Diaryl methyl piperazine compounds and preparation methods, pharmaceutical compositions and applications thereof

Abstract

The present invention belongs to the field of chemical medicine technology, and specifically relates to a diaryl methyl piperazine compound and a preparation method, a pharmaceutical composition and an application thereof. The structural formula of the diaryl methyl piperazine compound is shown in Formula I, wherein R is any one of an alkane, a cycloalkane, and a substituted acyl group. The preparation method of the present invention is simple and can be prepared in one step, and the prepared diaryl methyl piperazine compound or a pharmaceutically acceptable salt thereof has the activity of efficiently inhibiting WDR5-MLL1, providing a novel structure, strong efficacy, safe and effective potential drug molecule for treating WDR5-MLL1 acute myeloid leukemia.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical medicines, and specifically relates to a diaryl methyl piperazine compound and a preparation method, a pharmaceutical composition and application thereof. Background Art

[0002] MLL1, also known as histone lysine methyltransferase 2 (KMT2A), is named because it can induce mixed lineage leukemia. The main biological function of MLL1 is to maintain the expression of downstream Hox (homeobox) genes by regulating the methylation status of histone H3K4 during embryonic development, hematopoiesis and neural development. Hox genes play an important role in physiological processes such as hematopoiesis and stem cell self-renewal. MLL1 can also recognize dimethylated and trimethylated H3K4 (H3K4me2 and H3K4me3), recruit MLL1 to target genes, and further activate the expression of downstream Hox genes. During infant development, MLL promotes the differentiation of hematopoietic stem cells, and in adults, MLL helps maintain blood cell renewal. In addition, MLL1 is also involved in angiogenesis, regulating tumor suppressor factors, and participating in the regulation of genes related to tissue growth and development.

[0003] The MLL gene can be rearranged with other genes. This phenomenon is common in leukemia patients, with about 10% of leukemia patients having MLL gene rearrangement. MLL gene rearrangement is closely related to the occurrence of acute myeloid leukemia (AML), lymphocytic leukemia (ALL), biphenotypic or mixed leukemia. MLL gene rearrangement mainly occurs in infants under 1 year old (mainly ALL) and young and middle-aged patients (mainly AML).

[0004] The MLL gene can fuse with more than 80 different partner genes, most of which encode transcription factors. The MLL fusion proteins that induce leukemia mainly come from six fusion genes: MLL-AF4, MLL-AF6, MLL-AF9, MLL-AF10, MLL-ELL and MLL-ENL. The MLL fusion protein lacks the C-terminal TAD, Win and SET domains, and thus loses the relevant functions of the WT-MLL1-C terminus. The lack of SET structure causes MLL-FPs to be unable to catalyze H3K4 methylation; the AT-hook domain, CXXC domain, MBD and SNL are retained in the WT-MLL1-N structure, so that it still retains the ability to recognize and bind to related histone methylation marks. However, due to the fusion of other partner genes, MLL-FPs acquire new functions from the partner genes. Although the mechanism by which MLL-FPs induce tumors has not been fully determined, studies have shown that some MLL-FPs can induce abnormal expression of related genes by regulating RNA polymerase II, thereby inducing leukemia; MLL-FPs also recruit other proteins to specifically activate downstream gene expression, leading to abnormal expression of downstream genes, thereby inducing or promoting the progression of leukemia. In short, MLL-FPs can cause the occurrence of leukemia and maintain the development of leukemia through a variety of mechanisms.

[0005] One of the strategies for treating fusion protein-induced leukemia is to destroy the normal physiological function of the MLL1 methyltransferase complex, reduce the methylation level of H3K4, reduce the binding sites of MLL1-FPs, and thus reduce the probability of MLL1-FPs being recruited to the target gene. WDR5 is a core component of the MLL1 methyltransferase complex and one of the cornerstones for the normal physiological function of the MLL1 complex. WDR5 interacts with the Win sequence of MLL1, recruits other members of the MLL1 complex (RbBP5, Ash2L and DPY-30) to form a fully functional MLL1 methyltransferase complex and stabilize its conformation. The MLL1 protein alone can only slowly catalyze the monomethylation of H3K4. In the absence of WDR5, even if other components of the MLL1 complex are present, MLL1 cannot exert its full methyltransferase activity. Therefore, WDR5 is a necessary condition for MLL1 to exert its full methyltransferase activity and further dimethylate and trimethylate H3K4. Blocking the MLL1-WDR5 PPI, reducing the MLL1 methyltransferase activity, and further reducing the methylation of histone H3K4 is a potential approach to treat MLL1-FPs-induced leukemia.

