Phenyltriazole inhibitors of MLL1-WDR5 protein-protein interaction

Abstract

The present invention discloses a class of phenyltriazole MLL1-WDR5 protein-protein interaction inhibitors (I) and a preparation method thereof. Pharmacodynamic experiments show that the compounds of the present invention have strong MLL1-WDR5 protein-protein interaction inhibitory activity.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a class of phenyltriazole MLL1-WDR5 protein-protein interaction inhibitors, and their preparation and medical use. Background Art

[0002] Histone methylation plays a key role in many biological processes and is the main research topic in the field of epigenetic regulation. Translocation and rearrangement of the histone H3K4 methyltransferase MLL1 gene can lead to mixed lineage leukemia (MLL1, acute myeloid leukemia and acute lymphocytic leukemia). About 10% of leukemia patients have rearrangement of the MLL1 gene. After the MLL1 gene is rearranged, it fuses with other partner protein genes to form a fusion gene, expressing the MLL fusion protein with carcinogenic effects. The fusion protein can interact with RNA polymerase II (Pol II)-related elongation factors to form a super elongation complex (SEC). This complex causes abnormal expression of Hox genes regulated by MLL1 through Pol II, which in turn causes a series of serious consequences and induces the occurrence of MLL leukemia.

[0003] The chromosomal translocation of MLL1 only occurs on a single allele, and there is also a wild-type MLL1. If the wild-type MLL1 allele is knocked out, the MLL fusion protein alone cannot cause leukemia. The enzymatic activity of wild-type MLL1 is necessary for the MLL1 fusion protein to induce leukemia. Therefore, specifically inhibiting the enzymatic activity of wild-type MLL1 can achieve the effect of treating leukemia.

[0004] MLL1 has poor H3K4 methylation activity alone and can only catalyze monomethylation; after forming the MLL1 core catalytic complex, the enzyme catalytic activity is greatly improved, especially the catalytic activity for H3K4me2. The MLL-C-terminal WIN motif part can bind to WDR5, RbBP5, Ash2L and DPY30 to form a complex. MLL1 directly interacts with WDR5 through its C-terminal WIN motif part, mediating the interaction between the MLL1SET catalytic domain and other protein complexes. After knocking out WDR5, H3K4me2 / 3 levels decreased and the expression of Hox genes was downregulated.

[0005] Therefore, using small molecule inhibitors to interfere with the protein-protein interaction of MLL1-WDR5 is an effective means to inhibit the enzymatic activity of MLL1, downregulate the expression of Hox and Meis-1 genes, and thus block the progression of leukemia. Summary of the invention

[0006] The present invention discloses a small molecule compound that can regulate the MLL1-WDR5 protein-protein interaction, which can interfere with the MLL1-WDR5 protein-protein interaction, inhibit the enzymatic activity of MLL1, downregulate the methylation level of H3K4, the expression level of Hox and Meis-1 genes, thereby inducing apoptosis of leukemia cells, and is used for treating leukemia. The structure of the compound of the present invention is as follows:

[0007]

[0008] wherein X represents hydrogen, methyl, methoxy or halogen;

[0009] Y represents -CH2-, -O-, -S-, -CO-, -CH2O-, -NR5-, -CONR6- or -NR7CO-, wherein R5, R6, and R7 each independently represent hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl or substituted phenyl, and the substituent is halogen, C1-C4 alkyl, C1-C4 alkoxy, amino, hydroxyl, mercapto, carboxyl, cyano, trifluoromethyl or imidazolyl;

[0010] m represents 0 to 6;

[0011] R1 represents hydrogen, amino, hydroxyl, mercapto, carboxyl, cyano, -CONH2, C1-C4 alkyl, C1-C4 alkoxy, phenyl, substituted phenyl, substituted or unsubstituted nitrogen- or oxygen-containing 3-7 membered heterocyclic ring, -NR8COR9, -CONR 10 R 11 or -NR 10 R 11 , wherein R8 represents hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl or substituted phenyl, R9 represents amino, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, phenyl or substituted phenyl, substituted or unsubstituted nitrogen-containing or oxygen-containing 3-7 membered heterocyclic ring, R 10 , R 11 independently represents hydrogen, C1-C4 alkyl, phenyl or substituted phenyl, substituted or unsubstituted nitrogen- or oxygen-containing 3-7 membered heterocyclic ring or R 10 , R 11 connected to form a nitrogen- or oxygen-containing 3- to 7-membered heterocyclic ring, wherein the substituent is a halogen, a C1-C4 alkyl, a C1-C4 alkoxy, an amino, a hydroxyl, a thiol, a carboxyl, a cyano, a trifluoromethyl or an imidazolyl;

[0012] R2 represents disubstituted or trisubstituted halogen, C1-C4 alkyl, C1-C4 alkoxy, trifluoromethyl, nitro or cyano;

[0013] R3 represents amino, methylamino, aminomethyl, hydroxyl, hydroxymethyl, mercapto or -CONH2;

[0014] R4 represents N-methylpiperazine, 1,2-dimethylpiperazine or N-methylhomopiperazine.

[0015] X preferably represents hydrogen, fluorine, chlorine or methyl.

[0016] Y preferably represents -NR5-, -CONR6- or -NR7CO-; R5, R6, R7 each independently represent hydrogen, methyl, ethyl, propyl, cyclopropyl or isopropyl.

[0017] Y also preferably represents -NR5-, -CONR6- or -NR7CO-; R5, R6 and R7 each independently represent substituted phenyl, the substituent being methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, methoxy, cyano, halogen, trifluoromethyl or imidazolyl.

[0018] The substituted or unsubstituted nitrogen-containing or oxygen-containing 3-7 membered heterocycle described above is preferably aziridine, azetidine, pyrrolidine, piperidine, cycloheximide, lactam, tetrahydrofuran, tetrahydropyran, morpholine, 1,4-oxazaalkane, hexahydropyridazine, imidazoline, pyrazolidine, piperazine, and the substituent is halogen, methyl, ethyl, phenyl, hydroxyl, amino, hydroxymethyl or aminomethyl.

