,110.48,109.37,105.33,103.59,103.36,45.57,18.69.HRMS(ESI + )m / s calcd for C 23 H 17 FN8[M+H] + :425.1633; found,425.1637.

[0198] Example 29: Preparation of Compound 29

[0199] Preparation of 3-(2-amino-6-(1-((6-fluoro-1H-indol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)2-methylbenzonitrile

[0200]

[0201] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-5-fluoro-1H-indole. A white solid product (22 mg, 12%) is obtained by separation through column chromatography (dichloromethane / methanol=50 / 1-30 / 1).

[0202] 1H NMR (400MHz, DMSO-d6) δ11.36(s,J=2.5Hz,1H),8.47(s,1H),7.92(dd,J=7.8,1.3Hz,1H),7.76(dd,J=7.8,1.3Hz,1H),7.64(d,J=2.3Hz,1H) ,7.61(dd,J=8.8,5.4Hz,1H),7.53(t,J=7.8Hz,1H),7.28–7.19(m,2H),6.95(td,J=9.3,2.4Hz,1H),6.89(s,1H),5.86(s,2H),2.55(s,3H). 13 C NMR(101MHz,DMSO-d6)δ167.05,163.92,160.68,158.59,158.35,146.18,140.40,139.53,134.07,133.71,127 .40,126.98,124.35,123.31,119.80,118.46,113.63,109.30,108.48,105.33,98.42,45.65,18.69.HRMS(ESI + )m / s calcd for C 23 H 17 FN8[M+H] + :425.1633; found,425.1641.

[0203] Example 30: Preparation of Compound 30

[0204] Preparation of methyl 3-((4-(2-amino-6-(3-cyano-2-methylphenyl)pyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-5-carboxylate.

[0205]

[0206] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-1H-indole-5-carboxylic acid methyl ester. A white solid product (34 mg, 17%) is obtained by separation through column chromatography (dichloromethane / methanol=50 / 1-30 / 1).

[0207] 1H NMR (400MHz, DMSO-d6) δ11.66(s,1H),8.46(s,1H),8.35(d,J=1.5Hz,1H),7.89(dd,J=7.8,1.3Hz,1H),7.78(dd,J=8.6,1. 7Hz,1H),7.76–7.70(m,2H),7.51(dd,J=8.2,6.8Hz,2H),7.23(s,1H),6.83(s,2H),5.91(s,2H),3.85(s,3H),2.53(s,3H). 13 C NMR(101MHz,DMSO-d6)δ167.05,166.59,163.53,158.14,145.76,139.96,139.03,138.87,133.55,133.20,127.96,126 .89,125.70,123.83,122.64,120.88,120.86,117.94,113.17,111.83,110.18,104.87,51.72,44.88,18.18.HRMS(ESI + )m / s calcd for C 25 H 20 N8O2[M+H] + :465.1782; found,465.1792.

[0208] Example 31: Preparation of Compound 31

[0209] Preparation of methyl 3-((4-(2-amino-6-(3-cyano-2-methylphenyl)pyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)1H-indole-6-carboxylate.

[0210]

[0211] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-1H-indole-6-carboxylic acid methyl ester. A white solid product (29 mg, 15%) is obtained by separation through column chromatography (dichloromethane / methanol=50 / 1-30 / 1).

[0212] 1H NMR (600MHz, DMSO-d6) δ11.66(s,1H),8.46(s,1H),8.08(s,1H),7.88(dd,J=7.8,1.3Hz,1H),7.85(d,J=2.2Hz,1H),7.75–7.6 9(m,2H),7.66(dd,J=8.4,1.4Hz,1H),7.50(t,J=7.8Hz,1H),7.21(s,1H),6.82(s,2H),5.87(s,2H),3.85(s,3H),2.52(s,3H). 13 CNMR(151MHz,DMSO-d6)δ167.51,167.07,164.02,158.62,146.25,140.44,139.52,136.00,134.06,133.70,130.35,13 0.10,127.40,124.38,123.24,120.41,118.59,118.45,114.28,113.65,109.74,105.35,52.34,45.46,18.69.HRMS(ESI + )m / s calcd for C 25 H 20 N8O2[M+H] + :465.1782; found,465.1788.

[0213] Example 32: Preparation of Compound 32

[0214] Preparation of 3-(2-amino-6-(1-((5-(methylsulfonyl)-1H-indol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile.