[0006] However, research on small molecule inhibitors of WDR5-MLL1 is still in its early stages. Although small molecule inhibitors have been found to have the potential to inhibit WDR5-MLL1 in recent years, further research and optimization are still needed to develop novel, highly effective and stable WDR5-MLL1 inhibitors for disease treatment. Summary of the invention

[0007] The purpose of the present invention is to solve the deficiencies of the prior art and provide a diaryl methyl piperazine compound and a preparation method, a pharmaceutical composition and application thereof, specifically adopting the following technical scheme:

[0008] In a first aspect of the present invention, a diaryl methyl piperazine compound is provided, and the structural formula of the diaryl methyl piperazine compound is shown in Formula I:

[0009] Formula I; wherein R is any one of an alkane, a cycloalkane, and a substituted acyl group.

[0010] As a further preferred embodiment, the structure of the diaryl methyl piperazine compound is any one of the following compounds 4a-4o:

[0011] .

[0012] The second aspect of the present invention provides a method for preparing the above-mentioned diaryl methyl piperazine compound, and the preparation route thereof is as follows:

[0013] ;

[0014] Wherein, R is any one of an alkane, a cycloalkane, and a substituted acyl group.

[0015] The invention uses piperonal and various N-substituted piperazines to form imine, and then reacts with 3,5-dimethoxybromobenzene under the action of n-butyl lithium to undergo a nucleophilic substitution reaction, thereby obtaining diaryl methyl piperazine compounds through a one-pot method.

[0016] The third aspect of the present invention provides the use of the above-mentioned diarylmethylpiperazine compounds or their pharmaceutically acceptable salts in the preparation of WDR5-MLL1 inhibitors.

[0017] The fourth aspect of the present invention provides a WDR5-MLL1 inhibitor, wherein the WDR5-MLL1 inhibitor comprises the above-mentioned diaryl methyl piperazine compound or a pharmaceutically acceptable salt thereof as a main active ingredient.

[0018] The fifth aspect of the present invention provides use of the above-mentioned WDR5-MLL1 inhibitor in the preparation of a drug for treating and / or preventing cancer.

[0019] As a further preferred embodiment, the above cancer is acute myeloid leukemia cells.

[0020] The sixth aspect of the present invention provides a pharmaceutical composition, which comprises the above-mentioned diaryl methyl piperazine compound or a pharmaceutically acceptable salt thereof.

[0021] As a further preferred embodiment, the above-mentioned pharmaceutical composition further comprises an excipient.

[0022] As a further preferred embodiment, the excipient is at least one of gum arabic, syrup, lanolin and starch.

[0023] The beneficial effects of the present invention are:

[0024] The preparation method of the present invention is simple and can be prepared in one step. The prepared diaryl methyl piperazine compound or a pharmaceutically acceptable salt thereof has the activity of effectively inhibiting WDR5-MLL1, providing a potential drug molecule with novel structure, strong efficacy, safety and effectiveness for treating WDR5-MLL1 acute myeloid leukemia. DETAILED DESCRIPTION

[0025] The following will be combined with the embodiments to clearly and completely describe the concept, specific structure and technical effects of the present invention, so as to fully understand the purpose, scheme and effect of the present invention. It should be noted that the embodiments and features in the embodiments of this application can be combined with each other without conflict.

[0026] The present invention provides a diaryl methyl piperazine compound, the structural formula of which is shown in Formula I:

[0027] Formula I, wherein R is any one of an alkane, a cycloalkane, and a substituted acyl group.

[0028] The present invention also provides a method for preparing the above-mentioned diaryl methyl piperazine compound, and the preparation route thereof is as follows:

[0029] .

[0030] The specific preparation process is as follows:

[0031] Take eggplant-shaped flask a, dissolve piperonal 1 (1.0 mmol, 1.0 eq) and substituted piperazine 2 (1.1 mmol, 1.1 eq) in dry tetrahydrofuran (10.0 mL), and stir at room temperature for 1 hour under argon protection; take another eggplant-shaped flask b, add 1-bromo-3,5-dimethoxybenzene (2.0 mmol, 2.0 eq) and dissolve it in dry tetrahydrofuran (10.0 mL), cool to -78°C under argon protection, slowly add n-butyl lithium (2.0 eq) and stir for 30 minutes; then move eggplant-shaped flask a to -78°C, and slowly transfer the solution in eggplant-shaped flask b to eggplant-shaped flask a, and continue to react for 2 hours; slowly add saturated ammonium chloride to the system to quench the reaction, extract with ethyl acetate (3 × 20 mL), dry the organic phase with anhydrous sodium sulfate, concentrate, and purify the obtained crude product by silica gel column chromatography to obtain the target compound 4.

