Compound and salt thereof, use in preparation of drug for treating cancer and kinase inhibitor, and drug for treating cancer

Abstract

The present invention belongs to the technical field of drug synthesis, and particularly relates to a compound and a salt thereof, the use in the preparation of a drug for treating cancer and a kinase inhibitor, and a drug for treating cancer. Provided in the present invention are a CHMFL-FLT3-122 compound deuterated at a specific position and a pharmaceutically acceptable salt thereof. Provided is the use of the compound or the pharmaceutically acceptable salt thereof in the preparation of a drug for treating cancer and a kinase inhibitor. Also provided is a drug for treating cancer. The compound and the pharmaceutically acceptable salt thereof provided by the present invention have a strong anti-cancer activity, good metabolic stability and pharmacokinetic properties, and have excellent application prospects.

Description

Compound and salt thereof, use thereof in preparing cancer treatment drugs and kinase inhibitors, and cancer treatment drugs Technical Field

[0001] The present invention belongs to the technical field of drug synthesis, and relates to a compound and a salt thereof, uses thereof in preparing drugs for treating cancer and kinase inhibitors, and drugs for treating cancer. Background Art

[0002] Blood cells in blood or tissues all originate from hematopoietic stem cells. Hematopoietic stem cells undergo a gradual differentiation process, producing various mature blood cells in a process known as hematopoiesis. The body's physiological functions can only function normally if the number of mature blood cells and platelets is maintained at a certain level. When blood cell differentiation is blocked and proliferation becomes uncontrolled, the number of mature blood cells cannot be replenished. Immature blood cells are produced in large numbers, occupying the living space of normal blood cells, competing for nutrients, and causing functional impairments in the body, leading to the development of leukemia. Leukemia patients are prone to persistent bleeding and decreased immunity, which can seriously endanger their lives.

[0003] Leukemia can be divided into four main types: acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), and chronic lymphocytic leukemia (CLL). AML is the most common type of leukemia and also has the highest mortality rate. With the continuous advancement of gene sequencing technology, researchers have discovered that an increasing number of gene mutations play a significant role in the development of AML. Among them, FLT3 kinase mutations are the most common mutation in AML, and patients with FLT3 gene mutations tend to have a poor prognosis.

[0004] The FLT3 kinase structure consists of an extracellular domain; a transmembrane domain, a juxtamembrane domain, two kinase domains separated by an intervening intercalating structure, and finally a C-terminal terminus. Under normal physiological conditions, in the absence of FLT3 ligand (FL), the juxtamembrane domain of FLT3 inhibits FLT3 dimerization. However, in the presence of FL, it binds to the extracellular receptor domain, triggering FLT3 dimerization. This changes the structure of the kinase domain, phosphorylating downstream signaling proteins such as PI3K, Ras, and STAT5, thereby activating downstream signaling pathways. Through a series of signaling pathways, these mutations regulate cell growth and proliferation. In 1996, researchers examining AML patients found FLT3-ITD (tandem duplication in the juxtamembrane domain of FLT3 kinase) mutations in up to 30% of patient samples. A subsequent study in 2001 found FLT3-TKD (tyrosine kinase domain point mutation) mutations in 5% of patients. Both mutations can activate FLT3 kinase independently of FL binding. When FLT3-ITD mutation is present, it causes FL-independent activation and activates the PI3K, Ras, and STAT5 downstream signaling pathways, promoting cell proliferation and leading to the occurrence of AML.

[0005] The first-generation FLT-3 inhibitors currently on the market are all multi-target inhibitors, represented by sorafenib (2005), sunitinib (2006), ponatinib (2013), and cabozantinib (2013). Because these first-generation drugs are multi-targeted, they are associated with unavoidable side effects, such as diarrhea, anorexia, fatigue, nausea, rash, acne, and arthralgia. Consequently, more potent FLT-3 inhibitors have been developed and approved for marketing, primarily for the treatment of acute myeloid leukemia. Midostaurin received FDA breakthrough designation, becoming the first kinase inhibitor targeting FLT3. Quizartinib, a second-generation FLT3 inhibitor, exhibits excellent selectivity and inhibitory activity against FLT3. Currently developed FLT3 kinase inhibitors have demonstrated promising therapeutic effects in clinical trials. However, as FLT3 inhibitors continue to advance in clinical testing, drug resistance has rapidly emerged, creating a significant unmet medical need for FLT3-ITD-positive AML.

