Ceritinib derivative as well as preparation method, application and medicine thereof

Abstract

The invention provides a ceritinib derivative, a preparation method and application thereof and a medicine, and relates to the technical field of pharmacy. According to the invention, a boric acid derivative or a boric acid ester derivative is used for modifying a piperidine region of ceritinib, and a reversible covalent bond is formed by an empty orbit of sp2 of a boron atom and nucleophilic residues in protein, so that cytotoxicity caused by off-target and cytotoxicity to normal cells are reduced; meanwhile, the compound has broad-spectrum cytotoxicity on tumor cells. Experimental data show that when the ceritinib derivative provided by the invention is applied as a medicine, the ceritinib derivative has cytotoxicity to tumor cells such as H228 cells, MCF7 cells, HeLa cells, U251 cells, MDA-MB-231 cells and the like, and has relatively low cytotoxicity to normal LO2 cells of a human body. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and in particular to a ceritinib derivative, a preparation method, an application and a medicine thereof. Background Art

[0002] Cancer is one of the major diseases that endanger human health. Lung cancer ranks at the forefront of cancer morbidity and mortality, and non-small cell lung cancer is the main type of lung cancer that causes death. For non-small cell lung cancer, the anti-tumor drugs that have been marketed, such as ceritinib, alectinib, and brigatinib, mainly target protein kinases. Protein kinases are enzymes that catalyze protein phosphorylation and participate in the regulation of key cell processes such as cell growth, differentiation, and apoptosis. The abnormal activation of their functions is closely related to the occurrence and development of tumors. Ceritinib can target multiple protein kinases and is used clinically as an anaplastic lymphoma kinase (ALK) inhibitor to treat non-small cell lung cancer. However, while ceritinib has good anti-tumor activity, it also has strong toxicity to normal cell lines, that is, the cytotoxicity to tumor cells and normal human cells is not much different. Structural modification of ceritinib is expected to further regulate its drug activity, improve its efficacy, enhance its targeting to tumor cells, and reduce toxic side effects.

[0003] The main structure of the Ceritinib molecule is a pyrimidine structure substituted by two aromatic amines, one of which has a sulfone substituent and the other has a piperidine structure. The diarylamine pyrimidine structure binds to the target protein, and the piperidine structure is exposed to the solvent. Therefore, the modification of Ceritinib is mainly focused on the piperidine structure in the solvent region. At present, the modification to reduce the toxicity of Ceritinib to normal cells will also reduce its toxicity to other tumor cells. Therefore, it is of great significance to modify Ceritinib to obtain a drug with broad-spectrum tumor cell toxicity and low normal cell toxicity. Summary of the invention

[0004] In view of this, the present invention provides a ceritinib derivative, a preparation method, application and medicine thereof. The present invention modifies the piperidine region of ceritinib by using a boronic acid derivative or a boronic ester derivative, and utilizes the boron atom to reversibly covalently bind to the nucleophilic residues in the protein, thereby reducing the cytotoxicity of ceritinib to normal cells while maintaining the broad-spectrum cytotoxicity of the drug to different tumor cells.

[0005] The present invention first provides a ceritinib derivative having a structure of formula (I):

[0006]

[0007] Among them, X is selected from or a C1-C6 alkylene group;

[0008] Y is selected from C1-C6 alkylene or C2-C6 alkenyl;

[0009] R is R1 and R2 are independently selected from hydrogen or C1-C6 alkyl; or at least one of R1 and R2 forms a 5-10 membered heterocyclic ring with the O connected thereto and the B connected thereto.

[0010] The present invention mainly aims at the problem that Ceritinib has cytotoxicity to normal cells. By introducing a boron-containing group on the piperidine ring of Ceritinib, the boron atom can form a covalent reversible bond with the nucleophilic residues on the protein, such as the hydroxyl groups of serine and tyrosine, thereby enhancing the anti-tumor cell proliferation effect. The modified Ceritinib derivatives retain the cytotoxicity to tumor cells while weakening the cytotoxicity to normal cells; at the same time, the modified Ceritinib has good cytotoxicity to cancer cells such as breast cancer, cervical cancer, and glioma in addition to being cytotoxic to non-small cell lung cancer (NSCLC).

[0011] In the present invention, R1 and R2 in the R can be independently selected from hydrogen or C1-C6 alkyl, preferably hydrogen; the C1-C6 alkyl can be a straight chain alkyl or a branched chain alkyl, and the present invention has no special restrictions on this; or at least one of the R1 and R2 forms a 5-10 membered heterocyclic ring with the O connected thereto and the B connected thereto. In some specific implementations, the R is selected from the structure of formula (R-1), formula (R-2) or formula (R-3):

[0012]

[0013] wherein n, m, p and q are independently selected from integers of 0 to 3;

[0014] R3-R8 are independently selected from hydrogen or C1-C6 alkyl;

[0015] R9 and R 10 Independently selected from carbonyl, C1-C6 alkylene or C1-C6 alkylene substituted with at least one substituent selected from C1-C6 alkyl;

[0016] Ring A is selected from C3~C 10 A monocyclic alkyl group, a C3-C 10 Monocyclic alkyl, C4~C 10 bicycloalkyl, C4~C 10 Bicycloalkyl, C6~C 12 C6~C 12 The aromatic group, the substituent is a C1-C3 alkyl group;

[0017] Z is selected from NH, NR 11 , O or S;

[0018] The R 11 An alkyl group selected from C1 to C6.

[0019] In some specific implementations, the R is preferably the following structure:

[0020]

[0021] In some specific implementations of the present invention, the ceritinib derivative has the following structure, which cannot cover all the ceritinib derivatives described in the present invention, and the protection scope of the present invention is not limited thereto;

[0022]

[0023]

[0024] wherein a, b, c, d, and e are independently selected from integers of 0 to 4.

[0025] The present invention also provides a method for preparing a ceritinib derivative, comprising:

[0026] A boronic acid derivative or a boronic ester derivative having a structure of formula (II) reacts with ceritinib to obtain a ceritinib derivative having a structure of formula (I);

[0027] R′—X—Y—R (II);

[0028]

[0029] Wherein, R' is selected from halogen, hydroxyl, C6~C 12 C6~C 12 Aryloxy;

[0030] X is selected from or a C1-C6 alkylene group;

[0031] Y is selected from C1-C6 alkylene or C2-C6 alkenyl;

[0032] R is R1 and R2 are independently selected from hydrogen or C1-C6 alkyl; or at least one of R1 and R2 forms a 5-10 membered heterocyclic ring with the O connected thereto and the B connected thereto.

[0033] The present invention reacts a series of boronic acid derivatives or boronic ester derivatives with ceritinib to obtain a series of ceritinib derivatives. In the present invention, the boronic acid derivatives or boronic ester derivatives can be synthesized by themselves or directly purchased, and the present invention has no special restrictions on this.

[0034] The present invention provides the synthesis steps of some boronic acid derivatives or boronic ester derivatives. Those skilled in the art can refer to the synthesis steps provided by the present invention for synthesis, but the synthesis steps provided by the present invention cannot cover the synthesis steps of all boronic acid derivatives or boronic ester derivatives.