[0019] R1 preferably represents -NR8COR9, -CONR 10 R 11 or -NR 10 R 11 , R8, R9, R 10 , R 11 Represents C1-C4 alkyl.

[0020] R2 preferably represents trisubstitution, the substituent being fluorine, chlorine, bromine, methyl, methoxy, nitro, trifluoromethyl or cyano.

[0021] The present invention also includes pharmaceutically acceptable salts of compound (I) and solvates thereof, which have the same pharmacological effects as compound (I).

[0022] The present invention discloses a pharmaceutical composition, which comprises a compound (I) or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers, diluents and excipients.

[0023] The present invention also provides the use of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for treating diseases mediated by the enzyme by inhibiting the MLL1-WDR5 protein-protein interaction, such as MLL gene fusion leukemia, which can be treated by inhibiting the enzyme activity of MLL1.

[0024] The clinical dosage of the compound of the present invention is 0.01 mg to 1000 mg / day, and may deviate from this range depending on the severity of the disease or the dosage form.

[0025] In certain embodiments, the compounds according to formula (I) may contain a basic functional group sufficient to form a salt. Representative salts include pharmaceutically acceptable inorganic acid salts, such as hydrochlorides, hydrobromides and sulfates; pharmaceutically acceptable organic acid salts, such as acetates, trifluoroacetates, lactates, succinates, fumarates, maleates, citrates, benzoates, methanesulfonates, p-benzoates and p-toluenesulfonates.

[0026] The present invention also discloses a method for preparing a compound of formula (I), comprising the following steps:

[0027]

[0028] Wherein R1, R2, R3, R4, X, Y, and n are as defined above;

[0029] The intermediate Ia can be synthesized by the following formula:

[0030]

[0031] The following are some pharmacodynamic tests and results of the compounds of the present invention:

[0032] The protein-protein interaction between MLL1 and WDR5 determines the enzymatic activity of MLL1; the enzymatic activity of MLL1 affects the methylation level of H3K4. In MLL fusion leukemia, the methylation level of H3K4 is abnormally increased, and the expression of downstream Hox and Meis-1 genes is abnormally upregulated. When the protein-protein interaction of MLL1-WDR5 is inhibited, the enzymatic activity of MLL1 decreases, the methylation level of H3K4 decreases, the expression of Hox and Meis-1 genes is downregulated, and the proliferation of leukemia cells is inhibited.

[0033] The biphenyl compound DDO-2084 is a small molecule inhibitor that has been reported to inhibit MLL1-WDR5 protein-protein interaction, reduce MLL1 enzyme catalytic activity, and downregulate Hox and Meis-1 gene expression (Eur. J. Med. Chem. 2016, 124, 480-489.). In the present invention, DDO-2084 is used as a positive control compound.

[0034] Table 1. MLL1-WDR5 protein-protein interaction inhibitory activity and related biological activities of the compounds of the present invention

[0035]

[0036] aThe structures of the compounds are shown in the specific examples; b Structure of DDO-2084:

[0037] As can be seen from Table 1, the compounds of the present invention have strong MLL1-WDR5 protein-protein interaction inhibitory activity.

[0038] At the same time, some compounds of the present invention were also subjected to RT-PCR experiments at the cell level. Table 1 shows the experimental results of whether some compounds of the present invention have an inhibitory effect on the expression levels of downstream Hox and Meis-1 genes. The experimental results show that the compounds of the present invention that have an inhibitory effect on the MLL1-WDR5 protein-protein interaction can inhibit the expression of downstream Hox and Meis-1 genes. The results of the inhibition of the expression levels of downstream Hox and Meis-1 genes at the cell level of some compounds are shown in Figure 1 ,pass Figure 1 It can be seen that the compound of Example 7 of the present invention, at a concentration of 2.5 μM, achieves the same level of activity in inhibiting the expression of Hoxa9 and Meis-1 genes as the positive control DDO-2084 at a concentration of 5 μM, and at the same concentration of 5 μM, the effect of Example 7 is better than that of DDO-2084.

[0039] In addition, some compounds of the present invention were also subjected to Western-blot experiments at the cellular level. Table 1 shows the experimental results of whether some compounds of the present invention have the effect of inhibiting the methylation level of H3K4. The experimental results show that the compounds of the present invention that have an inhibitory effect on the MLL1-WDR5 protein-protein interaction can all downregulate the methylation level of H3K4. The results of the catalytic inhibition of some compounds on MLL1 at the cellular level are shown in Table 1. Figure 2 .pass Figure 2 It can be seen that Example 7 can inhibit the enzymatic activity of MLL1 in a dose-dependent manner and reduce the expression level of H3K4me1 / 2 / 3, and it can be seen that at the same concentration of 10 μM, the effect of Example 7 is better than that of DDO-2084.

[0040] In addition, a series of biphenyl MLL1-WDR5 protein-protein interaction inhibitors were reported in a published article (Eur. J. Med. Chem. 2016, 124, 480-489. hereinafter referred to as Article 1), and their structures are as follows: The difference between the compounds of the present invention and those of the present invention is that the structure of the two benzene rings connected is changed, and the 5-position is connected with a triazole group. Through such a modification, the compounds of the present invention greatly improve the water solubility, reduce the toxicity of the compounds, and maintain the original MLL1-WDR5 inhibitory activity. We selected some biphenyl compounds in Article 1 and some unreported biphenyl compounds, and used the same test method and the same batch as in the present invention to measure the solubility and toxicity. The results are compared as follows:

[0041] Table 2. Comparison of target activity and solubility of some compounds in the present invention and some compounds in Article 1

[0042]

[0043]

[0044] From the data comparison of the compounds in Table 2, it can be seen that, when other groups are the same, replacing the benzene ring with triazole in the present invention can maintain the target activity and significantly improve the water solubility of the compound.

