2-aminopyrimidine compound derivatives and uses thereof

Abstract

This invention relates to a 2-aminopyrimidine derivative of formula (I) and its applications, wherein such compounds contain adenosine A. 2B R-inhibitory activity, promising applications in the preparation of drugs for the prevention or treatment of A 2B Medications for diseases related to R.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a 2-aminopyrimidine derivative and its role as adenosine A. 2B receptor (A) 2B The use of R) antagonists, these compounds possess adenosine A 2B R-inhibitory activity, promising applications in the preparation of drugs for the prevention or treatment of A 2B Medications for diseases related to R. Background Technology

[0002] Adenosine signaling plays a crucial role in human physiological and pathological functions. Adenosine receptors are class A G protein-coupled receptors, including A1R and A... 2A R, A 2B The four isoforms 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 isoform has a unique function, among which A... 2B R has attracted the attention of many scholars and companies, becoming a potential drug target for a variety of diseases, including inflammation, central nervous system and immune system diseases.

[0003] A 2B R 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, people are paying more and more attention to A. 2B R's therapeutic potential as a drug target.

[0004] A 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). Recent 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 in 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 limit 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 immune system.

[0005] To date, there have been a large number of A 2B Selective antagonists have been reported, and these antagonists are mainly divided into two categories: xanthines and non-xanthines. Xanthines are mainly xanthine derivatives related to natural products such as caffeine and theophylline (WO2023039125A1). Non-xanthines mainly include 2-aminopyrazines (WO2007017096 A1), thienopyrimidine diones (WO2018054846 A1), pyrazolotriazole pyrimidines (Pastorin, G, et al. J Med Chem, 2003, 46, 4287-4296.), and pyrimidine benzimidazoles (El Maatougui, A, et al. J Med Chem, 2016, 59, 1967-1983.).

[0006] In many reported A 2B Among R-selective antagonists, three compounds have entered clinical trials. PBF1129 has already begun a Phase 1 clinical trial (Clinical Trial No.: NCT03274479) for the treatment of non-small cell lung cancer. TT-4 is an A... 2B Solid tumors with R overexpression and A 2A R / A 2B Solid tumors that simultaneously overexpress R are also undergoing Phase 1 clinical trials (Clinical Trial No.: NCT04976660). Recently, TEON's TT-702 also entered Phase 1 / 2 clinical trials (Clinical Trial No.: NCT05272709) for the treatment of a range of refractory cancers, including metastatic castration-resistant prostate cancer, triple-negative breast cancer, and tumors associated with microsatellite instability / mismatch repair function. This indicates that A... 2BR-selective antagonists show promise for practical applications in cancer treatment.

[0007] Because xanthine-like skeletons generally suffer from poor water solubility and unfavorable physicochemical and pharmacokinetic properties, novel non-xanthine derivatives with good drug-like properties, such as A, have been discovered. 2B R-antagonists have enormous potential and market value as cancer immunotherapy drugs. Summary of the Invention

[0008] The purpose of this invention is to provide a class of compounds as novel adenosine A. 2B receptor (A) 2B R) inhibitors, containing adenosine A 2B R-inhibitory activity, promising applications in the preparation of drugs for the prevention or treatment of A 2B Medications for diseases related to R.

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

[0010]

[0011] Where Ar is or X is NH, S, or O; when in a connected position, Y, Z, W, U, and V are C; when not in a connected position, U is N or CR1, W is N or CR2, Y, Z, and V are independently N or CR3, and R1 and R2 are independently selected from H and C. 1-3 Alkyl groups, halogens (preferably Cl or F), and C atoms having one or more fluorine substitutions. 1-3 Alkyl, C 1-3 Alkoxy groups, C groups having one or more fluorine substitutions 1-3 Alkoxy, C 3-6 Cycloalkyloxy, C 1-3 Alkyl sulfone, C 1-3 The group consists of an alkoxyacyl group, an aminoacyl group, or a cyano group, and R3 is H, Cl, or F.

[0012] That is, Ar can be selected from

[0013] 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.

[0014] Preferably, at least one of R1 and R2 is H, and R3 is H.