[0032] Example 1

[0033] Preparation of diaryl methyl piperazine compounds (4a-4o), the structural formula of which is as follows:

[0034]

[0035] (1) Preparation of compound 4a. The specific process is as follows:

[0036] Take eggplant-shaped flask a, dissolve piperonal (1.0 mmol, 1.0 eq) and 1-cyclopropylpiperazine (1.1 mmol, 1.1 eq) in dry tetrahydrofuran (10.0 mL), and stir at room temperature for 1 hour under argon protection; take another eggplant-shaped flask b, add 1-bromo-3,5-dimethoxybenzene (2.0 mmol, 2.0 eq) and dissolve it in dry tetrahydrofuran (10.0 mL), cool to -78°C under argon protection, slowly add n-butyl lithium (2.0 eq) and stir for 30 minutes; then move eggplant-shaped flask a to -78°C, and slowly transfer the solution in eggplant-shaped flask b to eggplant-shaped flask a, and continue to react for 2 hours; slowly add saturated ammonium chloride to the system to quench the reaction, extract with ethyl acetate (3 × 20 mL), dry the organic phase with anhydrous sodium sulfate, concentrate, and purify the obtained crude product by silica gel column chromatography to obtain the target compound 4a (55 mg, yield 14%).

[0037] Compound 4a was tested and the results were as follows:

[0038] 1 H NMR (400 MHz, CDCl3): d 7.15 (dd, J = 2.0, 1.0 Hz, 1H), 6.87 (ddd,J =7.5, 2.0, 1.1 Hz, 1H), 6.77 (d, J = 7.5 Hz, 1H), 6.73 (dd, J = 1.9, 0.9 Hz, 2H),6.33 (t, J = 2.0 Hz, 1H), 5.87 (q, J = 4.9 Hz, 2H), 4.49 (t, J = 1.1 Hz, 1H), 3.81(s, 6H), 3.05 – 2.96 (m, 2H), 2.93 – 2.82 (m, 2H), 2.37 – 2.28 (m, 4H), 2.13(p, J = 7.0 Hz, 1H), 0.36 (tt, J = 7.1, 4.3 Hz, 2H), 0.27 – 0.17 (m, 2H) ppm. 13 CNMR (100 MHz, CDCl3): d 161.4, 148.2, 148.1, 138.2, 130.5, 123.5, 110.1, 109.5,106.8, 101.1, 100.0, 75.7, 57.0, 55.4, 51.3, 36.7, 7.6 ppm.

[0039] (2) Preparation of compound 4b. The preparation process was similar to that of step (1), except that 1-cyclopropylpiperazine was replaced by N-methylpiperazine to obtain the target compound 4b (77 mg, yield 21%).

[0040] Compound 4b was tested and the results were as follows:

[0041] 1 H NMR (400 MHz, CDCl3): d 7.15 (ddd, J = 7.5, 2.0, 0.9 Hz, 1H), 7.01 (dd, J = 1.9, 1.0 Hz, 1H), 6.80 (dd, J = 2.0, 1.0 Hz, 2H), 6.77 (d, J = 7.5 Hz, 1H),6.36 (t, J= 1.9 Hz, 1H), 5.86 – 5.78 (m, 2H), 4.12 (t, J = 1.1 Hz, 1H), 2.85(dddd, J = 12.3, 6.8, 5.2, 3.1 Hz, 2H), 2.68 (ddd, J = 12.3, 3.2, 1.8 Hz, 2H), 2.38 – 2.29 (m, 2H), 2.24 (s, 3H), 2.20 (td, J = 12.2, 3.0 Hz, 2H) ppm. 13 C NMR (100 MHz, CDCl3): d 161.3, 148.5, 148.1, 138.9, 130.5, 123.9, 110.1, 109.5,106.8, 101.5, 100.0, 75.7, 55.4, 53.4, 51.4, 45.2 ppm.

[0042] (3) Preparation of compound 4c. The preparation process was similar to that of step (1), except that 1-cyclopropylpiperazine was replaced by 1-(3-pentyl)-piperazine to obtain the target compound 4c (144 mg, yield 34%).

[0043] Compound 4c was tested and the results were as follows:

[0044] 1 H NMR (400 MHz, CDCl3): d 7.14 (ddd, J = 7.6, 2.0, 1.0 Hz, 1H), 6.88 (dd, J = 2.0, 1.0 Hz, 1H), 6.77 (d, J = 7.5 Hz, 1H), 6.68 (dd, J = 2.0, 1.1 Hz, 2H),6.39 (t, J = 2.0 Hz, 1H), 5.86 – 5.79 (m, 2H), 4.52 – 4.37 (m, 1H), 3.81 (s,6H), 2.94 (td, J = 13.2, 4.1 Hz, 2H), 2.72 – 2.57 (m, 2H), 2.58 – 2.44 (m, 4H), 2.18 (tt,J = 12.0, 2.5 Hz, 1H), 1.83 (dqd, J = 12.3, 7.9, 2.5 Hz, 2H), 1.18 –0.97 (m, 2H), 0.88 (t, J = 7.9 Hz, 6H) ppm. 13 C NMR (100 MHz, CDCl3): d 161.5,148.4, 148.5, 138.3, 130.6, 123.5, 110.1, 109.5, 106.7, 101.1, 100.0, 75.7,68.0, 55.4, 51.3, 51.2, 23.1, 10.8 ppm.

