Selective mTOR inhibitor as well as preparation method and application thereof

Abstract

The invention discloses a selective mTOR inhibitor and a preparation method and application thereof, and relates to the technical field of medicine, the selective mTOR inhibitor can specifically recognize an ATP pocket of mTOR, greatly reduce cross binding to a PI3K family and remarkably improve kinase selectivity, and experimental verification shows that the selective mTOR inhibitor has the advantages that the selective mTOR inhibitor can be used for preparing an mTOR inhibitor, and the selective mTOR inhibitor can be used for preparing the mTOR inhibitor. The compound has strong proliferation inhibition activity to non-small cell lung cancer cells, especially has prominent sensitivity to specific mutant tumor cells, is rapidly absorbed after being orally taken, is sufficiently exposed in vivo and has excellent bioavailability, the treatment application range of an mTOR inhibitor is expanded, and the application prospect is wide. The invention provides a tumor targeted therapy scheme with higher safety and more convenient medication, and has important clinical transformation value and scientific research reference significance.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a selective mTOR inhibitor, its preparation method, and its application. Background Technology

[0002] The target of rapamycin (mTOR) is a member of the phosphatidylinositol 3-kinase-associated kinase (PIKK) family. As a highly conserved eukaryotic serine / threonine protein kinase, it plays a central role in the regulation of cell growth, proliferation, metabolism, migration, autophagy, and apoptosis. mTOR is located downstream of the receptor tyrosine kinase (RTK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways. When RTKs bind to ligands such as insulin and insulin-like growth factor-1 (IGF-1), PI3K is activated and catalyzes the conversion of phosphatidylinositol (4,5)-bisphosphate to phosphatidylinositol (3,4,5)-triphosphate, which in turn activates protein kinase B (Akt) and phosphatidylinositol-dependent kinase 1 (PDK1). Activated Akt ultimately activates mTOR by phosphorylating tuberous sclerosis complex 1 / 2 (TSC1 / 2), promoting cell growth and survival.

[0003] Abnormal activation of the PI3K / Akt / mTOR signaling pathway is closely related to tumorigenesis. Mutations or overactivation of PI3K lead to the continuous activation of downstream Akt and mTOR, promoting tumor cell proliferation. Currently, dual-target inhibitors of PI3K and mTOR, used in clinical applications and research, often possess dual inhibitory activity due to the high homology of PI3K and mTOR's ATP pockets. However, long-term use can easily induce elevated glucagon levels, leading to side effects such as hyperglycemia, immunosuppression, and inflammatory signaling blockade. Furthermore, existing mTOR inhibitors are mainly used for breast cancer treatment, with limited efficacy against other tumor types, and generally suffer from low oral bioavailability, limiting their clinical application and efficacy.

[0004] Therefore, developing mTOR inhibitors with novel structures, high selectivity for mTOR, effectiveness against tumors such as non-small cell lung cancer, and excellent oral bioavailability has become a key requirement for current cancer treatment drug development. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the present invention aims to provide a selective mTOR inhibitor, its preparation method, and its application, thereby resolving at least one problem in the prior art.

[0006] A first aspect of the present invention is to provide a compound of formula (I) or (II) or (III) or (IV), or a prodrug, deuterated derivative, or pharmaceutically acceptable salt thereof, characterized in that, , In Formula I, R is selected from -H. , , , , , , , , , , ; In Equation II, R 1 Selected from , , R 2 Selected from , , , , , , , , , -H; In Formula III, Ar is selected from , , , , , ; In Equation IV, M is selected from , , , , X, Y, and Z are each independently selected from N, O, and S.

[0007] According to one aspect of the above technical solution, in formula II: When R 1 Selected from At that time, R 2 Selected from , , , , , , ; When R 1 Selected from At that time, R 2 Selected from ; When R 1 Selected from At that time, R 2 Selected from , , -H.

[0008] A second aspect of the present invention is to provide a pharmaceutical composition comprising the compounds described above as shown in formula (I) or (II) or (III) or (IV), or a prodrug, deuterated compound, pharmaceutically acceptable salt, and pharmaceutically acceptable excipients.

[0009] A third aspect of the present invention is to provide a selective mTOR inhibitor comprising the compounds described above as shown in formula (I) or (II) or (III) or (IV), or a prodrug, deuterated product, or pharmaceutically acceptable salt thereof.

[0010] A fourth aspect of the present invention is to provide a method for preparing a selective mTOR inhibitor, the method comprising: Starting with 2,4,6-trichloro-1,3,5-triazine, it was reacted with a nitrogen-containing heterocyclic compound to obtain intermediate I; In the presence of a catalyst and a base reagent, intermediate I is subjected to a Suzuki coupling reaction with pinacol 4-aminophenylboronic acid to generate intermediate II; Intermediate II was reacted with N,N'-thiocarbonyldiimidazole to give intermediate III; Intermediate III was reacted with an amine compound to obtain a selective mTOR inhibitor.

[0011] Furthermore, the method also includes: Starting with 2,4,6-trichloro-1,3,5-triazine, it was reacted with nitrogen-containing heterocyclic compounds to obtain a triazine ring monosubstituted intermediate; The triazine ring monosubstituted intermediate is subjected to secondary heterocyclic substitution to obtain intermediate I.

[0012] Furthermore, the catalyst is tetra-(triphenylphosphine)palladium, and the alkaline reagent is sodium carbonate.

[0013] The fifth aspect of the invention is to provide a compound of formula (I) or (II) or (III) or (IV), or a prodrug, deuterated product, or pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for treating mTOR overactivation-related diseases.

[0014] Furthermore, the mTOR overactivation-related diseases include non-small cell lung cancer, breast cancer, or renal cell carcinoma.

[0015] Furthermore, the dosage form of the drug is an oral preparation, which is selected from tablets, capsules, granules or suspensions.

[0016] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. The selective mTOR inhibitor developed in this application achieves specific recognition and binding to mTOR through precise structural optimization (introducing fluorinated heterocycles, bicycloalkyl groups, etc.), significantly reducing cross-inhibition of the PI3K family and exhibiting selectivity far exceeding that of the existing drug PKI-587. This characteristic fundamentally avoids the side effects of existing dual-target inhibitors, such as glucose metabolism disorders and immunosuppression, caused by simultaneous inhibition of PI3K, providing core support for safe clinical use.

[0017] 2. The optimized selective mTOR inhibitor exhibited significant inhibitory activity against the non-small cell lung cancer lines PC-9 and HCC-827, with particularly high sensitivity against EGFR-mutant PC-9 cells, filling the gap in existing mTOR inhibitors that primarily target breast cancer. Its potent mTOR inhibitory effect ensures that tumor cell growth signals can be blocked at extremely low concentrations, laying the foundation for low-dose clinical administration and reducing cumulative toxicity.

[0018] 3. The optimized selective mTOR inhibitor is rapidly absorbed after oral administration, achieving sufficient and stable drug exposure in the body. It can reach effective therapeutic concentrations without relying on intravenous injection, and its bioavailability is significantly superior to the existing drug PKI-587. The development of oral dosage forms such as tablets and capsules greatly improves patient medication adherence and addresses the key pain point of poor oral absorption of existing mTOR inhibitors.

[0019] 4. Optimized selective mTOR inhibitors exert their antitumor effects by specifically inhibiting the phosphorylation of key downstream signaling molecules of mTOR. The inhibitory effect exhibits a clear concentration- and time-dependent relationship, without off-target effects such as non-specific protein inhibition or degradation. The well-defined mechanism of action ensures the predictability of clinical efficacy and facilitates precise regulation of pathway inhibition through dose adjustments, achieving a balance between efficacy and safety.

[0020] 5. The synthetic route requires only four key reactions (triazine ring substitution → Suzuki coupling → isothiocyanation → aminolysis), with mild reaction conditions, no need for extreme temperature and pressure environments, and stable and controllable intermediate yields. Solvents, catalysts, and other consumables can be reused during the synthesis process, post-processing is simple, and different compounds can be prepared simply by replacing specific raw materials. It is highly versatile, facilitating large-scale production and providing a flexible and efficient technical platform for the development of subsequent derivatives. Attached Figure Description

[0021] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which: Figure 1 The general structural formulas of the compounds shown in formulas (I) and (II) and (III) and (IV) of this invention are as follows; Figure 2 This is a graph showing the inhibitory activity of HYX-21 of the present invention against the non-small cell lung cancer line HCC-827 / PC-9. Figure 3 This is a graph showing the activity inhibition of the present invention's gidaride against the non-small cell lung cancer cell line HCC-827 / PC-9; Figure 4 This is a Western blot image of HYX-21 of the present invention; Figure 5 This is a pharmacokinetic curve of HYX-21 and gidalisol administered orally according to the present invention. Detailed Implementation

[0022] To make the objectives, features, and advantages of the present invention more apparent and understandable, specific embodiments of the present invention will be described in detail below with reference to the accompanying drawings. Several embodiments of the present invention are shown in the drawings. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that the disclosure of the present invention will be more thorough and complete.