[0015] Preferably, Ar is or Even

[0016] The selected location, Ar is or

[0017] Preferably, Ar is selected from

[0018] Preferably, R1 is selected from H and C. 1-3 Alkyl, Cl, F, C 1-3 Alkoxy, C 3-6 Cycloalkyloxy, C 1-3 Alkyl sulfone, C 1-3 alkoxyacyl or cyano group, R2 is selected from H, C 1-3 Alkyl, Cl, F, C 1-3 Alkoxy, C 3-6 Cycloalkyloxy, C 1-3 Alkyl sulfone, C 1-3 Alkoxy acyl, amino acyl, or cyano groups.

[0019] More preferably, Ar is selected from

[0020] The above-mentioned compound of the present invention (Ar is an indole or indole-like structure) exhibits superior A structure compared to AB928 (WO2018136700A1). 2B It has antagonistic activity against R and possesses A 2B The antagonistic selectivity of R. Indole rings or indole-like rings exhibit excellent A-type selectivity when linked to triazole via a methylene group at positions 3, 5, or 6. 2B R inhibits activity and selectivity, especially when the indole ring or indole-like ring is linked to triazole via a methylene group at the 3- or 5-position. When the indole-3-methylene group is linked to triazole, it is preferable that the pyrrole ring is unsubstituent (especially unsubstituent at the N-position), and the benzene ring is preferably unsubstituent or has one substituent (especially a substituent at the 5- or 6-position). If there is a substituent at the 5-position of the indole ring, the compound inhibits A. 2A R and A 2B R all exhibit good inhibitory activity, as shown by 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 inhibits activity, against A 2A The inhibitory activity of R is weakened, exhibiting high selectivity for A. 2B R inhibitors. When the N on the indole ring is replaced with S, the compound still exhibits A. 2B R inhibitory activity was slightly weakened, while A 2AThe inhibitory activity of R is enhanced. It is also advantageous for one of the carbon atoms at positions 2, 4, 5, 6, or 7 of the indole ring to be replaced by a nitrogen atom, especially when one of the carbon atoms at positions 5 or 6 is replaced by a nitrogen atom, exhibiting particularly superior A activity. 2B It inhibits R activity and has high selectivity.

[0021] 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.

[0022] Thirdly, the present invention provides a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the preparation of a treatment or prevention of A 2B Application in drugs for diseases related to R.

[0023] Preferably, the one with A 2B Diseases associated with R include cancer, inflammation, diabetes, pain, asthma, and Alzheimer's disease.

[0024] Fourthly, the present invention provides an adenosine A 2B R inhibitors, including compounds as described above or pharmaceutically acceptable salts thereof. Attached Figure Description

[0025] Figure 1 The experimental results show the effect of compound 34 prepared in Example 34 on the expression of the immunosuppressive molecule PD-1.

[0026] Figure 2 The experimental results show the effect of compound 34 prepared in Example 34 on the expression of the immunosuppressive molecule TIM-3.

[0027] Figure 3 and Figure 4 Experimental results show the effect of compound 34 prepared in Example 34 on the T cell-mediated killing ability of cancer cells. Detailed Implementation

[0028] 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. The same or corresponding reference numerals in the drawings denote the same parts, and repeated descriptions are omitted.

[0029] As described above, the present invention provides a 2-aminopyrimidine derivative:

[0030]

[0031] When Ar is The compound can be prepared by the following method:

[0032]

[0033] The definitions of X, Y, Z, W, U, and V are the same as above. Reagents and conditions: (a) Triisopropylsilylacetylene, bis(triphenylphosphine)palladium(II) dichloride, cuprous iodide, dioxane / triethylamine, 100℃, 4 hours, 61-92%; (b) Tetrabutylammonium fluoride, 0℃, 15 minutes, 80-95%; (c) Anhydrous copper sulfate, sodium vitamin C, tert-butanol / water = 2 / 1, 6 hours, 25%-64%. That is, starting material 1.1 reacts with triisopropylsilylacetylene via a coupling reaction to obtain intermediate 1.2, which then reacts with tetrabutylammonium fluoride to obtain intermediate 1.3, followed by an azide-acetylene cycloaddition reaction with the corresponding azide derivative to obtain the final product 1.4.

