CN117903141A

CN117903141A - Compound and salt thereof, application of compound in preparation of medicines and kinase inhibitors for treating cancers and medicines for treating cancers

Info

Publication number: CN117903141A
Application number: CN202311747732.2A
Authority: CN
Inventors: 范方田; 何其伟; 陶羽; 代文婷
Original assignee: BENGBU MEDICAL COLLEGE
Current assignee: BENGBU MEDICAL COLLEGE
Priority date: 2023-12-19
Filing date: 2023-12-19
Publication date: 2024-04-19

Abstract

The invention belongs to the technical field of medicine synthesis, and in particular relates to a compound and salt thereof, application of the compound in preparation of medicines for treating cancers and kinase inhibitors, and medicines for treating cancers. The invention provides a compound CHMFL-FLT3-122 with deuterated at a specific position and pharmaceutically acceptable salt thereof, application of the compound or the pharmaceutically acceptable salt thereof in preparing medicaments and kinase inhibitors for treating cancers, and also provides medicaments for treating cancers. The compound and the pharmaceutically acceptable salt thereof provided by the invention have strong anticancer activity, good metabolic stability and pharmacokinetic properties and good application prospect.

Description

Compound and salt thereof, application of compound in preparation of medicines and kinase inhibitors for treating cancers and medicines for treating cancers

Technical Field

The invention belongs to the technical field of medicine synthesis, and relates to a compound and a salt thereof, application of the compound in preparation of medicines for treating cancers and kinase inhibitors, and medicines for treating cancers.

Background

Blood cells in blood or tissue are derived from hematopoietic stem cells. Hematopoietic stem cells produce a variety of mature blood cells by progressive differentiation, a process known as hematopoiesis. Only if the number of mature blood cells and platelets is maintained at a certain level, the physiological functions of the body can be operated normally. When the differentiation and proliferation of blood cells are blocked, the mature blood cells cannot be supplemented, and the immature blood cells are produced in large quantity, occupy the living space of normal blood cells, compete for nutrients, and lead the body to be dysfunctional, namely leukemia. Leukemia patients easily suffer from bleeding, and have lowered immunity, which seriously endangers the lives of the patients.

Leukemia can be divided into four main types, namely acute myeloid leukemia (Acute Myeloid Leukemia, AML), chronic myeloid leukemia (Chronic Myeloid Leukemia, CML), acute lymphoid leukemia (Acute Lymphocytic Leukemia, ALL) and chronic lymphoid leukemia (Chronic Lymphocytic Leukemia, CLL). AML is the most common type of leukemia and is also the highest mortality type of leukemia. With the continued development of gene sequencing technology, researchers have found that more and more genetic mutations play an important role in the pathogenesis of AML, with FLT3 kinase mutation being one of the most common mutations in AML, and patients with FLT3 genetic mutations often have a poorer prognosis.

The FLT3 kinase structure includes an extracellular region; the transmembrane region, the membrane-proximal region, 2 kinase regions divided by the intermediate insertion structure, and finally the c-terminal end structure. Under normal physiological conditions, in the absence of FLT3 ligand (FL), the membrane-proximal structure of FLT3 inhibits FLT3 dimerization, and when FL is present, its binding to the extracellular receptor domain causes FLT3 dimerization, which results in a change in the structure of the kinase domain, phosphorylates downstream signaling proteins such as PI3K, ras, STAT, and thus activates downstream signaling pathways that regulate cell growth, proliferation, etc. via a series of signaling. In 1996, researchers found that up to 30% of patient samples detected mutations in FLT3-ITD (FLT 3 kinase membrane proximal region tandem repeat mutation) upon examination of AML patients, followed by 5% of patients in 2001 with FLT3-TKD point mutations (tyrosine kinase region point mutations). Both mutations allow FLT3 kinase to be activated independent of FL binding, which, when present, leads to FL independent activation and activation of PI3K, ras, STAT downstream signaling pathways, promoting cell proliferation leading to AML.