[0023] The present invention is further illustrated below with specific embodiments: Example 1 Example 1 of this invention provides a compound as shown in formula (I) or (II) or (III) or (IV), or a prodrug, deuterated product, or pharmaceutically acceptable salt (such as... Figure 1 Specifically, HYX-1 (as shown in Equation I-1): .

[0024] The specific preparation method is as follows: The synthetic route is as follows: .

[0025] Preparation of Intermediate I: A solution of 2,4,6-trichloro-1,3,5-triazine (6.0 g, 32 mmol) in acetone (33 mL) was mixed with crushed ice (160.0 g) in a reactor. At -10 °C, a mixed solution of morpholine (5.7 mL, 65 mmol) and triethylamine (13.7 mL) was added dropwise to the reactor, and the mixture was stirred at room temperature for 5 hours. The reaction endpoint was monitored by thin-layer chromatography (petroleum ether: ethyl acetate = 3:1). After the reaction was complete, the reaction solution was diluted with 20 mL of water and filtered through a Buchner funnel to obtain a residue. The residue was dried in an oven to obtain a white solid, 2,4-morpholine-6-chloro-1,3,5-triazine, designated as Intermediate I (7.6 g, 26 mmol, 82% yield).

[0026] Preparation of Intermediate II: Intermediate I (1.0033 g, 3.5 mmol), pinacol ester of 4-aminophenylboronic acid (1.1517 g, 5 mmol), sodium carbonate (0.7450 g, 7 mmol), and tetra-(triphenylphosphine)palladium (55.6 mg, 0.048 mmol) were added to a reactor. 20 mL of 1,4-dioxane and 4 mL of water were pipetted into the reactor and stirred for 16 hours in an oil bath at 100 °C. The reaction endpoint was monitored by thin-layer chromatography (petroleum ether: ethyl acetate = 3:1). After the reaction was complete, ice water was added to the reaction mixture and stirred. The residue was filtered through a Buchner funnel and dried in an oven to obtain a brown solid, 4-(4,6-dimorpholino-1,3,5-triazin-2-yl)aniline, designated as Intermediate II (1.1986 g, 3.5 mmol, 99% yield).

[0027] Preparation of intermediate III: Intermediate II (1.0037 g, 2.9 mmol) and N,N'-thiocarbonyldiimidazole (0.5321 g, 2.9 mmol) were added to the reactor. Then, dichloromethane (8 mL) was pipetted to dissolve the two completely. The reactor was then placed in an ice bath at 0 °C and triethylamine (0.7 mL, 4.8 mmol) was added dropwise and stirred for 1 hour. Finally, the reactor was transferred to room temperature and a mixed solution of concentrated hydrochloric acid (0.75 mL) and n-hexane (10 mL) was added and stirred for 18 hours. The reaction endpoint was monitored by thin-layer chromatography (petroleum ether: ethyl acetate = 4:1). After the reaction was completed, water (50 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (50 mL). The upper organic layer was collected, silica gel powder was added, and the volatile solvent was removed by vacuum evaporation. The mixture was then purified by column chromatography with petroleum ether-ethyl acetate (5:1) as the mobile phase. The solvent in the sample solution was removed by vacuum evaporation to obtain a white solid, 4,4'-(6-(4-isothiocyanophenyl)-1,3,5-triazine-2,4-diyl)dimorpholine, designated as intermediate III (0.8024 g, 2.0 mmol, 70% yield).

[0028] Preparation of the product: 0.7 ml of ammonia was added to a solution containing intermediate III (114.3 mg, 0.3 mmol) of dichloromethane:acetonitrile (1:1), and the mixture was stirred at room temperature. The reaction was monitored by thin-layer chromatography (TLC) using petroleum ether:ethyl acetate (1:1). At this point, the reaction system was a milky white suspension. After the reaction was complete, the reaction system was filtered, and the solid was dried to obtain compound HYX-1 (95.9 mg, 80% yield).

[0029] The structural identification data are as follows: 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 2H), 8.28 (d, J =8.7 Hz, 1H), 8.07-7.86 (br, 1H), 7.59 (d, J = 8.7 Hz, 1H), 3.83 (s, 8H), 3.71-3.51 (m, 8H); 13 C NMR (101 MHz, DMSO) δ 181.4, 169.3, 165.0, 142.8, 132.4,129.0, 121.9, 66.4, 43.8; found, [M+1] + :420.1707.

[0030] Example 2 Example 2 of the present invention provides a compound as shown in formula (I) or (II) or (III) or (IV), or a prodrug, deuterated product, or pharmaceutically acceptable salt (such as...) Figure 1 Specifically, HYX-2, as shown in equation (I-2): .

[0031] The specific preparation method is as follows: The difference from Example 1 is that ammonia was replaced with ethanolamine (60.2 mg, 0.3 mmol) to prepare compound HYX-2 (108.8 mg, 0.2 mmol, 67% yield).

[0032] The structural identification data are as follows: 1 H NMR (400 MHz, DMSO) δ 9.84 (s, 1H), 8.24 (d, J = 8.0Hz, 2H), 7.89 (s, 1H), 7.59 (d, J = 8.0 Hz, 2H), 4.82 (s, 1H), 3.98-3.71(m,8H), 3.6.-3.428 (m, 12H); 13 C NMR (101 MHz, DMSO) δ 180.6, 169.3, 165.0, 143.1,132.0, 128.9, 121.5, 66.4, 59.5, 46.9, 43.7; found, [M+1] + : 446.1970.

[0033] Example 3 Example 3 of the present invention provides a compound as shown in formula (I) or (II) or (III) or (IV), or a prodrug, deuterated product, or pharmaceutically acceptable salt (such as... Figure 1 Specifically, HYX-3, as shown in equation (I-3): .

[0034] The specific preparation method is as follows: The difference from Example 1 lies in the preparation steps of the product.

[0035] Preparation of the product: Intermediate III (101.4 mg, 0.26 mmol) was added to the reactor, and dichloromethane (2 mL) was pipetted in to dissolve it completely. Propanolamine (22.5 μL, 0.26 mmol) was then slowly added dropwise to the mixture. The mixture was stirred at room temperature for 24 hours, and the reaction endpoint was monitored by thin-layer chromatography (petroleum ether: ethyl acetate = 2:1). Upon completion of the reaction, a white precipitate was formed. This precipitate was filtered through a Buchner funnel, and the residue was dried in an oven to obtain a white solid, designated as HYX-3 (49.9 mg, 0.11 mmol, 41.78% yield).

[0036] The structural identification data are as follows: 1 H NMR (400 MHz, DMSO) δ 9.77 (s, 1H), 8.27 (d, J = 7.9Hz, 2H), 7.94 (s, 1H), 7.57 (d, J = 7.9 Hz, 2H), 4.58 (s, 1H), 3.94-3.70 (m,8H), 3.69-3.63 (m, 8H), 3.59-3.43 (m, 4H), 2.01-1.55 (m, 2H); 13 C NMR (101 MHz, DMSO) δ 180.4, 169.3, 165.0, 143.0, 132.0, 129.0, 121.6, 66.4, 59.2, 43.7,42.1, 31.9; found, [M+1] + : 460.2131.

[0037] Example 4 Example 4 of the present invention provides a compound as shown in formula (I) or (II) or (III) or (IV), or a prodrug, deuterated product, or pharmaceutically acceptable salt (such as... Figure 1 Specifically, HYX-4, as shown in equation (I-4): .

[0038] The specific preparation method is as follows: The difference from Example 3 is that propanolamine in the product preparation step was replaced with 2-methoxyethylamine (22.5 μL, 0.26 mmol), and a white solid was obtained, which was designated as HYX-4 (49.9 mg, 0.11 mmol, 42% yield).

[0039] The structural identification data are as follows: 1 H NMR (400 MHz, DMSO) δ 9.86 (s, 1H), 8.28 (d, J = 8.2Hz, 2H), 7.94 (s, 1H), 7.63 (d, J = 8.2 Hz, 2H), 3.98-3.71 (m, 8H), 3.69-3.61(m, 10H), 3.29 (s, 3H), 3.50 (t, J = 5.5 Hz, 2H); 13 C NMR (101 MHz, DMSO) δ180.7, 169.3, 165.0, 143.1, 132.0, 128.9, 121.6, 70.4, 66.4, 58.4, 43.8, 43.7found, [M+1] + : 460.2131.

