A sorafenib derivative, a preparation method and application thereof, and a medicine

Abstract

The application provides a sorafenib derivative, a preparation method and application thereof, and a medicine, and relates to the technical field of pharmacy. 2 The boron atom sp of the sorafenib derivative provided by the application has a broad-spectrum cytotoxicity on tumor cells, and the cytotoxicity on human normal L02 cells is low.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmacy, in particular to a ceritinib derivative, a preparation method and application thereof, and a medicine. BACKGROUND

[0002] Cancer is one of the major diseases that endanger human health, and lung cancer ranks high in the incidence and mortality of cancer. 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 such as ceritinib, alectinib and brigatinib that have been marketed mainly target protein kinases. Protein kinases are enzymes that catalyze protein phosphorylation and are involved in the regulation of key cellular processes such as cell growth, differentiation and apoptosis. Abnormal activation of their functions is closely related to the occurrence and development of tumors. Ceritinib can target multiple protein kinases and is clinically used as an anaplastic lymphoma kinase (ALK) inhibitor for the treatment of non-small cell lung cancer. However, ceritinib has strong toxicity to normal cell lines while having good anti-tumor activity, i.e., the cytotoxicity to tumor cells and human normal cells is not significantly different. Structural modification of ceritinib is expected to further regulate its drug activity, improve its efficacy, enhance its targeting of tumor cells, and reduce its side effects.

[0003] The main structure of ceritinib molecule is a pyrimidine structure substituted with two arylamines, 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 mainly focuses on the piperidine structure in the solvent region. Current modifications to reduce the toxicity of ceritinib to normal cells 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

[0004] Therefore, the present application provides a ceritinib derivative, a preparation method and application thereof, and a medicine. The present application modifies the piperidine region of ceritinib using boronic acid derivatives or boronic ester derivatives, reversibly covalently binds boron atoms to nucleophilic residues in proteins, reduces the cytotoxicity of ceritinib to normal cells, and maintains the broad-spectrum cytotoxicity of the drug to different tumor cells.

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

[0006]

[0007] wherein X is selected from or C1-C6 alkylene.

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

[0009] R is R1and R2are independently selected from hydrogen or C1-C6 alkyl; or at least one of said R1and R2, together with the O to which it is attached and the B to which the O is attached, forms a 5-10 membered heterocyclic ring.

[0010] The present application is mainly directed to the problem of cytotoxicity of normal cells for selumetinib, by introducing a boron-containing group on the piperidine ring of selumetinib, the boron atom can form a covalent reversible combination with the nucleophilic residues on the protein such as the hydroxyl group of serine and tyrosine, thereby enhancing the anti-tumor cell proliferation effect. The modified selumetinib derivative retains the cytotoxicity to tumor cells while reducing the cytotoxicity to normal cells; at the same time, the modified selumetinib has good cytotoxicity to breast cancer, cervical cancer, glioma and other cancer cells in addition to non-small cell lung cancer (NSCLC).

[0011] In the present application, R1and R2in 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, which is not particularly limited in the present application; or at least one of said R1and R2, together with the O to which it is attached and the B to which the O is attached, forms a 5-10 membered heterocyclic ring. In some specific implementations, 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 an integer from 0 to 3;

[0014] R3-R8are independently selected from hydrogen or C1-C6 alkyl;

[0015] R9and R 10 are 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 monocyclic alkyl, C3-C 10 monocyclic alkyl substituted with at least one substituent, C4-C 10 bicyclic alkyl, C4-C 10 bicyclic alkyl substituted with at least one substituent, C6-C 12 aromatic group or C6-C 12 aromatic group substituted with at least one substituent, said substituent being C1-C3 alkyl;

[0017] Z is selected from NH, N-R 11 , O or S;

[0018] said R 11 is selected from C1-C6 alkyl.

[0019] In some specific embodiments, said R is preferably of the following structure:

[0020]

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

[0022]

[0023]

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

[0025] The present application also provides a preparation method of the ceritinib derivative, comprising:

[0026] The boronic acid derivative or boronic ester derivative having the structure of formula (II) is reacted with ceritinib to obtain the ceritinib derivative having the structure of formula (I);

[0027] R'—X—Y—R (II);

[0028]

[0029] wherein R' is selected from halogen, hydroxyl, C6-C 12 aryloxy or nitro-substituted C6-C 12 aryloxy;

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

[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 said R1 and R2 and the O to which it is connected and the B to which the O is connected form a 5-10 membered heterocyclic ring.

