Pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivatives and uses thereof

Abstract

The present application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a pyrimidine-triazole-fluorine-substituted phenylcyclopropylamine derivative and application thereof. The pyrimidine-triazole-fluorine-substituted phenylcyclopropylamine derivative of the present application is a compound shown in formula (I) or a pharmaceutically acceptable salt thereof: Test proves that the above-mentioned compound provided by the present application has nanomolar-level inhibitory effect on LSD1 at the enzyme level, and exhibits significant biological inhibitory activity on LSD1. In particular, by further studying the anti-cancer activity of the above-mentioned pyrimidine-triazole-fluorine-substituted phenylcyclopropylamine derivative on acute myeloid leukemia, it is found that the compound has strong anti-proliferation effect on acute myeloid leukemia cells. Therefore, the present application can provide more skeleton structure selection of lead compounds for the treatment of acute myeloid leukemia, and can provide a new direction for the research and development of inhibitors based on the LSD1 target, and has good application prospect.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to a pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative and its applications. Background Technology

[0002] Leukemia is a disease in which, under certain external pathogenic factors, some hematopoietic cells gradually lose their terminal differentiation ability, thus arresting at a certain differentiation stage and ceasing to differentiate normally. This ultimately leads to the continuous proliferation of incompletely differentiated hematopoietic cells at that stage, causing an influx of cells from the bone marrow into the peripheral blood. Leukemia is a serious malignant tumor of the hematopoietic system that severely endangers human health. Acute myeloid leukemia (AML) is the most common and most dangerous type, with the lowest 5-year survival rate compared to other types of leukemia, at only 28.3%. AML is an aggressive malignant disease of hematopoietic cells with a very complex pathogenesis, typically progressing from the initial stage to the terminal stage within just a few months. To date, the treatment of AML remains a major challenge for the medical community.

[0003] Currently, the main treatments for AML include chemotherapy, targeted therapy, differentiation therapy, immunotherapy, and hematopoietic stem cell transplantation. Furthermore, studies on the genetic and molecular characteristics of AML indicate that the disease is often associated with dysregulation of epigenetic mechanisms. In the context of hematologic malignancies, histone demethylase 1 (LSD1) has been found to be overexpressed in approximately 60% of acute myeloid leukemia (AML) cases. Studies have shown that LSD1 promotes leukemia development and proliferation by imposing myeloid maturation arrest and promoting myeloid progenitor cell proliferation. Given the important role of LSD1 in regulating oncogene expression and in hematopoietic systemogenesis and erythrocyte differentiation, LSD1 may become an important target for the treatment of AML.

[0004] Pyrimidines and their derivatives possess a wide range of biological and pharmacological activities, including antitumor, anti-anxiety, antioxidant, antiviral, antifungal, anticonvulsant, antidepressant, and antibacterial effects. As a heterocyclic aromatic system, pyrimidines have attracted considerable attention due to their broad biological and pharmacological activities. To date, several drugs containing pyrimidine structures have been marketed. Triazoles possess various biological activities, including antibacterial, antiviral, and cell growth-inhibiting effects. They are stable in vivo, resistant to metabolic and chemical degradation, heat-resistant, and exhibit strong resistance to hydrolysis, oxidation, and reduction. In drug design, triazoles can also serve as connectors, assembling two or more active groups into a single molecule. This not only preserves the original group's activity but may also produce synergistic effects, increasing effective activity and reducing toxic side effects.

[0005] Patent application No. 202010401690.7 discloses an aromatic ring / heterocyclic triazole-methylene-TCP derivative, which connects a portion of the aromatic ring or heterocyclic ring to triazole to prepare a novel TCP derivative. This derivative exhibits good inhibitory activity against LSD1 and also shows some inhibitory activity against gastric cancer cell lines (MGC-803, SGC-7901), breast cancer cell line (MCF-7), and prostate cancer cell line (PC-3). However, the prior art has not confirmed whether this compound has inhibitory activity against acute myeloid leukemia cells, and no compound structure suitable for development as a lead drug for acute myeloid leukemia has been reported in the prior art.

[0006] Therefore, how to structurally improve and scientifically design the aforementioned compounds to develop novel compounds with good inhibitory activity against acute myeloid leukemia (AML) cells has become a pressing technical problem to be solved in this invention. Furthermore, the development of novel compounds that inhibit AML cells has significant research value and potential application value for the treatment of AML and the development of lead drugs. Summary of the Invention

[0007] To overcome the shortcomings of existing technologies, the primary objective of this invention is to provide a pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative. This invention, by modifying the structure of the aromatic ring, aromatic heterocyclic ring, and benzene ring, yields a novel class of pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivatives, which exhibit good inhibitory activity against LSD1. In particular, verification revealed that this class of compounds possesses strong inhibitory activity against acute myeloid leukemia MV-4-11 cells, and can be developed as LSD1 inhibitors or lead compounds for anti-acute myeloid leukemia drugs.

[0008] A second object of the present invention is to provide the application of the above-mentioned pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative.

[0009] To achieve the aforementioned first objective, the technical solution adopted by the present invention is as follows:

[0010] A pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative, which is a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0011]

[0012] In equation (I), R1 is selected from One of them;

[0013] R2 is selected from H, One of them;

[0014] R3 is H or F; R4 is selected from H, F, CF3, One of them; R5 is H or F; R6 is H or F; wherein R3, R4, R5, and R6 are not all H at the same time.

[0015] Preferably, the pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative is selected from compounds with the following structures or pharmaceutically acceptable salts thereof:

[0016]

[0017]

[0018]

[0019]

[0020] Based on the consideration of improving the inhibitory activity of the compound against LSD1 and enhancing the antiproliferative effect on acute myeloid leukemia cells, the pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative is selected from compounds with the following structures or pharmaceutically acceptable salts thereof:

[0021]

[0022] Preferably, the pharmaceutically acceptable salt is one of hydrochloride or trifluoroacetate.

[0023] To achieve the second objective mentioned above, the technical solution adopted by the present invention is as follows:

[0024] The use of a pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative as described above in the preparation of an LSD1-targeting inhibitor; or in the preparation of a medicament for treating acute myeloid leukemia.

[0025] Preferably, the drug is a drug that inhibits the proliferation of acute myeloid leukemia cells.

[0026] More preferably, the acute myeloid leukemia cells are MV4-11 cells.

[0027] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0028] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative provided by this invention contains characteristic groups such as pyrimidine, triazole, cyclopropylamine, and fluorosubstituted phenyl groups. In the compound structure design, the phenyl group at the 1-position of the triazole is replaced with pyrimidine, and the fluorine substitution position of the phenyl ring in phenylcyclopropylamine is changed or the fluorine atom is replaced with other groups. Through the comprehensive structural design of the above characteristic groups, a novel compound type is obtained. Experiments have confirmed that the pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative provided by this invention exhibits nanomolar-level inhibitory activity against LSD1 at the enzymatic level, demonstrating significant biological inhibitory activity against LSD1. It can be used to prepare inhibitory drugs targeting LSD1, enriching the types of LSD1 inhibitors containing TCP structures and laying the foundation for the development of novel LSD1 targeted inhibitors. In particular, further research on the anticancer activity of the pyrimidine-triazole-fluoro-substituted phenylcyclopropylamine derivative of this invention in acute myeloid leukemia revealed that this type of compound exhibits strong antiproliferative activity against acute myeloid leukemia cells, thus demonstrating good therapeutic efficacy for acute myeloid leukemia and showing promising drug development potential. It can be developed as a lead drug for treating acute myeloid leukemia. In summary, this invention, through compound structure design and experimental verification, can provide more skeletal structure options for the treatment of acute myeloid leukemia and also offer new directions for the development of LSD1-targeted inhibitors, demonstrating promising application prospects. Detailed Implementation

[0029] The present invention is further described below with reference to embodiments. These embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. In the following embodiments, the pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivatives involved all satisfy the following general formula (I):

[0030]

[0031] The overall preparation route for the pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivatives in the following examples is as follows:

[0032]

[0033]

[0034] Example 1

[0035] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-1 of this embodiment satisfies the general formula (I), where R1 is R2 is H, R3 is H, R4 is F, R5 is F, and R6 is H, which is the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(2-(methanesulfonyl)pyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process is as follows:

[0036] (1) Synthesis of Compound 12: 4-Chloro-2-methylthiopyrimidine 11 (2.00 g, 12.5 mmol) was dissolved in 35 mL of DMF, followed by the addition of NaN3 (2.43 g, 37.4 mmol). The system was stirred at room temperature for 72 h, and the reaction was monitored by TLC. After the reaction was complete, 200 mL of water was added to the mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residual DMF in the system was removed by azeotropic distillation with heptane to produce a white solid 12 (1.95 g, 11.7 mmol), with a yield of 93.7%. The analytical data of the product are as follows: 1 H NMR (600MHz, DMSO-d6) δ8.38 (d, J = 6.3 Hz, 1H), 8.00 (d, J = 6.3 Hz, 1H), 2.81 (s, 3H); 13 C NMR (151MHz, DMSO-d6) δ152.4,149.6,146.5,105.8,13.7.

[0037] (2) Synthesis of Compound 13: Intermediate 12 (850 mg, 5.08 mmol) was dissolved in 10 mL of ethyl acetate, and potassium peroxide monosulfonate (9.40 g, 27.8 mmol) was dissolved in 50 mL of water. The two systems were mixed and added to a 100 mL round-bottom flask. The mixture was stirred at room temperature for 3 h, and the reaction was monitored by TLC. After the reaction was complete, the aqueous layer of the system was extracted with ethyl acetate (60 mL × 3), and the organic phases were combined. The organic layer was washed with saturated brine, dried on anhydrous Na2SO4, and the solvent was removed to give a white solid 13 (900 mg, 4.52 mmol), with a yield of 88.9%. The analytical data of the product are as follows: 1 H NMR (600MHz, DMSO) δ8.90 (d, J = 5.5Hz, 1H), 7.40 (d, J = 5.5Hz, 1H), 3.42 (s, 3H).

[0038] (3) Synthesis of Compound 9: 2.0 g (15 mmol) of free 8(1R,2S)-3,4-difluorophenylcyclopropylamine was placed in a 100 mL round-bottom flask. 50 mL of dichloromethane and 4.2 g (40 mmol) of Na₂CO₃ were added. Di-tert-butyl dicarbonate (4.36 g, 20 mmol) was added dropwise at 0 °C. The mixture was stirred at room temperature for 2 h. After the reaction was complete as monitored by TLC, the mixture was extracted with 100 mL of water and 3 x 100 mL of dichloromethane. The organic phases were then combined, washed with 10 mL of saturated brine (3 x 10 mL), dried over anhydrous sodium sulfate, concentrated by vacuum distillation, and separated by column chromatography to obtain a white solid 9 (3.72 g, 16 mmol), with a yield of 95%. Analytical data are as follows: 1 HNMR(600MHz, CDCl3)δ7.03(q,J=8.8Hz,3H),6.95-6.93(m,1H),6.93-6.86(m,1H),4 .85(brs,1H),2.67-2.62(m,1H),2.05-1.98(m,1H),1.45(s,9H),1.15-1.07(m,2H).

[0039] (4) Synthesis of compound 10e: Compound 9 (3.24 g, 10 mmol) was placed in a 100 mL round-bottom flask, and 20 mL of N,N-dimethylformamide was added. After stirring until completely dissolved, sodium hydride (0.42 g, 10.3 mmol) was slowly added at 0 °C, and the mixture was stirred at 0 °C for 30 min. Then, bromopropyne (1.24 g, 10.5 mmol) was added, and the reaction was carried out at room temperature for 2 h. After the reaction was monitored by TLC until complete, ice water was slowly added dropwise at 0 °C to quench the reaction. The mixture was extracted with water (50 mL) and ethyl acetate (50 mL × 3). The organic phases were then combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, concentrated by vacuum distillation, and separated by column chromatography to obtain green oil 11 (2.12 g, 7.8 mmol), with a yield of 79%. The product analysis data are as follows: 1 H NMR (600MHz, CDCl3) δ7.03 (q, J = 8.8Hz, 3H), 6.95-6.93 (m, 1H), 6.93-6.86 (m, 1H), 4 .85(brs,1H),2.67-2.62(m,1H),2.05-1.98(m,1H),1.45(s,9H),1.15-1.07(m,2H).

