Phenyl-pyrazole-benzene ring propylamine derivative and application thereof

Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a phenyl-pyrazole-benzene ring propylamine derivative and application thereof. The phenyl-pyrazole-benzene ring propylamine derivative disclosed by the invention is a compound shown as a formula (I) or a pharmaceutically acceptable salt thereof. The compound provided by the invention simultaneously contains characteristic groups such as substituted phenyl, pyrazole, cyclopropylamine and the like. Tests prove that the phenyl-pyrazole-benzene ring propylamine derivative disclosed by the invention has a nanomole-level inhibition effect on LSD1 at an enzyme level, shows remarkable biological inhibition activity on the LSD1, and can be used for preparing drugs for targeted inhibition of the LSD1. The compound is further subjected to anti-cancer activity research on acute myelogenous leukemia, and the compound is found to have a relatively strong anti-proliferation effect on acute myelogenous leukemia cells, so that the compound has a relatively good treatment effect on acute myelogenous leukemia, and can be developed as a lead medicine for resisting acute myelogenous leukemia.

Description

Technical Field

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

[0002] One of the most common types of leukemia is acute myeloid leukemia (AML), accounting for about one-third of all leukemia cases. AML is a highly aggressive malignant disease of hematopoietic cells with a very complex pathogenesis. It usually progresses from the initial stage to the final stage in just a few months, posing a huge threat to human health.

[0003] Currently, the main treatments for AML include chemotherapy, targeted therapy, differentiation therapy, immunotherapy, and hematopoietic stem cell transplantation. Significant progress has been made in molecular targeted therapy; for example, FLT3 inhibitors (midotoxorin and giretinib) and IDH1 / 2 inhibitors (evanixipine and ensidipin) are already in clinical trials.

[0004] Existing research indicates that lysine-specific demethylase 1 (LSD1) is abnormally overexpressed in AML, and inhibitors of LSD1 can exert anti-AML effects through mechanisms such as epigenetic remodeling, differentiation induction, and activation of apoptosis. Therefore, LSD1 is an important target for molecular targeted therapy of AML.

[0005] Therefore, developing small molecule inhibitory compounds that have inhibitory activity against LSD1 and good inhibitory activity against AML is of great research significance and potential application value for the treatment of acute myeloid leukemia and the development of lead drugs. Summary of the Invention

[0006] To address the shortcomings of the existing technology, the present invention aims to provide a phenyl-pyrazole-phenylcyclopropylamine derivative and its applications. The phenyl-pyrazole-phenylcyclopropylamine derivative provided by the present invention, by modifying the structure of the substituents on the benzene ring and pyrazole ring, yields a class of phenyl-pyrazole-phenylcyclopropylamine derivatives that exhibit good inhibitory activity against LSD1. In particular, verification revealed that this class of compounds possesses strong anti-proliferative activity against acute myeloid leukemia cells, thus it can be developed as an LSD1 inhibitor or a lead drug for treating acute myeloid leukemia.

[0007] To achieve the above objectives, the present invention adopts the following technical solution:

[0008] A phenyl-pyrazole-phenylcyclopropylamine derivative, which is a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0009]

[0010] In equation (I), R1 is selected from H. One of them; R2 is H or R3 is H or R4 is selected from H. One of them; R5 is H or F; R6 is selected from H, F, Cl; R7 is selected from H, F, Cl; R8 is H or F; and R5, R6, R7, and R8 are not all H at the same time.

[0011] Based on considerations of enhancing the LSD1 inhibitory activity and acute myeloid leukemia cell inhibitory activity of the compound, as a preferred embodiment, the phenyl-pyrazole-phenylcyclopropylamine derivative is selected from compounds with the following structures or pharmaceutically acceptable salts thereof:

[0012]

[0013]

[0014] As a preferred option, the pharmaceutically acceptable salt is a hydrochloride salt.

[0015] The use of a phenyl-pyrazole-phenylcyclopropylamine derivative as described above in the preparation of a drug that targets and inhibits LSD1.

[0016] The use of a phenyl-pyrazole-phenylcyclopropylamine derivative as described above in the preparation of a medicament for treating acute myeloid leukemia.

[0017] As a preferred embodiment, the drug is a drug that inhibits the proliferation of acute myeloid leukemia cells.

[0018] As a preferred embodiment, the acute myeloid leukemia cells are MV4-11 cells.

[0019] The technical solution of the present invention has the following advantages and beneficial effects:

[0020] The phenyl-pyrazole-phenylcyclopropylamine derivative provided by this invention contains characteristic groups such as substituted phenyl groups, pyrazole groups, and cyclopropylamine groups. In designing the compound structure, different substituents are introduced at the ortho, meta, and para positions of the phenyl group at the 1-position of the pyrazole ring. Simultaneously, the fluorine substitution position of the phenyl ring in phenylcyclopropylamine is changed, or a chlorine atom is replaced with a fluorine atom. Through the comprehensive structural design of these characteristic groups, a novel type of compound is obtained.

[0021] Experiments have confirmed that the phenyl-pyrazole-phenylcyclopropylamine derivative provided by this invention exhibits nanomolar-level inhibitory activity against LSD1 at the enzymatic level, demonstrating significant bioinhibitory activity against LSD1 and can be used to prepare drugs targeting and inhibiting LSD1. In particular, this invention further investigated the anticancer activity of the phenyl-pyrazole-phenylcyclopropylamine derivative against acute myeloid leukemia (AML), finding that this type of compound has a strong antiproliferative effect on AML cells, thus demonstrating a good therapeutic effect on AML. Therefore, this invention not only enriches the types of LSD1 inhibitory drugs containing phenylcyclopropylamine derivative structures, laying the foundation for the development of novel LSD1-targeted inhibitory drugs, but also shows good drug development potential and can be developed as a lead drug for treating AML.

[0022] In summary, through compound structure design and experimental verification, this invention can provide more choices of lead compound scaffold structures for the treatment of acute myeloid leukemia, and can also provide new directions for the development of inhibitory drugs based on the LSD1 target. Detailed Implementation

[0023] The technical solution of the present invention will be clearly and completely described below with reference to specific embodiments. However, those skilled in the art should understand that the embodiments are only used to illustrate the technical solution of the present invention and should not be regarded as limiting the scope of protection of the present invention. In the present invention, the room temperature is 25±5℃.

[0024] In the following embodiments of the present invention, the phenyl-pyrazole-phenylcyclopropylamine derivatives involved satisfy the following general structural formula (I):

[0025]

[0026] More specifically, Examples 1 to 25 of the present invention respectively demonstrate the preparation of phenyl-pyrazole-phenylcyclopropylamine derivatives I-1 to I-25, and the overall preparation routes are shown below:

[0027]

[0028]

[0029] Example 1

[0030] The phenyl-pyrazole-phenylcyclopropylamine derivative I-1 of this embodiment satisfies the general formula (I), where R1 is H, R2 is H, R3 is H, R4 is H, R5 is H, R6 is H, R7 is F, and R8 is F, namely the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-phenyl-1H-pyrazole-4-yl)methyl)cyclopropyl-1-amine, and the preparation process is as follows:

[0031] Compound 1 (R1 = H, 2.15 mmol) and compound 5 (2.15 mmol) were dissolved in 10 mL of methanol and reacted at 25 °C for 3 h with stirring to form an imine intermediate. Sodium triacetoxyborohydride (8.6 mmol) was then added to the imine intermediate, and the reaction was carried out at room temperature for 24 h. After the reaction, 10 mL of water was added, the organic solvent was removed under reduced pressure, and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phases were combined, dried, concentrated, and separated by silica gel column chromatography to obtain compound 6a. Compound 6a was then dissolved in dichloromethane, and a 4 M hydrochloric acid-ethyl acetate solution was added. The resulting reaction system was stirred at 25 °C for 6 h, and finally filtered. The resulting white solid was the product, namely phenyl-pyrazole-phenylcyclopropylamine derivative I-1, with a yield of 45%. The NMR analysis data of the product are as follows: 1 H NMR(600MHz,DMSO-d6)δ10.12(brs,2H),8.59(s,1H),7.91(s,1H),7.72(d,J=7.8Hz,2H),7 .51(t,J=7.9Hz,2H),7.34(t,J=7.4Hz,1H),7.29(dt,J=19.2,8.6Hz,1H),7.23(ddd,J=11. 7,7.7,1.8Hz,1H),7.00(d,J=8.1Hz,1H),4.24(d,J=13.7Hz,1H),4.22(d,J=13.7Hz,1H),2 .91(brs,1H),2.56(ddd,J=9.9,6.3,3.6Hz,1H),1.67-1.57(m,1H),1.33(q,J=6.5Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ149.8(dd,J FC =244.9,12.6Hz),148.6(dd,J FC =244.7,12.8Hz),142.5,139.8,137.3(dd,J FC =6.2,3.6Hz),130.1(2C),129.6,127.1,123.9(dd,J FC =6.0,2.9Hz),118.8(2C),117.7(d,J FC =17.0Hz), 115.8(d,J) FC =17.7Hz),114.3,41.3,37.5,20.4,13.1.

[0032] Example 2

[0033] The phenyl-pyrazole-phenylcyclopropylamine derivative I-2 of this embodiment satisfies the general formula (I), where R1 is H, R2 is H, and R3 is... R4 is H, R5 is H, R6 is H, R7 is F, and R8 is F, which is the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(4-(methanesulfonyl)phenyl)-1H-pyrazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process is as follows:

[0034] (1) Compound 2a (5.9 mmol, R1 = 4-SO2Me) was dissolved in ethanol, and then 1,1,3,3-tetramethoxypropane (7.1 mmol) and 100 μL of concentrated hydrochloric acid were added to the reaction system. The mixture was stirred at 80 °C for 2 h. Subsequently, the ethanol was removed under reduced pressure, and the mixture was extracted with dichloromethane (3 × 25 mL). The organic phases were combined, dried, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain a white solid, which was compound 3a, with a yield of 21%. The analytical data of compound 3a are as follows: 1 H NMR (600MHz, CDCl3) δ8.06-8.01(m,3H),7.94-7.90(m,2H),7.78(s,1H),6.55(s,1H),3.09(s,3H).

[0035] (2) Compound 3a (0.83 mmol, R1 = 4-SO2Me) was dissolved in N,N-dimethylformamide, and then phosphorus oxychloride (2.50 mmol) was added to the reaction system. The mixture was stirred at 70 °C for 12 h, followed by the addition of 15 mL of water. The mixture was then extracted with ethyl acetate (3 × 25 mL), and the organic phases were combined, dried, concentrated under vacuum, and purified by silica gel column chromatography to obtain a white solid, which was compound 4a, with a yield of 56%. The analytical data of compound 4a are as follows: 1 13C NMR (151MHz, DMSO-d6) δ185.5,142.7,142.5,139.8,133.7,129.4(2C),126.5,120.1(2C),44.0.

[0036] (3) Compound 4a (2.15 mmol) and compound 5 (2.15 mmol) were dissolved in 10 mL of methanol and reacted at 25 °C for 3 h to form an imine intermediate. Then, sodium triacetoxyborohydride (8.6 mmol) was added to the imine intermediate and reacted at room temperature for 24 h. After the reaction, 10 mL of water was added, the organic solvent was removed under reduced pressure, and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phases were combined, dried, concentrated, and separated by silica gel column chromatography to obtain compound 6a. Subsequently, compound 6a was dissolved in dichloromethane, and then a 4 M hydrochloric acid-ethyl acetate solution was added. The reaction system was stirred at 25 °C for 5 h, and finally filtered. The resulting white solid was the product, namely phenyl-pyrazole-phenylcyclopropylamine derivative I-2, with a yield of 19%. The NMR analysis data of the product are as follows: 1 H NMR(600MHz,DMSO-d6)δ9.94(s,2H),8.73(s,1H),8.08-8.05(m,2H),8.03-7.99(m,3H),7.32-7.26(m,1H),7.24-7.19(m,1H),7.02-6.97(m,1H) ),4.27(d,J=13.5Hz,1H),4.23(d,J=13.6Hz,1H),3.26(s,3H),2.97-2. 91(m,1H),2.54-2.52(m,1H),1.61-1.54(m,1H),1.34(q,J=6.7Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ149.8(dd,J FC =245.0,12.9Hz),148.6(dd,J FC =244.9,12.4Hz),143.7,143.1,138.8,137.2(dd,J FC =5.7,3.8Hz),130.3,129.4(2C),123.9(dd,J FC =6.1,3.2Hz),119.0(2C),117.7(d,J FC =17.1Hz), 115.8(d,J) FC =17.6Hz),115.4,44.1,41.3,37.6,20.5,13.2.