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

[0034] The present application provides the synthesis steps of some boronic acid derivatives or boronic ester derivatives, and those skilled in the art can refer to the synthesis steps provided by the present application to synthesize, but the synthesis steps provided by the present application 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 to occur coupling reaction under inert atmosphere to obtain compound Z3; then compound Z3 is mixed with compound Z4 to occur nucleophilic substitution reaction under alkaline condition to obtain compound X12. Specifically, the boronic acid derivative X12 can be synthesized according to the following route:

[0036]

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

[0038] In some specific embodiments, the specific way of the coupling reaction is that: first, compound Z2, catalyst, catalyst ligand and base are added into the reaction device, and then compound Z1 and solvent are added into the reaction device after three times of nitrogen replacement. In some specific embodiments, 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 embodiments, the base in the coupling reaction is an inorganic basic compound, preferably at least one of lithium methoxide, lithium tert-butoxide and sodium tert-butoxide, more preferably lithium methoxide. In some specific embodiments, 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 embodiments, the catalyst ligand of the coupling reaction is selected from triphenylphosphine, tris(2-methylphenyl)phosphine or 1,1'-binaphthalene-2,2'-diphenylphosphine (BINAP), preferably triphenylphosphine or tris(2-methylphenyl)phosphine, more preferably triphenylphosphine. In some specific embodiments, the molar ratio of compound Z1 to compound Z2 is 1:(1-2), preferably 1:(1-1.5), more preferably 1:(1-1.2). In some specific embodiments, the molar ratio of compound Z1 to the base is 1:(1-2), preferably 1:(1.5-2), more preferably 1:(1.8-2). In some specific embodiments, the molar ratio of compound Z1 to the catalyst is 1:(0.01-0.5), preferably 1:(0.05-0.3), more preferably 1:(0.1-0.2). In some specific embodiments, the molar ratio of compound Z1 to the catalyst ligand is 1:(0.01-0.5), preferably 1:(0.05-0.3), more preferably 1:(0.1-0.2). In some specific embodiments, the temperature of the coupling reaction is 0-40°C, preferably 10-30°C, more preferably 20-30°C. In some specific embodiments, the time of the coupling reaction is 8-24h, preferably 9-22h, more preferably 10-20h.

[0039] In some specific embodiments, the specific way of the nucleophilic substitution reaction is that after compound Z3 is dissolved in a solvent, a basic compound is added at room temperature, and then a solution of compound Z4 is added dropwise at low temperature to carry out the nucleophilic substitution reaction. In some specific embodiments, 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, and more preferably dichloromethane. In some specific embodiments, the basic condition in the nucleophilic substitution reaction is provided by a basic compound, which can be an organic base or an inorganic base. The organic base is preferably at least one of triethylamine and N,N-diisopropylethylamine, and 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 embodiments, 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 embodiments, the molar ratio of compound Z3 to the basic compound is 1:(1-3), preferably 1:(1.5-3), and more preferably 1:(1.8-2). In some specific embodiments, the temperature of the nucleophilic substitution reaction is 0-40°C, preferably 10-30°C, and more preferably 20-30°C. In some specific embodiments, 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 undergo borohydration reaction to obtain compound Z7; then compound Z7 and an acid are mixed to undergo deprotection reaction to obtain compound Z8; and compound Z8 and compound Z4 undergo nucleophilic substitution reaction to obtain boronic acid derivative X3. Specifically, boronic acid derivative X3 can be synthesized according to the following route:

[0041]

[0042] wherein g is an integer selected from 1-4.

[0043] In the present application, the specific way of the borohydration reaction of the compound Z5 and the compound Z6 is to add the compound Z5, the compound Z6, the schwarz reagent and the base into a reaction tube under inert atmosphere, then add solvent, seal and heat the reaction. In some specific implementations, the solvent of the borohydration 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 borohydration reaction is provided by a basic compound, which can be an organic base or an inorganic base, 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 and the compound Z6 is 1:(1-2), preferably 1:(1-1.5), more preferably 1:(1-1.2). In some specific implementations, the molar ratio of the compound Z5 and the basic compound is 1:(0.1-0.5), preferably 1:(0.1-0.4), more preferably 1:(0.1-0.2). In some specific implementations, the molar ratio of the compound Z5 and the schwarz reagent is 1:(0.1-0.5), preferably 1:(0.1-0.4), more preferably 1:(0.1-0.2). In some specific implementations, the temperature of the borohydration reaction is 0-80℃, preferably 20-80℃, more preferably 40-60℃. In some specific implementations, the time of the borohydration reaction is 1-16h, preferably 4-14h, more preferably 8-10h.

[0044] In some specific embodiments of the present application, the specific manner of deprotection reaction of compound Z7 after mixing with acid is that compound Z7 is dissolved in a solvent, and acid is slowly added at low temperature to generate deprotection reaction. In some specific embodiments, 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 embodiments, the acid is an organic acid, preferably pyridine 4-methylbenzenesulfonic acid (PPTS), trifluoroacetic acid or acetic acid, more preferably PPTS. In some specific embodiments, the molar ratio of compound Z7 to acid is 1:(0.1-0.5), preferably 1:(0.1-0.3), more preferably 1:(0.1-0.2). In some specific embodiments, the temperature of the deprotection reaction is 20-40°C, preferably 20-35°C, more preferably 20-30°C. In some specific embodiments, the time of the deprotection reaction is 0.5-24h, preferably 8-24h, more preferably 12-24h.