[0045] (4) Preparation of compound 4d. The preparation process was similar to that of step (1), except that 1-cyclopropylpiperazine was replaced by 1-cyclopentylpiperazine to obtain the target compound 4d (76 mg, yield 18%).

[0046] Compound 4d was tested and the results were as follows:

[0047] 1 H NMR (400 MHz, CDCl3): d 7.17 (ddd, J = 7.6, 2.0, 1.0 Hz, 1H), 6.90 (dd, J = 2.1, 1.0 Hz, 1H), 6.77 (d, J = 7.5 Hz, 1H), 6.68 (dd, J = 1.9, 0.9 Hz, 2H),6.39 (t, J = 1.9 Hz, 1H), 5.87 – 5.78 (m, 2H), 4.50 (t, J = 1.1 Hz, 1H), 3.81 (s,6H), 3.20 – 2.98 (m, 2H), 2.79 (p, J = 7.0 Hz, 1H), 2.48 – 2.38 (m, 2H), 2.36 –2.25 (m, 4H), 1.95 (ddt, J= 13.7, 6.8, 4.3 Hz, 2H), 1.72 – 1.62 (m, 2H), 1.60– 1.51 (m, 2H), 1.47 (dddd, J = 12.2, 8.9, 5.9, 3.0 Hz, 2H) ppm. 13 C NMR (100MHz, CDCl3): d 161.8, 148.4, 148.5, 138.3, 130.6, 123.6, 110.3, 109.6, 106.4,101.7, 100.4, 75.7, 67.0, 55.4, 51.3, 51.2, 30.4, 24.0 ppm.

[0048] (5) Preparation of compound 4e. The preparation process was similar to that of step (1), except that 1-cyclopropylpiperazine was replaced by N-tert-butylpiperazine to obtain the target compound 4e (156 mg, yield 38%).

[0049] Compound 4e was tested and the results were as follows:

[0050] 1 H NMR (400 MHz, CDCl3): d 7.17 (dd, J = 2.0, 1.1 Hz, 1H), 6.98 (ddd, J =7.5, 2.0, 0.9 Hz, 1H), 6.82 (dd, J = 1.9, 1.0 Hz, 2H), 6.77 (d, J = 7.5 Hz, 1H),6.29 (t, J = 2.0 Hz, 1H), 5.87 – 5.78 (m, 2H), 4.39 (t, J = 1.1 Hz, 1H), 3.81 (s,6H), 3.31 (dddd, J = 12.3, 7.1, 5.3, 3.5 Hz, 2H), 2.79 (dddd, J = 12.3, 7.0, 5.1,3.3 Hz, 2H), 2.73 – 2.64 (m, 0H), 2.36 (dddd, J = 12.3, 7.0, 4.9, 3.0 Hz, 2H),1.11 (s, 9H) ppm.13 C NMR (100 MHz, CDCl3): d 161.5, 148.9, 148.4, 138.6, 130.6,123.8, 110.3, 109.4, 106.8, 101.4, 100.6, 75.7, 55.4, 53.1, 51.3, 47.1, 26.6ppm.

[0051] (6) Preparation of compound 4f. The preparation process was similar to that of step (1), except that 1-cyclopropylpiperazine was replaced with 1-acetone, 2-dimethyl-1-(1-piperazinyl) to obtain the target compound 4f (105 mg, yield 24%).

[0052] Compound 4f was tested and the results were as follows:

[0053] 1 H NMR (400 MHz, CDCl3): d 7.18 (dd, J = 2.0, 1.0 Hz, 1H), 7.00 (ddd, J =7.5, 1.9, 1.0 Hz, 1H), 6.84 (dd, J = 1.9, 0.9 Hz, 2H), 6.77 (d, J = 7.5 Hz, 1H),6.31 (t, J = 2.0 Hz, 1H), 5.88 – 5.79 (m, 2H), 4.13 (t, J = 1.1 Hz, 1H), 4.01 –3.87 (m, 2H), 3.81 (s, 6H), 3.17 (dddd, J = 12.3, 6.6, 5.0, 3.1 Hz, 2H), 3.05(dddd, J = 12.3, 7.1, 5.5, 3.5 Hz, 2H), 2.29 (dddd, J = 12.3, 7.1, 5.5, 3.5 Hz,2H), 1.24 (s, 9H) ppm. 13 C NMR (100 MHz, CDCl3): d177.6, 161.4, 148.2, 148.1,138.5, 130.6, 123.4, 110.3, 109.5, 106.8, 101.1, 100.6, 75.7, 55.4, 52.1,46.7, 39.2, 28.1 ppm.