[0045] At the same time, some of the compounds of the present invention were also subjected to subacute toxicity tests on mice to evaluate the safety of the compounds of the present invention. Female balb / c mice were selected, with 6 mice in each group, and some of the triazole series compounds of the present invention (Examples 4, 6, 7, 16, 22) and some of the compounds DDO-2113 and DDO-2117 in Article 1 were respectively administered by intraperitoneal injection at a dosage of 80 mg / kg. After continuous administration for 10 days, the survival status and average weight changes of the mice were observed. Figure 3 As shown, some compounds of the present invention (Examples 4, 6, 7, 16, 22) did not die after 10 days of administration, and the body weight increased slightly, while after the administration of compounds DDO-2113 and DDO-2117 in the article (Eur. J. Med. Chem. 2016, 124, 480-489.), all mice died after 5 days of administration of DDO-2113 at 80 mg / kg, and the weight of mice decreased significantly after administration of DOO-2117. Comparing the survival and average weight changes of mice after administration, the phenyl triazole compounds of the present invention did not die after 10 days of administration, and the body weight increased slightly, while the biphenyl series compounds DDO-2113 and DDO-2117 died and lost weight after administration, showing the good drug safety of the phenyl triazole compounds of the present invention.

[0046] Among them, DDO-2113 and DDO-2117 are compounds reported in Article 1, and their structures are:

[0047]

[0048] Some compounds of the present invention were also tested for their anti-proliferative activity on leukemia cells. Table 3 shows the results of evaluating the inhibitory activity of some compounds of the present invention on the proliferation of acute leukemia cells, where MV4-11 is a human acute monocytic leukemia cell, Molm-13 is a human polar myeloid leukemia cell, and K562 is a human chronic myeloid leukemia cell. Table 3 shows that the compounds of the present invention have a good inhibitory effect on the proliferation of various leukemia cells.

[0049] Table 3. Antiproliferative activity of some compounds of the present invention on leukemia cells

[0050]

[0051]

[0052] a The structures of the compounds are shown in the specific examples; b ND means not tested;

[0053] The phenyltriazole compounds of the present invention have strong MLL1-WDR5 protein-protein interaction inhibitory activity, can reduce the MLL1 enzyme catalytic activity at the cellular level, down-regulate Hox and Meis-1 gene expression, and induce apoptosis of leukemia cells. In addition, the phenyltriazole compounds of the present invention exhibit good water solubility and drug safety, and can be used to treat leukemia. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 The RT-PCR experiment detected the down-regulation of Hoxa9 and Meis-1 gene expression in cells in Example 7.

[0055] Figure 2 Western-blot experiment to detect the effect of Example 7 on the catalytic activity of MLL1 enzyme in cells

[0056] Figure 3 Comparison of toxicity between some compounds of the present invention and some compounds in article 1 DETAILED DESCRIPTION

[0057] Example 1

[0058]

[0059] 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid methyl ester (1)

[0060] Preparation of 4-(4-methylpiperazine-1-yl)-3-nitroaniline (IIb):

[0061] Dissolve the compound 4-fluoro-3-nitroaniline (II) (6 g, 38.4 mmol) in 50 mL of acetonitrile, add N-methylpiperazine (5.8 g, 6.3 mL, 57.6 mmol) and N, N-diisopropylethylamine (9.5 mL, 57.6 mmol) and heat under reflux for 12 h. After drying, the crude product was separated and purified by silica gel column chromatography (dichloromethane: methanol = 20: 1) to obtain a reddish brown solid (8.9 g, 97.8%). 1 H NMR (300MHz, DMSO-d6) δ7.06 (d, J=8.6Hz, 1H), 6.76 (s, 1H), 6.69 (d, J=8.5Hz, 1H), 5.34 (s, 2H), 2.70 (t, J=4.4Hz, 4H), 2.27 (br s, 4H), 2.09 (s, 3H).m / z (EI-MS): 259.1[M+Na] + .

[0062] Preparation of 1-(4-azido-2-nitrophenyl)-4-methylpiperazine (Ia):

[0063] The compound 4-(4-methylpiperazine-1-yl)-3-nitroaniline (IIb) (4.0 g, 17.0 mmol) was dissolved in 100 mL of 2M / HCl, cooled to 0°C, and 10 mL of an aqueous solution of sodium nitrite (1.76 g, 25.5 mmol) was added dropwise. After stirring at 0°C for 30 min, 10 mL of an aqueous solution of sodium azide (2.2 g, 34.0 mmol) was added dropwise. After stirring at 0°C for 30 min, the mixture was stirred at room temperature for 2 h. The product was then precipitated with 2M / NaOH at pH = 9-10, and filtered and dried to obtain a reddish brown solid (4.0 g, 91.3%). 1 H NMR (300MHz, DMSO-d6) δ7.48 (d, J=2.2Hz, 1H), 7.34-7.20 (m, 2H), 2.85 (t, J=4.7Hz, 4H), 2.31 (t, J=4.8Hz, 4H), 2.11 (s, 3H).m / z (EI-MS): 261.1[MH] - .

[0064] Preparation of 1-(4-(4-methylpiperazine-1-yl)-3-nitrophenyl)-1H-1,2,3-triazole-4-carboxylic acid methyl ester (Ib):

[0065] The compound 1-(4-azido-2-nitrophenyl)-4-methylpiperazine (Ia) (1.0 g, 3.8 mmol) was dissolved in 50 mL of methanol, and methyl propiolate (0.96 g, 11.4 mmol), cuprous iodide (0.07 g, 0.38 mmol), and N,N-diisopropylethylamine (0.12 mL, 0.76 mmol) were added. After heating under reflux for 48 h, the mixture was filtered, concentrated, and beaten with ethyl acetate to obtain a reddish brown solid (0.8 g, 61.5%). 1 H NMR (300MHz, DMSO-d6) δ9.45 (s, 1H), 8.36 (d, J=2.7Hz, 1H), 8.11-8.01 (m, 1H), 7 .42 (d, J=9.1Hz, 1H), 3.80 (s, 3H), 2.99 (t, J=5.4Hz, 4H), 2.35 (t, J=5.2Hz, 4H), 2.13(s,3H).m / z(EI-MS): 369.2[M+Na] + .

