Novel SIRT3 inhibitors and their application in the treatment of AML

Abstract

The present invention relates to targeted SIRT3 inhibitors and their use in AML treatment, belonging to the technical field of tumor therapeutic drug discovery. The present invention provides a compound having the structural formula shown in Formula I or a pharmaceutically acceptable salt thereof, wherein R1 and n are as described in the claims and the specification. The present invention also provides an intermediate for preparing a compound of Formula I or a pharmaceutically acceptable salt thereof. The compound of Formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof can be used to prepare SIRT3 inhibitors and for anti-tumor use, particularly for the treatment of leukemia.

Description

Technical Field

[0001] The present invention relates to a targeted SIRT3 inhibitor and application thereof in AML therapeutic drugs, belonging to the technical field of tumor therapeutic drug discovery. Background Art

[0002] Malignant tumors pose a serious threat to human health and life. Approximately 7 million people die from cancer each year worldwide, accounting for approximately a quarter of all deaths. Currently, the mortality rate among cancer patients in my country exceeds 30%, making it the second leading cause of death among Chinese residents. Drug therapy has become an effective and widely used treatment for malignant tumors. Since 1942, when Gilman et al. at Yale University first demonstrated the therapeutic effect of nitrogen mustard hydrochloride against Gardner lymphoma in mice, drug therapy for tumors has made significant progress and has become an indispensable clinical approach. However, significant toxicity, side effects, and drug resistance remain major obstacles to clinical drug treatment. A wide variety of anti-tumor drugs are used clinically, including chemotherapeutic agents such as alkylating molybdenum complexes, anthracyclines, and DNA-damaging antibiotics. Furthermore, research on natural anti-tumor drugs also occupies a significant portion of the research landscape. For example, camptothecin, vincristine, and paclitaxel are currently commonly used in clinical practice.

[0003] In the field of drug treatment for malignant tumors, discovering new therapeutic targets, designing novel targeted small molecule drugs, and thoroughly exploring their mechanisms of action are key to solving clinical problems and hold significant research significance and value. SIRT3, a key oncogene, is abnormally overexpressed in malignant tumors. Designing targeted small molecule inhibitors is a crucial strategy for treating acute myeloid leukemia. Summary of the Invention

[0004] The technical problem solved by the present invention is to provide a compound as a SIRT3 inhibitor.

[0005] The present invention provides a compound having the structural formula shown in Formula I or a pharmaceutically acceptable salt thereof:

[0006]

[0007] in,

[0008] R1 is C6-C10 aryl, C1-C6 alkyl, or C3-C6 cycloalkyl, and R1 may be substituted by one or more R', wherein R' is hydrogen, nitro, cyano, halogen, hydroxyl, C1-C6 alkylamino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, or halogenated C1-C6 alkoxy;

[0009] n=0-2.

[0010] The present invention preferably comprises a compound having the following structure or a pharmaceutically acceptable salt thereof:

[0011] Wherein, R1 is phenyl, naphthyl, or cyclohexyl, and the R1 may be substituted by one or more R', and the R' is hydrogen, nitro, hydroxyl, cyano, halogen, C1-C4 alkylamino, C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkyl, or halogenated C1-C4 alkoxy;

[0012] n=0-2;

[0013] The present invention preferably comprises a compound having the following structure or a pharmaceutically acceptable salt thereof:

[0014] Wherein, R1 is phenyl, naphthyl, or cyclohexyl, and the phenyl group may be substituted by one or more R's, and R' is hydrogen, Cl, Br, F, cyano, C1-C4 alkyl, or CF3;

[0015] n=0-2;

[0016] The present invention preferably comprises a compound having the following structure or a pharmaceutically acceptable salt thereof:

[0017]

[0018] Wherein, R1 is phenyl or naphthyl, and the phenyl group may be substituted by one or more R', and R' is hydrogen, halogen, halogenated C1-C4 alkyl, cyano, or C1-C4 alkyl; preferably hydrogen, F, Cl, CF3, cyano, or C1-C4 alkyl;

[0019] The present invention preferably comprises a compound having the following structure or a pharmaceutically acceptable salt thereof:

[0020]

[0021] Wherein, R1 is phenyl, naphthyl, or cyclohexyl, and the phenyl group may be substituted by one or more R's, and R' is hydrogen, C1-C4 alkyl, halogen, halogenated C1-C4 alkyl, or cyano; preferably hydrogen, F, Cl, CF3, cyano, or C1-C4 alkyl;

[0022] The present invention preferably comprises a compound having the following structure or a pharmaceutically acceptable salt thereof:

[0023]

[0024] Wherein, R1 is phenyl or naphthyl, and the phenyl group may be substituted by one or more R', and R' is hydrogen, C1-C4 alkyl, halogen, halogenated C1-C4 alkyl, or cyano; preferably hydrogen, F, Cl, CF3, cyano, or C1-C4 alkyl;

[0025] The present invention preferably comprises a compound having the following structure or a pharmaceutically acceptable salt thereof:

[0026]

[0027]

[0028] The pharmaceutically acceptable salts of the compounds of the present invention may be nitrates, hydrochlorides, sulfates, phosphates or citrates of the compounds.

[0029] The present invention also provides an intermediate for preparing the compound shown or a pharmaceutically acceptable salt thereof:

[0030]

[0031] Wherein, R1 is C6-C10 aryl, C1-C6 alkyl, or C3-C6 cycloalkyl, and the R1 may be substituted by one or more R', wherein R' is hydrogen, nitro, cyano, halogen, hydroxyl, C1-C6 alkylamino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, or halogenated C1-C6 alkoxy;

[0032] n=0-2.

[0033] The present invention preferably prepares an intermediate of the compound shown or a pharmaceutically acceptable salt thereof as follows:

[0034]

[0035] R' is 4-CH3, 4-Cl, 3-Cl, 2-Cl, 4-CF3, 3,4-di-Cl, 2,4-di-F, 3,5-di-Cl, 3,5-di-CF3, 3-acetenyl, 3-phenyl, cyclohexyl;

[0036]

[0037] R' is 4-CH3, 4-Cl, 3-Cl, 2-Cl, 4-CF3, 3,4-di-Cl, 2,4-di-F, 3,5-di-Cl, 3,5-di-CF3, 3-acetenyl, 3-phenyl, cyclohexyl;

[0038]

[0039] R' is 4-CH3, 4-Cl, 3-Cl, 2-F, 3,4-di-Cl, 4-CF3, 2,4-di-F, 3,5-di-Cl, 3-acetenyl, 3-phenyl.

[0040] The present invention also provides a pharmaceutical composition comprising an effective dose of the above-mentioned compound or a pharmaceutically acceptable salt thereof. The compounds of the present invention can be formulated into the following forms by methods known in the art: tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely dispersed powders for inhalation, aerosols or sprays, sterile aqueous or oily solutions or suspensions, or sterile emulsions for parenteral administration (including intravenous, intramuscular, or infusion). Liquid formulations can be prepared using sterile water or water-propylene glycol solutions as solvents, and the active ingredient can also be formulated in aqueous polyethylene glycol solutions. Aqueous solutions for oral administration can be prepared by dissolving the active ingredient in water and adding appropriate colorants, flavorings, stabilizers, and thickeners as needed. Aqueous suspensions for oral administration can be prepared by dispersing the finely dispersed active ingredient in water along with a viscous material, such as natural or synthetic gums, resins, methylcellulose, carboxymethylcellulose, and other suspending agents known in the pharmaceutical art.

[0041] The pharmaceutical composition can be in unit dosage form. In these forms, the composition is divided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged preparation containing discrete quantities of the preparation, such as boxed tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet, or any of these packaged forms can be an appropriate number.

[0042] The active ingredient of the pharmaceutical composition of the present invention may be the compound of the present invention alone, or may be a combination of the compound and other anti-tumor compounds as the active ingredient.

[0043] The present invention provides use of the above-mentioned compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in the preparation of a SIRT3 inhibitor.

[0044] The present invention also provides use of the above compound or its pharmaceutically acceptable salt or its pharmaceutical composition in the preparation of anti-tumor drugs.

[0045] The anti-tumor drug is an anti-leukemia drug.

[0046] Furthermore, the leukemia is acute myeloid leukemia.

[0047] During the treatment of tumors, the pharmaceutical composition of the present invention can be used in combination with other anti-tumor drugs for treatment.

[0048] In the treatment of tumors, such combination therapy can be achieved by administering the various therapeutic components simultaneously, sequentially or separately. Such combination products utilize the compounds of this invention within their effective dosage ranges and the other pharmaceutically active agents within their approved dosage ranges. DETAILED DESCRIPTION

[0049] The specific embodiments of the present invention are further described below in conjunction with examples, but the present invention is not limited to the scope of the examples.

[0050] Example 1 Synthesis of Compounds 1 to 31

[0051] Compounds 1 to 31 were synthesized using the following reaction formula:

[0052] When R1 is a phenyl group substituted by R', the reaction process is as follows:

[0053]

[0054] When R1 is When the preparation method is the same as above, only the reaction Replace with Compounds 8, 20, 21 and 31 were obtained respectively.

[0055] Synthesis route and conditions (i) POCl3, 100℃, 2h; (ii) 2,2,6,6-tetramethylpiperidine, n-BuLi, THF, CO2, -78℃ to RT; (iii) SOCl2, DCM, 0.4M NH3 in dioxane; (iv) DIEA, DCM, RT (v) DCM, TFA; (vi) THF, TEA, 60℃;

[0056] Wherein, R' is as described above.