[0215]

[0216] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-5-(methylsulfonyl)-1H-indole. A white solid product (43 mg, 21%) is obtained by column chromatography (dichloromethane / methanol=50 / 1-30 / 1).

[0217] 1H NMR (400MHz, DMSO-d6) δ11.82(d,J=2.5Hz,0.5H),8.51(s,1H),8.30(d,J=1.6Hz,1H),7.90–7.86(m,1H),7.84(d,J=2.4Hz,1H),7.7 3(dd,J=7.8,1.4Hz,1H),7.70–7.60(m,2H),7.50(t,J=7.8Hz,1H),7.23(s,1H),6.83(s,1H),5.93(s,2H),3.16(s,3H),2.53(s,3H). 13 C NMR(101MHz,DMSO-d6)δ167.08,163.98,158.63,146.27,140.44,139.53,138.63,134.06,133.70,132.39,129.27 ,127.40,125.92,124.44,120.47,119.09,118.46,113.65,113.03,110.94,105.40,45.18,44.91,18.70.HRMS(ESI + )m / s calcd for C 24 H 20 N8O2S[M+H] + :485.1503; found,485.1513.

[0218] Example 33: Preparation of Compound 33

[0219] Preparation of 3-(2-amino-6-(1-((6-(methylsulfonyl)-1H-indol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile.

[0220]

[0221] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-6-(methylsulfonyl)-1H-indole. A white solid product (33 mg, 16%) is obtained by separation through column chromatography (dichloromethane / methanol=50 / 1-30 / 1).

[0222] 1H NMR (400MHz, DMSO-d6) δ11.85(d,J=2.6Hz,1H),8.50(s,1H),8.00(d,J=1.5Hz,1H),7.94(d,J=2.6Hz,1H),7.91–7.83(m,2H),7.73(dd, J=7.8,1.3Hz,1H),7.58(dd,J=8.4,1.7Hz,1H),7.50(t,J=7.7Hz,1H),7.23(s,1H),6.83(s,1H),5.91(s,2H),3.17(s,3H),2.52(s,3H). 13 C NMR(101MHz,DMSO-d6)δ167.08,164.02,158.61,146.28,140.44,139.52,135.31,134.27,134.06,133.70,130.99 ,129.85,127.40,124.42,119.47,118.45,117.92,113.65,112.21,109.96,105.37,45.37,44.81,18.69.HRMS(ESI + )m / scalcd for C 24 H 20 N8O2S[M+H] + :485.1503; found,485.1510.

[0223] Example 34: Preparation of Compound 34

[0224] Preparation of 3-((4-(2-amino-6-(3-cyano-2-methylphenyl)pyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-5-carbonitrile.

[0225]

[0226] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-1H-indole-5-carbonitrile. A white solid product (43 mg, 23%) is obtained by separation through column chromatography (dichloromethane / methanol=40 / 1-20 / 1).

[0227] 1H NMR (400MHz, DMSO-d6) δ11.83(d,1H),8.56(s,1H),8.26(s,1H),7.89(dd,J=7.8,1.3Hz,1H),7.82(d,J=2.5Hz,1H),7.7 4(dd,J=7.8,1.3Hz,1H),7.60(d,J=8.5Hz,1H),7.57–7.45(m,2H),7.24(s,1H),6.84(s,2H),5.90(s,2H),2.54(s,3H). 13 C NMR(101MHz,DMSO-d6)δ166.58,163.54,158.15,145.77,139.96,139.03,137.94,133.55,133.20,128.71,126 .90,125.97,124.34,124.06,124.02,120.51,117.95,113.17,109.94,104.93,101.44,44.60,18.19.HRMS(ESI + )m / s calcd for C 24 H 17 N9[M+H] + :432.1680; found,432.1683.

[0228] Example 35: Preparation of Compound 35

[0229] Preparation of 3-((4-(2-amino-6-(3-cyano-2-methylphenyl)pyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-6-carbonitrile.

[0230]

[0231] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-1H-indole-6-carbonitrile. A white solid product (37 mg, 20%) is obtained by separation through column chromatography (dichloromethane / methanol=40 / 1-20 / 1).