The marketed 1 st generation FLT-3 inhibitors are multi-target inhibitors, and the representative varieties are sorafenib (2005), sunitinib (2006), panatinib (2013), and cabotinib (2013), and because the 1 st generation drugs are multi-target drugs, there are some unavoidable side effects such as diarrhea, anorexia, fatigue, nausea, rash, acne, arthralgia, and the like. Thus, more potent FLT-3 inhibitors are developed successively and marketed in batches, and indications are mainly focused on acute myelogenous leukemia. Midostaurin gained FDA breakthrough and became the first kinase inhibitor targeting FLT 3. Quinizarinib is used as a second generation FLT3 inhibitor, and has good selectivity and inhibition activity on FLT 3. The FLT3 kinase inhibitor developed at present has a good treatment effect in clinical experiments, but with the continuous promotion of the FLT3 inhibitor in clinical detection, the drug resistance problem is rapidly displayed, and the medical requirements for FLT3-ITD positive AML are still not satisfied.

The structure of the ibrutinib which is a BTK kinase inhibitor recently reported in China is modified to obtain a compound CHMFL-FLT3-122 (D18 for short) with high-efficiency inhibition activity on an FLT3-ITD positive AML cell line, the compound influences an FLT3-ITD mediated signal path in a cell environment, selectivity is provided for BTK kinase and FLT3 kinase, and the compound is a potential candidate medicament for treating FLT3-ITD positive AML in a phase II clinical experiment at present.

In conclusion, it is of great practical significance to provide compounds with better performance and richer selection of high inhibitory activity for AML patients positive for FLT 3-itd.

Disclosure of Invention

The invention provides a deuterated CHMFL-FLT3-122 compound and pharmaceutically acceptable salt thereof, provides application of the compound or the pharmaceutically acceptable salt thereof in preparing medicines and kinase inhibitors for treating cancers, and also provides medicines for treating cancers, and aims to improve the curative effect of medication and/or improve the safety of medication.

The invention provides a compound or pharmaceutically acceptable salt thereof, which has the following structure:

The invention also provides another compound or pharmaceutically acceptable salt thereof, which has the following structure:

Further, pharmaceutically acceptable salts are salts of the compounds of the present invention with acids.

Further, the pharmaceutically acceptable salt is selected from one or more of phosphate, camphorsulfonate, hydrochloride, hydrobromide, hydrofluoric acid, sulfate, nitrate, formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, tartrate, citrate, picrate, methanesulfonate, trifluoromethanesulfonate, benzenesulfonate.

Preferably, the pharmaceutically acceptable salt is the hydrochloride salt.

The invention also provides application of the compound or pharmaceutically acceptable salt thereof in preparing a medicament for treating cancer.

Further, the use is the use of the above-described compound or a pharmaceutically acceptable salt thereof as a novel FLT3 kinase tyrosine kinase inhibitor for reducing or inhibiting mutant FLT3 kinase activity in a cell or subject and for preventing or treating a cell proliferative disorder and/or a FLT3 related disorder in a subject.

Further, the suitable 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, melanoma.

The invention also provides application of the compound or pharmaceutically acceptable salt thereof in preparing FLT3 kinase inhibitor.

The invention also provides a medicine for treating cancers, which is a preparation prepared by taking the compound or the pharmaceutically acceptable salt thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials.

Advantageous effects

The compound and the pharmaceutically acceptable salt thereof provided by the invention have stronger anticancer activity.

The compound and the pharmaceutically acceptable salt thereof provided by the invention have better metabolic stability and pharmacokinetics property.

Drawings

FIG. 1 shows the cell cycle distribution of MOLM-13 under the action of compounds D18 and D18-D6.

FIG. 2 shows the cell cycle distribution of MV4-11 under the action of compounds D18 and D18-D6.

FIG. 3 shows colonies of MOLM-13 and MV4-11 cells under the action of compounds D18 and D18-D6.