[0066] Preparation of methyl 1-(3-amino-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylate (Ic):

[0067] The compound 1-(4-(4-methylpiperazine-1-yl)-3-nitrophenyl)-1H-1,2,3-triazole-4-carboxylic acid methyl ester (Ib) (3.8 g, 12.0 mmol) was dissolved in 50 mL of methanol, a catalytic amount of Pd / C was added, hydrogen was introduced, and after stirring at room temperature for 7 h, the mixture was filtered and concentrated to obtain a pink solid (3.0 g, 78.9%). 1 H NMR (300MHz, DMSO-d6) δ9.28 (s, 1H), 7.28 (d, J = 1.9Hz, 1H), 7.07 (d, J = 1.9Hz, 2H), 5.15 (s, 2H), 3.90 (s, 3H), 2.87 (t, J = 4.5Hz, 4H), 2.53 (br s, 4H), 2.26 (s, 3H).m / z (ESI-MS): 317.1763[M+H] + .

[0068] Preparation of 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid methyl ester (1)

[0069] Compound 1-(3-amino-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid methyl ester (Ic) (1.7 g, 5.3 mmol) was dissolved in 100 mL of anhydrous dichloromethane, pyridine (0.43 mL, 5.3 mmol) was added, and 20 mL of dichloromethane solution of 2-chloro-3-methyl-4-fluoro-5-nitrobenzoyl chloride (1.6 g, 6.4 mmol) was added dropwise under ice-water bath, and stirred at room temperature for 2 h, filtered and dried to obtain a light yellow solid; the light yellow solid was purified by centrifugation and purifying. The solid (2.6 g, 4.9 mmol) was dissolved in ethyl acetate, stannous chloride (5.5 g, 24.4 mmol) was added, and the mixture was heated under reflux for 3 h and then cooled to room temperature. 100 mL of ethyl acetate was added for dilution, and then neutralized with saturated sodium bicarbonate solution until no more white colloid appeared. The mixture was filtered, the filter cake was washed with ethyl acetate until no UV absorption was observed, and the filtrate was extracted with ethyl acetate until no UV absorption was observed. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The off-white solid 1 (2.3 g, 93.9%) was filtered by slurrying with ethyl acetate. 1 H NMR (300MHz, DMSO-d6) δ9.52-9.45 (m, 2H), 8.69 (s, 1H), 7.73 (dd, J=8.7, 2.7Hz, 1H), 7.46 (d , J=8.6Hz, 1H), 6.92 (d, J=9.2Hz, 1H), 5.53 (s, 2H), 3.92 (s, 3H), 3.00-2.90 (m, 4H), 2.51 (br s, 4H), 2.28 (d, J=2.6Hz, 3H), 2.24 (s, 3H). (EI-MS): 502.9[M+H] + .

[0070] Example 2

[0071]

[0072] Preparation of 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (2):

[0073] Compound 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid methyl ester (1) (2.3 g, 4.6 mmol) was dissolved in THF, lithium hydroxide solution (1 M, 15 mL) was added, and the mixture was stirred at room temperature for 8 h, and then the THF was removed by spin drying, and then acidified with 2 M hydrochloric acid to obtain a white solid (1.7 g, 80.4%). 1H NMR (300MHz, DMSO-d6) δ9.52-9.45 (m, 2H), 8.69 (s, 1H), 7.73 (dd, J=8.7, 2.7Hz, 1H), 7.46 (d, J=8.6Hz, 1H), 6.92 (d, J=9.2Hz , 1H), 5.53 (s, 2H), 3.92 (s, 3H), 3.00-2.90 (m, 4H), 2.50 (brs, 4H), 2.28 (d, J=2.6Hz, 3H), 2.24 (s, 3H). (EI-MS): 488.9[M+H] + .

[0074] Example 3

[0075]

[0076] Preparation of 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-N,N-dimethyl-1H-1,2,3-triazole-4-carboxamide (3):

[0077] The compound 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxylic acid (2) (0.18 g, 0.36 mmol) was dissolved in 10 mL of DMF, and BOP (0.32 g, 0.72 mmol), triethylamine (0.10 mL, 0.72 mmol) and dimethylamino hydrochloride (58.7 mg, 0.72 mmol) were added, and stirred at room temperature for 4 h. Then, the reaction solution was diluted with 50 mL of ethyl acetate, and DMF was washed away with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, and the organic solvent was dried to obtain a crude product, which was separated and purified by silica gel column chromatography (dichloromethane: methanol = 50: 1) to obtain an off-white solid. The yield was 78.4%. 1 H NMR (300MHz, DMSO-d6) δ9.59 (s, 1H), 9.18 (s, 1H), 8.63 (d, J=2.5Hz, 1H), 7.71 (dd, J =8.6, 2.6Hz, 1H), 7.42 (d, J = 8.6Hz, 1H), 6.83 (d, J = 9.2Hz, 1H), 5.50 (s, 2H), 3.11 (br s, 10H), 3.02 (s, 3H), 2.70-2.69 (m, 4H), 2.24 (d, J=2.5Hz, 3H). (EI-MS): 515.9[M+H] + .

[0078] Example 4

[0079]

[0080] Preparation of 5-amino-2-chloro-4-fluoro-3-methyl-N-(2-(4-methylpiperazin-1-yl)-5-(4-(morpholine-4-carbonyl)-1H-1,2,3-triazol-1-yl)phenyl)benzamide (4):

[0081] According to the method of Example 3, dimethylamino hydrochloride was replaced by morpholine to obtain an off-white solid. Yield: 67.5%. 1 HNMR (300MHz, DMSO-d6) δ9.61 (s, 1H), 9.24 (s, 1H), 8.64 (d, J = 2.5Hz, 1H), 7.73 (dd, J = 8.6, 2.6Hz, 1H), 7.44 (d, J=8.7Hz, 1H), 6.86 (d, J=9.2Hz, 1H), 5.52 (s, 2H), 4.06 (s, 2H), 3.68 (s, 6H), 3.12 (br s, 8H), 2.69 (s, 3H), 2.26 (d, J=2.6Hz, 3H). (EI-MS): 558.9[M+H] + .