[0006] Based on the structure of a recently reported BTK kinase inhibitor, ibrutinib, China has carried out structural modification to obtain the compound CHMFL-FLT3-122 (abbreviated as D18), which has high inhibitory activity against FLT3-ITD-positive AML cell lines. In the cellular environment, it affects the FLT3-itd-mediated signaling pathway and is selective between BTK kinase and FLT3 kinase. It has now entered Phase II clinical trials and is a potential candidate drug for the treatment of FLT3-itd-positive AML, but there is still uncertainty as to whether it can be successfully launched on the market.

[0007] In summary, for FLT3-itd-positive AML patients, providing compounds with better performance and richer selections and high inhibitory activity is of great practical significance.

[0008] Summary of the Invention

[0009] The present invention provides deuterated CHMFL-FLT3-122 compounds and pharmaceutically acceptable salts thereof, provides the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof in the preparation of cancer treatment drugs and kinase inhibitors, and also provides cancer treatment drugs, with the purpose of enhancing the efficacy and / or improving the safety of the drugs.

[0010] The present invention provides a compound or a pharmaceutically acceptable salt thereof, the structure of which is as follows:

[0011] The present invention also provides another compound or a pharmaceutically acceptable salt thereof, the structure of which is as follows:

[0012] Furthermore, pharmaceutically acceptable salts are salts formed between the compounds of the present invention and acids.

[0013] Furthermore, the pharmaceutically acceptable salt is selected from one or more of phosphate, camphorsulfonate, hydrochloride, hydrobromide, hydrofluoride, sulfate, nitrate, formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, tartrate, citrate, picrate, methanesulfonate, trifluoromethanesulfonate, toluenesulfonate, and benzenesulfonate.

[0014] Preferably, the pharmaceutically acceptable salt is hydrochloride.

[0015] The present invention also provides a use of the above compound or a pharmaceutically acceptable salt thereof in preparing a drug for treating cancer.

[0016] Furthermore, the use is the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof as a novel FLT3 kinase tyrosine kinase inhibitor to reduce or inhibit the mutant FLT3 kinase activity of cells or subjects and to prevent or treat cell proliferative disorders and / or FLT3-related disorders in subjects.

[0017] Furthermore, the cancer is selected from lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, liver cancer, glioblastoma, solid tumors, non-small cell lung cancer, papillary renal cell carcinoma, and melanoma.

[0018] The present invention also provides a use of the above compound or a pharmaceutically acceptable salt thereof for preparing a FLT3 kinase inhibitor.

[0019] The present invention also provides a drug for treating cancer, which is a preparation prepared with the above compound or a pharmaceutically acceptable salt thereof as an active ingredient and pharmaceutically acceptable excipients. Beneficial effects

[0020] The compound provided by the present invention and its pharmaceutically acceptable salt have strong anti-cancer activity.

[0021] The compounds and pharmaceutically acceptable salts provided by the present invention also have good metabolic stability and pharmacokinetic properties. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 shows the cell cycle distribution of MOLM-13 cells under the action of compounds D18 and D18-D6.

[0023] Figure 2 shows the cell cycle distribution of MV4-11 cells under the action of compounds D18 and D18-D6.

[0024] Figure 3 shows the MOLM-13 and MV4-11 cell colonies under the action of compounds D18 and D18-D6.

[0025] Figure 4A shows the changes in mouse body weight after administration, Figure 4B shows the changes in tumor size in mice after administration, Figure 4C shows a physical photo of the final tumor in mice after administration, and Figure 4D shows the final tumor weight in mice after administration. DETAILED DESCRIPTION

[0026] Deuterium's spatial shape and volume are essentially the same as those of hydrogen. When hydrogen in a drug's molecular structure is replaced by deuterium, the biological activity and selectivity of the original drug are typically retained in the deuterated drug. The resulting deuterated drug exhibits an isotope effect, regulating drug metabolism. However, due to the complexity of biological metabolic processes, the pharmacokinetic properties of drugs in vivo are also subject to corresponding complexity, influenced by multiple factors. Consequently, compared to non-deuterated drugs, the pharmacokinetic properties of deuterated drugs exhibit significant contingency and unpredictability. For example, deuteration at certain sites may not only fail to extend the half-life but may actually shorten it (Scott L. Harbeson, Roger D. Tung. Deuterium in Drug Discovery and Development, pp. 405-406).

