WO2021110009A1 - 新型极光激酶抑制剂及其用途 - Google Patents

新型极光激酶抑制剂及其用途 Download PDF

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WO2021110009A1
WO2021110009A1 PCT/CN2020/133235 CN2020133235W WO2021110009A1 WO 2021110009 A1 WO2021110009 A1 WO 2021110009A1 CN 2020133235 W CN2020133235 W CN 2020133235W WO 2021110009 A1 WO2021110009 A1 WO 2021110009A1
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compound
alkyl
formula
pharmaceutically acceptable
aurora
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PCT/CN2020/133235
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English (en)
French (fr)
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谢雨礼
樊后兴
钱立晖
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微境生物医药科技(上海)有限公司
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Priority to CN202080056887.XA priority Critical patent/CN114222740A/zh
Priority to BR112022008717A priority patent/BR112022008717A2/pt
Priority to JP2022533482A priority patent/JP2023505239A/ja
Priority to CA3160577A priority patent/CA3160577A1/en
Priority to AU2020396753A priority patent/AU2020396753A1/en
Priority to MX2022006608A priority patent/MX2022006608A/es
Priority to KR1020227019110A priority patent/KR20220108070A/ko
Priority to US17/640,813 priority patent/US20220324857A1/en
Priority to EP20895356.2A priority patent/EP4289839A1/en
Publication of WO2021110009A1 publication Critical patent/WO2021110009A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention belongs to the field of medicinal chemistry, and more specifically, to a new compound with Aurora Kinase inhibitory effect, a preparation method thereof, and application of the compound in the preparation of anti-tumor drugs.
  • Aurora kinases are a type of threonine/serine protein kinases that play a vital role in important mitotic events such as centrosome replication, bipolar spindle formation, chromosome rearrangement, and chromosome checkpoint monitoring. [Cancer Metastasis Rev., 2003, 22, 451]. It is currently known that there are three Aurora kinase subtypes that are highly related in structure and function in human cells: Aurora-A, Aurora-B and Aurora-C. Aurora-A is located around the centrosome in the early stage of division, the microtubules near the spindle in the middle stage, and the polar microtubules in the later and terminal stages.
  • Aurora-B is located in the centromeric region of the chromosome in the early stage of mitosis, and moves from the centromere to the microtubule in the late stage. Aurora-B regulates centromere function, chromosome arrangement and separation, spindle checkpoint, cytokinesis [Mol. Cancer Ther., 2009, 8, 2046-2056]. Aurora-C is specifically expressed at high levels in the testis and may play a special role in male animals [Proc Natl Acad Sci USA, 2002, 99(24): 15440-15445.].
  • Aurora-A The gene encoding Aurora-A is located at 20q13.2, which is ubiquitously amplified in many tumors, such as breast cancer, colon cancer, ovarian cancer, and thyroid cancer.
  • Over-expression of Aurora-A in cells causes cells to display various characteristics of cancer cells such as centrosome expansion, aneuploidy, chromosomal instability, and telomere extension [J.Cell Sci.,2007,120,2987].
  • Overexpression of Aurora-A or co-expression with TPX-2 can induce chromosomal instability.
  • Aurora-A can also interfere with the functions of important tumor suppressors and pro-apoptotic proteins such as p53.
  • the phosphorylation of Ser215 by Aurora-A interferes with the normal function of p53, and the phosphorylation of Ser315 site of p53 causes the degradation of p53.
  • Aurora-B is located at 17p13.1. Unlike Aurora-A, this area has no significant expansion in many cancers except gliomas[J.Clin.Pathol.,2007,60(2):218 -221]. However, Aurora-B mRNA and protein are overexpressed in rapidly proliferating cells, such as many tumors, such as colon cancer, oral cancer, and non-small cell lung cancer. Therefore, tumor cells up-regulate the expression of Aurora family proteins in different ways.
  • the chromosome passenger protein complex (CPC) is an important complex that regulates mitosis, and Aurora-B is its core member.
  • the main substrates phosphorylated by Aurora-B include INCENP, CENP-A, Survivin, etc. Aurora-B regulates mitosis through phosphorylation of its substrates. In addition to mitosis, Aurora-B overexpression can also enhance the oncogene ras signal transduction pathway.
  • LY-3295668 is an Aurora-A kinase inhibitor containing a pyridine main ring [WO2016077161], currently in phase 1 clinical phase.
  • the structural formula of LY-3295668 is as follows:
  • LY-3295668 and other Aurora-A kinase inhibitors have some disadvantages.
  • Aurora kinase activity is not high enough, oral absorption properties are poor, and anti-tumor activity in vivo needs to be improved. Therefore, in view of the existing problems of Aurora kinase inhibitors, it is of great significance to find new Aurora inhibitors with stronger in vitro and in vivo activities.
  • the present invention aims to provide a novel Aurora Kinase inhibitor with a structure represented by formula (1), or its optical isomers, crystal forms, pharmaceutically acceptable salts or esters:
  • L is CH 2 or CO
  • R 1 and R 2 are independently H, halogen, CN, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen substituted C1-C3 alkyl, halogen substituted C1-C3 alkoxy;
  • R 3 is C2-C3 alkyl, C3-C6 cycloalkyl, halogen substituted C1-C3 alkyl, -(C1-C3)alkyl-OH, -(C1-C3)alkyl-(C1-C3)alkane Oxy, -(C1-C3)alkyl-CN or -(C1-C3)alkyl-NR 5 R 6 , wherein R 5 and R 6 are independently H or C1-C3 alkyl, or R 5 and R 6 A total of N atoms form a 4-7 membered heterocycloalkyl;
  • R 4 is H or F
  • W is Wherein R 7 is H, C1-C3 alkyl or C3-C6 cycloalkyl.
  • R 3 is the following group: Et, n- Pr, i- Pr, CH 2 F, CHF 2 , CF 3 , CH 2 OH, CH 2 OMe, CH 2 OEt, CH 2 CN,
  • W is the following group:
  • the representative compound of the present invention has one of the following structures:
  • Another object of the present invention is to provide a pharmaceutical composition, which contains a pharmacologically acceptable excipient or carrier, and the compound of formula (1) of the present invention, or each of its optical isomers, and each crystal form , Pharmaceutically acceptable salt or ester as the active ingredient.
  • Another object of the present invention provides the use of the above-mentioned compound of the present invention, or each of its optical isomers, crystal forms, pharmaceutically acceptable salts or esters, for preparing and treating Aurora-related diseases, especially anti-tumor drugs .
  • the compound of formula (1) described above can be synthesized using standard synthesis techniques or well-known techniques and methods combined in the text. In addition, the solvent, temperature and other reaction conditions mentioned here can be changed.
  • the starting materials used for the synthesis of the compounds of 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 well-known techniques and raw materials, including those found 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), Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd Ed., (Wiley 1999).
  • the general method of compound preparation can be changed by using appropriate reagents and conditions for introducing different groups in the molecular formula provided herein.
  • the compound of formula (1) described herein is according to methods well known in the art.
  • the conditions of the method such as reactants, solvents, bases, amounts of compounds used, reaction temperature, time required for the reaction, etc. are not limited to the following explanations.
  • the compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.
  • the present invention also provides a method for preparing the compound represented by formula (1), which is prepared by the following method A, method B or method C:
  • Method A includes the following steps: First, compound A is hydrogenated and reduced to compound B under a catalyst. Compound B and fragment S1 form compound C under alkaline conditions, and compound C is docked with fragment S2 under alkaline conditions to form compound D and compound D. And fragment S3 react under basic conditions and the presence of metal palladium catalysts and ligands to form compound E, and compound E undergoes ester hydrolysis under acidic or basic conditions to obtain the target compound (1a).
  • R 1 , R 2 , R 3 , R 4 , L and W are as defined above, and X is a group such as I, Br, Cl, OTf or OH.
  • Method B includes the following steps: first compound B is protected by Boc under appropriate conditions to obtain compound F, compound F reacts with fragment S2 under alkaline conditions to obtain compound G, compound G reacts with fragment S3 in the presence of a metal palladium catalyst and ligand Compound H is produced.
  • Compound H is deprotected from Boc under acidic conditions to obtain compound I.
  • Compound I reacts with fragment S1 under alkaline conditions to form compound J.
  • Compound J undergoes ester hydrolysis under acidic or alkaline conditions to obtain target compound (1b). ).
  • R 1 , R 2 , R 3 , R 4 , L and W are as defined above, and X is a group such as I, Br, Cl, OTf or OH.
  • Method C includes the following steps: First, compound G is deprotected from Boc under acidic conditions to obtain compound K, compound K is condensed with fragment S1 to obtain compound L, and compound L reacts with fragment S3 in the presence of a metal palladium catalyst and ligand to form compound M. Compound M undergoes ester hydrolysis under acidic or basic conditions to obtain the target compound (1c).
  • R 1 , R 2 , R 3 , R 4 , L and W are as defined above, and X is a group such as I, Br, Cl, OTf or OH.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • halo appearing in front of a group name means that the group is partially or fully halogenated, that is, substituted by F, Cl, Br, or I in any combination, preferably by 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 group as defined above that contains one or more halogen atom substituents.