[0040] (5) Synthesis of compound 14: Compound 13 (360 mg, 1.81 mmol) was added to tetrahydrofuran and 10 mL of water (THF:H2O = 1:1), followed by 10e (1.90 g, 6.02 mmol), then copper(II) sulfate pentahydrate (22.6 mg, 0.09 mmol) and sodium ascorbate (71.7 mg, 0.36 mmol). The reaction was carried out at room temperature for 12 h. After the reaction was completed by TLC monitoring, the mixture was extracted with water (20 mL) and dichloromethane (20 mL × 3). The organic phases were then combined, washed with saturated brine (5 mL × 3), dried with anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain crude product 14 containing BOC.

[0041] (6) Synthesis of compound I-1: Crude product 14 was dissolved in 10 mL of dichloromethane, and then dissolved in 5 mL of dichloromethane. A solution of 2 M / L hydrochloric acid in ethyl acetate was added dropwise at 0 °C. The reaction was carried out at 0 °C for 4 h. After the reaction was completed by TLC monitoring, a white solid 1d (313 mg, 0.71 mmol) was obtained by filtration, with a yield of 39.3%. The analytical data of compound I-1 are as follows: 1 H NMR (600MHz, DMSO-d6) δ10.41(brs,2H),9.33(d,J=5.5Hz,1H),9.28(s,1H),8.49(d,J=5.5Hz,1H),7.31(dt,J=10.5,8.6Hz,1H),7.24(ddd,J=11.8,7. 7,1.9Hz,1H),7.04-6.99(m,1H),4.55(q,J=14.2Hz,2H),3.53(s,3H),3.04 -2.98(m,1H),2.58-2.53(m,1H),1.66-1.60(m,1H),1.35(q,J=6.5Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ165.7,162.9,155.6,149.8(dd,J FC =245.1,12.7Hz),148.6(dd,J FC =244.2,12.5Hz),141.0,137.1(dd,J FC =6.2,3.5Hz),124.4,124.0(dd,J FC =6.3,3.1Hz), 117.7(d,J) FC =17.0Hz), 116.0(d,J) FC =17.6Hz),113.4,41.7,39.6,37.8,20.5,13.2.

[0042] Example 2

[0043] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-2 of this embodiment satisfies the general formula (I), where R1 is R2 is H, R3 is H, R4 is F, R5 is F, and R6 is H, which is the compound 4-(4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)-1H-1,2,3-triazol-1-yl)pyrimidine-2-amine. The preparation process is as follows:

[0044] (1) Synthesis of compound 15a: Compound 14 (1.00 g, 1.97 mmol) was placed in a round-bottom flask and dissolved in 10 mL of tetrahydrofuran. After stirring for 10 min, triethylamine (600 mg, 5.92 mmol) and a methanol solution of ammonia (101 mg, 5.92 mmol) were added. The system was heated to 60 °C and stirred for 5 h, and the reaction was monitored by TLC. After the reaction, the system was concentrated to obtain an oily liquid, 15a.

[0045] (2) Synthesis of compound I-2: The crude product 15a was dissolved in 10 mL of dichloromethane, and then dissolved in 5 mL of dichloromethane. A solution of 2 M / L hydrochloric acid in ethyl acetate was added dropwise at 0 °C. The reaction was carried out at 0 °C for 4 h. After the reaction was completed by TLC monitoring, a white solid I-2 (200 mg, 0.53 mmol) was obtained by filtration, with a yield of 27.3%. The analytical data of the product are as follows: 1 H NMR (600MHz, DMSO-d6) δ10.56(s,2H),8.93(s,1H),8.61(d,J=5.9Hz,1H),7.92(brs,3H),7.41(d,J=5.9Hz,1H),7.36-7.29(m,1H), 7.27-7.21(m,1H),7.04-6.99(m,1H),4.53(s,2H),3.02-2.94(m,1H),2.63-2.55(m,1H),1.68-1.61(m,1H),1.33(q,J=6.6Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ163.3,161.3,155.8,149.8(dd,J FC =245.0,12.7Hz),148.7(dd,J FC =244.2,12.5Hz),140.1,137.1(dd,J FC =6.2,3.5Hz),123.9(dd,J FC =6.2,3.3Hz),123.1,117.7(d,J) FC =17.1Hz), 116.0(d,JFC =17.7Hz),98.3,41.8,37.7,20.5,13.1.

[0046] Example 3

[0047] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-3 of this embodiment satisfies the general formula (I), where R1 is R2 is H, R3 is H, R4 is F, R5 is F, and R6 is H, namely compound 4-(4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)-1H-1,2,3-triazol-1-yl)-az-methylpyrimidine-2-amine. Its preparation process was carried out according to Example 2, except that the methanol solution of ammonia in step (1) was replaced with methylamine. The analytical data of the product are as follows: 1 H NMR (600MHz, DMSO-d6) δ10.54(brs,2H),8.82(s,1H),8.58(d,J=5.6Hz,1H),7.35-7.28(m,2H),7.26-7.21(m,1H),7.02-6.98(m, 1H),4.52(s,2H),3.02-2.97(m,1H),2.95-2.94(m,1H),2.92(s,3H),2.59-2.53(m,1H),1.67-1.61(m,1H),1.33(q,J=6.6Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ161.0,159.3,159.2,156.1,149.7(dd,J FC =245.1,12.7Hz),148.6(dd,J FC =244.3,12.6Hz),142.4,140.3,137.1(dd,J FC =6.2,3.5Hz),123.9(dd,J FC =6.0, 2.8Hz), 117.7 (d, J) FC =17.0Hz), 115.9(d,J) FC =17.7Hz),41.8,37.8,34.2,20.5,13.1.

[0048] Example 4

[0049] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-4 of this embodiment satisfies the general formula (I), where R1 is R2 is H, R3 is H, R4 is F, R5 is F, and R6 is H, namely compound 4-(4-((((1R,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)methyl)-1H-1,2,3-triazol-1-yl)-az-methylpyrimidine-2-amine. The preparation process was carried out according to Example 2, except that the methanol solution of ammonia in step (1) was replaced with dimethylamine. The analytical data of the product are as follows: 1 H NMR(600MHz, DMSO-d6)δ10.45(br,2H),9.52-9.20(m,1H),9.12(s,1H),8.60(d,J=5.3Hz,1H),7.32-7.26(m,1H),7.25-7.19(m,2H),7 .00-6.96(m,1H),4.51(d,J=4.2Hz,2H),3.20(s,6H),3.04-2.95(m,1H),2.54-2.53(m,1H),1.70-1.59(m,1H),1.33(q,J=6.6Hz,1H); 13 CNMR(151MHz,DMSO-d6)δ161.3,161.2,155.2,149.7(dd,J FC =244.9,12.6Hz),148.6(dd,J FC =244.2,12.5Hz),140.1,137.1(dd,J FC =6.2,3.5Hz),123.9(dd,J FC =6.2,3.2Hz),123.6,117.7(d,J) FC =17.0Hz), 115.9(d,J) FC =17.6Hz),97.0,41.8,37.8,37.1(2C),20.5,13.1.

[0050] Example 5

[0051] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-5 of this embodiment satisfies the general formula (I), where R1 is... R2 is H, R3 is H, R4 is F, R5 is F, and R6 is H, namely the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(2-morpholinylpyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process was carried out according to Example 2, except that the methanol solution of ammonia in step (1) was replaced with morpholine. The analytical data of the product are as follows: 1H NMR (600MHz, DMSO-d6) δ10.30(br,2H),9.08(s,1H),8.64(d,J=5.2Hz,1H),7.32-7.24(m,2H),7.22-7.17(m,1H),6.99-6.94(m,1H),4. 54-4.43(m,2H),3.83-3.75(m,4H),3.73-3.66(m,4H),3.03-2.94(m,1H),2.48-2.42(m,1H),1.68-1.52(m,1H),1.34(q,J=6.7Hz,1H); 13 CNMR(151MHz,DMSO-d6)δ162.2,161.3,155.2,149.7(dd,J FC =245.0,12.7Hz),148.6(dd,J FC =243.9,13.0Hz),140.0,137.1(dd,J FC =6.0,3.3Hz),123.8(dd,J FC =6.2,3.0Hz),123.6,117.7(d,J) FC =17.1Hz), 115.9(d,J) FC =17.9Hz),98.2,66.3(2C),44.4(2C),41.8,37.7,20.6,13.2.

[0052] Example 6

[0053] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-6 of this embodiment satisfies the general formula (I), where R1 is... R2 is H, R3 is H, R4 is F, R5 is F, and R6 is H, namely the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(2-thiomorpholinylpyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process was carried out according to Example 2, except that the methanol solution of ammonia in step (1) was replaced with thiomorphine. The analytical data of the product are as follows: 1H NMR(600MHz,DMSO-d6)δ10.28(brs,2H),9.08(s,1H),8.64(d,J=5.2Hz,1H),7.32-7.25(m,2H),7.23-7.17(m,1H),7.02-6.91(m,1H),4 .57-4.44(m,2H),4.16-4.09(m,4H),3.05-2.93(m,1H),2.69-2.64(m,4H),2.49-2.44(m,1H),1.63-1.54(m,1H),1.34(q,J=6.5Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ162.0,160.7,155.3,149.7(dd,J FC =245.1,12.7Hz),148.6(dd,J FC =244.3,12.6Hz),140.1,137.1(dd,J FC =6.1,3.5Hz),123.9(dd,J FC =6.2,3.1Hz),123.7,117.7(d,J) FC =17.0Hz), 115.9(d,J) FC =17.6Hz),97.9,46.6(2C),41.8,37.8,26.6(2C),20.5,13.1.

[0054] Example 7

[0055] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-7 of this embodiment satisfies the general formula (I), where R1 is... R2 is H, R3 is H, R4 is F, R5 is F, and R6 is H, namely the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(2-piperidinylpyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process was carried out according to Example 2, except that the methanol solution of ammonia in step (1) was replaced with piperidine. The analytical data of the product are as follows: 1H NMR (600MHz, DMSO-d6) δ10.49(br,2H),9.12(brs,1H),8.59(d,J=5.3Hz,1H),8.23(brs,1H),7.31-7.25(m,1H),7.24-7.19(m,2H),7.00-6.96( m,1H),4.56-4.44(m,2H),3.88-3.75(m,4H),3.04-2.93(m,1H),2.52-2 .50(m,1H),1.69-1.62(m,3H),1.60-1.54(m,4H),1.34(q,J=6.5Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ161.2,160.3,155.4,149.7(dd,J FC =245.2,12.6Hz),148.6(dd,J FC =244.2,12.4Hz),140.1,137.1(dd,J FC =6.1,3.4Hz),123.8(dd,J FC =6.2,3.0Hz),123.6,117.6(d,J) FC =17.0Hz), 115.9(d,J) FC =17.5Hz),97.2,44.9(2C),41.8,37.7,25.7(2C),24.5,20.5,13.1.

[0056] Example 8

[0057] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-8 of this embodiment satisfies the general formula (I), where R1 is... R2 is H, R3 is H, R4 is F, R5 is F, and R6 is H, namely the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(2-tetrahydropyrrolidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process was carried out according to Example 2, except that the methanol solution of ammonia in step (1) was replaced with pyrrolidine. The analytical data of the product are as follows: 1HNMR(600MHz,DMSO-d6)δ10.55(brs,2H),9.81(brs,1H),9.11(s,1H),8.60(d,J=5.6Hz,1H),7.33-7.26(m,2H),7.25-7.20(m,1H),7.01-6.96(m, 1H),4.52(d,J=3.1Hz,2H),3.62-3.50(m,4H),3.04-2.96(m,1H),2.57-2 .54(m,1H),2.05-1.93(m,4H),1.69-1.62(m,1H),1.34(q,J=6.6Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ159.5,158.0,155.6,149.7(dd,J FC =245.1,12.7Hz),148.6(dd,J FC =244.2,12.5Hz),140.2,137.1(dd,J FC =6.2,3.5Hz),123.9(dd,J FC =6.1,3.1Hz),123.7,117.7(d,J) FC =17.0Hz), 115.9(d,J) FC =17.6Hz),97.3,47.4(2C),41.8,37.7,25.5,25.1,20.5,13.1.

