Diaryl methyl pyrimidine piperazine compound as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention belongs to the technical field of chemistry, and particularly relates to a diaryl methyl pyrimidine piperazine compound as well as a preparation method, a pharmaceutical composition and application thereof. The structural formula of the diaryl methyl pyrimidine piperazine compound is shown as a formula I, and R is a substituted aromatic group. The preparation process is simple, the prepared diaryl methyl pyrimidine piperazine compound or the pharmaceutically acceptable salt thereof has the activity of efficiently inhibiting WDR5-MLL 1, and a targeted therapy scheme and novel, safe and efficient candidate drug molecules are provided for treating acute myeloid leukemia with WDR5-MLL fusion mutation. Experimental results show that the tumor inhibition rates of mouse tumor-bearing groups treated by the compounds 5c, 5k and 5l prepared by the invention are 79%, 85% and 75% respectively and are superior to those of a positive control group, and the compounds have good development prospects.

Description

Technical Field

[0001] The invention belongs to the field of chemical technology, and specifically relates to a diarylmethylpyrimidine 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 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.

[0004] 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 MLL1-WDR5 PPI, reducing MLL1 methyltransferase activity, and further reducing histone H3K4 methylation is a potential method for treating MLL1-FPs-induced leukemia. The development of small molecule inhibitors in recent years has also proved the feasibility of this method, but it is of great significance to continue to develop some new small molecule inhibitors for the treatment of diseases. Summary of the invention

[0005] The purpose of the present invention is to solve the deficiencies of the prior art and provide a diarylmethylpyrimidine piperazine compound and a preparation method, a pharmaceutical composition and application thereof, which specifically adopts the following technical scheme: In a first aspect of the present invention, a diarylmethylpyrimidine piperazine compound is provided, and the structural formula of the diarylmethylpyrimidine piperazine compound is shown in Formula I: Formula I, wherein R is a substituted aromatic group.

[0006] As a further preferred embodiment, the structure of the diarylmethylpyrimidine piperazine compound is any one of the following compounds 5a-51: .

[0007] The second aspect of the present invention provides a method for preparing the above-mentioned diarylmethylpyrimidine piperazine compound. The preparation route of the diarylmethylpyrimidine piperazine compound is as follows: ; Wherein, R is a substituted aromatic group.

[0008] In the present invention, aromatic acids with different substituent groups are reacted with piperonyl ring under acid catalysis through Friedel-Crafts acylation to generate diaryl ketone compounds, which are then subjected to reductive amination reaction with piperazine compounds to obtain compound 5.

[0009] The third aspect of the present invention provides the use of the above-mentioned diarylmethylpyrimidine piperazine compounds or pharmaceutically acceptable salts thereof in the preparation of WDR5-MLL1 inhibitors.

[0010] The fourth aspect of the present invention provides a WDR5-MLL1 inhibitor, wherein the WDR5-MLL1 inhibitor comprises the above-mentioned diarylmethylpyrimidine piperazine compound or a pharmaceutically acceptable salt thereof as a main active ingredient.

[0011] 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.

[0012] As a further preferred embodiment, the above cancer is acute myeloid leukemia cells.

[0013] In a sixth aspect of the present invention, a pharmaceutical composition is provided, which comprises the above-mentioned diarylmethylpyrimidine piperazine compound or a pharmaceutically acceptable salt thereof. The pharmaceutical composition also comprises an excipient. The excipient is at least one of gum arabic, syrup, lanolin, and starch. The excipient is stable in nature, has no incompatibility with the main drug, does not produce side effects, does not affect the efficacy, is not easy to deform, crack, mildew, or be eaten by insects at room temperature, is harmless to the human body, has no physiological effect, does not produce chemical or physical effects with the main drug, and does not affect the content determination of the main drug.

[0014] The beneficial effects of the present invention are: The preparation process of the present invention is simple, and the prepared diarylmethylpyrimidine piperazine compound or its pharmaceutically acceptable salt has the activity of effectively inhibiting WDR5-MLL1, providing a targeted treatment scheme and a novel safe and efficient candidate drug molecule for treating acute myeloid leukemia with WDR5-MLL fusion mutation. According to the experimental results of the present invention, the tumor inhibition rates of the tumor-bearing mouse group treated with the compounds 5c, 5k and 5l prepared by the present invention were 79%, 85% and 75%, respectively, which were better than the positive control group, and had good development prospects. DETAILED DESCRIPTION

[0015] 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.

[0016] The present invention provides a diarylmethylpyrimidine piperazine compound, the structural formula of the diarylmethylpyrimidine piperazine compound is shown in Formula I: Formula I, wherein R is a substituted aromatic group.