[0040] Example 5 Example 5 of the present invention provides a compound as shown in formula (I) or (II) or (III) or (IV), or a prodrug, deuterated product, or pharmaceutically acceptable salt (such as... Figure 1 Specifically, HYX-5, as shown in equation (I-5): .

[0041] The specific preparation method is as follows: The difference from Example 3 is that propanolamine in the product preparation step was replaced with cyclopropylamine (18 μL, 0.26 mmol), and a white solid was obtained, which was denoted as HYX-5 (71.2 mg, 0.16 mmol, 62% yield).

[0042] The structural identification data are as follows: 1 H NMR (400 MHz, DMSO) δ 9.57 (s, 1H), 8.27 (d, J = 8.5Hz, 3H), 8.21-7.98 (m, 1H), 7.61 (d, J= 8.5 Hz, 2H), 3.97-3.71 (m, 8H), 3.67-3.52 (m, 8H), 3.14-2.93 (m, 1H), 0.80-0.70 (m, 2H), 0.65-0.50 (m, 2H); found,[M+1] + : 442.2021.

[0043] Example 6 Example 6 of the present invention provides a compound as shown in formula (I) or (II) or (III) or (IV), or a prodrug, deuterated product, or pharmaceutically acceptable salt (such as...) Figure 1 Specifically, HYX-6, as shown in equation (I-6): .

[0044] The specific preparation method is as follows: The difference from Example 3 is that propanolamine in the product preparation step was replaced with tert-butylamine (27 μL, 0.26 mmol), and a white solid was obtained, which was designated as HYX-6 (58.7 mg, 0.13 mmol, 49% yield).

[0045] The structural identification data are as follows: 1 H NMR (400 MHz, DMSO) δ 9.55 (s, 1H), 8.26 (d, J = 8.7Hz, 2H), 7.63 (d, J = 8.7 Hz, 2H), 7.58 (s, 1H), 3.96-3.74 (m, 8H), 3.66-3.57(m, 8H), 1.50 (s, 9H); 13 C NMR (101 MHz, DMSO) δ 179.5, 169.3, 165.0, 143.4,131.6, 128.8, 121.5, 66.4, 53.3, 43.7, 28.9; found, [M+1] + : 458.2333.

[0046] Example 7 Example 7 of the present invention provides a compound as shown in formula (I) or (II) or (III) or (IV), or a prodrug, deuterated product, or pharmaceutically acceptable salt (such as... Figure 1 Specifically, HYX-7, as shown in equation (I-7): .

[0047] The specific preparation method is as follows: The difference from Example 3 is that the propanolamine in the product preparation step was replaced with (R)-(-)-1-amino-2-propanol (20.5 μL, 0.26 mmol), and a white solid was obtained, which was designated as HYX-7 (67.8 mg, 0.14 mmol, 57% yield).

[0048] The structural identification data are as follows: 1 H NMR (400 MHz, DMSO) δ 9.92 (s, 1H), 8.27 (d, J = 8.5Hz, 2H), 7.85 (s, 1H), 7.66 (d, J = 8.5 Hz, 2H), 4.89 (s, 1H), 3.98-3.73 (m,8H), 3.68-3.57 (m, 10H), 3.33-3.21 (m, 1H), 1.09 (d, J = 6.1 Hz, 3H); 13 C NMR(101 MHz, DMSO) δ 180.6, 169.3, 165.0, 143.2, 131.9, 128.9, 121.4, 66.4,64.9, 55.3, 51.7, 43.7, 21.7; found, [M+1] + : 460.2123.

[0049] Example 8 Example 8 of the present invention provides a compound as shown in formula (I) or (II) or (III) or (IV), or a prodrug, deuterated product, or pharmaceutically acceptable salt (such as...) Figure 1 Specifically, HYX-8, as shown in equation (I-8): .

[0050] The specific preparation method is as follows: The difference from Example 3 is that propanolamine in the product preparation step was replaced with mercaptoethylamine (22 μL, 0.26 mmol), and a white solid was obtained, which was designated as compound HYX-8 (87.6 mg, 0.19 mmol, 73% yield).

[0051] The structural identification data are as follows: 1 H NMR (400 MHz, DMSO) δ 9.93 (s, 1H), 8.28 (d, J = 8.1Hz, 2H), 8.11 (s, 1H), 7.57 (d, J= 8.1 Hz, 2H), 3.97-3.78 (m, 8H), 3.75-3.60(m, 12H), 3.01 (t, J = 6.2 Hz, 2H); found, [M+1] + : 462.1748.

[0052] Example 9 Example 9 of the present invention provides a compound as shown in formula (I) or (II) or (III) or (IV), or a prodrug, deuterated product, or pharmaceutically acceptable salt (such as... Figure 1 Specifically, HYX-9, as shown in equation (I-9): .

[0053] The specific preparation method is as follows: The difference from Example 3 is that propanolamine in the product preparation step was replaced with (1R,2R)-2-aminocyclopentanol (21.5 μL, 0.26 mmol), and a white solid was obtained, which was designated as compound HYX-9 (49.5 mg, 0.10 mmol, 39% yield).

[0054] The structural identification data are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ 9.66 (s, 1H), 8.27 (d, J =8.3 Hz, 2H), 7.89 (s, 1H), 7.64 (d, J = 8.3 Hz, 2H), 4.82 (s, 1H), 4.29 (s,1H), 3.97 (t, J = 5.5 Hz, 1H), 3.92-3.72 (m, 8H), 3.69-3.57 (m, 8H), 2.10 (dd, J = 13.7, 6.9 Hz, 1H), 1.84 (q, J = 6.9 Hz, 1H), 1.72-1.55 (m, 2H), 1.54-1.32 (m,2H); found, [M+1] + : 486.2277.

[0055] Example 10 Example 10 of the present invention provides a compound as shown in formula (I) or (II) or (III) or (IV), or a prodrug, deuterated product, or pharmaceutically acceptable salt (such as... Figure 1Specifically, HYX-10, as shown in formula (I-10): .

[0056] The specific preparation method is as follows: The difference from Example 3 is that propanolamine in the product preparation step was replaced with 2-aminobutane (26.0 μL, 0.26 mmol). After the reaction was completed, silica gel powder was added to the reaction solution and the solvent was evaporated under reduced pressure. The product was purified and separated by column chromatography with petroleum ether-ethyl acetate (2:1) as the mobile phase. The solvent in the sample solution was evaporated under reduced pressure to obtain a white solid, and the compound HYX-10 (123.5 mg, 0.27 mmol, 93% yield) was obtained.

[0057] The structural identification data are as follows: 1 H NMR (400 MHz, DMSO) δ 9.59 (s, 1H), 8.27 (d, J = 8.7Hz, 2H), 7.76 (d, J = 7.5 Hz, 1H), 7.61 (d, J = 8.7 Hz, 2H), 4.27 (s, 1H), 3.95-3.70 (m, 9H), 3.69-3.55 (m, 8H), 1.67-1.43 (m, 1H), 1.14 (d, J = 6.5 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H); found, [M+23] + : 458.2331.

[0058] Example 11 Example 11 of the present invention provides a compound as shown in formula (I) or (II) or (III) or (IV), or a prodrug, deuterated product, or pharmaceutically acceptable salt (such as... Figure 1 Specifically, HYX-11, as shown in equation (I-11): .

[0059] The specific preparation method is as follows: The difference from Example 3 is that the propanolamine in the product preparation step was replaced with 2-furanylamine (23 μL, 0.26 mmol), and a white solid was obtained, which was designated as compound HYX-11 (66.1 mg, 0.14 mmol, 53% yield).

[0060] The structural identification data are as follows: 1H NMR (400 MHz, DMSO) δ 9.85 (s, 1H), 8.32-8.23 (m,3H), 7.62 (d, J = 8.7 Hz, 3H), 6.50-6.39 (m, 1H), 6.36 (d, J = 3.1 Hz, 1H), 4.74(d, J = 5.2 Hz, 2H), 3.9-3.71 (m, 8H), 3.68-3.60 (m, 8H); 13 C NMR (101 MHz, DMSO)δ 180.7, 169.3, 165.0, 151.9, 142.9, 142.7, 132.3, 128.9, 121.9, 111.0,107.9, 66.4, 43.7, 41.0; found, [M+1] + : 482.1971.

[0061] Example 12 Example 12 of the present invention provides a compound as shown in formula (I) or (II) or (III) or (IV), or a prodrug, deuterated product, or pharmaceutically acceptable salt (such as...) Figure 1 Specifically, HYX-12, as shown in equation (I-12): .

