CN105001203B - A kind of Bcr Abl amphiploid inhibitor and its production and use - Google Patents

Abstract

A Bcr-Abl diploid inhibitor and its preparation method and application. The present invention discloses a compound of formula I or a pharmaceutically acceptable salt thereof, and its structural formula is as follows. The compound of formula I provided by the present invention or a pharmaceutically acceptable salt thereof, as a Bcr-Abl diploid inhibitor, can effectively inhibit the activity of tyrosine kinase, and can be effectively used for the treatment of diseases related to abnormal activation of such kinases. The malignant tumor has a good therapeutic effect, and the preparation method of this type of inhibitor is simple and low in cost, and has a good application prospect. .

Description

A kind of Bcr-Abl diploid inhibitor and its preparation method and application

technical field

The invention relates to a Bcr-Abl diploid inhibitor, a preparation method and application thereof.

Background technique

Chronic myelogenous leukemia is a chromosomal gene mutation [t(9:22)(q34;q11)] reciprocal translocation, the ABL gene at chromosome 9 and the BCR gene at chromosome 22 are fused to produce BCR-ABL, the fused gene Encodes a 210kDa tyrosine kinase Bcr-Abl, which is the main cause of chronic myelogenous leukemia. c-Abl is a haploid tyrosine kinase that exists in the cytoplasm in normal cells. After fusion with Bcr, its morphology changes from haploid to tetramer, so the kinase is always activated. lead to the occurrence of tumors. The presence of amino acid sequences that can cause multimerization in the Bcr protein sequence leads to Bcr-Abl tetramerization. Since c-Abl plays an important role in normal cells such as cardiac muscle, if inhibitors that selectively inhibit oncogenic Bcr-Abl but not Abl are developed, it is expected to greatly reduce the extensive side effects of such inhibitors such as cardiotoxicity.

In 2001, the FDA approved the marketing of the first tyrosine kinase inhibitor (TKI), imatinib (Imatinib), for the treatment of chronic myeloid leukemia (CML). As the first-generation Bcr-Abl inhibitor, imatinib has become the first-line drug for the treatment of CML. But most patients eventually develop resistance to imatinib. Subsequent studies have shown that the occurrence of IM drug resistance may be related to gene mutations in the active region of Abl kinases such as G250E, Q252H, Y253F, Y253H, E255K, E355G, E255V, T315A, T315I, F317L, F317V, M351T, F359V, H396P, and M244V , gene mutations lead to a decrease in the affinity of imatinib to Abl kinase. Most gene mutations reduce the affinity of imatinib by 5-30 times, which is the main reason for drug resistance. Among them, T315I is special, and the decrease is the most obvious, and the IC ₅₀ drops to about 6400nM. The recently developed ponatinib is not only effective for T315I, but also effective for wild type and most of the mutant strains.

From the x-Ray co-crystal structure of the kinase part of imatinib and Abl protein, the nitrogen methyl part of the alpha-piperazine part in the structure is exposed in the solvent, and the straight line between the nitrogen atoms of the two inhibitors The distance is about 24 amps. Since Bcr-Abl is a tetramer, it can combine with four inhibitors at the same time. If the two inhibitors are connected by a chain, it is expected to greatly improve the affinity for tetramerized Bcr-Abl, thereby playing a role Selectively inhibit the action of Bcr-Abl, and because Abl is haploid, it can only be combined with one inhibitor, and the affinity of the double inhibitor to the enzyme will not be greatly affected.

Contents of the invention

The object of the present invention is to provide a Bcr-Abl diploid inhibitor and its preparation method and application.

The compound of formula I provided by the present invention or a pharmaceutically acceptable salt thereof has a structural formula as follows:

In the present invention, Linker means linker molecule.