[0037] Example 3

[0038] The phenyl-pyrazole-phenylcyclopropylamine derivative I-3 of this embodiment satisfies the general formula (I), where R1 is H and R2 is... R3 is H, R4 is H, R5 is H, R6 is H, R7 is F, and R8 is F, which is the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(3-(methanesulfonyl)phenyl)-1H-pyrazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process is as follows:

[0039] (1) The synthesis process of compound 3b is basically the same as step (1) in Example 2, except that compound 2a is changed to compound 2b (R1 = 3-SO2Me) to prepare compound 3b with a yield of 51%. The analytical data of the product are as follows: 1 HNMR (600MHz, CDCl3) δ8.27 (s, 1H), 8.05-8.01 (m, 1H), 8.02 (d, J = 2.3Hz, 1H), 7.85 ( d,J=7.7Hz,1H),7.77(s,1H),7.67(t,J=8.0Hz,1H),6.54-6.52(m,1H),3.12(s,3H).

[0040] (2) The synthesis process of compound 4b is basically the same as step (2) in Example 2, except that compound 3a is replaced with compound 3b to prepare compound 4b, with a yield of 46%. The analytical data of the product are as follows: 1 H NMR(600MHz,DMSO-d6)δ9.95(s,1H),9.44(s,1H),8.46-8.45(m,1H),8.36(s, 1H),8.31-8.28(m,1H),7.97-7.94(m,1H),7.85(t,J=8.0Hz,1H),3.34(s,3H); 13 C NMR (151MHz, DMSO-d6) δ185.5,142.9,142.2,139.7,133.5,131.6,126.3,126.1,124.3,118.1,43.8.

[0041] (3) The synthesis process of phenyl-pyrazole-phenylcyclopropylamine derivative I-3 is basically the same as step (3) in Example 2, except that compound 4a is changed to compound 4b to prepare phenyl-pyrazole-phenylcyclopropylamine derivative I-3 with a yield of 46%. The NMR analysis data of the product are as follows: 1H NMR(600MHz,DMSO-d6)δ10.02(s,2H),8.74(s,1H),8.27(s,1H),8.09(dd,J=8.2,1.0Hz,1 H),7.99(s,1H),7.89(d,J=7.8Hz,1H),7.81(t,J=8.0Hz,1H),7.31-7.25(m,1H),7.24-7.1 7(m,1H),7.01-6.97(d,J=8.2Hzm,1H),4.27(d,J=13.6Hz,1H),4.22(d,J=13.6Hz,1H),3. 31(s,3H),2.95-2.91(m,1H),2.54-2.52(m,1H),1.62–1.56(m,1H),1.35(q,J=6.6Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ149.8(dd,J FC =245.2,12.7Hz),148.6(dd,J FC =244.0,12.8Hz),143.3,142.8,140.1,137.2(dd,J FC =6.1,3.6Hz),131.6,130.2,125.2,123.8(dd,J FC =6.2,3.1Hz),123.3,117.7(d,J) FC =16.9Hz), 117.0, 115.8 (d, J) FC =17.6Hz),115.1,43.8,41.2,37.5,20.5,13.2.

[0042] Example 4

[0043] The phenyl-pyrazole-phenylcyclopropylamine derivative I-4 of this embodiment satisfies the general formula (I), where R1 is R2 is H, R3 is H, R4 is H, R5 is H, R6 is H, R7 is F, and R8 is F, which is the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(2-(methanesulfonyl)phenyl)-1H-pyrazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process is as follows:

[0044] (1) The synthesis process of compound 3c is basically the same as step (1) in Example 2, except that compound 2a is changed to compound 2c (R1 = 2-SO2Me) to prepare compound 3c with a yield of 49%. The analytical data of the product are as follows: 1HNMR(600MHz, CDCl3)δ8.25-8.22(d,J=7.9Hz,1H),7.88-7.86(m,1H),7.78-7.73(m,1H),7. 74(d,J=7.7Hz,1H),7.66(t,J=7.7Hz,1H),7.50(d,J=7.8Hz,1H),6.52(s,1H),3.02(s,3H).

[0045] (2) The synthesis process of compound 4c is basically the same as step (2) in Example 2, except that compound 3a is replaced with compound 3c to prepare compound 4c, with a yield of 31%. The analytical data of the product are as follows: 1 H NMR(600MHz,DMSO-d6)δ9.94(s,1H),8.86(s,1H),8.28(s,1H),8.16(dd,J=7.9,1.4Hz,1H),7.9 4(td,J=7.7,1.5Hz,1H),7.86(td,J=7.8,1.2Hz,1H),7.72(dd,J=7.8,1.0Hz,1H),3.34(s,3H); 13 C NMR (151MHz, DMSO-d6) δ185.5,141.1,138.4,137.9,136.9,135.6,131.2,131.0,129.8,125.4,45.1.

[0046] (3) The synthesis process of phenyl-pyrazole-phenylcyclopropylamine derivative I-4 is basically the same as step (3) in Example 2, except that compound 4a is changed to compound 4c to prepare phenyl-pyrazole-phenylcyclopropylamine derivative I-4 with a yield of 21%. The NMR analysis data of the product are as follows: 1 H NMR(600MHz,DMSO-d6)δ10.02(brs,2H),8.22(s,1H),8.14(d,J=7.9Hz,1H),7.9 3(s,1H),7.90(t,J=7.7Hz,1H),7.81(t,J=7.7Hz,1H),7.49(d,J=7.8Hz,1H),7. 37-7.32(m,1H),7.29-7.24(m,1H),7.06(d,J=8.2Hz,1H),4.26(s,2H),3.33(s, 3H),2.92-2.86(m,1H),2.60-2.54(m,1H),1.64-1.56(m,1H),1.34-1.27(m,1H); 13 C NMR(151MHz,DMSO-d6)δ149.8(dd,J FC=245.0,12.6Hz),148.6(dd,J FC =244.1,12.3Hz),142.4,138.6,137.3(dd,J FC =5.7,3.6Hz),136.7,135.5,134.6,130.9,130.4,129.3,124.0(dd,J FC =6.1,3.0Hz), 117.8(d,J) FC =17.0Hz), 115.9(d,J) FC =17.7Hz),113.5,45.1,41.1,37.2,20.2,13.4.

[0047] Example 5

[0048] The phenyl-pyrazole-phenylcyclopropylamine derivative I-5 of this embodiment satisfies the general formula (I), where R1 is H, R2 is H, R3 is F, R4 is H, R5 is H, R6 is H, R7 is F, and R8 is F, namely the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(4-fluorophenyl)-1H-pyrazole-4-yl)methyl)cyclopropyl-1-amine, and the preparation process is as follows:

[0049] (1) The synthesis process of compound 3d is basically the same as step (1) in Example 2, except that compound 2a is changed to compound 2d (R1 = 4-F) to prepare compound 3d with a yield of 42%. The analytical data of the product are as follows: 1 H NMR (600MHz, DMSO-d6) δ8.49(s,1H),7.89(dd,J=8.9,4.8Hz,2H),7.76(s,1H),7.35(t,J=8.4Hz,2H),6.55(s,1H).

[0050] (2) The synthesis process of compound 4d is basically the same as step (2) in Example 2, except that compound 3a is replaced with compound 3d to prepare compound 4d, with a yield of 58%. The analytical data of the product are as follows: 1 H NMR (600MHz, DMSO-d6) δ9.92 (s, 1H), 9.22 (d, J = 2.1Hz, 1H), 8.28 (d, J = 2.2Hz, 1H), 8.01-7.93 (m, 2H), 7.44-7.38 (m, 2H).

[0051] (3) The synthesis process of phenyl-pyrazole-phenylcyclopropylamine derivative I-5 is basically the same as step (3) in Example 2, except that compound 4a is changed to compound 4d to prepare phenyl-pyrazole-phenylcyclopropylamine derivative I-5 with a yield of 35%. The NMR analysis data of the product are as follows: 1 H NMR(600MHz,DMSO-d6)δ10.04(s,2H),8.56(s,1H),7.91(s,1H),7.79-7.72(m,2 H),7.38-7.35(m,2H),7.32-7.27(m,1H),7.22(ddd,J=11.7,7.7,1.9Hz,1H),7. 00-6.99(m,1H),4.25(d,J=13.6Hz,1H),4.21(d,J=13.6Hz,1H),2.96-2.88(m,1 H),2.54(ddd,J=10.0,6.4,3.6Hz,1H),1.65-1.57(m,1H),1.34(q,J=6.5Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ160.9(d,J FC =243.3Hz), 149.8(dd,J FC =245.2,12.7Hz),148.6(dd,J FC =244.1,12.6Hz),142.6,137.2(dd,J FC =6.2,3.5Hz), 136.4(d,J) FC =2.5Hz), 129.8, 123.9 (dd, J FC =6.2,3.2Hz),120.9(d,J) FC =8.5Hz, 2C), 117.7(d, J) FC =17.0Hz), 116.8(d,J) FC =23.0Hz,2C),115.8(d,J) FC =17.6Hz),114.4,41.3,37.5,20.5,13.1.

[0052] Example 6

[0053] The phenyl-pyrazole-phenylcyclopropylamine derivative I-6 of this embodiment satisfies the general formula (I), where R1 is H, R2 is H, and R3 is... R4 is H, R5 is H, R6 is H, R7 is F, and R8 is F, which is the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(4-(methoxy)phenyl)-1H-pyrazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process is as follows:

[0054] (1) The synthesis process of compound 3e is basically the same as step (1) in Example 2, except that compound 2a is changed to compound 2e (R1 = 4-OMe) to prepare compound 3e with a yield of 27%. The analytical data of the product are as follows: 1 H NMR (400MHz, CDCl3): δ (ppm) = 7.75 (d, J = 4Hz, 1H), 7.65-7.62 (m, 1H), 7.54-7.50 (m, 2H), 6.92-6.88 (m, 2H), 6.38-6.37 (m, 1H), 2.10 (s, 3H).

[0055] (2) The synthesis process of compound 4e is basically the same as step (2) in Example 2, except that compound 3a is replaced with compound 3e to prepare compound 4e, with a yield of 51%. The analytical data of the product are as follows: 1 H NMR (600MHz, DMSO-d6) δ9.90 (s, 1H), 9.12 (s, 1H), 8.23 ​​(s, 1H), 7.82 (d, J = 8.7Hz, 2H), 7.10 (d, J = 8.7Hz, 2H), 3.82 (s, 3H).

[0056] (3) The synthesis process of phenyl-pyrazole-phenylcyclopropylamine derivative I-6 is basically the same as step (3) in Example 2, except that compound 4a is changed to compound 4e to prepare phenyl-pyrazole-phenylcyclopropylamine derivative I-6 with a yield of 28%. The NMR analysis data of the product are as follows: 1 H NMR(600MHz,DMSO-d6)δ10.05(m,2H),8.47-8.45(m,1H),7.85-7.83(m,1H),7. 63-7.61(m,2H),7.31-7.27(m,1H),7.24-7.21(m,1H),7.09-7.04(m,2H),7.03 -6.98(m,1H),4.23(d,J=13.6Hz,1H),4.20(d,J=13.6Hz,1H),3.81-3.78(m,3H ),2.96-2.89(m,1H),2.59-2.54(m,1H),1.66-1.53(m,1H),1.37-1.30(m,1H); 13CNMR(151MHz,DMSO-d6)δ158.4,149.8(dd,J FC =245.3,12.7Hz),148.6(dd,J FC =244.6,12.4Hz),142.0,137.2(dd,J FC =6.1,3.3Hz),133.5,129.4,123.9(dd,J FC =6.0,2.9Hz),120.5(2C),117.7(d,J FC =17.0Hz), 115.9(d,J) FC =17.6Hz),115.1(2C),113.9,55.9,41.4,37.5,20.5,13.1.