[0062] The specific preparation method is as follows: The difference from Example 3 is that the propanolamine in the product preparation step was replaced with 2-thiophene ethylamine (30.5 μL, 0.26 mmol), and a white solid was obtained, which was designated as compound HYX-12 (115.1 mg, 0.22 mmol, 87% yield).

[0063] The structural identification data are as follows: 1 H NMR (400 MHz, DMSO) δ 9.87 (s, 1H), 8.27 (d, J = 8.6Hz, 2H), 7.99 (s, 1H), 7.55 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 5.0 Hz, 1H), 6.99(dd, J = 5.0, 3.5 Hz, 1H), 6.94 (d, J= 3.5 Hz, 1H), 3.94-3.71 (m, 10H), 3.68-3.62 (m, 8H), 3.12 (t, J = 7.2 Hz, 2H); 13 found, [M+1] + : 512.1898.

[0064] Example 13 Example 13 of the present invention provides a compound as shown in formula (I) or (II) or (III) or (IV), or a prodrug, deuterated product, or pharmaceutically acceptable salt thereof, HYX-13, as shown in formula (II-1): .

[0065] The specific preparation method is as follows: The synthetic route is as follows: .

[0066] Preparation of Intermediate I: A triazine-monosubstituted intermediate (4-(4,6-dichloro-1,3,5-triazine-2-yl)morpholine, 1 mmol) and (R)-3-methylmorpholine (1 mmol) were added to a reactor. Tetrahydrofuran (6 mL) was pipette-dissolved the intermediate completely, and N,N-diisopropylethylamine (1.5 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 21 hours, and the reaction endpoint was monitored by thin-layer chromatography (petroleum ether: ethyl acetate = 3:1). After the reaction was complete, water (50 mL) was added to the reaction solution, followed by extraction three times with dichloromethane (50 mL). The combined organic layers were back-extracted once with saturated NaCl solution (50 mL). The lower organic layer was then removed, and silica gel powder was added to evaporate the solvent under reduced pressure. The mixture was purified and separated by column chromatography using petroleum ether-ethyl acetate (10:1) as the mobile phase. The solvent in the solution containing the sample was evaporated under reduced pressure to obtain Intermediate I (228.0 mg, 0.76 mmol, 76% yield).

[0067] Preparation of Intermediate II: Under nitrogen protection, intermediate I (1 mmol), 4-aminophenylboronic acid pinacol ester (1.5 mmol), sodium carbonate (2 mmol), and tetra-(triphenylphosphine)palladium (0.14 mmol) were added sequentially to a reactor. Then, 1,4-dioxane (5 mL) and water (1 mL) were pipetted together and added to the reactor. The mixture was stirred in an oil bath at 100 °C for 18 hours. The reaction endpoint was monitored by thin-layer chromatography (petroleum ether: ethyl acetate = 3:1). After the reaction was completed, ice water was added to the reaction solution and stirred. The residue was filtered through a Buchner funnel and dried in an oven to obtain a brown solid, which yielded intermediate II (208.8 mg, 0.59 mmol, 77% yield).

[0068] Preparation of Intermediate III: Intermediate II (1 mmol) and N,N'-thiocarbonyldiimidazole (1.2 mmol) were added to the reactor, and then dichloromethane (4 mL) was pipetted to dissolve them completely. The reactor was then placed in an ice bath at 0 °C and triethylamine (1.67 mmol) was added dropwise and stirred for 1 hour. Finally, the mixture was transferred to room temperature and a mixture of concentrated hydrochloric acid (150 μL) and n-hexane (2 mL) was added and stirred for 27 hours. The reaction endpoint was monitored by thin-layer chromatography (petroleum ether: ethyl acetate = 3:1). After the reaction was completed, water (50 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (50 mL). The upper organic layer was collected, silica gel powder was added, and the volatile solvent was removed by vacuum evaporation. The mixture was then purified by column chromatography with petroleum ether-ethyl acetate (8:1) as the mobile phase. The solvent in the solution containing the sample was removed by vacuum evaporation to obtain Intermediate III (161.2 mg, 0.40 mmol, 60% yield).

[0069] Preparation of the product: Intermediate III (0.4 mmol) was added to the reactor, and dichloromethane (4 mL) was pipetted in to dissolve it completely. Then, ethanolamine (1 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 16 hours. The reaction endpoint was monitored by thin-layer chromatography (petroleum ether: ethyl acetate = 2:1). After the reaction was completed, a white precipitate was formed. The precipitate was filtered through a Buchner funnel, and the residue was dried in an oven to obtain a white solid, designated as HYX-13 (119.5 mg, 0.26 mmol, 65% yield).

[0070] The structural identification data are as follows: 1 H NMR (400 MHz, DMSO) δ 9.87 (s, 1H), 8.27 (d, J = 8.4Hz, 2H), 7.91 (s, 1H), 7.63 (d, J= 8.4 Hz, 2H), 4.83 (s, 1H), 4.73-4.25 (m,2H), 3.98-3.86 (m, 2H), 3.86-3.62 (m, 9H), 3.61-3.53 (m, 4H), 3.41 (t, J = 10.8Hz, 1H), 3.18 (t, J = 11.7 Hz, 1H), 1.23 (d, J = 6.6 Hz, 3H); 13 C NMR (101 MHz, DMSO) δ 180.7, 169.3, 165.1, 164.7, 143.1, 132.1, 128.9, 121.6, 70.7, 66.6,66.4, 59.6, 46.9, 46.2, 43.7, 38.6, 14.4; found, [M+1] + : 460.2126.

[0071] Example 14 Example 14 of the present invention provides a compound as shown in formula (I) or (II) or (III) or (IV), or a prodrug, deuterated product, or pharmaceutically acceptable salt (such as... Figure 1 Specifically, HYX-14, as shown in equation (II-2): .

[0072] The specific preparation method is as follows: The difference from Example 13 is that (R)-3-methylmorpholine in the preparation step of intermediate I was replaced with (R)-2-methylmorpholine (1 mmol), and a white solid was obtained, which was designated as compound HYX-14 (46.9 mg, 0.10 mmol, 42% yield).

[0073] The structural identification data are as follows: 1 H NMR (400 MHz, DMSO) δ 9.88 (s, 1H), 8.28 (d, J = 8.5Hz, 2H), 7.91 (s, 1H), 7.64 (d, J= 8.5 Hz, 2H), 4.83 (s, 1H), 4.74-4.63 (m,1H), 4.55-4.41 (m, 1H), 3.94-3.73 (m, 4H), 3.71-3.54 (m, 8H), 3.53-3.41 (m,2H), 2.09-3.90 (m, 1H), 2.76-2.57 (m, 1H), 1.17 (d, J = 5.6 Hz, 3H); found, [M+1] + : 460.2126.

[0074] Example 15 Example 15 of the present invention provides a compound as shown in formula (I) or (II) or (III) or (IV), or a prodrug, deuterated product, or pharmaceutically acceptable salt (such as... Figure 1 Specifically, HYX-15, as shown in formula (II-3): .

[0075] The specific preparation method is as follows: The difference from Example 13 is that (R)-3-methylmorpholine in the preparation step of intermediate I was replaced with thiomorpholine (1.65 mmol, 166 μL), and a white solid was obtained, which was designated as compound HYX-15 (28.2 mg, 0.06 mmol, 82% yield).

[0076] The structural identification data are as follows: 1 H NMR (400 MHz, DMSO) δ 9.86 (s, 1H), 8.38-8.22 (m,2H), 7.67-7.53 (s, 1H), 7.62 (m, 2H), 4.83 (s, 1H), 4.313.98 (m, 4H), 3.89-3.72 (m, 4H), 3.66-3.45 (m, 4H), 2.79-2.57 (m, 2H); 13 C NMR (101 MHz, DMSO) δ180.6, 169.4, 165.1, 164.8, 143.1, 132.0, 128.9, 121.5, 66.4, 59.5, 46.9,45.8, 43.7, 26.9; found, [M+1] + : 462.1750.

[0077] Example 16 Example 16 of the present invention provides a compound as shown in formula (I) or (II) or (III) or (IV), or a prodrug, deuterated product, or pharmaceutically acceptable salt (such as...) Figure 1 Specifically, HYX-16, as shown in equation (II-4): .

[0078] The specific preparation method is as follows: The difference from Example 13 is that (R)-3-methylmorpholine in the preparation step of intermediate I was replaced with N-ethylpiperazine (1.2 mmol, 162 μL), and a white solid was obtained, which was designated as compound HYX-16 (57.9 mg, 0.12 mmol, 50% yield).