Further, in Formula I, Linker is (Z ₁ ) _a -(Z ₂ ) _b -(Z ₃ ) _c ;

Wherein, Z ₁ , Z ₂ , and Z ₃ are independently selected from C(O)(CH ₂ ) _d NH, CO(CH ₂ ) _e C(O), (CH ₂ CH ₂ ) _f NHC(O), ( CH ₂ CH ₂ ) _g -C(O)NH, (CH ₂ ) _h C(O)(OCH ₂ CH ₂ ) _i NHC(O)(CH ₂ ) _j C(O), NH(CH ₂ ) _k ( OCH ₂ CH ₂ ) _l -O(CH ₂ ) _m NH, (CH ₂ ) _n C(O)(OCH ₂ CH ₂ ) _O NH(C(O)(CH ₂ ) _p NH) _q C(O)- alkyl, C(O)NH(CH ₂ ) _r NHC(O)-(CH ₂ ) _s C(O)(NHCH ₂ CH ₂ ) _t NH(C(O)(CH ₂ ) _u NH) _v -C( O)-alkyl;

a to v are each independently selected from any value in 1 to 20.

Further, its structural formula is:

The present invention also provides a method for preparing the above-mentioned compound of formula I or a pharmaceutically acceptable salt thereof.

The present invention prepares the method for above-mentioned compound of formula I, and it comprises following operating steps:

Further, it includes the following steps:

(1) Preparation of compound 2:

(2) Preparation of compound BGC, which is a compound of formula I:

Further, it includes the following steps:

i. Preparation of compound 2:

Compound 1, triethylamine, and 4-(chloromethyl)benzoyl chloride were stirred and reacted at room temperature for 18 hours in dichloromethane to obtain a reaction solution; the reaction solution was separated and purified to obtain compound 2;

ii. Preparation of compound 6:

①. Preparation of compound 4

Compound 3, triethylamine, and glutaryl chloride were reacted in dichloromethane with stirring at room temperature for 6 hours to obtain a reaction solution; the reaction solution was separated and purified to obtain compound 4;

②, preparation of compound 6

Compound 4, 1-hydroxybenzotriazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N-methylmorpholine in dichloromethane, in ice bath After reacting under the conditions for 0.5 hours, compound 5 was added, and the reaction was completed at room temperature to obtain a reaction liquid; the reaction liquid was separated and purified to obtain compound 6;

iii. Preparation of compound BGC

Compound 2, compound 6, and potassium carbonate were reacted in N,N-dimethylformamide with stirring at 100° C. for 18 hours to obtain a reaction liquid; the reaction liquid was separated and purified to obtain compound BGC.

further,

In step i, the molar ratio of the compound 1, triethylamine, and 4-(chloromethyl)benzoyl chloride is 18:35.6:21.3; the molar volume ratio of the compound 1 to dichloromethane is 18:400mmol/ ml;

In step ① of step ii, the molar ratio of the compound 3, triethylamine and glutaryl chloride is 45.4:68.1:22.7; the molar volume ratio of the compound 3 to dichloromethane is 45.4:300mmol/ml;

In ② of step ii, the compound 4, 1-hydroxybenzotriazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N-methylmorpholine, The molar ratio of compound 5 is: 1:1.2:1.2:3:2.1; the molar volume ratio of compound 4 and dichloromethane is 1:20mmol/ml;

In step iii, the molar ratio of compound 2, compound 6, and potassium carbonate is 0.28:0.09:2.69; the molar volume ratio of compound 2 to N,N-dimethylformamide is 0.28:20mmol/ml.

The invention also provides the use of the above-mentioned compound and its pharmaceutically acceptable salts in the preparation of medicines for treating cell proliferation diseases.

Use of the above compounds and pharmaceutically acceptable salts thereof in the preparation of medicines for treating cell proliferation diseases.

Further, the drug is a tyrosine kinase inhibitor.

Further, the drug is an ABL inhibitor drug.

Further, the drug is an inhibitor of BCR-ABL or its mutant strain.

Further, the BCR-ABL mutant is a T315I mutant.

Further, the cell proliferative disease is cancer.

Further, the cancer is chronic myeloid leukemia, intestinal stromal tumor, gynecological tumor, dermatofibrosarcoma protuberans, Ph+ALL.

The compound of formula I provided by the present invention or a pharmaceutically acceptable salt thereof, as a Bcr-Abl diploid inhibitor, can effectively inhibit the activity of tyrosine kinase, and can be effectively used for the treatment of diseases related to abnormal activation of such kinases. The malignant tumor has a good therapeutic effect, and the preparation method of this type of inhibitor is simple and low in cost, and has a good application prospect.

Apparently, according to the above content of the present invention, according to common technical knowledge and conventional means in this field, without departing from the above basic technical idea of the present invention, other various forms of modification, replacement or change can also be made.