[0035] Synthesis of boronic acid derivative X12: First, compound Z1, compound Z2, catalyst, catalyst ligand and base are mixed and subjected to coupling reaction under an inert atmosphere to obtain compound Z3; then compound Z3 is mixed with compound Z4 and subjected to nucleophilic substitution reaction under alkaline conditions to obtain compound X12. Specifically, boronic acid derivative X12 can be synthesized according to the following route:

[0036]

[0037] Here, f is an integer selected from 0 to 4.

[0038] In some specific implementations, the specific method of the coupling reaction is: first, compound Z2, catalyst, catalyst ligand and base are added to the reaction device, and compound Z1 and solvent are added to the reaction device after nitrogen replacement three times. In some specific implementations, the solvent of the coupling reaction is selected from at least one of DMSO, tetrahydrofuran, N, N-dimethylformamide, preferably at least one of tetrahydrofuran and N, N-dimethylformamide, more preferably N, N-dimethylformamide. In some specific implementations, the base in the coupling reaction is an inorganic alkaline compound, preferably at least one of lithium methoxide, lithium tert-butoxide and sodium tert-butoxide, more preferably lithium methoxide. In some specific implementations, the catalyst of the coupling reaction is selected from cuprous iodide, cuprous oxide, cuprous bromide or cuprous chloride, preferably cuprous iodide, cuprous oxide or cuprous bromide, more preferably cuprous iodide. In some specific implementations, the catalyst ligand of the coupling reaction is selected from triphenylphosphine, tri(2-methylphenyl)phosphine or 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP), preferably triphenylphosphine or tri(2-methylphenyl)phosphine, and more preferably triphenylphosphine. In some specific implementations, the molar ratio of the compound Z1 to the compound Z2 is 1:(1-2), preferably 1:(1-1.5), and more preferably 1:(1-1.2). In some specific implementations, the molar ratio of the compound Z1 to the base is 1:(1-2), preferably 1:(1.5-2), and more preferably 1:(1.8-2). In some specific implementations, the molar ratio of the compound Z1 to the catalyst is 1:(0.01-0.5), preferably 1:(0.05-0.3), and more preferably 1:(0.1-0.2). In some specific implementations, the molar ratio of the compound Z1 to the catalyst ligand is 1:(0.01-0.5), preferably 1:(0.05-0.3), and more preferably 1:(0.1-0.2). In some specific implementations, the temperature of the coupling reaction is 0-40°C, preferably 10-30°C, and more preferably 20-30°C. In some specific implementations, the time of the coupling reaction is 8-24h, preferably 9-22h, and more preferably 10-20h.

[0039] In some specific implementations, the specific method of the nucleophilic substitution reaction is: after dissolving compound Z3 with a solvent, adding a basic compound at room temperature, and then dropping a solution of compound Z4 at low temperature to carry out a nucleophilic substitution reaction. In some specific implementations, the solvent of the nucleophilic substitution reaction is at least one of dichloromethane, acetone, tetrahydrofuran, methanol, acetonitrile and N, N-dimethylformamide, preferably at least one of dichloromethane, acetone and N, N-dimethylformamide, more preferably dichloromethane. In some specific implementations, the alkaline conditions in the nucleophilic substitution reaction are provided by a basic compound, and the basic compound can be an organic base or an inorganic base, and the organic base is preferably at least one of triethylamine and N, N-diisopropylethylamine, more preferably N, N-diisopropylethylamine; the inorganic base is preferably at least one of sodium bicarbonate, sodium carbonate, sodium hydroxide and potassium carbonate. In some specific implementations, the molar ratio of compound Z3 to compound Z4 is 1:(1-2), preferably 1:(1-1.5), and more preferably 1:(1-1.2). In some specific implementations, the molar ratio of compound Z3 to the alkaline compound is 1:(1-3), preferably 1:(1.5-3), and more preferably 1:(1.8-2). In some specific implementations, the temperature of the nucleophilic substitution reaction is 0-40°C, preferably 10-30°C, and more preferably 20-30°C. In some specific implementations, the time of the nucleophilic substitution reaction is 8-24h, preferably 9-22h, and more preferably 10-20h.

[0040] Synthesis of boronic acid derivative X3: First, compound Z5 and compound Z6 are subjected to a hydroboration reaction to obtain compound Z7; then compound Z7 is mixed with an acid and subjected to a deprotection reaction to obtain compound Z8; compound Z8 and compound Z4 are subjected to a nucleophilic substitution reaction to obtain boronic acid derivative X3. Specifically, boronic acid derivative X3 can be synthesized according to the following route:

[0041]

[0042] Here, g is selected from integers of 1 to 4.

[0043] In the present invention, the specific method for the hydroboration reaction of the compound Z5 and the compound Z6 is to add the compound Z5, the compound Z6, the Schwartz reagent and the base to the reaction tube under an inert atmosphere, add the solvent, seal and heat the reaction. In some specific implementations, the solvent of the hydroboration reaction is at least one of dichloromethane, acetone, tetrahydrofuran, methanol, acetonitrile and N, N-dimethylformamide, preferably at least one of dichloromethane, acetone and N, N-dimethylformamide, more preferably dichloromethane. In some specific implementations, the base in the hydroboration reaction is provided by a basic compound, and the basic compound can be an organic base or an inorganic base, and the organic base is preferably at least one of triethylamine and N, N-diisopropylethylamine, more preferably triethylamine; the inorganic base is preferably at least one of sodium bicarbonate, sodium carbonate, sodium hydroxide and potassium carbonate. In some specific implementations, the molar ratio of the compound Z5 to the compound Z6 is 1: (1-2), preferably 1: (1-1.5), and more preferably 1: (1-1.2). In some specific implementations, the molar ratio of the compound Z5 to the alkaline compound is 1: (0.1-0.5), preferably 1: (0.1-0.4), and more preferably 1: (0.1-0.2). In some specific implementations, the molar ratio of the compound Z5 to the Schwartz reagent is 1: (0.1-0.5), preferably 1: (0.1-0.4), and more preferably 1: (0.1-0.2). In some specific implementations, the temperature of the hydroboration reaction is 0-80°C, preferably 20-80°C, and more preferably 40-60°C. In some specific implementations, the time of the hydroboration reaction is 1-16h, preferably 4-14h, and more preferably 8-10h.

[0044] In some specific implementations of the present invention, the specific method for the deprotection reaction of the compound Z7 after mixing with the acid is to dissolve the compound Z7 in a solvent, slowly add the acid at low temperature, and the deprotection reaction occurs. In some specific implementations, the solvent of the deprotection reaction is at least one of dichloromethane, acetone, tetrahydrofuran, methanol, acetonitrile and N,N-dimethylformamide, preferably at least one of tetrahydrofuran, methanol, acetonitrile and N,N-dimethylformamide, more preferably tetrahydrofuran. In some specific implementations, the acid is an organic acid, preferably 4-methylbenzenesulfonic acid pyridine (PPTS), trifluoroacetic acid or acetic acid, more preferably PPTS. In some specific implementations, the molar ratio of the compound Z7 to the acid is 1: (0.1-0.5), preferably 1: (0.1-0.3), more preferably 1: (0.1-0.2). In some specific implementations, the temperature of the deprotection reaction is 20-40°C, preferably 20-35°C, more preferably 20-30°C. In some specific implementations, the deprotection reaction time is 0.5 to 24 hours, preferably 8 to 24 hours, and more preferably 12 to 24 hours.