[0027] The present invention prepares a series of deuterated products based on the CHMFL-FLT3-122 (abbreviated as D18) compound, from which two new compounds with significant inhibitory effects on the human acute monocytic leukemia cell line MV4-11 and the human acute myeloid leukemia cell line MOLM-13 are unexpectedly discovered.

[0028] The structure of compound D18:

[0029] The series of compounds tested in the present invention include compounds 2 to 15, the structures of which are as follows.

[0030] The structure of compound 2:

[0031] The structure of compound 3:

[0032] The structure of compound 4:

[0033] The structure of compound 5:

[0034] The structure of compound 6:

[0035] The structure of compound 7:

[0036] The structure of compound 8:

[0037] The structure of compound 9:

[0038] The structure of compound 10:

[0039] The structure of compound 11:

[0040] The structure of compound 12:

[0041] The structure of compound 13:

[0042] The structure of compound 14:

[0043] The structure of compound 15:

[0044] The study found that among the above compounds, compounds 2 and 3 have unique and significant inhibitory effects on the human acute monocytic leukemia cell line MV4-11 and the human acute myeloid leukemia cell line MOLM-13. In addition, compounds 2 and 3 exhibited superior pharmacokinetic properties compared to D18, which can significantly reduce the dosage and toxic side effects.

[0045] Experimental instruments and reagents used in the present invention

[0046] Experimental instruments: Bruker AVIII 400 MHz nuclear magnetic resonance instrument; Bruker AV NEO 600 MHz nuclear magnetic resonance instrument; Nicolet Nexus 470 FT-IR infrared spectrometer; Waters ACQUITY Arc high-performance liquid chromatograph; QDA (ESI) mass spectrometer detector; Agilent G7890-5975C (EI) gas chromatograph-mass spectrometer; Thermo Scientific LTQ Orbitrap XL high-resolution mass spectrometer.

[0047] Reagent: Compound C 27 H 30 N₂O₃, ethyl acetate, dioxane, sodium bicarbonate, hydrogen chloride, 2-dimethylaminoacetic acid, HATU, DIPEA, EtOAc, dichloromethane, chloroacetyl chloride, MeOH, deuterated dimethylamine d₆ hydrochloride, triethylamine, potassium iodide, anhydrous sodium sulfate, petroleum ether, anhydrous ethanol, acetonitrile, etc. All reagents were commercially available as analytical grade and used directly after purchase.

[0048] Synthesis of compound D18

[0049] According to the following reaction formula, the raw material (1 g, 2.06 mmol) was weighed and dissolved in ethyl acetate (20 mL). A 4N hydrogen chloride-dioxane solution was added under an ice-water bath, and the mixture was reacted at room temperature for 2 hours. The reaction was complete when detected by TLC. The solvent was evaporated under reduced pressure to obtain a white solid. Ethyl acetate and water were added, followed by a 2N sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layers were combined, washed with saturated brine, dried, and the solvent was evaporated under reduced pressure to obtain 865 mg of a white solid.

[0050] According to the following reaction formula, 2-dimethylaminoacetic acid (22 mg, 0.21 mmol), HATU (80 mg, 0.21 mmol), and DIPEA (35 μL, 0.20 mmol) were added to a solution of the starting material (80 mg, 0.21 mmol) in DMF (4 mL). The reaction mixture was stirred for 5 h. It was then diluted with EtOAc (50 mL) and washed with water (20 mL × 3) and saturated brine (30 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (0-10% MeOH in dichloromethane) to give compound D-18 (67 mg, 68%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ H 8.26(d,J=8.2Hz,1H),7.71–7.61(m,2H),7.43(t,J=7.8Hz,2H),7.24–7.08(m ,5H),4.83(m,0.5H),4.66(s,0.5H),4.46(dd,J=12.6,4.3Hz,1H),4.24–4.08( m,1H),3.93(d,J=13.4Hz,1H),3.65(s,0.5H),3.56–3.05(m,3H),2.92(s,0.5 H),2.36(s,4H),2.27(s,4H),2.12(d,J=4.3Hz,1H),1.90(m,1H),1.69(s,1H). 13 C NMR (100 MHz, DMSO-d6) δ C 166.7,158.2,157.1,156.3,155.7,153.9,143.3,130.1,127.9,123.8,120.1,119.0,97.4,60.7,52.6,52.0,49.0,45.4,44.9,44.8,41.4,29.4,24.5.