[0232] 1H NMR (600MHz, DMSO-d6) δ11.82(s,1H),8.5(s,1H),7.93(d,J=1.3Hz,1H),7.90(s,1H),7.88(dd,J=7.7,1.3Hz,1H),7.80(d,J=8.2Hz,1H ),7.72(dd,J=7.8,1.3Hz,1H),7.50(t,J=7.7Hz,1H),7.40(dd,J=8.3,1.4Hz,1H),7.21(s,1H),6.82(s,2H),5.88(s,2H),2.52(s,3H). 13 C NMR(151MHz,DMSO-d6)δ167.08,164.02,158.61,146.27,140.44,139.52,135.49,134.06,133.70,130.91,129.67, 127.40,124.46,122.53,120.83,119.90,118.45,117.31,113.65,110.25,105.37,103.64,45.23,18.69.HRMS(ESI + )m / s calcd for C 24 H 17 N9[M+H] + :432.1680; found,432.1684.

[0233] Example 36: Preparation of Compound 36

[0234] Preparation of 3-(2-amino-6-(1-((5-(trifluoromethyl)-1H-indol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile.

[0235]

[0236] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-5-(trifluoromethyl)-1H-indole. A white solid product (21 mg, 10%) is obtained by separation through column chromatography (dichloromethane / methanol=40 / 1-20 / 1).

[0237] 1H NMR (600MHz, DMSO-d6) δ11.70(d,J=2.6Hz,1H),8.50(s,1H),8.08(s,1H),7.88(dd,J=7.8,1.3Hz,1H),7.79(d,J=2.4Hz,1H),7.73(dd,J=7.8,1 .3Hz,1H),7.61(d,J=8.6Hz,1H),7.50(t,J=7.7Hz,1H),7.43(dd,J=8.6,1.7Hz,1H),7.22(s,1H),6.82(s,2H),5.91(s,2H),2.52(s,3H).MS(ESI + )m / s:476.6[M+H] + .

[0238] Example 37: Preparation of Compound 37

[0239] Preparation of 3-(2-amino-6-(1-((6-(trifluoromethyl)-1H-indol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile.

[0240]

[0241] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-6-(trifluoromethyl)-1H-indole. A white solid product (28 mg, 14%) is obtained by separation through column chromatography (dichloromethane / methanol=40 / 1-20 / 1).

[0242] 1 H NMR (600MHz, DMSO-d6) δ7.91(dd,J=7.8,1.3Hz,1H),7.78(dd,J=7.8,1.3Hz,1H),7.57–7.47(m,2H),7.40(s,1H),7.38(dt ,J=7.8,1.4Hz,1H),7.30(t,J=7.6Hz,1H),7.23–7.15(m,3H),5.03(s,1H),4.52(s,2H),2.55(s,3H),1.42(s,6H).MS(ESI + )m / s:476.6[M+H] + .

[0243] Example 38: Preparation of Compound 38

[0244] Preparation of 3-(2-amino-6-(1-((5-(trifluoromethoxy)-1H-indol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile.

[0245]

[0246] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-5-(trifluoromethoxy)-1H-indole. A white solid product (17 mg, 8%) is obtained by separation through column chromatography (dichloromethane / methanol=40 / 1-20 / 1).

[0247] 1 H NMR (600MHz, DMSO-d6) δ11.53(d,J=2.6Hz,1H),8.50(s,1H),7.95–7.82(m,1H),7.76–7.68(m,2H),7.69–7.58(m ,1H),7.50(dd,J=8.3,6.6Hz,2H),7.22(s,1H),7.14–7.03(m,1H),6.82(s,2H),5.85(s,2H),2.52(s,3H).MS(ESI + )m / s:491.5[M+H] + .

[0248] Example 39: Preparation of Compound 39

[0249] Preparation of 3-((4-(2-(2-amino-6-(3-cyano-2-methylphenyl)pyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indole-5-carboxamide.

[0250]

[0251] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-1H-indole-5-carboxamide. A white solid product (35 mg, 12%) is obtained by separation through column chromatography (dichloromethane / methanol=40 / 1-20 / 1).

[0252] 1H NMR (600MHz, DMSO-d6) δ11.49(d,J=2.6Hz,1H),8.39(s,1H),8.30–8.22(m,1H),7.88(dd,J=7.7,1.3Hz,1H),7.87–7.81(m,1H),7.75 –7.68(m,3H),7.50(t,J=7.7Hz,1H),7.43(d,J=8.5Hz,1H),7.22(s,1H),7.15(s,1H),6.82(s,2H),5.85(s,2H),2.52(s,3H).MS(ESI + )m / s:450.2[M+H] + .