[0057] Synthesis of intermediate 2

[0058] Thieno[3,2-d]pyrimidin-4-one (1) (0.5 g, 3.30 mmol) was dissolved in phosphorus oxychloride (3.3 mL, 35.4 mmol) and heated under reflux at 100°C for 2 h under argon protection. The mixture was detected by thin layer chromatography. After the raw material was completely consumed, the turbid reaction solution was cooled to room temperature for quenching. A saturated sodium bicarbonate solution was then added, followed by water (30 mL). The organic phase was extracted with dichloromethane (3×30 mL). The combined organic phases were washed with saturated brine (×3) and then dried over anhydrous sodium sulfate solid. The solvent was removed under reduced pressure and concentrated to obtain a crude mixture. Silica gel flash column chromatography (DCM:MeOH=20:1) was used to obtain intermediate 2 as a white solid (0.4 g) with a yield of 85%-96%.

[0059]

[0060] Intermediate 2 1H-NMR (600MHz, CDCl3), δ (ppm): 9.00 (1H, s), 8.06 (1H, d, J = 5.4Hz), 7.61 (1H, d, J = 5.4Hz). 13 C-NMR (150 MHz, CDCl3), δ (ppm): 161.8, 154.9, 154.2, 137.0, 130.6.2, 125.0. Synthesis of Intermediate 3

[0061] Compound 2,2,6,6-tetramethylpiperidine (1.484 mL, 1.5 eq) was dissolved in anhydrous tetrahydrofuran (15 mL). The reaction mixture was placed at 0°C under argon protection and stirred for 5 minutes. Then, a 2.5 M BuLi hexane solution (3.52 mL, 1.5 eq) was slowly added dropwise. After keeping the reaction at 0°C for 30 minutes, the reaction was transferred to -78°C and stirred for 40-50 minutes. Subsequently, compound 2 (1 g, 1 eq) dissolved in tetrahydrofuran was added dropwise and reacted for 1 hour. Then, dry ice (2.58 g, 10 eq) was added and reacted at -78°C for 20-30 minutes. The mixture was returned to room temperature and stirred for reaction. The reaction was monitored by thin-layer chromatography. After completion of the reaction, the reaction solution was distilled under reduced pressure to obtain a concentrated solution. A small amount of distilled water (10 mL) was added, and the pH of the reaction solution was adjusted to about 2 with HCl solution (5%). Solid precipitation was observed. Finally, the reaction solution was filtered and the filter residue was retained to obtain intermediate 3 as a light yellow solid (755.7 mg) with a yield of 60%.

[0062]

[0063] Intermediate 3 1 H-NMR (600MHz, DMSO-d6), δ (ppm) 14.5 (1H, s), 9.16 (1H, s), 8.27 (1H, s); 13 C-NMR (150MHz, DMSO-d6), δ (ppm): 162.5, 157.7, 155.0, 145.2, 133.5, 134.6, 120.5.

[0064] Synthesis of intermediate 4

[0065] Take intermediate 3 (0.5 g, 0.5 eq), add dichlorothionyl (10 mL), reflux and stir at 65 ° C for 2 h, concentrate the reaction solvent by circulating water vacuum pump, wash the concentrate with dry dichloromethane (× 3), and redissolve the reaction concentrate with dichloromethane for the last time. Then, slowly add it dropwise to 0.4 M, 1,4-dioxane ammonia solution (11.5 mL, 2 eq) at 0 ° C. After continuing the reaction at 0 ° C for 10-20 min, return to room temperature and stir. The reaction was continued for 30 min and monitored by thin-layer chromatography. After the reaction of the raw materials was completed, the turbid reaction solution was poured into (100 mL) of water and extracted with (100 × 3) dichloromethane. The organic layer reaction solution was selected and washed with saturated NaCl solution (×3). Finally, anhydrous sodium sulfate solid was added for drying. The reaction solution was distilled under reduced pressure on a rotary evaporator to obtain a concentrate, which was purified by silica gel flash chromatography (DCM:MeOH=30:1) to obtain intermediate 4 as an off-white solid 329 mg in a yield of 67%.

[0066]

[0067] Intermediate 4 1 H-NMR (600MHz, DMSO-d6), δ (ppm): 9.10 (1H,s), 8.63 (1H,s), 8.34 (1H,s), 8.14 (1H,s); 13 C-NMR (150 MHz, DMSO-d6), δ (ppm): 162.2, 157.4, 156.8, 147.4, 147.2, 126.1, 125.6. Synthesis of intermediates 7a-i

[0068] Compound 6-(tert-Butyloxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane 10 (0.2 g, 1 eq) was dissolved in an appropriate amount of dichloromethane (10 mL). Isocyanate (0.194 g, 1.2 eq) was then added. DIEA (0.421 mL, 2.2 eq) was added with stirring. The reaction was allowed to react at room temperature. The reaction solution changed from clear to suspended, and a precipitate was finally formed. After 8 h of reaction, the reaction solution was monitored by thin-layer chromatography. When the reaction was complete, distilled water (100 mL) was added to the reaction solution, and the solution was extracted with (100 × 3) dichloromethane. The organic layer reaction solution was washed with saturated NaCl solution (×3) and finally dried over anhydrous sodium sulfate solid. The reaction solution was distilled under reduced pressure on a rotary evaporator to obtain a concentrate, which was purified by silica gel flash chromatography (DCM:MeOH = 25:1) to obtain intermediate 7a as an off-white solid (350 mg) with a yield of 85%-92%.

[0069]

[0070] Intermediate 7b-i was prepared by the same method, where R' is 4-CH3,4-Cl,3-Cl,2-Cl,4-CF3,3,4-di-Cl,2,4-di-F,3,5-di-Cl,3,5-di-CF3,3-acetenyl,3-phenyl,cyclohexyl.

[0071] Intermediate 7a 1 H-NMR (600MHz, CDCl3), δ (ppm): 7.24 (1H,s), 7.20 (1H,s), 7.11 (1H,s), 7.10 (1H,s), 6.35 (1H,s), 3.48 (8H,s), 2.31 (3H,s), 1.49 (9H,s); 13 C-NMR (150MHz, CDCl3), δ (ppm): 155.2, 154.6, 136.0, 133.0, 129.4, 129.4, 120.3, 120.3, 80.3, 43.8, 43.8, 42.7, 42.7, 28.3, 28.3, 28.3, 20.7;

[0072] Intermediate 7b 1 H-NMR(600MHz, CDCl3), δ(ppm):7.31(1H,s),7.30(1H,s),7.25(1H,s),7.24(1H,s),6.54(1H,s),3.48(8H,s)1.49(9H,s); 13 C-NMR (150MHz, CDCl3), δ (ppm): 154.6, 154.5, 137.3, 128.9, 128.9, 128.3 ,121.3,121.3,80.7,58.5,57.3,45.2,45.1,43.8,42.7,28.3,28.3,28.3;

[0073] Intermediate 7c 1 H-NMR(600MHz, CDCl3), δ(ppm):7.45(1H,m),7.22(1H,m),7.19(1H,m),7.01(1H,m),6.71(1H,s),3.48(8H,s),1.49(9H,s); 13 C-NMR (150MHz, CDCl3), δ (ppm): 154.7, 154.5, 139.9, 134.5, 129.5, 123.2, 119.9, 117.9, 80.4, 51.2, 45.5, 45.5, 45.5, 28.2, 28.2, 28.2;

[0074] Intermediate 7d 1 H-NMR (600MHz, CDCl3), δ (ppm): 8.06 (IH, m), 7.11 (1H, m), 7.06 (1H, m), 6.99 (1H, m), 6.60 (1H, s), 3.52 (8H, s), 1.49 (9H, s); 13 C-NMR (150MHz, CDCl3), δ (ppm): 154.8, 154.5, 154.2, 127.1, 124.5, 123.1, 121.1,114.7,114.5,80.3,45.7,45.7,43.7,43.7,42.5,28.3,28.3,28.3;

[0075] Intermediate 7e 1 H-NMR (600MHz, CDCl3), δ (ppm): 7.58 (1H, d, J = 8.7Hz), 7.33 (1H, d, J = 8.7Hz), 7.20 (1H, m), 6.61 (1H, s), 3.49 (8H, s), 1.49 (9H, s); 13 C-NMR (150MHz, CDCl3), δ (ppm): 154.6, 154.3, 138.4, 132.5, 130.3, 126.3, 121.5, 119.2, 80.5, 45.3, 45.3, 43.7, 42.6, 28.3, 28.3, 28.3;

[0076] Intermediate 7f 1 H-NMR (600MHz, CDCl3), δ (ppm): 7.95 (1H, m), 7.69 (2H, m), 6.47 (1H, s), 3.50 (8H, s), 1.48 (9H, s); 13 C-NMR (150MHz, CDCl3), δ (ppm): 154.6, 154.3, 138.4, 132.5, 130.3, 126.3, 121.5, 119.2, 80.5, 45.3, 45.3, 43.7, 42.6, 28.3, 28.3, 28.3;

[0077] Intermediate 7g 1 H-NMR (600MHz, CDCl3), δ (ppm): 7.33 (2H, m), 7.02 (1H, m), 6.77 (1H, s), 3.49 (8H, s), 1.50 (9H, s); 13C-NMR (150MHz, CDCl3), δ (ppm): 154.5, 154.1, 140.7, 135.0, 135.0, 123.1, 117.9, 117.9, 80.5, 44.9, 43.8, 42.5, 42.5, 28.3, 28.3, 28.3;