[0082] Example 5

[0083]

[0084] Preparation of 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazole-4-carboxamide (5):

[0085] According to the method of Example 3, 4-aminotetrahydropyran was used to replace dimethylamino hydrochloride to obtain an off-white solid. The yield was 82.9%. 1 H NMR (300MHz, DMSO-d6) δ9.52 (s, 1H), 9.26-9.24 (m, 1H), 8.65 (s, 2H), 7.71 (d, J = 8.7Hz, 1H), 7.42 (d, J = 9.4Hz, 1H), 6.89 (s, 1H), 5 .53(s, 2H), 4.06(s, 1H), 3.9-3.86(m, 2H), 2.99(s, 6H), 2.71(s, 4H), 2.38(s, 3H), 2.25(s, 3H), 1.71(s, 4H). (EI-MS): 572.0[M+H] + .

[0086] Example 6

[0087]

[0088] Preparation of 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-N-(1-methylpiperidin-4-yl)-1H-1,2,3-triazole-4-carboxamide (6):

[0089] According to the method of Example 3, 4-amino-1-methylpiperidine was used to replace dimethylamino hydrochloride to obtain an off-white solid. The yield was 49.9%. 1 H NMR (300MHz, DMSO-d6) δ9.48 (s, 1H), 9.22 (s, 1H), 8.65 (d, J=2.6Hz, 1H), 8.52 (d, J=8. 2Hz, 1H), 7.70 (dd, J=8.5, 2.7Hz, 1H), 7.42 (d, J=8.6Hz, 1H), 6.89 (d, J=9.2Hz, 1H), 5.5 4 (s, 2H), 3.78 (s, 1H), 2.92 (t, J = 4.6Hz, 4H), 2.82-2.78 (m, 2H), 2.26 (d, J = 2.7Hz, 3H) , 2.22(s, 3H), 2.19(s, 3H), 2.07-1.86(m, 4H), 1.75-1.66(m, 4H). (EI-MS): 585.0[M+H] + .

[0090] Example 7

[0091]

[0092] Preparation of 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-morpholinopropyl)-1H-1,2,3-triazole-4-carboxamide (7):

[0093] According to the method of Example 3, dimethylamino hydrochloride was replaced by N-(3-aminopropyl)morpholine to obtain an off-white solid. Yield 94.2%. 1H NMR (300MHz, DMSO-d6) δ9.51 (s, 1H), 9.22 (s, 1H), 8.85 (t, J=5.8Hz, 1H), 8.66 (s, 1H ), 7.71 (dd, J=8.6, 2.7Hz, 1H), 7.43 (d, J=8.8Hz, 1H), 6.89 (d, J=9.2Hz, 1H), 5.53 (s, 2H), 3.62 (t, J=4.6Hz, 4H), 2.98-2.97 (m, 4H), 2.63 (s, 4H), 2.54 (s, 2H), 2.46-2.36 (m, 6H), 2.33 (s, 3H), 2.26 (d, J=2.6Hz, 3H), 1.74-1.70 (m, 2H). (EI-MS): 615.1[M+H] + .

[0094] Example 8

[0095]

[0096] Preparation of 5-amino-2-chloro-4-fluoro-3-methyl-N-(2-(4-methylpiperazin-1-yl)-5-(4-(4-methylpiperazine-1-carbonyl)-1H-1,-1H-1,2,3-triazol-1-yl)phenyl)benzamide (8):

[0097] According to the method of Example 3, dimethylamino hydrochloride was replaced by N-methylpiperazine to obtain an off-white solid. Yield 94.2%. 1 H NMR (300MHz, DMSO-d6) δ9.51 (s, 1H), 9.22 (s, 1H), 8.85 (t, J=5.8Hz, 1H), 8.66 (s, 1H ), 7.71 (dd, J=8.6, 2.7Hz, 1H), 7.43 (d, J=8.8Hz, 1H), 6.89 (d, J=9.2Hz, 1H), 5.53 (s, 2H), 3.62 (t, J=4.6Hz, 4H), 2.98-2.97 (m, 4H), 2.63 (s, 4H), 2.54 (s, 2H), 2.46-2.36 (m, 6H), 2.33 (s, 3H), 2.26 (d, J=2.6Hz, 3H), 1.74-1.70 (m, 2H). (EI-MS): 571.0[M+H] + .

[0098] Example 9

[0099]

[0100] Preparation of 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-N-(2-morpholinoethyl)-1H-1,2,3-triazole-4-carboxamide (9):

[0101] According to the method of Example 3, dimethylamino hydrochloride was replaced by N-(2-aminoethyl)morpholine to obtain an off-white solid. Yield 72.5%. 1 H NMR (300MHz, DMSO-d6) δ9.51 (s, 1H), 9.24 (s, 1H), 8.66 (d, J=2.4Hz, 1H), 8.56 (t, J= 5.8Hz, 1H), 7.71 (dd, J=8.7, 2.6Hz, 1H), 7.43 (d, J=8.7Hz, 1H), 6.89 (d, J=9.2Hz, 1H) , 5.54 (s, 2H), 3.58 (t, J = 4.6Hz, 4H), 3.44 (s, 2H), 2.96 (t, J = 4.8Hz, 4H), 2.59 (s, 4H) , 2.54(s, 2H), 2.44(s, 4H), 2.30(s, 3H), 2.26(d, J=2.6Hz, 3H). (EI-MS): 601.0[M+H] + .

[0102] Example 10

[0103]

[0104] Preparation of 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-N-(3-aminopropyl)-1H-1,2,3-triazole-4-carboxamide (10):

[0105] According to the method of Example 3, 1,3-propylenediamine was used to replace dimethylamino hydrochloride to obtain an off-white solid. The yield was 64.5%. 1 H NMR (300MHz, DMSO-d6) δ8.85 (s, 1H), 8.70 (s, 1H), 8.45 (d, J=2.1Hz, 1H), 7. 36 (dd, J=7.5, 2.0Hz, 1H), 7.25 (s, 1H), 6.84 (d, J=7.5Hz, 1H), 6.78 (d, J=5. 7Hz, 1H), 4.13 (s, 2H), 3.25-3.19 (m, 6H), 2.98 (t, J=4.9Hz, 4H), 2.67-2.58 (m, 5H), 2.39 (s, 3H), 2.19-2.13 (m, 2H), 1.14 (s, 2H). (EI-MS): 545.0[M+H] + .