[0058] Example 9

[0059] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-9 of this embodiment satisfies the general formula (I), where R1 is R2 is H, R3 is H, R4 is F, R5 is F, and R6 is H, which is the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(2-methylpyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process is as follows:

[0060] (1) Synthesis of compound 17a: 4-chloro-2-methylpyrimidine 16a (800 mg, 6.22 mmol) was dissolved in 15 mL of DMF, followed by the addition of NaN3 (808.6 mg, 12.44 mmol). The system was stirred at room temperature for 72 h, and the reaction was monitored by TLC. After the reaction was complete, 200 mL of water was added to the mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residual DMF in the system was removed by azeotropic distillation with heptane, yielding a white solid 17a (750 g, 5.55 mmol), with a yield of 89.3%. The analytical data are as follows: 1 H NMR (600MHz, CDCl3) δ8.28 (d, J = 6.4Hz, 1H), 7.85 (d, J = 6.4Hz, 1H), 3.20 (s, 3H).

[0061] (2) Synthesis of compound 18a: Compound 17a (300 mg, 2.22 mmol) was taken, and 10 mL of tetrahydrofuran and water (THF:H2O = 1:1) was added. Then 10e (682 g, 2.22 mmol) was added, followed by copper(II) sulfate pentahydrate (28 mg, 0.05 mmol) and sodium ascorbate (88 mg, 0.44 mmol). The reaction was carried out at room temperature for 12 h. After the reaction was monitored by TLC, the mixture was extracted with water (20 mL) and dichloromethane (20 mL × 3). The organic phases were then combined, washed with saturated brine (5 mL × 3), dried with anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain crude product 18a containing BOC.

[0062] (3) Synthesis of compound I-9: The crude product 18a was dissolved in 10 mL of dichloromethane, and then dissolved in 5 mL of dichloromethane. A solution of 2 M / L hydrochloric acid in ethyl acetate was added dropwise at 0 °C. The reaction was carried out at 0 °C for 4 h. After the reaction was completed by TLC monitoring, a white solid I-9 (348 mg, 0.92 mmol) was obtained by filtration, with a yield of 41.5%. The analytical data of the product are as follows: 1H NMR(600MHz,DMSO-d6)δ10.31(brs,2H),9.04(s,1H),8.98(d,J=5.5Hz,1H),8.01(d, J=5.5Hz,1H),7.28(dt,J=10.7,8.6Hz,1H),7.20(ddd,J=11.9,7.7,2.0Hz,1H),6.97- 6.96(m,1H),4.55(d,J=14.1Hz,1H),4.50(d,J=14.1Hz,1H),3.00-2.98(m,1H),2.70 (s,3H),2.47(ddd,J=10.0,6.4,3.6Hz,1H),1.62-1.57(m,1H),1.33(q,J=6.5Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ168.8,161.3,154.6,149.7(dd,J FC =245.3,12.7Hz),148.6(dd,J FC =244.2,12.4Hz),140.4,137.1(dd,J FC =6.1,3.6Hz),123.8(dd,J FC =6.2,3.2Hz),123.7,117.7(d,J) FC =17.0Hz), 115.9(d,J) FC =17.6Hz),107.5,41.7,37.7,26.0,20.6,13.2.

[0063] Example 10

[0064] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-10 of this embodiment satisfies the general formula (I), where R1 is... R2 is H, R3 is H, R4 is F, R5 is F, and R6 is H, namely the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(2-(trifluoromethyl)pyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process was carried out according to Example 9, except that 4-chloro-2-methylpyrimidin in step (1) was replaced with 4-chloro-2-trifluoromethylpyrimidin. The analytical data of the product are as follows: 1H NMR(600MHz,DMSO-d6)δ10.35(brs,1H),9.33(d,J=5.6Hz,1H),9.10(s,1H),8.51 (d,J=5.5Hz,1H),7.25(dt,J=10.6,8.6Hz,1H),7.18(ddd,J=11.9,7.7,2.1Hz,1H) ,6.96-6.95(m,1H),4.57(d,J=14.1Hz,1H),4.53(d,J=14.1Hz,1H),3.00-2.97(m, 1H),2.45(ddd,J=10.1,6.4,3.6Hz,1H),1.63-1.58(m,1H),1.34(q,J=6.5Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ162.7,155.6(q,J=36.9Hz),155.6,149.7(dd,J FC =245.5,12.9Hz),148.6(dd,J FC =244.3,12.2Hz),140.9,137.1(dd,J FC =6.1,3.6Hz),124.3,123.8(dd,J FC =6.1,3.1Hz),119.5(q,J) FC =275.4Hz), 117.6(d,J) FC =17.1Hz), 115.8(d,J) FC =17.6Hz),113.5,41.6,37.7,20.6,13.2.

[0065] Example 11

[0066] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-11 of this embodiment satisfies the general formula (I), where R1 is... R2 is H, R3 is H, R4 is F, R5 is F, and R6 is H, namely the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(2-cyclopropylpyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process was carried out according to Example 9, except that 4-chloro-2-methylpyrimidin in step (1) was replaced with 4-chloro-2-cyclopropylpyrimidin. The analytical data of the product are as follows: 1H NMR (600MHz, DMSO-d6) δ10.38(s,1H),10.25(s,1H),9.06(s,1H),8.90(d,J=5.4Hz,1H),7.92(d,J=5.4 Hz,1H),7.27(dt,J=10.7,8.6Hz,1H),7.19(ddd,J=11.9,7.7,2.1Hz,1H),6.97-6.96(m,1H),4.54(d,J= 14.1Hz,1H),4.51(d,J=14.1Hz,1H),3.02-2.97(m,1H),2.47(ddd,J=10.1,6.4,3.6Hz,1H),2.31-2.24( m,1H),1.60(ddd,J=10.6,6.3,4.7Hz,1H),1.34(q,J=6.5Hz,1H),1.18-1.15(m,2H),1.10-1.07(m,2H); 13 C NMR(151MHz,DMSO-d6)δ172.8,161.1,154.6,149.8(dd,J FC =245.3,12.8Hz),148.6(dd,J FC =244.5,12.5Hz),140.3,137.05(dd,J=6.2,3.4Hz),123.8(dd,J FC =6.2,3.1Hz),123.7,117.7(d,J) FC =17.1Hz), 115.8(d,J) FC =17.7Hz),107.0,41.8,37.7,20.6,18.4,13.2,11.6,11.5.

[0067] Example 12

[0068] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-12 of this embodiment satisfies the general formula (I), where R1 is R2 is H, R3 is H, R4 is F, R5 is F, and R6 is H, namely the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(2-phenylpyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process was carried out according to Example 9, except that 4-chloro-2-methylpyrimidin in step (1) was replaced with 4-chloro-2-phenylpyrimidin. The analytical data of the product are as follows: 1H NMR(600MHz,DMSO-d6)δ10.34(brs,2H),9.36(s,1H),9.18(d,J=5.4Hz,1H) ,8.52-8.42(m,2H),8.11(d,J=5.4Hz,1H),7.68-7.57(m,3H),7.31-7.19(m, 2H),6.98-7.00(m,1H),4.58(d,J=14.1Hz,1H),4.54(d,J=14.1Hz,1H),3.0 5-3.02(m,1H),2.50-2.48(m,1H),1.65-1.59(m,1H),1.35(q,J=6.6Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ164.3,161.8,155.1,149.7(dd,J FC =245.4,12.8Hz),148.6(dd,J FC =244.6,12.7Hz),140.5,137.1(dd,J FC =6.0,3.5Hz),136.2,132.3,129.4(2C),128.5(2C),124.0,123.8(dd,J FC =6.0, 3.2Hz), 117.7 (d, J) FC =17.0Hz), 115.9(d,J) FC =17.7Hz),108.4,41.8,37.8,20.6,13.3.

[0069] Example 13

[0070] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-13 of this embodiment satisfies the general formula (I), where R1 is R2 is H, R3 is H, R4 is F, R5 is F, and R6 is H, which is the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(2-(ethylsulfonyl)pyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process is as follows:

[0071] (1) Synthesis of compound 20a: Compound 19 (3g, 23.4mmol) was added to a 50mL round-bottom flask, followed by the addition of 25mL DMF and 3.6g iodoethane (23.1mmol). The mixture was stirred at 60℃ for 6h, and the reaction was monitored by TLC. After the reaction was complete, 30mL of water was added to the system, and the mixture was extracted with ethyl acetate (60mL × 3). The organic phases were combined. The organic phases were washed with saturated NaCl solution and dried over anhydrous sodium sulfate. The dried organic phases were concentrated and subjected to column chromatography to obtain a white solid 21a (1.30g, 5.33mmol), with a yield of 35.6%. The analytical data of the product are as follows: 1 H NMR (600MHz, DMSO) δ12.69 (s, 1H), 7.85 (s, 1H), 6.09 (s, 1H), 3.10 (q, J = 7.3Hz, 2H), 1.28 (t, J = 7.3Hz, 3H).

[0072] (2) Synthesis of compound 21a: Compound 20a (1.30 g, 5.33 mmol) was added to a 50 mL round-bottom flask, followed by 25 mL of POCl3. The mixture was stirred at 110 °C for 2 h, and the reaction was monitored by TLC. After the reaction was complete, 30 mL of ice water was added to the system, and the mixture was extracted with ethyl acetate (60 mL × 3). The organic phases were combined. The organic phases were washed with saturated NaCl solution and then dried over anhydrous sodium sulfate. The dried organic phases were concentrated and subjected to column chromatography to obtain a yellow liquid 21a (0.85 g, 4.88 mmol), with a yield of 91.5%. The analytical data of the product are as follows: 1 H NMR (600MHz, CDCl3) δ8.37 (d, J = 5.2Hz, 1H), 6.99 (d, J = 5.2Hz, 1H), 3.16 (q, J = 7.4Hz, 2H), 1.40 (t, J = 7.4Hz, 3H).

[0073] (3) Synthesis of compound 22a: 21a (0.85 g, 4.88 mmol) was dissolved in 5 mL of DMF, followed by the addition of NaN3 (2.43 g, 37.4 mmol). The system was stirred at room temperature for 72 h, and the reaction was monitored by TLC. After the reaction was complete, 10 mL of water was added to the mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. A white solid 22a was obtained and directly added to the next step.

[0074] (4) Synthesis of compound 23a: 22a (710 mg, 3.92 mmol) was dissolved in 10 mL of ethyl acetate, and potassium peroxide monosulfonate (7.23 g, 11.8 mmol) was dissolved in 30 mL of water. The two systems were mixed and added to a 100 mL round-bottom flask. The mixture was stirred at room temperature for 6 h, and the reaction was monitored by TLC. After the reaction was complete, the aqueous layer of the system was extracted with ethyl acetate (60 mL × 3), and the organic phases were combined. The organic layer was washed with saturated brine, dried on anhydrous Na2SO4, and the solvent was removed to obtain a white solid 23a (560 mg, 2.63 mmol), with a yield of 67.1%. The analytical data of the product are as follows: 1 H NMR (600MHz, CDCl3) δ8.72(d,J=5.5Hz,1H),7.01(d,J=5.5Hz,1H),3.57(q,J=7.4Hz,2H),1.46(t,J=7.4Hz,3H); 13 C NMR (151MHz, CDCl3) δ165.27,164.30,159.23,113.22,45.76,6.84.

[0075] (5) Synthesis of compound 24a: Compound 23a (350 mg, 1.93 mmol) was taken, and 10 mL of tetrahydrofuran and water (THF:H2O = 1:1) was added. Then 10e (593 mg, 1.93 mmol) was added, followed by copper(II) sulfate pentahydrate (24 mg, 0.1 mmol) and sodium ascorbate (76 mg, 0.39 mmol). The reaction was carried out at room temperature for 12 h. After the reaction was monitored by TLC, the mixture was extracted with water (20 mL) and dichloromethane (20 mL × 3). The organic phases were then combined, washed with saturated brine (5 mL × 3), dried with anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain crude product 24a containing BOC.

[0076] (6) Synthesis of compound I-13: The crude product 24a was dissolved in 10 mL of dichloromethane, and then dissolved in 5 mL of dichloromethane. A solution of 2 M / L hydrochloric acid in ethyl acetate was added dropwise at 0 °C. The reaction was carried out at 0 °C for 4 h. After the reaction was completed by TLC monitoring, a white solid I-13 (466.5 mg, 1.02 mmol) was obtained by filtration, with a yield of 53%. The analytical data of the product are as follows: 1H NMR (600MHz, DMSO-d6) δ10.32(brs,2H),9.33(d,J=5.5Hz,1H),9.23(s,1H),8.49(d,J=5.5Hz, 1H),7.30(dt,J=10.6,8.6Hz,1H),7.24(ddd,J=11.9,7.7,2.0Hz,1H),7.01(dd,J=5.4,3.0Hz,1 H),4.57(d,J=14.2Hz,1H),4.54(d,J=14.2Hz,1H),3.71(q,J=7.4Hz,2H),3.02-2.99(m,1H),2 .54(ddd,J=10.2,6.5,3.6Hz,1H),1.64-1.58(m,1H),1.37-1.33(m,1H),1.31(t,J=7.4Hz,3H); 13 C NMR(151MHz,DMSO-d6)δ165.1,163.0,155.7,149.8(dd,J FC =245.4,12.8Hz),148.6(dd,J FC =244.5,12.5Hz),141.0,137.1(dd,J FC =6.1,3.5Hz),124.3,124.0(dd,J FC =6.1,3.2Hz), 117.7(d,J) FC =17.0Hz), 115.9(d,J) FC =17.6Hz),113.6,45.8,41.7,37.8,20.6,13.2,7.2.