[0057] Example 7

[0058] The phenyl-pyrazole-phenylcyclopropylamine derivative I-7 of this embodiment satisfies the general formula (I), where R1 is H, R2 is H, and R3 is... R4 is H, R5 is H, R6 is H, R7 is F, and R8 is F, which is the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process is as follows:

[0059] (1) The synthesis process of compound 3f is basically the same as step (1) in Example 2, except that compound 2a is changed to compound 2f (R1 = 4-OCF3) to prepare compound 3f with a yield of 51%. The analytical data of the product are as follows: 1 H NMR (600MHz, DMSO-d6) δ8.55(d,J=2.4Hz,1H),7.97(d,J=9.0Hz,2H),7.78(s,1H),7.51(d,J=8.7Hz,2H),6.62–6.55(m,1H).

[0060] (2) The synthesis process of compound 4f is basically the same as step (2) in Example 2, except that compound 3a is replaced with compound 3f to prepare compound 4f, with a yield of 67%. The analytical data of the product are as follows: 1 H NMR (600MHz, DMSO-d6) δ9.93 (s, 1H), 9.29 (s, 1H), 8.31 (s, 1H), 8.05 (d, J = 9.0Hz, 2H), 7.58 (d, J = 8.8Hz, 2H).

[0061] (3) The synthesis process of phenyl-pyrazole-phenylcyclopropylamine derivative I-7 is basically the same as step (3) in Example 2, except that compound 4a is changed to compound 4f to prepare phenyl-pyrazole-phenylcyclopropylamine derivative I-7 with a yield of 43%. The NMR analysis data of the product are as follows: 1 H NMR (600MHz, DMSO-d6) δ10.01(s,2H),8.61(s,1H),7.94(s,1H),7.85(d,J=8.8Hz,2H),7.53(d,J=8.5Hz,2H),7.30-7.25(m,1H),7.22-7.18(m,1 H),7.00-6.96(m,1H),4.26(d,J=13.6Hz,1H),4.21(d,J=13.6Hz,1H),2 .92(s,1H),2.54-2.52(s,1H),1.62-1.55(m,1H),1.34(q,J=6.7Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ149.8(dd,J=245.4,12.7Hz),148.6(dd,J FC =244.9,11.6Hz),146.8,143.0,138.7,137.2(dd,J FC =5.2,3.1Hz),130.0,123.8(dd,J FC =6.2,2.9Hz),122.9(2C),120.6(q,J FC =256.4Hz), 120.5(2C),117.7(d,J FC =17.0Hz), 115.8(d,J) FC =17.7Hz),114.8,41.3,37.5,20.5,13.2.

[0062] Example 8

[0063] The phenyl-pyrazole-phenylcyclopropylamine derivative I-8 of this embodiment satisfies the general formula (I), where R1 is H, R2 is H, and R3 is... R4 is H, R5 is H, R6 is H, R7 is F, and R8 is F, which is the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process is as follows:

[0064] (1) The synthesis process of compound 3g is basically the same as step (1) in Example 2, except that compound 2a is changed to compound 2g (R1 = 4-CF3) to prepare compound 3g with a yield of 23%. The analytical data of the product are as follows: 1 H NMR (600MHz, DMSO-d6) δ8.66 (d, J = 2.4Hz, 1H), 8.09 (d, J = 8.5Hz, 2H), 7.87 (d, J = 8.6Hz, 2H), 7.83 (s, 1H), 6.62 (s, 1H).

[0065] (2) The synthesis process of compound 4g is basically the same as step (2) in Example 2, except that compound 3a is replaced with compound 3g to prepare compound 4g, with a yield of 43%. The analytical data of the product are as follows: 1 H NMR (600MHz, DMSO-d6) δ9.95 (s, 1H), 9.40 (s, 1H), 8.35 (s, 1H), 8.17 (d, J = 8.4Hz, 2H), 7.95 (d, J = 8.5Hz, 2H).

[0066] (3) The synthesis process of phenyl-pyrazole-phenylcyclopropylamine derivative I-8 is basically the same as step (3) in Example 2, except that compound 4a is changed to compound 4g to prepare phenyl-pyrazole-phenylcyclopropylamine derivative I-8 with a yield of 17%. The NMR analysis data of the product are as follows: 1 H NMR (600MHz, DMSO-d6) δ10.03(brs,2H),8.72(s,1H),7.99(s,1H),7.97(d,J=8.5Hz,2H),7.89(d,J=8.6Hz,2H),7.30-7.25(m,1H),7.24-7.16(m,1H ),7.10-6.97(m,1H),4.27(d,J=13.7Hz,1H),4.23(d,J=13.6Hz,1H),2.96 -2.92(m,1H),2.55-2.52(m,1H),1.62-1.56(m,1H),1.34(q,J=6.7Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ149.8(dd,J FC =245.2,12.8Hz),148.6(dd,J FC =244.1,12.5Hz),143.5,142.5,137.2(dd,J FC =6.2,3.3Hz),130.2,127.5(q,J) FC=3.6Hz,2C),127.1(q,J FC =32.8Hz), 124.5(q,J FC =271.9Hz), 123.8(dd,J FC =6.2,2.9Hz),119.0(2C),117.7(d,J FC =17.0Hz), 115.8(d,J) FC =17.5Hz),115.2,41.3,37.5,20.5,13.2.

[0067] Example 9

[0068] The phenyl-pyrazole-phenylcyclopropylamine derivative I-9 of this embodiment satisfies the general formula (I), where R1 is H, R2 is H, and R3 is H. R4 is R5 is H, R6 is H, R7 is F, and R8 is F, which is the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((3-methyl-1-(4-(methanesulfonyl)phenyl)-1H-pyrazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process is as follows:

[0069] (1) Compound 2a (6 mmol) was dissolved in 15 mL of ethanol, then acetone (6 mmol) was added to the reaction system, and the mixture was refluxed and stirred for 2 h. The mixture was then extracted with dichloromethane (3 × 25 mL), the organic phases were combined, dried, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 7a. Compound 7a (6 mmol) was dissolved in 10 mL of phosphorus oxychloride, then N,N-dimethylformamide (18 mmol) was added to the reaction system, and the mixture was refluxed and stirred for 2 h. The mixture was then extracted with dichloromethane (3 × 25 mL), the organic phases were combined, dried, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the yellow oily product compound 8a, with a yield of 17%. The analytical data of the product are as follows: 1 H NMR (600MHz, DMSO-d6) δ9.97(s,1H),9.33(s,1H),8.16(d,J=8.8Hz,2H),8.08(d,J=8.8Hz,2H),3.27(s,3H),2.89(s,1H),2.73(s,1H); 13 C NMR (151MHz, DMSO-d6) δ185.7,152.0,142.5,139.4,135.4,129.4(2C),123.8,119.6(2C),44.0,13.4.

[0070] (2) Compound 8a (2.15 mmol) and compound 5 (2.15 mmol) were dissolved in 10 mL of methanol and stirred at 25 °C for 3 h to form an imine intermediate. Then, sodium triacetoxyborohydride (8.6 mmol) was added to the imine intermediate, and the reaction was carried out at room temperature for 24 h. 10 mL of water was added, the organic solvent was removed under reduced pressure, and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phases were combined, dried, concentrated, and separated by silica gel column chromatography to obtain compound 9a. Subsequently, compound 9a was dissolved in dichloromethane, and then a 4 M hydrochloric acid solution in ethyl acetate was added. The reaction system was stirred at 25 °C for 5 h, and then filtered to obtain a white solid, namely the phenyl-pyrazole-phenylcyclopropylamine derivative I-9, with a yield of 45%. The NMR analysis data of the product are as follows: 1 H NMR (600MHz, DMSO-d6) δ9.98 (s, 2H), 8.66 (s, 1H), 8.03 (d, J = 8.4Hz, 2H), 7. 92(d,J=8.4Hz,2H),7.32-7.26(m,1H),7.25-7.19(m,1H),7.02-6.97(m,1H ),4.20(d,J=13.5Hz,1H),4.16(d,J=13.3Hz,1H),3.25(s,3H),3.01-2.93( m,1H),2.52(s,1H),2.33(s,3H),1.67-1.57(m,1H),1.34(q,J=6.5Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ151.6,149.8(dd,J FC =245.1,12.7Hz),148.6(dd,J FC =243.8,13.5Hz),143.0,138.2,137.2(dd,J FC =5.9,3.6Hz),131.3(2C),129.4,123.8(dd,J FC =5.9,2.8Hz),118.4(2C),117.7(d,J FC =16.9Hz), 115.8(d,J) FC =17.7Hz),113.7,44.1,40.6,37.6,20.6,13.3,12.2.

[0071] Example 10

[0072] The phenyl-pyrazole-phenylcyclopropylamine derivative I-10 of this embodiment satisfies the general formula (I), where R1 is H, R2 is H, and R3 is... R4 is R5 is H, R6 is H, R7 is F, and R8 is F, which is the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((3-ethyl-1-(4-(methanesulfonyl)phenyl)-1H-pyrazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process is as follows:

[0073] (1) The synthesis process of compound 8b is basically the same as step (1) in Example 9, except that acetone is replaced with butan-2-one to prepare compound 8b with a yield of 25%. The analytical data of the product are as follows: 1 H NMR (600MHz, CDCl3) δ10.04(s,1H),8.49(s,1H),8.10-8.06(m,2H),7.97-7.94(m,2H),3.10(s,3H),3.01(q,J=7.5Hz,2H),1.36(t,J=7.5Hz,3H); 13 C NMR (151MHz, CDCl3) δ184.0,158.2,142.9,139.0,132.3,129.3(2C),123.4,119.5(2C),44.6,21.1,13.0.

[0074] (2) The synthesis process of phenyl-pyrazole-phenylcyclopropylamine derivative I-10 is basically the same as step (2) in Example 9, except that compound 8a is changed to compound 8b to obtain phenyl-pyrazole-phenylcyclopropylamine derivative I-10 with a yield of 52%. The NMR analysis data of the product are as follows: 1 H NMR(600MHz,DMSO-d6)δ9.95-9.65(m,2H),8.70-8.62(m,1H),8.04(d,J=8.6Hz,2H) ,7.93(d,J=8.4Hz,2H),7.33-7.27(m,1H),7.24-7.18(m,1H),7.02-6.96(m,1H),4.2 2(d,J=13.9Hz,1H),4.17(d,J=13.7Hz,1H),3.25(s,3H),2.98(s,1H),2.75-2.70(m, 2H),2.49-2.45(m,1H),1.63-1.53(m,1H),1.38-1.31(m,1H),1.22(t,J=7.5Hz,3H); 13 C NMR(151MHz,DMSO-d6)δ156.3,149.8(dd,J FC =245.1,12.4Hz),148.6(dd,J FC=243.3,13.7Hz),143.0,138.2,137.2,131.1,129.4(2C),123.8(dd,J FC =6.3,3.1Hz),118.5(2C),117.7(d,J FC =16.9Hz), 115.8(d,J) FC =17.8Hz),113.2,44.2,40.6,37.7,20.7,19.5,13.4,13.2.