[0045] In some specific embodiments of the present application, the specific manner of nucleophilic substitution reaction of compound Z8 and compound Z4 is that compound Z8 is dissolved in a solvent, and a base is added at room temperature, and then compound Z4 is added dropwise at low temperature to generate nucleophilic substitution reaction. In some specific embodiments, 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 embodiments, the basic condition in the nucleophilic substitution reaction is provided by a basic compound, which can be an organic base or an inorganic base, the organic base is preferably at least one of triethylamine and N,N-diisopropyl ethylamine, more preferably N,N-diisopropyl ethylamine; the inorganic base is preferably at least one of sodium bicarbonate, sodium carbonate, sodium hydroxide and potassium carbonate. In some specific embodiments, the molar ratio of compound Z8 to compound Z4 is 1:(1-1.5), preferably 1:(1-1.4), more preferably 1:(1-1.2). In some specific embodiments, the molar ratio of compound Z8 to the basic compound is 1:(1-2), preferably 1:(1.5-2), more preferably 1:(1.8-2). In some specific embodiments, the temperature of the nucleophilic substitution reaction is 0-40°C, preferably 10-30°C, more preferably 20-30°C. In some specific embodiments, the time of the nucleophilic substitution reaction is 8-24h, preferably 9-22h, more preferably 10-20h.

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

[0047]

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

[0049] In some specific embodiments of the present application, the specific mode of hydrogenation reduction reaction of compound Z9 and compound Z6 is that compound Z9 and compound Z6 are added into a reaction device, and heated under inert atmosphere to undergo hydrogenation reduction reaction. In some specific embodiments, the hydrogenation metal reagent is selected from Schwarz reagent, lithium aluminum hydride reagent or sodium borohydride reagent, preferably lithium aluminum hydride reagent or sodium borohydride reagent, more preferably lithium aluminum hydride reagent. In some specific embodiments, the molar ratio of compound Z9 and compound Z6 is 1:(1-1.5), preferably 1:(1-1.4), more preferably 1:(1-1.2). In some specific embodiments, the molar ratio of compound Z9 and hydrogenation metal reagent is 1:(0.1-0.5), preferably 1:(0.1-0.3), more preferably 1:(0.1-0.2). In some specific embodiments, the temperature of the hydrogenation reduction reaction is 80-120°C, preferably 90-110°C, more preferably 100-110°C. In some specific embodiments, the time of the hydrogenation reduction reaction is 0.5-8h, preferably 0.5-6h, more preferably 0.5-4h.

[0050] After obtaining the boronic acid derivative or boronic ester derivative with the structure of formula (II), the present application mixes it with ceritinib to undergo reaction, to obtain ceritinib derivative with the structure of formula (I). The structure of formula (I) is the same as the structure of formula (II), which will not be described here again.

[0051] In some specific embodiments, the molar ratio of the boronic acid derivative or boronic ester derivative and ceritinib undergoing reaction is 1:(0.8-2), preferably 1:(0.8-1.8), more preferably 1:(0.8-1.5). In some specific embodiments, the reaction condition of the boronic acid derivative or boronic ester derivative and ceritinib is alkaline condition, the alkaline condition is provided by an alkaline compound, and the molar ratio of the boronic acid derivative or boronic ester derivative and the alkaline compound is 1:(1-5), preferably 1:(1.3-5), more preferably 1:(1.5-5). In some specific embodiments, the time of the reaction is 0.5-24h, preferably 5-24h, more preferably 8-24h; the temperature of the reaction is 0-40°C, preferably 10-40°C, more preferably 20-40°C.

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

[0053]

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

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

[0056]

[0057] Wherein, g is selected from an integer from 1 to 4.

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

[0059]

[0060] Wherein, h is selected from an integer 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 application gives some derivative reactions based on ceritinib derivatives, the derivative reactions provided by the present application cannot cover all cases, and the protection scope of the present application is not limited by such derivative reactions.

[0062] Boronic acid derivative Z10 reacts with ceritinib to obtain ceritinib derivative ZX-C; ceritinib derivative ZX-C and compound Z12 are subjected to condensation reaction to obtain ceritinib derivative ZX-D, and the reaction process is as follows:

[0063]

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

[0065] The reaction conditions of the boronic acid derivative Z10 with the sorafenib are the same as the above preparation method, which will not be repeated here. In some specific embodiments, 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 embodiments, the molar ratio of the sorafenib 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 embodiments, the condensation reaction is carried out at a temperature of 0-40°C, preferably 10-30°C, and more preferably 20-30°C, for a time period of 0.5-24h, preferably 5-24h, and more preferably 8-24h.

[0066] The boronic acid derivative X45 is subjected to a condensation reaction with the sorafenib to obtain the sorafenib derivative ZX-E, and the sorafenib derivative ZX-E is subjected to a hydrolysis reaction under acidic conditions to obtain the sorafenib derivative ZX-F, and the reaction process is as shown below:

[0067]