[0034] For other compounds, the synthesis scheme can be determined by referring to the specific examples below and existing knowledge in the art.

[0035] The "compounds" described in this invention include all stereoisomers, geometric isomers, tautomers, and isotopes.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] "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 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, mucoconic acid, or their analogues.

[0040] The compounds according to the present invention can also exist in their solvated forms, such as hydrates (hemihydrates, monohydrates, dihydrates, trihydrates, etc.).

[0041] “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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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).

[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] In summary, this invention provides a class of compounds with the general formula (I). Studies have shown that these compounds can effectively inhibit adenosine A. 2B Receptors regulate the body's immune physiological responses and can be used for treatment or prevention in relation to A. 2B Drugs related to R-related diseases.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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 analysis (G254); P-TLC: preparation of thin-layer silica gel plates.

[0056] Example 1: Preparation of Compound 1

[0057] 3-(6-(1-((1H-indol-5-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-aminopyrimidin-4-yl)2-methylbenzonitrile

[0058]

[0059] Step 1: Preparation of 3-(2-amino-6-((triisopropylsilyl)ethynyl)pyrimidin-4-yl)-2-methylbenzonitrile

[0060] 3-(2-amino-6-chloropyrimidin-4-yl)-2-methylbenzonitrile (1.22 g, 5 mmol), triisopropylsilylacetylene, bis(triphenylphosphine)palladium dichloride (175 mg, 0.25 mmol), and cuprous iodide (95 mg, 0.5 mmol) were placed in a 50 mL flask, and 10 mL of dioxane and 10 mL of triethylamine were added, followed by complete nitrogen purging. The flask was then placed in an oil bath at 100 °C and reacted for 4 h. The reaction was monitored by TLC. After the reaction was complete, the flask was cooled to room temperature. It was diluted with ethyl acetate and then washed successively with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate. After concentration, the product was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 15 / 1 to 5 / 1) to obtain a pale yellow solid product (1.40 g, 71.8%).

[0061] Step 2: Preparation of 3-(2-amino-6-ethynylpyrimidin-4-yl)-2-methylbenzonitrile

[0062] Take 1.40 g (3.6 mmol) of the product from step 1 into a 50 mL flask, add 30 mL of tetrahydrofuran, and add tetrabutylammonium fluoride (940 mg, 3.6 mmol) in tetrahydrofuran solvent dropwise at 0 °C. Monitor the reaction by TLC. After the reaction is complete, dilute with ethyl acetate, then wash successively with water and saturated brine. Dry the organic phase over anhydrous sodium sulfate. Concentrate and separate by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to obtain a white solid product (700 mg, 83%).

[0063] 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

[0064] The products from step 2, 3-(2-amino-6-ethynylpyrimidin-4-yl)-2-methylbenzonitrile (100 mg, 0.42 mmol) and 5-(azidomethyl)-1H-indole (110 mg, 0.64 mmol), were placed in a 50 mL flask, 6 mL of tert-butanol was added, followed by 3 mL of ultrapure water. Anhydrous copper sulfate (27 mg, 0.17 mmol) and sodium vitamin C (68 mg, 0.34 mol) were then added, and the mixture was placed in an oil bath at 60 °C and reacted for 4 h. The reaction was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature, diluted with ethyl acetate, and then washed successively with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate. After concentration, the product was separated by silica gel column chromatography (dichloromethane / methanol = 50 / 1 to 30 / 1) to obtain a white solid product (51 mg, 29.5%).

[0065] 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.

[0066] Example 2: Preparation of Compound 2

[0067] Preparation of 3-(6-(1-((1H-indol-4-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-aminopyrimidin-4-yl)-2-methylbenzonitrile

[0068]

[0069] The synthetic route was followed as described in Example 1. The azide derivative was selected from 4-(azidomethyl)-1H-indole. The product was separated by silica gel column chromatography (dichloromethane / methanol = 50 / 1 to 30 / 1) to give a white solid product (60 mg, 35%).

[0070] 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.