[0051] Synthesis of compound 2 (D18-D6)

[0052] According to the following reaction formula, DIPEA (36.5 μL, 0.21 mmol) and chloroacetyl chloride (17 μL, 0.21 mmol) were added to a solution of the raw material (80 mg, 0.21 mmol) in dichloromethane (10 mL) at 0°C. The resulting mixture was stirred for 3 minutes. The mixture was then quenched with MeOH (5 mL), concentrated, and purified by silica gel column chromatography (dichloromethane: methanol 100: 1 to 30: 1) to give an amide compound (89 mg) as a white solid.

[0053] The above white solid was dissolved in dry acetonitrile (5 mL) and deuterated dimethylamine d6 hydrochloride (88 mg, 1 mmol), triethylamine (140 μL, 2 mmol) and potassium iodide (17 mg, 0.1 mmol) were added. The temperature was raised to 40°C and the reaction was allowed to react for 12 hours. The mixture was quenched with water and extracted three times with ethyl acetate. After drying, the mixture was purified by silica gel column chromatography (dichloromethane: methanol 50:1 to 10:1). The product D-18-d6 was 75 mg of a white solid with a total yield of 75%. 1 H NMR (400 MHz, DMSO-d6): δ H 8.28(d,J=8.3Hz,1H),7.68(d,J=8.2Hz,2H),7.49–7.39(m,2H),7.16(m,5H),4.83(m,0.5H),4.66(m,0.5H),4.49(dd,J=12.5,4.2Hz,1 H),4.19(m,1H),4.10–3.95(m,1H),3.63(dd,J=13.2,9.7Hz,1H),3.35–2.81(m,4H),2.36–2.05(m,2H),1.91(m,1H),1.77–1.42(m,1H). 13 C NMR (100 MHz, DMSO-d6): δ C 167.6,158.2,157.1,156.3,155.6,153.9,143.3,130.1,127.9,123.8,118.9,97.5,61.4,53.1,52.1,49.3,45.4,45.4,45.1,41.7,29.5,24.7.

[0054] Synthesis of compound 3 (D18-D3)

[0055] According to the following reaction formula, DIPEA (36.5 μL, 0.21 mmol) and chloroacetyl chloride (17 μL, 0.21 mmol) were added to a solution of the raw material (80 mg, 0.21 mmol) in dichloromethane (10 mL) at 0°C. The resulting mixture was stirred for 3 minutes. The mixture was then quenched with MeOH (5 mL), concentrated, and purified by silica gel column chromatography (dichloromethane: methanol 100: 1 to 30: 1) to give an amide compound (89 mg) as a white solid. The above solid was dissolved in dry acetonitrile (5 mL) and deuterated dimethylamine d3 hydrochloride (88 mg, 1 mmol), triethylamine (140 μL, 2 mmol) and potassium iodide (17 mg, 0.1 mmol) were added. The temperature was raised to 40°C and the reaction was allowed to react for 12 hours. The reaction was then quenched with water and extracted three times with ethyl acetate. After drying, the product was purified by silica gel column chromatography (dichloromethane: methanol 50:1 to 10:1). The product D-18-d3 was obtained as a white solid (71 mg) with a total yield of 70%.

[0056] Effects of D18 and deuterated drugs on cancer cell proliferation

[0057] The inhibitory effect on cancer cell proliferation was evaluated by measuring the effects of D18 and a series of deuterated drugs on cancer cell growth. Human acute monocytic leukemia cell line MV4-11 (expressing FLT3 / ITD mutant gene) and human acute myeloid leukemia cell line MOLM-13 (expressing FLT3 / ITD mutant gene and wild-type FLT3 gene) were selected. Different concentrations of the above compounds (25nM, 50nM, 100nM, 200nM, 400nM in DMSO) were added to the above cells and incubated for 72 hours. The absorbance at 450nm was measured in a microplate reader using Cell Counting Kit-8 (abbreviated as CCK-8) reagent to obtain the OD value, which was further calculated to obtain the IC50. The experimental results are shown in the figure.