[0079] The structural identification data are as follows: 1 H NMR (400 MHz, DMSO) δ 9.88 (s, 1H), 8.27 (d, J = 8.7Hz, 2H), 7.91 (s, 1H), 7.63 (d, J = 8.7 Hz, 2H), 4.83 (s, 1H), 3.79-3.73 (m,8H), 3.67-3.60 (m, 4H), 3.59-3.49 (m, 4H), 2.44-2.37 (m, 4H), 2.38-2.25 (m,2H), 1.03 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, DMSO) δ 180.6, 169.3, 165.1,164.8, 143.0, 132.1, 128.9, 121.6, 66.4, 59.6, 52.6, 52.1, 46.9, 43.7, 43.2,12.4; found, [M+1] + : 473.2444.

[0080] Example 17 Example 17 of the present invention provides a compound as shown in formula (I) or (II) or (III) or (IV), or a prodrug, deuterated product, or pharmaceutically acceptable salt (such as... Figure 1 Specifically, HYX-17, as shown in equation (II-5): .

[0081] The specific preparation method is as follows: The difference from Example 13 is that (R)-3-methylmorpholine in the preparation step of intermediate I was replaced with 1-isopropylpiperazine (1 mmol, 140 μL), and a white solid was obtained, which was designated as compound HYX-17 (21.1 mg, 0.04 mmol, 37% yield).

[0082] The structural identification data are as follows: 1 H NMR (400 MHz, DMSO) δ 9.87 (s, 1H), 8.27 (d, J = 8.6Hz, 2H), 7.91 (s, 1H), 7.62 (d, J = 8.6 Hz, 2H), 4.84 (s, 1H), 3.96-3.71 (m,8H), 3.67-3.61 (m, 4H), 3.60-3.50 (m, 4H), 2.69 (dd, J = 12.9, 6.5 Hz, 1H),2.48-2.39 (m, 4H), 0.98 (d, J = 6.5 Hz, 3H); 13 found, [M+1] + : 487.2602.

[0083] Example 18 Example 18 of the present invention provides a compound as shown in formula (I) or (II) or (III) or (IV), or a prodrug, deuterated product, or pharmaceutically acceptable salt (such as...) Figure 1 Specifically, HYX-18, as shown in formula (II-6): .

[0084] The specific preparation method is as follows: The difference from Example 13 is that (R)-3-methylmorpholine in the preparation step of intermediate I was replaced with 3,3-difluoro-1-methylpyrrolidine (1.5 mmol, 183.7 mg), and a white solid was obtained, which was designated as compound HYX-18 (200.2 mg, 0.43 mmol, 83% yield).

[0085] The structural identification data are as follows: 1H NMR (400 MHz, DMSO) δ 9.87 (s, 1H), 8.29 (d, J = 7.7Hz, 2H), 7.92 (s, 1H), 7.64 (d, J = 7.9 Hz, 2H), 4.83 (s, 1H), 4.63-3.72 (m,10H), 3.70-3.61 (m, 4H), 3.59-3.53 (s, 4H); 13 C NMR (101 MHz, DMSO) δ 180.6,169.2, 164.7, 163.9, 143.2, 131.8, 129.0, 128.6 (t, J = 246.2 Hz), 121.6, 66.4,59.5, 52.84 (d, J = 27.7 Hz), 46.9, 43.7, 40.63, 40.42, 40.22, 33.3 (t, J = 20.4Hz); found, [M+1] + : 466.1830.

[0086] Example 19 Example 19 of the present invention provides a compound as shown in formula (I) or (II) or (III) or (IV), or a prodrug, deuterated product, or pharmaceutically acceptable salt (such as... Figure 1 Specifically, HYX-19, as shown in equation (II-7): .

[0087] The specific preparation method is as follows: The difference from Example 13 is that (R)-3-methylmorpholine in the preparation step of intermediate I was replaced with 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (0.8 mmol, 118.5 mg), and a white solid was prepared, which was designated as compound HYX-18 (68.7 mg, 0.15 mmol, 86% yield).

[0088] The structural identification data are as follows: 1H NMR (400 MHz, DMSO) δ 9.85 (s, 1H), 8.36-8.18 (m,2H), 7.89 (s, 1H), 7.72-7.45 (m, 2H), 4.81 (s, 1H), 4.67-4.55 (m, 1H), 3.95-3.72 (m, 4H), 3.68-3.53 (m, 12H), 2.02-1.92 (m, 2H), 1.90-1.84 (m, 4H); 13 C NMR(101 MHz, DMSO) δ 180.7, 169.6, 165.2, 163.6, 143.1, 132.0, 128.9, 121.5,71.5, 71.1, 66.4, 59.6, 54.8, 54.5, 46.9, 43.7, 26.9; found, [M+1] + :472.2136.

[0089] Example 20 Example 20 of the present invention provides a compound as shown in formula (I) or (II) or (III) or (IV), or a prodrug, deuterated product, or pharmaceutically acceptable salt (such as...) Figure 1 Specifically, HYX-20, as shown in equation (II-8): .

[0090] The specific preparation method is as follows: The synthetic route is as follows: .

[0091] Preparation of Intermediate II: Under nitrogen protection, intermediate I, which was started from 2,4,6-trichloro-1,3,5-triazine and substituted with specific nitrogen-containing heterocyclic compounds, was added sequentially to the reactor: 2-chloro-4-(4,4-difluoropiperidin-1-yl)-6-(3,3-difluoropyrrolidone-1-yl)-1,3,5-triazine (100.5 mg, 0.30 mmol), pinacol 4-aminophenylboronic acid (97.1 mg, 0.44 mmol), sodium carbonate (63.4 mg, 0.60 mmol), and tetra-(triphenylphosphine)palladium (4.6 mg, 0.0040 mmol). Then, 1,4-dioxane (5 mL) and water (1 mL) were mixed thoroughly at room temperature and added to the reactor. The reactor was then stirred in an oil bath at 100 °C for 20 hours. The reaction endpoint was monitored by thin-layer chromatography (petroleum ether: ethyl acetate = 3:1). After the reaction was complete, ice water was added to the reaction solution and stirred. The residue was then filtered through a Buchner funnel and dried in an oven to obtain a brown solid, which was 4-(4-(4,4-difluoropiperidin-1-yl)-6-(3,3-difluoropyrrolidine-1-yl)-1,3,5-triazin-2-yl)aniline (93.6 mg, 0.24 mmol, 80% yield), denoted as intermediate II.

[0092] Preparation of intermediate III: Intermediate II (90.1 mg, 0.23 mmol) and N,N'-thiocarbonyldiimidazole (40.0 mg, 0.27 mmol) were added to the reactor. Then, dichloromethane (2 mL) was pipetted to dissolve the two substances completely. The reactor was then placed in an ice bath at 0 °C and triethylamine (52.6 μL, 0.38 mmol) was slowly added dropwise and stirred for 1 hour. Finally, the reactor was transferred to room temperature and a mixed solution of concentrated hydrochloric acid (67.5 μL) and n-hexane (900 μL) was added and stirred for 23 hours. The reaction endpoint was monitored by thin-layer chromatography (petroleum ether: ethyl acetate = 100:1). After the reaction was completed, water (50 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (50 mL). The upper organic layer was collected, silica gel powder was added, and the volatile solvent was removed by vacuum evaporation. The mixture was then purified by column chromatography with petroleum ether-ethyl acetate (100:1) as the mobile phase. The solvent in the solution containing the sample was removed by vacuum evaporation to obtain 2-(4,4-difluoropiperidin-1-yl)-4-(3,3-difluoropyrrolidine-1-yl)-6-(4-isothiocyanophenyl)-1,3,5-triazine (70.5 mg, 0.16 mmol, 70% yield), which was designated as intermediate III.

[0093] Preparation of the product: Intermediate III (70.0 mg, 0.16 mmol) was added to the reactor, and dichloromethane (2 mL) was pipetted in to dissolve it completely. Then, ethanolamine (10.0 μL, 0.16 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 20 hours. The reaction endpoint was monitored by thin-layer chromatography (petroleum ether: ethyl acetate = 1:1). After the reaction was completed, a white precipitate was formed. The precipitate was filtered through a Buchner funnel, and the residue was dried in an oven to obtain a white solid, designated as HYX-20 (57.6 mg, 0.12 mmol, 72% yield).

[0094] The structural identification data are as follows: 1 H NMR (400 MHz, DMSO) δ 9.89 (s, 1H), 8.30 (d, J = 8.7Hz, 2H), 7.93 (s, 1H), 7.65 (d, J = 8.7 Hz, 2H), 4.84 (s, 1H), 4.19-3.92 (m,6H), 3.90-3.67 (m, 2H), 3.60-3.48 (m, 4H), 2.65-2.50 (m, 2H), 2.14-1.92 (m,4H); 13 C NMR (101 MHz, DMSO) δ 180.6, 169.5, 164.6, 163.9, 143.2, 131.7, 129.0,128.5 (t, J = 259.8 Hz), 123.6 (t, J = 255.0 Hz), 121.5, 59.5, 52.8 (t, J = 35.8Hz), 46.9, 43.8, 33.6 (t, J = 23.3 Hz); found, [M+1] + : 500.1850.