[0071] Example 3: Preparation of Compound 3

[0072] Preparation of 3-(6-(1-((1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-aminopyrimidin-4-yl)-2-methylbenzonitrile

[0073]

[0074] The synthetic route was followed as described in Example 1. The azide derivative was selected from 6-(azidomethyl)-1H-indole. The product was separated by column chromatography (dichloromethane / methanol = 50 / 1 to 30 / 1) to give a white solid product (40 mg, 23%).

[0075] 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.

[0076] Example 4: Preparation of Compound 4

[0077] Preparation of 3-(6-(1-((1H-indol-7-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-aminopyrimidin-4-yl)2-methylbenzonitrile

[0078]

[0079] The synthetic route was followed as described in Example 1. The azide derivative was selected from 7-(azidomethyl)-1H-indole. The product was separated by column chromatography (dichloromethane / methanol = 50 / 1 to 30 / 1) to give a white solid product (43 mg, 25%).

[0080] 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 forC 23 H 18 N8[M+H] + :407.1727; found,407.1735.

[0081] Example 5: Preparation of Compound 5

[0082] Preparation of 3-(6-(1-((1H-indol-2-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-aminopyrimidin-4-yl)2-methylbenzonitrile

[0083]

[0084] The synthetic route was followed as described in Example 1. The azide derivative was selected from 2-(azidomethyl)-1H-indole. The product was separated by column chromatography (dichloromethane / methanol = 50 / 1 to 30 / 1) to give a white solid product (35 mg, 20%).

[0085] 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.

[0086] Example 6: Preparation of Compound 6

[0087] Preparation of 3-(6-(1-((1H-indol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-aminopyrimidin-4-yl)2-methylbenzonitrile

[0088]

[0089] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-1H-indole. The product was separated by column chromatography (dichloromethane / methanol = 50 / 1 to 30 / 1) to give a white solid product (40 mg, 23%).

[0090] 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.

[0091] Example 7: Preparation of Compound 7

[0092] 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

[0093]

[0094] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-1-methyl-1H-indole. The product was separated by column chromatography (dichloromethane / methanol = 90 / 1 to 50 / 1) to give a white solid product (12 mg, 7%).

[0095] 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.

[0096] Example 8: Preparation of Compound 8

[0097] Preparation of 3-(6-(1-((1H-indazol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)-2-aminopyrimidin-4-yl)2-methylbenzonitrile

[0098]

[0099] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-1H-indazole. The product was separated by column chromatography (dichloromethane / methanol = 40 / 1 to 20 / 1) to give a white solid product (55 mg, 32%).

[0100] 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.

[0101] Example 9: Preparation of Compound 9

[0102] 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

[0103]

[0104] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)imidazo[1,2-a]pyridine. The product was separated by column chromatography (dichloromethane / methanol = 50 / 1 to = 30 / 1) to give a white solid product (41 mg, 24%).

[0105] 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.

[0106] Example 10: Preparation of Compound 10

[0107] Preparation of 3-(2-amino-6-(1-(benzo[b]thiophene-3-ylmethyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0108]

[0109] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)benzo[b]thiophene. The product was separated by column chromatography (dichloromethane / methanol = 70 / 1 to 50 / 1) to give a white solid product (59 mg, 34%).

[0110] 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.

[0111] Example 11: Preparation of Compound 11

[0112] 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

[0113]

[0114] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-4-chloro-1H-indole. The product was separated by column chromatography (dichloromethane / methanol = 60 / 1 to 40 / 1) to give a white solid product (14 mg, 8%).

[0115] 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 forC 23 H 17 ClN8[M+H] + :441.1337; found,441.1343.

[0116] Example 12: Preparation of Compound 12

[0117] 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

[0118]

[0119] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-5-chloro-1H-indole. The product was separated by column chromatography (dichloromethane / methanol = 60 / 1 to 40 / 1) to give a white solid product (21 mg, 11%).

[0120] 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.

[0121] Example 13: Preparation of Compound 13

[0122] 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

[0123]

[0124] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-6-chloro-1H-indole. The product was separated by column chromatography (dichloromethane / methanol = 60 / 1 to 40 / 1) to give a white solid product (33 mg, 18%).