[0106] Embodiment 11

[0107]

[0108] 5-Amino-2-chloro-4-fluoro-3-methyl-N-(2-(4-methylpiperazin-1-yl)-5-(1H-1,2,3-triazol-1-yl)phenyl)benzamide (11)

[0109] According to the method of Example 1, trimethylethynylsilane replaced methyl propiolate, and an off-white solid was obtained in three steps. The three-step yield was 23.8%. 1 H NMR (300MHz, DMSO-d6) δ8.76-8.68 (m, 2H), 8.49 (d, J=2.1Hz, 1H), 8.18 (d, J=7.5Hz, 1H), 7.27 (dd, J=7.5, 2.0Hz, 1H), 6.82 (d, J=7.5Hz , 1H), 6.75 (d, J=5.7Hz, 1H), 4.15 (s, 2H), 3.20 (t, J=5.1Hz, 4H), 2.98 (t, J=5.0Hz, 4H), 2.60 (s, 3H), 2.39 (s, 3H). (EI-MS): 444.9[M+H] + .

[0110] Example 12

[0111]

[0112] Tert-butyl (1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)carbamate (12)

[0113] According to the method of Example 1, tert-butyl ethynyl carbamate replaced methyl propiolate, and an off-white solid was obtained in three steps. The three-step yield was 20.1%. 1 H NMR (300MHz, DMSO-d6) δ8.70 (s, 1H), 8.59 (d, J=2.0Hz, 1H), 8.08 (s, 1H), 7.25 (dd, J=7.5, 2.0Hz, 1H), 7.18 (s, 1H), 6.80 (dd, J=19.7 , 6.6Hz, 2H), 4.17 (s, 2H), 3.20 (t, J=5.1Hz, 4H), 2.98 (t, J=5.1Hz, 4H), 2.60 (s, 3H), 2.39 (s, 3H), 1.50 (s, 9H). (EI-MS): 560.0[M+H] + .

[0114] Example 13

[0115]

[0116] 5-Amino-N-(5-(4-amino-1H-1,2,3-triazol-1-yl)-2-(4-methylpiperazin-1-yl)phenyl)-2-chloro-4-fluoro-3-methylbenzamide (13)

[0117] The compound tert-butyl (1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)carbamate (12) (1.0 g, 2.2 mmol) was dissolved in 20 mL of dichloromethane, and 10 mL of trifluoroacetic acid was added. After stirring at room temperature for 1 h, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and then spin-dried to obtain a gray solid. The yield was 87.3%. 1 H NMR (300MHz, DMSO-d6) δ 8.70 (s, 1H), 8.49 (d, J = 2.0Hz, 1H), 8.08 (s, 1H), 7.25 (dd, J = 7.5, 2.0Hz, 1H), 6.80 (d, J = 7.5Hz, 1H), 6.70 (d, J=5.7Hz, 1H), 5.80 (s, 2H), 4.15 (s, 2H), 3.20 (t, J=5.3Hz, 4H), 2.98 (t, J=5.2Hz, 4H), 2.60 (s, 3H), 2.39 (s, 3H). (EI-MS): 459.9[M+H] + .

[0118] Embodiment 14

[0119]

[0120] N-(1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazolopyridin-4-yl)-1-methylpiperidine-4-carboxamide (14)

[0121] The compound 5-amino-N-(5-(4-amino-1H-1,2,3-triazol-1-yl)-2-(4-methylpiperazine-1-yl)phenyl)-2-chloro-4-fluoro-3-methylbenzamide (13) (0.2 g, 0.34 mmol) was dissolved in 5 mL of DMF, and BOP (0.30 g, 0.68 mmol), triethylamine (0.09 mL, 0.68 mmol) and 1-methylpiperidine-4-carboxylic acid (97.3 mg, 0.68 mmol) were added, and stirred at room temperature for 4 h. Then, the reaction solution was diluted with 50 mL of ethyl acetate, and DMF was washed away with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, and the organic solvent was dried to obtain a crude product, which was separated and purified by silica gel column chromatography (dichloromethane: methanol = 20: 1) to obtain an off-white solid. The yield was 73.9%. 1 H NMR (300MHz, DMSO-d6) δ8.72-8.64 (m, 2H), 8.08 (s, 1H), 7.71 (s, 1H), 7.25 (dd, J= 7.5, 2.0Hz, 1H), 6.87 (d, J=7.5Hz, 1H), 6.69 (d, J=5.7Hz, 1H), 4.16 (s, 2H), 3.20 (t , J=5.3Hz, 4H), 3.05-2.95(m, 6H), 2.60(s, 3H), 2.50-2.45(m, 1H), 2.39-2.37(m, 6 H), 2.14-2.09(m, 2H), 2.05-1.98(m, 2H), 1.81-1.70(m, 2H). (EI-MS): 485.1[M+H] + .

[0122] Embodiment 15

[0123]

[0124] N-(1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,3-triazolopyridin-4-yl)piperidine-4-carboxamide (15)

[0125] According to the method of Example 14, 4-piperidinic acid was used to replace 1-methylpiperidin-4-carboxylic acid to obtain an off-white solid. The yield was 88.7%. 1H NMR (300MHz, DMSO-d6) δ8.70 (s, 1H), 8.55 (d, J = 2.0Hz, 1H), 8.08 (s, 1H), 7.71 ( s, 1H), 7.26 (dd, J=7.5, 2.0Hz, 1H), 6.80 (dd, J=23.8, 6.6Hz, 2H), 4.15 (s, 2H), 3 .27-3.17(m, 6H), 2.98(t, J=5.0Hz, 4H), 2.82-2.65(m, 3H), 2.60(s, 3H), 2.39( s, 3H), 2.03-1.96 (m, 2H), 1.74-1.69 (m, 2H), 1.22 (s, 1H). (EI-MS): 571.1[M+H] + .