[0054] (7) Preparation of compound 4g. The preparation process is similar to that of step (1), except that 1-cyclopropylpiperazine is replaced by cyclopentyl (piperazine-1-yl)methanone to obtain the target compound 4g (122 mg, yield 27%).

[0055] Compound 4g was tested and the results were as follows:

[0056] 1 H NMR (400 MHz, CDCl3): d 7.09 (dd, J = 2.0, 1.1 Hz, 1H), 6.92 (ddd, J =7.5, 1.9, 1.0 Hz, 1H), 6.77 (d, J = 7.5 Hz, 1H), 6.72 (dd, J = 1.9, 1.0 Hz, 2H),6.39 (t, J = 1.9 Hz, 1H), 5.92 – 5.82 (m, 2H), 4.53 (t, J = 1.0 Hz, 1H), 4.05(dddd, J = 12.3, 6.6, 5.2, 3.3 Hz, 2H), 3.81 (s, 7H), 3.30 – 3.19 (m, 2H), 3.14(ddd, J = 12.5, 3.2, 1.4 Hz, 2H), 2.86 (p, J = 6.9 Hz, 1H), 2.46 (td, J = 12.3, 3.6Hz, 2H), 2.02 – 1.88 (m, 2H), 1.71 (dddd, J = 11.8, 9.0, 5.9, 2.4 Hz, 2H), 1.56– 1.32 (m, 4H) ppm. 13 C NMR (100 MHz, CDCl3): d179.6, 161.5, 148.3, 148.8,138.3, 130.4, 123.4, 110.6, 109.4, 106.2, 101.1, 100.3, 75.7, 55.4, 52.1,46.3, 45.1, 32.1, 25.9 ppm.

[0057] (8) Preparation of compound 4h. The preparation process was similar to that of step (1), except that 1-cyclopropylpiperazine was replaced by 1-cyclopropylcarbonylpiperazine to obtain the target compound 4h (135 mg, yield 32%).

[0058] Compound 4h was tested and the results were as follows:

[0059] 1 H NMR (400 MHz, CDCl3): d 7.02 (dd, J = 2.0, 1.0 Hz, 1H), 6.96 (ddd, J =7.5, 2.0, 0.9 Hz, 1H), 6.80 – 6.73 (m, 3H), 6.39 (t, J = 2.0 Hz, 1H), 5.92 –5.84 (m, 2H), 4.61 – 4.45 (m, 3H), 3.81 (s, 6H), 3.45 (dddd, J = 12.3, 6.6,5.2, 3.4 Hz, 2H), 3.18 (dddd, J = 12.3, 7.0, 5.6, 3.7 Hz, 2H), 2.52 (dddd, J =12.5, 7.1, 5.7, 3.8 Hz, 2H), 1.78 (p, J = 7.0 Hz, 1H), 1.15 – 1.04 (m, 2H), 0.92 (tt, J = 7.2, 4.3 Hz, 2H) ppm. 13 C NMR (100 MHz, CDCl3): d 172.7, 161.4,148.5, 148.1, 138.9, 130.5, 123.5, 110.1, 109.5, 106.8, 101.1, 100.6, 75.7,55.4, 52.1, 46.3, 15.3, 10.4 ppm.

[0060] (9) Preparation of compound 4i. The preparation process was similar to that of step (1), except that 1-cyclopropylpiperazine was replaced by 1-acetylpiperazine to obtain the target compound 4i (183 mg, yield 46%).

[0061] Compound 4i was tested and the results were as follows:

[0062] 1 H NMR (400 MHz, CDCl3): d 7.18 (dd, J = 2.0, 1.0 Hz, 1H), 7.00 (ddd, J =7.5, 1.9, 1.0 Hz, 1H), 6.84 (dd, J = 1.9, 0.9 Hz, 2H), 6.77 (d, J = 7.5 Hz, 1H),6.31 (t, J = 2.0 Hz, 1H), 5.89 – 5.79 (m, 2H), 4.14 (t, J = 1.1 Hz, 1H), 4.00 –3.90 (m, 2H), 3.81 (s, 7H), 3.28 (dddd, J = 12.5, 6.6, 5.1, 3.1 Hz, 2H), 3.07(dddd, J = 12.5, 7.1, 5.6, 3.6 Hz, 2H), 2.31 (dddd, J = 12.3, 7.1, 5.6, 3.7 Hz,2H), 1.99 (s, 3H) ppm. 13 C NMR (100 MHz, CDCl3): d 169.5, 161.3, 148.5, 148.3,138.6, 130.1, 123.2, 110.8, 109.3, 106.1, 101.4, 100.6, 75.7, 55.4, 52.1,45.5, 21.3 ppm.