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

[0069] In some specific embodiments of the present application, the specific mode of the condensation reaction is that the boronic acid derivative X45 is dissolved with a solvent, an amide condensing agent is added at low temperature and stirred, then ceritinib and a basic compound are added to react. In some specific embodiments, the stirring time is 0.15-1.5 h, preferably 0.3-1.3 h, more preferably 0.5-1 h. In some specific embodiments of the present application, 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 embodiments, the condensation reaction is carried out under basic conditions, which are provided by a basic compound. In some specific embodiments, 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 embodiments, the amide condensing agent is HATU, DCC, EDCI or HOBt, preferably HATU, EDCI or HOBt, more preferably HATU. In some specific embodiments, the molar ratio of the boronic acid derivative X45 and ceritinib is 1:(0.8-1.5), preferably 1:(0.8-1.3), more preferably 1:(0.9-1). In some specific embodiments, the molar ratio of the boronic acid derivative X45 and the basic compound is 1:(1-2), preferably (1-1.5), more preferably 1:(1-1.2). In some specific embodiments, the molar ratio of the boronic acid derivative X45 and the amide condensing agent is 1:(1-2), preferably (1-1.5), more preferably 1:(1-1.2). In some specific embodiments, the condensation reaction is carried out at a temperature of 0-40°C, preferably 10-30°C, more preferably 20-30°C, for a time of 0.5-12 h, preferably 5-12 h, more preferably 8-10 h.

[0070] In some specific embodiments, 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 embodiments, the acidic condition is provided by an acidic compound, which is an organic acid or an inorganic acid. In some specific embodiments, the organic acid is preferably trifluoroacetic acid or p-toluenesulfonic acid; the inorganic acid is preferably at least one of hydrochloric acid and amine chloride, more preferably hydrochloric acid. In some specific embodiments, the molar ratio of the ceritinib derivative ZX-E and the acid is 1:(0.8-1.5), preferably 1:(0.8-1.3), more preferably 1:(0.9-1). In some specific embodiments, the temperature for the hydrolysis reaction is 0-40℃, preferably 10-30℃, more preferably 20-30℃; the time is 0.5-8h, preferably 0.5-6h, more preferably 0.5-4h.

[0071] The above obtained ceritinib derivative ZX-F is reacted with a diol compound to obtain a ceritinib derivative ZX-G, and the reaction process is as shown below:

[0072]

[0073] wherein Y, R1 and R2 are selected from the same range as above, which will not be repeated herein.

[0074] The structures of some diol compounds are given herein, which cannot cover all the diol compounds described in the present application, and those skilled in the art can select them according to needs;

[0075]

[0076] In some specific embodiments, the solvent in which the seribantin derivative ZX-F and the diol compound react 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 embodiments, the reaction further comprises a drying reagent, which is preferably anhydrous magnesium sulfate or anhydrous sodium sulfate, and more preferably anhydrous magnesium sulfate. In some specific embodiments, the molar ratio of the seribantin derivative ZX-F and the diol compound is 1:(0.8-1.5), preferably 1:(0.8-1.4), and more preferably 1:(0.9-1.2). In some specific embodiments, the molar ratio of the seribantin derivative ZX-D and the drying reagent is 1:(1-10), preferably 1:(3-10), and more preferably 1:(5-10). In some specific embodiments, the reaction is carried out at a temperature of 0-40°C, preferably 10-30°C, and more preferably 20-30°C, for a time period of 0.5-8h, preferably 0.5-6h, and more preferably 0.5-4h.

[0077] After obtaining the seribantin derivative ZX-G, the present application preferably purifies it to obtain a pure compound. The present application does not have special limitations on the purification method, which can be selected by those skilled in the art as needed, for example, the separation can be carried out by column chromatography, thin layer chromatography or mixing solvent beating. In some specific embodiments of the present application, the purification method is column chromatography, and the column chromatography eluent combination used 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, and more preferably dichloromethane / methanol. In some specific embodiments of the present application, the volume ratio of dichloromethane to methanol is (30-500):1, preferably (30-300):1, and more preferably (50-150):1.

[0078] The seribantin derivative provided by the present application has low toxicity to normal cells and has toxicity to various tumor cells, so the present application is used for preparing an antitumor drug, and a drug is provided. The present application does not have special requirements for other components of the drug, which can include a pharmaceutically acceptable salt and a pharmaceutically acceptable other excipient, which can be selected by those skilled in the art as needed.

[0079] In summary, the seribantin derivative provided by the present application utilizes the sp 2The empty orbital of the boron atom can form a reversible covalent bond with the nucleophilic residues (such as the hydroxyl group of serine and tyrosine) in the protein, and the spatial configuration of the boron atom is also changed from sp 2 Hybridization becomes sp 3 Hybridization, which can reduce off-target cytotoxicity and reduce cytotoxicity to normal cells while maintaining broad-spectrum cytotoxicity. Experimental data show that the sorafenib derivative provided by the present application has cytotoxicity to H228 cells, MCF7 cells, HeLa cells, U251 cells and MDA-MB-231 cells, and has low cytotoxicity to human normal L02 cells. BRIEF DESCRIPTION OF DRAWINGS

[0080] Figure 1 The reaction flow chart of the drug ZX-1 and ZX-2 provided by the present application is shown in the following figure:

[0081] Figure 2 The reaction flow chart of the drug ZX-3 provided by the present application is shown in the following figure:

[0082] Figure 3 The reaction flow chart of the drug ZX-4 provided by the present application is shown in the following figure:

[0083] Figure 4 The reaction flow chart of the drug ZX-5 provided by the present application is shown in the following figure:

[0084] Figure 5 The reaction flow chart of the drug ZX-6 provided by the present application is shown in the following figure:

[0085] Figure 6 The reaction flow chart of the drug ZX-7 provided by the present application is shown in the following figure:

[0086] Figure 7 The reaction flow chart of the drug ZX-8 provided by the present application is shown in the following figure:

[0087] Figure 8 The reaction flow chart of the drug ZX-9 provided by the present application is shown in the following figure:

[0088] Figure 9 The cell survival rate of H228 cells under different concentrations of the drug provided by the present application is shown in the following figure:

[0089] Figure 10 The cell survival rate of MCF7 cells under different concentrations of the drug provided by the present application is shown in the following figure. DETAILED DESCRIPTION

[0090] It should be understood that the expression "one or more of the listed items" includes each of the listed items individually as well as various combinations of two or more of the listed items, unless otherwise explicitly stated or understood from the context and use. The expression "and / or" in combination with two or more listed items should be understood to have the same meaning, unless otherwise explicitly stated or understood from the context.

[0091] The use of the terms "including", "has", "having" or "contains" and variations thereof, does not limit the item or steps to which the terms describe - for example, a composition, process, method, object, article, or apparatus - to a "consisting of", and the terms are therefore to be interpreted open rather than as a "consisting of", unless otherwise stated or understood from the context.

[0092] It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present application remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0093] The use of any and all examples, or exemplary language herein, for example, only the better illustrate the present application, and is not intended to be limiting of the scope of the application unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the application.

[0094] Further, the numerical ranges and parameters setting forth the broadest scope of the application are approximations, and are merely intended to convey general information as to the scope of the application. Consistent with the application as taught herein, various numerical ranges and parameters are approximations. Accordingly, unless otherwise indicated, all ranges, numbers, values and percentages set forth herein are to be read as "about" or "approximately." It will be further understood that any numerical range recited is intended to include all sub-ranges subsumed therein.

[0095] The present application is further illustrated by the following examples. The scope of the application is not limited by the 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, 1400 mg (5.43 mmol, 1.5 eq) B2pin2 were added into a Schlerk tube, replaced with nitrogen for 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 dissolve thoroughly, stirred at room temperature for 18 h, TLC was used to monitor the reaction, after completion, the system was transferred to a separatory funnel with 20 mL dichloromethane, washed with 20 mL water for 3 times, 20 mL saturated brine for 1 time, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to obtain the crude product B, a yellowish viscous liquid, 437 mg, yield 65%.

[0098] (2) 437 mg (2.22 mmol, 1 eq) of the crude product B obtained in step (1), N,N-diisopropylethylamine (772 μL, 4.44 mmol) and 4 mL DCM were added into a flask, 675 mg (2.22 mmol, 1 eq) of bis(p-nitrophenyl) carbonate was slowly added at zero degree, stirred at room temperature for 12 h, TLC was used to monitor the reaction, after completion, column chromatography was used to separate (dichloromethane / methanol = 20:1). 725 mg of the crude product C was obtained, yield 89%.

[0099] (3) 50 mg (0.089 mmol, 1 eq) of ceritinib, 16 μL (0.089 mmol, 2 eq) of N,N-diisopropylethylamine, 2 mL DCM were added into a flask, 33 mg (0.089 mmol, 1 eq) of the crude product C was slowly added at zero degree, stirred at room temperature for 6 h, TLC was used to monitor the reaction, after completion, column chromatography was used to separate (dichloromethane / methanol = 20:1). 58 mg of ceritinib derivative ZX-1 was obtained, yield 85%, which was the drug prepared in the embodiment. 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), 4.55 (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] Referring to Figure 1 ,Figure 1 The reaction flow chart of the drug ZX-1 prepared in this example, wherein compound A is 3-bromo-1-propanol (n = 1), the resulting 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 changed 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 Example 1, to obtain 45 mg of the sorafenib derivative ZX-2, a light yellow solid, which is the drug prepared in this example, with a yield of 89%. 1 H NMR (500M, CDCI3): 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] Reference is made to Figure 1 , Figure 1 The reaction flow chart of the drug ZX-2 prepared in this example, wherein compound A is 6-bromo-n-hexanol (n = 4), the resulting product is the drug ZX-2 prepared in this example.

[0104] Example 3

[0105] (1) 208 mg (1.82 mmol, 1 eq) (propargyloxy)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, DCM were added into a reaction tube, stirred at 55°C for 18 h. TLC monitoring reaction completion, after quenching with water, liquid separation, the water phase was extracted with DCM once, the synthesized organic phase was dried over anhydrous sodium sulfate, and 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 the crude product D obtained in step (1), 30 mg (0.12 mmol, 0.1 eq) of PPTS, 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, and after quenching with water, extracted with DCM three times, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain 119 mg of the crude product F, with a yield of 49%.