[0017] The present invention also provides a method for preparing the above-mentioned diarylmethylpyrimidine piperazine compounds, and the preparation route thereof is as follows: ; The specific preparation process is as follows: (1) Preparation of compound 3: The substituted aromatic acid 1 (1.0 mmol, 1.0 eq), piperonyl 2 (1.5 mmol, 1.5 eq) and trifluoroacetic anhydride (2.0 mmol, 2.0 eq) were dissolved in trifluoroacetic acid (10.0 mL), reacted at room temperature for 12 hours, quenched with water, extracted with ethyl acetate (3 × 20 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography to obtain the intermediate diaryl ketone compound 3.

[0018] (2) Preparation of compound 5: At zero degrees Celsius, the intermediate diaryl ketone compound 3 (1.0 mmol, 1.0 eq) was dissolved in a mixed solvent of tetrahydrofuran and methanol, and then piperidine 4 (1.2 mmol, 1.2 eq) and sodium cyanoborohydride (2.0 mmol, 2.0 eq) were added. After TLC detection showed that the reaction of the raw materials was complete, saturated sodium bicarbonate was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography to obtain the target compound 5.

[0019] Example 1 Preparation of diarylmethylpyrimidine piperazine compounds (5a-5l), whose structural formula is as follows: (1) Preparation of compound 5a. The specific process is as follows: Step 1, preparation of compound 3a, the structure of which is as follows: ; The specific preparation process is as follows: piperic acid (1.0 mmol, 1.0 eq), piperonyl ring (1.5 mmol, 1.5 eq) and trifluoroacetic anhydride (2.0 mmol, 2.0 eq) were dissolved in trifluoroacetic acid (10.0 mL), reacted at room temperature for 12 hours, quenched the reaction with water, extracted with ethyl acetate (3 × 20 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography to obtain the intermediate diaryl ketone compound 3a (172 mg, yield 64%).

[0020] Compound 3a was tested and the results were as follows: 1 H NMR (400 MHz, CDCl3): d 7.47 – 7.38 (m, 4H), 6.99 (d, J = 7.3 Hz, 2H), 6.07 (s, 4H) ppm. 13 C NMR (100 MHz, CDCl3): d 196.6, 147.7, 133.6, 124.2, 109.3, 108.1, 101.5 ppm.

[0021] Step 2, preparation of compound 5a: At zero degrees Celsius, the intermediate diaryl ketone compound 3a (1.0 mmol, 1.0 eq) was dissolved in a mixed solvent of tetrahydrofuran and methanol, and then piperidine 4 (1.2 mmol, 1.2 eq) and sodium cyanoborohydride (2.0 mmol, 2.0 eq) were added. After TLC detection showed that the reaction of the raw materials was complete, saturated sodium bicarbonate was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography to obtain the target compound 5a (175 mg, yield was 42%).

[0022] Compound 5a was tested and the results were as follows: 1 H NMR (400 MHz, CDCl3): d 8.31 (d, J = 4.6 Hz, 2H), 6.81 (ddd, J = 8.4,1.8, 0.8 Hz, 2H), 6.77 (d, J = 8.3 Hz, 2H), 6.75 (dd, J= 1.7, 0.8 Hz, 2H), 6.55(t, J = 4.5 Hz, 1H), 5.92 (s, 4H), 4.58 (t, J = 0.8 Hz, 1H), 3.73 (ddd, J = 12.8,6.8, 4.1 Hz, 4H), 2.53 (dddd, J = 96.7, 12.5, 6.9, 4.1 Hz, 4H) ppm. 13 C NMR (100MHz, CDCl3): d 161.7, 157.6, 147.8, 147.6, 134.4, 122.1, 110.0, 109.3, 109.1,101.0, 72.8, 52.1, 45.1 ppm.

[0023] (2) Preparation of compound 5b. The specific process is as follows: Step 1, preparation of compound 3b, the structure of which is as follows: ; The specific process is similar to the preparation process of compound 3a, the only difference is that piperic acid is replaced with 3-trifluoromethylbenzoic acid to obtain the intermediate diaryl ketone compound 3b (111 mg, yield 38%).

[0024] Compound 3b was tested and the results were as follows: 1 H NMR (400 MHz, CDCl3): d 7.93 (dt, J = 7.5, 2.0 Hz, 1H), 7.87 – 7.80 (m,1H), 7.69 – 7.60 (m, 1H), 7.43 (dd, J = 7.5, 2.0 Hz, 1H), 7.40 (d, J = 2.1 Hz,1H), 7.29 (t, J = 7.5 Hz, 1H), 6.99 (d, J = 7.5 Hz, 1H), 6.07 (s, 2H) ppm. 13 C NMR (100 MHz, CDCl3): d196.6, 147.7, 136.8, 136.7, 136.7, 133.6, 132.7, 132.2,131.9, 131.7, 131.4, 130.3, 130.2, 130.2, 130.2, 129.6, 129.6, 129.6, 126.7,126.4, 126.4, 126.4, 126.3, 124.5, 124.2, 122.4, 120.3, 109.3, 108.1, 101.5ppm.