[0095] Example 21 Example 21 of the present invention provides a compound as shown in formula (I) or (II) or (III) or (IV), or a prodrug, deuterated product, or pharmaceutically acceptable salt (such as... Figure 1 Specifically, HYX-21, as shown in equation (II-9): .

[0096] The specific preparation method is as follows: The synthetic route is as follows: .

[0097] Preparation of the triazine ring monosubstituted intermediate: 2,4,6-trichloro-1,3,5-triazine (500.8 mg, 2.7 mmol) was dissolved in dichloromethane (5 mL) in an ice bath at -10 °C. 3,3-difluoro-1-methylpyrrolidine (290.6 mg, 2.7 mmol) was thoroughly dissolved in dichloromethane (5 mL) using a pipette, and then N,N-diisopropylethylamine (710 μL, 4.1 mmol) was added. The mixed solution was then added dropwise to the reactor and stirred for 26 hours. The reaction endpoint was monitored by thin-layer chromatography (petroleum ether: ethyl acetate = 5:1). After the reaction was completed, water (50 mL) was added to the reaction solution, and the mixture was extracted three times with dichloromethane (50 mL). The organic layers were combined and back-extracted with saturated NaCl solution (50 mL). The lower organic layer was removed and silica gel powder was added to evaporate the organic solvent under reduced pressure. The mixture was then purified and separated by column chromatography with petroleum ether-ethyl acetate (40:1) as the mobile phase. The solution containing the sample was collected and the organic solvent was evaporated under reduced pressure to obtain 2,4-dichloro-6-(3,3-difluoropyrrolidone-1-yl)-1,3,5-triazine (245.3 mg, 0.97 mmol, 36% yeiLd), which was designated as the triazine ring monosubstituted intermediate.

[0098] Preparation of Intermediate I: The triazine monosubstituted intermediate (203.8 mg, 0.80 mmol) was added to the reactor, and tetrahydrofuran (3 mL) was pipetted to dissolve it. 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (118.5 mg, 0.79 mmol) was dissolved in tetrahydrofuran (3 mL), and N,N-diisopropylethylamine (410 μL, 2.4 mmol) was added to the solution. Then, the mixed solution containing 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride was added dropwise to the reactor. Finally, the reactor was placed in an ice bath at 0 °C and stirred for 21 hours. The reaction endpoint was monitored by thin-layer chromatography (petroleum ether: ethyl acetate = 20:1). After the reaction was completed, water (50 mL) was added to the reaction solution, and then the mixture was extracted three times with dichloromethane (50 mL). The organic layers were combined and back-extracted with saturated NaCl solution (50 mL). The lower organic layer was removed and silica gel powder was added to evaporate the organic solvent under reduced pressure. The mixture was then purified and separated by column chromatography with petroleum ether-ethyl acetate (10:1) as the mobile phase. The solution containing the sample was collected and the organic solvent was evaporated under reduced pressure to obtain (1R,5S)-8-(4-chloro-6-(3,3-difluoropyrrolidine-1-yl)-1,3,5-triazine-2-yl)-3-oxo-8-nitrobicyclo[3.2.1]octadecane (240.2 mg, 0.73 mmol, 90% yield), which was designated as intermediate I.

[0099] Preparation of intermediate II: Under nitrogen protection, intermediate I (240.2 mg, 0.73 mmol), 4-aminophenylboronic acid pinacol ester (203.0 mg, 0.93 mmol), sodium carbonate (131.5 mg, 1.2 mmol), and tetra-(triphenylphosphine)palladium (8.5 mg, 0.0073 mmol) were added to the reactor in sequence. Then, 1,4-dioxane (5 mL) and water (1 mL) were mixed thoroughly and added to the reactor. The mixture was stirred in an oil bath at 100 °C for 19 hours. The reaction endpoint was monitored by thin-layer chromatography (petroleum ether: ethyl acetate = 5:1). After the reaction was complete, ice water was added to the reaction solution and stirred. The mixture was then filtered through a Buchner funnel. The filter residue was dried in an oven to obtain a brown solid, which yielded 4-(4-((1R,5S)-3-oxy-8-azabicyclo[3.2.1]octane-8-yl)-6-(3,3-difluoropyrrolidine-1-yl)-1,3,5-triazin-2-yl)aniline (404.1 mg, 1.04 mmol, 93% yield), denoted as intermediate II.

[0100] Preparation of intermediate III: Intermediate II (404.1 mg, 1.04 mmol) and N,N'-thiocarbonyldiimidazole (222.6 mg, 1.2 mmol) were added to the reactor. Then, dichloromethane (5 mL) was pipetted to dissolve the two substances completely. The reactor was then placed in an ice bath at 0 °C and triethylamine (241.1 μL, 1.7 mmol) was added dropwise and stirred for 1 hour. Finally, the reactor was transferred to room temperature and a mixed solution of concentrated hydrochloric acid (300 μL) and n-hexane (4 mL) was added and stirred for 17 hours. The reaction endpoint was monitored by thin-layer chromatography (petroleum ether: ethyl acetate = 3:1). After the reaction was completed, water (50 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (50 mL). The upper organic layer was collected, silica gel powder was added, and the volatile solvent was removed by vacuum evaporation. The mixture was then purified by column chromatography with petroleum ether-ethyl acetate (10:1) as the mobile phase. The solvent in the solution containing the sample was removed by vacuum evaporation to obtain (1R,5S)-8-(4-(3,3-difluoropyrrolidine-1-yl)-6-(4-phenyl isothiocyanate)-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octadecane (197.3 mg, 0.46 mmol, 44% yield), which was designated as intermediate III.

[0101] Preparation of the product: Intermediate III (169.6 mg, 0.39 mmol) was added to the reactor, and dichloromethane (4 mL) was pipetted in to dissolve it completely. Then, ethanolamine (23 μL, 0.39 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 3 hours, and the reaction endpoint was monitored by thin-layer chromatography (petroleum ether: ethyl acetate = 1:1). After the reaction was completed, a white precipitate was formed. The precipitate was filtered through a Buchner funnel, and the residue was dried in an oven to obtain a white solid, designated as HYX-21 (166.2 mg, 0.34 mmol, 86% yield).

[0102] The structural identification data are as follows: 1 H NMR (400 MHz, DMSO) δ 9.88 (s, 1H), 8.29 (d, J = 8.6Hz, 2H), 7.92 (s, 1H), 7.63 (d, J = 8.6 Hz, 2H), 4.91-4.75 (m, 2H), 4.64 (s,1H), 4.12-3.91 (m, 2H), 3.88-3.82 (m, 2H), 3.77-3.68 (m, 2H), 3.66-3.51 (m,8H), 2.67-2.51 (m, 2H), 2.04-1.93 (m, 2H), 1.91-1.84 (m, 2H); 13 C NMR (101 MHz, DMSO) δ 180.7, 169.5, 164.0, 163.3, 143.2, 131.9, 129.0, 128.6 (t, J = 246.2Hz), 121.60, 71.5, 71.1, 59.6, 54.8, 54.6, 52.8 (t, J = 31.0 Hz), 46.9, 43.8,33.2 (d, J = 30.0 Hz), 26.9; found, [M+1] + : 492.1990.

[0103] Example 22 Example 22 of the present invention provides a compound as shown in formula (I) or (II) or (III) or (IV), or a prodrug, deuterated product, or pharmaceutically acceptable salt (such as... Figure 1 Specifically, HYX-22, as shown in equation (II-10): .

[0104] The specific preparation method is as follows: The synthetic route is as follows: .

[0105] Preparation of intermediate I: At room temperature, a dichloromethane solution (6.7 mL) containing 2,4,6-trichloro-1,3,5-triazine (499.5 mg, 2.7 mmol) was added to the reactor; 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (811.8 mg, 5.4 mmol) was dissolved in dichloromethane (6.7 mL) using a pipette, and N,N-diisopropylethylamine (1.9 mL, 11.1 mmol) was added dropwise to the solution. The mixed solution was then added dropwise to the reactor and stirred at room temperature for 17 hours. The reaction endpoint was monitored by thin-layer chromatography (petroleum ether: ethyl acetate = 5:1). After the reaction was completed, water (50 mL) was added to the reaction solution, and the mixture was extracted three times with dichloromethane (50 mL). The organic layers were combined and back-extracted with saturated NaCl solution (50 mL). The lower organic layer was removed and silica gel powder was added to evaporate the organic solvent under reduced pressure. The mixture was then purified and separated by column chromatography with petroleum ether-ethyl acetate (10:1) as the mobile phase. The solution containing the sample was collected and the organic solvent was evaporated under reduced pressure to obtain 8-(4-((1R,5S)-3-oxa-8-azaoxobicyclo[3.2.1]octadecane-8-yl)-6-chloro-1,3,5-triazin-2-yl)-3-oxa-8-azabicyclo[3.2.1]octadecane (833.6 mg, 2.5 mmol, 91% yield), which was designated as intermediate I.