[0107] (3) 119 mg (0.59 mmol, 1 eq) of the crude product F obtained in step (2), 205 μL (1.18 mmol, 2 eq) of N,N-diisopropylethylamine, 2 mL of DCM were added to a flask, and 179 mg (0.59 mmol, 1 eq) of bis(p-nitrophenyl) carbonate was slowly added at 0°C, and stirred at room temperature for 12 h. The reaction was monitored by thin layer chromatography, and after the reaction was completed, column chromatography was used for separation (dichloromethane / methanol = 20:1) to obtain 175 mg of the 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, 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 0°C, and stirred at room temperature for 6 h. The reaction was monitored by thin layer chromatography, and after the reaction was completed, column chromatography was used for separation (dichloromethane / methanol = 20:1) 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 Figure 2 , Figure 2 Reaction flow diagram of the drug ZX-3 prepared in this example.

[0112] Example 4

[0113] The crude product F was prepared according to the same method as step (1) and step (2) in Example 3, 11 mg (0.0537 mmol, 1 eq) of crude product F, DCM was added into the reaction tube, 20 mg (0.0537 mmol, 1 eq) of HATU was added portionwise at 0 °C, and stirred at room temperature for 1 h. Then 30 mg (0.0537 mmol, 1 eq) of ceritinib was added slowly, 18 μL (0.107 mmol, 2 eq) of N,N-diisopropylethylamine was added dropwise, and stirred for 2.5 h. The reaction was monitored by thin layer chromatography, and 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 (500 MHz, CDC13) δ 9.51 (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] Reference is made to Figure 3 , Figure 3 The reaction flow chart of the drug ZX-4 prepared in this example.

[0115] Example 5

[0116] The crude product G was prepared according to the same method as step (1), step (2) and step (3) in Example 3, 14 mg (0.0537 mmol, 1 eq) of crude product G, 2 mL of DCM was added into the reaction tube, 20 mg (0.0537 mmol, 1 eq) of HATU was added at 0 °C, and stirred at room temperature for 1 h. Then 30 mg (0.0537 mmol, 1 eq) of ceritinib was added slowly, 18 μL (0.107 mmol, 2 eq) of N,N-diisopropylethylamine was added dropwise, and stirred for 2.5 h. The reaction was monitored by thin layer chromatography, and 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 (500 MHz, CDC13) δ 9.50 (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, 1H), 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] Reference is made to Figure 4 , Figure 4 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-bromopropene (compound H), 22 mg (0.59 mmol, 0.1 eq) of lithium aluminum hydride, 1.03 mL (6.45 mmol, 1.1 eq) of HBpin were added into a reaction tube under nitrogen protection, and heated at 110°C for 4 h. After quenching the reaction with water, the organic phase was extracted with dichloromethane, washed with saturated brine, dried over sodium sulfate, and the solvent was removed by rotary evaporation to obtain 2.16 g of a light yellow viscous liquid, which was the crude product I, with a yield of 86%.

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

[0121] (3) Dissolve 9 mg (0.047 mmol, 1 eq) of the crude product J from step (2) in dichloromethane, add 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, and react at room temperature for 24 h. After the reaction is completed, remove the magnesium sulfate by filtration, and separate using column chromatography (dichloromethane / methanol = 20:1). This results in 32 mg of the sorafenib derivative ZX-6, which is the drug prepared in this example, in a yield of 49.5%. 1 H NMR (500 MHz, CDC13): 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 Figure 5 , Figure 5 Reaction scheme for the drug ZX-6 prepared in this example.

[0123] Example 7

[0124] Prepare the compound ZX-5 in the same manner as in Example 5, and add 72 mg (0.098 mmol, 1 eq) of ZX-5, 29 mg (0.49 mmol, 5 eq) of methylboronic acid, 98 μL of HCl (aq, 1M), and 3 ml of acetonitrile to a reaction tube under nitrogen protection, stir at room temperature for 2 h, quench the reaction with water, extract the organic phase with ethyl acetate, then wash with saturated brine, and dry with sodium sulfate. After the solvent is evaporated, separate using column chromatography (dichloromethane:methanol = 10:1) to obtain 54 mg of the sorafenib derivative ZX-7, a yellowish viscous liquid, which is the drug prepared in this example, in a yield of 84.5% 1H NMR (400 MHz, 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), 2.95 (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] Reference is made to Figure 6 , Figure 6 Reaction flow chart of the drug ZX-7 prepared in this example.

[0126] Example 8

[0127] The compound ZX-7 was prepared according to the same method as Example 7. 30 mg (0.046 mmol, 1 eq) of ZX-7, 9 mg (0.051 mmol, 1.1 eq) of (1S,2S,3R,5S)-(+)-2,3-pinanediol, 34 mg of magnesium sulfate, and 2 mL of anhydrous dichloromethane were added to a reaction tube under nitrogen protection. After stirring at room temperature for 2 h, the reaction was quenched with water, and the organic phase was extracted with ethyl acetate, then washed with saturated brine and dried over sodium sulfate. After the solvent was evaporated, column chromatography (dichloromethane:methanol=10:1) was used to separate 34 mg of the ceritinib derivative ZX-8, which was the drug prepared in this example, with a yield of 95%. 1H NMR (400 MHz, CDC13): 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] Reference is made to Figure 7 , Figure 7 Reaction scheme for the preparation of the drug ZX-8 prepared in this example.