[0075] Example 11

[0076] The phenyl-pyrazole-phenylcyclopropylamine derivative I-11 of this embodiment satisfies the general formula (I), where R1 is H, R2 is H, and R3 is H. R4 is R5 is H, R6 is H, R7 is F, and R8 is F, which is the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(4-(methanesulfonyl)phenyl)-3-propyl-1H-pyrazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process is as follows:

[0077] (1) The synthesis process of compound 8c is basically the same as step (1) in Example 9, except that acetone is replaced with pent-2-one to prepare compound 8c with a yield of 61%. The analytical data of the product are as follows: 1 H NMR (600MHz, CDCl3) δ10.00-9.97(m,1H),8.50-8.48(m,1H),8.05-8.01(m,2H),7.95-7.9 1(m,2H),3.06(t,J=2.6Hz,3H),1.81-1.71(m,2H),1.21-1.20(m,2H),1.02-0.96(m,3H); 13 C NMR (151MHz, CDCl3) δ184.1,162.6,142.9,139.0,132.3,129.3(2C),123.7,119.6(2C),44.6,36.5,31.4,14.2.

[0078] (2) The synthesis process of phenyl-pyrazole-phenylcyclopropylamine derivative I-11 is basically the same as step (2) in Example 9, except that compound 8a is changed to compound 8c to obtain phenyl-pyrazole-phenylcyclopropylamine derivative I-11 with a yield of 28%. The NMR analysis data of the product are as follows: 1H NMR(600MHz,DMSO-d6)δ9.97(s,2H),8.72(s,1H),8.04(d,J=8.8Hz,2H),7.92(d,J=8.8Hz, 2H),7.30(dt,J=10.6,8.6Hz,1H),7.22(ddd,J=11.8,7.7,2.0Hz,1H),7.01-6.97(m,1H),4 .21(d,J=14.0Hz,1H),4.17(d,J=14.0Hz,1H),3.25(s,3H),3.00-2.95(m,1H),2.69-2.63( m,2H),2.55-2.52(m,1H),1.70-1.59(m,3H),1.34(q,J=6.4Hz,1H),0.95(t,J=7.3Hz,3H); 13 C NMR(151MHz,DMSO-d6)δ155.1,149.8(dd,J FC =245.1,12.4Hz),148.6(dd,J FC =243.8,12.4Hz),143.0,138.2,137.3(dd,J FC =5.6,3.7Hz),131.1,129.4(2C),123.8(dd,J FC =6.1,3.0Hz),118.5(2C),117.7(d,J FC =17.0Hz), 115.8(d,J) FC =17.7Hz),113.5,44.2,40.6,37.6,28.0,22.0,20.6,14.3,13.3.

[0079] Example 12

[0080] The phenyl-pyrazole-phenylcyclopropylamine derivative I-12 of this embodiment satisfies the general formula (I), where R1 is H, R2 is H, and R3 is... R4 is R5 is H, R6 is H, R7 is F, and R8 is F, which is the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((3-tert-butyl-1-(4-(methanesulfonyl)phenyl)-1H-pyrazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process is as follows:

[0081] (1) The synthesis process of compound 8d is basically the same as step (1) in Example 9, except that acetone is replaced with 3,3-dimethylbut-2-one to prepare compound 8d with a yield of 45%. The analytical data of the product are as follows: 1H NMR (400MHz, DMSO-d6) δ10.00(s,1H),9.41(s,1H),8.15(d,J=8.5Hz,2H),8.09(d,J=8.5Hz,2H),3.28(s,3H),1.41(s,9H).

[0082] (2) The synthesis process of phenyl-pyrazole-phenylcyclopropylamine derivative I-12 is basically the same as step (2) in Example 9, except that compound 8a is changed to compound 8d to obtain phenyl-pyrazole-phenylcyclopropylamine derivative I-12 with a yield of 28%. The NMR analysis data of the product are as follows: 1 H NMR (600MHz, DMSO-d6) δ10.07(s,2H),8.99(s,1H),8.07(d,J=8.7Hz,2H),7.91(d ,J=8.7Hz,2H),7.37-7.31(m,1H),7.26(ddd,J=11.6,7.7,1.7Hz,1H),7.06-7.02 (m,1H),4.40(d,J=14.4Hz,1H),4.36(d,J=14.4Hz,1H),3.25(s,3H),3.16-3.12( m,1H),2.68(ddd,J=9.9,6.3,3.6Hz,1H),1.76-1.70(m,1H),1.39-1.33(m,10H); 13 C NMR(151MHz,DMSO-d6)δ160.6,149.8(dd,J FC =245.2,12.8Hz),148.7(dd,J FC =244.3,12.5Hz),143.0,138.2,137.3(dd,J FC =6.1,3.3Hz),131.3,129.5(2C),124.0(dd,J FC =6.2,3.1Hz),118.4(2C),117.8(d,J FC =17.0Hz), 115.9(d,J) FC =17.6Hz),113.2,44.2,42.7,38.2,33.5,30.3(9C),20.7,13.3.

[0083] Example 13

[0084] The phenyl-pyrazole-phenylcyclopropylamine derivative I-13 of this embodiment satisfies the general formula (I), where R1 is H, R2 is H, and R3 is H. R4 is R5 is H, R6 is H, R7 is F, and R8 is F, which is the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(4-(methanesulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process is as follows:

[0085] (1) The synthesis process of compound 8e is basically the same as step (1) in Example 9, except that acetone is changed to 1,1,1-trifluoroprop-2-one to prepare compound 8e with a yield of 32%. The analytical data of the product are as follows: 1 H NMR (600MHz, DMSO-d6) δ 10.00 (s, 1H), 9.65 (s, 1H), 8.24 (d, J = 8.5Hz, 2H), 8.16 (d, J = 8.6Hz, 2H), 3.31 (s, 4H).

[0086] (2) The synthesis process of phenyl-pyrazole-phenylcyclopropylamine derivative I-13 is basically the same as step (2) in Example 9, except that compound 8a is changed to compound 8e to obtain phenyl-pyrazole-phenylcyclopropylamine derivative I-13 with a yield of 38%. The NMR analysis data of the product are as follows: 1 H NMR(600MHz,DMSO-d6)δ10.34(brs,2H),9.25-9.05(m,1H),8.15(d,J=8.7 Hz,2H),8.04(d,J=8.3Hz,2H),7.36-7.28(m,1H),7.25-7.18(m,1H),7.02- 6.97(m,1H),4.36(d,J=14.5Hz,1H),4.31(d,J=14.5Hz,1H),3.29(s,3H),3 .10-3.05(m,1H),2.63-2.52(m,1H),1.68-1.57(m,1H),1.37-1.31(m,1H); 13 C NMR(151MHz,DMSO-d6)δ149.8(dd,J FC =245.6,12.1Hz),148.6(dd,J FC =244.1,12.9Hz),142.1,142.0(d,J FC =36.5Hz), 140.4, 137.1 (dd, J FC =6.2,3.0Hz),133.7,129.7(2C),23.9(dd,J FC =6.0,3.1Hz),121.4(d,J FC=269.7Hz),120.1(2C),117.7(d,J=18.3Hz),115.8(d,J FC =17.6Hz),113.6,100.0,44.0,37.8,20.7,13.3.

[0087] Example 14

[0088] The phenyl-pyrazole-phenylcyclopropylamine derivative I-14 of this embodiment satisfies the general formula (I), where R1 is H, R2 is H, and R3 is... R4 is R5 is H, R6 is H, R7 is F, and R8 is F, which is the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(4-(methanesulfonyl)phenyl)-3-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process is as follows:

[0089] (1) The synthesis process of compound 8f is basically the same as step (1) in Example 9, except that acetone is replaced with 4,4,4-trifluorobut-2-one to prepare compound 8f with a yield of 64%. The analytical data of the product are as follows: 1 H NMR (600MHz, DMSO-d6) δ10.05(s,1H),9.47(s,1H),8.21(d,J=8.6Hz,2H),8.16(d,J=8.6Hz,2H),4.12(q,J=10.9Hz,2H),3.34(s,3H).

[0090] (2) The synthesis process of phenyl-pyrazole-phenylcyclopropylamine derivative I-14 is basically the same as step (2) in Example 9, except that compound 8a is changed to compound 8f to obtain phenyl-pyrazole-phenylcyclopropylamine derivative I-14 with a yield of 45%. The NMR analysis data of the product are as follows: 1 H NMR(600MHz,DMSO-d6)δ10.08(brs,2H),8.85-8.81(s,1H),8.09(d,J=8.7Hz,2H), 7.95(d,J=8.6Hz,2H),7.32-7.26(m,1H),7.23-7.18(m,1H),7.00-6.96(d,J=7.8Hz ,1H),4.28(d,J=14.0Hz,1H),4.24(d,J=14.0Hz,1H),4.10-3.94(m,2H),3.26(s,3H ),3.05-2.99(m,1H),2.56-2..52(m,1H),1.65-1.58(m,1H),1.34(q,J=6.7Hz,1H);13 C NMR(151MHz,DMSO-d6)δ149.8(dd,J FC =245.3,12.9Hz),148.6(dd,J FC =244.4,12.6Hz),144.9,142.6,139.1,137.2(dd,J FC =6.2,3.6Hz),132.1,129.5(2C),126.2(d,J FC =276.8Hz), 123.8(dd,J FC =6.2,3.0Hz),119.0(2C),117.7(d,J FC =17.0Hz), 115.7(d,J) FC =17.7Hz),114.9,44.1,40.5,37.59,31.4(q,J FC =31.5Hz), 20.5, 13.3.

[0091] Example 15

[0092] The phenyl-pyrazole-phenylcyclopropylamine derivative I-15 of this embodiment satisfies the general formula (I), where R1 is H, R2 is H, and R3 is... R4 is R5 is H, R6 is H, R7 is F, and R8 is F, which is the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(4-(methanesulfonyl)phenyl)-3-(isopropyl)-1H-pyrazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process is as follows:

[0093] (1) The synthesis process of compound 8g is basically the same as step (1) in Example 9, except that acetone is replaced with 3-methylbut-2-one to prepare compound 8g with a yield of 61%. The analytical data of the product are as follows: 1 H NMR (600MHz, CDCl3) δ10.05 (s, 1H), 8.46 (s, 1H), 8.07 (d, J = 8.7Hz, 2H), 7.95 (d, J = 8.8Hz, 2H), 3.53-3.46 (m, 1H), 3.09 (s, 3H), 1.40 (d, J = 6.9Hz, 6H); 13 C NMR (151MHz, CDCl3) δ183.9,162.1,142.9,138.9,132.4,129.3(2C),123.1,119.6(2C),44.6,27.6,21.7.

[0094] (2) The synthesis process of phenyl-pyrazole-phenylcyclopropylamine derivative I-15 is basically the same as step (2) in Example 9, except that compound 8a is changed to compound 8g to obtain phenyl-pyrazole-phenylcyclopropylamine derivative I-15 with a yield of 41%. The NMR analysis data of the product are as follows: 1 H NMR(600MHz,DMSO-d6)δ9.98(s,2H),8.73(s,1H),8.05(d,J=8.4Hz,2H),7.92(d,J=8 .4Hz,2H),7.34-7.27(m,1H),7.25–7.18(m,1H),7.02-6.96(m,1H),4.23(d,J=14.0H z,1H),4.20(d,J=14.2Hz,1H),3.25(s,3H),3.21-3.13(m,1H),3.02-2.96(m,1H),2. 59-2.52(m,1H),1.67-1.59(m,1H),1.38-1.31(m,1H),1.23(dd,J=11.8,6.8Hz,6H); 13 C NMR(151MHz,DMSO-d6)δ160.0,149.8(dd,J FC =245.2,12.5Hz),148.6(dd,J FC =244.1,12.6Hz),143.1,138.2,137.3(dd,J FC =6.5,3.6Hz),130.9,129.5(2C),123.8(dd,J FC =5.6,3.4Hz),118.5(2C),117.7(d,J FC =17.1Hz), 115.8(d,J) FC =17.7Hz),112.7,44.2,40.6,37.7,25.8,22.9,22.6,20.6,13.3.