[0045] In some specific implementations of the present invention, the specific method for the nucleophilic substitution reaction of the compound Z8 and the compound Z4 is as follows: dissolving the compound Z8 in a solvent, adding a base at room temperature, and then dropping the compound Z4 at a low temperature to cause a nucleophilic substitution reaction. In some specific implementations, the solvent for the nucleophilic substitution reaction is at least one of dichloromethane, acetone, tetrahydrofuran, methanol, acetonitrile and N, N-dimethylformamide, preferably at least one of dichloromethane, acetone and N, N-dimethylformamide, more preferably dichloromethane. In some specific implementations, the alkaline conditions in the nucleophilic substitution reaction are provided by a basic compound, which may be an organic base or an inorganic base, and the organic base is preferably at least one of triethylamine and N, N-diisopropylethylamine, more preferably N, N-diisopropylethylamine; the inorganic base is preferably at least one of sodium bicarbonate, sodium carbonate, sodium hydroxide and potassium carbonate. In some specific implementations, the molar ratio of the compound Z8 to the compound Z4 is 1: (1-1.5), preferably 1: (1-1.4), and more preferably 1: (1-1.2). In some specific implementations, the molar ratio of the compound Z8 to the alkaline compound is 1: (1-2), preferably 1: (1.5-2), and more preferably 1: (1.8-2). In some specific implementations, the temperature of the nucleophilic substitution reaction is 0-40°C, preferably 10-30°C, and more preferably 20-30°C. In some specific implementations, the time of the nucleophilic substitution reaction is 8-24h, preferably 9-22h, and more preferably 10-20h.

[0046] Synthesis of boronic acid derivative Z10: Compound Z9 and compound Z6 are subjected to a hydride reduction reaction under the action of a metal hydride reagent to obtain compound Z10. The reaction process is as follows:

[0047]

[0048] Here, h is an integer selected from 0 to 4.

[0049] In some specific implementations of the present invention, the specific method for the hydride reduction reaction of the compound Z9 and the compound Z6 is to add the compound Z9 and the compound Z6 into a reaction device, and heat them under an inert atmosphere to cause the hydride reduction reaction. In some specific implementations, the metal hydride reagent is selected from Schwartz reagent, lithium aluminum hydride reagent or sodium borohydride reagent, preferably lithium aluminum hydride reagent or sodium borohydride reagent, and more preferably lithium aluminum hydride reagent. In some specific implementations, the molar ratio of the compound Z9 and the compound Z6 is 1: (1 to 1.5), preferably 1: (1 to 1.4), and more preferably 1: (1 to 1.2). In some specific implementations, the molar ratio of the compound Z9 and the metal hydride reagent is 1: (0.1 to 0.5), preferably 1: (0.1 to 0.3), and more preferably 1: (0.1 to 0.2). In some specific implementations, the temperature of the hydrogenation reduction reaction is 80-120° C., preferably 90-110° C., and more preferably 100-110° C. In some specific implementations, the time of the hydrogenation reduction reaction is 0.5-8 h, preferably 0.5-6 h, and more preferably 0.5-4 h.

[0050] After obtaining the boronic acid derivative or boronic ester derivative having the structure of formula (II), the present invention mixes it with ceritinib and reacts it to obtain a ceritinib derivative having the structure of formula (I). The structure of formula (I) is the same as that of formula (II) and the present invention will not be repeated here.

[0051] In some specific implementations, the molar ratio of the boronic acid derivative or boronic ester derivative to Ceritinib is 1:(0.8-2), preferably 1:(0.8-1.8), and more preferably 1:(0.8-1.5). In some specific implementations, the conditions for the reaction of the boronic acid derivative or boronic ester derivative with Ceritinib are alkaline conditions, and the alkaline conditions are provided by alkaline compounds, and the molar ratio of the boronic acid derivative or boronic ester derivative to the alkaline compound is 1:(1-5), preferably 1:(1.3-5), and more preferably 1:(1.5-5). In some specific implementations, the reaction time is 0.5-24h, preferably 5-24h, and more preferably 8-24h; the reaction temperature is 0-40°C, preferably 10-40°C, and more preferably 20-40°C.

[0052] Specifically, when the boronic acid derivative or boronic ester derivative is a boronic acid derivative X12, it reacts with ceritinib to obtain a ceritinib derivative ZX-A, and the specific reaction process is as follows:

[0053]

[0054] Here, f is an integer selected from 0 to 4.

[0055] Specifically, when the boronic acid derivative or boronic ester derivative is a boronic acid derivative X3, it reacts with ceritinib to obtain a ceritinib derivative ZX-B, and the specific reaction process is as follows:

[0056]

[0057] Here, g is selected from integers of 1 to 4.

[0058] Specifically, when the boronic acid derivative or boronic ester derivative is a boronic acid derivative Z10, it reacts with ceritinib to obtain a ceritinib derivative ZX-C, and the specific reaction process is as follows:

[0059]

[0060] Here, h is an integer selected from 0 to 4.

[0061] On the basis of the above preparation method, in order to simplify the reaction process and reduce the synthesis cost, the present invention provides some derivatization reactions based on ceritinib derivatives. The derivatization reactions provided by the present invention cannot cover all situations, and the protection scope of the present invention is not limited by such derivatization reactions.

[0062] The boronic acid derivative Z10 reacts with ceritinib to obtain a ceritinib derivative ZX-C; the ceritinib derivative ZX-C and compound Z12 undergo a condensation reaction to obtain a ceritinib derivative ZX-D. The reaction process is as follows:

[0063]

[0064] Here, h is an integer selected from 0 to 4.

[0065] The conditions for the reaction of the boronic acid derivative Z10 with Ceritinib are the same as those of the above-mentioned preparation method, and the present invention will not be repeated here. In some specific implementations, the solvent of the condensation reaction is at least one of dichloromethane, acetone, tetrahydrofuran, methanol, acetonitrile and N,N-dimethylformamide, preferably at least one of dichloromethane, acetone, tetrahydrofuran and N,N-dimethylformamide, and more preferably dichloromethane. In some specific implementations, the molar ratio of the Ceritinib derivative ZX-A and the compound Z12 is 1: (0.8-1.5), preferably 1: (1.0-1.5), and more preferably 1: (1.1-1.5). In some specific implementations, the temperature of the condensation reaction is 0-40°C, preferably 10-30°C, and more preferably 20-30°C; the time is 0.5-24h, preferably 5-24h, and more preferably 8-24h.

[0066] The boronic acid derivative X45 is subjected to a condensation reaction with ceritinib to obtain a ceritinib derivative ZX-E; the ceritinib derivative ZX-E is subjected to a hydrolysis reaction under acidic conditions to obtain a ceritinib derivative ZX-F. The reaction process is as follows:

[0067]

[0068] Wherein, Y is selected from C1-C6 alkylene or C2-C6 alkenyl.