[0063] (10) Preparation of compound 4j. The preparation process was similar to that of step (1), except that 1-cyclopropylpiperazine was replaced with 1-(piperazin-1-yl)propan-2-ol to obtain the target compound 4j (128 mg, yield 31%).

[0064] Compound 4j was tested and the results were as follows:

[0065] 1 H NMR (400 MHz, CDCl3): d 7.00 (dd, J = 1.9, 1.0 Hz, 1H), 6.97 (ddd, J =7.5, 2.0, 1.1 Hz, 1H), 6.81 – 6.73 (m, 3H), 6.37 (t, J = 2.0 Hz, 1H), 5.86 (q, J = 5.0 Hz, 2H), 4.41 (t, J = 1.1 Hz, 1H), 3.81 (s, 6H), 2.93 (tt, J = 9.6, 2.6 Hz,4H), 2.55 – 2.46 (m, 2H), 2.43 (dddd, J = 10.5, 8.9, 6.4, 2.8 Hz, 2H), 1.42 (s,3H), 1.37 (s, 3H), 1.35 (s, 1H) ppm. 13 C NMR (100 MHz, CDCl3): d 161.3, 148.4,148.2, 138.5, 130.4, 123.3, 110.1, 109.7, 106.1, 101.2, 100.6, 85.2, 75.7,55.4, 51.3, 47.6, 26.6 ppm.

[0066] (11) Preparation of compound 4k. The preparation process was similar to that of step (1), except that 1-cyclopropylpiperazine was replaced by N-phenylpiperazine to obtain the target compound 4k (95 mg, yield 22%).

[0067] Compound 4k was tested and the results were as follows:

[0068] 1 H NMR (400 MHz, CDCl3): d 7.25 (t, J = 7.4 Hz, 2H), 7.20 (dd, J = 2.0, 1.0Hz, 1H), 7.00 (ddd, J= 7.3, 1.9, 1.0 Hz, 1H), 6.95 – 6.89 (m, 2H), 6.87 – 6.80(m, 3H), 6.77 (d, J = 7.5 Hz, 1H), 6.33 (t, J = 2.0 Hz, 1H), 5.89 – 5.79 (m, 2H), 4.12 (t, J = 1.1 Hz, 1H), 3.81 (s, 6H), 3.64 – 3.54 (m, 2H), 3.17 – 3.07 (m,2H), 3.04 – 2.94 (m, 2H), 2.49 – 2.37 (m, 2H) ppm. 13 C NMR (100 MHz, CDCl3): d 161.4, 150.7, 148.2, 148.1, 138.2, 130.5, 129.1, 123.5, 118.5, 116.2, 110.1,109.5, 106.8, 101.1, 100.0, 75.7, 55.4, 52.0, 49.0 ppm.

[0069] (12) Preparation of compound 4l. The preparation process was similar to that of step (1), except that 1-cyclopropylpiperazine was replaced by benzylpiperazine to obtain the target compound 4l (49 mg, yield 11%).

[0070] Compound 41 was tested and the results were as follows:

[0071] 1 H NMR (400 MHz, CDCl3): d 7.26 (s, 5H), 7.18 (dd, J = 1.8, 1.0 Hz, 1H),6.98 (ddd, J = 7.5, 2.0, 1.1 Hz, 1H), 6.82 (dd, J = 2.0, 1.1 Hz, 2H), 6.77 (d, J =7.5 Hz, 1H), 6.30 (t, J = 2.0 Hz, 1H), 5.82 (q, J = 5.0 Hz, 2H), 4.26 – 4.21 (m,1H), 4.10 (d, J= 12.4 Hz, 1H), 3.81 (s, 6H), 3.38 (d, J = 12.4 Hz, 1H), 3.30(td, J = 12.2, 2.1 Hz, 2H), 3.21 (td, J = 12.2, 2.0 Hz, 2H), 2.61 – 2.51 (m, 2H), 2.43 (dt, J = 12.2, 2.5 Hz, 2H) ppm. 13 C NMR (100 MHz, CDCl3): d 161.5, 148.7,148.2, 138.1, 138.4, 130.7, 128.1, 128.8, 127.2, 123.2, 110.2, 109.9, 106.2,101.2, 100.8, 75.7, 63.7, 55.4, 52.3, 51.3 ppm.

[0072] (13) Preparation of compound 4m. The preparation process was similar to that of step (1), except that 1-cyclopropylpiperazine was replaced by 1-benzoylpiperazine to obtain the target compound 4m (41 mg, yield 9%).