[0125] 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.

[0126] Example 14: Preparation of Compound 14

[0127] 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

[0128]

[0129] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-7-chloro-1H-indole. The product was separated by column chromatography (dichloromethane / methanol = 60 / 1 to 40 / 1) to give a white solid product (12 mg, 7%).

[0130] 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.

[0131] Example 15: Preparation of Compound 15

[0132] 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

[0133]

[0134] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-5,6-dichloro-1H-indole. The product was separated by column chromatography (dichloromethane / methanol = 60 / 1 to 40 / 1) to give a white solid product (33 mg, 16%).

[0135] 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.

[0136] Example 16: Preparation of Compound 16

[0137] 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

[0138]

[0139] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-1H-pyrrole[3,2-b]pyridine. The product was separated by column chromatography (dichloromethane / methanol = 40 / 1 to 20 / 1) to give a white solid product (35 mg, 20%).

[0140] 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

[0141] Example 17: Preparation of Compound 17

[0142] 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

[0143]

[0144] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-1H-pyrrole[3,2-c]pyridine. The product was separated by column chromatography (dichloromethane / methanol = 40 / 1 to 20 / 1) to give a white solid product (19 mg, 11%).

[0145] 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] + :408.1680found,408.1690.

[0146] Example 18: Preparation of Compound 18

[0147] 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

[0148]

[0149] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-1H-pyrrole[2,3-c]pyridine. The product was separated by column chromatography (dichloromethane / methanol = 40 / 1 to 20 / 1) to give a white solid product (64 mg, 37%).

[0150] 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.

[0151] Example 19: Preparation of Compound 19

[0152] 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

[0153]

[0154] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-1H-pyrrole[2,3-b]pyridine. The product was separated by column chromatography (dichloromethane / methanol = 40 / 1 to 20 / 1) to give a white solid product (51 mg, 29%).

[0155] 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.

[0156] Example 20: Preparation of Compound 20

[0157] 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

[0158]

[0159] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-5-methyl-1H-indole. The product was separated by column chromatography (dichloromethane / methanol = 50 / 1 to 30 / 1) to give a white solid product (11 mg, 6%).

[0160] 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.

[0161] Example 21: Preparation of Compound 21

[0162] 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

[0163]

[0164] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-6-methyl-1H-indole. The product was separated by column chromatography (dichloromethane / methanol = 50 / 1 to 30 / 1) to give a white solid product (17 mg, 10%).

[0165] 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.

[0166] Example 22: Preparation of Compound 22

[0167] 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

[0168]

[0169] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-5-methoxy-1H-indole. The product was separated by column chromatography (dichloromethane / methanol = 50 / 1 to 30 / 1) to give a white solid product (34 mg, 18%).

[0170] 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.

[0171] Example 23: Preparation of Compound 23

[0172] 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

[0173]

[0174] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-6-methoxy-1H-indole. The product was separated by column chromatography (dichloromethane / methanol = 50 / 1 to 30 / 1) to give a white solid product (26 mg, 14%).

[0175] 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.

[0176] Example 24: Preparation of Compound 24

[0177] 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

[0178]

[0179] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-5-isopropoxy-1H-indole. The product was separated by column chromatography (dichloromethane / methanol = 50 / 1 to 30 / 1) to give a white solid product (41 mg, 21%).

[0180] 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 forC 26 H 24 N8O[M+H] + :465.2146; found,465.2158.

[0181] Example 25: Preparation of Compound 25

[0182] 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

[0183]

[0184] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-6-isopropoxy-1H-indole. The product was separated by column chromatography (dichloromethane / methanol = 50 / 1 to 30 / 1) to give a white solid product (33 mg, 17%).

[0185] 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.

[0186] Example 26: Preparation of Compound 26

[0187] Preparation of 3-(2-amino-6-(1-((5-(cyclopentoxy)-1H-indol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0188]

[0189] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-5-(cyclopentoxy)-1H-indole. The product was separated by column chromatography (dichloromethane / methanol = 50 / 1 to 30 / 1) to give a white solid product (40 mg, 19%).