[0069] In some specific implementations of the present invention, the specific method of the condensation reaction is: dissolving the boronic acid derivative X45 with a solvent, adding an amide condensation agent at low temperature for stirring, and then adding ceritinib and a basic compound to react. In some specific implementations, the stirring time is 0.15 to 1.5 hours, preferably 0.3 to 1.3 hours, and more preferably 0.5 to 1 hour. In some specific implementations of the present invention, the solvent of the condensation reaction is at least one of dichloromethane, acetone, tetrahydrofuran, methanol, acetonitrile and N, N-dimethylformamide, preferably at least one of dichloromethane, acetone, tetrahydrofuran and N, N-dimethylformamide, more preferably dichloromethane. In some specific implementations, the condensation reaction is carried out under alkaline conditions, and the alkaline conditions are provided by alkaline compounds. In some specific implementations, the basic compound is an organic base or an inorganic base, the organic base is preferably triethylamine or N,N-diisopropylethylamine, more preferably N,N-diisopropylethylamine; the inorganic base is preferably at least one of sodium bicarbonate, sodium carbonate, sodium hydroxide and potassium carbonate. In some specific implementations, the amide condensation agent is HATU, DCC, EDCI or HOBt, preferably HATU, EDCI or HOBt, more preferably HATU. In some specific implementations, the molar ratio of the boronic acid derivative X45 to Ceritinib is 1: (0.8-1.5), preferably 1: (0.8-1.3), more preferably 1: (0.9-1). In some specific implementations, the molar ratio of the boronic acid derivative X45 to the basic compound is 1: (1-2), preferably (1-1.5), more preferably 1: (1-1.2). In some specific implementations, the molar ratio of the boronic acid derivative X45 to the amide condensation agent is 1:(1-2), preferably (1-1.5), and more preferably 1:(1-1.2). In some specific implementations, the temperature of the condensation reaction is 0-40°C, preferably 10-30°C, and more preferably 20-30°C; the time is 0.5-12h, preferably 5-12h, and more preferably 8-10h.

[0070] In some specific implementations, the solvent for the hydrolysis reaction of the Ceritinib derivative ZX-E is at least one of dichloromethane, acetone, tetrahydrofuran, methanol, acetonitrile and N,N-dimethylformamide, preferably at least one of methanol, acetonitrile and N,N-dimethylformamide, more preferably acetonitrile. In some specific implementations, the acidic condition is provided by an acidic compound, and the acidic compound is an organic acid or an inorganic acid. In some specific implementations, the organic acid is preferably trifluoroacetic acid or p-toluenesulfonic acid; the inorganic acid is preferably at least one of hydrochloric acid and ammonium chloride, more preferably hydrochloric acid. In some specific implementations, the molar ratio of the Ceritinib derivative ZX-E to the acid is 1: (0.8-1.5), preferably 1: (0.8-1.3), more preferably 1: (0.9-1). In some specific implementations, the temperature of the hydrolysis reaction is 0-40°C, preferably 10-30°C, more preferably 20-30°C; the time is 0.5-8h, preferably 0.5-6h, more preferably 0.5-4h.

[0071] The obtained Ceritinib derivative ZX-F is reacted with a diol compound to obtain a Ceritinib derivative ZX-G. The reaction process is as follows:

[0072]

[0073] The selection ranges of Y, R1 and R2 are the same as those described above, and the present invention will not be repeated here.

[0074] The present invention provides the structures of some diol compounds here. The above structures cannot cover all diol compounds described in the present invention. Those skilled in the art can select them according to their needs.

[0075]

[0076] In some specific implementations, the solvent for the reaction between the ceritinib derivative ZX-F and the diol compound is at least one of dichloromethane, acetone, tetrahydrofuran, methanol, acetonitrile and N,N-dimethylformamide, preferably at least one of dichloromethane, acetone, tetrahydrofuran and N,N-dimethylformamide, more preferably dichloromethane. In some specific implementations, the reaction further includes a drying agent, and the drying agent is preferably anhydrous magnesium sulfate or anhydrous sodium sulfate, more preferably anhydrous magnesium sulfate. In some specific implementations, the molar ratio of the ceritinib derivative ZX-F and the diol compound is 1: (0.8-1.5), preferably 1: (0.8-1.4), more preferably 1: (0.9-1.2). In some specific implementations, the molar ratio of the ceritinib derivative ZX-D and the drying agent is 1: (1-10), preferably 1: (3-10), more preferably 1: (5-10). In some specific implementations, the reaction temperature is 0-40°C, preferably 10-30°C, more preferably 20-30°C; the reaction time is 0.5-8h, preferably 0.5-6h, more preferably 0.5-4h.

[0077] After obtaining the Ceritinib derivative ZX-G, the present invention preferably purifies it to obtain a pure compound. The present invention has no special restrictions on the purification method, and those skilled in the art can choose according to their needs, for example, separation can be performed by column chromatography, thin layer chromatography or mixed solvent beating. In some specific implementations of the present invention, the purification method is column chromatography, and the column chromatography eluent combination used in the column chromatography separation is preferably dichloromethane / methanol, dichloromethane / petroleum ether, dichloromethane / n-hexane or petroleum ether / ethyl acetate, preferably dichloromethane / methanol, dichloromethane / petroleum ether or petroleum ether / ethyl acetate, more preferably dichloromethane / methanol. In some specific implementations of the present invention, the volume ratio of dichloromethane and methanol is (30-500):1, preferably (30-300):1, and more preferably (50-150):1.

[0078] The ceritinib derivatives provided by the present invention have low toxicity to normal cells and are toxic to a variety of tumor cells, so the present invention applies them to the preparation of anti-tumor drugs and provides a drug. The present invention has no special requirements for other components of the drug, for example, it can include pharmaceutically acceptable salts and other pharmaceutically acceptable excipients, and those skilled in the art can choose them according to their needs.

[0079] In summary, the ceritinib derivatives provided by the present invention utilize the sp of the boron atom in the borate ester or boric acid warhead 2The empty orbital can form a reversible covalent bond with nucleophilic residues in proteins (such as the hydroxyl groups of serine and tyrosine), and the spatial configuration of the boron atom is also changed from the original sp 2 Hybridization to sp 3 Hybridization can reduce the cytotoxicity caused by off-target and normal cell cytotoxicity while maintaining a broad spectrum of cytotoxicity. Experimental data show that when the ceritinib derivatives provided by the present invention are used as drugs, they are cytotoxic to tumor cells such as H228 cells, MCF7 cells, HeLa cells, U251 cells and MDA-MB-231 cells, and have low cytotoxicity to normal human LO2 cells. BRIEF DESCRIPTION OF THE DRAWINGS

[0080] Figure 1 The reaction flow chart of the drugs ZX-1 and ZX-2 provided by the present invention;

[0081] Figure 2 A reaction flow chart of the drug ZX-3 provided by the present invention;

[0082] Figure 3 A reaction flow chart of the drug ZX-4 provided by the present invention;

[0083] Figure 4 A reaction flow chart of the drug ZX-5 provided by the present invention;

[0084] Figure 5 A reaction flow chart of the drug ZX-6 provided by the present invention;

[0085] Figure 6 A reaction flow chart of the drug ZX-7 provided by the present invention;

[0086] Figure 7 A reaction flow chart of the drug ZX-8 provided by the present invention;

[0087] Figure 8 A reaction flow chart of the drug ZX-9 provided by the present invention;

[0088] Fig. 9 The cell survival rate of H228 cells at different concentrations of the drug provided by the present invention;

[0089] Fig.10 The cell survival rates of MCF7 cells at different concentrations of the drugs provided by the present invention. DETAILED DESCRIPTION

[0090] It should be understood that the expression "one or more of..." includes each of the items recited after the expression individually and in various different combinations of two or more of the recited items, unless otherwise understood from the context and usage. The expression "and / or" in combination with three or more recited items should be understood to have the same meaning, unless otherwise understood from the context.