[0095] Example 16

[0096] The phenyl-pyrazole-phenylcyclopropylamine derivative I-16 of this embodiment satisfies the general formula (I), where R1 is H, R2 is H, and R3 is... R4 is R5 is H, R6 is H, R7 is F, and R8 is F, which is the compound (1R,2S)-N-((3-cyclopentyl-1-(4-(methanesulfonyl)phenyl)-1H-pyrazol-4-yl)methyl)-2-(3,4-difluorophenyl)cyclopropyl-1-amine. The preparation process is as follows:

[0097] (1) The synthesis process of compound 8h is basically the same as step (1) in Example 9, except that acetone is replaced with 1-cyclopentylethyl ketone to prepare compound 8h with a yield of 46%. The analytical data of the product are as follows: 1 H NMR (400MHz, DMSO-d6) δ9.98 (s, 1H), 9.33 (s, 1H), 8.11 (dd, J = 28.2, 8.8Hz, 4H),3.61-3.46(m,1H),3.27(s,3H),2.12-1.95(m,2H),1.94-1.53(m,6H).

[0098] (2) The synthesis process of phenyl-pyrazole-phenylcyclopropylamine derivative I-16 is basically the same as step (2) in Example 9, except that compound 8a is changed to compound 8h to obtain phenyl-pyrazole-phenylcyclopropylamine derivative I-16 with a yield of 37%. The NMR analysis data of the product are as follows: 1 H NMR(600MHz,DMSO-d6)δ10.08(brs,2H),8.78-8.68(m,1H),8.06-8.02(m,2H),7. 93-7.88(m,2H),7.34-7.26(m,1H),7.24-7.18(m,1H),7.01-6.96(d,J=6.3Hz,1H) ,4.25-4.17(m,1H),3.27-3.20(m,4H),3.00-2.95(m,1H),2.60-2.50(d,J=5.7Hz ,1H),2.01-1.90(m,2H),1.82-1.73(m,3H),1.71-1.53(m,4H),1.37-1.30(m,1H); 13 C NMR(151MHz,DMSO-d6)δ158.5,149.8(dd,J FC =245.4,12.9Hz),148.6(dd,J FC =245.1,13.7Hz),143.1,138.2,137.3,137.3(dd,J FC =5.5,2.5Hz),129.5(2C),123.8(dd,J FC =5.8,2.8Hz),118.5(2C),117.7(d,J FC =16.1Hz), 115.8(d,J) FC =17.8Hz),113.3,44.2,40.6,37.7,36.7,32.8,32.5,25.6,25.5,20.6,13.3.

[0099] Example 17

[0100] The phenyl-pyrazole-phenylcyclopropylamine derivative I-17 of this embodiment satisfies the general formula (I), where R1 is H, R2 is H, and R3 is H. R4 is R5 is H, R6 is H, R7 is F, and R8 is F, which is the compound (1R,2S)-N-((3-cyclohexyl-1-(4-(methanesulfonyl)phenyl)-1H-pyrazol-4-yl)methyl)-2-(3,4-difluorophenyl)cyclopropyl-1-amine. The preparation process is as follows:

[0101] (1) The synthesis process of compound 8i is basically the same as step (1) in Example 9, except that acetone is replaced with 1-cyclohexylethyl ketone to prepare compound 8i with a yield of 55%. The analytical data of the product are as follows: 1 H NMR (400MHz, DMSO-d6) δ9.97(s,1H),9.31(s,1H),8.11(dd,J=25.9,8.6Hz,4H),3.27(s,3H),3.12(t,J=11.5Hz,1H),1. 93(d,J=12.1Hz,2H),1.79(d,J=12.4Hz,2H),1.70(d,J=11.8Hz,1H),1.57(dd,J=23.5,11.3Hz,2H),1.45-1.15(m,3H).

[0102] (2) The synthesis process of phenyl-pyrazole-phenylcyclopropylamine derivative I-17 is basically the same as step (2) in Example 9, except that compound 8a is changed to compound 8i to obtain phenyl-pyrazole-phenylcyclopropylamine derivative I-17 with a yield of 44%. The NMR analysis data of the product are as follows: 1 H NMR(600MHz,DMSO-d6)δ9.94(brs,2H),8.72(s,1H),7.98(d,J=81.1Hz,4H),7.35-7.15(m,2H),7.05-6.90(m,1H),4.21(s,2H),3.24(s,3 H),3.05-2.95(m,1H),2.85-2.75(m,1H),2.60-2.53(m,1H),1.90-1.73(m,4H),1.77-1.60(m,2H),1.60-1.40(m,2H),1.40-1.20(m,4H); 13 C NMR(151MHz,DMSO-d6)δ159.3,149.8(dd,J FC =245.3,12.5Hz),148.6(dd,J FC=243.5,13.7Hz),143.1,138.2,137.3,130.8,129.4(2C),123.8,118.5(2C),117.7(d,J FC =17.0Hz), 115.7(d,J) FC =17.6Hz),112.8,44.2,37.7,35.2,33.0,32.5,26.4,26.3,26.1,20.6,13.5.

[0103] Example 18

[0104] The phenyl-pyrazole-phenylcyclopropylamine derivative I-18 of this embodiment satisfies the general formula (I), where R1 is H, R2 is H, and R3 is... R4 is R5 is H, R6 is H, R7 is F, and R8 is F, which is the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(4-(methanesulfonyl)phenyl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process is as follows:

[0105] (1) The synthesis process of compound 8j is basically the same as step (1) in Example 9, except that acetone is replaced with 1-(tetrahydro-2H-pyran-4-yl)ethyl ketone to prepare compound 8i with a yield of 31%. The analytical data of the product are as follows: 1 HNMR (600MHz, CDCl3) δ10.05(s,1H),8.53(s,1H),8.08(d,J=8.7Hz,2H),7.97(d,J=8.8Hz,2H),4.13-4 .05(m,2H),3.60(td,J=11.6,2.2Hz,2H),3.44(tt,J=11.3,3.9Hz,1H),3.11(s,3H),2.06-1.93(m,4H).

[0106] (2) The synthesis process of phenyl-pyrazole-phenylcyclopropylamine derivative I-18 is basically the same as step (2) in Example 9, except that compound 8a is changed to compound 8j to obtain phenyl-pyrazole-phenylcyclopropylamine derivative I-18 with a yield of 21%. The NMR analysis data of the product are as follows: 1H NMR (600MHz, DMSO-d6) δ10.03(brs,2H),8.73(s,1H),8.05(d,J=8.6Hz,2H),7.92(d,J=8.6Hz ,2H),7.33-7.26(m,1H),7.24-7.17(m,1H),7.02-6.96(m,1H),4.26(d,J=14.1Hz,1H),4.22( d,J=14.1Hz,1H),3.96-3.88(m,2H),3.46-3.41(m,2H),3.25(s,3H),3.17-3.09(m,1H),3.02 -2.96(m,1H),2.57-2.52(m,1H),1.86-1.69(m,4H),1.67-1.61(m,1H),1.34(q,J=6.6Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ158.1,149.8(dd,J FC =245.1,13.0Hz),148.6(dd,J FC =244.1,12.3Hz),143.0,138.3,137.3(dd,J FC =6.2,3.4Hz),131.1,129.4(2C),123.8(dd,J FC =6.1,2.9Hz),118.6(2C),117.7(d,J FC =17.0Hz), 115.7(d,J) FC =17.6Hz),112.8,67.4(2C),44.2,40.57,37.6,32.7,32.4,32.3,20.6,13.4.

[0107] Example 19

[0108] The phenyl-pyrazole-phenylcyclopropylamine derivative I-19 of this embodiment satisfies the general formula (I), where R1 is H, R2 is H, and R3 is... R4 is R5 is H, R6 is H, R7 is F, and R8 is F, which is the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(4-(methanesulfonyl)phenyl)-3-phenyl-1H-pyrazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process is as follows:

[0109] (1) The synthesis process of compound 8k is basically the same as step (1) in Example 9, except that acetone is replaced with acetophenone to prepare compound 8k with a yield of 75%. The analytical data of the product are as follows: 1H NMR(600MHz,DMSO-d6)δ10.02(s,1H),9.51(s,1H),8.29(d,J=8.8Hz,2H),8.13 (d, J=8.8Hz, 2H), 7.95 (dd, J=7.9, 1.5Hz, 2H), 7.57-7.49 (m, 3H), 3.29 (s, 3H).

[0110] (2) The synthesis process of phenyl-pyrazole-phenylcyclopropylamine derivative I-19 is basically the same as step (2) in Example 9, except that compound 8a is changed to compound 8k to obtain phenyl-pyrazole-phenylcyclopropylamine derivative I-19 with a yield of 63%. The NMR analysis data of the product are as follows: 1 H NMR(600MHz,DMSO-d6)δ9.97(brs,2H),9.02(s,1H),8.12(d,J=8.7Hz,2H),8.05( d,J=8.7Hz,2H),7.72(d,J=7.2Hz,2H),7.53-7.49(m,2H),7.49-7.45(m,1H),7.34 -7.28(m,1H),7.20-7.13(m,1H),7.00-6.93(m,1H),4.45-4.34(m,2H),3.28(s,3H ),3.05-2.99(m,1H),2.56-2.52(m,1H),1.63-1.56(m,1H),1.28(q,J=6.6Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ153.0,149.8(dd,J FC =245.2,12.7Hz),148.7(dd,J FC =244.0,12.6Hz),142.9,139.0,137.1(dd,J FC =6.4,3.4Hz),132.0,131.9,129.6(2C),129.3(2C),129.2,128.6(2C),123.8(dd,J FC =6.1,3.2Hz),119.0(2C),117.8(d,J FC =17.2Hz), 115.8(d,J) FC =17.7Hz),113.4,44.1,41.7,37.9,20.7,13.5.

[0111] Example 20

[0112] The phenyl-pyrazole-phenylcyclopropylamine derivative I-20 of this embodiment satisfies the general formula (I), where R1 is H, R2 is H, and R3 is... R4 is R5 is H, R6 is H, R7 is F, and R8 is F, which is the compound (1R,2S)-2-(3,4-difluorophenyl)-N-((1-(4-(methanesulfonyl)phenyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process is as follows:

[0113] (1) The synthesis process of compound 8l is basically the same as step (1) in Example 9, except that acetone is replaced with 1-(pyridin-4-yl)ethyl ketone to prepare compound 8l with a yield of 51%. The analytical data of the product are as follows: 1 H NMR (400MHz, DMSO-d6) δ10.04 (s, 1H), 9.58 (s, 1H), 8.73 (d, J = 7.5Hz, 2H), 8.28 (d, J=12.7Hz, 2H), 8.14 (d, J=12.7Hz, 2H), 7.97 (d, J=7.6Hz, 2H), 3.31 (s, 1H).

[0114] (2) The synthesis process of phenyl-pyrazole-phenylcyclopropylamine derivative I-20 is basically the same as step (2) in Example 9, except that compound 8a is changed to compound 8l to obtain phenyl-pyrazole-phenylcyclopropylamine derivative I-20 with a yield of 56%. The NMR analysis data of the product are as follows: 1 H NMR (600MHz, DMSO-d6) δ10.43(s,2H),9.18(brs,1H),8.96(s,2H),8.36(s,2H),8.13(d,J=29.6Hz,4H),7.35-7.12(m,2H),7. 00-6.90(m,1H),4.61-4.43(m,2H),3.30(s,3H),3.10-2.97(m,1H),2.64-2.54(m,1H),1.75-1.57(m,1H),1.35-1.20(m,1H); 13 C NMR(151MHz,DMSO-d6)δ149.8(dd,J FC =245.3,11.6Hz),148.6(dd,J) FC =244.0,12.2Hz),148.3,146.4,144.1,142.4,139.9,137.2,134.0,129.6,125.2,123.8,119.6,117.7(d,J FC =17.0Hz), 115.7(d,J)FC =17.4Hz),115.0,44.1,41.0,37.7,20.5,13.4.