[0073] Compound 4m was tested and the results were as follows:

[0074] 1 H NMR (400 MHz, CDCl3): d 7.46 (dd, J = 7.6, 2.1 Hz, 2H), 7.43 – 7.37 (m,2H), 7.31 (ddt, J = 7.3, 5.8, 2.0 Hz, 1H), 7.17 (dd, J = 2.0, 1.0 Hz, 1H), 6.99(ddd, J = 7.5, 1.9, 1.0 Hz, 1H), 6.81 (dd, J = 1.9, 0.9 Hz, 2H), 6.77 (d, J = 7.5Hz, 1H), 6.37 (t, J = 2.0 Hz, 1H), 5.85 – 5.79 (m, 2H), 4.13 (t, J= 1.1 Hz, 1H), 3.81 (s, 6H), 3.75 (dddd, J = 12.3, 6.6, 5.1, 3.1 Hz, 2H), 3.41 – 3.32 (m, 2H), 3.09 (dddd, J = 12.3, 7.3, 5.6, 3.6 Hz, 2H), 2.34 (dddd, J = 12.3, 6.9, 5.4, 3.3Hz, 2H) ppm. 13 C NMR (100 MHz, CDCl3): d 170.2, 161.8, 148.4, 148.6, 138.3,136.7, 131.1, 130.8, 128.5, 128.4, 123.4, 110.6, 109.1, 106.4, 101.6, 100.3,75.7, 55.4, 52.1, 46.2 ppm.

[0075] (14) Preparation of compound 4n. The preparation process is similar to that of step (1), except that 1-cyclopropylpiperazine is replaced by 1-(4-methoxybenzyl)piperazine to obtain the target compound 4n (71 mg, yield 15%).

[0076] Compound 4n was tested and the results were as follows:

[0077] 1 H NMR (400 MHz, CDCl3): d 7.30 (dt, J = 7.6, 1.2 Hz, 2H), 7.17 (dd, J =2.0, 1.0 Hz, 1H), 6.99 (ddd, J = 7.5, 2.0, 0.9 Hz, 1H), 6.86 – 6.81 (m, 2H), 6.81 – 6.73 (m, 3H), 6.36 (t, J = 1.9 Hz, 1H), 5.88 – 5.80 (m, 2H), 4.28 – 4.22(m, 1H), 4.06 (dd, J = 12.2, 1.1 Hz, 1H), 3.80 (d, J = 4.9 Hz, 9H), 3.41 – 3.13(m, 5H), 2.59 (ddd,J = 11.6, 2.8, 1.7 Hz, 2H), 2.51 – 2.39 (m, 2H) ppm. 13 C NMR (100 MHz, CDCl3): d 161.9, 158.2, 148.5, 148.1, 138.6, 130.8, 129.3, 124.8,123.4, 113.3, 110.7, 109.7, 106.8, 101.3, 100.6, 75.7, 62.5, 55.4, 55.3,52.3, 51.3 ppm.

[0078] (15) Preparation of compound 4o. The preparation process was similar to that of step (1), except that 1-cyclopropylpiperazine was replaced by 1-(4-methoxybenzoyl)piperazine to obtain the target compound 4o (83 mg, yield 17%).

[0079] Compound 4o was tested and the results are as follows:

[0080] 1 H NMR (400 MHz, CDCl3): d 7.65 – 7.56 (m, 2H), 7.16 (dd, J = 1.9, 1.0 Hz,1H), 7.00 (ddd, J = 7.5, 2.0, 1.1 Hz, 1H), 6.97 – 6.90 (m, 2H), 6.81 (dd, J =2.0, 0.9 Hz, 2H), 6.77 (d, J = 7.4 Hz, 1H), 6.37 (t, J = 1.9 Hz, 1H), 5.86 – 5.78(m, 2H), 4.18 – 4.12 (m, 1H), 3.86 – 3.74 (m, 11H), 3.42 – 3.28 (m, 2H), 3.02(dddd, J = 12.2, 7.3, 5.6, 3.6 Hz, 2H), 2.34 (dddd, J = 12.4, 6.9, 5.4, 3.2 Hz,2H) ppm. 13 C NMR (100 MHz, CDCl3): d170.2, 162.2, 161.0, 148.2, 148.6, 138.2,132.9, 130.5, 128.2, 123.5, 113.5, 110.1, 109.5, 106.8, 101.5, 100.0, 75.7, 55.4, 55.3, 52.1, 46.2 ppm.

[0081] Example 2

[0082] In this example, the compound synthesized in Example 1 was subjected to WDR5-MLL1 enzymatic test.