[0025] Step 2, preparation of compound 5b: The preparation process was similar to that of compound 5a, except that compound 3a was replaced by compound 3b to obtain the target compound 5b (216 mg, yield 49%).

[0026] Compound 5b was tested and the results were as follows: 1 H NMR (400 MHz, CDCl3): d 8.31 (d, J = 4.6 Hz, 2H), 7.57 – 7.54 (m, 2H), 7.50 (dd, J = 10.8, 7.5 Hz, 1H), 7.37 – 7.34 (m, 1H), 6.81 (dd, J = 8.2, 1.5 Hz,1H), 6.77 (d, J = 8.3 Hz, 1H), 6.76 – 6.75 (m, 1H), 6.55 (t, J = 4.5 Hz, 1H),5.92 (s, 2H), 4.57 (t, J = 0.9 Hz, 1H), 3.79 (dddd, J = 44.5, 12.3, 6.5, 4.4 Hz,4H), 3.53 – 3.42 (m, 4H) ppm. 13 C NMR (100 MHz, CDCl3): d161.7, 157.6, 147.8,147.6, 139.1, 139.1, 134.5, 130.4, 130.2, 129.5, 129.5, 129.5, 129.5, 127.9,127.5, 127.4, 127.4, 127.4, 125.1, 124.1, 124.0, 124.0, 124.0, 123.0, 122.1, 110.0, 109.3, 109.1, 101.0, 72.5, 52.1, 45.1 ppm.

[0027] (3) Preparation of compound 5c. The specific process is as follows: Step 1, preparation of compound 3c, the structure of which is as follows: ; The specific process is similar to the preparation process of compound 3a, the only difference is that piperic acid is replaced with 3,5-bis(trifluoromethyl)benzoic acid to obtain the intermediate diaryl ketone compound 3c (163 mg, yield 45%).

[0028] Compound 3c was tested and the results were as follows: 1 H NMR (400 MHz, CDCl3): d 8.01 (d, J = 2.2 Hz, 2H), 7.86 – 7.78 (m, 1H), 7.48 – 7.36 (m, 2H), 6.99 (d, J = 7.5 Hz, 1H), 6.07 (s, 2H) ppm. 13 C NMR (100MHz, CDCl3): d 194.7, 147.7, 137.7, 137.6, 137.6, 132.9, 132.9, 132.9, 132.7,132.6, 132.6, 132.6, 132.4, 132.4, 132.4, 132.1, 132.1, 132.1, 128.1, 128.1,128.0, 128.0, 127.2, 125.1, 124.2, 123.5, 123.5, 123.4, 123.4, 123.4, 122.9,120.5, 109.3, 108.1, 101.5 ppm.

[0029] Step 2, preparation of compound 5c: The preparation process was similar to that of compound 5a, except that compound 3a was replaced by compound 3c to obtain the target compound 5c (377 mg, yield 74%).

[0030] Compound 5c was tested and the results were as follows: 1 H NMR (400 MHz, CDCl3): d 8.31 (d, J = 4.6 Hz, 2H), 7.78 (t, J = 2.2 Hz,1H), 7.58 (dd, J = 2.1, 1.0 Hz, 2H), 6.81 (dd, J = 8.2, 1.5 Hz, 1H), 6.77 (d, J =8.3 Hz, 1H), 6.76 – 6.75 (m, 1H), 6.55 (t, J = 4.5 Hz, 1H), 5.92 (s, 2H), 4.58(d, J = 0.9 Hz, 1H), 3.79 (dddd, J = 44.5, 12.3, 6.5, 4.4 Hz, 4H), 3.54 – 3.39(m, 4H) ppm. 13 C NMR (100 MHz, CDCl3): d 161.7, 157.6, 147.8, 147.6, 141.1,141.1, 141.1, 134.3, 132.2, 132.2, 132.0, 131.9, 127.4, 127.4, 127.3, 127.3,126.8, 124.6, 122.5, 122.3, 122.2, 122.2, 122.2, 122.1, 122.1, 120.3, 110.0,109.3, 109.1, 101.0, 72.4, 52.1, 45.1 ppm.

[0031] (4) Preparation of compound 5d. The specific process is as follows: Step 1, preparation of compound 3d, the structure of which is as follows: ; The specific process is similar to the preparation process of compound 3a, the only difference is that piperic acid is replaced with 1-methyl-1H-indole-6-carboxylic acid to obtain the intermediate diaryl ketone compound 3d (136 mg, yield 49%).