[0091] The use of the terms "comprising", "having" or "containing", including their grammatical synonyms, should generally be understood as open and non-restrictive, for example not excluding other unrecited elements or steps, unless otherwise specifically stated or otherwise understood from the context.

[0092] It should be understood that the order of steps or the order in which certain actions are performed is not important as long as the present invention remains operable. In addition, two or more steps or actions may be performed simultaneously.

[0093] The use of any and all examples or exemplary language, such as "for example" or "including", herein is intended only to better illustrate the invention and does not limit the scope of the invention unless otherwise claimed. No language in this specification should be construed as indicating that any non-claimed element is essential to the practice of the invention.

[0094] In addition, the numerical ranges and parameters used to define the present invention are approximate values, and the relevant values ​​in the specific embodiments have been presented as accurately as possible. However, any numerical value inherently inevitably contains standard deviations due to individual test methods. Therefore, unless otherwise expressly stated, it should be understood that all ranges, quantities, values ​​and percentages used in this disclosure are modified by "about". Here, "about" generally means that the actual value is within plus or minus 10%, 5%, 1% or 0.5% of a specific value or range.

[0095] The present invention is further described below in conjunction with the following examples. The protection scope of the present invention is not limited by the following examples.

[0096] Example 1

[0097] (1) 70 mg (0.36 mmol, 0.1 eq) CuI, 125 mg (0.48 mmol, 0.13 eq) PPh3, 290 mg (7.24 mmol, 2 eq) LiOMe, and 1400 mg (5.43 mmol, 1.5 eq) B2pin2 were added to a Schlerk tube, and the atmosphere was replaced with nitrogen three times. 499 mg (3.62 mmol, 1.0 eq) 3-bromo-1-propanol (Compound A) and 7 mL N,N-dimethylformamide were added to fully dissolve the mixture, and the mixture was stirred at room temperature for 18 h. The reaction was monitored by TLC. After completion, the system was transferred to a separatory funnel with 20 mL of dichloromethane, washed three times with 20 mL of water, and once with 20 mL of saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to obtain a crude product B as a light yellow viscous liquid, 437 mg, with a yield of 65%.

[0098] (2) 437 mg (2.22 mmol, 1 eq) of crude product B obtained in step (1), N,N-diisopropylethylamine (772 μL, 4.44 mmol) and 4 mL of DCM were added to a flask, and 675 mg (2.22 mmol, 1 eq) of di(p-nitrobenzene) carbonate was slowly added at zero degrees. The mixture was stirred at room temperature for 12 h, and the reaction was monitored by thin layer chromatography. After completion, column chromatography was used for separation (dichloromethane / methanol = 20:1). 725 mg of crude product C was obtained with a yield of 89%.

[0099] (3) 50 mg (0.089 mmol, 1 eq) of ceritinib, 16 μL (0.089 mmol, 2 eq) of N,N-diisopropylethylamine, and 2 mL of DCM were added to a flask, and 33 mg (0.089 mmol, 1 eq) of crude product C was slowly added at zero degrees, and stirred at room temperature for 6 hours. The reaction was monitored by thin layer chromatography, and after completion, column chromatography was used for separation (dichloromethane / methanol = 20:1). 58 mg of ceritinib derivative ZX-1, which is the drug prepared in this example, was obtained with a yield of 85%. 1 H NMR(500M, CDCl3):9.49(s,1H),8.57(d,1H),8.15(s,1H),8.00(s,1H),7.92(d,1H),7.61(dt,1H),7.55(s,1H),7.25(t,2H),6.70(s,1H),4.5 5(m,1H),4.06(t,2H),3.23(m,1H),2.83(m,3H),2.15(s,3H),1.77(m, 4H),1.56(m,2H),1.35(d,6H),1.30(d,6H),1.25(s,12H),0.84(t,2H).

[0100] See also Figure 1 , Figure 1 : is a reaction flow chart of the drug ZX-1 prepared in this example, wherein when compound A is 3-bromo-1-propanol (n=1), the obtained product is the drug ZX-1 prepared in this example.

[0101] Example 2

[0102] The difference between this example and example 1 is that the reactant compound A in step (1) is adjusted from 499 mg (3.62 mmol, 1.0 eq.) 3-bromo-1-propanol to 699 mg (3.62 mmol, 1.0 eq.) 6-bromo-n-hexanol, and the rest is the same as in example 1, to obtain 45 mg of the ceritinib derivative ZX-2, a light yellow solid, which is the drug prepared in this example, with a yield of 89%. 1 H NMR(500M, CDCl3):9.51(s,1H),8.59(d,1H),8.15(s,1H),8.00(s,1H),7.92(d,1H) ,7.61(dt,1H),7.55(s,1H),7.25(t,2H),6.70(s,1H),4.55(m,1H),4.30(m,2H),4. 09(m,2H),3.64(t,1H),3.24(m,1H),2.85(m,3H),2.17(s,3H),1.77(m,2H),1.51~1 .69(m,6H),1.40~1.45(m,3H),1.36(d,6H),1.32(d,6H),1.24(s,12H),0.76(t,2H).

[0103] See also Figure 1 , Figure 1 : is a reaction flow chart of the drug ZX-2 prepared in this example, wherein when compound A is 6-bromohexanol (n=4), the obtained product is the drug ZX-2 prepared in this example.

[0104] Example 3

[0105] (1) Under nitrogen protection, 208 mg (1.82 mmol, 1 eq) (propynyloxy) trimethylsilane (compound D), 265 μL (2.07 mmol, 1.1 eq) HBpin, 47 mg (0.18 mmol, 1 eq) Schwartz reagent, 28 μL (0.18 mmol, 1 eq) triethylamine, and DCM were added to a reaction tube and stirred at 55° C. for 18 h. The reaction was monitored by thin layer chromatography. After quenching with water, the liquid was separated, the aqueous phase was extracted once with DCM, and the organic phase was synthesized. After drying over anhydrous sodium sulfate, the solvent was removed by rotary evaporation to obtain 302 mg of crude product E with a yield of 65%.

[0106] (2) 302 mg (1.18 mmol, 1 eq) of crude product D obtained in step (1), 30 mg (0.12 mmol, 0.1 eq) of PPTS, and 3 mL of THF were added to a reaction tube and stirred at room temperature for 18 h. The reaction was monitored by thin layer chromatography to be complete. After quenching with water, the mixture was extracted three times with DCM to synthesize the organic phase. After drying over anhydrous sodium sulfate, the solvent was removed by rotary evaporation to obtain 119 mg of crude product F with a yield of 49%.

[0107] (3) 119 mg (0.59 mmol, 1 eq) of crude product F obtained in step (2), 205 μL (1.18 mmol, 2 eq) of N,N-diisopropylethylamine, and 2 mL of DCM were added to a flask, and 179 mg (0.59 mmol, 1 eq) of di(p-nitrobenzene) carbonate was slowly added at zero degrees, and stirred at room temperature for 12 hours. The reaction was monitored by thin layer chromatography. After the reaction was completed, column chromatography was used for separation (dichloromethane / methanol = 20:1) to obtain 175 mg of crude product G, with a yield of 85%.