Fig. 4A shows the change in body weight of mice after administration, fig. 4B shows the change in tumor size in mice after administration, fig. 4C shows a physical photograph of the final tumor in mice after administration, and fig. 4D shows the weight of the final tumor in mice after administration.

Detailed Description

The spatial shape and volume of deuterium are basically the same as those of hydrogen, and when the hydrogen in the molecular structure of the drug is replaced by deuterium, the biological activity and selectivity of the original drug can be generally maintained in the deuterated drug, so that the formed deuterated drug has isotope effect and can regulate the relevant process of drug metabolism. However, since the metabolic processes of biological systems are very complex, the pharmacokinetic properties of drugs in living organisms also show corresponding complexity due to the influence of various factors. Thus, changes in the pharmacokinetic properties of deuterated drugs exhibit great contingency and unpredictability compared to non-deuterated drugs, e.g., deuteration at certain sites may not only extend the half-life but may instead shorten it (Scott l.harbeson, roger d.tune. Deuterimin Drug Discovery andDevelopment, P405-406).

The invention prepares a series of deuterated products based on CHMFL-FLT3-122 (D18 for short), and unexpectedly discovers two novel compounds with obvious inhibition effects on both human acute monocytic leukemia cell strain MV4-11 and human acute myelogenous leukemia cell strain MOLM-13.

Structure of compound D18:

The series of compounds tested in the present invention include compounds 2-15, which have the following structures.

Structure of compound 2:

structure of compound 3:

structure of compound 4:

structure of compound 5:

Structure of compound 6:

Structure of compound 7:

structure of compound 8:

structure of compound 9:

structure of compound 10:

structure of compound 11:

Structure of compound 12:

structure of compound 13:

structure of compound 14:

structure of compound 15:

It was found that, among the above compounds, compound 2 and compound 3 have unique remarkable inhibitory effects on human acute monocytic leukemia cell line MV4-11 and human acute myelogenous leukemia cell line MOLM-13. In addition, the compound 2 and the compound 3 show better pharmacokinetic properties compared with D18, so that the dosage of the drug can be reduced to a large extent, and the toxic and side effects are reduced.

Experimental apparatus and reagent used in the invention

Experimental instrument: bruker AVIII 400MHz nuclear magnetic resonance apparatus; bruker AV NEO 600MHz nuclear magnetic resonance apparatus; NICOLET Nexus 470FT-IR spectrometer; waters ACQUITY Arc high performance liquid chromatograph; QDA (ESI) mass spectrometry detector; agilent G7890-5975C (EI) gas chromatograph-mass spectrometer; thermo SCIENTIFIC LTQ Orbitrap XL high resolution mass spectrometer.

Reagent: compound C ₂₇H₃₀N₆O₃, ethyl acetate, hydrogen chloride dioxane, sodium bicarbonate, hydrogen chloride, 2-dimethylaminoacetic acid, HATU, DIPEA, etOAc, dichloromethane, chloroacetyl chloride, meOH, deuterated dimethylamine d ₆ hydrochloride, triethylamine, potassium iodide, anhydrous sodium sulfate, petroleum ether, anhydrous ethanol, acetonitrile, and the like. The reagents were all commercially available analytically pure products and were used directly after purchase.

Synthesis of Compound D18

According to the following reaction scheme, the starting material (1 g,2.06 mmol) was weighed and dissolved in ethyl acetate (20 mL), 4N hydrogen chloride dioxane solution was added under ice water bath, then the reaction was carried out at room temperature for 2 hours, TLC detection was complete, the solvent was distilled off under reduced pressure to give a white solid, ethyl acetate and water were added, 2N sodium bicarbonate solution was added, ethyl acetate extraction was carried out, the ethyl acetate layers were combined and washed with saturated brine, and after drying, the solvent was distilled off under reduced pressure to give 865mg of a white solid.