[0032] Compound 3d was tested and the results were as follows: 1 H NMR (400 MHz, CDCl3): d 7.79 (d, J = 1.7 Hz, 1H), 7.61 (dd, J = 7.5, 1.5Hz, 1H), 7.49 (dd, J = 7.5, 1.6 Hz, 1H), 7.34 – 7.27 (m, 2H), 7.21 (d, J = 7.4Hz, 1H), 6.85 (d, J = 7.4 Hz, 1H), 6.52 (dd, J = 7.4, 1.5 Hz, 1H), 6.07 (s, 2H), 3.86 (s, 3H) ppm. 13 C NMR (100 MHz, CDCl3): d 196.6, 147.7, 136.3, 133.6, 132.1,126.6, 126.3, 124.4, 124.2, 120.6, 111.1, 109.3, 108.1, 101.5, 101.3, 32.9ppm.

[0033] Step 2, preparation of compound 5d: The preparation process was similar to that of compound 5a, except that compound 3a was replaced by compound 3d to obtain the target compound 5d (282 mg, yield 66%).

[0034] Compound 5d was tested and the results were as follows: 1 H NMR (400 MHz, CDCl3): d 8.31 (d, J = 4.6 Hz, 2H), 7.50 – 7.43 (m, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.24 – 7.20 (m, 1H), 7.15 (dd, J = 8.0, 2.0 Hz, 1H),6.81 (dd,J = 8.1, 1.5 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 6.76 – 6.75 (m, 1H), 6.59 – 6.50 (m, 2H), 5.92 (s, 2H), 4.58 (s, 1H), 3.86 – 3.71 (m, 7H), 3.53 –3.41 (m, 4H) ppm. 13 C NMR (100 MHz, CDCl3): d 161.7, 157.6, 147.8, 147.6, 137.0,136.1, 134.5, 130.6, 128.7, 124.0, 122.1, 120.3, 110.0, 109.3, 109.1, 102.4,101.0, 72.8, 52.1, 45.1, 33.0 ppm.

[0035] (5) Preparation of compound 5e. The specific process is as follows: Step 1, preparation of compound 3e, the structure of which is as follows: ; The specific process is similar to the preparation process of compound 3a, the only difference is that piperic acid is replaced by veratric acid to obtain the intermediate diaryl ketone compound 3e (203 mg, yield 71%).

[0036] Compound 3e was tested and the results were as follows: 1 H NMR (400 MHz, CDCl3): d 7.49 (dd, J = 8.6, 2.0 Hz, 2H), 7.31 (dd, J =8.5, 1.9 Hz, 2H), 7.01 (d, J = 8.6 Hz, 1H), 6.89 (d, J = 8.6 Hz, 1H), 6.01 (s,2H), 3.86 (d, J = 2.2 Hz, 6H) ppm. 13 C NMR (100 MHz, CDCl3): d195.2, 154.3, 149.7,149.5, 147.9, 132.5, 132.3, 125.3, 124.6, 113.3, 112.1, 109.7, 108.9, 101.5,55.9, 55.8 ppm.

[0037] Step 2, preparation of compound 5e: The preparation process was similar to that of compound 5a, except that compound 3a was replaced by compound 3e to obtain the target compound 5e (186 mg, yield 43%).

[0038] Compound 5e was tested and the results were as follows: 1 H NMR (400 MHz, CDCl3): d 8.31 (d, J = 4.6 Hz, 2H), 6.84 (d, J = 8.3 Hz,1H), 6.82 (dd, J = 1.5, 0.8 Hz, 1H), 6.82 – 6.80 (m, 1H), 6.80 (d, J = 1.2 Hz,1H), 6.77 (d, J = 8.3 Hz, 1H), 6.76 – 6.75 (m, 1H), 6.55 (t, J = 4.5 Hz, 1H), 5.92 (s, 2H), 4.59 (q, J = 0.9 Hz, 1H), 3.86 – 3.71 (m, 10H), 3.52 – 3.41 (m, 4H) ppm. 13 C NMR (100 MHz, CDCl3): d 161.7, 157.6, 149.5, 149.0, 147.8, 147.6,134.4, 134.4, 122.5, 122.1, 112.9, 112.7, 110.0, 109.3, 109.1, 101.0, 72.8,55.8, 52.1, 45.1 ppm.

[0039] (6) Preparation of compound 5f. The specific process is as follows: Step 1, preparation of compound 3f, the structure of which is as follows: ; The specific process is similar to the preparation process of compound 3a, the only difference is that piperic acid is replaced with 3-methoxybenzoic acid to obtain the intermediate diaryl ketone compound 3f (161 mg, yield 63%).

[0040] Compound 3f was tested and the results were as follows: 1 H NMR (400 MHz, CDCl3): d 7.57 (ddd, J = 7.9, 2.6, 1.1 Hz, 1H), 7.49 (dd, J = 6.8, 1.8 Hz, 1H), 7.48 – 7.45 (m, 1H), 7.37 (t, J = 2.2 Hz, 1H), 7.30 (s,1H), 7.05 (ddd, J = 7.9, 1.8, 0.9 Hz, 1H), 7.01 (d, J = 8.6 Hz, 1H), 6.01 (s, 2H), 3.82 (s, 3H) ppm. 13 C NMR (100 MHz, CDCl3): d 195.4, 159.6, 149.7, 147.9,137.7, 132.5, 129.7, 124.6, 124.1, 117.9, 113.8, 109.7, 108.9, 101.5, 55.4ppm.