[0115] Example 21

[0116] The phenyl-pyrazole-phenylcyclopropylamine derivative I-21 of this embodiment satisfies the general formula (I), where R1 is H, R2 is H, and R3 is... R4 is H, R5 is F, R6 is F, R7 is H, and R8 is H, which is the compound (1R,2S)-2-(2,3-difluorophenyl)-N-((1-(4-(methanesulfonyl)phenyl)-1H-pyrazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process is as follows:

[0117] (1) 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 10a (R1 is F, R2 is F, R3 is H, R4 is H, 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 mixture was concentrated to obtain a transparent oily liquid, namely compound 11a, with a yield of 98%. The analytical data of the product are as follows: 1 H NMR (600MHz, CDCl3) δ7.32-7.28(m,1H),7.16-7.10(m,2H),5.26-5.22(m,1H),3.72-3.70(m,1H),3.57-3.60(dd,J=10.1,8.6Hz,1H); 13 C NMR(151MHz,CDCl3)δ150.3(dd,J FC =248.6,12.7Hz),147.7(dd,J FC =248.2,13.4Hz),130.0(d,J) FC =10.1Hz), 124.4(dd,J FC =6.6,4.6Hz),122.1(t,J FC =3.1Hz), 117.0(d,J FC =17.0Hz), 68.0, 38.4.

[0118] (2) Compound 11a (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 (8.40 mmol) were added. The mixture was stirred at 40 °C for 6 h. 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. Then, a 1 L round-bottom flask was used. Under argon protection, sodium hydride (12.1 mmol) and toluene (10 mL) were added. A toluene solution of triethyl phosphonoacetate (12.6 mmol) was added dropwise under ice bath conditions. After the addition was completed, the mixture was stirred at room temperature for 2 h. Then, the temperature was raised to 50 °C, and toluene (9.70 mmol) was slowly added dropwise. After the addition was completed, the mixture was stirred at 60 °C for 24 h, and the reaction was monitored by TLC. After the reaction was completed, 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 give a brownish-yellow liquid compound 14a in 67% yield. The analytical data of the product are as follows: 1 H NMR (600MHz, CDCl3) δ7.05-6.94(m,2H),6.73-6.69(m,1H),4.19(q,J=7.1Hz,2H),2.71-2.64(m,1 H),1.98-1.92(m,1H),1.67-1.60(m,1H),1.34(ddd,J=8.4,6.6,4.7Hz,1H),1.30(q,J=7.4Hz,3H); 13 C NMR(151MHz,CDCl3)δ172.9,150.6(dd,J FC =248.1,12.9Hz),149.7(dd,J FC =248.1, 13.0 Hz), 129.7 (d, J) FC =10.8Hz), 123.8(dd,J FC =7.0, 4.9Hz), 121.5, 115.2 (d, J) FC =17.2Hz),60.9,26.9,22.9,15.7,14.2.

[0119] (3) Compound 14a (4.34 mmol) was placed in a 100 mL flask, and 30% sodium hydroxide solution (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; then ethyl acetate (60 mL × 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a brownish-yellow oily liquid with a strong sour smell, which was directly added to the next step. The brownish-yellow oily liquid (2.18 mmol), ultra-dry triethylamine (2.50 mmol), anhydrous tert-butanol (21.8 mmol), and diphenyl azidophosphate (3.30 mmol) were dissolved in anhydrous toluene (85 mL) under argon protection. The resulting mixture was refluxed for 18 h, and di-tert-butyl carbonate (3.30 mmol) was added to the reaction mixture. The mixture was heated for 2 h and then 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 solution, and 10 mL of saturated brine, respectively. After washing, the solution was concentrated and purified by column chromatography to obtain a white solid, compound 15a, in 30% yield. The analytical data of the product are as follows: 1 H NMR (600MHz, CDCl3) δ6.99-6.94(m,2H),6.72(s,1H),2.86-2.78(s,1H),2.18(ddd,J=9.7,6.5,3.3Hz,1H),1.45(s,9H),1.28-1.19(m,2H); 13 C NMR(151MHz,CDCl3)δ156.2,150.5(dd,J FC =247.4,13.0Hz),149.6(dd,J FC =246.7,12.9Hz),130.3(d,J) FC =11.4Hz), 123.8(dd,J FC =6.7,5.2Hz),114.7(d,J) FC =17.2Hz),79.8,31.9,28.3(3C),18.4,15.9.

[0120] (4) Under argon protection, compound 15a (1.57 mmol) was dissolved in 20 mL of dichloromethane, and 2 mL of ethyl acetate solution containing 4 M hydrochloric acid was added. After stirring for 6 h, the pH was adjusted to ≥14, and dichloromethane (10 mL × 3) was added for extraction. The organic phases were combined. The organic phase was washed with 10 mL of saturated sodium chloride solution, concentrated, and subjected to column chromatography to obtain a brown oily liquid compound 16a in 59% yield. The analytical data of the product are as follows: 1H NMR (600MHz, DMSO-d6) δ8.76 (s, 3H), 7.32-7.26 (m, 1H), 7.17-7.12 (m, 1H), 6.95-6.90 (m, 1H), 2.93 (dt, J = 8. 0,4.2Hz,1H),2.59(ddd,J=10.0,6.3,3.7Hz,1H),1.54(ddd,J=10.4,6.0,4.7Hz,1H),1.29(q,J=6.3Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ150.1(dd,J FC =245.3,12.7Hz),149.2(dd,J FC =245.2,12.9Hz),129.3(d,J) FC =10.8Hz), 125.2(dd,J FC =7.3,4.7Hz),122.8,115.8(d,J) FC =16.9Hz), 30.4, 14.7, 13.1.

[0121] (5) Compounds D-7a (2.15 mmol) and 16a (2.15 mmol) were dissolved in 10 mL of methanol and stirred at 25 °C for 3 h to form an imine intermediate. Sodium triacetoxyborohydride (8.6 mmol) was added to the obtained imine intermediate, and the reaction was carried out at 25 °C for 1 day. The organic solvent was then removed by vacuum distillation, and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phases were combined, dried, concentrated, and separated by silica gel column chromatography to obtain compound 17a. Compound 17a was then dissolved in dichloromethane, and a solution of 4 M hydrochloric acid in ethyl acetate was added. The resulting reaction mixture was stirred at room temperature for 6 h and filtered to obtain a white solid, namely the phenyl-pyrazole-phenylcyclopropylamine derivative I-21, in 16% yield. The NMR analysis data of the product are as follows: 1 H NMR(600MHz,DMSO-d6)δ9.75(brs,2H),8.72(s,1H),8.06(d,J=8.8Hz,2H),8.02(d,J=8.7Hz,2H),7.97(s,1H),7.30-7.24(m,1H),7.16-7.11(m,1H) ,6.94-6.89(m,1H),4.30(d,J=13.6Hz,1H),4.24(d,J=13.6Hz,1H),3.14- 3.10(m,1H),2.65-2.59(s,1H),1.65-1.57(m,1H),1.40(q,J=6.7Hz,1H); 13C NMR(151MHz,DMSO-d6)δ149.5(d,J=258.3,14.4Hz),148.6(dd,J=241.7,12.7 Hz),143.0,142.5,138.2,129.6,128.9(2C),128.1(d,J=11.1Hz),124.7(dd,J FC =6.4,4.1Hz),122.3,118.5(2C),115.4(d,J FC =16.3Hz),114.8,43.5,40.9,36.2,14.4,12.0.

[0122] Example 22

[0123] The phenyl-pyrazole-phenylcyclopropylamine derivative I-22 of this embodiment satisfies the general formula (I), where R1 is H, R2 is H, and R3 is... R4 is H, R5 is F, R6 is H, R7 is F, and R8 is H, which is the compound (1R,2S)-2-(2,4-difluorophenyl)-N-((1-(4-(methanesulfonyl)phenyl)-1H-pyrazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process is as follows:

[0124] (1) 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 12 (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 mixture was concentrated to obtain a transparent oily liquid, namely compound 13, with a yield of 91%. The analytical data of the product are as follows: 1 H NMR(600MHz, DMSO-d6)δ7.61-7.56(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).

[0125] (2) In a 1L round-bottom flask under argon protection, sodium hydride (12.1 mmol) and toluene (10 mL) were added dropwise. A toluene solution of triethyl phosphonoacetate (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 13 (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, compound 14a, with a yield of 98%. 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),2.6 4-2.57(m,1H),1.94-1.85(m,1H),1.58(dt,J=9.5,4.9Hz,1H),1.29(t,J=7.1Hz,3H).

[0126] (3) Compound 14a (4.34 mmol) was placed in a 100 mL flask, and 30% sodium hydroxide solution (7.80 mmol) and 10 mL of methanol were added. The temperature was controlled at 60 °C, and the mixture was stirred for 8 h. 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. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a brownish-yellow oily liquid with a strong sour smell, which was directly added to the next step. A brownish-yellow oily liquid (2.18 mmol), ultra-dry triethylamine (2.50 mmol), anhydrous tert-butanol (21.8 mmol), and diphenyl azidophosphate (3.30 mmol) were dissolved in anhydrous toluene (85 mL) under argon protection. The mixture was refluxed for 18 h, and then di-tert-butyl carbonate (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 solution, and 100 mL of saturated brine, respectively. After washing, the mixture was concentrated and purified by column chromatography to give a white solid, compound 15b, in 21% yield. The analytical data of the product are as follows: 1H NMR (600MHz, DMSO-d6) δ7.28 (s, 1H), 7.19-7.13 (m, 1H), 7.12-7.05 (d, J = 6.5Hz, 1H), 7.01-6.05 (t, J = 8.2Hz, 1H),2.75-2.69(m,1H),1.99-1.92(m,1H),1.45-1.30(s,9H),1.14(dt,J=9.7,5.0Hz,1H),1.11-1.04(m,1H); 13 C NMR (151MHz, DMSO-d6) δ161.1 (dd, J=245.9, 12.1Hz), 160.7 (dd, J=244.2, 12.1Hz), 156.4, 128.3, 124.9 (dd, J=14.6, 3.4Hz), 111.7 (dd, J=20.5, 2.7Hz), 103.9 (t, J=26.2Hz), 78.4, 32.5, 28.7 (9C), 17.3, 14.8.

[0127] (4) Under argon protection, compound 15b (1.57 mmol) was dissolved in 20 mL of dichloromethane, and 2 mL of ethyl acetate solution containing 4 M hydrochloric acid was added. After stirring for 6 h, the pH was adjusted to ≥14, and dichloromethane (10 mL × 3) was added for extraction. The organic phases were combined. After washing the organic phase with 10 mL of saturated sodium chloride solution, the solution was concentrated and subjected to column chromatography to obtain a brown oily liquid, namely compound 16b, with a yield of 67%. The analytical data of the product are as follows: 1 H NMR(600MHz,DMSO-d6)δ8.70-8.52(m,3H),7.26-7.21(m,1H),7.20-7.15(m,1H),7.03(t, J=8.5Hz,1H),2.91-2.86(m,1H),2.49-2.43(m,1H),1.47-1.40(m,1H),1.27-1.22(m,1H); 13 C NMR(151MHz,DMSO-d6)δ161.4(dd,J FC =246.0,6.0Hz),161.3(dd,J FC =245.9,6.0Hz),129.0(dd,J FC =9.6,5.1Hz),122.8(dd,J FC =14.4,3.7Hz),111.9(dd,J FC =21.1,3.6Hz),104.1(t,J FC =26.0Hz), 30.0, 14.5(d,J) FC=4.0Hz), 12.5.