[0106] Preparation of intermediate II: Under nitrogen protection, intermediate I (615.6 mg, 1.8 mmol), 4-aminophenylboronic acid pinacol ester (598.4 mg, 2.7 mmol), sodium carbonate (386.1 mg, 3.6 mmol), and tetra-(triphenylphosphine)palladium (28.1 mg, 0.024 mmol) were added to the reactor in sequence. Then, 1,4-dioxane (15 mL) and water (3 mL) were mixed thoroughly and added to the reactor. The mixture was stirred in an oil bath at 100 °C for 2 hours. The reaction endpoint was monitored by thin-layer chromatography (petroleum ether: ethyl acetate = 3:1). After the reaction was completed, water (50 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (50 mL). The upper organic layer was taken and silica gel powder was added to remove the volatile solvent by vacuum evaporation. The mixture was then purified by column chromatography with petroleum ether-ethyl acetate (5:1) as the mobile phase. The solvent in the solution containing the sample was removed by vacuum evaporation to obtain 4-(4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octane-8-yl)-6-(3-oxa-8-azabicyclo[3.2.1]octane-8-yl)-1,3,5-triazin-2-yl)aniline (182.8 mg, 0.46 mmol, 25% yield), which was designated as intermediate II.

[0107] Preparation of intermediate III: Intermediate II (85.9 mg, 0.25 mmol) and N,N'-thiocarbonyldiimidazole (42.4 mg, 0.24 mmol) were added to the reactor. Then, dichloromethane (3 mL) was pipetted to dissolve the two substances completely. The reactor was then placed in an ice bath at 0 °C and triethylamine (46 μL, 0.33 mmol) was added dropwise and stirred for 1 hour. Finally, the reactor was transferred to room temperature and a mixed solution of concentrated hydrochloric acid (75 μL) and n-hexane (1 mL) was added and stirred for 17 hours. The reaction endpoint was monitored by thin-layer chromatography (petroleum ether: ethyl acetate = 5:1). After the reaction was completed, water (50 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (50 mL). The upper organic layer was then removed by adding silica gel powder and evaporating under reduced pressure to remove the volatile solvent. The mixture was then purified by column chromatography with petroleum ether-ethyl acetate (10:1) as the mobile phase. The solvent in the solution containing the sample was removed by evaporating under reduced pressure to obtain 8-(4-((1R,5S)-3-oxa-8-azacyclo[3.2.1]octacyclo-8-yl)-6-(4-isothiocyanate phenyl)-1,3,5-triazine-2-yl)-3-oxa-8-azacyclo[3.2.1]octacyclo (76.4 mg, 0.18 mmol, 82% yield), which was designated as intermediate III.

[0108] Preparation of the product: Intermediate III (76.4 mg, 0.18 mmol) was added to the reactor, and dichloromethane (3 mL) was pipetted in to dissolve it completely. Then, ethanolamine (10.5 μL, 0.17 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 3 hours, and the reaction endpoint was monitored by thin-layer chromatography (dichloromethane:methanol = 20:1). After the reaction was completed, a white precipitate was formed. The precipitate was filtered through a Buchner funnel, and the residue was dried in an oven to obtain a white solid, designated as HYX-22 (66.2 mg, 0.13 mmol, 72% yield).

[0109] The structural identification data are as follows: 1 H NMR (400 MHz, DMSO) δ 9.89 (s, 1H), 8.26 (d, J = 8.6Hz, 2H), 7.92 (s, 1H), 7.63 (d, J = 8.6 Hz, 2H), 4.88-4.80 (m, 2H), 4.61 (s,1H), 3.70-3.58 (m, 8H), 3.57-3.53 (m, 4H), 3.40-3.32 (m, 1H), 2.58-2.50 (m,1H), 2.05-1.93 (m, 4H), 1.90-1.85 (m, 4H); 13 C NMR (101 MHz, DMSO) δ 180.6,169.9, 163.7, 143.0, 132.0, 128.9, 121.5, 71.4, 71.1, 63.6, 59.6, 54.7, 54.4,46.9, 44.4, 26.9; found, [M+1] + : 498.2286.

[0110] Comparative Example 1 Comparative Example 1 of this invention is PKI-587 (Giddarice).

[0111] mTOR inhibitory activity assay (Lance Ultra method): Prepare the reaction system (50 μL / well): containing 50 mM HEPES (pH=7.5) buffer, supplemented with 1.0 mM EGTA, 3.0 mM MnCl2, 10 mM NaCl, 2.0 mM DTT and 0.01% Tween-20; the test compounds (Examples 1 to 22) are pre-dissolved in 100% DMSO to prepare stock solutions, and then diluted in a gradient of 0.05 nM to 1.0 mM (final DMSO concentration ≤1%). Reaction system construction: The total reaction volume was 10 μL. The final system components included: 6.0 nM mTOR enzyme, 50 nM light-4E-BP1 peptide, and 8 mM ATP. Each component was prepared with HEPES buffer as the solvent. Incubation and termination: After mixing the dilution of the test compound (Examples 1 to 22) with the reaction system, incubate at room temperature for 45 minutes, and then add 10 μL of detection solution (containing 2 times excess kinase quenching buffer + Eu-labeled antiphosphorylated 4E-BP1 antibody, diluted to the final concentration with Lance detection buffer) to terminate the reaction.

[0112] Detection and Analysis: Fluorescence signals were acquired using the Envision system, and dose-response curves were fitted using GraphPad Prism 10.0 to calculate the IC50 of mTOR inhibitory activity. 50 value.

[0113] Table 1:

[0114] As shown in Table 1, HYX-21 (1.35 nM), HYX-19 (1.59 nM), and HYX-13 (1.62 nM) exhibited the strongest mTOR inhibitory activity (IC50). 50 <2 nM); most compounds (such as HYX-2, 14, etc.) have moderate activity, while some compounds (such as HYX-10 / 11 / 12 / 20) have extremely weak activity (IC50 < 2 nM). 50 (>1000nM), some compounds have a strong inhibitory effect on mTOR.

[0115] PI3Kα inhibitory activity assay (ADP-Glo ​​method): Prepare the reaction system (50 μL / well): containing 50 mM HEPES (pH=7.5) buffer, supplemented with 1.0 mM EGTA, 3.0 mM MgCl2, 100 mM NaCl, 2.0 mM DTT and 0.03% CHAPS; the test compounds (Examples 2-3, Examples 13-14, Examples 18-19, Examples 21-22, Comparative Example 1) were pre-dissolved in 100% DMSO to prepare stock solutions, and then diluted in a gradient of 0.05 nM to 1.0 mM (final DMSO concentration ≤1%).

[0116] Reaction system construction: The total reaction volume was 10 μL. The final system components included: corresponding isotype PI3K enzymes (PI3Kα 0.15 mg / mL, PI3Kδ 0.6 mg / mL, PI3Kβ 1.0 mg / mL, PI3Kγ 1.5 mg / mL), 50 μM PIP2, and 25 μM ATP. Each component was prepared in HEPES buffer as the solvent. Incubation and termination: After mixing the dilution of the test compound (Examples 2-3, Examples 13-14, Examples 18-19, Examples 21-22, and Comparative Example 1) with the reaction system, the mixture was incubated at room temperature for 1 hour, and then 10 μL of ADP-Glo ​​reagent was added to terminate the reaction. Detection and Analysis: After amplifying the luminescent signal according to the kit instructions, the luminescence values ​​were acquired using the Envision system. A dose-response curve was fitted using GraphPad Prism 10.0, and the IC50 of the inhibitory activity of each PI3K isoform was calculated. 50 value.

[0117] Table 2:

[0118] As shown in Table 2, in terms of mTOR / PI3Kα selectivity, HYX-22 (1181 times) and HYX-21 (984.5 times) showed significantly higher selectivity for mTOR (PI3Kα / mTOR) than the control drug PKI-587 (only 1.7 times). This means that HYX-21 / 22 can reduce side effects such as hyperglycemia and immunosuppression caused by inhibiting the PI3K pathway, and has better safety.