[0058] Table 1 IC values ​​of compounds against MOLM-13 and MV4-11 cells 50 value

[0059] The results showed that among the deuterated compounds, compounds 2 and 3 showed unique inhibitory effects on cancer cell proliferation. IC values ​​of compounds 2 and 3 on MOLM-13 and MV4-11 cells were 50 The values ​​were significantly lower than those of other deuterated compounds and also significantly lower than those of compound D18, indicating that its inhibitory effect on MOLM-13 and MV4-11 cells was not only significantly better than that of other deuterated compounds, but also significantly better than that of compound D18. (IC 50, half maximal inhibitory concentration, also known as 50% inhibitory concentration, refers to the concentration of drug that induces 50% apoptosis of tumor cells, that is, the drug concentration corresponding to the ratio of apoptotic cells to the total number of cells is equal to 50%. IC 50 The value can be used to measure the ability of a drug to induce tumor cell apoptosis. The lower the value, the stronger the induction ability.

[0060] Effects of D18 and D18-D6 on cell cycle

[0061] The effects of D18 and D18-D6 on the cell cycle distribution of human acute monocytic leukemia cell lines MV4-11 and acute myeloid leukemia cell lines MOLM-13 were tested. Different concentrations of the two compounds (100nM, 200nM, 300nM, 400nM in DMSO) were used to act on acute myeloid leukemia cell lines MV4-11 and MOLM-13 carrying FLT3 / ITD mutation genes. After 24 hours, the cells were collected, washed twice with 1X PBS buffer, fixed with 75% ethanol at -20°C for 24 hours, washed twice with 1X PBS buffer, and 0.5mL of 1X PBS buffer and 0.5mL of PI staining solution (purchased from BD Bioscience, USA) were added to the cells and the cells were placed in the dark at 37°C for staining for 15 minutes. The cell cycle distribution was detected by flow cytometry (BD FACS Calibur) and the data were analyzed using FlowJo software (Ashland OR).

[0062] The experimental results are shown in Figures 1 and 2. Under the action of D18 and D18-D6, the cell cycle of MOLM-13 cells (Figure 1) and MV4-11 cells (Figure 2) was arrested at the G0-G1 phase in a dose-dependent manner.

[0063] Effects of D18 and D18-D6 on cell clone formation

[0064] The proliferation capacity of MOLM-13 and MV-4-11 cells carrying the FLT3 / ITD mutation was assessed using a soft agar colony formation assay. Different concentrations of the two compounds (2.5nM, 5nM, 10nM, and 20nM in DMSO) were used to treat MOLM-13 and MV-4-11 cells carrying the FLT3 / ITD mutation. Sufficient colony formation typically occurred within 15 days, with medium changes twice weekly.

[0065] The experimental results are shown in Figure 3. When the drug dose was increased, the clones formed by MOLM-13 and MV4-11 cells were significantly reduced, and the number of colonies in the D18-D6 drug group was significantly reduced, indicating that D18-D6 has a stronger ability to weaken the proliferation of AML cells than D18.

[0066] D18 and D18-D6 in the treatment of acute myeloid leukemia

[0067] In order to test the inhibitory effect on tumors in vivo, a nude mouse subcutaneous tumor-bearing model was introduced. More than 30 5-week-old mice (Balb / c-nu male mice, purchased from Hangzhou Ziyuan Experimental Animal Technology Co., Ltd.) were subcutaneously inoculated with 1×10 M0LM-13 cells. 7 The weight changes and tumor volume (tumor volume = tumor length × tumor width) of the mice were recorded daily. 2 / 2). After 10 days, when the tumor volume of the mice reached 200-400mm 3 Mice were randomly divided into three groups, each consisting of 6-10 mice, namely, the vehicle group, the D18 50 mg / kg group, and the D18-D6 50 mg / kg group. The first group received daily oral gavage of the vehicle (5% DMSO, 40% PEG-400, and 55% saline); the second group received daily oral gavage of the D18 mixture at 50 mg / kg; and the third group received daily oral gavage of the D18-D6 mixture at 50 mg / kg. The day of the first dose was designated as day 0, and treatment was continued for 2 to 3 weeks.