[0041] Step 2, preparation of compound 5f: The preparation process was similar to that of compound 5a, except that compound 3a was replaced by compound 3f to obtain the target compound 5f (210 mg, yield 52%).

[0042] Compound 5f was tested and the results were as follows: 1 H NMR (400 MHz, CDCl3): d 8.31 (d, J = 4.6 Hz, 2H), 7.28 (t, J = 8.0 Hz,1H), 6.92 (dq, J = 8.2, 1.1 Hz, 1H), 6.84 (t, J = 1.2 Hz, 1H), 6.83 (d, J= 1.2 Hz,1H), 6.81 (dd, J = 8.5, 1.9 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 6.76 – 6.75 (m,1H), 6.55 (t, J = 4.5 Hz, 1H), 5.92 (s, 2H), 4.63 – 4.55 (m, 1H), 3.86 – 3.71 (m, 7H), 3.52 – 3.42 (m, 4H) ppm. 13 C NMR (100 MHz, CDCl3): d 161.7, 158.3,157.6, 147.8, 147.6, 140.4, 134.3, 129.5, 122.1, 122.1, 114.8, 114.6, 110.0,109.3, 109.1, 101.0, 72.9, 55.2, 52.1, 45.1 ppm.

[0043] (7) Preparation of compound 5g. The specific process is as follows: Step 1, preparation of compound 3g, the structure of which is as follows: ; The specific process is similar to the preparation process of compound 3a, the only difference is that piperic acid is replaced with 3,5-difluorobenzoic acid to obtain the intermediate diaryl ketone compound 3g (76 mg, yield 29%).

[0044] Compound 3g was tested and the results were as follows: 1 H NMR (400 MHz, CDCl3): d 7.50 (dd, J = 8.5, 1.9 Hz, 1H), 7.49 – 7.46 (m,2H), 7.32 (d, J = 1.9 Hz, 1H), 7.06 (tt, J = 8.1, 2.2 Hz, 1H), 7.02 (d, J = 8.6 Hz,1H), 6.01 (s, 2H) ppm. 13 C NMR (100 MHz, CDCl3): d194.5, 194.5, 194.4, 163.8,163.8, 161.8, 161.7, 149.7, 147.9, 138.9, 138.8, 138.7, 132.7, 124.6, 114.2,114.1, 114.0, 114.0, 109.7, 108.9, 107.9, 107.8, 107.6, 101.5 ppm.

[0045] Step 2, preparation of compound 5g: The preparation process was similar to that of compound 5a, except that compound 3a was replaced by compound 3g to obtain the target compound 5g (291 mg, yield 71%).

[0046] Compound 5g was tested and the results were as follows: 1 H NMR (400 MHz, CDCl3): d 8.31 (d, J = 4.6 Hz, 2H), 7.04 (ddt, J = 7.2,2.1, 0.9 Hz, 2H), 6.94 (tt, J = 7.9, 2.2 Hz, 1H), 6.81 (dd, J = 8.2, 1.6 Hz, 1H),6.77 (d, J = 8.3 Hz, 1H), 6.76 – 6.75 (m, 1H), 6.55 (t, J = 4.5 Hz, 1H), 5.92 (s, 2H), 4.55 (d, J = 0.9 Hz, 1H), 3.79 (dddd, J = 44.5, 12.3, 6.5, 4.4 Hz, 4H), 3.55– 3.40 (m, 4H) ppm. 13 C NMR (100 MHz, CDCl3): d 163.8, 163.7, 161.8, 161.7,157.6, 147.8, 147.6, 141.7, 141.6, 141.5, 134.3, 122.1, 112.9, 112.8, 112.7,112.7, 110.0, 109.3, 109.1, 104.8, 104.7, 104.5, 101.0, 72.6, 72.5, 72.5,52.1, 45.1 ppm.

[0047] (8) Preparation of compound 5h. The specific process is as follows: Step 1, preparation of compound 3h, the structure of which is as follows: ; The specific process is similar to the preparation process of compound 3a, the only difference is that piperic acid is replaced with benzofuran-6-carboxylic acid to obtain the intermediate diaryl ketone compound 3h (85 mg, yield 32%).