To a solution of starting material (80 mg,0.21 mmol) in DMF (4 mL) was added 2-dimethylaminoacetic acid (22 mg,0.21 mmol), HATU (80 mg,0.21 mmol) and DIPEA (35. Mu.L, 0.20 mmol) according to the following reaction scheme. The reaction mixture was stirred for 5h. Then diluted with EtOAc (50 mL), washed with water (20 mL. Times.3) and saturated brine (30 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (MeOH in 0-10% dichloromethane) to give the compound as a white solid D-18(67mg,68％).¹H NMR(400MHz,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,0.5H),2.36(s,4H),2.27(s,4H),2.12(d,J＝4.3Hz,1H),1.90(m,1H),1.69(s,1H).¹³C NMR(100MHz,DMSO-d₆)δ_C166.7,158.2,157.1,156.3,155.7,153.9,143.3,130.1,127.9,123.8,120.1,119.0,97.4,60.7,52.6,52.0,49.0,45.4,44.9,44.8,41.4,29.4,24.5.

Synthesis of Compound 2 (D18-D6)

DIPEA (36.5. Mu.L, 0.21 mmol) and chloroacetyl chloride (17. Mu.L, 0.21 mmol) were added to a solution of the starting material (80 mg,0.21 mmol) in methylene chloride (10 mL) at 0deg.C according to the following reaction scheme. The resulting mixture was stirred for 3 minutes. Then quenched with MeOH (5 mL), concentrated, and purified by column chromatography on silica gel (dichloromethane: methanol 100:1 to 30:1) to give the amide compound (89 mg) as a white solid.

The above white solid was dissolved in dry acetonitrile (5 mL), deuterated dimethylamine D ₆ hydrochloride (88 mg,1 mmol), triethylamine (140. Mu.L, 2 mmol) and potassium iodide (17 mg,0.1 mL) were added, reacted for 12 hours at 40℃and then quenched with water, extracted three times with ethyl acetate, dried and purified by silica gel column chromatography (dichloromethane: methanol 50:1 to 10:1), the product D-18-D ₆ was a white solid 75mg, total yield 75％.¹H NMR(400MHz,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,1H),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).¹³C NMR(100MHz,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.

Synthesis of Compound 3 (D18-D3)

DIPEA (36.5. Mu.L, 0.21 mmol) and chloroacetyl chloride (17. Mu.L, 0.21 mmol) were added to a solution of the starting material (80 mg,0.21 mmol) in methylene chloride (10 mL) at 0deg.C according to the following reaction scheme. The resulting mixture was stirred for 3 minutes. Then quenched with MeOH (5 mL), concentrated, and purified by column chromatography on silica gel (dichloromethane: methanol 100:1 to 30:1) to give the amide compound (89 mg) as a white solid. The above solid was dissolved in dry acetonitrile (5 mL), deuterated dimethylamine D ₃ hydrochloride (88 mg,1 mmol), triethylamine (140. Mu.L, 2 mmol) and potassium iodide (17 mg,0.1 mL) were added, reacted for 12 hours at 40℃and then quenched with water, extracted three times with ethyl acetate, dried and purified by silica gel column chromatography (dichloromethane: methanol 50:1 to 10:1), the product D-18-D ₃ was a white solid 71mg, total yield 70%.

Effects of D18 and deuterated series of drugs on proliferation of cancer cells

Inhibition of cancer cell proliferation was assessed by measuring the effect of D18 and deuterated series drugs on cancer cell proliferation on cancer cell growth. Human acute monocytic leukemia cell strain MV4-11 (expressing FLT3/ITD mutant gene) and human acute myelogenous leukemia cell strain MOLM-13 (expressing FLT3/ITD mutant gene and wild type FLT3 gene) are selected. Different concentrations of the above compounds (25 nM,50nM,100nM,200nM,400nM in DMSO) were added to the cells and incubated for 72 hours. Detecting the absorbance at 450nm in an enzyme-labeled instrument by using Cell Counting Kit-8 (CCK-8) reagent to obtain an OD value, and further calculating to obtain an IC50, wherein the experimental result is shown.