[0068] The experimental results are shown in Figure 4. Figure 4A shows the changes in mouse body weight after administration, Figure 4B shows the changes in tumor size in mice after administration, Figure 4C shows a photo of the final tumor in the mouse after administration, and Figure 4D shows the final tumor weight in the mouse after administration. The results showed that after treating mice with D18, the growth of tumors in mice was significantly inhibited, and the growth of tumor volume in mice was significantly slowed down; after treating mice with D18-D6, the growth of tumors in mice was strongly inhibited; the growth of tumor volume in mice in the D18 group was significantly slowed down, and the tumors in mice in the D18-D6 group hardly grew. Data from the tumor transplantation mouse model showed that both D18 and D18-D6 can inhibit the growth of acute myeloid leukemia (AML) tumors in mice, and the inhibitory effect of D18-D6 is significantly stronger than that of D18.

[0069] Differences in pharmacokinetics between D18 and D18-D6

[0070] The present invention also evaluated the pharmacokinetic PK properties of D18 and D18-D6 in rats after intravenous and oral administration. The results are shown in Tables 2 and 3. The half-life of D18 was approximately 1.5 hours for intravenous administration and approximately 3.6 hours for oral administration, and the bioavailability was approximately 35.93%; the half-life of D18-D6 was approximately 1.9 hours for intravenous administration and approximately 4.3 hours for oral administration, and the bioavailability was approximately 42.51%, indicating that the pharmacokinetic properties of D18-D6 were significantly improved compared to D18.

[0071] Table 2 Pharmacokinetic properties of D18

[0072] Table 3 Pharmacokinetic properties of D18-D6

[0073] As used herein, the term "deuterated" refers to a compound or group in which one or more hydrogen atoms are replaced by deuterium. Deuteration can be mono-, di-, poly-, or per-substitution. After deuteration, the deuterium isotope content of the deuterium at the deuterium-substituted position is greater than the natural deuterium isotope content (0.015%), more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, more preferably greater than 97%, more preferably greater than 99%, and more preferably greater than 99.5%.

[0074] The term "pharmaceutically acceptable salt" used in the present invention refers to a salt formed by the compound of the present invention with an acid or base that is suitable for use as a drug. Pharmaceutically acceptable salts may include both inorganic salts and organic salts.

[0075] The term "active ingredient" as used in the present invention refers to any substance or mixture of substances used in the manufacture of pharmaceuticals, which has pharmacological activity or other direct effects in the diagnosis, treatment, symptom relief, management or prevention of diseases or can affect the function or structure of the body.

[0076] As used herein, the term "pharmaceutically acceptable excipient" refers to an ingredient that possesses certain physiological activity, but whose addition does not alter the dominant role of the pharmaceutical composition in the treatment of a disease. Instead, the ingredient merely provides auxiliary benefits, which are simply a utilization of the ingredient's known activity and are commonly used in the pharmaceutical field as auxiliary treatments. If such auxiliary ingredients are used in conjunction with the pharmaceutical composition of the present invention, they remain within the scope of protection of the present invention.

[0077] The above embodiments are exemplary and intended to illustrate the technical concepts and features of the present invention so that those skilled in the art can understand the present invention and implement it accordingly. They are not intended to limit the scope of protection of the present invention. Any equivalent changes or modifications made in accordance with the spirit of the present invention are intended to be included within the scope of protection of the present invention.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is of formula (I):

2. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is of formula (II):

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that: The pharmaceutically acceptable salt is a salt formed between the compound and an acid.

4. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that: The pharmaceutically acceptable salt is selected from one or more of phosphate, camphorsulfonate, hydrochloride, hydrobromide, hydrofluoride, sulfate, nitrate, format, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, tartrate, citrate, picrate, methanesulfonate, trifluoromethanesulfonate, toluenesulfonate, and benzenesulfonate.

5. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that: The pharmaceutically acceptable salt is hydrochloride.

6. Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that: The compound or its pharmaceutically acceptable salt is used in preparing medicine for treating cancer.

7. Use of the compound or a pharmaceutically acceptable salt thereof according to claim 6, characterized in that: The cancer is leukemia.

8. The use of the compound or pharmaceutically acceptable salt thereof according to claim 6, characterized in that: The cancer is one or more of lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, liver cancer, glioblastoma, solid tumor, non-small cell lung cancer, papillary renal cell carcinoma, and melanoma.

9. Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that: The compound or a pharmaceutically acceptable salt thereof is used for preparing a FLT3 kinase inhibitor.

10. A drug for treating cancer, characterized in that: The drug is prepared by using the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient and adding pharmaceutically acceptable excipients.

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