[0048] Compound 3h was tested and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 8.13 (d, J = 1.6 Hz, 1H), 7.86 (t, J = 1.0 Hz,2H), 7.82 – 7.79 (m, 1H), 7.50 (dd, J = 8.5, 1.9 Hz, 1H), 7.32 (d, J = 2.0 Hz,1H), 7.03 (p, J = 0.6 Hz, 1H), 7.01 (d, J = 8.6 Hz, 1H), 6.01 (s, 2H) ppm. 13 C NMR (100 MHz, CDCl3): d 195.4, 154.5, 149.7, 147.9, 145.1, 134.3, 133.4, 132.6, 124.6, 124.5, 123.6, 110.6, 109.7, 108.9, 108.4, 101.5 ppm.

[0049] Step 2, preparation of compound 5h: The preparation process was similar to that of compound 5a, except that compound 3a was replaced by compound 3h to obtain the target compound 5h (211 mg, yield 51%).

[0050] Compound 5h was tested and the results were as follows: 1 H NMR (400 MHz, CDCl3): d 8.31 (d, J = 4.6 Hz, 2H), 7.72 (dd, J = 8.0, 1.1Hz, 1H), 7.69 (d,J = 1.6 Hz, 1H), 7.33 (d, J = 1.8 Hz, 1H), 7.10 (dd, J = 8.3, 1.9Hz, 1H), 6.82 – 6.80 (m, 1H), 6.79 (d, J = 1.6 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H),6.76 – 6.75 (m, 1H), 6.55 (t, J = 4.5 Hz, 1H), 5.92 (s, 2H), 4.62 (d, J = 0.7 Hz,1H), 3.83 (ddd, J = 12.5, 6.7, 4.4 Hz, 2H), 3.74 (ddd, J = 12.3, 6.5, 4.4 Hz,2H), 3.55 – 3.40 (m, 4H) ppm. 13 C NMR (100 MHz, CDCl3): d 161.7, 157.6, 155.4,147.8, 147.6, 144.9, 137.7, 134.3, 129.9, 124.7, 123.1, 122.1, 111.4, 110.0,109.3, 109.1, 108.2, 101.0, 72.3, 52.1, 45.1 ppm.

[0051] (9) Preparation of compound 5i. The specific process is as follows: Step 1, preparation of compound 3i, the structure of which is as follows: , The specific process is similar to the preparation process of compound 3a, the only difference is that piperic acid is replaced with 3-fluoro-5-methoxybenzoic acid to obtain the intermediate diaryl ketone compound 3i (112 mg, yield 41%).

[0052] Compound 3i was tested and the results were as follows: 1 H NMR (400 MHz, CDCl3): d 7.49 (dd, J = 8.5, 1.9 Hz, 1H), 7.42 (dt, J=8.1, 2.1 Hz, 1H), 7.30 (s, 1H), 7.13 (t, J = 2.2 Hz, 1H), 7.02 (d, J = 8.6 Hz,1H), 6.81 (dt, J = 8.1, 2.2 Hz, 1H), 6.01 (s, 2H), 3.81 (s, 3H) ppm. 13 C NMR (100MHz, CDCl3): d 194.4, 194.3, 163.3, 161.3, 161.0, 160.9, 149.7, 147.9, 139.1,139.0, 132.6, 124.6, 112.0, 111.9, 111.5, 111.5, 109.7, 108.9, 105.4, 105.3, 101.5, 55.6 ppm.

[0053] Step 2, preparation of compound 5i: The preparation process was similar to that of compound 5a, except that compound 3a was replaced by compound 3i to obtain the target compound 5i (219 mg, yield 52%).

[0054] Compound 5i was tested and the results were as follows: 1 H NMR (400 MHz, CDCl3): d 8.31 (d, J = 4.6 Hz, 2H), 6.95 (dtd, J = 7.9,2.0, 0.9 Hz, 1H), 6.81 (dd, J = 8.5, 1.9 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 6.76– 6.75 (m, 1H), 6.67 (td, J = 2.0, 1.0 Hz, 1H), 6.64 (dt, J = 7.9, 2.1 Hz, 1H),6.55 (t, J = 4.5 Hz, 1H), 5.92 (s, 2H), 4.59 (t, J = 0.9 Hz, 1H), 3.87 – 3.69 (m,7H), 3.54 – 3.40 (m, 4H) ppm. 13C NMR (100 MHz, CDCl3): d 164.1, 162.1, 161.7,160.4, 160.3, 157.6, 147.8, 147.6, 142.3, 142.3, 134.3, 122.1, 110.8, 110.6,110.6, 110.0, 109.3, 109.1, 101.0, 101.0, 100.8, 72.8, 72.8, 55.6, 52.1, 45.1ppm.

[0055] (10) Preparation of compound 5j. The specific process is as follows: Step 1, preparation of compound 3j, the structure of which is as follows: ; The specific process is similar to the preparation process of compound 3a, the only difference is that piperic acid is replaced with 3-methoxy-5-methylbenzoic acid to obtain the intermediate diaryl ketone compound 3j (140 mg, yield 52%).