[0078] Intermediate 7h 1 H-NMR (600MHz, CDCl3), δ (ppm): 7.86 (2H, m), 7.69 (1H, d, J = 8.22Hz), 7.60 (1H ,d,J=8.22Hz),7.50(2H,m),7.45(1H,m),6.74(1H,s)3.50(8H,s)1.50(9H,s); 13 C-NMR (150MHz, CDCl3), δ (ppm): 156.1, 154.6, 134.2, 133.7, 128.6, 128.3, 126.1, 125.9,125.7,125.5,121.3,121.3,80.2,45.5,45.5,43.9,43.9,28.3,28.3,28.3;

[0079] Intermediate 7i 1 H-NMR (600MHz, CDCl3), δ (ppm): 4.31 (1H, m), 3.65 (1H, m), 3.44 (4H, s), 3.33 (4H, s), 1.95 (2H, m), 1.7 0(2H,m),1.61(1H,m),1.47(9H,s),1.38(m,1H),1.34(1H,m),1.13(1H,m),1.11(1H,m),1.07(1H,m); 13 C-NMR (150MHz, CDCl3), δ (ppm): 156.9, 154.6, 80.1, 49.5, 43.5, 43.5, 42.5, 42.5, 33.9, 28.3, 28.3, 28.3, 25.6, 25.6, 25.0, 25.0;

[0080] Synthesis of intermediates 11a-1

[0081] Compound 6-(tert-Butyloxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane 10 (0.2 g, 1 eq) was dissolved in an appropriate amount of dichloromethane (10 mL). Isocyanate (0.194 g, 1.2 eq) was then added. DIEA (0.421 mL, 2.2 eq) was added with stirring. The reaction was allowed to react at room temperature. The reaction solution changed from clear to suspended, and a precipitate was finally formed. After 8 h of reaction, the reaction solution was monitored by thin-layer chromatography. When the reaction was complete, distilled water (100 mL) was added to the reaction solution, and the solution was extracted with (100 × 3) dichloromethane. The organic layer reaction solution was washed with saturated NaCl solution (×3) and finally dried over anhydrous sodium sulfate solid. The reaction solution was distilled under reduced pressure on a rotary evaporator to obtain a concentrate, which was purified by silica gel flash chromatography (DCM:MeOH = 25:1) to obtain intermediate 11a as an off-white solid (350 mg) in a yield of 85%-92%.

[0082]

[0083] Intermediates 11b-1 were prepared by the same method, wherein R' is 4-CH3, 4-Cl, 3-Cl, 2-Cl, 4-CF3, 3,4-di-Cl, 2,4-di-F, 3,5-di-Cl, 3,5-di-CF3, 3-acetenyl, 3-phenyl, or cyclohexyl.

[0084] Intermediate 11a 1 H-NMR (600MHz, CDCl3), δ (ppm): 7.29 (2H, d, J = 8.34Hz), 7.10 (2H, d, J = 8.34Hz), 6.36 (1H,s),4.21(4H,m),3.46(2H,s),2.63(1H,m),2.3(3H,s),1.48(1H,s),1.42(9H,s); 13 C-NMR (150MHz, CDCl3), δ (ppm): 156.4, 155.6, 136.1, 132.7, 129.3, 129.3 ,120.2,120.2,80.7,58.4,57.2,45.1,44.4,28.4,28.3,28.3,28.3,20.7.

[0085] Intermediate 11b 1H-NMR (600MHz, CDCl3), δ (ppm): 7.37 (2H, d, J = 8.82Hz), 7.25 (2H, d, J = 8.82Hz) ,6.55(1H,s),4.21(4H,m),3.46(2H,s),2.63(1H,m),1.78(1H,s),1.42(9H,s); 13 C-NMR (150MHz, CDCl3), δ (ppm): 156.5, 155.3, 137.4, 128.8, 128.8, 128.1, 121.2, 121.2, 80.8, 58.4, 57.2, 45.1, 44.4, 28.4, 28.3, 28.3, 28.3.

[0086] Intermediate 11c 1 H-NMR(600MHz, CDCl3)δ(ppm):7.58(1H,s),7.26(1H,s),7.20(1H,m),7.01(1H,m ),6.58(1H,s),4.11(4H,m),3.47(2H,s),2.63(1H,m),1.69(1H,s),1.42(9H,s); 13 C-NMR (150MHz, CDCl3), δ (ppm): 156.4, 155.0, 138.4, 132.5, 130.2, 126.2, 121.4, 119.0, 80.9, 58.4, 57.2, 45.1, 44.4, 28.4, 28.3, 28.3, 28.3.

[0087] Intermediate 11d 1 H-NMR (600MHz, CDCl3), δ (ppm): 8.02 (1H, s), 7.42 (2H, m), 7.30 (1H, m), 7.16 (1H, m), 4.44 (2H, s), 4.20 (2H, m), 3.9 (1H, s), 3.6 (1H, s), 1.48 (9H, s); 13 C-NMR (150MHz, CDCl3), δ (ppm): 182.0, 156.4, 136.2, 129.2, 129.2, 128.0, 126.7, 126.7, 81.2, 58.6, 56.9, 50.8, 46.7, 28.3, 28.2, 28.2, 28.2.

[0088] Intermediate 11e 1H-NMR (600MHz, CDCl3) δ (ppm): 7.55 (4H, m), 6.69 (1H, s), 4.24 (4H, m), 3.49 (2H, s), 2.66 (1H, m), 1.70 (1H, s), 1.45 (9H, s); 13 C-NMR (150MHz, CDCl3), δ (ppm): 156.4, 155.0, 142.0, 126.1, 125.1, 124.9, 124.7,123.3,119.1,80.9,58.4,57.1,45.1,44.3,28.4,28.2,28.2,28.2.

[0089] Intermediate 11f 1 H-NMR (600MHz, CDCl3), δ (ppm): 7.68 (1H, d, J = 8.70Hz), 7.33 (1H, d, J = 8.70Hz), 7.25 ( 1H,m),6.58(1H,s),4.11(1H,m),3.47(2H,s),2.63(1H,m),1.69(1H,s),1.42(s,9H); 13 C-NMR (150MHz, CDCl3), δ (ppm): 156.4, 155.0, 138.4, 132.5, 130.2, 126.2, 121.4, 119.0, 80.9, 58.4, 57.2, 45.1, 44.4, 28.4, 28.3, 28.3, 28.3.

[0090] Intermediate 11g 1 H-NMR (600MHz, CDCl3), δ (ppm): 8.07 (1H, m), 6.85 (2H, m), 6.45 (1H, m), 4.11 (4H, m), 3.47 (2H, s), 2.63 (1H, m), 1.69 (1H, s), 1.42 (9H, s); 13 C-NMR (150MHz, CDCl3), δ (ppm): 156.4, 155.0, 138.4, 132.5, 130.2, 126.2, 121.4, 119.0, 80.9, 58.4, 57.2, 45.1, 44.4, 28.4, 28.3, 28.3, 28.3;

[0091] Intermediate 11h 1H-NMR(600MHz, CDCl3), δ(ppm):7.41(2H,m),7.04(1H,s),6.99(1H,m),4.18(4H,m),3.45(2H,s),2.62(1H,m),1.46(1H,s),1.43(9H,s); 13 C-NMR (150MHz, CDCl3), δ (ppm): 156.5, 155.1, 141.0, 134.8, 134.8, 122.8, 118.1, 118.1, 81.0, 58.4, 57.2, 45.1, 44.4, 28.4, 28.3, 28.3, 28.3;

[0092] Intermediate 11i 1 H-NMR (600MHz, CDCl3), δ (ppm): 7.99 (2H, m), 7.55 (2H, m), 4.13 (4H, m), 3.51 (2H, s), 2.6 (1H, m), 1.43 (2H, m), 1.48 (9H, s); 13 C-NMR (150MHz, CDCl3), δ (ppm): 156.8, 155.2, 140.8, 132.0, 131.8, 125.9, 124 .1,122.3,119.4,116.0,81.2,58.6,56.9,50.8,46.7,28.3,28.2,28.2,28.2;

[0093] Intermediate 11j 1 H-NMR (600MHz, CDCl3), δ (ppm): 7.83 (1H, s), 7.66 (1H, m), 7.3 (1H, m), 7.26 (1H, m),7.1(1H,s),4.19(4H,m),3.48(2H,m),2.62(1H,m),1.43(1H,s),1.42(9H,s); 13 C-NMR (150MHz, CDCl3), δ (ppm): 156.5, 155.3, 140.0, 129.6, 126.3, 124.2, 123 .0,123.0,118.8,112.4,81.0,58.4,57.2,45.1,44.4,28.4,28.3,28.3,28.3;

[0094] Intermediate 11k 1H-NMR (600MHz, CDCl3), δ (ppm): 7.86 (2H, m), 7.78 (1H, d, J = 7.44Hz), 7.67 (1H, d, J = 7. 44Hz),7.48(3H,m),6.74(1H,s),4.23(4H,m),3.76(2H,mz),2.65(1H,m),1.48(9H,s); 13 C-NMR (150MHz, CDCl3), δ (ppm): 156.5, 156.2, 134.1, 133.4, 128.6, 128.0, 126.0, 125 .8,125.7,125.1,121.1,120.9,80.7,58.5,57.3,45.1,44.3,28.5,28.2,28.2,28.2;

[0095] Intermediate 11l 1 H-NMR (600MHz, CDCl3), δ (ppm): 7.58 (1H, s), 7.26 (1H, s), 7.20 (1H, d, J = 8.04Hz), 7.01 (1H, d,J=8.04Hz),6.58(1H,s),4.11(4H,m),3.47(2H,s),2.63(1H,m),1.69(1H,s),1.42(9H,s); 13 C-NMR (150MHz, CDCl3), δ (ppm): 156.4, 155.0, 138.4, 132.5, 130.2, 126.2, 121.4, 119.0, 80.9, 58.4, 57.2, 45.1, 44.4, 28.4, 28.3, 28.3, 28.3;

[0096] Synthesis of intermediates 15a-j

[0097] Compound 3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester 14 (0.2 g, 1 eq) was dissolved in an appropriate amount of dichloromethane (10 mL), and then isocyanate (0.194 g, 1.2 eq) was added. DIEA (0.421 mL, 2.2 eq) was added while stirring. The reaction was allowed to react at room temperature. The reaction solution changed from clear to suspended, and finally a precipitate was formed. After 8 h of reaction, the reaction solution was monitored by thin layer chromatography. After the reaction was complete, distilled water (100 mL) was added to the reaction solution, and the solution was extracted with (100 × 3) dichloromethane. The organic layer reaction solution was selected and washed with saturated NaCl solution (×3). Finally, anhydrous sodium sulfate solid was added for drying. The reaction solution was distilled under reduced pressure on a rotary evaporator to obtain a concentrate, which was purified by silica gel flash chromatography (DCM:MeOH = 25:1) to obtain compound 15a as an off-white solid 350 mg with a yield of 85%-92%.