[0077] Example 14

[0078] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-14 of this embodiment satisfies the general formula (I), where R1 is R2 is H, R3 is H, R4 is F, R5 is F, and R6 is H, namely the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(2-(propylsulfonyl)pyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process was carried out according to Example 13, except that iodoethane in step (1) was replaced with iodopropane. The analytical data of the product are as follows: 1H NMR (600MHz, DMSO-d6) δ10.29(brs,2H),9.32(d,J=5.5Hz,1H),9.22(s,1H),8.48(d,J= 5.5Hz,1H),7.30(q,J=9.0Hz,1H),7.23(ddd,J=12.0,7.7,2.3Hz,1H),7.00(dt,J=7.5, 2.7Hz,1H),4.59-4.52(m,2H),3.71-3.64(m,2H),3.03-2.98(m,1H),2.56-2.51(m,1H) ,1.82-1.74(m,2H),1.59(q,J=5.1Hz,1H),1.34(q,J=6.9Hz,1H),1.03(t,J=7.4Hz,3H); 13 C NMR (151MHz, DMSO-d6)δ

[0079] 164.9, 162.5, 155.2, 149.3 (dd, J FC =245.2,12.8Hz),148.1(dd,J FC =244.5,12.6Hz),140.5,136.6(dd,J FC =6.1,3.1Hz),123.8,123.5(dd,J FC =6.5,3.1Hz), 117.2(d,J) FC =17.0Hz), 115.4(d,J) FC =17.7Hz),113.1,52.1,41.3,37.4,20.1,15.6,12.8,12.7.

[0080] Example 15

[0081] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-15 of this embodiment satisfies the general formula (I), where R1 is R2 is H, R3 is H, R4 is F, R5 is F, and R6 is H, namely the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(2-(butylsulfonyl)pyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process was carried out according to Example 13, except that iodoethane in step (1) was replaced with iodobutane. The analytical data of the product are as follows: 1H NMR(600MHz,DMSO-d6)δ10.42(brs,2H),9.32(s,1H),9.24(s,1H),8.48(s,1H),7. 33-7.25(m,1H),7.22(s,1H),7.00(d,J=9.2Hz,1H),4.65-4.44(m,2H),3.68(t,J= 7.9Hz,2H),2.99(s,1H),2.55(d,J=8.6Hz,1H),1.78-1.67(m,2H),1.62(dt,J=10. 9,5.3Hz,1H),1.44(q,J=7.8Hz,2H),1.33(q,J=7.0Hz,1H),0.89(t,J=7.5Hz,3H); 13 C NMR(151MHz,DMSO-d6)δ164.8,162.5,155.2,149.3(dd,J FC =245.1,12.8Hz),148.1(dd,J FC =244.9,12.3Hz),140.5,136.6(dd,J FC =6.0,3.1Hz),123.8,123.5(dd,J FC =6.2,4.1Hz),117.2(d,J) FC =17.0Hz), 115.5(d,J) FC =17.6Hz),113.1,50.2,41.2,37.3,23.6,21.0,20.1,13.4,12.7.

[0082] Example 16

[0083] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-16 of this embodiment satisfies the general formula (I), where R1 is R2 is H, R3 is H, R4 is F, R5 is F, and R6 is H, namely the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(2-(isopropylsulfonyl)pyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process was carried out according to Example 13, except that iodoethane in step (1) was replaced with 2-iodopropane. The analytical data of the product are as follows: 1HNMR(600MHz,DMSO-d6)δ10.29(brs,2H),9.34(d,J=5.5Hz,1H),9.19(s,1H),8.50(d,J=5 .5Hz,1H),7.30(dt,J=10.6,8.6Hz,1H),7.23(ddd,J=11.9,7.7,2.1Hz,1H),7.03-6.99(m, 1H),4.60-4.51(m,2H),4.07-4.00(m,1H),3.00(dt,J=8.0,4.1Hz,1H),2.53(td,J=6.5,3. 3Hz,1H),1.61(ddd,J=10.5,6.2,4.7Hz,1H),1.37-1.34(m,1H),1.33(s,3H),1.32(s,3H); 13 C NMR(151MHz,DMSO-d6)δ164.1,162.4,155.3,149.3(dd,J FC =245.0,12.7Hz),148.1(dd,J FC =244.3,12.4Hz),140.5,136.6(dd,J FC =6.1,3.5Hz),123.8,123.5(dd,J FC =6.3,3.2Hz), 117.2(d,J) FC =17.0Hz), 115.4(d,J) FC =17.6Hz),113.1,50.9,41.2,37.3,20.1,14.6,14.6,12.7.

[0084] Example 17

[0085] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-17 of this embodiment satisfies the general formula (I), where R1 is R2 is H, R3 is H, R4 is F, R5 is F, and R6 is H, namely the compound (1R,2S)-N-((1-(2-(cyclopentylsulfonyl)pyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-2-(3,4-difluorophenyl)cyclopropyl-1-amine. The preparation process was carried out according to Example 13, except that iodoethane in step (1) was replaced with iodocyclopentane. The analytical data of the product are as follows: 1H NMR(600MHz,DMSO-d6)δ10.31(brs,2H),9.33(d,J=5.5Hz,1H),9.22(s,1H),8.49( d,J=5.5Hz,1H),7.30(q,J=8.7Hz,1H),7.26-7.20(m,1H),7.00(d,J=7.7Hz,1H),4 .65-4.50(m,2H),4.38-4.23(m,1H),3.00(dt,J=7.8,4.0Hz,1H),2.56-2.52(m,1H ),2.09-2.02(m,2H),2.02-1.95(m,2H),1.74-1.57(m,5H),1.35(q,J=6.7Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ165.0,162.5,155.1,149.3(dd,J FC =245.3,12.8Hz),148.1(dd,J FC =244.3,12.5Hz),140.5,136.6(dd,J FC =6.0,3.5Hz),123.8,123.4(dd,J FC =6.3,3.1Hz), 117.2(d,J) FC =16.9Hz), 115.4(d,J) FC =

[0086] 17.6Hz),113.0,58.9,41.3,37.3,26.5,26.5,25.7(2C),20.1,12.7.

[0087] Example 18

[0088] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-18 of this embodiment satisfies the general formula (I), where R1 is... R2 is H, R3 is H, R4 is F, R5 is F, and R6 is H, namely the compound (1R,2S)-N-((1-(2-(cyclohexylsulfonyl)pyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-2-(3,4-difluorophenyl)cyclopropyl-1-amine. The preparation process was carried out according to Example 13, except that iodoethane in step (1) was replaced with iodocyclohexane. The analytical data of the product are as follows: 1H NMR(600MHz,DMSO-d6)δ10.32(brs,2H),9.33(d,J=5.5Hz,1H),9.21(s,1H),8.49(d,J=5.5Hz,1H), 7.31(q,J=8.6Hz,1H),7.27-7.20(m,1H),7.01(d,J=7.9Hz,1H),4.61-4.52(m,2H),3.83(ddd,J=11 .9,8.7,3.3Hz,1H),3.00(dt,J=7.7,4.0Hz,1H),2.54(ddd,J=9.9,6.4,3.6Hz,1H),2.07-1.97(m,2 H),1.86-1.77(m,2H),1.69-1.58(m,2H),1.53-1.43(m,2H),1.43-1.32(m,3H),1.25-1.15(m,1H); 13 C NMR(151MHz,DMSO-d6)δ164.6,162.9,155.8,149.8(dd,J FC =245.3,12.6Hz),148.6(dd,J FC =244.3,12.4Hz),141.0,137.1(dd,J FC =6.1,3.5Hz),124.3,123.9(dd,J FC =6.1,3.0Hz), 117.7(d,J) FC =17.0Hz), 115.9(d,J) FC =17.6Hz),113.6,58.7,41.8,37.9,25.3,24.8,24.8,24.7(2C),20.6,13.2.

[0089] Example 19

[0090] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-19 of this embodiment satisfies the general formula (I), where R1 is... R2 is H, R3 is H, R4 is F, R5 is F, and R6 is H, namely the compound (1R,2S)-N-((1-(2-(cyclohexylsulfonyl)pyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-2-(3,4-difluorophenyl)cyclopropyl-1-amine. The preparation process was carried out according to Example 13, except that iodoethane in step (1) was replaced with benzyl bromide. The analytical data of the product are as follows: 1HNMR (600MHz, DMSO-d6) δ10.29(brs,2H),9.33(d,J=5.3Hz,1H),9.29(s,1H),8.49(d,J=5.3Hz,1H),7.45-7.33(m,5H),7.34-7.27(m,1H ),7.27-7.21(m,1H),7.02(s,1H),5.09(s,2H),4.64-4.46(m,2H),3.01(brs,1H),2.55(brs,1H),1.67-1.55(m,1H),1.39-1.31(m,1H); 13 C NMR(151MHz,DMSO-d6)δ164.8,162.4,155.1,149.0(dd,J FC =245.3,13.2Hz),148.1(dd,J FC =244.3,12.4Hz),140.6,136.6,131.5(2C),128.7,128.5(2C),127.0,123.9,123.5(dd,J FC =5.9, 2.7Hz), 117.2 (d,

[0091] J FC =17.0Hz), 115.5(d,J) FC =17.6Hz),113.1,56.5,41.3,37.4,20.1,12.7.

[0092] Example 20

[0093] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-20 of this embodiment satisfies the general formula (I), where R1 is R2 is R3 is H, R4 is F, R5 is F, and R6 is H, which is the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(6-methyl-2-(methylsulfonyl)pyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process is as follows:

[0094] (1) Synthesis of compound 28a: 27a (4-chloro-6-methyl-2-methylthiopyrimidine, 800 mg, 4.60 mmol) was dissolved in 5 mL of DMF, followed by the addition of NaN3 (897 mg, 13.8 mmol). The system was stirred at room temperature for 72 h, and the reaction was monitored by TLC. After the reaction was complete, 10 mL of water was added to the mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The resulting yellow liquid was directly used in the next step. The analytical data of the product are as follows: 1 H NMR (600MHz, CDCl3) δ6.30(s,1H),2.56(s,3H),2.40(s,3H).

[0095] (2) Synthesis of compound 29a: 28a (800 mg, 3.92 mmol) was dissolved in 10 mL of ethyl acetate, and potassium peroxide monosulfonate (800 mg, 12.3 mmol) was dissolved in 30 mL of water. The two systems were mixed and added to a 100 mL round-bottom flask. The mixture was stirred at room temperature for 6 h, and the reaction was monitored by TLC. After the reaction was complete, the aqueous layer of the system was extracted with ethyl acetate (60 mL × 3), and the organic phases were combined. The organic layer was washed with saturated brine, dried on anhydrous Na₂SO₄, and the solvent was removed to obtain a white solid 29a (700 mg, 3.55 mmol), with a yield of 90.5%. The analytical data of the product are as follows: 1 H NMR (600MHz, CDCl3) δ6.80(s,1H),3.36(s,3H),2.61(s,3H); 13 C NMR (151MHz, CDCl3) δ171.1,165.4,163.9,112.0,39.0,24.1.

[0096] (3) Synthesis of compound 30a: Compound 29a (400 mg, 1.88 mmol) was taken, and 10 mL of tetrahydrofuran and water (THF:H2O = 1:1) was added. Then 10e (577.2 mg, 1.88 mmol) was added, followed by copper(II) sulfate pentahydrate (23.5 mg, 0.9 mmol) and sodium ascorbate (74.4 mg, 0.38 mmol). The reaction was carried out at room temperature for 12 h. After the reaction was monitored by TLC, the mixture was extracted with water (20 mL) and dichloromethane (20 mL × 3). The organic phases were then combined, washed with saturated brine (5 mL × 3), dried with anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain crude product 30a containing BOC.