[0253] Example 40: Preparation of Compound 40

[0254] Preparation of 3-((4-(2-amino-6-(3-cyano-2-methylphenyl)pyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indazole-5-carbonitrile.

[0255]

[0256] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-1H-indazole-5-carbonitrile. A white solid product (14 mg, 8%) is obtained by separation through column chromatography (dichloromethane / methanol=40 / 1-20 / 1).

[0257] 1 H NMR (600MHz, DMSO-d6) δ13.73(s,1H),8.72(s,1H),8.54(t,J=1.2Hz,1H),7.89(dd,J=7.7,1.3Hz,1H) ,7.79–7.68(m,3H),7.51(t,J=7.7Hz,1H),7.24(s,1H),6.87(s,2H),6.15(s,2H),2.54(s,3H).MS(ESI + )m / s:433.5[M+H] + .

[0258] Example 41: Preparation of Compound 41

[0259] Preparation of 3-((4-(2-amino-6-(3-cyano-2-methylphenyl)pyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indazole-6-carbonitrile.

[0260]

[0261] Refer to the synthetic route of Example 1. The azide derivative is selected from 3-(azidomethyl)-1H-indazole-6-carbonitrile. A white solid product (26 mg, 14%) is obtained by separation through column chromatography (dichloromethane / methanol=40 / 1-20 / 1).

[0262] 1 H NMR (600MHz, DMSO-d6) δ13.79(s,1H),8.68(s,1H),8.20(t,J=1.1Hz,1H),8.00(dd,J=8.4,0.9Hz,1H),7.89(dd,J=7.7, 1.3Hz,1H),7.74(dd,J=7.8,1.3Hz,1H),7.58–7.43(m,2H),7.24(s,1H),6.87(s,2H),6.16(s,2H),2.53(s,3H).MS(ESI + )m / s:433.5[M+H] + .

[0263] Example 42: Compound A 2B R cAMP signaling pathway inhibitory activity test

[0264] HEK293 cells in 10 cm dishes were incubated with 3.0 μg human A 2B R plasmid and 3.0 μg pGloSensor-22F cAMP plasmid (Promega, USA) were co-transfected for 24 hours. The cells were harvested and re-seeded into 384-well white plates (2×10 4 Cells / well) (Costar, USA) were equilibrated with CO2-independent medium (Gibco, USA) containing 1% GloSensor cAMP reagent (Promega, USA). After incubation at room temperature for 1.5 hours, the cells were pretreated with different concentrations of compounds for another 30 minutes and then stimulated with 5'-N-ethylcarboxamidoadenosine (NECA) (MCE, USA) 625nM. The luminescence signal was continuously measured using a Cytation5 imaging reader (BioTek, USA). Data analysis was performed using GraphPad Prism to determine the IC of the tested compounds. 50 The measurement results are shown in Table 1.

[0265] Table 1. Example Compounds A 2A R and A 2B cAMP inhibitory activity of R (IC 50 , nM)

[0266] Table 1 A 2B The experimental results of R-cAMP signaling pathway showed that the compounds of the present invention (Ar is an indole or indole-like structure) have an effect on A 2B R had good inhibitory activity, and most of the compounds showed different degrees of A 2B R selectivity. The indole ring or indole-like ring exhibits excellent A when connected to triazole via a methylene group at the 3, 5 or 6 position. 2B R inhibits activity and selectivity, especially when the indole ring or indole-like ring is connected to the triazole through a methylene group at the 3-position or the 5-position. When the indole-3-methylene group is connected to the triazole, it is preferred that the pyrrole ring has no substituent (especially no substituent at N), and the benzene ring has no substituent or has one substituent (especially a substituent at the 5-position or the 6-position). If there is a substituent at the 5-position of the indole, the compound is effective for A 2A R and A 2B R have good inhibitory activity, showing A 2A R and A 2B R dual-target inhibitor; if there is a substituent at the 6-position of indole, the compound still maintains a high A 2B R inhibitory activity, 2A The inhibitory activity of R was weakened, showing a high selectivity for A 2B R inhibitor. When N on the indole ring is replaced by S, the compound still has A 2B R inhibitory activity was slightly weakened, and the 2A The inhibitory activity of R is enhanced. It is also advantageous that one of the carbon atoms at positions 2, 4, 5, 6, and 7 on the indole ring can be changed to a nitrogen atom. In particular, when one of the carbon atoms at positions 5 and 6 is changed to a nitrogen atom, A exhibits particularly excellent 2B R inhibitory activity with high selectivity.