[0098]

[0099] 15b-j were prepared by the same method, where R' is 4-CH3, 4-Cl, 3-Cl, 2-F, 3,4-di-Cl, 4-CF3, 2,4-di-F, 3,5-di-Cl, 3-acetenyl, 3-phenyl.

[0100] Intermediate 15a 1 H-NMR (600MHz, CDCl3), δ (ppm): 7.36 (1H, s), 7.34 (1H, s), 7.25 (1H, s), 7.24 (1H, s), 6.65 (1H, s), 4.29 (2H, m), 3.89 (1H, d, J = 12.60 Hz),3.75(1H,d,J=12.60Hz),3.16(1H,d,J=12.66Hz),3.05(1H,d,J=12,66Hz),2.3(3H,s),1.95(2H,m),1.79(2H,m),1.47(9H,s); 13 C-NMR (150MHz, CDCl3), δ (ppm): 155.9, 153.6, 136.0, 132.8, 129.4, 129.4, 12 0.0,120.0,80.1,54.1,53.6,49.6,48.4,28.3,28.3,28.3,27.2,26.9,20.7;

[0101] Intermediate 15b 11H-NMR (600 MHz, CDCl3), δ (ppm): 7.36 (1H, s), 7.34 (1H, s), 7.25 (1H, s), 7.24 (1H, s), 6.65 (1H, s), 4.29 (2H, m), 3.89 (1H, d, J = 12.60 Hz), 3.75 (1H, d, J = 12.60 Hz), 3.16 (1H, d, J = 12.66 Hz), 3.05 (1H, d, J = 12.66 Hz), 1.95 (2H, m), 1.79 (2H, m), 1.47 (9H, s); 13 13C-NMR (150 MHz, CDCl3), δ (ppm): 155.9, 153.1, 137.3, 128.8, 128.8, 128.1, 120.9, 120.9, 80.2, 54.1, 53.6, 49.6, 48.4, 28.3, 28.3, 28.3, 27.2, 26.9;

[0102] Intermediate 15c 1 1H-NMR (600 MHz, CDCl3), δ (ppm): 7.53 (1H, m), 7.27 (1H, m), 7.21 (1H, m), 7.09 (1H, m), 6.85 (1H, s), 4.29 (2H, m), 3.89 (1H, d, J = 12.60 Hz), 3.75 (1H, d, J = 12.60 Hz), 3.16 (d, J = 12.66 Hz, 1H), 3.05 (1H, d, J = 12.66 Hz), 1.95 (2H, m), 1.79 (2H, m), 1.47 (9H, s); 13 13C-NMR (150 MHz, CDCl3), δ (ppm) 155.9, 153.0, 140.0, 134.5, 129.8, 123.1, 119.7, 117.6, 80.2, 54.1, 53.4, 49.7, 48.5, 28.3, 28.3, 28.3, 27.2, 26.9;

[0103] Intermediate 15d 1 1H-NMR (600 MHz, CDCl3), δ (ppm): 8.13 (1H, m), 7.11 (1H, m), 7.21 (1H, m), 6.97 (1H, m), 6.58 (1H, m), 4.29 (2H, m), 3.89 (1H, d, J = 12.60 Hz), 3.75 (1H, d, J = 12.60 Hz), ३.16 (1H, d, J = 12.66 Hz), 3.05 (1H, d, J = 12.66 Hz), 1.95 (2H, m), 1.79 (2H, m), 1.47 (9H, s);13 C-NMR (150MHz, CDCl3), δ (ppm) 155.8, 153.1, 152.5, 127.2, 124.5, 122.9, 121.2, 114.6, 80.2, 54.1, 53.6, 49.6, 48.4, 28.3, 28.3, 28.3, 27.2, 27.0;

[0104] Intermediate 15e 1 H-NMR (600MHz, CDCl3), δ (ppm): 7.60 (1H, m), 7.31 (1H, m), 7.25 (1H, m), 6.85 (1H, s,), 4.29 (2H, m), 3.89 (1H, d, J = 12.60 Hz), 3.75 (1H, d, J = 12.60Hz), 3.16 (1H, d, J = 12.66Hz), 3.05 (1H, d, J = 12, 66Hz), 1.95 (2H, m), 1.79 (2H, m), 1.47 (9H, s); 13 C-NMR (150MHz, CDCl3), δ (ppm): 155.9, 152.8, 138.4, 132.5, 130.3, 126.1 ,121.2,118.9,80.3,54.1,53.4,49.7,48.5,28.3,28.3,28.3,27.2,26.9;

[0105] Intermediate 15f 1 H-NMR (600MHz, CDCl3), δ (ppm) 7.54 (4H, m), 6.67 (1H, s), 4.32 (2H, m), 3.94 (1H, d, J = 12.54Hz), 3.78 ( 1H,d,J=5.4Hz),0(1H,d,J=12.60Hz),3.09(1H,d,J=12.60Hz),2.00(2H,m),1.82(2H,m),1.49(9H,s); 13 C-NMR (150MHz, CDCl3), δ (ppm): 158.8, 152.6, 126.2, 125.1, 124.9, 124.7 ,123.3,118.8,80.3,54.2,53.5,49.7,48.5,28.3,28.3,28.3,27.2,26.9.

[0106] Intermediate 15g 11H-NMR (600 MHz, CDCl3), δ (ppm): 7.36 (1H, s), 7.34 (1H, s), 7.25 (1H, s), 7.24 (1H, s), 6.65 (1H, s), 4.29 (2H, m), 3.89 (1H, d, J = 12.60 Hz), 3.75 (1H, d, J = 12.60 Hz), 3.16 (1H, d, J = 12.66 Hz), 3.05 (1H, d, J = 12.66 Hz), 2.3 (3H, s), 1.95 (2H, m), 1.79 (2H, m), 1.47 (9H, s); 13 13C-NMR (150 MHz, CDCl3), δ (ppm): 155.9, 153.6, 136.0, 132.8, 129.4, 129.4, 120.0, 120.0, 80.1, 54.1, 53.6, 49.6, 48.4, 28.3, 28.3, 28.3, 27.2, 26.9, 20.7.

[0107] Intermediate 15h 1 1H-NMR (600 MHz, CDCl3), δ (ppm): 7.36 (1H, d, J = 1.8 Hz), 7.06 (1H, s), 6.99 (1H, m), 6.54 (1H, m), 4.29 (2H, m), 3.89 (1H, d, J = 12.60 Hz), 3.75 (1H, d, J = 12.60 Hz), 3.16 (1H, d, J = 12.66 Hz), 3.05 (1H, d, J = 12.66 Hz), 1.95 (2H, m), 1.79 (2H, m), 1.47 (9H, s); 13 13C-NMR (150 MHz, CDCl3), δ (ppm): 155.9, 152.7, 140.9, 134.9, 134.9, 122.8, 117.8, 117.8, 80.4, 54.0, 53.4, 49.7, 48.6, 28.3, 28.3, 28.3, 27.2, 26.9.

[0108] Intermediate 15i 1H-NMR (600MHz, CDCl3), δ (ppm): 7.77 (1H, m), 7.73 (1H, m), 7.36 (1H, m), 7.29 (1H, s), 7.26 (1H, s), 4.37 (2H, s), 3.90 (2H, d, J= 12.54Hz), 3.77(2H,d,J=12.54Hz), 3.18(2H,d,J=12.60Hz), 3.07(2H,d,J=12.60Hz), 1.97(2H,m), 1.79(2H,m), 1.47(9H,s); 13 C-NMR (150MHz, CDCl3), δ (ppm): 154.9, 153.9, 129.7, 126.2, 124.0, 122.6 ,118.9,112.4,80.3,53.9,53.7,49.7,48.6,28.3,28.3,28.3,27.2,26.9.

[0109] Intermediate 15j 1 H-NMR (600MHz, CDCl3), δ (ppm): 7.87 (1H, m), 7.84 (1H, m), 7.71 (1H, d, J = 7.65 Hz),7.68(1H,d,J=7.65Hz),7.51(2H,m),7.45(1H,m),6.75(1H,s),4.29(2H, m),3.90(1H,d,J=12.60Hz),3.78(1H,d,J=12.60Hz),3.22(1H,d,J=12.66Hz) ,3.18(1H,d,J=12,66Hz),1.98(2H,m),1.81(1H,m),1.74(1H,m),1.47(9H,s); 13 C-NMR (150MHz, CDCl3), δ (ppm): 155.9, 154.5, 134.2, 133.4, 128.7, 127.9, 126.2, 125.9 ,125.8,125.2,120.9,120.9,80.1,54.3,53.7,49.6,48.4,28.3,28.3,28.3,27.2,27.0.