[0097] (4) Synthesis of compound I-20: The crude product 30a was dissolved in 10 mL of dichloromethane, and then dissolved in 5 mL of dichloromethane. A solution of 2 M / L hydrochloric acid in ethyl acetate was added dropwise at 0 °C. The reaction was carried out at 0 °C for 4 h. After the reaction was completed by TLC monitoring, a white solid I-20 (454.5 mg, 0.99 mmol) was obtained by filtration, with a yield of 53%. The analytical data of the product are as follows: 1 H NMR(600MHz,DMSO-d6)δ10.34(s,2H),9.23(brs,1H),8.43(s,1H),7.31(dt,J=10.6, 8.6Hz,1H),7.24(ddd,J=11.9,7.7,2.0Hz,1H),7.01(dd,J=5.4,3.0Hz,1H),4.56(d,J =14.2Hz,1H),4.53(d,J=14.2Hz,1H),3.50(d,J=7.8Hz,3H),3.02-3.00(m,1H),2.77 (s,3H),2.54(ddd,J=10.1,6.4,3.6Hz,1H),1.64-1.58(m,1H),1.35(q,J=6.6Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ173.7,164.8,154.7,149.2(dd,J FC =245.3,12.7Hz),148.1(dd,J FC =244.3,12.5Hz),140.29,136.5(dd,J FC =6.2,3.5Hz),123.9,123.4(dd,J FC =6.2,3.1Hz),117.2(d,J) FC =17.0Hz), 115.4(d,J) FC =17.6Hz),111.7,41.2,39.0,37.3,24.0,20.0,12.6.

[0098] Example 21

[0099] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-21 of this embodiment satisfies the general formula (I), where R1 is R2 is R3 is H, R4 is F, R5 is F, and R6 is H, namely the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(6-ethyl-2-(methylsulfonyl)pyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process was carried out according to Example 20, except that 4-chloro-6-methyl-2-methylthiopyrimidine in step (1) was replaced with 4-chloro-6-ethyl-2-methylthiopyrimidine. The analytical data of the product are as follows: 1 H NMR (600MHz, DMSO-d6) δ10.30(brs,2H),9.22(s,1H),8.39(s,1H),7.29(q,J=8.7Hz,1H),7.26-7.19(m,1H),7.00( s,1H),4.63-4.48(m,2H),3.50(s,3H),3.11-2.94(m,3H),2.58-2.50(m,1H),1.66-1.54(m,1H),1.42-1.26(m,4H); 13 C NMR(151MHz,DMSO-d6)δ178.5,165.6,155.5,149.7(dd,J FC =245.1,12.1Hz),148.6(dd,J FC =244.7,13.8Hz),140.9,137.1(dd,J FC =5.4,2.8Hz),124.5,123.9,117.7(d,J FC =16.8Hz), 116.0(d,J FC =17.7Hz),111.3,41.8,39.5,37.8,30.8,20.6,13.2,12.7.

[0100] Example 22

[0101] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-22 of this embodiment satisfies the general formula (I), where R1 is R2 is R3 is H, R4 is F, R5 is F, and R6 is H, namely the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(6-propyl-2-(methylsulfonyl)pyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process was carried out according to Example 20, except that 4-chloro-6-methyl-2-methylthiopyrimidine in step (1) was replaced with 4-chloro-6-propyl-2-methylthiopyrimidine. The analytical data of the product are as follows: 1H NMR (600MHz, DMSO-d6) δ10.29(s,2H),9.22(s,1H),8.39(s,1H),7.30(dt,J= 10.6,8.6Hz,1H),7.23(ddd,J=11.9,7.7,2.0Hz,1H),7.03-6.99(m,1H),4.54 (q,J=14.2Hz,2H),3.50(s,3H),3.03-2.98(m,3H),2.54-2.51(m,1H),1.87- 1.77(m,2H),1.63-1.57(m,1H),1.34(q,J=6.5Hz,1H),0.98(t,J=7.4Hz,3H); 13 C NMR(151MHz,DMSO)δ177.4,165.6,155.5,149.7(dd,J FC =245.1,12.4Hz),148.6(dd,J FC =244.3,12.4Hz),140.9,137.1(dd,J FC =6.1,3.4Hz),124.4,123.9(dd,J FC =6.1,3.1Hz), 117.7(d,J) FC =16.9Hz), 116.0(d,J FC =17.8Hz),111.8,41.8,39.5,39.3,37.8,21.8,20.6,13.9,13.2.

[0102] Example 23

[0103] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-23 of this embodiment satisfies the general formula (I), where R1 is... R2 is R3 is H, R4 is F, R5 is F, and R6 is H, namely the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(6-methoxy-2-(methylsulfonyl)pyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process was carried out according to Example 20, except that 4-chloro-6-methyl-2-methylthiopyrimidine in step (1) was replaced with 4-chloro-6-methoxy-2-methylthiopyrimidine. The analytical data of the product are as follows: 1H NMR (600MHz, DMSO-d6) δ10.26(brs,2H),9.17(s,1H),7.78(s,1H),7.34-7.22(m,1H),7.27-7.20(m,1H),7.02-7.00(m,1H),4.55(d,J=14. 2Hz,1H),4.51(d,J=14.2Hz,1H),4.15(s,3H),3.50(s,3H),3.02-2.99(m,1H),2.54-2.53(m,1H),1.63-1.57(m,1H),1.35(q,J=6.6Hz,1H). 13 C NMR(151MHz,DMSO-d6)δ173.0,165.6,156.0,149.8(dd,J FC =245.0,12.5Hz),148.6(dd,J FC =243.8,12.1Hz),140.7,137.1(dd,J FC =6.2,3.6Hz),124.6,124.0(dd,J FC =6.0,3.1Hz), 117.7(d,J) FC =17.0Hz), 116.0(d,J) FC =17.6Hz),98.6,56.6,41.8,39.4,37.9,20.6,13.2.

[0104] Example 24

[0105] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-24 of this embodiment satisfies the general formula (I), where R1 is... R2 is R3 is H, R4 is F, R5 is F, and R6 is H, namely the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(6-ethoxy-2-(methylsulfonyl)pyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process was carried out according to Example 20, except that 4-chloro-6-methyl-2-methylthiopyrimidine in step (1) was replaced with 4-chloro-6-ethoxy-2-methylthiopyrimidine. The analytical data of the product are as follows: 1H NMR (600MHz, DMSO-d6) δ10.21(brs,2H),9.14(s,1H),7.72(s,1H),7.31(q,J=8.7Hz,1H),7.27-7.20(m,1H),7.01(s,1H),4.63-4.57(m,2H),4.5 6-4.49(m,2H),3.49(s,3H),3.00(dd,J=7.5,3.8Hz,1H),2.52(s,1H),1. 58(dt,J=10.4,5.8Hz,1H),1.42(t,J=7.0Hz,3H),1.34(q,J=6.7Hz,1H); 13 C NMR(101MHz,DMSO-d6)δ172.5,165.6,156.0,149.8(dd,J FC =244.8,12.7Hz),148.6(dd,J FC =244.3,12.3Hz),140.7,137.1(dd,J=6.2,3.6Hz),124.6,123.9(dd,J FC =6.3,3.1Hz), 117.7(d,J) FC =17.0Hz), 115.9(d,J) FC =17.6Hz),98.6,65.6,41.8,39.4,37.9,20.6,14.5,13.2.

[0106] Example 25

[0107] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-25 of this embodiment satisfies the general formula (I), where R1 is... R2 is R3 is H, R4 is F, R5 is F, and R6 is H, namely the compound (1R,2S)-N-((1-(6-benzyloxy-2-(methylsulfonyl)pyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)-2-(3,4-difluorophenyl)cyclopropyl-1-amine. The preparation process was carried out according to Example 20, except that 4-chloro-6-methyl-2-methylthiopyrimidine in step (1) was replaced with 4-chloro-6-benzyloxy-2-methylthiopyrimidine. The analytical data of the product are as follows: 1H NMR(600MHz,DMSO-d6)δ10.17(brs,1H),9.14(s,1H),7.82(s,1H),7.56(d,J=7 .2Hz,1H),7.46-7.38(m,2H),7.34-7.26(m,1H),7.26-7.20(m,1H),7.02-6.98( m,1H),5.64(s,1H),4.55(d,J=14.2Hz,1H),4.51(d,J=14.2Hz,1H),3.50(s,1H ),3.04-2.97(m,1H),2.49-2.47(m,1kH),1.60-1.54(m,1H),1.40-1.30(m,1H); 13 C NMR(151MHz,DMSO-d6)δ171.8,165.0,155.7,149.3(dd,J FC =245.1,12.5Hz),147.9(dd,J FC =244.2,12.4Hz),140.2,136.6,135.0,128.6(2C),128.6,128.6(2C),124.1,123.4(dd,J FC =6.1,2.7Hz),117.2(d,J) FC =16.9Hz), 115.4(d,J) FC =17.7Hz),98.4,70.2,41.3,38.9,37.4,20.1,12.7.

[0108] Example 26

[0109] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-26 of this embodiment satisfies the general formula (I), where R1 is R2 is R3 is H, R4 is F, R5 is F, and R6 is H, which is the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(2-(methanesulfonyl)-6-(thiophen-2-yl)pyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process is as follows:

[0110] (1) Synthesis of compound 27a: Compound 26a (4 g, 20.6 mmol) was added to a 100 mL round-bottom flask, followed by the addition of thiophene-2-boronic acid (2.9 g, 22.7 mmol), sodium carbonate (4.4 g, 41.2 mmol), tetrakis(triphenylphosphine)palladium (7.14 mg, 0.03 mmol), 40 mL of DME, and 20 mL of H2O. The mixture was stirred under reflux for 2 h under nitrogen protection, and the reaction was monitored by TLC. After the reaction was complete, 30 mL of water was added to the system, and the mixture was extracted with ethyl acetate (60 mL × 3). The organic phases were combined. The organic phases were washed with saturated NaCl solution and dried over anhydrous sodium sulfate. The dried organic phases were concentrated and subjected to column chromatography to give a white solid 27a (2 g, 8.26 mmol), with a yield of 40.1%. 1 H NMR (600MHz, CDCl3) δ7.78-7.75(m,1H),7.56(dd,J=5.0,0.8Hz,1H),7.22(s,1H),7.16(dd,J=4.9,3.9Hz,1H),2.62(s,3H).

[0111] (2) Synthesis of compound 28h: 27a (2 g, 8.26 mmol) was dissolved in 5 mL of DMF, followed by the addition of NaN3 (805 mg, 12.4 mmol). The system was stirred at room temperature for 72 h, and the reaction was monitored by TLC. After the reaction was complete, 10 mL of water was added to the mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. A white solid 28h (1.87 g, 7.53 mmol) was obtained, with a yield of 91.2%.

[0112] (3) Synthesis of compound 29h: 28h (1.87 g, 7.53 mmol) was dissolved in 10 mL of ethyl acetate, and potassium peroxide monosulfonate (13.89 g, 22.59 mmol) was dissolved in 30 mL of water. The two systems were mixed and added to a 100 mL round-bottom flask. The mixture was stirred at room temperature for 6 h, and the reaction was monitored by TLC. After the reaction was complete, the aqueous layer of the system was extracted with ethyl acetate (60 mL × 3), and the organic phases were combined. The organic layer was washed with saturated brine, dried on anhydrous Na2SO4, and the solvent was removed to obtain a white solid 29h (1.3 g, 4.63 mmol), with a yield of 61.5%. The analytical data of the product are as follows: 1 H NMR (600MHz, DMSO-d6) δ8.26(dd,J=3.8,1.0Hz,1H),7.98(dd,J=4.9,0.9Hz,1H),7.84(s,1H),7.31(dd,J=4.9,3.9Hz,1H),3.44(s,3H); 13C NMR (151MHz, DMSO-d6) δ165.7,164.3,161.6,134.0,133.9,131.6,129.9,106.8,39.4.

[0113] (4) Synthesis of compound 30h: Compound 29h (500mg, 1.78mmol) was taken, and 10mL of tetrahydrofuran and water (THF:H2O=1:1) were added. Then 10e (660.4mg, 1.78mmol) was added, followed by copper(II) sulfate pentahydrate (22.5mg, 0.09mmol) and sodium ascorbate (70.5mg, 0.36mmol). The reaction was carried out at room temperature for 12 hours. After the reaction was monitored by TLC, the mixture was extracted with water (20mL) and dichloromethane (20mL×3). The organic phases were then combined, washed with saturated brine (5mL×3), dried with anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain crude product 30h containing BOC.