[0129] Example 9

[0130] The compound ZX-7 was prepared in the same manner as Example 7, 15 mg (0.023 mmol, 1 eq) of ZX-7, 3 mg (0.025 mmol, 1.1 eq) of neopentyl glycol, 34 mg of magnesium sulfate, and 1 mL of anhydrous dichloromethane were added to a reaction tube under nitrogen protection, stirred at room temperature for 3 h, then quenched with water, the organic phase was extracted with ethyl acetate, then washed with saturated brine, dried with sodium sulfate. After the solvent was rotary evaporated, column chromatography was used for separation (dichloromethane:methanol = 10:1), 15 mg of ceritinib derivative ZX-9 was obtained, which was the drug prepared in this example, the yield was 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 Figure 8 , Figure 8 This is a reaction flow diagram of the drug ZX-9 prepared in this embodiment.

[0132] Experimental Example 1

[0133] The IC50 values ​​of the drugs prepared in Examples 1-9 and ceritinib against H2228 cells were tested using the MTT assay. 50 The specific steps are as follows: First, remove the culture medium from the cell culture dish, wash the cells with 3 mL of PBS, and then digest the cells with 2 mL of trypsin for 3 min. Remove the trypsin, resuspend the cells in complete culture medium, and add a total of 5 × 10⁶ cells / well to the 96-well plate. 3 Cells were incubated overnight in a cell culture incubator. The supernatant was aspirated and added to complete culture medium containing different concentrations of drugs. The cells were incubated for 48 hours. Each sample group had 3 replicate wells.

[0134] After incubation, 10 μL of MTT solution was added, and the cells were returned to the incubator for another 4 hours. The supernatant was gently aspirated, and 150 μL of dimethyl sulfoxide was added to each well. After vortexing and mixing, the OD value at 490 nm was measured. Data were processed using GraphPad Prism software, and the IC50 was calculated based on drug concentration and cell viability. 50 The cell viability was calculated using the following formula: Cell viability (%) = (Average OD490 of experimental group) / (Average OD490 of control group) × 100%.

[0135] The drugs prepared in Examples 1-9 and the IC50 of ceritinib on H2228 cells 50 The values ​​are listed in Table 1, showing the survival rate of H2228 cells at different drug concentrations. Figure 9 As shown. Among them Figure 9 A represents the survival rate of H2228 cells at different concentrations of drugs ZX-1, ZX-3, ZX-4, and ZX-5 and ceritinib.Figure 9 B is the H2228 cell survival rate of drugs ZX-7, ZX-8 and ZX-9 at different concentrations of sorafenib.

[0136] Table 1 IC50values of drugs prepared in Examples 1-9 and sorafenib on H2228 cells 50

[0137]

[0138]

[0139] From Table 1 and Figure 9 It can be seen that the borate / boric acid modified sorafenib derivatives generally maintain the cytotoxicity on H2228 cell lines compared with sorafenib, in which the cytotoxicity of ZX-3 and ZX-5 is slightly improved. However, the cytotoxicity of ZX-2 and ZX-6 is significantly reduced, and the IC50values are greater than 64 μM. According to the results of protein and molecular docking simulation, the cytotoxicity of ZX-6 is reduced because the introduction of the borate structure with larger steric hindrance on the piperidine ring is not conducive to the binding of the borate modified drug to the target protein, thus causing the reduction of cytotoxicity. The cytotoxicity of ZX-2 is reduced because the borate is connected to the piperidine ring through a long alkyl chain, and the long alkyl chain has greater flexibility, which is not conducive to the interaction of the borate target protein, and the cytotoxicity is reduced. 50

[0140] Test Example 2

[0141] The IC50values of the drugs prepared in Examples 1-9 and sorafenib on MCF7 cells were tested by MTT colorimetric method, and the specific method was the same as that of Test Example 1. The IC50values of the drugs prepared in Examples 1-9 and sorafenib on MCF7 cells are listed in Table 2, and the MCF7 cell survival rates at different drug concentrations are shown in Table 2. Among them 50 50 The IC50values of the drugs prepared in Examples 1-9 and sorafenib on MCF7 cells are listed in Table 2, and the MCF7 cell survival rates at different drug concentrations are shown in Table 2. Among them Figure 10 Figure 10 A is the H2228 cell survival rate of drugs ZX-1, ZX-3, ZX-4 and ZX-5 at different concentrations of sorafenib, Figure 10 B is the H2228 cell survival rate of drugs ZX-7, ZX-8 and ZX-9 at different concentrations of sorafenib.

[0142] Table 2 IC50values of drugs prepared in Examples 1-9 and sorafenib on MCF7 cells 50

[0143]

[0144]

[0145] From Table 2 and​​​​​Figure 10 It can be seen that for the MCF7 cell line, the cytotoxicity of the modified small molecules is significantly improved compared with sorafenib, except for ZX-2. The decrease in cytotoxicity of ZX-2 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 sorafenib, the cytotoxicity of ZX-2 is significantly reduced.