IC ₅₀ values of the compounds of Table 1 for MOLM-13 and MV4-11 cells

The results indicate that among the series of deuterated compounds, compound 2 and compound 3 exhibit unique inhibition of cancer cell proliferation. The IC ₅₀ values of compound 2 and compound 3 on MOLM-13 and MV4-11 cells were significantly lower than other deuterated compounds, and also significantly lower than compound D18, indicating that their inhibition on MOLM-13 and MV4-11 cells was significantly better than other deuterated compounds, and also significantly better than compound D18. ( IC ₅₀, half maximal inhibitory concentration, also referred to as 50% inhibition concentration, refers to the concentration of drug that induces tumor cells to undergo apoptosis by 50%, i.e., the concentration of drug corresponding to a ratio of apoptotic cells to total cell number equal to 50%. The IC ₅₀ value can be used to measure the ability of a drug to induce apoptosis in tumor cells, with lower values indicating greater induction. )

Effects of D18 and D18-D6 on cell cycle

The effect of D18 and D18-D6 on the cell cycle distribution of the human acute monocytic leukemia cell MV4-11 cell line and acute myelogenous leukemia cell MOLM-13 was tested. Cells were collected after 24 hours of action on acute myelogenous leukemia cell lines MV4-11, MOLM-13 carrying the FLT3/ITD mutant gene with two compounds at different concentrations (100 nM, 200nM, 300nM, 400nM in DMSO), washed twice with IXPBS buffer, fixed with 75% ethanol at-20℃for 24 hours, washed twice with IXPBS buffer, added with 0.5mLIXPBS buffer and 0.5mL of PI staining solution (from BD Bioscience, america) to the cells and the cells were stained for 15 minutes in the dark at 37℃and the cell cycle distribution was examined with a flow cytometer (BD FACS Calibur) and analyzed by FlowJo software (Ashland OR).

The experimental results are shown in FIGS. 1 and 2, and the MOLM-13 cells (FIG. 1) and MV4-11 cells (FIG. 2) were prevented from the cell cycle in the G0-G1 phase and were dose-dependent by the action of D18 and D18-D6.

Effects of D18 and D18-D6 on cell clone formation

Proliferation capacity of MOLM-13, MV-4-11 cells carrying FLT3/ITD mutant genes was examined by experiments on soft agar colony formation. The time required for adequate colony formation in MOLM-13, MV-4-11 cell lines carrying the FLT3/ITD mutant gene was typically 15 days with varying concentrations of the two compounds (2.5 nM, 5nM, 10nM, 20nM in DMSO) and 2 changes per week.

As shown in FIG. 3, clones formed by MOLM-13, MV4-11 cells were significantly reduced and the number of colonies in the D18-D6 drug group was significantly reduced after the drug dose was increased, indicating that D18-D6 had a greater capacity to attenuate proliferation of AML cells than D18.

D18 and D18-D6 for the treatment of acute myelogenous leukemia

In order to detect the inhibition effect on tumors in vivo, a nude mouse subcutaneous tumor-bearing model was introduced. Over 30 mice (Balb/c-nu male mice, available from hangzhou child source laboratory animal technologies limited) were inoculated subcutaneously with 1x10 ⁷ M-13 cells per mouse, and the weight change and tumor volume (tumor volume = tumor length x tumor width ²/2) were recorded daily. After 10 days, after the tumor volume of the mice reached 200-400mm ³, the mice were randomly divided into veccles, D18-D6 50mg/kg dose groups, 3 groups of 6-10 mice each. The following treatments were performed respectively: a first group was orally administered daily with a gastric lavage vehicle (vehicle), i.e. 5% DMSO,40% PEG-400, 55% saline solution; the second group of D18 mixed liquid preparations which are orally infused with 50mg/kg of stomach every day; the third group is orally administrated with 50mg/kg D18-D6 mixed liquid preparation per day. The first administration was noted on day 0 and the continuous administration was observed for 2 to 3 weeks.