[0119] Cell proliferation inhibition activity assay (CCK-8 assay): Cell lines: non-small cell lung cancer cells HCC-827 and PC-9.

[0120] Cell seeding and adherence: HCC-827 / PC-9 cells were seeded at a density of 3000 cells / well in 96-well plates, and 100 μL of DMEM medium was added to each well. The plates were then incubated at 37°C in a 5% CO2 incubator for 12 hours to adhere to the cell walls. Compound treatment: Discard the original culture medium and replace it with fresh culture medium (DMEM) containing (HYX-21, PKI-587), concentration gradient: 0.01 μM~100 μM, final DMSO concentration ≤1%, 100 μL per well; at the same time, a negative control group (DMEM containing 1% DMSO) was set up. Incubation and detection: After culturing for another 48 hours, the culture medium was discarded, and 100 μL of fresh culture medium containing 10% CCK-8 reagent was added to each well. The mixture was then incubated at 37°C and 5% CO2 for 2 hours. Data processing: The absorbance at 450 nm was measured using a Molecular Devices microplate reader, and cell viability was calculated (with the negative control group as 100%). The dose-response curve was fitted using GraphPad Prism 8.0 to obtain the IC50. 50 value.

[0121] from Figures 2-3 It can be seen that HYX-21 is compatible with HCC-827 (IC). 50 =5.76μM), PC-9 (IC 50 Both PKI-587 and HYX-21 (IC50 = 1.37 μM) showed clear inhibitory effects on cell proliferation, and PKI-587 exhibited similar and relatively balanced inhibitory efficacy against both HCC-827 (IC50 = 2.25 μM) and PC-9 (IC50 = 2.28 μM) cell lines. HYX-21, however, showed stronger selectivity, particularly effective against the PC-9 cell line, with a significantly higher IC50 value. 50 (1.37µM) was significantly lower than its IC50 value for HCC-827 cells. 50 (2.28µM), which is also lower than the IC50 of PKI-587 for both cell types. 50 .

[0122] mTOR signaling pathway mechanism verification (Western blot): Cell processing and lysis: HCC-827 non-small cell lung cancer cells were treated with 5µM HYX-21 for 24 hours, then the cells were collected and lysed on ice for 30 minutes with RIPA lysis buffer; the lysis buffer was centrifuged at 4°C and 12000rpm for 20 minutes, and the supernatant was collected. Protein quantification and separation: After quantifying protein concentration using the BCA method, 30 µg of protein was loaded onto an SDS-PAGE gel, separated by electrophoresis, and then transferred to a nitrocellulose membrane (Merck Millipore, Biller Ricard, Massachusetts, USA). Antibody incubation: The membrane was blocked with 5% skim milk / TBST at room temperature for 1 hour, and then incubated overnight at 4°C with primary antibody (4EBP1 / p-4EBP1: 1:1000 dilution; GAPDH: 1:2000 dilution); after washing the membrane 3 times with TBST, it was incubated with HRP-labeled secondary antibody (1:5000 dilution) at room temperature for 1 hour. Signal detection: After the chemiluminescent reagent develops the signal, the imaging system acquires the signal.

[0123] from Figure 4 It was observed that with increasing HYX-21 concentration (0.1µM~10µM) and prolonged treatment time (24h~48h), the band signal of p-4EBP1 (S65 site) downstream of mTOR significantly weakened. This indicates that the efficacy of HYX-21 increases with increasing concentration and time, and can remain effective over time.

[0124] The bands of total 4EBP1 protein and the internal reference GAPD protein remained relatively stable across all treatment groups, indicating that HYX-21 did not reduce the expression levels of total 4EBP1 protein and internal reference GAPD protein, but rather specifically inhibited their phosphorylation process. This confirms that HYX-21 exerts its anti-tumor effect by specifically inhibiting the mTOR pathway.

[0125] Oral bioavailability testing (pharmacokinetic studies): Animals: SPF-grade male ICR mice (weight 20g ± 2g, n=3).

[0126] Animal adaptation and pretreatment: Mice were adapted to a 12-hour light-dark cycle and a constant temperature and humidity environment for 7 days (free access to food and water); they were fasted for 12 hours at night before drug administration (with continuous water supply).

[0127] Administration and blood collection: HYX-21 and PKI-587 (10 mg / kg) were administered orally by gavage. 50 µL of blood samples were collected from the posterior orbital venous plexus at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 12 h after administration.

[0128] Plasma processing: Blood samples were centrifuged at 4°C and 6000 rpm for 3 minutes to separate plasma, and then frozen at -20°C for analysis. Samples with concentrations exceeding the detection limit were diluted with blank plasma to the quantitative range.

[0129] LC-MS / MS detection: A C18 column (2.1×50mm, 1.8µm) was used with gradient elution of acetonitrile-0.1% formic acid water as the mobile phase, and plasma drug concentration was quantified in MRM mode; Parameter calculation: Pharmacokinetic parameters were calculated using Phoenix WinNonlin 6.3 software (non-compartmental model).

[0130] from Figure 5 It can be seen that the C of HYX-21 max The maximum plasma concentration was as high as 3772 ng / mL, and the AUC (area under the curve, representing the total exposure) was as high as 5428 µg / L. h, respectively, was 52 times (72 ng / mL) and 26.9 times (202 µg / L) that of PKI-587. (h) This demonstrates that HYX-21 has an order-of-magnitude advantage in oral bioavailability; that is, HYX-21 not only has good in vitro activity but also excellent in vivo pharmacokinetic properties, especially extremely high oral bioavailability. This directly addresses the core pain point of many targeted drugs (including existing mTOR inhibitors) that have poor oral absorption and require injection administration, and is a key differentiating advantage for its successful drug development.

[0131] In the description of this specification, references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0132] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this patent should be determined by the appended claims.

Claims

1. A compound of formula (I), (II), (III), or (IV), or a prodrug, deuterated derivative, or pharmaceutically acceptable salt thereof, characterized in that, ， In Formula I, R is selected from -H. , , , , , , , , , , ; In Equation II, R 1 Selected from , , R 2 Selected from , , , , , , , , , -H; In Formula III, Ar is selected from , , , , , ; In Equation IV, M is selected from , , , , X, Y, and Z are each independently selected from N, O, and S.

2. The compound of formula (I), (II), (III), or (IV) according to claim 1, or its prodrug, deuterated derivative, or pharmaceutically acceptable salt, characterized in that, In Formula II: When R 1 Selected from At that time, R 2 Selected from , , , , , , ; When R 1 Selected from At that time, R 2 Selected from ; When R 1 Selected from At that time, R 2 Selected from , , -H.

3. A pharmaceutical composition, characterized in that, It includes the compound of formula (I), (II), (III), or (IV) as claimed in any one of claims 1 to 2, or its prodrug, deuterated derivative, pharmaceutically acceptable salt, and pharmaceutically acceptable excipient.

4. A selective mTOR inhibitor, characterized in that, Includes the compound of formula (I), (II), (III), or (IV) as described in any one of claims 1 to 2, or its prodrug, deuterated derivative, or pharmaceutically acceptable salt.

5. A method for preparing a selective mTOR inhibitor, characterized in that, The preparation method is used to prepare the selective mTOR inhibitor according to claim 4, and the preparation method includes: Starting with 2,4,6-trichloro-1,3,5-triazine, it was reacted with a nitrogen-containing heterocyclic compound to obtain intermediate I; In the presence of a catalyst and a base reagent, intermediate I is subjected to a Suzuki coupling reaction with pinacol 4-aminophenylboronic acid to generate intermediate II; Intermediate II was reacted with N,N'-thiocarbonyldiimidazole to give intermediate III; Intermediate III was reacted with an amine compound to obtain a selective mTOR inhibitor.

6. The method for preparing the selective mTOR inhibitor according to claim 5, characterized in that, The method further includes: Starting with 2,4,6-trichloro-1,3,5-triazine, it was reacted with nitrogen-containing heterocyclic compounds to obtain a triazine ring monosubstituted intermediate; The triazine ring monosubstituted intermediate is subjected to secondary heterocyclic substitution to obtain intermediate I.

7. The method for preparing the selective mTOR inhibitor according to claim 6, characterized in that, The catalyst is tetra-(triphenylphosphine)palladium, and the alkaline reagent is sodium carbonate.

8. The use of a compound of formula (I), (II), (III), or (IV) as described in any one of claims 1 to 2, or a prodrug, deuterated derivative, or pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating mTOR overactivation-related diseases.

9. The application according to claim 8, characterized in that, The diseases associated with mTOR overactivation include non-small cell lung cancer, breast cancer, or renal cell carcinoma.

10. The application according to claim 8, characterized in that, The drug is an oral preparation, which is selected from tablets, capsules, granules or suspensions.

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