The above-mentioned content of the present invention will be further described in detail below through specific implementation in the form of examples. However, this should not be construed as limiting the scope of the above-mentioned subject matter of the present invention to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Description of drawings

Figure 1. Effect of BGC on tumor volume in KBM5 tumor-bearing mice.

detailed description

The raw materials and equipment used in the specific embodiment of the present invention are all known products, obtained by purchasing commercially available products.

Abbreviated Chinese name:

HOBT: 1-hydroxybenzotriazole; EDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; NMM: N-methylmorpholine; DMSO: dimethyl sulfoxide.

Embodiment 1 The preparation of compound BGC of the present invention

The synthetic route is as follows:

(2) Preparation of compound BGC:

Concrete synthetic steps are as follows:

a) preparation of compound 2

Compound 1 (5.0g, 18.0mmol; manufacturer: Shanghai Xugang Biotechnology Co., Ltd.), triethylamine (3.6g, 35.6mmol) were dissolved in dichloromethane (400ml), and 4-(chloromethyl) Benzoyl chloride (4.0g, 21.3mmol) was dissolved in dichloromethane (100ml), and was added dropwise to the reaction solution at 0°C. After the addition, it was naturally raised to room temperature and stirred for 18h. A solid precipitated in the reaction bottle. The reaction mixture was filtered, and the collected solid was washed with dichloromethane and water to obtain compound 2 as a yellow solid (5.3 g; yield 68%).

¹ H NMR (400MHz, DMSO-d6): δ10.23(s, 1H), 9.28(s, 1H), 8.97(s, 1H), 8.69(d, J=4.4Hz, 1H), 8.52(m, 2H),8.09(s,1H),7.97(d,J=7.6Hz,2H),7.59-7.42(m,5H),7.22(d,J=8.0Hz,1H),4.84(s,2H), 2.23(s,3H). MS (ESI+) m/z: 430[M+1] ⁺ .

b) preparation of compound 4

At room temperature, compound 3 (10.0g, 45.4mmol; manufacturer: Sigma-Aldrich.) was dissolved in dichloromethane (250ml), triethylamine (6.9g, 68.1mmol) was added, and glutaryl chloride ( 3.8g, 22.7mmol) was dissolved in dichloromethane (50ml), and slowly added dropwise to the reaction solution. After the addition was completed, the reaction was stirred at room temperature for 6h, and then the reaction solution was washed with water (200ml×2). Dry over sodium sulfate and concentrate in vacuo to dry the solvent. The residue was purified by silica gel column chromatography (dichloromethane/methanol=20/1) to obtain compound 4. (4.3 g; yield 35.4%).

c) preparation of compound 6

Under ice bath, compound 4 (2.7g, 5.0mmol) was dissolved in dichloromethane (100ml), HOBT (0.81g, 6.0mmol), EDC (0.59g, 6.0mmol), NMM (1.52g, 15mmol) were added ) was reacted for half an hour, compound 5 (1.67g, 10.5mmol, manufacturer: Bailingwei Technology Co., Ltd.) was added to the reaction solution in batches, after the addition was completed, it was gradually raised to room temperature, and the reaction was carried out overnight. The reaction solution was washed with saturated sodium chloride The organic phase was washed with an aqueous solution (100ml×2), dried over sodium sulfate, concentrated in vacuo and evaporated to dryness, and the residue was purified by silica gel column chromatography to obtain compound 6 (1.3g; yield 31.8%).

¹ H NMR (400MHz, D ₂ O) 3.62 (30H, m), 3.53 (14H, m), 3.21 (8H, q, J = 7, 2Hz). 2.77 (4H, t, J = 6.8Hz). 2.21 (4H,t,J=7.6Hz).1.82(2H,m).

d) Preparation of compound BGC

Add compound 6 (72mg, 0.09mmol), compound 2 (120mg, 0.28mmol), K ₂ CO ₃ (350mg, 2.69mmol), N,N-dimethylformamide (20ml) into a round bottom flask, The reaction was stirred at 100°C for 18 hours. After the reaction solution was cooled to room temperature, the reaction solution was poured into vigorously stirred ice water to precipitate a solid, which was filtered and collected. The residue was purified by preparative high performance liquid phase to obtain an orange solid BGC (18 mg; yield 12%).