[0114] (5) Synthesis of compound I-26: The crude product was dissolved in 10 mL of dichloromethane for 30 h, and then dissolved in 5 mL of dichloromethane. A solution of 2 M / L hydrochloric acid in ethyl acetate was added dropwise at 0 °C. The reaction was carried out at 0 °C for 4 h. After the reaction was completed by TLC monitoring, a white solid I-26 (494.3 mg, 0.94 mmol) was obtained by filtration, with a yield of 53%. The analytical data of the product are as follows: 1 H NMR(600MHz,DMSO-d6)δ10.30(brs,2H),9.28-9.23(m,1H),8.85-8.78(m,1H),8.59-8.52(m,1H),8.13-8.05(m,1H),7.37-7.26(m, 3H),7.07-6.98(m,1H),4.65-4.51(m,2H),3.54(s,3H),3.06-2.98(m,1H),2.61-2.53(m,1H),1.68-1.58(m,1H),1.30-1.28(m,1H); 13 C NMR(151MHz,DMSO-d6)δ166.0,163.4,156.2,149.8(dd,J FC =245.4,10.9Hz),148.6(dd,J FC =243.2,10.0Hz),140.9,139.9,137.1(dd,J FC =5.9,2.7Hz),135.1,133.0,130.3,124.5,124.0(d,J FC =2.8Hz), 117.7(d,J FC=16.7Hz), 116.0(d,J FC =17.7Hz),106.1,41.8,39.5,37.9,20.6,13.2.

[0115] Example 27

[0116] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-27 of this embodiment satisfies the general formula (I), where R1 is R2 is R3 is H, R4 is F, R5 is F, and R6 is H, namely the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(2-(methanesulfonyl)-6-(furan-2-yl)pyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process was carried out according to Example 26, except that thiophene-2-boric acid in step (1) was replaced with furan-2-boric acid. The analytical data of the product are as follows: 1 H NMR (600MHz, DMSO-d6) δ10.28(brs,2H),9.24(s,1H),8.48(s,1H),8.21(s,1H),7.87(d,J=3.5Hz,1H),7.34-7.29(m,1H),7.25(ddd,J=11.7,7.7 ,1.8Hz,1H),7.03-7.01(m,1H),6.90(dd,J=3.5,1.6Hz,1H),4.58(d,J=1 4.2Hz,1H),4.54(d,J=14.2Hz,1H),3.55(s,3H),3.03-3.00(m,1H),2.56 -2.52(m,1H),1.63-1.58(m,1H),1.36(q,J=6.6Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ166.3,158.8,156.2,149.9,149.8(dd,J FC =245.2,12.5Hz),149.2,148.6(dd,J FC =244.7,12.7Hz),140.9,137.1(dd,J FC =6.2,3.4Hz),124.4,124.0(dd,J FC =6.2,3.0Hz), 117.7(d,J) FC =17.0Hz), 117.6, 116.0 (d, J) FC =17.6Hz),114.3,105.3,41.8,37.9,20.6,13.2.

[0117] Example 28

[0118] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-28 of this embodiment satisfies the general formula (I), where R1 is R2 is R3 is H, R4 is F, R5 is F, and R6 is H, namely the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(6-(1-methyl-1H-pyrazol-5-yl)-2-(methylsulfonyl)pyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process was carried out according to Example 26, except that thiophene-2-boric acid in step (1) was replaced with 1-methyl-1H-pyrazol-5-boric acid. The analytical data of the product are as follows: 1 H NMR (600MHz, DMSO) δ10.19(s,2H),9.24(s,1H),8.75(s,1H),7.69(s,1H),7.60(s,1H),7.32(dd,J=18.7,8.9Hz,1H),7.29-7.23(m,1H),7.03(s ,1H),4.59(d,J=14.5Hz,1H),4.56(d,J=14.5Hz,1H),,4.31(s,3H),3.5 8(s,3H),3.02(s,1H),2.53(s,1H),1.59(s,1H),1.36(q,J=6.6Hz,1H); 13 C NMR(151MHz,DMSO)δ165.1,159.5,155.8,149.2(dd,J FC =245.5,13.1Hz),148.1(dd,J FC =244.6,11.8Hz),140.4,138.5,136.6,136.5(dd,J FC =7.2,5.0Hz),123.9,123.4(dd,J FC =6.3,3.2Hz), 117.2(d,J) FC =16.9Hz), 115.4(d,J) FC =

[0119] 17.4Hz),111.2,108.8,41.3,40.7,39.9,37.4,20.0,12.7.

[0120] Example 29

[0121] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-29 of this embodiment satisfies the general formula (I), where R1 is R2 is R3 is H, R4 is F, R5 is F, and R6 is H, namely the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(2-(methanesulfonyl)-6-phenylpyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process was carried out according to Example 26, except that thiophene-2-boronic acid in step (1) was replaced with phenylboronic acid. The analytical data of the product are as follows: 1 H NMR(600MHz,DMSO-d6)δ10.31(brs,2H),9.28(s,1H),8.89(s,1H),8.46-8.45(m,2H),7.72 -7.70(m,1H),7.67-7.65(m,2H),7.31(dt,J=10.5,8.6Hz,1H),7.26(ddd,J=11.7,7.7,1.9H z,1H),7.04-7.02(m,1H),4.59(d,J=14.2Hz,1H),4.56(d,J=14.2Hz,1H),3.60(s,3H),3.04 -3.01(m,1H),2.55(ddd,J=10.0,6.4,3.6Hz,1H),1.65-1.59(m,1H),1.36(q,J=6.6Hz,1H); 13 C NMR (151MHz, DMSO-d6) δ168.4,166.1,156.7,149.8(dd,J=245.2,12.4Hz),148.6(dd,J=244.5,12.6Hz),140.9,137.1(dd,J=6.2,3.5Hz),134.4 ,133.5,129.9(2C),128.6(2C),124.6,124.0(dd,J=6.3,3.1Hz),117.7( d,J=17.0Hz),116.0(d,J=17.6Hz),108.1,41.8,39.6,37.9,20.6,13.2.

[0122] Example 30

[0123] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-30 of this embodiment satisfies the general formula (I), where R1 is R2 is H, R3 is H, R4 is CF3, R5 is F, and R6 is H, which is the compound (1R,2S)-2-(4-fluoro-3-(trifluoromethyl)-phenyl)-N-((1-(2-(methanesulfonyl)pyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process is as follows:

[0124] (1) Synthesis of compound 2a: In a 1L round-bottom flask under argon protection, 1.5 mL of (S)-2-methyl-CBS-oxazolylborane solution and 11 mL of toluene solution of boron tetrahydrofuran complex were added. After stirring in an ice bath for 1 h, a toluene solution of compound 1a (2-bromo-1-(4-fluoro-3-(trifluoromethyl)phenyl)ethyl-1-one, 4.50 g, 15.8 mmol) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 3 h. Finally, under ice bath conditions, sulfuric acid solution (450 μL H2SO4 + 40 mL H2O) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 30 min. After standing and separating the phases, the organic phase was washed with saturated sodium bicarbonate solution (100 mL), water (100 mL), and saturated sodium chloride solution (100 mL), respectively. After drying with anhydrous sodium sulfate, the solution was concentrated to obtain a transparent oily liquid 2a (4.00 g, 13.1 mmol), with a yield of 88.3%. The analytical data of the product are as follows: 1 H NMR (600MHz, CDCl3) δ7.64 (dd, J=6.6, 1.6Hz, 1H), 7.59-7.50 (m, 1H), 7.19 (t, J=9.3H z,1H),4.95(dd,J=8.4,3.4Hz,1H),3.55(ddd,J=19.1,10.7,6.0Hz,2H),3.41(s,1H); 13 C NMR(151MHz,CDCl3)δ159.6(dd,J FC =

[0125] 256.9 (1.8Hz), 136.9 (d, J) FC =3.7Hz), 131.8(d,J FC =8.6Hz), 125.0(d,J FC =3.9Hz), 122.6(d,J FC =272.4Hz), 118.6(qd,J FC =33.0, 12.7 Hz), 117.3 (d, J) FC =21.0Hz), 72.7, 39.4.

[0126] (2) Synthesis of compound 3a: Intermediate 2a (2.00 g, 7.00 mmol) was added to a 500 mL round-bottom flask. Under light-protected conditions, 5 mL of toluene and 5 mL of an aqueous solution of sodium hydroxide (334 mg, 8.40 mmol) were added. The mixture was stirred for 6 h at 40 °C. After the reaction was completed by TLC monitoring, 60 mL of water was added to the system, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a transparent oily liquid 3a (1.35 g, 6.60 mmol), with a yield of 94.0%. The analytical data of the product are as follows: 1 HNMR(600MHz,MeOD)δ7.58-7.56(m,1H),7.56-7.53(m,1H),7.28-7.24(m,1H),3.9 5(dd,J=3.9,2.6Hz,1H), 3.15(dd,J=5.3,4.1Hz,1H), 2.77(dd,J=5.3,2.5Hz,1H); 13 CNMR (151MHz, MeOD) δ 159.3 (dd, J FC =254.9, 1.8 Hz), 134.8 (d, J) FC =3.5Hz), 131.2(d,J FC =8.8Hz), 123.90(q,J FC =4.2Hz), 122.6(d,J FC =271.6Hz), 117.9(qd,J FC =33.0,13.0Hz), 116.8(d,J) FC =21.3Hz).

[0127] (3) Synthesis of compound 6a: In a 1L round-bottom flask under argon protection, sodium hydride (485 mg, 12.1 mmol) and toluene (10 mL) were added. A toluene solution of triethyl phosphonoacetate (2.80 g, 12.6 mmol) was added dropwise under ice bath conditions. After the addition was complete, the mixture was stirred at room temperature for 2 h, then heated to 50 °C. A toluene solution of compound 3a (2.00 g, 9.70 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at 60 °C for 24 h, and the reaction was monitored by TLC. After the reaction was complete, the system was cooled to room temperature. 100 mL of water was added to the reaction system, and the mixture was extracted with toluene (60 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a brownish-yellow liquid 6a (2.30 g, 8.30 mmol), with a yield of 85.8%. The analytical data of the product are as follows: 1H NMR (600MHz, CDCl3) δ7.33 (dd, J=6.6, 1.9Hz, 1H), 7.29 -7.26(m,1H),7.11(t,J=9.3Hz,1H),4.19(qd,J=7.1,1.2Hz,2H),2.57-2.52(m,1H), 1.89(ddd,J=8.6,5.3,4.3Hz,1H), 1.64(dt,J=9.3,5.1Hz,1H), 1.29(t,J=7.2Hz,4H); 13 C NMR(151MHz,CDCl3)δ172.9,158.5(dd,J FC =255.0, 2.0Hz), 136.5 (d, J) FC =3.7Hz), 131.8(d,J FC =8.3Hz), 125.1(q,J FC =4.2Hz), 122.6(d,J FC =272.3Hz), 118.4(qd,J FC =33.1,12.9Hz), 117.0(d,J) FC =20.8Hz),61.0,25.0,24.1,16.9,14.3.

[0128] (4) Synthesis of compound 7a: Compound 6a (1.20 g, 4.34 mmol) was placed in a 100 mL flask, and 30% sodium hydroxide solution (312 mg, 7.80 mmol) and 10 mL of methanol were added. The mixture was stirred at 60 °C for 8 h, and the system was monitored by TLC. When the reaction was complete, dilute hydrochloric acid solution was added dropwise to adjust the pH to 3-4. Ethyl acetate (60 mL × 3) was added for extraction, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a brownish-yellow oily liquid 7a (1.02 g, 4.10 mmol) with a strong sour smell, which was directly added to the next step.