[0128] (5) Compound 4a (2.15 mmol) and compound 16b (2.15 mmol) were dissolved in 10 mL of methanol and stirred at 25 °C for 3 h to form an imine intermediate. Sodium triacetoxyborohydride (8.6 mmol) was added to the obtained imine intermediate, and the reaction was carried out at 25 °C for 1 day. The organic solvent was then removed by vacuum distillation, and the mixture was extracted with dichloromethane (3 × 10 mL). The organic phases were combined, dried, concentrated, and separated by silica gel column chromatography to obtain compound 17b. Compound 17b was then dissolved in dichloromethane, and a solution of 4 M hydrochloric acid in ethyl acetate was added. The reaction mixture was stirred at room temperature for 6 h, and filtered to obtain a white solid, which was the phenyl-pyrazole-phenylcyclopropylamine derivative I-22, in 43% yield. The NMR analysis data of the product are as follows: 1 H NMR (600MHz, DMSO-d6) δ10.07(brs,2H),8.77(s,1H),8.07(d,J=8.8Hz,2H),8.04-8.00(m,3H),7.20-7.14(m,2H),7.04-7.00(m,1H),4. 28(d,J=13.6Hz,1H),4.22(d,J=13.6Hz,1H),3.26(s,3H),3.0-3.02(m,1H),2.67-2.61(s,1H),1.64-1.58(m,1H),1.33(q,J=6.6Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ160.8(dd,J FC =246.2,5.4Hz),160.8(dd,J FC =245.9,5.2Hz),143.2,142.5,138.2,129.7,128.9(2C),128.6(dd,J FC =9.6,5.1Hz),121.8(dd,J FC =14.4,3.4Hz),118.5(2C),114.9,111.3(dd,J FC =21.1,3.3Hz),103.5(t,J FC =25.9Hz),43.5,40.7,35.9,14.1,11.4.

[0129] Example 23

[0130] The phenyl-pyrazole-phenylcyclopropylamine derivative I-23 of this embodiment satisfies the general formula (I), where R1 is H, R2 is H, and R3 is... R4 is H, R5 is F, R6 is H, R7 is H, and R8 is F, which is the compound (1R,2S)-2-(3,5-difluorophenyl)-N-((1-(4-(methanesulfonyl)phenyl)-1H-pyrazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process is as follows:

[0131] (1) The synthesis process of compound 11b is basically the same as step (1) of Example 21, except that compound 10a is changed to compound 10b (R1 is F, R2 is H, R3 is F, and R4 is H) to prepare compound 11b with a yield of 98%. The analytical data of the product are as follows: 1 H NMR (600MHz, DMSO-d6) δ7.15-7.09(m,3H),6.04(d,J=4.9Hz,1H),4.87(dd,J=10.8,4.8Hz,1H),3.72(dd,J=10.4,4.3Hz,1H),3.62(dd,J=10.4,6.5Hz,1H); 13 CNMR(151MHz,DMSO-d6)δ162.6(dd,J FC =245.8,13.0Hz,2C),148.0(t,J) FC =8.5Hz), 109.9(dd,J FC =20.4, 5.0 Hz, 2C), 103.2 (t, J) FC =25.9Hz), 71.2, 25.6.

[0132] (2) The synthesis process of compound 14c is basically the same as step (2) of Example 21, except that compound 11a is changed to 11b to prepare compound 14c, with a yield of 45%. The analytical data of the product are as follows: 1 H NMR (600MHz, CDCl3) δ6.72-6.55(m,3H),4.18(q,J=7.1Hz,2H),2.52-2.45(m,1H),1.94-1.86(m,1H),1.65-1.60(m,1H),1.31-1.25(m,4H).

[0133] (3) The synthesis process of compound 15c is basically the same as step (3) in Example 21, except that compound 14a is changed to 14c to prepare compound 15c, with a yield of 21%. The analytical data of the product are as follows: 1H NMR (600MHz, CDCl3) δ6.70-6.57(m,3H),4.85(s,1H),2.75-2.65(m,1H),2.06-1.99(m,1H),1.45(s,9H),1.21-1.12(m,2H); 13 C NMR(151MHz,CDCl3)δ163.1(dd,J FC =247.7,13.2Hz,2C),156.2,145.0(t,J FC =9.4Hz,2C),109.3(dd,J) FC =20.4, 4.0 Hz), 101.5 (t, J) FC =25.4Hz),79.9,32.9,28.4(3C),25.1,16.5.

[0134] (4) The synthesis process of compound 16c is basically the same as step (4) in Example 21, except that compound 15a is changed to 15c to prepare compound 16c, with a yield of 63%. The analytical data of the product are as follows: 1 H NMR(600MHz,DMSO-d6)δ8.43(d,J=3.0Hz,1H),7.06-6.95(m,1H),6.9-6.85(m ,2H),2.84-2.80(m,1H),2.07(ddd,J=9.4,6.5,3.2Hz,1H),1.31-1.21(m,2H); 13 C NMR(151MHz,DMSO-d6)δ162.9(dd,J FC =245.2,13.7Hz,2C),156.7,146.5(t,J FC =9.9Hz), 109.6(dd,J FC =20.3,4.9Hz),101.6(t,J) FC =25.9Hz), 34.2, 24.5, 16.0.

[0135] (5) The synthesis process of phenyl-pyrazole-phenylcyclopropylamine derivative I-23 is basically the same as step (5) in Example 21, except that compound 16a is changed to compound 16c to prepare phenyl-pyrazole-phenylcyclopropylamine derivative I-23 with a yield of 41%. The NMR analysis data of the product are as follows: 1H NMR (600MHz, DMSO-d6) δ10.08(brs,2H),8.74(s,1H),8.08-8.05(m,2H),8.02-7.99(m,3H),7.05-7.00(m,1H),6.91-6.86(m,2H),4.27(d,J=13 .6Hz,1H),4.23(d,J=13.5Hz,1H),3.27(s,3H),3.02-2.97(m,1H),2.55(ddd,J=9.9,6.3,3.5Hz,1H),1.67-1.60(m,1H),1.41(q,J=6.6Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ162.9(dd,J FC =245.6,13.7Hz,2C),144.2(t,J) FC =9.8Hz),143.8,143.0,138.8,130.3,129.4(2C),119.0(2C),115.4,110.12(dd,J=20.4,5.1Hz,2C),102.3(t,J FC =25.8Hz),44.1,41.2,37.8,21.1,13.6.

[0136] Example 24

[0137] The phenyl-pyrazole-phenylcyclopropylamine derivative I-24 of this embodiment satisfies the general formula (I), where R1 is H, R2 is H, and R3 is... R4 is H, R5 is H, R6 is H, R7 is F, and R8 is Cl, which is the compound ((1R,2S)-2-(3-chloro-4-fluorophenyl)-N-((1-(4-(methanesulfonyl)phenyl)-1H-pyrazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process is as follows:

[0138] (1) The synthesis process of compound 11c is basically the same as step (1) in Example 21, except that compound 10a is changed to compound 10c (R1 is H, R2 is H, R3 is F, and R4 is Cl) to prepare compound 11c with a yield of 95%. The analytical data of the product are as follows: 1 H NMR (600MHz, CDCl3) δ7.47 (dd, J=7.0, 2.1Hz, 1H), 7.27-7.23 (m, 2H), 7.14 (t, J=8 .6Hz,1H),4.89(dd,J=8.7,3.2Hz,1H),3.61(dd,J=10.5,3.4Hz,1H),3.51-3.47(m 1H).

[0139] (2) The synthesis process of compound 14d is basically the same as step (2) of Example 21, except that compound 11a is changed to 11c to prepare compound 14d, with a yield of 61%. The analytical data of the product are as follows: 1 H NMR (600MHz, CDCl3) δ7.12-7.11(m,1H),7.06-7.00(m,1H),6.99-6.94(m,1H),4.17(q,J=7.1Hz,2H),2.51 -2.45(m,1H),1.88-1.81(m,1H),1.62-1.56(td,J=9.7,5.0Hz,1H),1.31-1.28(m,3H),0.90-0.80(m,1H); 13 C NMR(151MHz,CDCl3)δ172.8,156.9(d,J FC =247.7Hz), 137.2(d,J FC =3.7Hz), 128.4, 126.1 (d, J) FC =7.0Hz), 120.9(d,J FC =17.9Hz), 116.4(d,J) FC =21.2Hz),60.8,25.0,24.0,16.7,14.2.

[0140] (3) The synthesis process of compound 15d is basically the same as step (3) in Example 21, except that compound 14a is changed to 14d to prepare compound 15d, with a yield of 18%. The analytical data of the product are as follows: 1 H NMR (600MHz, CDCl3) δ7.19-7.16(m,1H),7.06-7.00(m,2H),2.70-2.63(m,1H),2.04-1.98(m,1H),1.57(s,1H),1.46(s,9H),1.16-1.08(m,2H); 13 C NMR(151MHz,CDCl3)δ156.7(d,J FC =246.7Hz), 156.2, 137.7 (d, J) FC =3.6Hz), 126.6(d,J FC =6.6Hz), 120.6(d,J FC =17.6Hz), 116.3(d,J) FC =21.1Hz),79.8,32.3,28.4,24.4,15.8.

[0141] (4) The synthesis process of compound 16d is basically the same as step (4) in Example 21, except that compound 15a is changed to 15d to prepare compound 16d, with a yield of 71%. The analytical data of the product are as follows: 1 H NMR(600MHz,DMSO-d6)δ8.81(s,3H),7.43(dd,J=7.1,2.0Hz,1H),7.34(t,J=9.0Hz,1H),7.26-7.21(m,1H) ,2.82(dt,J=7.9,4.1Hz,1H),2.45(ddd,J=9.9,6.3,3.6Hz,1H),1.53-1.44(m,1H),1.25(q,J=6.4Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ156.4(d,J FC =245.0Hz), 137.8(d,J) FC =3.6Hz), 128.9, 127.8 (d, J) FC =7.2Hz), 119.9(d,J FC =17.7Hz), 117.1(d,J FC =20.9Hz), 31.0, 20.3, 13.6.

[0142] (5) The synthesis process of phenyl-pyrazole-phenylcyclopropylamine derivative I-24 is basically the same as step (5) in Example 21, except that compound 16a is changed to compound 16d to prepare phenyl-pyrazole-phenylcyclopropylamine derivative I-24 with a yield of 28%. The NMR analysis data of the product are as follows: 1 H NMR (600MHz, DMSO-d6) δ10.03(brs,2H),8.74(s,1H),8.06(d,J=8.5Hz,2H),8.01-7.98(m,3H),7.36-7.32(m,1H),7.30-7.25(m,1H),7.17-7.12(m ,1H),4.27(d,J=13.6Hz,1H),4.23(d,J=13.6Hz,1H),3.26(s,3H),2.98- 2.93(m,1H),2.55-2.53(m,1H),1.61-1.55(m,1H),1.36(q,J=6.5Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ156.4(d,J FC =245.1Hz),143.8,143.0,138.8,137.2(d,J FC=3.5Hz),130.3,129.4(2C),128.8,127.6(d,J FC =7.1Hz), 119.9(d,J FC =17.9Hz),119.0(2C),117.1(d,J FC =20.9Hz),115.5,44.1,41.2,37.5,20.4,13.1.

[0143] Example 25

[0144] The phenyl-pyrazole-phenylcyclopropylamine derivative I-25 of this embodiment satisfies the general formula (I), where R1 is H, R2 is H, and R3 is... R4 is H, R5 is H, R6 is H, R7 is Cl, and R8 is F, which is the compound ((1R,2S)-2-(4-chloro-3-fluorophenyl)-N-((1-(4-(methanesulfonyl)phenyl)-1H-pyrazol-4-yl)methyl)cyclopropyl-1-amine. The preparation process is as follows:

[0145] (1) The synthesis process of compound 11d is basically the same as step (1) in Example 21, except that compound 10a is changed to compound 10d (R1 is H, R2 is H, R3 is Cl, and R4 is F) to prepare compound 11d with a yield of 93%. The analytical data of the product are as follows: 1 H NMR (600MHz, CDCl3) δ7.40 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 9.7 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 4.95-4.87 (m, 1H), 3.66-3.60 (m, 1H), 3.53-3.44 (m, 1H).