[0110] General Synthesis of Compounds 1-31

[0111] Intermediates 7a-i, 11a-l, and 15a-j as above, where R1 is R'-substituted phenyl; and intermediates with the same parent nucleus where R1 is naphthyl or cyclohexane (0.173 g, 1.2 eq) were dissolved in an appropriate amount of tetrahydrofuran (10 mL), and the intermediate 3,4-chlorothieno[3,2-D]pyrimidine-6-carboxamide (0.128 g, 1 eq) was added under stirring, and finally DIEA (0.125 mL, 1.5 eq) was added. The mixture was refluxed and stirred overnight at 65°C and monitored by thin layer chromatography. After the reaction of the raw materials was completed, pure water (100 mL) was added to the reaction solution, and then an organic solvent DCM (100 mL×3) was added for extraction. The organic layer reaction solution was selected and washed with saturated NaCl solution (×3), and finally anhydrous sodium sulfate solid was added for drying. The reaction solution was distilled under reduced pressure on a rotary evaporator to obtain a concentrated solution. The compound 1-31 of the present invention was purified by silica gel flash column chromatography (DCM:MEOH=50:1) with a yield of 75%-86%. The following is the NMR analysis result of compound 1-31.

[0112] Compound 1 1 H-NMR(600MHz,DMSO-d6),δ(ppm):8.54(1H,s),8.52(1H,s),8.42(1H,s),8.07(1H,s),7.89( 1H,s),7.35(2H,d,J=8.27Hz),7.04(2H,d,J=8.27Hz),4.01(4H,m),3.65(4H,m),2.22(3H,s); 13 C-NMR (150MHz, DMSO-d6), δ (ppm): 161.9, 160.2, 157.1, 154.6, 153.9, 144.8, 137.2, 13 0.2,128.3,128.3,124.6,119.4,119.4,115.7,44.8,44.8,42.7,42.7,19.8.HRMS(ESI) + calculated for C 19 H 20 N6O2S,[M+H] + :m / z 397.1441, found397.1434; HPLC (tR=17.31min, 100%).

[0113] Compound 2 11H-NMR (600 MHz, DMSO-d6), δ (ppm): 8.76 (1H, s), 8.54 (1H, s), 8.43 (1H, s), 8.07 (1H, s), 7.89 (1H, s), 7.52 (2H, d, J = 8.88 Hz), 7.29 (2H, d, J = 8.88 Hz), 4.02 (4H, m), 3.67 (4H, m); 13 13C-NMR (150 MHz, DMSO-d6), δ (ppm): 162.4, 160.8, 157.6, 154.8, 154.5, 145.4, 139.5, 128.3, 128.3, 125.5, 125.2, 121.1, 121.1, 116.3, 45.3, 45.3, 43.3, 43.3. HRMS (ESI) + calculated for C 18 H 17 ClN6O2S, [M + H] + : m / z 417.0895, found 417.0887; HPLC (tR = 21.82 min, 100%).

[0114] Compound 3 1 1H-NMR (600 MHz, DMSO-d6), δ (ppm): 8.78 (1H, s), 8.51 (1H, s), 8.40 (1H, s), 8.04 (1H, s), 7.86 (1H, s), 7.64 (1H, m), 7.38 (1H, m), 7.24 (1H, m), 6.95 (1H, m), 3.99 (4H, m), 3.64 (4H, m); 13 13C-NMR (150 MHz, DMSO-d6), δ (ppm): 162.6, 160.9, 157.8, 154.8, 154.6, 145.5, 142.2, 133.0, 130.2, 125.3, 121.6, 119.1, 117.9, 116.4, 45.4, 45.4, 43.5, 43.5. HRMS (ESI) + calculated for C 18 H 17 ClN6O2S, [M + H] + : m / z 417.0895, found 417.0887; HPLC (tR = 21.74 min, 100%).

[0115] Compound 4 11H-NMR(600MHz, DMSO-d6), δ(ppm): 8.54(1H, s), 8.41(2H, m), 8.07(1H, s), 7.89(1H, s), 7.46(1H, m), 7.19(1H, m), 7.12(2H, m), 4.02(4H, m), 3.66(4H, m); 13 13C-NMR(150MHz, DMSO-d6), δ(ppm): 162.5, 160.9, 157.8, 155.2, 154.6, 145.5, 127.6, 127.6, 126.3, 125.3, 124.2, 116.4, 115.7, 115.6, 45.4, 45.4, 43.5, 43.5. HRMS(ESI) + calculated for C 18 H 17 FN₆O₂S, [M + H] + : m / z 401.1190, found 401.1183; HPLC(tR = 21.63 min, 99.7%).

[0116] Compound 5 1 1H-NMR(600MHz, DMSO-d6), δ(ppm): 8.92(1H, s), 8.54(1H, s), 8.43(1H, s), 8.07(1H, s), 7.89(1H, s), 7.86(1H, d, J = 8.94 Hz), 7.85(1H, d, J = 8.94 Hz), 7.85(1H, m), 4.03(4H, m), 3.68(4H, m); 13 13C-NMR(150MHz, DMSO-d6), δ(ppm): 162.7, 161.1, 157.9, 154.8, 154.8, 145.7, 141.1, 131.0, 130.6, 125.5, 123.4, 120.8, 119.7, 116.6, 45.5, 45.5, 43.6, 43.6. HRMS(ESI) + calculated for C 18 H 16 Cl₂N₆O₂S, [M + H] + : m / z 451.0505, found 451.0500; HPLC(tR = 19.54 min, 96.2%).

[0117] Compound 6 1H-NMR(600 MHz, DMSO-d6), δ(ppm): 8.54(1H, s), 8.43(2H, s), 8.07(1H, s), 7.89(1H, s), 7.42(1H, m), 7.25(1H, m), 7.02(1H, m), 4.02(4H, m), 3.65(4H, m); 13 C-NMR(150 MHz, DMSO-d6), δ(ppm): 164.4, 162.3, 160.3, 156.6, 155.1, 154.1, 145.9, 137.5, 135.6, 124.8, 123.7, 114.8, 111.3, 104.9, 51.6, 51.6, 45.2, 45.2. HRMS(ESI) + calculated for C 18 H 16 F2N6O2S, [M + H] + : m / z 419.1096, found 419.1087; HPLC(tR = 17.60 min, 100%).

[0118] Compound 7 <000010​​​​​​​​​​​​​​​1H-NMR (600 MHz, DMSO-d6), δ (ppm): 8.73 (1H, s), 8.56 (1H, s), 8.44 (1H, s), 8.09 (1H, s), 7.98 (1H, m), 7.92 (2H, m), 7.74 (1H, m), 7.51 (2H, m), 7.46 (2H, m), 4.09 (4H, t, J = 9.19 Hz), 3.76 (4H, t, J = 11.27 Hz); 13 13C-NMR (150 MHz, DMSO-d6), δ (ppm): 162.6, 161.0, 157.8, 156.3, 154.6, 145.5, 135.5, 133.9, 129.6, 128.1, 126.0, 125.7, 125.7, 125.3, 125.2, 123.8, 123.1, 116.4, 45.6, 45.6, 43.6, 43.6. HRMS (ESI) + calculated for C 22 H 20 N6S, [M + H] + : m / z 433.1441, found 433.1483; HPLC (tR = 19.7 min, 95.0%).

[0120] Compound 9 1 1H-NMR (600 MHz, DMSO-d6), δ (ppm): 8.52 (1H, s), 8.42 (1H, s), 8.06 (1H, s), 7.88 (1H, s), 6.27 (1H, m), 3.93 (4H, t, J = 12.36 Hz), 3.49 (4H, t, J = 12.36 Hz), 1.76 (2H, m), 1.67 (2H, m), 1.57 (1H, m), 1.23 (6H, m); 13 13C-NMR (150 MHz, DMSO-d6), δ (ppm): 162.6, 160.9, 157.8, 156.9, 154.6, 145.4, 125.3, 116.4, 49.4, 45.5, 45.5, 43.2, 43.2, 33.3, 33.3, 25.6, 25.3, 25.3. HRMS (ESI) + calculated for C 18 H 24 N6O2S, [M + H] + : m / z 389.1854, found 389.1847; HPLC (tR = 19.18 min, 95.4%).

[0121] Compound 10 1 1H-NMR (600 MHz, DMSO-d6), δ (ppm): 8.57 (1H, s), 8.44 (1H, s), 8.05 (1H, s), 8.04 (1H, s), 7.91 (1H, s), 7.67 (2H, d, J = 8.40 Hz), 7.28 (2H, d, J = 8.40 Hz), 4.81 (2H, s), 4.09 (2H, s), 3.65 (2H, s), 2.88 (1H, m), 2.18 (3H, s), 1.75 (1H, m); 13 13C-NMR (150 MHz, DMSO-d6), δ (ppm): 162.4, 160.1, 157.5, 155.6, 155.0, 147.0, 137.7, 130.8, 128.8, 128.8, 125.0, 120.2, 120.2, 117.3, 59.8, 59.8, 46.2, 46.2, 29.5, 20.5. HRMS (ESI) + calculated for C 20 H 20 N6O2S, [M + H] + : m / z 409.1442, found 409.1433; HPLC (tR = 13.2 min, 100%).