[0146] Test Example 3

[0147] The IC50values of the drug ZX-5 prepared in Example 5 and sorafenib (positive control) on LO2 cells were tested by MTT method, and the specific method was the same as that in Test Example 1. The results are shown in Table 3. 50

[0148] Table 3 IC50values of ZX-5 and sorafenib on LO2 cells 50

[0149] Compound IC 50 / μM Sarilumab 2.12±0.12 ZX-5 4.34±0.25

[0150] As can be seen from Table 3, the cytotoxicity of ZX-5 on normal cell line LO2 is reduced compared with sorafenib, reducing the original side effects of sorafenib.

[0151] Test Example 4

[0152] The IC50values of the drug ZX-5 prepared in Example 5 on HeLa cells, U251 cells and MDA-MB-231 cells were tested by MTT method, and the specific method was the same as that in Test Example 1. The results are shown in Table 4. 50

[0153] Table 4 IC50values of ZX-5 on HeLa cells, U251 cells and MDA-MB-231 cells 50

[0154]

[0155] Comparative Example 1

[0156] Compound VII was prepared according to the method provided in Patent CN118684691A, and the structure is shown below; and the cytotoxicity IC50values of compound VII on HeLa cells, U251 cells and MDA-MB-231 cells were tested by MTT method, and the specific method was the same as that in Test Example 1. The results are shown in Table 5. 50

[0157] Table 5 IC50values of compound VII on HeLa cells, U251 cells and MDA-MB-231 cells 50

[0158] ​​​​​​

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

[0160]

[0161] Structure of the compound VII prepared in the present embodiment

[0162] In combination with the above experimental results, the trend of the effect of the drug is not completely the same after different boron-containing groups are modified on ceritinib. The cytotoxicity of ZX-2 to MCF7 and H2228 is significantly reduced compared to ceritinib. The cytotoxicity of ZX-1, ZX-3, and ZX-5 to H2228 is not significantly increased compared to ceritinib, but the cytotoxicity to MCF7 cell line is significantly improved. The cytotoxicity of ZX-5 to normal cells is significantly reduced compared to ceritinib. The IC 50 value of ZX-5 to LO2 is 4.34 μM, while the IC 50 value of ceritinib is 2.12 μM. In addition, compared with the ROS-responsive ceritinib prodrug modified by borate, it also has obvious cytotoxicity to MCF7 cells, HeLa cells, and U251 cells.

[0163] The above describes only the preferred specific embodiments of the present application, but the protection scope of the present application is not limited thereto. Any person skilled in the art can make equivalent substitutions or changes to the technical solutions and inventive concepts of the present application within the technical scope disclosed by the present application, which should be covered within the protection scope of the present application.

Claims

1. A derivative of ceritinib, characterized in that, having the structure of formula (I): wherein X is selected from or C1-C6 alkylene; Y is selected from C1-C6 alkylene or C2-C6 alkenyl; R is R1and R2are independently selected from hydrogen or C1-C6alkyl; or at least one of said R1and R2and the O to which it is attached and the B to which the O is attached form a 5-10 membered heterocyclic ring.

2. The derivative of ceritinib according to claim 1, characterized in that, said 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 an integer from 0 to 3; R3-R8 are independently selected from hydrogen or C1-C6 alkyl; R9and R 10 are independently selected from carbonyl, C1-C6alkylene or C1-C6alkylene substituted with at least one substituent selected from C1-C6alkyl; Ring A is selected from C3 to C4. 10 Monocyclic alkyl groups, C3-C6 substituted with at least one substituent 10 Monocyclic alkyl, C4-C 10 Bicycloalkyl, C4-C substituted with at least one substituent 10 Bicycloalkyl, C6-C 12 The aromatic group or at least one substituent substituted C6-C 12 The aromatic group, wherein the substituent is a C1-C3 alkyl group; Z is selected from NH, N-R 11 O or S; said R 11 selected from C1-C6alkyl.

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

4. The derivative of ceritinib according to claim 1, characterized in that, having the structure of formula (I): wherein a, b, c, d and e are independently selected from an integer from 0 to 4.

5. A method of preparing a derivative of ceritinib, characterized in that, comprising: a boronic acid derivative or boronic ester derivative having the structure of formula (II) is reacted with ceritinib to obtain a ceritinib derivative having the structure of formula (I); R'-X-Y-R (II); R' is selected from halogens, hydroxyl groups, and C6-C6 groups. 12 aryloxy or nitro-substituted C6-C 12 aryloxy groups; X is selected from or C1-C6 alkylene; Y is selected from C1-C6 alkylene or C2-C6 alkenyl; R is R1and R2are independently selected from hydrogen or C1-C6alkyl; or at least one of said R1and R2and the O to which it is attached and the B to which the O is attached form a 5-10 membered heterocyclic ring.

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

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

8. The preparation method according to claim 5, characterized in that, the reaction time is 0.5-24 h, and the reaction temperature is 0-40℃.

9. Use of the ceritinib derivative of any one of claims 1-4 or the ceritinib derivative prepared by the method of any one of claims 5-8 in the preparation of an antitumor drug.

10. A medicament, characterized by comprising: comprising: the ceritinib derivative of any one of claims 1-4 or the ceritinib derivative prepared by the method of any one of claims 5-8, a pharmaceutically acceptable salt and other pharmaceutically acceptable excipients.

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