[0190] 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.

[0191] Example 27: Preparation of Compound 27

[0192] Preparation of 3-(2-amino-6-(1-((6-(cyclopentoxy)-1H-indol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile

[0193]

[0194] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-6-(cyclopentoxy)-1H-indole. The product was separated by column chromatography (dichloromethane / methanol = 50 / 1 to 30 / 1) to give a white solid product (49 mg, 23%).

[0195] 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.

[0196] Example 28: Preparation of Compound 28

[0197] 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

[0198]

[0199] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-5-fluoro-1H-indole. The product was separated by column chromatography (dichloromethane / methanol = 50 / 1 to 30 / 1) to give a white solid product (28 mg, 13%).

[0200] 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.

[0201] Example 29: Preparation of Compound 29

[0202] 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

[0203]

[0204] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-5-fluoro-1H-indole. The product was separated by column chromatography (dichloromethane / methanol = 50 / 1 to 30 / 1) to give a white solid product (22 mg, 12%).

[0205] 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 forC 23 H 17 FN8[M+H] + :425.1633; found,425.1641.

[0206] Example 30: Preparation of Compound 30

[0207] 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-carboxylic acid.

[0208]

[0209] The synthetic route was followed as described in Example 1. The azide derivative was selected from methyl 3-(azidomethyl)-1H-indole-5-carboxylate. The product was separated by column chromatography (dichloromethane / methanol = 50 / 1 to 30 / 1) to give a white solid product (34 mg, 17%).

[0210] 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.

[0211] Example 31: Preparation of Compound 31

[0212] 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-carboxylic acid.

[0213]

[0214] The synthetic route was followed as described in Example 1. The azide derivative was selected from methyl 3-(azidomethyl)-1H-indole-6-carboxylate. The product was separated by column chromatography (dichloromethane / methanol = 50 / 1 to 30 / 1) to give a white solid product (29 mg, 15%).

[0215] 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.

[0216] Example 32: Preparation of Compound 32

[0217] Preparation of 3-(2-amino-6-(1-((5-(methanesulfonyl)-1H-indol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile.

[0218]

[0219] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-5-(methanesulfonyl)-1H-indole. The product was separated by column chromatography (dichloromethane / methanol = 50 / 1 to 30 / 1) to give a white solid product (43 mg, 21%).

[0220] 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 forC 24 H 20 N8O2S[M+H] + :485.1503; found,485.1513.

[0221] Example 33: Preparation of Compound 33

[0222] Preparation of 3-(2-amino-6-(1-((6-(methanesulfonyl)-1H-indol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile.

[0223]

[0224] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-6-(methanesulfonyl)-1H-indole. The product was separated by column chromatography (dichloromethane / methanol = 50 / 1 to 30 / 1) to give a white solid product (33 mg, 16%).

[0225] 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.

[0226] Example 34: Preparation of Compound 34

[0227] 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-carboxynitrile.

[0228]

[0229] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-1H-indole-5-carboxynitrile. The product was separated by column chromatography (dichloromethane / methanol = 40 / 1 to 20 / 1) to give a white solid product (43 mg, 23%).

[0230] 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.

[0231] Example 35: Preparation of Compound 35

[0232] 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-carboxynitrile.

[0233]

[0234] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-1H-indole-6-carboxynitrile. The product was separated by column chromatography (dichloromethane / methanol = 40 / 1 to 20 / 1) to give a white solid product (37 mg, 20%).

[0235] 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 forC 24 H 17 N9[M+H] + :432.1680; found,432.1684.

[0236] Example 36: Preparation of Compound 36

[0237] 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.

[0238]

[0239] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-5-(trifluoromethyl)-1H-indole. The product was separated by column chromatography (dichloromethane / methanol = 40 / 1 to 20 / 1) to give a white solid product (21 mg, 10%).

[0240] 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] + .

[0241] Example 37: Preparation of Compound 37

[0242] 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.

[0243]

[0244] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-6-(trifluoromethyl)-1H-indole. The product was separated by column chromatography (dichloromethane / methanol = 40 / 1 to 20 / 1) to give a white solid product (28 mg, 14%).