[0083] The buffer used in this example contained 100 mM KH2PO4, 25 mM KCl and 0.01% Triton X-100, with a pH of 6.5; 10mer Thr-FAM was used as a probe, and the reaction was carried out in a 384-well black plate (No. 3575, Corning), with a total reaction volume of 60 μL (20 μL WDR5 protein, 20 μL FAM-based probe and 20 μL test compound). FPassay (λex=485±25nm; λem=535±25nm) was recorded using a SpectraMax GeminiXS (Molecular Devices, Sunnyvale, CA) instrument. The data were analyzed using GraphPad Prism version 6.0 software, and the IC50 values ​​represent three independent repeated measurements ± standard deviation; the results are shown in Table 1.

[0084] Table 1 WDR5-MLL1 enzymatic assay

[0085]

[0086] As can be seen from the above table, the positive drug DDO-2231 exhibits strong WDR5-MLL1 protein complex inhibitory activity. Although the compounds designed and synthesized by the present invention have similar structures, they exhibit differentiated IC50 data; relative to the positive drug, compounds 4a, 4d, 4j, 4k, 4m, 4n and 4o exhibit stronger activity than the positive drug, the N-alkyl acyl substituted structures 4f-4i lose their activity, and the N-aromatic acyl substituted molecules exhibit extremely strong activity.

[0087] Example 3

[0088] In this example, the activity of compound 4a-compound 4o was detected by CCK-8 method.

[0089] MV-4-11 cells were seeded in 96-well plates with 4000 cells per well and treated with different concentrations of inhibitors in culture medium for 72 hours. Cell viability was determined using a CCK8 kit (Biyuntian) according to the manufacturer's instructions. The results of the CCK8 activity test are shown below (Table 2): Although the positive drugs have strong inhibitory activity at the protein level, they show moderate activity in cells. Compounds 4a, 4b, 4c, 4d, 4e, 4k, 4l, 4m, 4n and 4o show strong inhibitory activity on AML cell proliferation.

[0090] Table 2 CCK-8 activity detection

[0091]

[0092] Example 4

[0093] In this example, subcutaneous tumor bearing experiments were performed on compounds 41 and 4o.

[0094] Nude mice aged 6-8 weeks were selected and injected subcutaneously with 1×10 7 MV-4-11 cells. The tumor hardened after about 10 days. Then the mice were randomly divided into 6 groups; divided into modeling groups: normal saline, DDO-2213 (oral administration, 100 mg / kg, once a day), compounds 4l and 4o (oral administration, 25 mg / kg, once a day), tumor volume and mouse body weight were measured every 3 days, and mice were killed after 21 days of administration. The results are shown in Table 3.

[0095] Table 3 In vivo tumor inhibition experiment

[0096]

[0097] As can be seen from the above table, the average tumor inhibition rate of mice treated with the positive drug (DDO-2213) was 68%, while the tumor inhibition rates of the tumor-bearing mice treated with compounds 4l and 4o were 94% and 92%, respectively, both of which are better than the positive drugs and have good development prospects.

[0098] Although the description of the present invention has been quite detailed and specifically describes several described embodiments, it is not intended to be limited to any of these details or embodiments or any particular embodiment, but should be regarded as providing a broad possible interpretation of these claims in view of the prior art by reference to the appended claims, thereby effectively covering the intended scope of the present invention. In addition, the above description of the present invention is based on the embodiments foreseeable by the inventor, and its purpose is to provide a useful description, and those non-substantial changes to the present invention that have not yet been foreseen may still represent equivalent changes to the present invention.

Claims

1. A diaryl methyl piperazine compound, characterized in that: The structure of the diaryl methyl piperazine compound is any one of the following compounds 4a-4e and 4j-4o: 。 2. A method for preparing the diaryl methyl piperazine compound according to claim 1, characterized in that: The preparation route of the diaryl methyl piperazine compound is as follows: ； Among them, R is , , , , , , , , , , Any one of .

3. Use of the diarylmethylpiperazine compound or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a WDR5-MLL1 inhibitor.

4. A WDR5-MLL1 inhibitor, characterized in that The main active ingredient is the diaryl methyl piperazine compound or a pharmaceutically acceptable salt thereof as described in claim 1.

5. Use of the WDR5-MLL1 inhibitor according to claim 4 in the preparation of a drug for treating and / or preventing cancer, characterized in that: The cancer is acute myeloid leukemia.

6. A pharmaceutical composition, characterized in that It includes the diaryl methyl piperazine compound or a pharmaceutically acceptable salt thereof as described in claim 1.

7. The pharmaceutical composition according to claim 6, characterized in that The pharmaceutical composition further includes an excipient.

8. The pharmaceutical composition according to claim 7, characterized in that The excipient is at least one of gum arabic, syrup, lanolin and starch.

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