[0129] (5) Synthesis of compound 9a: Compound 7a (540 mg, 2.18 mmol), ultradry triethylamine (253 mg, 2.50 mmol), anhydrous tert-butanol (1.61 g, 21.8 mmol), and diphenyl azidophosphate (659 mg, 3.30 mmol) were dissolved in anhydrous toluene (85 mL) under argon protection. After reflux of the mixture for 18 h, ditert-butyl carbonate (712 mg, 3.30 mmol) was added to the reaction mixture. After heating for another 2 h, the mixture was cooled to room temperature. The residue was concentrated under vacuum and diluted with ethyl acetate (70 mL). The organic phase was washed with 100 mL of 10% NH4Cl, 100 mL of water, 100 mL of saturated NaHCO3, and 100 mL of saturated brine, respectively. After washing, the mixture was concentrated and purified by column chromatography to obtain a white solid 9a (120 mg, 0.400 mmol), with a yield of 17.3%. The analytical data of the product are as follows: 1 H NMR (600MHz, CDCl3) δ7.42-7.29(m,2H),7.08(t,J=9.4Hz,1H),4.95(s,1H),2.68(s,1H),2.16-1.99(m,1H),1.46(s,9H),1.20-1.04(m,2H); 13 CNMR(151MHz,CDCl3)δ158.2(dd,J FC =254.2,2.0Hz),156.3,137.0(d,J FC =3.7Hz), 132.2, 125.3 (d, J) FC =3.9Hz), 122.6(d,J FC =272.3Hz), 121.7, 118.0(qd, J FC =32.7,12.5Hz), 116.7(d,J) FC =20.8Hz),79.8,32.4,28.4,24.4,15.8.

[0130] (6) Synthesis of compound 10a: After purging a 500 mL round-bottom flask with argon, compound 10a (500 mg, 1.57 mmol) and 40 mL of ultra-dry DMF were added under ice bath conditions. NaH (65 mg, 1.61 mmol) was slowly added, and the mixture was stirred in an ice bath for 30 min. Then, bromopropyne (196 mg, 1.64 mmol) was slowly added dropwise, followed by stirring for 2 h. The reaction was monitored by TLC. After the reaction was complete, saturated ammonium chloride solution was added to quench the reaction, and EA (30 mL × 3) was added for extraction. The organic phases were combined, washed with 60 mL of water and 60 mL of saturated sodium chloride solution, and then concentrated. Column chromatography (PE:EA = 30:1) was used to separate the product into a yellow oily liquid 10a (440 mg, 1.23 mmol), with a yield of 77.3%. The analytical data of the product are as follows: 1 H NMR (600MHz, CDCl3) δ7.43-7.34(m,2H),7.14-7.07(m,1H),4.15(d,J=18.0Hz,1H),3.98(d,J=17.4Hz,1H) ,2.82-2.77(m,1H),2.27-2.22(m,1H),2.21(s,1H),1.45(s,9H),1.41-1.36(m,1H),1.20(q,J=6.5Hz,1H); 13 C NMR(151MHz,CDCl3)δ158.3(dd,J FC =254.4,1.7Hz),155.8,137.0(d,J FC =3.7Hz), 132.1(d,J FC =4.7Hz), 125.3(q,J FC =4.2Hz), 122.7(d,J FC =272.3Hz), 118.0(qd,J FC =33.1,12.9Hz), 116.7 (d,J) FC =20.7Hz),80.9,79.8,71.3,38.3,37.2,28.4,25.6,16.6.

[0131] (7) Synthesis of compound 31a: Compound 13 (500 mg, 1.78 mmol) was taken, and 10 mL of tetrahydrofuran and water (THF:H2O = 1:1) was added. Then 10a (660.4 mg, 1.78 mmol) was added, followed by copper(II) sulfate pentahydrate (22.5 mg, 0.09 mmol) and sodium ascorbate (70.5 mg, 0.36 mmol). The reaction was carried out at room temperature for 12 h. After the reaction was completed by TLC monitoring, the mixture was extracted with water (20 mL) and dichloromethane (20 mL × 3). The organic phases were then combined, washed with saturated brine (5 mL × 3), dried with anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain crude product 31a containing BOC.

[0132] (8) Synthesis of compound I-30: The crude product 31a was dissolved in 10 mL of dichloromethane, and then dissolved in 5 mL of dichloromethane. A solution of 2 M / L hydrochloric acid in ethyl acetate was added dropwise at 0 °C. The reaction was carried out at 0 °C for 4 h. After the reaction was completed by TLC monitoring, a white solid I-30 (332.7 mg, 0.68 mmol) was obtained by filtration, with a yield of 38%. The analytical data of the product are as follows: 1 H NMR (600MHz, DMSO-d6) δ10.22(brs,2H),9.33(d,J=5.2Hz,1H),9.24(s,1H),8.48(d,J=5.4Hz,1H),7.59-7.50(m,2H),7.46- 7.39(m,1H),4.65-4.49(m,2H),3.52(s,3H),3.14-3.02(m,1H),2.68-2.57(m,1H),1.67-1.56(m,1H),1.43(q,J=6.4Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ165.4,162.4,157.5(d,J FC =251.5Hz),155.1,142.5,140.6,135.9,133.2(d,J FC =8.6Hz), 125.4(d,J) FC =4.3Hz), 123.8, 122.5 (dd, J FC =139.1,139.1Hz),117.1(d,J) FC =20.5Hz),112.9,41.3,39.1,37.3,20.0,12.6.

[0133] Example 31

[0134] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-31 of this embodiment satisfies the general formula (I), where R1 is R2 is R3 is H, R4 is R5 is F, R6 is H, that is, the compound (1R,2S)-2-(3-(benzyloxy)-4-difluorophenyl)-N-((1-(6-methoxy-2-(methylsulfonyl)pyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)cyclopropyl-1-amine, the preparation process is the same as in Example 30, the only difference is that 2-bromo-1-(4-fluoro-3-(trifluoromethyl)phenyl)ethyl-1-one in step (1) is replaced with 2-bromo-1-(4-fluoro-3-(phenoxymethyl)phenyl)ethyl-1-one. The analytical data of the product are as follows: 1 H NMR(600MHz,DMSO-d6)δ10.25(s,2H),9.20-9.16(m,1H),7.80-7.74(m,Hz,1 H),7.49-7.37(m,4H),7.38-7.30(m,1H),7.13-7.00(m,2H),6.70(s,1H),5. 20-5.08(m,2H),4.53(s,2H),4.18-4.12(m,3H),3.55-3.45(d,J=5.1Hz,3H) ,3.02-2.96(m,1H),2.54-2.52(m,1H),1.61-1.54(m,1H),1.34-1.26(m,1H); 13 C NMR(151MHz,DMSO-d6)δ173.0,165.6,156.0,151.1(d,J FC =242.8Hz), 146.4(d,J) FC =10.9Hz),140.8,137.0,135.9(d,J FC =2.8Hz),129.0,128.6,128.3,124.6,119.4(d,J FC =7.1Hz), 116.2(d,J FC =18.2Hz),114.4,98.6,70.8,56.6,41.9,39.8,39.4,37.8,21.0,13.1.

[0135] Example 32

[0136] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-32 of this embodiment satisfies the general formula (I), where R1 is R2 is R3 is H, R4 is F, R5 is H, and R6 is F, namely the compound (1R,2S)-2-(3,5-difluorophenyl)-N-((1-(6-methoxy-2-(methylsulfonyl)pyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process is the same as in Example 30, except that 2-bromo-1-(4-fluoro-3-(trifluoromethyl)phenyl)ethyl-1-one in step (1) is replaced with 2-bromo-1-(3,5-difluorophenyl)ethyl-1-one. The analytical data of the product are as follows: 1 H NMR (600MHz, DMSO-d6) δ10.29(s,2H),9.15(s,1H),7.78(s,1H),7.02(t,J=9.3Hz,1H),6.89(d,J=6.9Hz,2H),4.55(d,J=14.1Hz,1H), 4.51(d,J=14.1Hz,1H),4.15(s,3H),3.50(s,3H),3.06(dt,J=7.7,3.9Hz,1H),2.53(s,1H),1.66-1.60(m,1H),1.42(q,J=6.7Hz,1H); 13 CNMR(151MHz,DMSO-d6)δ172.46,165.02,162.27(dd,J FC =245.6,13.7Hz),155.38,143.52(t,J FC =9.8Hz),140.12,124.04,109.61(dd,J FC =20.5, 5.0 Hz), 101.75 (t, J) FC =25.7Hz),98.00,56.01,41.20,38.84,37.57,20.56,12.99.

[0137] Example 33

[0138] The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative I-33 of this embodiment satisfies the general formula (I), where R1 is R2 is R3 is F, R4 is H, R5 is F, and R6 is H, which is the compound (1R,2S)-2-(2,4-difluorophenyl)-N-((1-(6-methoxy-2-(methylsulfonyl)pyrimidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)cyclopropyl-1-amine. The process is as follows:

[0139] (1) Synthesis of Compound 5: Under argon protection, 1.5 mL of (S)-2-methyl-CBS-oxazolium borane solution and 11 mL of toluene solution of boron tetrahydrofuran complex were added to a 1 L round-bottom flask. After stirring in an ice bath for 1 h, a toluene solution of Compound 4 (3.0 g, 15.8 mmol) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 3 h. Finally, under ice bath conditions, sulfuric acid solution (450 μL H2SO4 + 40 mL H2O) was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 30 min. The mixture was allowed to stand and separate into layers. The organic phase was washed with saturated sodium bicarbonate solution (100 mL), water (100 mL), and saturated sodium chloride solution (100 mL), respectively. After drying with anhydrous sodium sulfate, the product was concentrated to obtain a transparent oily liquid 5 (2.73 g, 14.2 mmol), with a yield of 90.1%. The analytical data of the product are as follows: 1 HNMR(600MHz,DMSO-d6)δ7.60-7.55(m,1H),7.21(ddd,J=10.9,9.6,2.5Hz,1H),7.11(td,J=8.5,2.2Hz,1H),6 .01(d,J=5.0Hz,1H),5.02(dd,J=11.3,5.2Hz,1H),3.77(dd,J=11.1,4.9Hz,1H),3.71(dd,J=11.1,6.6Hz,1H).

[0140] (2) Synthesis of compound 6d: In a 1L round-bottom flask, under argon protection, sodium hydride (485 mg, 12.1 mmol) and toluene (10 mL) were added. A toluene solution of triethyl phosphonoacetate (2.80 g, 12.6 mmol) was added dropwise in an ice bath. After the addition was complete, the mixture was stirred at room temperature for 2 h, then heated to 50 °C, and a toluene solution of compound 3a (2.00 g, 9.70 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at 60 °C for 24 h, and the reaction was monitored by TLC. After the reaction was complete, the system was cooled to room temperature. 100 mL of water was added to the reaction system, and the mixture was extracted with dichloromethane (60 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a brownish-yellow liquid 6a (2.30 g, 8.30 mmol), with a yield of 85.8%. The analytical data of the product are as follows: 1 H NMR (600MHz, CDCl3) δ6.98-6.91(m,1H),6.80-6.75(m,2H),4.18(q,J=7.1Hz,2H),2.64 -2.57(m,1H),1.94-1.85(m,1H),1.58(dt,J=9.5,4.9Hz,1H),1.29(t,J=7.1Hz,4H).

[0141] (3) Synthesis of compound 7d: Compound 6a (1.20 g, 4.34 mmol) was placed in a 100 mL flask, and 30% sodium hydroxide solution (312 mg, 7.80 mmol) and 10 mL of methanol were added. The mixture was stirred at 60 °C for 8 h, and the system was monitored by TLC. When the reaction was complete, dilute hydrochloric acid solution was added dropwise to adjust the pH to 3-4. Ethyl acetate (60 mL × 3) was added for extraction, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a brownish-yellow oily liquid 7d (1.02 g, 4.10 mmol) with a strong sour smell, which was directly added to the next step.

[0142] (4) Synthesis of compound 9d: Compound 7d (540 mg, 2.18 mmol), ultradry triethylamine (253 mg, 2.50 mmol), anhydrous tert-butanol (1.61 g, 21.8 mmol), and diphenyl azidophosphate (659 mg, 3.30 mmol) were dissolved in anhydrous toluene (85 mL) under argon protection. After refluxing the mixture for 18 h, ditert-butyl carbonate (712 mg, 3.30 mmol) was added to the reaction mixture. After heating for another 2 h, the mixture was cooled to room temperature. The residue was concentrated under vacuum and diluted with ethyl acetate (70 mL). The organic phase was washed with 100 mL of 10% NH4Cl, 100 mL of water, 100 mL of saturated NaHCO3, and 100 mL of saturated brine, respectively. After washing, the mixture was concentrated and purified by column chromatography (cyclohexane:ethyl acetate = 50:1) to give a white solid 9d (120 mg, 0.400 mmol), in a yield of 17.3%. The analytical data of the product are as follows: 1 H NMR(600MHz,DMSO-d6)δ7.28(s,1H),7.19-7.14(m,1H),7.12-7.05(m,1H),7.01-6.96(m,1H),2. 74-2.72(m,1H),1.99-1.92(m,1H),1.38(s,9H),1.14(dt,J=9.7,5.0Hz,1H),1.12-1.05(m,1H); 13 C NMR (151MHz, DMSO) 13 C NMR(151MHz,DMSO-d6)δ161.1(dd,J FC =246.2,12.2Hz),160.7(dd,J FC =54.4,12.2Hz),156.4,128.3,124.9(dd,J FC =14.6,3.4Hz),111.7(dd,J FC =20.5,2.7Hz),103.9(t,J) FC=26.2Hz),78.4,32.5,28.7,17.3,14.8.