¹ H NMR (400MHz, D ₂ O): δ9.40(s, 2H), 9.12(d, J=8Hz, 2H,), 8.87(d, J=5.2Hz, 2H), 8.50(bs, 2H) ,8.13(t,J=6.8Hz,2H),7.95(d,J=7.6Hz,4H),7.90(s,2H),7.65(d,J=8Hz,4H),7.45(d,J=5.2 Hz, 2H), 7.36(d, J=8Hz, 2H), 7.24(d, J=7.6Hz, 2H), 4.43(s, 4H), 3.66-3.44(m, 44H), 3.28(t, J= 6.8Hz, 4H), 3.22(t, J=6.8Hz, 4H), 2.78(t, J=6.8Hz, 4H), 2.26(s, 6H), 2.22(t, J=7.2Hz, 4H), 1.87 -1.70(m,10H).MS(ESI+) m/z: 1604[M+1] ⁺ .

The beneficial effects of the present invention will be specifically described below through test examples.

Test Example 1 Medicinal activity of the compounds of the present invention

1. Tyrosine Kinase Inhibition

Reference: Amy Card et al., Journal of Biomolecular Screening 14(1) 2009; Jude Dunne et al., Assay & Drug Development Technologies Vol.2, No.2, 2004.

Utilize the method of Mobility Shift Assay, carry out the screening of compound BGC of the present invention to in vitro kinase Abl, compound BGC concentration is diluted to 0.005 μ M successively with 100% DMSO by 100 μ M triple dilution method, totally 10 concentration points, detect (2 duplicate holes ), the compound staurosporine was used as a standard control, and a vehicle control (10% DMSO) and a negative control (EDTA) were set up.

On the 384-well reaction plate, the inhibition of the kinase Abl by the compound BGC of each concentration was detected by enzyme-linked immunoreaction, and the conversion rate data was read on the Caliper, and the conversion rate was converted into an inhibition rate.

Percent inhibition=(max-conversion)/(max-min)*100. Wherein max refers to the conversion rate of DMSO control, and min refers to the conversion rate of no enzyme activity control. The half inhibitory concentration IC ₅₀ of compound BGC to tyrosine kinase Abl was calculated according to the inhibition rate of each concentration.

The suppression results are as follows:

IC ₅₀ of compound BGC: 0.02 μM;

The test results show that the compound BGC of the present invention has strong inhibitory activity on c-Abl tyrosine kinase.

2. Compound BGC of the present invention inhibits proliferation of KBM5 (Bcr-Abl positive) tumor cells in vitro

Use the ATP method to measure the cytotoxicity of the BGC series compounds of the present invention, adjust the appropriate cell density of KBM5 cells, inoculate a 96-well plate with 140ul cell suspension per well, and the inoculation density of each cell is: 2000-6000; the above-mentioned cell culture Place it in the plate incubator for 24 hours to make it completely adhere to the wall of the hole. The compound BGC of the present invention is prepared into different appropriate concentrations by the three-fold dilution method, and added to the corresponding wells of the 96-well plate inoculated with cells in advance. Well 10 μL, so that the final concentrations are: 100 μM, 33.3 μM, 11.1 μM, 3.70 μM, 1.23 μM, 0.41 μM, 0.14 μM, 0.046 μM, 0.015 μM. Three replicate wells were set up for each concentration, and after incubation in a 37°C incubator for 72 hours, the cell proliferation in each well was measured by ATP method, and the IC ₅₀ of each drug concentration on the proliferation of KBM5 cells was calculated.

test results:

The cytotoxicity of compound BGC to KBM5 (human-derived wild-type Bcr-Abl) tumor cells is as follows:

IC ₅₀ of compound BGC: 9 μM;

The test results show that the compound BGC of the present invention has strong inhibitory activity at the cell level in vitro.

3. In vivo leukemia subcutaneous xenograft proliferation inhibition test of compound BGC of the present invention

According to the results of the in vitro proliferation inhibition test, the growth inhibitory effect of BGC on the subcutaneous transplantation of human leukemia KBM5 cells in C57BL/6(Es-1 ^c ) nude mice was evaluated.

The administration dosage of compound BGC of the present invention is respectively: 80mg/Kg, 160mg/Kg, 350mg/Kg, establish positive control group (160mg/Kg imatinib Imatinib) and blank control group (normal saline) simultaneously, tumor-bearing The mice were grouped and administered once a day, and after two weeks of continuous administration, the tumor volume was detected.

To see if tumor growth can be inhibited, delayed or cured. Tumor diameters were measured with vernier calipers twice a week or every other day. The formula for calculating the tumor volume is: V=0.5a×b ² , where a and b represent the long diameter and short diameter of the tumor, respectively.

Data analysis: T test was used for comparison between two groups; one-way ANOVA was used for comparison between three or more groups. If there is a significant difference in F values, multiple comparisons should be performed after ANOVA analysis. Two-way ANOVA was used to analyze the potential synergistic effects of the co-administered groups. All data analyzes were performed using SPSS 17.0; p<0.05 was considered significant difference.

Test results: the in vivo pharmacodynamic study results of the compound BGC of the present invention on KBM5 cell subcutaneously transplanted tumor models are shown in FIG. 1 .

In the subcutaneous tumor model, the compound BGC of the present invention has an antitumor effect, which is equivalent to the inhibitory effect of imatinib 160 mg/kg at a dose of 350 mg/kg.

4. Preliminary pharmacokinetic study of the compound BGC of the present invention

Female C57BL/6 (Es-1 ^c ) nude mice were subjected to a single-dose intravenous test of the compound BGC of the present invention, and its concentration in main tissues and blood drug concentration were quantitatively determined by liquid chromatography tandem mass spectrometry, and the effect of the test drug on female Differences in distribution between blood and major tissues in C57BL/6(Es-1 ^c ) nude mice; compared with imatinib.

The experimental method and process are as follows: female C57BL/6(Es-1 ^c ) nude mice, body weight 18-25g, 6-8 weeks old, in addition, 3 female C57BL/6(Es-1 ^c ) nude mice were used to collect blank samples, and prepare the standard curve required for analysis. The dosage for intravenous injection is 1mg/kg, and the administration volume is 5mL/kg. Vehicle for intravenous injection: DMSO:Solutol HS15:Saline=5:5:90, v/v/v. Establish the LC-MS/MS method, and use the internal standard method to quantitatively determine the blood drug concentration and tissue concentration of the tested drug. The linear range is 1-1000 ng/mL, and the lower limit of quantification is generally 1 ng/mL. Female C57BL/6 (Es-1 ^c ) nude mice were administered intravenously, and about 20 μL of whole blood was collected from the tail vein of the mice at 0.25h, 2h, 8h and 24h, anticoagulated with K ₂ EDTA, and added according to the volume ratio Blood samples were diluted with 3 times redistilled water and stored at -70°C until analysis. At the same time, tissue samples such as heart, liver, spleen, lung, kidney, stomach, small intestine, and pancreas were collected, washed with normal saline, blotted dry with filter paper, weighed and recorded, and then stored at -70°C until analysis. After thawing the weighed organ tissues, add 3 times PBS buffer salt to the heart, liver, spleen, lung, kidney, stomach, small intestine and pancreas and use Beadbeater to homogenize; when collecting bone marrow samples, use 0.3mL PBS buffer salt to wash, Then centrifuge at 12000 rpm for 5 minutes, remove 0.25 mL of supernatant, and add 150 mL of PBS buffer to the remaining cell samples for homogenization.

Data analysis: WinNonlin (version 6.2) software was used to calculate pharmacokinetic parameters according to non-compartmental model.

The experimental results show that the half-life (t _1/2 ) of the compound BGC of the present invention is 3.5 hours, which is far greater than the half-life (t _1/2 is 1.5h) of imatinib; compared with imatinib, the compound of the present invention BGC has very obvious advantages in pharmacokinetic properties after intravenous injection.

In summary, the compound of formula I or its pharmaceutically acceptable salt provided by the present invention, as a Bcr-Abl diploid inhibitor, can effectively inhibit the activity of tyrosine kinases, and can be effectively used in the treatment of abnormal activation of such kinases. It has good therapeutic effect on malignant tumors, and the preparation method of this kind of inhibitor is simple and low in cost, and has good application prospect.

Claims (13)

1. Formula I compound or its pharmaceutically acceptable salt, its structural formula is as follows: In formula Ⅰ, Linker is (Z ₁ ) _a –(Z ₂ ) _b –(Z ₃ ) _c ; Wherein, Z ₁ , Z ₂ , and Z ₃ are independently selected from C(O)(CH ₂ ) _d NH, CO(CH ₂ ) _e C(O), (CH ₂ CH ₂ ) _f NHC(O), (CH ₂ CH ₂ ) _g -C(O)NH, (CH ₂ ) _h C(O)(OCH ₂ CH ₂ ) _i NHC(O)(CH ₂ ) _j C(O), NH(CH ₂ ) _k (OCH ₂ CH ₂ ) _l -O(CH ₂ ) _m NH, (CH ₂ ) _n C(O)(OCH ₂ CH ₂ ) _o NH(C(O)(CH ₂ ) _p NH) _q C(O)-alkyl, C(O)NH(CH ₂ ) _r NHC(O)-(CH ₂ ) _s C(O)(NHCH ₂ CH ₂ ) _t NH(C(O)(CH ₂ ) _u NH) _v -C(O) -alkyl; a to v are each independently selected from any value in 1 to 20. 2. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: its structural formula is: 3. the method for preparing claim 1 formula I compound is characterized in that: it comprises the following operation steps: 4. The preparation method according to claim 3, characterized in that: it comprises the following steps: (1) Preparation of compound 2: (2) Preparation of compound BGC, which is a compound of formula I: 5. The preparation method according to claim 4, characterized in that: it comprises the following steps: i. Preparation of compound 2: Compound 1, triethylamine, and 4-(chloromethyl)benzoyl chloride were stirred and reacted at room temperature for 18 hours in dichloromethane to obtain a reaction solution; the reaction solution was separated and purified to obtain compound 2; ii. Preparation of compound 6: ①. Preparation of compound 4 Compound 3, triethylamine, and glutaryl chloride were reacted in dichloromethane with stirring at room temperature for 6 hours to obtain a reaction solution; the reaction solution was separated and purified to obtain compound 4; ②, preparation of compound 6 Compound 4, 1-hydroxybenzotriazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N-methylmorpholine in dichloromethane, in ice bath After reacting under the conditions for 0.5 hours, compound 5 was added, and the reaction was completed at room temperature to obtain a reaction liquid; the reaction liquid was separated and purified to obtain compound 6; iii. Preparation of compound BGC Compound 2, compound 6, and potassium carbonate were reacted in N,N-dimethylformamide with stirring at 100° C. for 18 hours to obtain a reaction liquid; the reaction liquid was separated and purified to obtain compound BGC. 6. The preparation method according to claim 5, characterized in that: In step i, the molar ratio of the compound 1, triethylamine, and 4-(chloromethyl)benzoyl chloride is 18:35.6:21.3; the molar volume ratio of the compound 1 to dichloromethane is 18:400mmol/ ml; In step ① of step ii, the molar ratio of the compound 3, triethylamine and glutaryl chloride is 45.4:68.1:22.7; the molar volume ratio of the compound 3 to dichloromethane is 45.4:300mmol/ml; In ② of step ii, the compound 4, 1-hydroxybenzotriazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N-methylmorpholine, The molar ratio of compound 5 is: 1:1.2:1.2:3:2.1; the molar volume ratio of compound 4 and dichloromethane is 1:20mmol/ml; In step iii, the molar ratio of compound 2, compound 6, and potassium carbonate is 0.28:0.09:2.69; the molar volume ratio of compound 2 to N,N-dimethylformamide is 0.28:20mmol/ml. 7. Use of the compound according to any one of claims 1 to 2 and pharmaceutically acceptable salts thereof in the preparation of medicines for treating cell proliferation diseases. 8. The use according to claim 7, characterized in that the drug is a tyrosine kinase inhibitor. 9. The use according to claim 7 or 8, characterized in that: the drug is an ABL inhibitor drug. 10. The use according to claim 7 or 8, characterized in that the drug is an inhibitor of BCR-ABL or its mutant strain. 11. The use according to claim 10, characterized in that: the BCR-ABL mutant is a T315I mutant. 12. The use according to any one of claims 7-8, characterized in that the cell proliferative disease is cancer. 13. The use according to claim 12, characterized in that: the cancer is chronic myeloid leukemia, intestinal stromal tumor, gynecological tumor, dermatofibrosarcoma protuberans, Ph+ALL.