[0108] (4) 50 mg (0.089 mmol, 1 eq) of ceritinib, 16 μL (0.089 mmol, 2 eq) of N,N-diisopropylethylamine, and 4 mL of DCM were added to a flask, and 31 mg (0.089 mmol, 1 eq) of the crude product G obtained in step (3) was slowly added at zero degrees, and stirred at room temperature for 6 h. The reaction was monitored by thin layer chromatography, and after the reaction was completed, column chromatography (dichloromethane / methanol = 20:1) was used for separation to obtain 62 mg of ZX-3, with a yield of 90%.

[0109] 1 H NMR(500M, CDCl3):9.53(s,1H),8.57(d,1H),8.16(s,1H),8.00(s,1H),7.99(d,1H),7.63(t,1H),7.58(s,1H),7.29( t,1H),6.67(m,2H),5.69(d,1H),4.70(s,2H),4.55(m,1H),4.35(m,2H),3.24(m,1H),2.78~3.00(m,3H),2.17(s,3H),

[0110] 1.55~1.79(m,4H),1.36(d,6H),1.32(d,6H),1.27(s,12H).

[0111] See also Figure 2 , Figure 2 This is a reaction flow chart of the drug ZX-3 prepared in this example.

[0112] Example 4

[0113] The crude product F was prepared in the same manner as step (1) and step (2) in Example 3. 11 mg (0.0537 mmol, 1 eq) of crude product F and DCM were added to a reaction tube, and 20 mg (0.0537 mmol, 1 eq) of HATU were added in batches at zero degrees, and stirred at room temperature for 1 hour. At zero degrees, 30 mg (0.0537 mmol, 1 eq) of ceritinib was slowly added, and 18 μL (0.107 mmol, 2 eq) of N,N-diisopropylethylamine was added dropwise, and stirred for 2.5 hours. The reaction was monitored by thin layer chromatography. After the reaction was completed, column chromatography was used for separation (dichloromethane / methanol = 10:1) to obtain 32 mg of ceritinib derivative ZX-4, which was the drug prepared in this example, with a yield of 81%. 1 H NMR(500MHz, CDCl3)δ9.51(s,1H),8.57(d,1H),8.16(s,1H),8.02(s,1H),7.94(d,1H) ,7.62(t,1H),7.56(s,1H),7.26(t,1H),6.68(s,1H),4.78(d,1H),4.55(m,1H),3.99( d,1H),3.26(m,1H),3.12(m,1H),2.89(m,1H),2.65(m,1H),2.52(m,2H),2.17(s,3H), 1.82(m,2H),1.52~1.56(m,2H),1.37(m,6H),1.31(d,6H),1.26(s,12H),0.98(t,3H).

[0114] See also Figure 3 , Figure 3 This is a reaction flow chart of the drug ZX-4 prepared in this example.

[0115] Example 5

[0116] The crude product G was prepared in the same manner as step (1), step (2) and step (3) in Example 3. 14 mg (0.0537 mmol, 1 eq) of the crude product G and 2 mL of DCM were added to a reaction tube. 20 mg (0.0537 mmol, 1 eq) of HATU was added at zero degrees. The mixture was stirred at room temperature for 1 hour. Then, 30 mg (0.0537 mmol, 1 eq) of ceritinib was slowly added. 18 μL (0.107 mmol, 2 eq) of N,N-diisopropylethylamine was added dropwise. The mixture was stirred for 2.5 hours. The reaction was monitored by thin layer chromatography. After the reaction was completed, column chromatography was used for separation (dichloromethane / methanol = 10:1) to obtain 34 mg of ceritinib derivative ZX-5, which was the drug prepared in this example, with a yield of 85%. 1H NMR(500MHz, CDCl3)δ9.50(s,1H),8.57(d,1H),8.15(s,1H),8.02(s,1H),7.93(d,1H),7 .64(t,1H),7.55(s,1H),7.26(m,1H),7.16(d,1H),6.67(s,1H),6.63(d,1H),4.86(m,1H) ,4.54(m,1H),4.21(m,1H),3.26(m,1H),3.25,3.20,3.18(m,1H),2.92(m,1H),2.73(m,1 H),2.18(s,3H),1.84(m,2H),1.53~1.64(m,2H),1.36(d,6H),1.32(d,6H),1.29(s,12H).

[0117] See also Figure 4 , Figure 4 This is a reaction flow chart of the drug ZX-5 prepared in this example.

[0118] Example 6

[0119] (1) 500 μL (5.86 mmol, 1 eq) of 3-bromopropylene (compound H), 22 mg (0.59 mmol, 0.1 eq) of lithium aluminum hydride, and 1.03 mL (6.45 mmol, 1.1 eq) of HBpin were added to a reaction tube under nitrogen protection, heated at 110° C. for 4 h, and then water was added to quench the reaction. The organic phase was extracted with dichloromethane, then washed with saturated brine and dried with sodium sulfate. After the solvent was removed by rotary evaporation, 2.16 g of a light yellow viscous liquid was obtained, which was the crude product I with a yield of 86%.

[0120] (2) 30 mg (0.0538 mmol, 1 eq) of ceritinib and 1 mL of DMF were added to a reaction tube, 30 μL (0.215 mmol, 4 eq) of triethylamine was slowly added dropwise into the reaction tube, and then 27 μL (0.108 mmol, 2 eq) of the crude product I obtained in step (1) was slowly added dropwise, and the reaction was carried out at 35° C. for 12 h. Water was added to quench the reaction, and the organic phase was extracted with dichloromethane, then washed with water and saturated brine, and the crude product obtained after drying with sodium sulfate was directly used for the next step reaction.

[0121] (3) 9 mg (0.047 mmol, 1 eq) of the crude product J obtained in step (2) was dissolved in dichloromethane, and 34 mg (0.28 mmol, 6 eq) of magnesium sulfate and 12 mg (0.0705 mmol, 1.5 eq) of 3,4-diethylhexane-3,4-diol were added to react at room temperature for 24 h. After the reaction was completed, the magnesium sulfate was filtered out and separated by column chromatography (dichloromethane / methanol = 20:1). 32 mg of the ceritinib derivative ZX-6, which is the drug prepared in this example, was obtained with a yield of 49.5%. 1 H NMR(500M, CDCl3):9.49(s,1H),8.57(d,1H),8.16(s,1H),8.00(s,1H),7.93(d,1H ),7.63(t,1H),7.58(s,1H),7.29(t,1H),6.86(s,1H),5.69(d,1H),4.59(m,1H),3 .27(m,1H),2.69~2.88(m,3H),2.56(m,2H),2.22(t,2H),2.16(s,3H),2.01(m,2H) ,1.85(m,4H),1.65(dd,8H),1.36(d,6H),1.32(d,6H),0.91(t,12H),0.83(t,3H).

[0122] See also Figure 5 , Figure 5 This is a reaction flow chart of the drug ZX-6 prepared in this example.