The experimental results are shown in fig. 4, in which fig. 4A shows the change of the body weight of the mice after administration, fig. 4B shows the change of the tumor size in the mice after administration, fig. 4C shows the physical photograph of the final tumor in the mice after administration, and fig. 4D shows the weight of the final tumor in the mice after administration. The results show that after the mice are treated by D18, the tumor growth of the mice is obviously inhibited, and the tumor volume increase of the mice is obviously slowed down; after treatment of mice with D18-D6, tumor growth was strongly inhibited; the tumor volume increase of the mice in the D18 group is obviously slowed down, and the tumors of the mice in the D18-D6 group hardly increase. The data of the tumor-transplanted mouse model show that both D18 and D18-D6 can play a role in inhibiting the growth of Acute Myelogenous Leukemia (AML) tumors in mice, and the inhibition effect of D18-D6 is obviously stronger than that of D18.

Differences in pharmacokinetics between D18 and D18-D6

The present invention also evaluates the pharmacokinetic PK profile of D18, D18-D6 in rats administered intravenously and orally, and the half-life of D18 is about 1.5h, po about 3.6h, and the bioavailability is about 35.93% for veins as shown in tables 2 and 3; the half-life of D18-D6 was about 1.9h for veins, about 4.3h for po, and about 42.51% bioavailability, indicating a significant improvement in the pharmacokinetic profile of D18-D6 over D18.

Table 2 d18 pharmacokinetic properties

TABLE 3 pharmacokinetic properties of D18-D6

The term "deuterated" as used herein refers to compounds or groups in which one or more hydrogens are replaced with deuterium. Deuteration may be mono-, di-, poly-or full-substituted. After deuteration, the deuterium isotope content of deuterium at the deuterium substitution site 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%, more preferably greater than 99.5%.

The term "pharmaceutically acceptable salt" as used herein refers to salts of the compounds of the invention with acids or bases that are suitable for use as medicaments. Pharmaceutically acceptable salts may include both inorganic and organic salts.

The term "active ingredient" as used herein refers to any substance or mixture of substances used in pharmaceutical manufacturing that has pharmacological activity or other direct effect or can affect the function or structure of the body in the diagnosis, treatment, symptomatic relief, management or prevention of a disease.

The term "pharmaceutically acceptable auxiliary material" used in the present invention has a certain physiological activity, but the addition of the component does not change the dominant position of the pharmaceutical composition in the disease treatment process, but only exerts auxiliary effects, which are only the utilization of the known activity of the component, and are auxiliary treatment modes which are conventional in the medical field. If the auxiliary components are used together with the pharmaceutical composition of the present invention, the auxiliary components still fall within the scope of the present invention.

The above embodiments are illustrative for the purpose of illustrating the technical concept and features of the present invention so that those skilled in the art can understand the content of the present invention and implement it accordingly, and thus do not limit the scope of the present invention. All equivalent changes or modifications made in accordance with the spirit of the present invention should be construed to be included in the scope of the present invention.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that: the compound has a structure shown in a formula (I):

2. a compound or a pharmaceutically acceptable salt thereof, characterized in that: the compound has a structure of formula (II):

3. a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: the pharmaceutically acceptable salt is a salt of the compound with an acid.

4. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: the pharmaceutically acceptable salt is selected from one or more of phosphate, camphorsulfonate, hydrochloride, hydrobromide, hydrofluoric acid, sulfate, nitrate, formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, tartrate, citrate, picrate, mesylate, triflate, benzoate, and benzenesulfonate.

5. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: the pharmaceutically acceptable salt is hydrochloride.

6. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein: the compound or the pharmaceutically acceptable salt thereof is used for preparing medicines for treating cancers.

7. The use of a compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein: the cancer is leukemia.

8. The use of a compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein: 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 a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein: the compound or the pharmaceutically acceptable salt thereof is used for preparing the FLT3 kinase inhibitor.

10. A medicament for treating cancer, characterized in that: the medicament is prepared by taking the compound or the pharmaceutically acceptable salt thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials.