Novel aurora kinase inhibitors and uses thereof

Abstract

The present invention relates to a novel pyridine compound and its preparation method and use. Specifically, the present invention relates to the compound of formula (1) and its preparation method, as well as the application of the compound of formula (1) and its pharmaceutically acceptable salts as Aurora kinase inhibitors in the preparation of antitumor drugs. [Formula 1] TIFF2023505239000039.tif36168

Description

[Technical Field]

[0001] This application claims the benefit of Chinese patent application CN201911256773.5, filed on December 3, 2019, the contents of which are incorporated herein by reference in their entirety.

[0002] FIELD OF THE INVENTION The present invention relates to the field of medicinal chemistry, and in particular to a series of compounds having inhibitory effects on Aurora kinases, as well as methods for their preparation and use. [Background technology]

[0003] Background of the Invention Aurora kinases are threonine / serine protein kinases that play important roles in key mitotic events, such as centrosome duplication, bipolar spindle formation, chromosome rearrangement, and chromosome checkpoint monitoring (Cancer Metastasis Rev., 2003, 22, 451). Currently, three structurally and functionally related Aurora kinase subtypes, Aurora A, Aurora B, and Aurora C, are known to exist in human cells. Aurora A resides around the centrosome during prophase, on microtubules near the spindle during metaphase, and on polar microtubules during anaphase and telophase. It is primarily involved in centrosome duplication and separation, bipolar spindle assembly, mitotic initiation and termination, centrosome maturation, and spindle assembly (Nat. Rev. Cancer, 2005, 5, 42). Aurora B resides at the centromeric regions of chromosomes during early mitosis and translocates from the centromere to microtubules during metaphase. Aurora B regulates centromere function, chromosome alignment and segregation, the spindle checkpoint, and cytokinesis (Mol. Cancer Ther., 2009, 8, 2046-2056). Aurora C is highly expressed in the testis and is thought to play a special role in males (Proc Natl Acad Sci USA, 2002, 99(24):15440-15445).

[0004] The gene encoding Aurora A is located at 20q13.2, a region commonly amplified in many tumors, including breast, colon, ovarian, and thyroid cancers. Overexpression of Aurora A in cells leads to the development of various cancer cell characteristics, including centrosome amplification, aneuploidy, chromosomal instability, and telomere elongation (J. Cell Sci., 2007, 120, 2987). Overexpression of Aurora A or its coexpression with TPX-2 induces chromosomal instability. Furthermore, Aurora A interferes with the function of important tumor suppressor and proapoptotic proteins, such as p53. Aurora A phosphorylation of p53 at Ser215 and Ser315 interferes with the normal function of p53 and leads to its degradation, respectively.

[0005] Aurora B is located at 17p13.1, and unlike Aurora A, this region is not significantly amplified in most cancers other than brain gliomas (J. Clin. Pathol., 2007, 60(2):218-221). However, Aurora B mRNA and protein are overexpressed in many tumors, including rapidly proliferating cells in colon cancer, oral cancer, and non-small cell lung cancer. Thus, tumor cells upregulate the expression of Aurora family proteins in various ways. The chromosomal passenger protein complex (CPC) is a key complex that regulates mitosis, and Aurora B is a central member of this complex. Aurora B phosphorylates substrates, primarily INCENP, CENP-A, and survivin. Aurora B regulates mitosis by phosphorylating its substrates. Furthermore, overexpression of Aurora B enhances mitosis as well as the ras signaling pathway.

[0006] Aurora kinases have become important targets in antitumor drug research due to their unique pharmacological mechanism of action and their relationship to malignant tumors. Aurora kinase inhibitors are also promising candidates for development as novel antitumor drugs. LY-3295668 is an Aurora A kinase inhibitor with a pyridine ring (WO2016077161) and is currently undergoing phase 1 clinical trials. LY-3295668 has the following structural formula: [ka] [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2016 / 077161 [Non-patent literature]

[0008] [Non-Patent Document 1] Cancer Metastasis Rev.,2003,22,451 [Non-patent document 2] Nat.Rev.Cancer,2005,5,42 [Non-patent document 3] Mol.Cancer Ther.,2009,8,2046-2056 [Non-patent document 4] Proc Natl Acad Sci USA,2002,99 (24):15440-15445 [Non-Patent Document 5] J. Cell Sci.,2007,120,2987 [Non-patent document 6] J. Clin. Pathol.,2007,60(2):218-221 Summary of the Invention [Problem to be solved by the invention]

[0009] However, Aurora A kinase inhibitors such as LY-3295668 have drawbacks such as insufficient Aurora kinase activity, poor oral absorption, and limited in vivo antitumor activity. Therefore, in light of the problems with existing Aurora kinase inhibitors, it is of great significance to discover novel Aurora inhibitors with better in vitro and in vivo activity. [Means for solving the problem]

[0010] Summary of the Invention The present invention provides a novel series of Aurora kinase inhibitors having the structure shown in formula (1), or an optical isomer, crystalline form, pharmaceutically acceptable salt or ester thereof. [ka] Here, in equation (1), "*" indicates a chiral center, L is CH2 or CO; R 1 and 2 are independently H, halogen, CN, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C1-C3 haloalkyl or C1-C3 haloalkoxy; R 3 is C2-C3 alkyl, C3-C6 cycloalkyl, C1-C3 haloalkyl, -(C1-C3)alkyl-OH, -(C1-C3)alkyl-(C1-C3)alkoxy, -(C1-C3)alkyl-CN or -(C1-C3)alkyl-NR 5 R 6 , where R 5 and R 6 are independently H or C1-C3 alkyl, or R 5 and R 6 together with the N atom form a 4- to 7-membered heterocycloalkyl; R 4 is H or F, W is [ka] and where R 7 is H, C1-C3 alkyl or C3-C6 cycloalkyl.

[0011] In another preferred embodiment, in the formula (1), [ka] teeth, [ka] is.

[0012] In another preferred embodiment, in the formula (1), R 3 is the following group: Et, n- Pr, i- Pr, [ka] CH2F, CHF2, CF3, CH2OH, CH2OMe, CH2OEt, CH2CN, [ka] is.

[0013] In another preferred embodiment, in the formula (1), W is the following group: [ka] is.

[0014] In various embodiments, representative compounds of the present invention have one of the following structures: [ka] TIFF0007777528000010.tif235168

[0015] Another object of the present invention is to provide a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and a compound of formula (1) disclosed herein, or an optical isomer, crystalline form, pharmaceutically acceptable salt, or ester thereof, as an active ingredient.

[0016] Yet another object of the present invention is to provide the use of the above compound, or an optical isomer, crystalline form, pharmaceutically acceptable salt or ester thereof, in the preparation of a medicament for treating Aurora-related diseases, in particular an antitumor medicament. DETAILED DESCRIPTION OF THE INVENTION

[0017] Compound synthesis Methods for preparing compounds of general formula (1) are described in detail below, but these specific methods do not constitute any limitations on the present invention.

[0018] The compounds of formula (1) described above can be synthesized using standard synthetic techniques or well-known techniques in combination with the methods described herein. Additionally, the solvents, temperatures, and other reaction conditions described herein may vary. Starting materials for the synthesis of the compounds in Table 1 can be synthesized or obtained from commercial sources, such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wis.) or Sigma Chemical Co. (St. Louis, Mo.). The compounds described herein and other related compounds with different substituents can be synthesized using methods described in March, Advanced Organic Chemistry, 4 th Ed.,(Wiley 1992);Carey and Sundberg,Advanced Organic Chemistry,4 th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., (Wiley 1999). General methods for the preparation of compounds can be varied by using appropriate reagents and conditions to introduce different groups into the formulas provided herein.

[0019] In one aspect, the compound of formula (1) described herein is prepared according to a known method. However, conditions such as reactants, solvents, bases, amounts of compounds used, reaction temperature, and reaction time are not limited to those described below. In addition, the compounds disclosed herein can be easily prepared by any combination of various synthetic methods described herein or known methods, and such combinations can be easily determined by those skilled in the art to which the present invention pertains. In another aspect, the present invention provides a method for preparing a compound of formula (1) by the following Method A, Method B, or Method C.

[0020] Method A includes the following steps: first, a step of hydrogenating compound A to compound B in the presence of a catalyst; a step of reacting compound B with fragment S1 under alkaline conditions to produce compound C; a step of directly contacting compound C with fragment S2 under alkaline conditions to produce compound D; a step of reacting compound D with fragment S3 under alkaline conditions in the presence of a metal palladium catalyst and a ligand to produce compound E; and a step of subjecting compound E to ester hydrolysis under acidic or alkaline conditions to obtain target compound (1a).

[0021] [ka]

[0022] In the above reaction, R 1 , R 2 , R 3 , R 4 , L and W are as defined above, and X is I, Br, Cl, OTf, OH, or the like.

[0023] Method B involves the following steps: first, compound B is Boc-protected under appropriate conditions to obtain compound F; compound F is reacted with fragment S2 under alkaline conditions to obtain compound G; compound G is reacted with fragment S3 in the presence of a metal palladium catalyst and a ligand to produce compound H; compound H is deprotected with Boc under acidic conditions to obtain compound I; compound I is reacted with fragment S1 under alkaline conditions to produce compound J; and compound J is subjected to an ester hydrolysis reaction under acidic or alkaline conditions to obtain the target compound (1b).

[0024] [ka]

[0025] In the above reaction, R 1 , R 2 , R 3 , R 4 , L and W are as defined above, and X is I, Br, Cl, OTf, OH, or the like.

[0026] Method C includes the steps of firstly performing Boc deprotection of compound G under acidic conditions to obtain compound K, condensing compound K with fragment S1 to obtain compound L, reacting compound L with fragment S3 in the presence of a metal palladium catalyst and a ligand to produce compound M, and subjecting compound M to ester hydrolysis under acidic or alkaline conditions to obtain target compound (1c). [ka]

[0027] In the above reaction, R 1 , R 2 , R 3 , R 4 , L and W are as defined above, and X is I, Br, Cl, OTf, OH, or the like.

[0028] Further forms of the compound

[0029] As used herein, including the appended claims, the aforementioned substituents have the following meanings:

[0030] "Halogen" (or halo) refers to fluorine, chlorine, bromine, or iodine. The term "halo" preceding a group name indicates that the group is partially or fully halogenated, i.e., substituted with F, Cl, Br, or I in any combination, preferably with F or Cl. "C1-3 alkyl" refers to a straight or branched chain alkyl group containing 1 to 3 carbon atoms. "C2-3 alkyl" refers to a straight or branched chain alkyl group containing 2 to 3 carbon atoms. "C1-3 haloalkyl" refers to a C1-3 alkyl, as defined above, containing one or more halogen atom substituents. "C3-6 cycloalkyl" refers to a non-aromatic cyclic group containing 3 to 6 carbon atoms. "C1-3 alkoxy" refers to a C1-3 alkyl-O- group attached to the parent moiety via oxygen: -(C1-C3)alkyl-OH, (C1-C3)alkyl-(C1-C3)alkoxy, -(C1-C3)alkyl-CN, and -(C1-C3)alkyl-NR 5 R 6 are the C1-C3 alkyl groups defined above, OH, (C1-C3)alkoxy, CN and NR 5 R 6 "4- to 7-membered heterocycloalkyl" refers to a non-aromatic saturated cyclic group containing 4 to 7 ring atoms.

[0031] The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant stimulation to a living body due to drug administration and does not lose the biological activity and properties of the compound. The salt of the compound of the present invention refers to a salt conventionally used in the field of organic chemistry, and for example, when the compound has a carboxyl group, it can be a base addition salt of the carboxyl group, and when the compound has an amino group or a basic heterocyclic group, it can be an acid addition salt of the amino group or a basic heterocyclic group.

[0032] Examples of base addition salts include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts, and organic amine salts such as trimethylamine salts, triethylamine salts, dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, procaine salts, N,N'-dibenzylethylenediamine salts, meglumine salts, arginine salts, and lysine salts.

[0033] Examples of acid addition salts include inorganic acid salts such as hydrochlorides, sulfates, nitrates, and phosphates; organic acid salts such as acetates, formates, maleates, fumarates, citrates, oxalates, and ascorbates; and sulfonates such as methanesulfonates, benzenesulfonates, and p-toluenesulfonates.

[0034] Reference to a pharmaceutically acceptable salt should be understood to include solvent addition forms or crystalline forms, particularly solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are preferentially formed upon crystallization with pharmaceutically acceptable solvents such as water and ethanol. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is ethanol. Solvates of the compound of formula (1) are conveniently prepared or formed according to the methods described herein. For example, hydrates of the compound of formula (1) are conveniently prepared by recrystallization in a water / organic solvent mixture, where the organic solvent used includes, but is not limited to, dioxane, tetrahydrofuran, ethanol, or methanol. Furthermore, the compounds described herein can exist in both unsolvated and solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0035] In another specific embodiment, the compound of Formula (1) is prepared in different forms, including, but not limited to, amorphous, crushed, and nanoparticle forms. Furthermore, the compound of Formula (1) may be in a crystalline form and may also be a polymorph. Polymorphs include different lattice arrangements of the same elements of a compound. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystalline shapes, optical properties, electrical properties, stability, and solubility. Various factors, such as recrystallization solvents, crystallization rates, and storage temperatures, may result in the predominance of a single crystalline form.

[0036] In another embodiment, the compounds of formula (1) have one or more stereocenters and therefore occur in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds, and single diastereomers. The possible asymmetric centers depend on the nature of the various substituents on the molecule. Each of these asymmetric centers independently generates two optical isomers, and all possible optical isomers, diastereomeric mixtures, and pure or partially pure compounds are within the scope of the present invention. The present invention is intended to include all such isomeric forms of these compounds.

[0037] therapeutic use The compounds or compositions described herein can generally be used to inhibit Aurora kinases and, therefore, can be used to treat one or more disorders associated with Aurora kinase activity. Accordingly, in certain embodiments, the present invention provides a method for treating an Aurora kinase-mediated disorder, comprising administering to a patient in need thereof a compound disclosed herein or a pharmaceutically acceptable composition thereof.

[0038] Cancers that can be treated with the compounds disclosed herein include, but are not limited to, hematological malignancies (leukemia, lymphoma, myeloma such as multiple myeloma, myelodysplastic syndrome, myeloproliferative disorder), solid tumors (soft tissue cancers such as prostate cancer, breast cancer, lung cancer, colon cancer, pancreatic cancer, kidney cancer, ovarian cancer, osteosarcoma, stromal tumors, etc.).

[0039] Administration route The compounds disclosed herein and their pharmaceutically acceptable salts can be prepared into various preparations containing a safe and effective amount of the compounds disclosed herein or their pharmaceutically acceptable salts and a pharmaceutically acceptable excipient or carrier, where "safe and effective amount" means that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound is determined according to the age, condition, course of treatment, and other specific conditions of the subject being treated.

[0040] A "pharmaceutically acceptable excipient or carrier" refers to one or more compatible solid or liquid fillers or gel substances that must be of sufficient purity and sufficiently low toxicity to be suitable for human use. "Compatible" means that the components of the composition are capable of being intermixed with the compounds disclosed herein without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable excipient or carrier components include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, or cellulose acetate), gelatin, talc, solid lubricants (e.g., stearic acid or magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, or olive oil), polyols (e.g., propylene glycol, glycerol, mannitol, or sorbitol), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

[0041] When administering the compounds disclosed herein, they may be administered orally, rectally, parenterally (intravenously, intramuscularly, subcutaneously), or topically.

[0042] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, such as hydroxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, such as glycerol; (D) disintegrating agents, such as agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retardants, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (H) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, and sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0043] Solid dosage forms such as tablets, sugar pills, capsules, pills, and granules can be prepared with other materials known in the art, such as coatings and shells, such as enteric coatings.They may also contain opacifiers, and the active compound or compounds in such compositions can be released in a delayed manner in a specific part of the digestive tract.Examples of embedding components that can be used include polymeric substances and wax-based materials.If necessary, the active compound can also be in the form of microcapsules with one or more of the above-mentioned excipients.

[0044] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0045] Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0046] In addition to the active compound, suspensions may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, methylated aluminum and agar, or mixtures of these substances.

[0047] Compositions for parenteral injection can include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0048] Dosage forms for topical administration of the compounds disclosed herein include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier, and any needed preservatives, buffers, or propellants, as may be required.

[0049] The compounds disclosed herein can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0050] When using the pharmaceutical composition of the present invention, a safe and effective amount of the compound disclosed herein is administered to a mammal (e.g., a human) to be treated, and the administered dose is a pharmaceutically effective dose. For a human weighing 60 kg, the daily dose is typically 1 to 1,000 mg, preferably 10 to 500 mg. The specific dose is determined taking into consideration factors such as the route of administration and the patient's health condition, which are well known to those skilled in the art.

[0051] The above features and the features described in the examples of the present invention can be combined in any combination. All features disclosed herein can be used in any composition, and various features disclosed herein can be replaced with any alternative features that serve the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the disclosed features are merely generic examples of equivalent or similar features.

[0052] Various specific aspects, features and advantages of the above compounds, methods and pharmaceutical compositions will be described in detail in the following description, thereby clarifying the present invention. It should be understood that the following detailed description and examples describe specific embodiments for reference. After reading the description of the present invention, those skilled in the art will be able to make various changes or modifications to the present invention, and such equivalents also fall within the scope of the present invention as defined herein.

[0053] In all examples, melting points were measured using an X-4 melting point apparatus with an uncalibrated thermometer. 1 H-NMR spectra were recorded on a Varian Mercury 400 nuclear magnetic resonance spectrometer, and chemical shifts were expressed in ppm. Unless otherwise specified, the silica gel used for separation was 200–300 mesh silica gel, and the eluent ratios were expressed by volume.

[0054] In the present invention, the following abbreviations are used: ACN represents acetonitrile, Ar represents argon, (Boc)2O represents di-tert-butyl dicarbonate, CDCl3 represents deuterated chloroform, CD3OD represents deuterated methanol, DCM represents dichloromethane, DIPEA represents diisopropylethylamine, Diox or Dioxane represents 1,4-dioxane, DMAP represents 4-dimethylaminopyridine, DMF represents dimethylformamide, DMSO represents dimethylsulfoxide, EA represents ethyl acetate, h represents hour, K2CO3 represents potassium carbonate, KI represents iodide A stands for potassium, K3PO4 stands for potassium phosphate, LC-MS stands for liquid crystal mass spectrometry, LDA stands for lithium diisopropylamide, LiOH stands for lithium hydroxide, mL stands for milliliter, MeOH stands for methanol, min stands for minute, MS stands for mass spectrum, NMR stands for nuclear magnetic resonance, Pd2(dba)3 stands for tris(dibenzylideneacetone)dipalladium, PE stands for petroleum ether, PtO2 stands for platinum dioxide, THF stands for tetrahydrofuran, and Xantphos stands for 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. [Example]

[0055] Detailed Description of the Invention

[0056] Example 1. Synthesis of 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-(thiazol-2-ylamino)pyridin-2-yl)methyl)-2-(trifluoromethyl)piperidine-4-carboxylic acid (Compound 1) [ka]

[0057] Methyl 2-(trifluoromethyl)piperidine-4-carboxylate (1-A) Methyl 2-trifluoromethylpyridine-4-carboxylate (5 g, 24.374 mmol), HOAc (100 mL), and PtO2 (0.5 g) were added to a 500 mL one-neck flask. The reaction mixture was purged with H2 three times, heated to 60 °C, and vigorously stirred for 1-3 days while the flask was connected to a hydrogen bag. After completion of the reaction as detected by LC-MS, the reaction mixture was cooled to room temperature, filtered with the aid of diatomaceous earth, and the filtrate was concentrated. The residue was added to EA (100 mL), and saturated sodium bicarbonate solution (50 mL) was slowly added at room temperature. The mixture was stirred, the liquids separated, and the aqueous phase was extracted with EA (25 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the product as a light brown oil (4.8 g, 93% yield). ESI-MS m / z: 212.0 [M+H] + .

[0058] Methyl 1-(3-chloro-2-fluorobenzyl)-2-(trifluoromethyl)piperidine-4-carboxylate (1-B) 1-A (4.8 g, 22.729 mmol), 2-fluoro-3-chlorobenzyl bromide (5.59 g, 25.0 mmol), K2CO3 (9.41 g, 68.2 mmol), KI (200 mg), and ACN (100 mL) were added to a 250 mL single-neck flask. The reaction mixture was heated to reflux and stirred under an Ar atmosphere for 20 h. After completion of the reaction as detected by LC-MS, EA (50 mL) / ice (100 mL) was added to the reaction mixture. The resulting mixture was stirred, the solution was separated, and the aqueous phase was extracted with EA (50 mL). The organic phases were combined, washed with saturated sodium chloride solution, and concentrated. The residue was purified by column chromatography (EA / PE = 0 / 20 to 1 / 20) to give the product as a colorless oil (4.3 g, 53.5% yield). ESI-MS m / z: 354.0 [M+H] + .

[0059] Methyl 4-((6-bromo-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzyl)-2-(trifluoromethyl)piperidine-4-carboxylate (1-C) 1-B (4.3 g, 12.156 mmol) and anhydrous THF (86 mL) were added to a 250 mL three-neck flask, and the reaction mixture was cooled to -60 °C under an Ar atmosphere. LDA (9.1 mL, 2 M in THF, 18.2 mmol) was added slowly dropwise, maintaining the temperature below -45 °C during the addition. After the addition was complete, the mixture was stirred at -50 °C ± 10 °C for 2 h. Next, a solution of 6-bromo-2-(bromomethyl)-3-fluoropyridine (3.923 g, 14.587 mmol) in THF (20 mL) was added dropwise at -60 °C ± 10 °C. After the addition was complete, the resulting reaction mixture was stirred at -60 °C ± 10 °C for 1 h, then slowly warmed to room temperature, and allowed to react for 1 h. After the reaction was complete as detected by TLC (EA / PE = 1 / 10) and LC-MS, the reaction was stopped by adding ammonium chloride solution (50 mL) and extracted with EA (50 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (50 mL x 2), concentrated, and the residue was purified by column chromatography (EA / PE = 1 / 20 to 1 / 10) to obtain the product in the form of a light brown liquid (5.12 g, 77.9% yield). ESI-MS m / z: 541.1 / 543.1 [M+H] + .

[0060] Methyl 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-(thiazol-2-ylamino)pyridin-2-yl)methyl)-2-(trifluoromethyl)piperidine-4-carboxylate (1-D) 1-C (2 g, 3.697 mmol), 2-aminothiazole (444 mg, 4.44 mmol), anhydrous K3PO4 (1.96 g, 9.243 mmol), Xantphos (214 mg, 0.37 mmol), and dioxane (50 mL) were added to a 250 mL single-neck flask. After purging with Ar, Pd2(dba)3 (174 mg, 0.19 mmol) was added, and the reaction was heated to reflux under Ar for 12 h. After completion of the reaction as detected by LC-MS, the reaction was cooled to room temperature, filtered, and the filtrate was concentrated to dryness. The residue was purified by column chromatography (DCM / MeOH = 100 / 1 → 40 / 1) to give the product as a brown oil (1.62 g, 78.1% yield). ESI-MS m / z: 561.1 [M+H]+ .

[0061] 1-(3-chloro-2-fluorobenzyl)-4-((3-fluoro-6-(thiazol-2-ylamino)pyridin-2-yl)methyl)-2-(trifluoromethyl)piperidine-4-carboxylic acid (1). 1-D (1.62 g, 2.888 mmol), water (32 mL), and concentrated hydrochloric acid (32 mL) were added to a 100 mL single-neck flask, and the reaction mixture was refluxed at 105 °C for 20 h. After completion of the reaction as detected by LC-MS, the reaction solution was concentrated to dryness under reduced pressure, and the residue was added to ACN (30 mL). The mixture was slurried at room temperature, then suction filtered. The filter cake was washed with ACN (5 mL × 2) and dried to give the product as an off-white solid (622 mg, 39.4% yield).

[0062] 1 H NMR(400MHz,CD3OD)δ 7.75(td,J=8.8,1.5Hz,1H),7.60(dd,J=4.4,1.9Hz,1H),7.57-7.46(m,2H),7.7(m,2H),7.28(dd,J=4.4,1.7Hz,1H),7.2 6-7.20(m,1H),7.17(dd,J=8.9,3.1Hz,1H),4.92-4.85(m,1H),4.47(d,J=13.13.8Hz),4.47(m,1H),7.26-7.20(m,1H),8. 9-16(1H),8.9-16(1H),8.9-16(1H)8Hz,1H),4.26(dd,J=40.5,13.7Hz,2H),3.51-3.33(m,2H),3.23-3.17(m,1H),2.39(d d,J=15.1,9.1),4.47(dd,J=13.1Hz,1H),2.25(dd,J=15.2,4.4Hz,1H),2.17-2.04(m,1H),1.95(d,J=14.7Hz,1H);ESI-MS m / z:547.1[M+H] + .

[0063] By chiral separation, four optical isomers of compound 1 can be obtained, the structural formulas of which are as follows: [ka]

[0064] Examples 2 to 28. Synthesis of Compounds 2 to 28 The target compounds 2 to 28 were obtained according to the same synthesis method as in Example 1 using different starting materials.

[0065] [Table 1] TIFF0007777528000017.tif244168TIFF0007777528000018.tif230168TIFF0007777528000019.tif121168

[0066] Example 29. Synthesis of 1-(3-chloro-2-fluorobenzyl)-2-ethyl-4-((3-fluoro-6-(thiazol-2-ylamino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid (Compound 29) [ka]

[0067] Starting from methyl 2-hydroxymethylpyridine-4-carboxylate, the synthetic method of Example 1 was used to obtain the intermediate 2-(3-chloro-2-fluorobenzyl)-5-((3-fluoro-6-(thiazol-2-ylamino)pyridin-2-yl)methyl)-7-oxa-2-azabicyclo[3.3.1]nonyl-6-one (29-D).

[0068] 1-(3-chloro-2-fluorobenzyl)-2-ethyl-4-((3-fluoro-6-(thiazol-2-ylamino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid (29) 29-D (25 mg, 0.051 mmol), THF (2 mL), and HO (1 mL) were added to a 10 mL single-neck flask, followed by the addition of LiOH HO (10.7 mg, 0.25 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction as detected by LC-MS, the mixture was purified by flash column chromatography to give the product (18 mg, 69.3% yield).

[0069] 1 H NMR(400MHz,CDCl3)δ 7.82(t,J=8.9Hz,1H),7.75(t,J=7.8Hz,1H),7.61(d,J=4.4Hz,1H),7.61(d,J=4.4Hz,1H),7.52(t,J=6.9Hz,1H),7.41(d,J=7.9 Hz,1H),7.32(d,J=4.3Hz,1H),7.22(dd,J=8.9,3.0Hz,1H),4.3(dd,J=4.3Hz,1H),4.5(t,J=4.5Hz,1H),7.6(d,J=4.6H,2H,2H)85 -4.75(m,2H),4.47(d,J=13.6Hz,1H),4.23(d,J=11.4Hz,1H),4.01(d,J=12.0Hz,1H),3.83-3.0(m,2H),4.75(d,J=13.6Hz,1H),4 .25(m,2H),4.25(d,J=13.5Hz,1H)62(m,2H),3.51-3.41(m,2H),2.47-2.36(m,1H),2.31-2.25(m,1H),2.11-1.85(m,2H);ESI-MS m / z:509.0[M+H] + .

[0070] Example 30. Synthesis of 1-(2,3-difluorobenzyl)-2-ethyl-4-((3-fluoro-6-(thiazol-2-ylamino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid (Compound 30) [ka]

[0071] 1-(tert-butyl) 4-methyl-2-ethylpiperidine-1,4-dicarboxylate (30-A) Methyl 2-ethylpiperidine-4-carboxylate (8.94 g, 52.24 mmol), DIPEA (20.3 g, 156.72 mmol), DMAP (638 mg, 5.224 mmol), and ACN (100 mL) were added to a 250 mL one-neck flask, and a solution of BocO (14.82 g, 67.92 mmol) in ACN (30 mL) was added dropwise at room temperature. After the addition was complete, the reaction was stirred at room temperature for 3 h. After completion of the reaction as detected by LC-MS, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (EA / PE = 1 / 20 to 1 / 10) to give the product in the form of a colorless liquid (13.5 g, 95% yield). ESI-MS m / z: 272.0 [M+H] + .

[0072] 1-(tert-butyl) 4-methyl 4-((6-bromo-3-fluoropyridin-2-yl)methyl)-2-ethylpiperidine-1,4-dicarboxylic acid (30-B) 30-A (10.5 g, 38.9 mmol) and anhydrous THF (200 mL) were added to a 500 mL three-neck flask, and the reaction mixture was cooled to -60 °C under an Ar atmosphere. LDA (29.2 mL, 2 M in THF, 58.4 mmol) was added slowly dropwise, maintaining the temperature below -50 °C during the addition. After the addition was complete, the mixture was stirred at -60 °C ± 10 °C for 1.5 h. Next, a solution of 6-bromo-2-(bromomethyl)-3-fluoropyridine (12.55 g, 46.68 mmol) in THF (50 mL) was added dropwise at -60 °C ± 10 °C. After the addition was complete, the resulting reaction mixture was stirred at -60 °C ± 10 °C for 1 h, then slowly warmed to room temperature, and allowed to react for 1 h. After the reaction was complete as detected by TLC (EA / PE = 1 / 5) and LC-MS, the reaction was stopped by adding ammonium chloride solution (100 mL) and extracted with EA (100 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (100 mL x 2), concentrated, and the residue was purified by column chromatography (EA / PE = 1 / 20 to 1 / 10) to obtain the product in the form of a yellow liquid (12.87 g, 72% yield). ESI-MS m / z: 459.0 / 461.0 [M+H] + .

[0073] 1-(tert-butyl) 4-methyl-2-ethyl-4-((3-fluoro-6-(thiazol-2-ylamino)pyridin-2-yl)methyl)-piperidine-1,4-dicarboxylate (30-C) 30-B (6.2 g, 13.5 mmol), 2-aminothiazole (1.35 g, 13.5 mmol), anhydrous potassium phosphate (7.2 g, 34.0 mmol), Xantphos (780 mg, 1.35 mmol), and dioxane (100 mL) were added to a 250 mL single-neck flask. After purging with Ar, Pd2(dba)3 (617 mg, 0.675 mmol) was added, and the reaction mixture was heated to reflux under Ar for 5 h. After completion of the reaction as detected by LC-MS, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM / MeOH = 40 / 0 to 40 / 1) to give a brown solid (5.23 g, 81% yield). ESI-MS m / z: 479.2 [M+H]. + .

[0074] Methyl 2-ethyl-4-((3-fluoro-6-(thiazol-2-ylamino)pyridin-2-yl)methyl)piperidine-4-carboxylate dihydrochloride (30-D) 30-C (5 g, 10.46 mmol), DCM (20 mL), and HCl / dioxane (26 mL, 4 M, 104 mmol) were added to a 100 mL one-neck flask, and the reaction was stirred at room temperature for 20 h. After completion of the reaction as detected by LC-MS, the reaction solution was concentrated, and the residue was added to EA (30 mL). The mixture was stirred at room temperature for 30 min, filtered, and dried over anhydrous Na2SO4 to give the product in the form of a yellow solid (4.8 g, 100% yield). ESI-MS m / z: 379.2 [M+H] + .

[0075] Methyl 1-(2,3-difluorobenzyl)-2-ethyl-4-((3-fluoro-6-(thiazol-2-ylamino)pyridin-2-yl)-methyl)piperidine-4-carboxylate (30-E) 30-D (413 mg, 0.92 mmol), 1-(bromomethyl)-2,3-difluorobenzene (226 mg, 1.1 mmol), K2CO3 (632 mg, 4.58 mmol), KI (20 mg), and ACN (10 mL) were added to a 100 mL single-neck flask, and the reaction mixture was allowed to react at room temperature for approximately 2 hours. After completion of the reaction as detected by LC-MS, water (100 mL) was added to precipitate the solid. The mixture was filtered under vacuum, and the filter cake was washed with water (20 mL x 2). PE (50 mL) was added to the mixture to form a slurry, followed by vacuum filtration. The filter cake was washed with PE (20 mL x 2) and air-dried to give the product (295 mg, 64% yield). ESI-MS m / z: 505.1 [M+H] + .

[0076] 1-(2,3-Difluorobenzyl)-2-ethyl-4-((3-fluoro-6-(thiazol-2-ylamino)pyridin-2-yl)methyl)piperidine-4-carboxylic acid (30) 30-E (295 mg, 0.585 mmol), water (5 mL), and concentrated hydrochloric acid (5 mL) were added to a 100 mL one-neck flask, and the reaction mixture was refluxed at 105 °C for 20 h. After completion of the reaction as detected by LC-MS, the reaction solution was concentrated to dryness under reduced pressure, and the residue was added to ACN (30 mL). The mixture was slurried at room temperature, suction filtered, and the filter cake was washed with ACN (5 mL × 2) and air-dried to obtain the product as a pale yellow powder (118 mg, 41% yield).

[0077] 1H NMR(400MHz,DMSO-d6)δ:11.31(s,1H),9.15(s,1H),7.85-7.72(m,2H),7.59-7.45(m,1H),7.3 3-7.19(m,2H),7.05-6.92(m,2H),4.75(d,J=13.4Hz,1H),4.26-4.0(1),7.5-6.5(2),7.5-7.5 (1),7.7-7.5(1H),7.6-7.5(1H),7.6-7.6(1H),7.6-7.6(1H)10(m,1H),3.24-3.06(m,2H),2.9 6-2.73(m,2H),2.41(d,J=13.7Hz,1H),2.21-2.02(m,2H),1.92-1.56(m,4H),0.91(dt,J=10.8 7.3Hz,3H);ESI-MS m / z:491.1[M+H] + .

[0078] Examples 31 to 34: Synthesis of Compounds 31 to 34 The target compounds 31 to 34 were obtained according to the same synthesis method as in Example 30, except that the starting materials were changed.

[0079] [Table 2]

[0080] Example 35. Synthesis of 1-(3-chloro-2-fluorobenzoyl)-4-((3-fluoro-6-(thiazol-2-ylamino)pyridin-2-yl)methyl)-2-(trifluoromethyl)piperidine-4-carboxylic acid (Compound 35) [ka]

[0081] 1-(tert-butyl) 4-methyl 2-(trifluoromethyl)piperidine-1,4-dicarboxylate (35-A) Methyl 2-(trifluoromethyl)piperidine-4-carboxylate (2.11 g, 10 mmol), DIPEA (3.87 g, 30 mmol), DMAP (244 mg, 24 mmol), and CAN (50 mL) were added to a 250 mL one-neck flask, followed by the dropwise addition of a solution of BocO (3.27 g, 15 mmol) in ACN (30 mL) at room temperature. After the addition was complete, the reaction was warmed to reflux and stirred for 3 h. After completion of the reaction as detected by LC-MS, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (EA / PE = 1 / 20 to 1 / 10) to give the product as a colorless liquid (2.3 g, 74% yield). ESI-MS m / z: 312.0 [M+H] + .

[0082] 1-(tert-butyl) 4-methyl 4-((6-bromo-3-fluoropyridin-2-yl)methyl)-2-(trifluoromethyl)piperidine-1,4-dicarboxylic acid (35-B) 35-A (2.2 g, 7.07 mmol) and anhydrous THF (50 mL) were added to a 250 mL three-neck flask, and the reaction mixture was cooled to -60 °C under an Ar atmosphere. LDA (5.3 mL, 2 M in THF, 10.6 mmol) was added dropwise slowly, maintaining the temperature below -50 °C during the addition. Next, a solution of 6-bromo-2-(bromomethyl)-3-fluoropyridine (2.09 g, 7.777 mmol) in THF (50 mL) was added dropwise at -60 ± 10 °C. After the addition was complete, the resulting reaction mixture was stirred at -60 ± 10 °C for 1 h, then slowly warmed to room temperature, and reacted for 1 h. After completion of the reaction as detected by TLC (EA / PE = 1 / 5) and LC-MS, the reaction was quenched with ammonium chloride solution (100 mL) and extracted with EA (100 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (100 mL x 2), concentrated, and the residue was purified by column chromatography (EA / PE = 1 / 20 to 1 / 10) to give the product as a yellow liquid (2.58 g, 73% yield). ESI-MS m / z: 499.0 / 501.0 [M+H] + .

[0083] Methyl 4-((6-bromo-3-fluoropyridin-2-yl)methyl)-2-(trifluoromethyl)piperidine-4-carboxylate dihydrochloride (35-C) 35-B (2.5 g, 5.01 mmol), DCM (25 mL), and HCl / dioxane (12.5 mL, 4 M, 50 mmol) were added to a 100 mL one-neck flask, and the reaction was stirred at room temperature for 20 h. After completion of the reaction as detected by LC-MS, the reaction solution was concentrated, and the residue was added to EA (10 mL). The mixture was stirred at room temperature for 30 min, filtered, and dried over anhydrous Na2SO4 to give the product in the form of a yellow solid (1.68 g, 71% yield). ESI-MS m / z: 399.0 / 401.0 [M+H] + .

[0084] Methyl 4-((6-bromo-3-fluoropyridin-2-yl)methyl)-1-(3-chloro-2-fluorobenzoyl)-2-(trifluoromethyl)piperidine-4-carboxylate (35-D) 35-C (1.68 g, 3.56 mmol), DMF (30 mL), DIPEA (2.3 g, 17.8 mmol), EDCI (1.023 g, 5.34 mmol), HOBt (721 mmol, 5.34 mmol), and 3-chloro-2-fluorobenzoic acid (746 mg, 4.27 mmol) were added to a 100 mL single-neck flask and stirred at 50 °C for 20 h under an Ar atmosphere. After completion of the reaction as detected by LC-MS, EA (50 mL) and HO (50 mL) were added to the reaction mixture. The resulting reaction mixture was stirred and separated. The organic phase was concentrated to dryness, and the residue was purified by column chromatography (EA / PE = 1 / 20 to 1 / 10) to give the product (1.4 g, 71% yield). ESI-MS m / z: 555.0 / 557.0 [M+H] + .

[0085] Methyl 1-(3-chloro-2-fluorobenzoyl)-4-((3-fluoro-6-(thiazol-2-ylamino)pyridin-2-yl)-methyl)-2-(trifluoromethyl)piperidine-4-carboxylate (35-E) 35-D (200 mg, 0.36 mmol), 2-aminothiazole (36 mg, 0.36 mmol), anhydrous K2CO3 (124 g, 0.9 mmol), Xantphos (42 mg, 0.072 mmol), and dioxane (10 mL) were added to a 250 mL single-neck flask. After purging with Ar, Pd2(dba)3 (33 mg, 0.036 mmol) was added, and the reaction mixture was heated to reflux under Ar and allowed to react for 5 h. After completion of the reaction as detected by LC-MS, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (DCM / MeOH = 40 / 0 to 40 / 1) to give a brown solid (126 mg, 61% yield). ESI-MS m / z: 575.1 [M+H] + .

[0086] 1-(3-chloro-2-fluorobenzoyl)-4-((3-fluoro-6-(thiazol-2-ylamino)pyridin-2-yl)methyl)-2-(trifluoromethyl)piperidine-4-carboxylic acid (35) 35-E (120 mg, 0.208 mmol), THF (5 mL), water (2 mL), and LiOH·HO (88 mg, 2.1 mmol) were added to a 100 mL single-neck flask, and the reaction mixture was heated to 50 °C under an Ar atmosphere for approximately 5 h. After completion of the reaction as detected by LC-MS, the reaction solution was adjusted to pH 4–5 and concentrated under reduced pressure. The residue was purified by flash column chromatography to give the product as a pale yellow powder (28 mg, 24% yield).

[0087] 1H NMR(400MHz,CD3OD)δ 7.78(t,J=9.0Hz,1H),7.61-7.52(m,2H),7.41(dt,J=12.0,7.9Hz,1H),7.26(d,J=7.5Hz,1H),7.20(d ,J=4.3Hz,1H),7.12(dd,J=8.9,3.3,1H),7.24(dd,J=7.4Hz,1H),7.25(dd,J=7.5Hz,1H),7.26(dt,J= 7.4Hz,1H),7.26(dt,J=7.4Hz,1H)0Hz,1H),4.52-4.47(m,1H),4.26-4.12(m,1H),3.50-3.38(m,2H), 3.25-3.19(m,2H),2.39-2.31(m,1H),2.25-2.19(m,1H),2.11-2.04(m,1H),1.95-1.84(m,1H);ESI-MS m / z:561.1[M+H] + .

[0088] Examples 36 and 37. Synthesis of Compounds 36 and 37 The target compounds 36 and 37 were obtained according to the same synthetic method as in Example 35 using different starting materials.

[0089] [Table 3]

[0090] Example 38. Assay of inhibitory activity against Aurora kinase In vitro assays of the inhibitory activity of the compounds disclosed herein against Aurora kinase activity were performed using the caliper mobility shift method. Each compound was subjected to a gradient dilution starting from 10 μM, resulting in a total of 10 concentrations. The enzyme and kinase reaction solution (20 mM HEPES, pH 7.5, 0.01% Triton X-100) were mixed, and then the gradient-diluted compound was added. The mixture was incubated at room temperature for 10 minutes to allow the compound and enzyme to bind well. Subsequently, FAM-labeled polypeptide was added as a substrate, and the kinase reaction was carried out at 25°C. After a certain period of time, a stop solution was added. The conversion rate was read using a caliper and converted to an inhibition rate, and the IC 50The values ​​were calculated. A blank solvent containing no drug was used as a negative control, and LY-3295668 was used as a positive control. The results for the above compounds are shown in Table 4.

[0091] Example 39. Antiproliferative activity assay against H69 cells Logarithmic growth phase tumor cells (human small cell lung cancer H69 cells) were cultured in a 384-well culture plate at 4 × 10 3 Cells were seeded at 1000μL per well, 50μL of medium was added to each well, and the mixture was cultured overnight in a 37℃ / 5% CO2 incubator. After the cells attached to the wall, appropriate concentrations of the test compound and positive control drug were added to prepare five samples with different concentrations. A blank group was used as a negative control, and the resulting mixture was cultured in an incubator for 72 hours. Then, 50μL of CTL plus was added to each well, and the cell number was evaluated by measuring the amount of ATP in the cells. The IC was approximated using GRAPHPAD. 50 The values ​​were calculated and the results are shown in Table 4.

[0092] [Table 4]

[0093] From the above data, it can be seen that the compounds disclosed herein have higher activity against Aurora kinase and anti-cell proliferation activity than the control drug LY-3295668, and that the compounds of formula (1) have R 3 When the group Me is changed to a larger group or replaced with a strong electron withdrawing group such as CF3, and / or W is [ka] When the compound is in the above range, it exhibits extremely high activity against Aurora A kinase, and significantly improves activity against Aurora B kinase and antiproliferative activity against H1975 cells.

[0094] Example 40. Evaluation of antitumor activity in mice Human lung cancer H69 cells were conventionally cultured in 1640 medium containing 10% fetal bovine serum in a 37°C / 5% CO2 incubator, and passaged and harvested when the cells reached the desired number. 7 H69 cells were injected into the right dorsal region of each nude mouse, and tumors were grown to 150 mm 3 After reaching maturity, the animals were randomly assigned to groups and administered the treatment. The groups were as follows: 1) Vehicle control group: 8 animals; 2) LY-3295668 group, Compound 1 group, Compound 5 group, and Compound 6 group: 8 animals each. Mice in the vehicle control group received intragastric administration of 0.5% CMC-Na twice daily. Mice in the LY-3295668 group, Compound 1 group, Compound 5 group, and Compound 6 group received intragastric administration of the compounds suspended in 0.5% CMC-Na twice daily. Tumor volume and body weight of the mice were measured every Tuesday and Thursday, and the nude mice were sacrificed on the 21st day of administration. The test results are shown in Table 5 below.

[0095] [Table 5]

[0096] As can be seen from Table 5 above, Compound 1 and Compound 6 have significantly increased in vivo antitumor activity compared to the positive control LY-3295668. This indicates that the compound of formula (1) 3 If the group is changed from Me to a group of appropriate size, e.g., CF3 or -CH2OMe, and / or W is [ka] When the compound is

Claims

1. A compound of formula (1), or an optical isomer, crystalline form, or pharmaceutically acceptable salt thereof, 【Chemistry 1】 Here, in formula (1), "*" indicates a chiral center; L is CH ２ or CO, 【Chemistry 2】 teeth, 【Transformation 3】 and ( ３ . |!|||||!|、 【Chemistry 4】 and R ４ is F, W is 【Transformation 5】 or an optical isomer, crystalline form, or pharmaceutically acceptable salt thereof.

2. The compound is 【Transformation 6】 2. The compound of claim 1, wherein:

3. 10. An Aurora kinase inhibitor comprising the compound according to claim 1, or an optical isomer, crystalline form, or pharmaceutically acceptable salt thereof, as an active ingredient.

4. A pharmaceutical composition comprising the compound according to claim 1, or an optical isomer, crystalline form, or pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier or diluent.

5. 10. Use of the compound of claim 1, or an optical isomer, a crystalline form, or a pharmaceutically acceptable salt thereof, as an Aurora kinase inhibitor in the preparation of an antitumor medicament.

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