[0122] Compound 11 1 1H-NMR (600 MHz, DMSO-d6), δ (ppm): 8.57 (1H, s), 8.44 (1H, s), 8.31 (1H, s), 8.08 (1H, s), 7.91 (1H, s), 7.62 (1H, m), 7.38 (1H, d, J = 8.40 Hz), 7.19 (1H, m), 6.94 (1H, d, J = 8.40 Hz), 4.81 (in2H, s), 3.99 (2H, s), 3.67 (2H, s), 2.89 (1H, m), 1.76 (1H, m); 13 13C-NMR (150 MHz, DMSO-d6), δ (ppm): 162.4, 160.1, 157.5, 155.3, 155.1, 147.0, 141.9, 132.8, 130.0, 125.0, 121.6, 119.1, 118.0, 117.3, 59.8, 59.8, 46.2, 46.2, 29.5. HRMS (ESI) + calculated for C 19 H 17 ClN6O2S, [M + H] + Note: In the original text, there is a possible error in the "4.81(2H,s)" in the 1H-NMR data of Compound 11 in the translation. It is translated as "4.81 (in2H, s)" here, and it should be corrected to "4.81 (2H, s)" according to the correct NMR data format. You can adjust it according to the actual situation.: m / z 429.0895, found 429.0887; HPLC (tR = 19.5 min, 100%).

[0123] Compound 12 1 1H-NMR (600 MHz, DMSO-d6), δ (ppm): 8.56 (1H, s), 8.44 (1H, s), 8.26 (1H, s), 8.08 (1H, s), 7.90 (1H, s), 7.46 (2H, d, J = 9.00 Hz), 7.20 (2H, d, J = 9.00 Hz), 4.81 (2H, s), 4.02 (2H, s), 3.66 (2H, s), 2.89 (1H, m), 1.76 (1H, m); 13 13C-NMR (150 MHz, DMSO-d6), δ (ppm): 162.2, 159.8, 157.1, 155.1, 154.7, 146.7, 139.0, 127.9, 127.9, 125.4, 124.7, 121.1, 121.1 117.0, 60.1, 60.1, 45.0, 45.0, 29.2. HRMS (ESI) + calculated for C 19 H 17 ClN6O2S, [M + H]​​​​​​​​​​​​​​ClN6O2S, [M+H] + : m / z 429.0895, found 429.0887; HPLC (tR = 13.5 min, 95.1%).

[0125] Compound 14 1 1H-NMR (600 MHz, DMSO-d6), δ (ppm): 8.57 (1H, s), 8.51 (1H, s), 8.45 (1H, s), 8.09 (1H, s), 7.91 (1H, s), 7.67 (2H, d, J = 8.70 Hz), 7.53 (2H, d, J = 8.70 Hz), 4.83 (2H, s), 4.15 (2H, s), 3.69 (2H, s), 2.90 (1H, m), 1.78 (1H, m); 13 13C-NMR (150 MHz, DMSO-d6), δ (ppm): 162.7, 160.3, 157.7, 155.4, 155.3, 147.2, 144.4, 125.9, 125.9, 125.3, 124.1, 122.2, 120.0, 119.5, 119.5, 60.0, 60.0, 45.5, 45.5, 29.7. HRMS (ESI) + calculated for C 20 H 17 F3N6O2S, [M+H] + : m / z 463.1159, found 463.1150; HPLC (tR = 17.6 min, 100%).

[0126] Compound 15 1 1H-NMR (600 MHz, DMSO-d6), δ (ppm): 8.57 (1H, s), 8.43 (two H, m), 8.08 (1H, s), 7.91 (1H, s), 7.81 (1H, m), 7.45 (1H, m), 7.42 (1H, m), 4.48 (2H, s), 4.01 (2H, s,), 3.66 (2H, s), 2.94 (1H, m), 1.78 (1H, m); 13 13C-NMR (150 MHz, DMSO-d6), δ (ppm): ①62.1, 159.8, 157.1, 154.8, 154.7, 146.7, 140.3, 130.③, 129.9, 124.7, 122.9, 120.4, 119.3, 116.9, <59.3, 59.3, 45.2, 45.2, 29.5. HRMS (ESI) + calculated for C Note: In the 13C-NMR data in item , the numbers in ①③< are likely incorrect or unclear in the original text, but they are preserved as per the instruction.19 H 16 Cl2N6O2S, [M+H] + : m / z 463.0506, found 463.0506; HPLC (tR = 19.6 min, 100%).

[0127] Compound 16 1 H-NMR (600 MHz, DMSO-d6), δ (ppm): 8.58 (1H, s), 8.44 (1H, s), 8.09 (1H, s), 7.99 (1H, s), 7.91 (1H, s), 7.33 (1H, m), 7.18 (1H, m), 6.95 (1H, m), 4.81 (2H, s), 3.98 (2H, s), 3.64 (2H, s), 2.91 (1H, m), 1.78 (1H, m); 13 C-NMR (150 MHz, DMSO-d6), δ (ppm): 162.6, 160.2, 157.6, 155.9, 155.2, 147.2, 128.3, 125.2, 124.0, 117.4, 111.1, 104.4, 104.2, 104.0, 60.0, 60.0, 45.6, 45.6, 29.7. HRMS (ESI) + calculated for C 19 H 16 F2N6O2S, [M+H] + : m / z 431.1097, found 431.1086; HPLC (tR = 10.4 min, 100%).

[0128] Compound 17 1 H-NMR (600 MHz, DMSO-d6), δ (ppm): 8.58 (1H, s), 8.46 (2H, m), 8.09 (1H, s), 7.92 (1H, s), 7.60 (2H, m), 7.09 (1H, m), 4.83 (2H, s), 4.14 (2H, s), 3.67 (2H, s), 2.91 (1H, m), 1.78 (1H, m); 13 C-NMR (150 MHz, DMSO-d6), δ (ppm): 162.5, 160.2, 157.2, 155.1, 155.0, 147.1, 143.0, 133.8, 133.8, 125.1, 121.0, 117.6, 117.6, 117.3, 59.7, 59.7, 46.3, 46.3, 29.5. HRMS (ESI) + calculated for C19 H 16 Cl₂N₆O₂S, [M+H] + : m / z 463.0506, found 463.0500; HPLC (tR = 19.3 min, 100%).

[0129] Compound 18 1 ¹H-NMR (600 MHz, DMSO-d₆), δ (ppm): 8.81 (1H, s), 8.56 (1H, s), 8.43 (1H, s), 8.20 (2H, s), 8.07 (1H, s), 7.90 (1H, s), 7.54 (2H, s), 4.83 (2H, s), 4.02 (2H, s), 3.69 (2H, s), 2.90 (1H, m), 1.78 (1H, m); 13 ¹³C-NMR (150 MHz, DMSO-d₆), δ (ppm): 162.4, 160.1, 157.4, 155.1, 155.0, 147.0, 142.4, 130.5, 130.2, 126.2, 125.0, 124.4, 122.6, 119.1, 117.3, 114.4, 59.5, 59.5, 46.1, 46.1, 29.4. HRMS (ESI) + calculated for C 21 H 16 F₆N₆O₂S, [M+H] + : m / z 531.1033, found 531.1010; HPLC (tR = 20.4 min, 100%).

[0130] Compound 19 1 ¹H-NMR (600 MHz, DMSO-d₆), δ (ppm): 9.10 (1H, s), 8.51 (1H, s), 8.41 (1H, s), 8.05 (1H, s), 8.01 (1H, m), 7.86 (1H, s), 7.77 (1H, s), 7.46 (1H, m), 7.39 (1H, m), 4.65 (2H, s), 4.47 (2H, m), 3.45 (2H, m), 1.90 (1H, m), 1.74 (1H, m); 1313C-NMR(150MHz, DMSO-d6), δ(ppm): 162.6, 160.9, 159.4, 154.4, 153.5, 145.6, 141.4, 130.2, 125.5, 125.2, 124.0, 122.1, 119.2, 116.7, 111.5, 59.5, 59.5, 46.4, 46.4, 29.5. HRMS(ESI) + calculated for C 20 H 17 N7O2S, [M+H] + : m / z 420.1237, found 420.1234;HPLC(tR=15.3min, 99.8%).

[0131] Compound 20 1 1H-NMR(600MHz, DMSO-d6), δ(ppm): 8.64(1H, s), 8.45(1H, s), 8.32(1H, s), 8.13(1H, s), 7.92(1H, s), 7.86(1H, m), 7.67(1H, m), 7.52(1H, m), 7.46(1H, m), 7.39(2H, m), 7.32(1H, m), 4.81(2H, s), 4.27(2H, s), 3.70(2H, s), 2.94(1H, m), 1.84(1H, m); 13 13C-NMR(150MHz, DMSO-d6), δ(ppm): 162.5, 160.1, 157.9, 156.7, 155.1, 147.0, 135.4, 133.8, 129.8, 128.0, 125.9, 125.6, 125.6, 125.2, 125.0, 123.5, 123.3, 117.3, 59.9, 59.9, 46.2, 46.2, 29.9. HRMS(ESI) + calculated for C 23 H 20 N6O2S, [M+H] + : m / z 445.1442, found 445.1432;HPLC(tR=12.6min, 100%).

[0132] Compound 21 11H-NMR (600 MHz, DMSO-d6), δ (ppm): 8.52 (1H, s), 8.42 (1H, s), 8.05 (1H, s), 7.88 (1H, s), 5.82 (1H, m), 4.73 (2H, s), 3.82 (1H, s), 3.34 (1H, s), 2.83 (1H, m), 1.76 (1H, m), 1.66 (1H, m), 1.60 (5H, m), 1.49 (2H, m), 1.32 (1H, s), 1.31, (1H, s), 1.27 (1H, s), 1.23 (2H, m); 13 13C-NMR (150 MHz, DMSO-d6), δ (ppm): 162.7, 160.3, 157.6, 157.4, 155.3, 147.1, 125.3, 117.4, 59.8, 59.8, 49.4, 49.4, 46.2, 33.5, 31.6, 30.3, 29.9, 25.7, 25.4. HRMS (ESI) + calculated for C 19 H 24 N6O2S, [M + H] + : m / z 401.1755, found 401.1747; HPLC (tR = 19.5 min, 100%).