[0126] Example 16

[0127]

[0128] 5-Amino-N-(5-(4-(4-aminobutyrylamino)-1H-1,2,3-triazol-1-yl)-2-(4-methylpiperazin-1-yl)phenyl)-2-chloro-4-fluoro-3-methylbenzamide (16)

[0129] According to the method of Example 14, γ-aminobutyric acid was used to replace 1-methylpiperidine-4-carboxylic acid to obtain an off-white solid. The yield was 88.7%. 1 H NMR (300MHz, DMSO-d6) δ8.70 (s, 1H), 8.08 (s, 1H), 7.71 (s, 1H), 7.25 (dd, J= 7.5, 2.0Hz, 1H), 6.80 (dd, J=21.4, 6.6Hz, 2H), 4.17 (s, 2H), 3.20 (t, J=5.1H z, 4H), 3.08-3.04 (m, 2H), 2.98 (t, J=5.1Hz, 4H), 2.60 (s, 3H), 2.50 (t, J=8. 2Hz, 2H), 2.39 (s, 3H), 2.10-2.04 (m, 2H), 1.19 (s, 2H). (EI-MS): 545.0[M+H] + .

[0130] Embodiment 17

[0131]

[0132] 5-amino-2-chloro-4-fluoro-N-(5-(4-(3-hydroxypropionylamino)-1H-1,2,3-triazol-1-yl)-2-(4-methylpiperazin-1-yl)phenyl)-3-methylbenzamide

[0133] According to the method of Example 14, 3-hydroxypropionic acid was used to replace 1-methylpiperidine-4-carboxylic acid to obtain an off-white solid. The yield was 84.9%. 1 H NMR (300MHz, DMSO-d6) δ8.70 (s, 1H), 8.57 (d, J=2.0Hz, 1H), 8.08 (s, 1H), 7.71 (s, 1H), 7.25 (dd, J=7.5, 2.0Hz, 1H), 6.80 (dd, J=21.8, 6.6Hz, 2H), 4.36 (t, J=5.0Hz, 1H), 4.17 (s, 2H), 3.83-3.79 (m, 2H), 3.20 (t, J=5.1Hz, 4H), 2 .98(t, J=5.0Hz, 4H), 2.60(s, 3H), 2.39-2.35(m, 5H). (EI-MS): 532.1[M+H] + .

[0134] Embodiment 18

[0135]

[0136] 5-Amino-2-chloro-N-(5-(4-(4-(dimethylaminomethyl)benzyl)-1H-1,2,3-triazol-1-yl)-2-(4-methylpiperazin-1-yl)phenyl)-4-fluoro-3-methylbenzoyl (18)

[0137] According to the method of Example 1, N,N-dimethyl-4-(prop-2-yn-1-yl)benzamide replaced propiolic acid methyl ester, and an off-white solid was obtained in three steps. The three-step yield was 34.4%. 1 H NMR (300MHz, DMSO-d6) δ8.70 (s, 1H), 8.49-8.44 (m, 2H), 7.74-7.68 (m, 2H), 7.56-7.50 (m, 2H), 7.26 (dd, J=7.4, 1.9Hz, 1H), 6.75 (d, J=5 .9Hz, 1H), 4.16 (s, 2H), 3.88 (d, J=1.2Hz, 2H), 3.20 (t, J=5.1Hz, 4H), 3.0-2.95 (m, 10H), 2.60 (s, 3H), 2.38 (s, 3H). (EI-MS): 606.1[M+H] + .

[0138] Embodiment 19

[0139]

[0140] 5-amino-2-chloro-N-(5-(4-(2-(dimethylamino)ethyl)-1H-1,2,3-triazol-1-yl)-2-(4-methylpiperazin-1-yl)phenyl)-4-fluoro-3-methylbenzoyl (19)

[0141] According to the method of Example 1, N,N-dimethyl-but-3-yn-1-amine replaced methyl propiolate, and an off-white solid was obtained in three steps. The three-step yield was 31.6%. 1 H NMR (300MHz, DMSO-d6) δ8.70 (s, 1H), 8.48 (d, J=2.0Hz, 1H), 8.28 (s, 1H), 7.26 (dd, J=7.5, 2.0Hz, 1H), 6.82 (d, J=7.5Hz, 1H), 6.74 (d, J=5.7 Hz, 1H), 4.15 (s, 2H), 3.20 (t, J=5.1Hz, 4H), 2.98 (t, J=5.0Hz, 4H), 2.71-2.61 (m, 4H), 2.60 (s, 3H), 2.40-2.39 (m, 9H). (EI-MS): 516.0[M+H] + .

[0142] Embodiment 20

[0143]

[0144] 5-Amino-2-chloro-N-(3-(4-ethoxy-1H-1,2,3-triazol-1-yl)-2-fluoro-6-(4-methylpiperazin-1-yl)phenyl)-4-fluoro-3-methylbenzoyl (20)

[0145] According to the method of Example 1, 2,4-difluoro-3-nitroaniline was substituted for 4-fluoro-3-nitroaniline, and ethyl ethynyl ether was substituted for methyl propiolate. A gray-white solid was obtained in five steps. The five-step yield was 12.8%. 1 H NMR (300MHz, DMSO-d6) δ8.70 (s, 1H), 7.98 (s, 1H), 7.30 (dd, J=7.5, 5.7Hz, 1H), 6.74 (d, J=5.7Hz, 1H), 6.59 (d, J=7.5Hz, 1H), 4.76-4.72 ( m, 2H), 4.15 (s, 2H), 3.20 (t, J=5.1Hz, 4H), 2.98 (t, J=5.0Hz, 4H), 2.60 (s, 3H), 2.39 (s, 3H), 1.56 (t, J=8.0Hz, 3H). (EI-MS): 507.1[M+H] + .