[0245] 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] + .

[0246] Example 38: Preparation of Compound 38

[0247] 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.

[0248]

[0249] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-5-(trifluoromethoxy)-1H-indole. The product was separated by column chromatography (dichloromethane / methanol = 40 / 1 to 20 / 1) to give a white solid product (17 mg, 8%).

[0250] 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] + .

[0251] Example 39: Preparation of Compound 39

[0252] 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.

[0253]

[0254] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-1H-indole-5-carboxamide. The product was separated by column chromatography (dichloromethane / methanol = 40 / 1 to 20 / 1) to give a white solid product (35 mg, 12%).

[0255] 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] + .

[0256] Example 40: Preparation of Compound 40

[0257] 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-carboxynitrile.

[0258]

[0259] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-1H-indazole-5-carboxynitrile. The product was separated by column chromatography (dichloromethane / methanol = 40 / 1 to 20 / 1) to give a white solid product (14 mg, 8%).

[0260] 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] + .

[0261] Example 41: Preparation of Compound 41

[0262] 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-carboxynitrile.

[0263]

[0264] The synthetic route was followed as described in Example 1. The azide derivative was selected from 3-(azidomethyl)-1H-indazole-6-carboxynitrile. The product was separated by column chromatography (dichloromethane / methanol = 40 / 1 to 20 / 1) to give a white solid product (26 mg, 14%).

[0265] 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] + .

[0266] Example 42: Compound A 2B Assay for the inhibitory activity of the R cAMP signaling pathway

[0267] HEK293 cells in a 10 cm culture dish were inoculated with 3.0 μg of human amino acids using polyethyleneimine (PEI) (18 μL, Yeasen, China). 2B R plasmid and 3.0 μg pGloSensor-22F cAMP plasmid (Promega, USA) were co-transfected for 24 hours. Cells were harvested and reseeded into 384-well white plates (2 × 10⁶ cells / wells). 4 Cells were equilibrated in CO2-independent medium (Gibco, USA) containing 1% GloSensorcAMP reagent (Promega, USA) in Costar (cells / well) wells. After incubation at room temperature for 1.5 hours, cells were pretreated for 30 minutes with different concentrations of the compound, followed by stimulation with 625 nM 5'-N-ethylformylaminoadenosine (NECA) (MCE, USA). The luminescence signal was continuously measured using a Cytation 5 imaging reader (BioTek, USA). Data analysis was performed using GraphPad Prism to determine the IC50 of the tested compounds. 50 Values. The measurement results are shown in Table 1.

[0268] Table 1. Effects of Compounds in Examples on A 2A R and A 2B R's cAMP inhibitory activity (IC50) 50 (nM)

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275] Table 1, A 2B Experimental results of the R-cAMP signaling pathway indicate that the compound of this invention (Ar is an indole or indole-like structure) affects A... 2B R exhibits good inhibitory activity, and most compounds show varying degrees of A inhibition. 2B R selectivity. Indole rings or indole-like rings exhibit excellent A selectivity when linked to triazole via a methylene group at positions 3, 5, or 6. 2B R inhibits activity and selectivity, especially when the indole ring or indole-like ring is linked to triazole via a methylene group at the 3- or 5-position. When the indole-3-methylene group is linked to triazole, it is preferable that the pyrrole ring is unsubstituent (especially unsubstituent at the N-position), and the benzene ring is preferably unsubstituent or has one substituent (especially a substituent at the 5- or 6-position). If there is a substituent at the 5-position of the indole ring, the compound inhibits A. 2A R and A 2B R all exhibit good inhibitory activity, as shown by 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 inhibits activity, against A 2A The inhibitory activity of R is weakened, exhibiting high selectivity for A. 2B R inhibitors. When the N on the indole ring is replaced with S, the compound still exhibits A. 2B R inhibitory activity was slightly weakened, while A 2A The inhibitory activity of R is enhanced. It is also advantageous for one of the carbon atoms at positions 2, 4, 5, 6, or 7 of the indole ring to be replaced by a nitrogen atom, especially when one of the carbon atoms at positions 5 or 6 is replaced by a nitrogen atom, exhibiting particularly superior A activity. 2B It inhibits R activity and has high selectivity.