[0133] Compound 22 1 1H-NMR (600 MHz, DMSO-d6), δ (ppm): 8.67 (1H, s), 8.50 (1H, s), 8.41 (1H, s), 8.04 (1H, s), 7.87 (1H, s), 7.38 (2H, d, J = 8.34 Hz), 7.05 (2H, d, J = 8.34 Hz), 4.62 (2H, s), 4.46 (2H, d, J = 12.00 Hz), 3.45 (2H, d, J = 12.00 Hz), 2.22 (3H, s), 1.89 (2H, m), 1.72 (2H, m);[[ID=十六]] 13 [[ID=十七]]13C-NMR (150 MHz, DMSO-d6), δ (ppm): 162.6, 160.8, 159.3, 154.4, 154.1, 145.5, 137.7, 130.9, 129.0, 129.0, 125.2, 119.8, 119.8, 116.6, 53.1, 53.1, 51.1, 51.1, 27.0, 27.0, 20.5. HRMS (ESI)[[ID=十八]] + [[ID=十九]]calculated for C[[ID=二十]] 21 [[ID=二十一]]H[[ID=二十二]] 22 [[ID=二十三]]N6O2S, [M + H]+ : m / z 423.1597, found 423.1588; HPLC (tR = 22.1 min, 100%).

[0134] Compound 23 1 1H-NMR (600 MHz, DMSO-d6), δ (ppm): 8.90 (1H, s), 8.51 (1H, s), 8.41 (1H, s), 8.05 (1H, s), 7.80 (1H, s), 7.56 (2H, d, J = 8.11 Hz), 7.30 (2H, d, J = 8.11 Hz), 4.64 (2H, s), 4.48 (2H, d, J = 12.00 Hz), 3.45 (2H, d, J = 12.00 Hz), 1.89 (2H, m), 1.72 (2H, m); 13 13C-NMR (150 MHz, DMSO-d6), δ (ppm): 162.7, 161.0, 159.5, 154.6, 154.4, 145.7, 127.4, 126.5, 125.5, 125.4, 124.4, 116.8, 115.8, 115.7, 53.5, 53.5, 51.1, 51.1, 26.7, 26.7. HRMS (ESI) + calculated for C 20 H 19 ClN6O2S, [M + H] + : m / z 443.1051, found 443.1044; HPLC (tR = 23.6 min, 100%).

[0135] Compound 24 1 1H-NMR (600 MHz, DMSO-d6), δ (ppm): 8.92 (1H, s), 8.49 (1H, s), 8.38 (1H, s), 8.02 (1H, s), 7.84 (1H, s), 7.69 (1H, m), 7.40 (1H, m), 7.25 (1H, m), 6.97 (2H, m), 4.61 (1H, s), 3.44 (2H, d, J = 12.0 Hz), 3.41 (2H, d, J = 12.0 Hz), 1.87 (2H, m), 1.70 (2H, m); 1313C-NMR(150MHz, DMSO-d6), δ(ppm): 162.7, 161.0, 159.5, 154.6, 154.4, 145.7, 127.4, 126.5, 125.5, 125.4, 124.4, 116.8, 115.8, 115.7, 53.5, 53.5, 51.1, 51.1, 26.4, 26.4. HRMS(ESI) + calculated for C 20 H 19 ClN6O2S, [M + H] + : m / z 433.1052, found 433.1046; HPLC(tR = 20.4min, 100%).

[0136] Compound 25 1 1H-NMR(600MHz, DMSO-d6), δ(ppm): 8.61(1H, s), 8.51(1H, s), 8.41(1H, s), 8.04(1H, s), 7.87(1H, s), 7.53(1H, m), 7.19(1H, m), 7.12(2H, m), 4.6(2H, s), 4.47(2H, d, J = 11.7Hz), 3.45(2H, d, J = 11.7Hz), 1.90(2H, m), 1.72(2H, m); 13 13C-NMR(150MHz, DMSO-d6), δ(ppm): 162.7, 161.0, 159.5, 156.3, 154.5, 154.38, 145.71, 127.4, 126.5, 125.3, 124.4, 116.7, 115.8, 115.7, 53.5, 53.5, 51.1, 51.1, 27.1, 27.1. HRMS(ESI) + calculated for C 20 H 19 FN6O2S, [M + H] + : m / z 427.1347, found 427.1333; HPLC(tR = 19.min, 98.0%).

[0137] Compound 26 11H-NMR(600MHz,DMSO-d6),δ(ppm):9.03(1H,s),8.51(1H,s),8.41(1H,s),8.05(1H,s),7.90(1H,m),7.87(1H,s),7.49(2H,s),4.63(2H,s),4.48(2H,d,J=11.28Hz),3.45(2H,d,J=11.28Hz),1.90(2H,m),1.73(2H,m); 13 13C-NMR(150MHz,DMSO-d6),δ(ppm):162.7,161.0,159.5,154.5,153.4,145.7,140.8,131.0,130.6,125.3,123.7,120.6,119.5,116.7,53.3,53.3,51.2,51.2,27.1,27.1.HRMS(ESI) + calculated for C 20 H 18 Cl2N6O2S,[M+H] + :m / z 477.0662,found 477.0663;HPLC(tR=26.4min,100%).

[0138] Compound 27 1 1H-NMR(600MHz,DMSO-d6),δ(ppm):9.14(1H,s),8.51(1H,s),8.41(1H,s),8.05(1H,s),7.87(1H,s),7.74(2H,d,J=8.97Hz),7.60(2H,d,J=8.97Hz),4.67(2H,s),4.49(2H,d,J=12.17Hz),3.45(2H,d,J=12.17Hz),1.90(2H,m),1.73(2H,m); 13 13C-NMR(150MHz,DMSO-d6),δ(ppm):162.5,160.9,159.4,154.4,153.4,145.5,144.2,125.9,125.2,123.9,122.0,121.8,118.9,118.9,116.6,53.2,53.2,51.1,51.1,26.9,26.9.HRMS(ESI) + calculated for C 21 H 19 F3N6O2S,[M+H] +: m / z 477.1316, found 4477.1316; HPLC (tR = 24.8 min, 100%).

[0139] Compound 28 1 1H-NMR (600 MHz, DMSO-d6), δ (ppm): 8.61 (1H, s), 8.50 (1H, s), 8.42 (1H, s), 8.04 (1H, s), 7.86 (1H, s), 7.48 (1H, m), 7.24 (1H, m), 7.01 (1H, m), 4.57 (2H, s), 4.46 (2H, m), 3.6 (2H, s), 1.89 (2H, m), 1.72 (2H, m); 13 13C-NMR (150 MHz, DMSO-d6), δ (ppm): 162.6, 160.8, 159.4, 154.5, 154.4, 145.6, 125.3, 123.7, 116.7, 111.2, 104.4, 104.2, 104.1, 53.4, 53.4, 50.9, 50.9, 27.0, 27.0. HRMS (ESI) + calculated for C 20 H 18 F2N6O2S, [M + H] + : m / z 455.1158, found 455.1158; HPLC (tR = 19.8 min, 96.2%).

[0140] Compound 29 1 1H-NMR (600 MHz, DMSO-d-six), δ (ppm): 9.08 (one H, s), 8.51 (one H, s), 8.41 (one H, s), 8.05 (one H, s), 7.87 (one H, s), 7.64 (two H, m), 7.14 (one H, m), 4.63 (two H, s), 4.46 (two H, d, J = 啥啥啥 Hz), 3.45 (two H, d, J = 啥啥啥 Hz), 1.89 (two H, m), 1.72 (two H, m); 13 13C-NMR (150 MHz, DMSO-d-six), δ (ppm): 162.6, 160.8, 159.4, 154.4, 153.1, 145.6, 143.0, 134.0, 133.0, 125.2, sixteen啥啥啥, 117.2, 117.2, 116.7, 53.2, 53.2, 51.1, 51.1, 27.1, 27.1. HRMS (ESI) + calculated for C 20 H Note: There seem to be some inconsistent or unclear notations in the original text (like "11.52Hz" not fully written out in some places and "sixteen啥啥啥" in the translated NMR part). It might be beneficial to double-check the accuracy of the original text for a more precise translation.18 Cl2N6O2S, [M+H] + : m / z 477.0662, found 477.0663; HPLC (tR = 27.8 min, 100%).

[0141] Compound 30 1 1H-NMR (600 MHz, DMSO-d6), δ (ppm): 9.10 (1H, s), 8.51 (1H, s), 8.41 (1H, s), 8.05 (1H, s), 8.01 (1H, m), 7.86 (1H, s), 7.77 (2H, s), 7.46 (1H, m), 4.65 (2H, s), 4.47 (2H, d, J = 11.83 Hz), 3.45 (2H, d, J = 11.83 Hz), 1.90 (2H, m), 1.74 (2H, m); 13 13C-NMR (150 MHz, DMSO-d6), δ (ppm): 162.6, 160.9, 159.4, 154.4, 153.5, 145.6, 141.4, 130.2, 125.5, 125.2, 124.0, 122.1, 119.2, 116.7, 111.5, 53.2, 53.2, 51.1, 51.1, 27.0, 27.0. HRMS (ESI) + calculated for C 21 H 19 N7O2S, [M+H] + : m / z 434.1394, found 434.1381; HPLC (tR = 24.7 min, 96.6%).