[0123] Example 7

[0124] Compound ZX-5 was prepared in the same manner as in Example 5. 72 mg (0.098 mmol, 1 eq) ZX-5, 29 mg (0.49 mmol, 5 eq) methylboronic acid, 98 μL HCl (aq, 1 M) and 3 ml acetonitrile were added to a reaction tube under nitrogen protection. After stirring at room temperature for 2 h, water was added to quench the reaction. The organic phase was extracted with ethyl acetate, then washed with saturated brine and dried with sodium sulfate. After the solvent was dried, column chromatography was used for separation (dichloromethane: methanol = 10: 1) to obtain 54 mg of the ceritinib derivative ZX-7, a light yellow viscous liquid, which was the drug prepared in this example, with a yield of 84.5%. 1H NMR(400M,d6-DMSO):9.46(s,1H),8.47(d,1H),8.25(s,1H),8.03(s,1H),8.02(s, 1H),7.83(d,1H),7.63(t,1H),7.53(s,1H),7.36(t,1H),7.17(d,1H),6.47(d,1H) ,5.83(d,1H),4.58~4.62(m,1H),3.80(m,1H),3.39~3.45(m,1H),3.20(m,2H),2.9 5(m,1H),2.74(m,1H),2.15(s,3H),1.61~1.82(m,4H),1.19(dd,6H),1.17(d,6H).

[0125] See also Figure 6 , Figure 6 This is a reaction flow chart of the drug ZX-7 prepared in this example.

[0126] Example 8

[0127] Compound ZX-7 was prepared in the same manner as in Example 7. 30 mg (0.046 mmol, 1 eq) ZX-7, 9 mg (0.051 mmol, 1.1 eq) (1S, 2S, 3R, 5S)-(+)-2,3-pinanediol, 34 mg magnesium sulfate and 2 mL anhydrous dichloromethane were added to a reaction tube under nitrogen protection. After stirring at room temperature for 2 h, water was added to quench the reaction. The organic phase was extracted with ethyl acetate, then washed with saturated brine and dried with sodium sulfate. The solvent was spin-dried and separated by column chromatography (dichloromethane: methanol = 10: 1) to obtain 34 mg of the ceritinib derivative ZX-8, which is the drug prepared in this example, with a yield of 95%. 1H NMR(400M, CDCl3):9.49(s,1H),8.49(d,1H),8.25(s,1H),8.10(s,1H),7.90(s,1H),7.85(d,1H),7.54(t,1H), 7.26(t,1H),7.12(d,1H),6.59(d,1H),6.60(s,1H),4.68(m,1H),4.49(m,1H),4.35(dd,1H),4.15(m,1H),3.30 (m,1H),2.95(m,1H),2.60(m,1H),2.36-2.28(m,1H),2.25~2.17(m,1H),2.13(s,3H),2.05~2.01(m,1H),1.95~ 1.83(m,4H),1.61~1.72(m,5H),1.44(s,1H),1.37(d,1H),1.28(s,3H),1.26(dd,6H),1.24(d,6H),0.84(S,3H).

[0128] See also Figure 7 , Figure 7 This is a reaction flow chart of the drug ZX-8 prepared in this example.

[0129] Example 9

[0130] Compound ZX-7 was prepared in the same manner as in Example 7. 15 mg (0.023 mmol, 1 eq) ZX-7, 3 mg (0.025 mmol, 1.1 eq) neopentyl glycol, 34 mg magnesium sulfate and 1 mL anhydrous dichloromethane were added to the reaction tube under nitrogen protection. After stirring at room temperature for 3 h, water was added to quench the reaction. The organic phase was extracted with ethyl acetate, then washed with saturated brine and dried with sodium sulfate. After the solvent was dried, column chromatography was used for separation (dichloromethane: methanol = 10: 1) to obtain 15 mg of the ceritinib derivative ZX-9, which is the drug prepared in this embodiment, with a yield of 93%. 1H NMR(400M, CDCl3):9.49(s,1H),8.56(d,1H),8.15(s,1H),8.00(s,1H),7.92(d,1H), 7.60(t,1H),7.54(s,1H),7.26(t,1H),7.10(d,1H),6.60(s,1H),6.56(d,1H),4.83(m ,1H),4.53(m,1H),4.24(m,1H),3.66(s,4H),3.25(m,1H),3.18(m,1H),2.92(m,1H), 2.69(m,1H),2.16(s,3H),1.68~1.50(m,4H),1.36(dd,6H),1.31(d,6H),1.24(S,6H).

[0131] See also Figure 8 , Figure 8 This is a reaction flow chart of the drug ZX-9 prepared in this example.

[0132] Test Example 1

[0133] The IC values ​​of the drugs prepared in Examples 1 to 9 and Ceritinib on H2228 cells were tested by MTT colorimetry. 50 Specifically, first remove the culture medium in the cell culture dish, wash the cells with 3 mL PBS, and then digest the cells with 2 mL trypsin for 3 min. Remove the trypsin, resuspend the cells with complete culture medium, and add 5×10 3 The cells were placed in a cell culture incubator and incubated overnight. The supernatant was aspirated and complete culture medium containing different concentrations of drugs was added and incubated for 48 hours. Each group of samples had 3 replicate wells.

[0134] After the incubation, 10 μL of MTT solution was added, and the cells were placed back in the incubator for 4 h. The supernatant was gently aspirated, and 150 μL of dimethyl sulfoxide was added to each well. After oscillation and mixing, the OD value at a wavelength of 490 nm was measured. The data were processed using Graphpad Prism software, and the IC was calculated based on the drug concentration and cell viability. 50 The cell survival rate was calculated according to the following formula: Cell survival rate (%) = (average OD490 of the experimental group) / (average OD490 of the control group)×100%.

[0135] IC of the drugs prepared in Examples 1 to 9 and Ceritinib on H2228 cells 50 The values ​​are listed in Table 1. The survival rates of H2228 cells at different drug concentrations are shown in Fig. 9 As shown. Fig. 9 A is the survival rate of H2228 cells under different concentrations of drugs ZX-1, ZX-3, ZX-4, ZX-5 and Ceritinib, Fig. 9 B is the survival rate of H2228 cells under different concentrations of drugs ZX-7, ZX-8, ZX-9 and ceritinib.

[0136] Table 1: Drugs prepared in Examples 1 to 9 and IC of Ceritinib on H2228 cells 50 value

[0137]

[0138]

[0139] From Table 1 and Fig. 9 As can be seen from the results, the boronate / boronic acid modified ceritinib derivatives generally maintained their cytotoxicity against the H2228 cell line compared to ceritinib, with the cytotoxicity of ZX-3 and ZX-5 slightly improved. However, the cytotoxicity of ZX-2 and ZX-6 decreased significantly, with IC 50 The value is greater than 64μM. According to the results of protein and molecular simulation docking, the cytotoxicity of ZX-6 decreased because a sterically hindered boronate structure was introduced on the piperidine ring, which was not conducive to the binding of the drug modified by the boronate to the target protein, thus resulting in a decrease in cytotoxicity. The cytotoxicity of ZX-2 decreased because the boronate was connected to the piperidine ring through a long alkyl chain. The long alkyl chain is more flexible, which is not conducive to the interaction between the boronate target protein and the cytotoxicity decreased.