[0056] Compound 3j was tested and the results were as follows: 1 H NMR (400 MHz, CDCl3): d 7.49 (dd, J = 8.6, 1.8 Hz, 1H), 7.44 (t, J = 2.4Hz, 1H), 7.28 (s, 1H), 7.18 (t, J = 2.2 Hz, 1H), 7.02 (d, J = 8.6 Hz, 1H), 6.74(t, J = 2.2 Hz, 1H), 6.01 (s, 2H), 3.82 (s, 3H) ppm. 13 C NMR (100 MHz, CDCl3): d 194.3, 159.8, 149.7, 147.9, 139.4, 137.7, 132.5, 125.2, 124.6, 117.5, 112.9,109.7, 108.9, 101.5, 55.6, 21.1 ppm.

[0057] Step 2, preparation of compound 5j: The preparation process was similar to that of compound 5a, except that compound 3a was replaced by compound 3j to obtain the target compound 5j (250 mg, yield 60%).

[0058] Compound 5j was tested and the results were as follows: 1 H NMR (400 MHz, CDCl3): d 8.31 (d, J = 4.6 Hz, 2H), 6.93 – 6.90 (m, 1H), 6.81 (dd, J = 8.5, 1.9 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 6.76 – 6.74 (m, 1H), 6.70 (td, J = 2.2, 0.9 Hz, 1H), 6.67 – 6.65 (m, 1H), 6.55 (t, J = 4.5 Hz, 1H), 5.92 (s, 2H), 4.57 (q, J = 0.9 Hz, 1H), 3.89 – 3.67 (m, 7H), 3.56 – 3.39 (m, 4H) ppm. 13 C NMR (100 MHz, CDCl3): d 161.7, 159.8, 157.6, 147.8, 147.6, 140.7,140.1, 134.3, 123.9, 122.1, 113.8, 111.5, 110.0, 109.3, 109.1, 101.0, 73.4, 55.6, 52.1, 45.1, 21.1 ppm.

[0059] (11) Preparation of compound 5k. The specific process is as follows: Step 1, preparation of compound 3k, the structure of which is as follows: ; The specific process is similar to the preparation process of compound 3a, the only difference is that piperic acid is replaced with 3,5-dimethoxybenzoic acid to obtain the intermediate diaryl ketone compound 3k (88 mg, yield 31%).

[0060] Compound 3k was tested and the results are as follows: 1 H NMR (400 MHz, CDCl3): d 7.48 (dd, J = 8.5, 1.9 Hz, 1H), 7.27 (s, 1H), 7.05 (d, J = 2.2 Hz, 2H), 7.02 (d, J = 8.6 Hz, 1H), 6.62 (t, J = 2.2 Hz, 1H), 6.01(s, 2H), 3.81 (s, 6H) ppm. 13 C NMR (100 MHz, CDCl3): d 194.3, 160.6, 149.7,147.9, 138.8, 132.5, 124.6, 109.7, 109.0, 108.9, 104.3, 101.5, 55.5 ppm.

[0061] Step 2, preparation of compound 5k: The preparation process was similar to that of compound 5a, except that compound 3a was replaced by compound 3k to obtain the target compound 5k (160 mg, yield 37%).

[0062] Compound 5k was tested and the results were as follows: 1 H NMR (400 MHz, CDCl3): d 8.31 (d, J = 4.6 Hz, 2H), 6.81 (dd, J = 8.5, 1.9Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 6.76 – 6.74 (m, 1H), 6.56 (dd, J = 2.2, 1.1Hz, 2H), 6.54 (d, J = 4.5 Hz, 1H), 6.47 (t, J = 2.1 Hz, 1H), 5.92 (s, 2H), 4.59(p, J = 1.1 Hz, 1H), 3.90 – 3.67 (m, 10H), 3.55 – 3.37 (m, 4H) ppm. 13 C NMR (100MHz, CDCl3): d161.7, 160.9, 157.6, 147.8, 147.6, 142.2, 134.3, 122.1, 110.0,109.3, 109.1, 108.4, 101.0, 100.1, 73.1, 55.5, 52.1, 45.1 ppm.

[0063] (12) The preparation of compound 51 is as follows: Step 1, preparation of compound 31, the structure of which is as follows: ; The specific process is similar to the preparation process of compound 3a, the only difference is that piperic acid is replaced with 3,4,5-trimethoxybenzoic acid to obtain the intermediate diaryl ketone compound 3l (132 mg, yield 42%).

[0064] Compound 31 was tested and the results were as follows: 1 H NMR (400 MHz, CDCl3): d 7.48 (dd, J = 8.6, 2.0 Hz, 1H), 7.28 (d, J = 1.9Hz, 1H), 7.04 (s, 2H), 7.02 (d, J = 8.6 Hz, 1H), 6.01 (s, 2H), 3.86 (s, 6H), 3.79 (s, 3H) ppm. 13 C NMR (100 MHz, CDCl3): d 194.2, 152.6, 149.7, 147.9, 143.6,132.5, 131.1, 124.6, 109.7, 108.9, 107.3, 101.5, 60.7, 56.2 ppm.