[0142] Compound 31 1 1H-NMR (600 MHz, DMSO-d6), δ (ppm): 8.90 (1H, s), 8.53 (1H, s), 8.42 (1H, s), 8.06 (1H, s), 8.00 (1H, m), 7.92 (1H, m), 7.88 (1H, m), 7.74 (1H, m), 7.53 (1H, m), 7.51 (2H, m), 7.46 (1H, m), 4.67 (2H, s), 4.49 (2H, d, J = 12.17 Hz), 3.45 (2H, d, J = 12.17 Hz), 1.90 (2H, m), 4.49 (2H, m); 13C-NMR (150MHz, DMSO-d6), δ (ppm): 162.6, 160.9, 159.4, 155.2, 154.5, 145.5, 135.0, 133.9, 129.4, 128.1 ,126.0,126.0,125.8,125.7,125.2,123.6,123.1,116.6,53.4,53.4,51.1,51.1,27.1,27.1.HRMS(ESI) + calculated for C 24 H 22 N6O2S,[M+H] + :m / z 459.1598, found459.1587; HPLC (tR=24.7min, 100%).

[0143] Test Example 1 Evaluation of SIRT3 Inhibitory Activity of Compounds 1 to 31

[0144] The purpose of this experiment is to detect the inhibitory activity of the compounds of the present invention on SIRT3 in vitro.

[0145] Enzo Life Sciences SIRT3 enzyme biopsy kit (BML-AK557-0001) was used for the assay. 10 μM fluoroacetylated peptide (p53(Gln-Pro-Lys-Lys)Ac) and 500 μM NAD + The cells were added to the SIRT3 assay buffer and then incubated with the test compound and 1 μg of recombinant SIRT3 at 37°C for 30 minutes. The assay was terminated using 1X Developer II / 2M mNicotinamide. The fluorophore was excited with 360 nm light and the emission light (460 nm) was detected on a fluorescence plate reader. The fluorescence intensity of the assay buffer was subtracted from each experimental sample. IC was calculated using Prism GraphPad 8.0 software. 50 .

[0146] Table 1 Enzyme activity test of compounds 1-31

[0147]

[0148]

[0149] The experimental results showed that at a concentration of 10.0 μM, compounds 1-31 of the present invention all had varying degrees of SIRT3 inhibitory activity. Among compounds 1-9, most showed SIRT3 inhibitory activity, with compound 1, compound 3, and compound 7 having inhibition rates greater than 90%. Although compounds 10-21 did not have inhibition rates greater than 90%, they all exhibited SIRT3 inhibitory activity. Compound 15 showed the best inhibitory activity of 88.7%, and most of compounds 22-31 showed inhibition rates greater than 90%.

[0150] Table 2 Compounds 23, 26, 27, 30IC 50 Determination of

[0151]

[0152] The results showed that compound 27 showed the strongest SIRT3 inhibitory activity, comparable to that of the positive drug 3-TYP (IC 50 =0.038 μM).

[0153] Anti-AML proliferation activity of the compound in Experimental Example 2

[0154] The purpose of this experiment is to detect the anti-AML proliferation activity of the compounds of the present invention. Three suspension cells HL60, MOLM13 and MV4-11 in the logarithmic growth phase were taken, and the cells were seeded in a 96-well plate at a density of 10,000 cells / well, with 50 μL of cell suspension per well. After incubation for 24 hours, 50 μL of compound 27 of different concentrations (100 μM, 50 μM, 25 μM, 12.5 μM, 6.25 μM, 3.125 μM, 1.5625 μM, 0.78125 μM) were added and incubated for 24 hours. After the drug incubation, 10 μL of MTT solution was added to each well, incubated at 37 ° C in the dark for 4 hours, and then 100 μL of triple solution was added to each well. After 12 hours, the OD value was detected at 490 nm, and the IC50 value was calculated based on the results of 3 parallel experiments. The IC 50 The value is used to express the anti-AML proliferation activity of the compound, and its IC 50 The values ​​were calculated using Prism GraphPad software.

[0155] Table 3 Anti-AML Proliferation Activity of Compounds 1-31

[0156]

[0157]

[0158] The results showed that compounds 1-31 showed different degrees of antitumor activity. The IC values ​​of compounds 23, 27 and 30 against MOLM13 were 50The values ​​were all around 1 μM, and 27 showed the best anti-proliferative activity.

[0159] Experimental Example 3 Molecular docking of compound 27 with SIRT3

[0160] In order to clarify the potential binding mode of 27 with SIRT3, molecular docking and molecular dynamics simulation experiments were performed, as well as MD simulation experiments of the complex of compound 27 with SIRT3 and calculation of binding free energy. The results showed that the pyrimidinofuranamide group of compound 27 occupied the SIRT3 coenzyme NAD. + In the nicotinamide binding site, the formamide group forms three conserved hydrogen bonds with residues Asp231 and Ile230, and the pyrimidofuran core forms hydrophobic and π-π stacking interactions with residues Ala146 and Phe157. In addition, the pyrimidine also forms a hydrogen bond with residue Phe157. The 3,8-diazabicyclo[3.2.1]octanelinker group occupies a hydrophobic cavity composed of residues Phe180, Asn229, Gln228, etc., which is the structural basis for the better activity of this type of compound. In addition, the trifluoromethylphenyl part forms a hydrogen bond with residue Gly295, a halogen bond with residue Glu296, and a π-π stacking interaction with residue His248. Compound 27 occupies both the coenzyme and substrate binding sites and is a new type of SIRT3 inhibitor. We further performed MD simulations on the 17f and SIRT3 complex. The results showed that in the 200ns MD simulation, the compound The root mean square deviation (RMSD) of nearby SIRT3 atoms fluctuated between 1 and 2, indicating that compound 27 binds to SIRT3 in a relatively stable conformation. Subsequently, residue energy decomposition revealed that residues phe157, phe180, Gln228, Asn229, He230, Asp231, and Val324 provide key amino acids for the binding of 17f to SIRT3. Furthermore, the binding free energy of this system indicated that compound 27 exhibited good binding to SIRT3, further confirming its strong enzyme inhibitory activity.

[0161] Experimental Example 4: Binding of Compound 27 to SIRT3 in AML cells

[0162] To determine whether compound 27 could directly bind to SIRT3 in AML cells, we performed a CETSA assay using AML cells. HL-60 cells, MOLM-13 cells, and MV4-11 cells were treated with DMSO and 10 μM compound 27 for 6 hours, respectively. The supernatants were collected and analyzed by Western Blot. The experimental results showed that as the temperature increased, the expression of SIRT3 in AML cells treated with compound 27 significantly increased compared to the control group. In other words, compound 27 increased the thermal stability of SIRT3 in AML cells and could directly bind to SIRT3 in AML cells.

[0163] Test Example 5 Compound 27 inhibits the proliferation of AML cells

[0164] To investigate the effect of compound 27 on AML cell proliferation, we used an EdU assay to examine its effect on AML cell DNA replication. The results showed that compound 27 also significantly reduced the green fluorescence intensity of EdU in HL-60, MOLM-13, and MV4-11 cells, demonstrating that compound 27 exhibited significant anti-proliferative activity in all three AML cell lines.

Claims

1. A compound represented by formula I or a pharmaceutically acceptable salt thereof: in, R1 is phenyl, naphthyl, or cyclohexyl, and the R1 may be substituted by one or more R', wherein R' is hydrogen, nitro, hydroxyl, cyano, halogen, C1-C4 alkylamino, C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkyl, or halogenated C1-C4 alkoxy; n= 0-2。 2. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof: in, R1 is phenyl or naphthyl, and the phenyl group may be substituted by one or more R's, and R' is hydrogen, halogen, halogenated C1-C4 alkyl, cyano, or C1-C4 alkyl.

3. The compound of formula I according to claim 1 or 2, or a pharmaceutically acceptable salt thereof: in, R1 is phenyl, naphthyl, or cyclohexyl, and the phenyl group may be substituted by one or more R's, and R' is hydrogen, C1-C4 alkyl, halogen, halogenated C1-C4 alkyl, or cyano.

4. The compound of formula I according to claim 1 or 2, or a pharmaceutically acceptable salt thereof: in, R1 is phenyl or naphthyl, and the phenyl group may be substituted by one or more R's, and R' is hydrogen, C1-C4 alkyl, halogen, halogenated C1-C4 alkyl, or cyano.

5. A compound having the following structure or a pharmaceutically acceptable salt thereof: 。 6. An intermediate for preparing the compound according to claim 5 or a pharmaceutically acceptable salt thereof: R' is 4-CH3, 4-Cl, 3-Cl, 2-Cl, 4-CF3, 3,4-di-Cl, 2,4-di-F, 3,5-di-Cl, 3,5-di-CF3, 3-ethynyl, 3-phenyl, or cyclohexyl; R' is 4-CH3, 4-Cl, 3-Cl, 2-Cl, 4-CF3, 3,4-di-Cl, 2,4-di-F, 3,5-di-Cl, 3,5-di-CF3, 3-ethynyl, 3-phenyl, or cyclohexyl; R' is 4-CH3, 4-Cl, 3-Cl, 2-F, 3,4-di-Cl, 4-CF3,2,4-di-F, 3,5-di-Cl, 3-ethynyl, 3-phenyl.

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

8. Use of the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7 in the preparation of a SIRT3 inhibitor.

9. Use of the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7 in the preparation of an anti-tumor drug.

10. The use according to claim 9, characterized in that The tumor is leukemia.

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