[0140] Test Example 2

[0141] The IC values ​​of the drugs prepared in Examples 1 to 9 and Ceritinib on MCF7 cells were tested by MTT colorimetry. 50 The specific method is the same as that of Experimental Example 1. The IC values ​​of the drugs prepared in Examples 1 to 9 and Ceritinib on MCF7 cells 50 The values ​​are listed in Table 2. The survival rates of MCF7 cells at different drug concentrations are shown in Fig.10 As shown. Fig.10 A is the survival rate of H2228 cells under different concentrations of drugs ZX-1, ZX-3, ZX-4, ZX-5 and Ceritinib, Fig.10 B is the survival rate of H2228 cells under different concentrations of drugs ZX-7, ZX-8, ZX-9 and ceritinib.

[0142] Table 2: IC values ​​of drugs prepared in Examples 1 to 9 and Ceritinib on MCF7 cells 50 value

[0143]

[0144]

[0145] From Table 2 and Fig.10 It can be seen that for the MCF7 cell line, the modified small molecules, except ZX-2, have significantly improved cytotoxicity compared to ceritinib. The decrease in ZX-2 cytotoxicity may be due to the longer alkyl chain connected to the piperidine ring, which greatly increases the steric hindrance between the small molecule and the target protein. Therefore, compared with ceritinib, the cytotoxicity of ZX-2 is significantly reduced.

[0146] Test Example 3

[0147] The IC values ​​of the drug ZX-5 and ceritinib (positive control) prepared in Example 5 on LO2 cells were tested using the MTT method. 50 The specific method is the same as that of Experimental Example 1. The results are shown in Table 3.

[0148] Table 3 IC of ZX-5 and Ceritinib on LO2 cells 50 value

[0149] Compound <![CDATA[IC 50 / μM]]> Ceritinib 2.12±0.12 ZX-5 4.34±0.25

[0150] As can be seen from Table 3, ZX-5 has lower cytotoxicity to the normal cell line LO2 than ceritinib, reducing the original toxic side effects of ceritinib.

[0151] Test Example 4

[0152] The IC values ​​of the drug ZX-5 prepared in Example 5 on HeLa cells, U251 cells and MDA-MB-231 cells were tested by MTT method. 50 The specific method is the same as that of Experimental Example 1. The results are shown in Table 4.

[0153] Table 4 IC of ZX-5 on HeLa cells, U251 cells and MDA-MB-231 cells 50 value

[0154]

[0155] Comparative Example 1

[0156] Compound VII was prepared according to the method provided in patent CN118684691A, and its structure is shown below; and the cytotoxicity IC of compound VII on HeLa cells, U251 cells and MDA-MB-231 cells was tested by MTT method. 50 The specific method is the same as that of Experimental Example 1, and the results are shown in Table 5.

[0157] Table 5 IC of compound VII on HeLa cells, U251 cells and MDA-MB-231 cells 50 value

[0158]

[0159] From the data in Table 5 and Table 4, it can be seen that ZX-5 is not only toxic to non-small cell lung cancer cells and breast cancer cell lines, but also has a broad spectrum of cytotoxicity compared to the reported compound VII to the cervical cancer cell line HeLa, the glioma cell line U251, and the triple-negative breast cancer cell line MDA-MB-231. According to the reported data, the ROS level of the U251 cell line is lower than that of the MDA-MB-231 cell line, which can explain the stronger cytotoxicity of compound VII to MDA-MB-231. The higher the ROS level, the higher the ROS response level of compound VII, and the stronger the cytotoxicity. ZX-5 does not have a ROS response and is less affected by the ROS level, so it has a broader spectrum of cytotoxicity.

[0160]

[0161] The structure of compound VII prepared in this example

[0162] Combined with the above experimental results, the trends of drug effects of ceritinib modified with different boron-containing groups are not exactly the same. Among them, ZX-2 has significantly lower cytotoxicity to MCF7 and H2228 cells compared with ceritinib. ZX-1, ZX-3, and ZX-5 have no significant increase in cytotoxicity to H2228 cells compared with ceritinib, but have significantly improved cytotoxicity to MCF7 cell line. ZX-5 has significantly reduced cytotoxicity to normal cells compared with ceritinib, and the IC of ZX-5 for LO2 is 50 The value was 4.34 μM, while the IC 50 The value was 2.12 μM. In addition, compared with the boronate-modified ROS-responsive ceritinib prodrug, it also had obvious cytotoxicity to MCF7 cells, HeLa cells, and U251 cells.

[0163] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A ceritinib derivative, characterized in that Having the structure of formula (I): Among them, X is selected from or a C1-C6 alkylene group; Y is selected from C1-C6 alkylene or C2-C6 alkenyl; R is R1 and R2 are independently selected from hydrogen or C1-C6 alkyl; or at least one of R1 and R2 forms a 5-10 membered heterocyclic ring with the O connected thereto and the B connected thereto.

2. The ceritinib derivative according to claim 1, characterized in that The R is selected from the structure of formula (R-1), formula (R-2) or formula (R-3): wherein n, m, p and q are independently selected from integers of 0 to 3; R3-R8 are independently selected from hydrogen or C1-C6 alkyl; R9 and R 10 Independently selected from carbonyl, C1-C6 alkylene or C1-C6 alkylene substituted with at least one substituent selected from C1-C6 alkyl; Ring A is selected from C3~C 10 A monocyclic alkyl group, a C3-C 10 Monocyclic alkyl, C4~C 10 bicycloalkyl, C4~C 10 Bicycloalkyl, C6~C 12 C6~C 12 The aromatic group, the substituent is a C1-C3 alkyl group; Z is selected from NH, NR 11 , O or S; The R 11 An alkyl group selected from C1 to C6.

3. The ceritinib derivative according to claim 1, characterized in that The R is selected from the following structures:

4. The ceritinib derivative according to claim 1, characterized in that It has the following structure: wherein a, b, c, d and e are independently selected from integers of 0 to 4.

5. A method for preparing a ceritinib derivative, characterized in that: include: A boronic acid derivative or a boronic ester derivative having a structure of formula (II) reacts with ceritinib to obtain a ceritinib derivative having a structure of formula (I); R′-XYR (II); Wherein, R' is selected from halogen, hydroxyl, C6~C 12 C6~C 12 Aryloxy; X is selected from or a C1-C6 alkylene group; Y is selected from C1-C6 alkylene or C2-C6 alkenyl; R is R1 and R2 are independently selected from hydrogen or C1-C6 alkyl; or at least one of R1 and R2 forms a 5-10 membered heterocyclic ring with the O connected thereto and the B connected thereto.

6. The preparation method according to claim 5, characterized in that: The molar ratio of the boric acid derivative or boric acid ester derivative to Ceritinib is 1:(0.8-2).

7. The preparation method according to claim 5, characterized in that: The reaction is carried out under alkaline conditions; The alkaline condition is provided by an alkaline compound, and the molar ratio of the boronic acid derivative or the boronic ester derivative to the alkaline compound is 1:(1-5).

8. The preparation method according to claim 5, characterized in that: The reaction time is 0.5 to 24 hours, and the reaction temperature is 0 to 40°C.

9. Use of the ceritinib derivative according to any one of claims 1 to 4 and the ceritinib derivative prepared by the preparation method according to any one of claims 5 to 8 in the preparation of antitumor drugs.

10. A drug, characterized in that include: A ceritinib derivative according to any one of claims 1 to 4 or a ceritinib derivative prepared by any one of the preparation methods of claims 5 to 8, a pharmaceutically acceptable salt and other pharmaceutically acceptable excipients.

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