[0065] Step 2, preparation of compound 5l: The preparation process was similar to that of compound 5a, except that compound 3a was replaced by compound 3l to obtain the target compound 5l (310 mg, yield 67%).

[0066] Compound 51 was tested and the results were as follows: 1 H NMR (400 MHz, CDCl3): d 8.31 (d, J = 4.6 Hz, 2H), 6.81 (dd,J = 8.5, 1.9Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 6.76 – 6.75 (m, 1H), 6.55 (d, J = 4.5 Hz, 1H),6.54 (d, J = 1.1 Hz, 2H), 5.92 (s, 2H), 4.68 – 4.52 (m, 1H), 3.86 – 3.71 (m,13H), 3.55 – 3.38 (m, 4H) ppm. 13 C NMR (100 MHz, CDCl3): d 161.7, 157.6, 152.7,147.8, 147.6, 138.8, 136.3, 134.3, 122.0, 110.0, 109.3, 109.1, 105.9, 101.0,73.0, 60.7, 56.1, 52.1, 45.1 ppm.

[0067] Example 2 In this example, the compounds (5a-5l) synthesized in Example 1 were subjected to WDR5-MLL1 enzymatic assay. 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. Using 10mer Thr-FAM as a probe, 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. IC50 values ​​represent three independent replicates ± standard deviation; the results are shown in Table 1.

[0068] Table 1 WDR5-MLL1 enzymatic assay 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 show differentiated IC50 data. Compared with the positive drugs, compounds 5b, 5c, 5d, 5e, 5j, 5k and 5l show similar or stronger inhibitory activity. Among them, compound 5k shows the strongest inhibitory activity, which is much stronger than the positive drugs, while compounds 5a, 5g, 5h and 5i have poor or no activity.

[0069] Example 3 In this example, the activity of compounds 5a to 5l was detected by CCK-8 method. 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 5b, 5c, 5d, 5e, 5j, 5k and 5l showed strong activity in inhibiting the proliferation of AML cells.

[0070] Table 2 CCK-8 activity detection Example 4 In this example, subcutaneous tumor bearing experiments were performed on compounds 5c, 5k and 5l. Nude mice aged 6-8 weeks were selected and injected subcutaneously with 1×10 7 MV-4-11 cells. The tumor can be felt to become hard after about 10 days. Then the mice were randomly divided into groups, with 6 mice in each group. They were divided into a control group and a modeling group, and were given normal saline, DDO-2213 (oral administration, 100 mg / kg, once a day) and compounds 5c, 5k and 5l (oral administration, 50 mg / kg, once a day). The tumor volume and mouse body weight were measured every 3 days, and the mice were killed after 21 days of administration. The results are shown in Table 3.

[0071] Table 3 In vivo tumor inhibition activity experiment As can be seen from the above table, the average tumor inhibition rate of mice treated with positive drugs was 65%, while the tumor inhibition rates of the tumor-bearing mouse groups treated with compounds 5c, 5k and 5l were 79%, 85% and 75%, respectively, which were all better than the positive control group and have good development prospects.

[0072] 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 diarylmethylpyrimidine piperazine compound, characterized in that: The structural formula of the diarylmethylpyrimidine piperazine compound is shown in Formula I: Formula I, wherein R is a substituted aromatic group.

2. The diarylmethylpyrimidine piperazine compound according to claim 1, characterized in that: The structure of the diarylmethylpyrimidine piperazine compound is any one of the following compounds 5a-51: 。 3. A method for preparing the diarylmethylpyrimidine piperazine compound according to any one of claims 1 to 2, characterized in that: The preparation route of the diarylmethylpyrimidine piperazine compound is as follows: ； Wherein, R is a substituted aromatic group.

4. Use of the diarylmethylpyrimidine piperazine compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 in the preparation of a WDR5-MLL1 inhibitor.

5. A WDR5-MLL1 inhibitor, characterized in that The main active ingredient is the diarylmethylpyrimidine piperazine compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 2.

6. Use of the WDR5-MLL1 inhibitor according to claim 5 in the preparation of a drug for treating and / or preventing cancer.

7. The use according to claim 6, characterized in that: The cancer is acute myeloid leukemia cells.

8. A pharmaceutical composition, characterized in that The invention comprises a diarylmethylpyrimidine piperazine compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2.

9. The pharmaceutical composition according to claim 8, characterized in that The pharmaceutical composition further includes an excipient.

10. The pharmaceutical composition according to claim 9, characterized in that The excipient is at least one of gum arabic, syrup, lanolin and starch.

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