[0143] (5) Synthesis of compound 10d: After purging a 500 mL round-bottom flask with argon, compound 9d (500 mg, 1.57 mmol) and 40 mL of ultra-dry DMF were added under ice bath conditions. NaH (65 mg, 1.61 mmol) was slowly added, and the mixture was stirred in an ice bath for 30 min. Then, bromopropyne (196 mg, 1.64 mmol) was slowly added dropwise, followed by stirring for 2 h. The reaction was monitored by TLC. After the reaction was complete, saturated ammonium chloride solution was added to quench the reaction, and EA (30 mL × 3) was added for extraction. The organic phases were combined, washed with 60 mL of water and 60 mL of saturated sodium chloride solution, and then concentrated. Column chromatography (PE:EA = 30:1) was used to separate the product into a yellow oily liquid 10d (440 mg, 1.23 mmol), with a yield of 77.3%. The analytical data of the product are as follows: 1 H NMR(600MHz,DMSO-d6)δ7.22-7.17(m,1H),7.14(dd,J=14.5,7.5Hz,1H),6.99(t d,J=8.5,2.3Hz,1H),4.08(d,J=17.7Hz,1H),4.03(dd,J=14.2,7.1Hz,1H),3.96( dd,J=17.7,2.3Hz,1H),3.17(t,J=2.3Hz,1H),2.79-2.75(m,1H),2.21(ddd,J=9. 8,6.7,3.3Hz,1H),1.45-1.42(m,1H),1.37(s,9H),1.27(dd,J=13.5,6.6Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ161.2(dd,J FC =246.3,12.2Hz),160.9(dd,J FC =244.3,12.2Hz),155.6,128.3,124.4(dd,J FC =14.4,3.6Hz),111.7(dd,J FC =21.0,3.5Hz),103.9(t,J) FC =26.1Hz),80.8,80.1,74.2,38.0,36.7,28.3,21.2,16.1,14.6.

[0144] (6) Synthesis of compound 34d: Compound 29d (500 mg, 1.78 mmol) was taken, and 10 mL of tetrahydrofuran and water (THF:H2O = 1:1) was added. Then 10d (660.4 mg, 1.78 mmol) was added, followed by copper(II) sulfate pentahydrate (22.5 mg, 0.09 mmol) and sodium ascorbate (70.5 mg, 0.36 mmol). The reaction was carried out at room temperature for 12 hours. After the reaction was monitored by TLC, the mixture was extracted with water (20 mL) and dichloromethane (20 mL × 3). The organic phases were then combined, washed with saturated brine (5 mL × 3), dried with anhydrous sodium sulfate, and concentrated by vacuum distillation to obtain crude product 34d containing BOC.

[0145] (7) Synthesis of compound I-33: The crude product 34d was dissolved in 10 mL of dichloromethane, and then dissolved in 5 mL of dichloromethane. A solution of 2 M / L hydrochloric acid in ethyl acetate was added dropwise at 0 °C. The reaction was carried out at 0 °C for 4 h. After the reaction was completed by TLC monitoring, a white solid I-33 (332.7 mg, 0.68 mmol) was obtained by filtration, with a yield of 38%. The analytical data of the product are as follows: 1 H NMR (600MHz, DMSO-d6) δ10.25(brs,2H),9.18(s,1H),7.78(s,1H),7.23-7.15(m,2H),7.02(td,J=8.5,2.1Hz,1H),4.56(d,J=14.1Hz,1H),4.5 1(d,J=14.1Hz,1H),4.15(s,3H),3.51(s,3H),3.12-3.10(m,1H),2.61( ddd,J=10.1,6.4,3.7Hz,1H),1.63-1.58(m,1H),1.34(q,J=6.6Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ173.0,165.6,161.4(dd,J FC =245.4,12.1Hz),161.3(dd,J FC =246.8,12.4Hz),156.0,140.7,129.2(dd,J FC =9.8,5.0Hz),124.6,122.3(dd,J FC =14.5,3.5Hz),111.9(dd,J FC =21.3,3.5Hz),104.1(t,J FC =26.0Hz),98.6,56.6,41.9,39.4,36.8,14.7,12.0.

[0146] Experimental Example 1: LSD1 Inhibitory Activity Test

[0147] 1. Experimental Methods:

[0148] (1) Prepare 1×Assaybuffer. (2) Compound concentration gradient configuration: The starting concentration of the test compound is 10 μM, diluted 3 times, and divided into 10 concentrations, each for single-well testing. The starting concentration of the positive control compound ORY-1001 is 100 nM, diluted 3 times, and also divided into 10 concentrations, each for replicate testing. Dilute to the corresponding 1000-fold final concentration in the 384-well Source plate, and then transfer 10 nL to the 384-well reaction plate for testing using Echo550. Transfer 10 nL of 100% DMSO to the Min and Max wells. (3) Prepare 2× enzyme solution using 1× reaction solution. (4) Prepare 2× substrate mixture using 1× reaction solution. (5) Add 5 μL of 2× enzyme solution to each well; add 5 μL of 1× reaction solution to the Min well, centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 15 min. (6) Add 5 μL of 2× substrate mixture to each well of the reaction plate to start the reaction, centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 1 h. (7) Add 10 μL of detection solution to each well, centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 60 min. (8) Use EnVision to read the signal Intensity (665 nm) / Intensity (615 nm).

[0149] 2. Detection of the inhibitory effect of MAO A / B activity

[0150] (1) Prepare 1×Assay buffer. (2) Compound preparation: The test concentration of the test compound is 10 μM, and the test is performed in duplicate. The initial test concentration of the positive control compound Clorgyline is 1 μM, diluted 3 times, and divided into 10 concentrations, with each concentration tested in duplicate. The initial test concentration of the positive control compound R(-)-deprenyl is 10 μM, diluted 3 times, and also divided into 10 concentrations, with each concentration tested in duplicate. Dilute to a final concentration of 100 times in a 384-well plate, and then transfer 200 nmol to the 384-well plate for testing using an Echo 550. Transfer 200 nmol of 100% DMSO to both Max and Min wells. (3) Prepare an enzyme solution with a final concentration of 2 times using 1×Assay buffer. (4) Add 10 μL of the enzyme solution with a final concentration of 2 times to the compound wells, positive compound wells, and corresponding positive control wells, and add 10 μL of 1×Assay buffer to the negative control wells. (5) Centrifuge at 1000 rpm for 1 minute, vortex to mix, and incubate at room temperature for 15 minutes. (6) Prepare a solution of 2 times the final concentration of the Substrate using 1×Assay buffer. (7) Add 10 μL of the 2 times final concentration of the Substrate solution to all wells to start the reaction. (8) Centrifuge the 384-well plate at 1000 rpm for 1 minute, vortex to mix, and incubate for one hour. (9) Add 20 μL of the stop detection solution to stop the reaction, centrifuge at 1000 rpm for 1 minute, and vortex to mix. (10) After standing for 30 minutes, read the values ​​using EnVision.

[0151] 3. Data Analysis

[0152] Calculation formula:

[0153] A dose-response curve was fitted. The X-axis represents the logarithmic value of the concentration, and the Y-axis represents the percentage inhibition rate. The dose-response curve was fitted using the log(inhibitor) vs. response-variable slope function of GraphPad Prism 5 to derive the IC50 of the compound's inhibition of LSD1 protein binding. 50 Values. The experimental results are shown in Table 1 below.

[0154] Table 1. Inhibitory effects of different compounds on LSD1 protein.

[0155]

[0156]

[0157]

[0158] As shown in Table 1, the pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivatives provided by this invention have nanomolar inhibitory effects on LSD1 at the enzyme level, exhibiting significant biological inhibitory activity against LSD1. Among them, compounds I-1, I-13 to I-19, I-23, I-25, and I-33 showed the best inhibitory activity against LSD1.

[0159] Experiment Example 2: In vitro proliferation experiment of anti-acute myeloid leukemia MV4-11 cells

[0160] This experiment investigated the in vitro anti-MV4-11 effects of compounds I-1, I-13 to I-19, I-23, I-25, and I-33. Procedure: (1) Dissolve the test compounds in cell culture-grade DMSO to prepare a 10 mM stock solution. (2) Collect MV-4-11 cell suspension from T25 culture flasks, centrifuge, passage, and count. Dilute the cell suspension with fresh IMDM medium. Spread the diluted cell suspension at a density of 500-1000 cells / well in black 96-well plates (or opaque 96-well plates). Dilute the compound with IMDM medium at a ratio of 2. Add 50 μL of drug-containing medium to each well (since there is already 100 μL of cell suspension in the well, the added drug concentration should be 3 times the intended concentration). Incubate at 37°C in a 5% CO2 incubator for 7 days. (3) After incubation, equilibrate at room temperature for 10 min. Add CellTiter-Glo reagent to each well and shake for 2 minutes to induce cell lysis. (4) After complete cell lysis, measure the absorbance of each well at 490 nm using a microplate reader. Export the data as an Excel spreadsheet and calculate the IC50 using SPSS. 50 Values. Statistical analysis was performed in an Excel spreadsheet, using the AVERAGE and STDEV formulas to calculate the relative mean and standard deviation of each group of data. SPSS software was used with the Probit Analysis method to calculate the IC. 50 Data are expressed as X ± SD. All experimental results were obtained from three independent replicate experiments. The results are shown in Table 2 below.

[0161] Table 2. Effects of different compounds on the inhibition of MV4-11 cell proliferation.

[0162]

[0163]

[0164] As shown in Table 2, compounds I-1, I-13–I-19, I-23, I-25, and I-33 exhibited strong inhibitory activity against MV-4-11 cells, with an IC50 concentration of [missing value]. 50The values ​​were all below 1 μM. In particular, compound I-1 showed an inhibitory activity of 181 nM against MV-4-11 cells, which fully demonstrates the strong anti-MV-4-11 cell proliferation activity of this compound.

[0165] In summary, the pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative provided by this invention contains characteristic groups such as pyrimidine, triazole, cyclopropylamine, and fluorosubstituted phenyl groups. Through comprehensive structural design of these characteristic groups, a novel compound type was obtained. Experiments have confirmed that the pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative provided by this invention exhibits nanomolar-level inhibitory activity against LSD1 at the enzymatic level, demonstrating significant bioinhibitory activity against LSD1. In particular, further studies on the anticancer activity of the pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative of this invention in acute myeloid leukemia revealed that this type of compound has a strong antiproliferative effect on acute myeloid leukemia cells. Therefore, through compound structural design and experimental verification, this invention can provide more lead compound skeletal structure options for the treatment of acute myeloid leukemia and can also provide new directions for the development of LSD1-targeted inhibitors, showing promising application prospects.

Claims

1. A pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative, characterized in that, The compound represented by formula (I) or a pharmaceutically acceptable salt thereof: In equation (I), R1 is selected from One of them; R2 is selected from H, One of them; R3 is H or F; R4 is selected from H, F, CF3, One of them; R5 is H or F; R6 is H or F; wherein R3, R4, R5, and R6 are not all H at the same time.

2. The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative according to claim 1, characterized in that, The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivatives are selected from compounds with the following structures or pharmaceutically acceptable salts thereof:

3. The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative according to claim 1, characterized in that, The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivatives are selected from compounds with the following structures or pharmaceutically acceptable salts thereof:

4. The pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative according to any one of claims 1 to 3, characterized in that, The pharmaceutically acceptable salt is one of hydrochloride or trifluoroacetate.

5. The application of a pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative as described in any one of claims 1 to 4, characterized in that, Applications in the preparation of LSD1-targeting inhibitors; or applications in the preparation of drugs for the treatment of acute myeloid leukemia.

6. The application of the pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative as described in claim 5, characterized in that, The drug is a drug that inhibits the proliferation of acute myeloid leukemia cells.

7. The application of the pyrimidine-triazole-fluorosubstituted phenylcyclopropylamine derivative as described in claim 6, characterized in that, The acute myeloid leukemia cells were MV4-11 cells.

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