[0146] (2) The synthesis process of compound 14e is basically the same as step (2) of Example 21, except that compound 11a is changed to 11d to prepare compound 14e with a yield of 42%. The analytical data of the product are as follows: 1 H NMR (600MHz, CDCl3) δ7.29-7.24(m,1H),6.88-6.81(m,2H),4.17(q,J=7.1Hz,2H),2.53-2.44(m,1H) ,1.91-1.84(m,1H),1.63-1.59(m,1H),1.31-1.27(m,3H),0.90-0.81(ddd,J=21.8,14.3,7.6Hz,1H); 13 C NMR(151MHz,CDCl3)δ172.7,158.1(d,J FC=248.8Hz), 141.3(d,J FC =6.9Hz), 130.5, 122.8 (d, J) FC =3.4Hz), 118.8(d,J FC =17.7Hz), 114.4(d,J FC =21.6Hz),60.9,25.2,24.3,17.0,14.2.

[0147] (3) The synthesis process of compound 15e is basically the same as step (3) in Example 21, except that compound 14a is changed to 14e to prepare compound 15e, with a yield of 25%. The analytical data of the product are as follows: 1 H NMR(600MHz, CDCl3)δ7.28-7.24(m,1H),6.94-6.86(dd,J=20.0,8.8Hz,2H),4.8 8(s,1H),2.70-2.64(m,1H),2.05-1.97(s,1H),1.45(s,9H),1.20-1.10(m,2H); 13 C NMR (151MHz, CDCl3) δ158.0 (d, J = 248.3Hz), 156.2, 141.9 (d, J = 6.8Hz), 130.3, 123.1, 118.3 (d, J FC =17.7Hz), 114.8(d,J) FC =17.2Hz),79.8,32.7,28.4,24.7,16.1.

[0148] (4) The synthesis process of compound 16e is basically the same as step (4) in Example 21, except that compound 15a is changed to 15e to prepare compound 16e, with a yield of 56%. The analytical data of the product are as follows: 1 H NMR(600MHz, DMSO-d6)δ8.75(s,3H),7.49(t,J=8.1Hz,1H),7.26(dd,J=10.8,2.0Hz,1H),7.09(dd,J=8.3,1.8Hz,1H), 2.88-2.81(m,1H),2.44(ddd,J=9.9,6.3,3.6Hz,1H),1.50(ddd,J=10.4,6.1,4.7Hz,1H),1.26(dt,J=7.7,6.3Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ157.7(d,J FC =246.0Hz), 142.0(d,J FC=7.3Hz), 130.8, 124.5 (d, J) FC =3.2Hz), 117.6(d,J FC =17.6Hz), 115.1(d,J FC =21.5Hz), 31.2, 20.7, 14.1.

[0149] (5) The synthesis process of phenyl-pyrazole-phenylcyclopropylamine derivative I-25 is basically the same as step (5) in Example 21, except that compound 16a is changed to compound 16e to prepare phenyl-pyrazole-phenylcyclopropylamine derivative I-25 with a yield of 35%. The NMR analysis data of the product are as follows: 1 H NMR (600MHz, DMSO-d6) δ10.09(brs,2H),8.72(s,1H),8.06(d,J=8.5Hz,2H),8.02-7.97(m,3H),7.44-7.39(m,1H),7.19-7.15(m,1H),6.99(d,J=8 .3Hz,1H),4.27(d,J=13.6Hz,1H),4.22(d,J=13.6Hz,1H),3.26(s,4H),2 .96(s,1H),2.56-2.51(m,1H),1.66-1.59(m,1H),1.37(q,J=6.5Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ157.6(d,J FC =246.1Hz),143.8,143.0,141.4(d,J FC =7.2Hz),138.7,130.8,130.3,129.4(2C),124.3(d,J FC =2.9Hz), 119.0(2C), 117.7(d,J) FC =16.8Hz), 115.4, 115.1 (d, J) FC =21.5Hz),44.1,41.2,37.7,20.7,13.4.

[0150] Experimental Example 1: Inhibitory Activity Test

[0151] 1. LSD1 inhibitory activity assay

[0152] (1) Prepare acetaldehyde dehydrogenase detection buffer (1×Assay buffer). (2) Prepare the concentration gradient of the compounds: The starting concentration of the test compounds (phenyl-pyrazole-phenylcyclopropylamine derivatives I-1 to I-25) is 10 μM, diluted 3 times, and divided into 10 concentrations, each for single-well testing. The positive control compound is the LSD1 inhibitor ORY-1001, which is tested at a starting concentration of 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. Transfer 10 nL of 100% DMSO to the Min and Max wells. (3) Prepare 2× enzyme solution with 1× reaction solution. (4) Prepare 2× substrate mixture solution with 1× reaction solution. (5) Add 5 μL of 2× enzyme solution to each well; add 5 μL of 1× reaction solution to each 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).

[0153] 2. Detection of the inhibitory effect of MAO A / B activity

[0154] (1) Prepare acetaldehyde dehydrogenase detection buffer (1×Assay buffer). (2) Compound preparation: The test concentration of the test compound (phenyl-pyrazole-phenylcyclopropylamine derivative I-22) is 10 μM, and the test is performed in duplicate. The positive control is the selective MAO-A inhibitor Clorgyline, with an initial test concentration of 1 μM, diluted 3 times, and divided into 10 concentrations, with each concentration set up in duplicate. The positive control compound is the selective MAO-B inhibitor R(-)-deprenyl, with an initial test concentration of 10 μM, diluted 3 times, and also divided into 10 concentrations, with each concentration set up in duplicate. Dilute to a final concentration of 100 times in a 384-well plate, and then transfer 200 nL to the 384-well plate for testing. Transfer 200 nL of 100% DMSO to both Max and Min wells. (3) Prepare enzyme solution with a final concentration of 2 times using 1×Assay buffer. (4) Add 10 μL of enzyme solution at twice the final concentration to the compound well, positive compound well, and corresponding positive control well, and add 10 μL of 1×Assay buffer to the negative control well. (5) Centrifuge at 1000 rpm for 1 min, vortex to mix, and incubate at room temperature for 15 min. (6) Prepare a substrate solution at twice the final concentration using 1×Assay buffer. (7) Add 10 μL of the substrate solution at twice the final concentration to all wells to start the reaction. (8) Centrifuge the 384-well plate at 1000 rpm for 1 min, vortex to mix, and incubate for 1 h. (9) Add 20 μL of stop detection solution to stop the reaction, centrifuge at 1000 rpm for 1 min, and vortex to mix. (10) After standing for 30 min, read the values ​​using EnVision.

[0155] 3. Data Analysis

[0156] The inhibitory activity of LSD1 was calculated and 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 method in GraphPad Prism 5 to derive the IC50 of the compound's inhibition of LSD1 protein binding. 50 The inhibitory effects of different compounds on LSD1 protein are shown in Table 1. The inhibitory effects of MAO A / B activity are shown in Table 2.

[0157] Table 1. Inhibitory effects of different compounds on LSD1 protein

[0158]

[0159]

[0160]

[0161] As shown in Table 1, the phenyl-pyrazole-phenylcyclopropylamine derivatives provided by this invention exhibit nanomolar-level inhibitory activity against LSD1 at the enzyme level, demonstrating significant bioinhibitory activity against LSD1. Among them, compounds I-1, I-2, I-5, I-6, I-7, I-8, I-9, I-10, I-12, I-22, I-23, I-24, and I-25 showed superior inhibitory activity against LSD1, with IC50 values ​​exceeding 100%. 50 All <10 nM.

[0162] Table 2. Inhibitory activity of compounds against MAOs

[0163]

[0164] Table 2 examines the selectivity of compound I-22 for LSD1 homologous proteins MAOs, with Clorgylin and R(-)-deprenyl used as positive control compounds for MAO-A and MAO-B assays, respectively. Compound I-22 showed selectivity for MAO-A (IC50-2000) and MAO-B (IC50-2000) assays. 50 =499.97nM) and MAO-B (IC 50 >10000nM) exhibits high selectivity, IC 50 These values ​​were more than 102.24 times and 2044.99 times higher than those of LSD1, respectively. These results indicate that compound I-22 has strong selectivity for LSD1.

[0165] Experimental Example 2: In vitro proliferation assay of anti-acute myeloid leukemia MV4-11 cells

[0166] This experiment investigated the in vitro anti-MV4-11 effects of phenylpyrazole-phenylcyclopropylamine derivatives I-1 to I-25. Procedure: (1) Dissolve the test compound 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, then shake for 2 min to induce cell lysis. (4) After complete cell lysis, measure the absorbance of each well at 490 nm using a microplate reader. The data were used to calculate the IC50 using SPSS. 50The relative mean and standard deviation of each group of data were calculated using the AVERAGE and STDEV formulas. The IC was calculated using SPSS software and the ProbitAnalysis method. 50 Data are expressed as X ± SD. All experimental results were obtained from three independent replicate trials. The results are shown in Table 3 below.

[0167] Table 3. Effects of different compounds on the inhibition of MV4-11 cell proliferation

[0168]

[0169]

[0170] As shown in Table 3, the phenyl-pyrazole-phenylcyclopropylamine derivatives provided by this invention exhibit good anti-proliferative activity against MV-4-11 cells. Among them, compounds I-6, I-22, and I-25 showed strong inhibitory activity against MV-4-11 cells, with IC50 values ​​of [missing value]. 50 The values ​​were all below 0.2 μM, which fully demonstrates that the compounds of the present invention have strong anti-MV-4-11 cell proliferation activity.

[0171] In summary, the phenyl-pyrazole-phenylcyclopropylamine derivatives provided by this invention simultaneously contain characteristic groups such as a benzene ring, substituted phenyl groups, pyrazole, and cyclopropylamine. Through comprehensive structural design of these characteristic groups, this invention yields a series of novel compound types. Experiments have confirmed that the phenyl-pyrazole-phenylcyclopropylamine derivatives provided by this invention exhibit 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 phenyl-pyrazole-phenylcyclopropylamine derivatives against acute myeloid leukemia (AML) revealed that these compounds possess strong antiproliferative activity against AML cells. Therefore, this invention, through compound structural design and experimental verification, can provide more lead compound skeletal structure options for the treatment of AML and also offer new directions for the development of LSD1-targeted inhibitory drugs, demonstrating promising application prospects.

Claims

1. A phenyl-pyrazole-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 H or R3 is H or R4 is selected from One of them; R5 is H or F; R6 is selected from H, F, Cl; R7 is selected from H, F, Cl; R8 is H or F; and R5, R6, R7, and R8 are not all H at the same time.

2. The phenyl-pyrazole-phenylcyclopropylamine derivative according to claim 1, characterized in that, The phenyl-pyrazole-phenylcyclopropylamine derivative is selected from compounds with the following structures or pharmaceutically acceptable salts thereof: 。 3. The phenyl-pyrazole-phenylcyclopropylamine derivative according to claim 1 or 2, characterized in that, The pharmaceutically acceptable salt is a hydrochloride salt.

4. The application of a phenyl-pyrazole-phenylcyclopropylamine derivative as described in claim 1 or 2, characterized in that, Application in the preparation of drugs that target and inhibit LSD1.

5. The application of a phenyl-pyrazole-phenylcyclopropylamine derivative as described in claim 1 or 2, characterized in that, Its application in the preparation of drugs for the treatment of acute myeloid leukemia.

6. The application of the phenyl-pyrazole-phenylcyclopropylamine derivative according to claim 5, characterized in that, The drug is a drug that inhibits the proliferation of acute myeloid leukemia cells.

7. The application of the phenyl-pyrazole-phenylcyclopropylamine derivative according to claim 6, characterized in that, The acute myeloid leukemia cells were MV4-11 cells.

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