[0146] Embodiment 21

[0147]

[0148] N-(3-(4-((2-amino-2-oxoethyl)amino)-1H-1,2,3-triazol-1-yl)-2-fluoro-6-(4-methylpiperazin-1-yl)phenyl)-2-chloro-4-fluoro-5-hydroxy-3-methylbenzoyl (21)

[0149] According to the method of Example 1, 2,4-difluoro-3-nitroaniline was substituted for 4-fluoro-3-nitroaniline, 2-(ethynylamino)acetamide was substituted for methyl propiolate, and 2-chloro-3-methyl-4-fluoro-5-hydroxybenzoyl chloride was substituted for 2-chloro-3-methyl-4-fluoro-5-nitrobenzoyl chloride. A white solid was obtained by five steps. The five-step yield was 9.7%. 1 H NMR (300MHz, DMSO-d6) δ8.70 (s, 1H), 8.07 (d, J = 10.4Hz, 2H), 7.34-7.24 (m, 2H), 6.59 (d, J = 7.5Hz, 1H), 5.98 (s, 2H), 5 .93 (s, 1H), 4.03 (s, 2H), 3.20 (t, J=5.1Hz, 4H), 2.98 (t, J=5.0Hz, 4H), 2.60 (s, 3H), 2.38 (s, 3H). (EI-MS): 536.2[M+H] + .

[0150] Embodiment 22

[0151]

[0152] 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-2-methyl-4-(4-methylpiperazin-1-yl)phenyl)-N-(2-morpholinoethyl)-1H-1,2,3-triazole-4-carboxamide (22)

[0153] According to the method of Example 3, 2-fluoro-4-methyl-3-nitroaniline was substituted for 4-fluoro-3-nitroaniline, and N-(2-aminoethyl)morpholine was substituted for dimethylamino hydrochloride to obtain an off-white solid. The yield in six steps was 8.8%. 1H NMR (300MHz, DMSO-d6) δ8.70 (s, 1H), 8.52 (s, 1H), 7.25 (s, 1H), 7.13 (d, J=7.5 Hz, 1H), 6.78 (d, J=5.7Hz, 1H), 6.72 (d, J=7.5Hz, 1H), 4.15 (s, 2H), 3.74 (t, J=4 .7Hz, 4H), 3.55-3.53 (m, 2H), 3.20 (t, J=5.1Hz, 4H), 2.98 (t, J=5.1Hz, 4H), 2.6 1-2.59 (m, 5H), 2.51 (t, J=4.7Hz, 4H), 2.40-2.39 (m, 6H). (EI-MS): 615.1[M+H] + .

[0154] Embodiment 23

[0155]

[0156] N-(3-(4-(3-aminopropionylamino)-1H-1,2,3-triazol-1-yl)-2-methyl-6-(4-methylpiperazin-1-yl)phenyl)-2-chloro-4-fluoro-5-hydroxy-3-methylbenzamide (23)

[0157] According to the method of Example 14, 2-fluoro-4-methyl-3-nitroaniline was substituted for 4-fluoro-3-nitroaniline, 2-chloro-3-methyl-4-fluoro-5-hydroxybenzoyl chloride was substituted for 2-chloro-3-methyl-4-fluoro-5-nitrobenzoyl chloride, and β-alanine was substituted for 1-methylpiperidine-4-carboxylic acid. A white solid was obtained in six steps. The six-step yield was 7.2%. 1 H NMR (300MHz, DMSO-d6) δ8.70 (s, 1H), 8.08 (s, 1H), 7.71 (s, 1H), 7.19 (d, J= 7.5Hz, 1H), 7.06 (d, J=5.7Hz, 1H), 6.72 (d, J=7.5Hz, 1H), 5.93 (s, 1H), 3.20 (t, J=5.1Hz, 4H), 3.01-2.93 (m, 4H), 2.93-2.91 (m, 1H), 2.60 (s, 3H), 2.45 (s, 3H), 2.44-2.42 (m, 2H), 2.38 (s, 3H), 1.24 (s, 2H). (EI-MS): 615.1[M+H] + .

[0158] Embodiment 24

[0159]

[0160] 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(4-methyl-1,4-diazepan-1-yl)phenyl)-N-(2-morpholinoethyl)-1H-1,2,3-triazole-4-carboxamide (24)

[0161] According to the method of Example 3, N-methyl homopiperazine was substituted for N-methyl piperazine, and N-(2-aminoethyl) morpholine was substituted for dimethylamino hydrochloride to obtain an off-white solid. The six-step yield was 7.3%. 1 H NMR (300MHz, DMSO-d6) δ8.79 (s, 1H), 8.70 (s, 1H), 7.31 (dd, J=7.5, 2.0Hz, 1H), 7.25 (s, 1H) ), 6.83 (d, J = 7.5Hz, 1H), 6.70 (d, J = 5.7Hz, 1H), 4.16 (s, 2H), 3.74 (t, J = 4.7Hz, 4H), 3.60 ( t, J=4.8Hz, 2H), 3.55-3.53(m, 2H), 3.46-3.44(m, 2H), 2.91-2.89(m, 2H), 2.61-2.58(m, 4 H), 2.52-2.50(m, 4H), 2.39(s, 3H), 2.31(s, 3H), 1.64-1.60(m, 2H). (EI-MS): 615.1[M+H] + .

[0162] Embodiment 25

[0163]

[0164] 1-(3-(5-amino-2-chloro-4-fluoro-3-methylbenzamido)-4-(3,4-dimethylpiperazin-1-yl)phenyl)-N-(2-morpholinoethyl)-1H-1,2,3-triazole-4-carboxamide (25)

[0165] According to the method of Example 3, 1,2-dimethylpiperazine was substituted for N-methylpiperazine, and N-(2-aminoethyl)morpholine was substituted for dimethylamino hydrochloride to obtain an off-white solid. The six-step yield was 7.3%. 1H NMR(300MHz,DMSO-d6)δ8.80(s,1H),8.70(s,1H),8.54(d,J=2.0Hz,1H),7.31(dd,J=7.5,2.0Hz,1H),7.25(s,1H),6.81(d,J=7.5Hz,1H),6.70(d,J=5.7Hz,1H),4.18-4.04(m,7H),3.66-3.53(m,2H),3.35-3.31(m,1H),3.20-3.07(m,4H),2.93-2.87(m,1H),2.73-2.58(m,2H),2.51-2.37(m,7H),2.34-2.20(m,3H),1.16(d,J=6.8Hz,3H).(EI-MS):615.1[M+H] + 。

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following structures:

2. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

3. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof for preparing a medicament for treating acute leukemia.

4. The use according to claim 3, wherein the acute leukemia is acute leukemia with MLL1 gene rearrangement.

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