[0267] Example 43: Inhibitory effect of compound 34 on the expression of immunosuppressive molecules PD-1 and TIM-3 in activated T cells

[0268] Jurkat T cells were stimulated with 20 ng / mL PMA (phorbol ester) and 1 μg / mL IONO (ionomycin) in the presence or absence of compound 34 (0.1, 1, 10 μM) for 5 h, and the gene expressions of PDCD1 (a) and TIM-3 (b) were determined by Q-PCR and normalized with GAPDH (glyceraldehyde-3-phosphate dehydrogenase) as an internal reference.

[0269] PD-1 (PDCD1) and TIM-3 are important immunosuppressive proteins expressed on the surface of T cells and are involved in tumor immune escape. Figure 1 and Figure 2 It can be seen that compound 34 can reverse the upregulation of the expression of immunosuppressive molecules (PD-1 and TIM-3) in activated T cells stimulated by PMA / IONO by NECA (5'-N-ethylamidoadenosine), and effectively inhibit the expression of immunosuppressive molecules PD-1 and TIM-3 in activated T cells.

[0270] Example 44: Compound 34 enhances T cell-mediated tumor cell killing

[0271] The cytotoxic T cell tumor killing test was carried out using the MC38-OVA (MC38 mouse colon cancer cells overexpressing OVA (chicken ovalbumin)) / OT-1 (OT-1 mouse spleen cytotoxic T lymphocytes) co-culture system. The OVA protein expressed by MC38-OVA can be specifically recognized by OT-1CTL, thereby activating OT-1 cells to kill tumor cells. OT-1CTL and MC38-OVA cells were co-incubated at a ratio of 6:1 for 48 hours, and then live MC38-OVA was labeled with green fluorescence (see Figure 3 , since the attached figure can only be displayed in black and white, the white bright spot is green fluorescence), the relative killing ability of OT-1 cells was quantified based on the fluorescence image (see Figure 4 ).

[0272] See also Figure 3 and Figure 4 It can be seen that OT-1 cytotoxic T lymphocytes can effectively kill MC38-OVA cancer cells, NECA weakened the cytotoxic activity of OT-1CTL, and compound 34 can reverse the damage of NECA to the cytotoxic ability of OT-1CTL. These data show that compound 34 can promote the cytotoxic ability of T cells and enhance the killing effect of tumor cells.

[0273] The above specific implementations further describe the purpose, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above is only a specific implementation of the present invention and is not limited to the protection scope of the present invention. Without departing from the purpose of the basic characteristics of the present invention, the present invention can be embodied in various forms. Therefore, the implementation forms in the present invention are used for illustration rather than limitation. Since the scope of the present invention is limited by the claims rather than the specification, and all changes within the scope defined by the claims or within the equivalent scope of the scope defined by the claims should be understood to be included in the claims. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: in, Ar or X is NH, S or O; when in the connecting position, Y, Z, W, U, V are C; when not in the connecting position, U is N or CR1, W is N or CR2, Y, Z, V are independently N or CR3, R1, R2 are independently selected from H, C 1-3 Alkyl, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C having one or more fluorine-substituted 1-3 Alkoxy, C 3-6 Cycloalkyloxy, C 1-3 Alkylsulfone, C 1-3 Alkoxyacyl, aminoacyl or cyano, R3 is H, Cl or F.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: At most one of Y, Z, W, U, V is N.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that: Ar or 4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, characterized in that: Ar or 5. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that: Ar is selected from 6. A pharmaceutical composition, characterized in that The invention comprises a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

7. A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6 for use in the preparation of a drug for treating or preventing 2B Application of drugs in R-related diseases.

8. The use according to claim 7, characterized in that: Said and A 2B The R-associated disease is selected from the group consisting of cancer, inflammation, diabetes, pain, asthma, and Alzheimer's disease.

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