[0276] Example 43: Inhibitory effect of compound 34 on the expression of immunosuppressive molecules PD-1 and TIM-3 in activated T cells

[0277] Jurkat T cells were stimulated with 20 ng / mL PMA (phorbol ester) and 1 μg / mL IONO (ionomycin) for 5 hours with or without compound 34 (0.1, 1, 10 μM). Gene expression of PDCD1 (a) and TIM-3 (b) was measured by Q-PCR and normalized using GAPDH (glyceraldehyde-3-phosphate dehydrogenase) as an internal reference.

[0278] PD-1 (PDCD1) and TIM-3 are important immunosuppressive proteins expressed on the surface of T cells, involved in tumor immune escape. See also Figure 1 and Figure 2 It is known that compound 34 can reverse the upregulation of immunosuppressive molecules (PD-1 and TIM-3) in PMA / IONO-stimulated activated T cells by NECA (5'-N-ethylamidoadenosine), and effectively inhibit the expression of immunosuppressive molecules PD-1 and TIM-3 in activated T cells.

[0279] Example 44: Compound 34 enhances T cell-mediated tumor cell killing.

[0280] A cytotoxic T-cell tumor-killing assay was conducted using a co-culture system of MC38-OVA (MC38 mouse colon cancer cells overexpressing OVA (chicken ovalbumin)) / OT-1 (OT-1 mouse spleen cytotoxic T lymphocytes). The OVA protein expressed by MC38-OVA was specifically recognized by OT-1 CTLs, thereby activating OT-1 cells to exert tumor cell killing effects. OT-1 CTLs and MC38-OVA cells were co-incubated at a 6:1 ratio for 48 hours, and then live MC38-OVA cells were labeled with green fluorescent dye (see [link to study]). Figure 3 (Since the attached image can only be displayed in black and white, the white bright spots represent green fluorescence). The relative killing ability of OT-1 cells is quantified based on the fluorescence image (see [link]). Figure 4 ).

[0281] See Figure 3 and Figure 4 It was found that OT-1 cytotoxic T lymphocytes could effectively kill MC38-OVA cancer cells, NECA weakened the cytotoxic activity of OT-1 CTLs, and compound 34 could reverse the damage of NECA to the cytotoxic ability of OT-1 CTLs. These data indicate that compound 34 can promote the cytotoxic ability of T cells and enhance the killing effect on tumor cells.

[0282] The above detailed embodiments further illustrate the purpose, technical solution, and beneficial effects of the present invention. It should be understood that the above are merely one specific embodiment of the present invention and are not limited to the scope of protection of the present invention. The present invention can be embodied in various forms without departing from its essential characteristics. Therefore, the embodiments described herein are for illustrative purposes only and not for limitation. Since the scope of the present invention is defined by the claims rather than the specification, all changes falling within the scope defined by the claims, or their equivalents, 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 within the scope of protection of the present invention.

Claims

1. A compound of Formula (I): ###0001### (I) or a pharmaceutically acceptable salt thereof. ； wherein Ar for or Y, Z, W, and U are independently N or CH; R1 and R2 are independently selected from H and C. 1-3 Alkyl, halogen, C having one or more fluorine substitutions 1-3 Alkyl, C 1-3 Alkoxy groups, C groups having one or more fluorine substitutions 1-3 Alkoxy, C 3-6 Cycloalkyloxy, C 1-3 alkylsulfonyl, C 1-3 The group can be alkoxycarbonyl, carbamoyl, or cyano, and at most one of Y, Z, W, and U is N.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, Ar is selected from the group consisting of: ###0002### 。 3. A pharmaceutical composition, characterized by, A pharmaceutical composition comprising a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

4. Use of a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 3, in the manufacture of a medicament for the treatment or prevention of a disease associated with A 2B R-related disease.

5. Use according to claim 4, characterized in that, The disease associated with A 2B The disease associated with R is selected from the group consisting of cancer, inflammation, diabetes, and asthma.

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