  • C3-6 cycloalkyl refers to a non-aromatic ring group containing 3 to 6 carbon atoms.
  • C1-3 alkoxy refers to a C1-3 alkyl-O- group, which is bonded to the parent moiety through oxygen.
  • -(C1-C3)alkyl-OH, -(C1-C3)alkyl-(C1-C3)alkoxy, -(C1-C3)alkyl-CN and -(C1-C3)alkyl-NR 5 R 6 refers to the group formed by connecting the above-defined C1-C3 alkyl group with OH, (C1-C3) alkoxy, CN and NR 5 R 6 groups, and through (C1-C3) alkyl Bonded to the parent body part.
  • "4-7 membered heterocycloalkyl” refers to a non-aromatic saturated ring group containing 4 to 7 ring atoms.
  • the term "pharmaceutically acceptable salt” refers to a form of a compound that does not cause important irritation to the administered organism and does not cause the biological activity and properties of the compound to disappear.
  • the salt of the compound of the present invention refers to a salt commonly used in the field of organic chemistry.
  • the base-added salt of the carboxy group when it has a carboxyl group, or the amino group or basic heterocyclic group when it has an amino group or a basic heterocyclic group can be cited.
  • Cyclic acid salt is added salt.
  • alkali metal salts such as sodium salt and potassium salt
  • alkaline earth metal salts such as calcium salt and magnesium salt
  • ammonium salt for example, trimethylamine salt, triethylamine salt, dicyclohexylamine salt, Ethanolamine salt, diethanolamine salt, triethanolamine salt, procaine salt, N,N'-dibenzylethylenediamine salt, meglumine, arginine, lysine and other organic amine salts.
  • alkali-added salt examples include inorganic acid salts such as hydrochloride, sulfate, nitric acid, and phosphate; for example, acetate, formate, maleate, fumarate, citrate, and oxalic acid.
  • Organic acid salts such as salt, ascorbate, etc.; for example, sulfonates such as methanesulfonate, benzene cyclate, and p-toluenesulfonate.
  • references to pharmaceutically acceptable salts include solvent-added forms or crystalline forms, especially solvates or polymorphs.
  • Solvates contain stoichiometric or non-stoichiometric solvents, and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc.
  • a hydrate is formed when the solvent is water, or an alcoholate is formed when the solvent is ethanol.
  • the solvate of the compound of formula (1) is conveniently prepared or formed according to the methods described herein.
  • the hydrate of the compound of formula (1) is conveniently prepared by recrystallization from a mixed solvent of water/organic solvent.
  • the organic solvent used includes, but is not limited to, dioxane, tetrahydrofuran, ethanol or methanol.
  • the compounds mentioned here can exist in unsolvated and solvated forms. In summary, for the purposes of the compounds and methods provided herein, the solvated form is considered equivalent to the unsolvated form.
  • the compound of formula (1) is prepared in different forms, including, but not limited to, amorphous, pulverized, and nano-particle size forms.
  • the compound of formula (1) includes a crystalline form, and may also be a polymorphic form.
  • Polymorphs include different lattice arrangements of the same elemental composition of the compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal forms, optical and electrical properties, stability, and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to dominate.
  • the compound of formula (1) has one or more stereocenters and is therefore in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers appear.
  • the asymmetric centers that can exist depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible mixtures of optical isomers and diastereomers and pure or partially pure compounds are included in the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.
  • the present invention provides a method for treating Aurora kinase-mediated disorders, the method comprising the step of administering a compound of the present invention, or a pharmaceutically acceptable composition thereof, to a patient in need .
  • Cancers that can be treated with the compounds of the present invention include, but are not limited to, hematological malignancies (leukemia, lymphoma, myeloma including multiple myeloma, myelodysplastic syndrome and myelodysplastic syndrome) and solid tumors (cancers such as prostate, breast , Lung, colon, pancreas, kidney, ovary and soft tissue cancer and osteosarcoma, and stromal tumor).
  • hematological malignancies leukemia, lymphoma, myeloma including multiple myeloma, myelodysplastic syndrome and myelodysplastic syndrome
  • solid tumors cancers such as prostate, breast , Lung, colon, pancreas, kidney, ovary and soft tissue cancer and osteosarcoma, and stromal tumor.
  • the compound of the present invention and its pharmaceutically acceptable salt can be prepared into various preparations, which contain a safe and effective amount of the compound of the present invention or its pharmaceutically acceptable salt and a pharmacologically acceptable excipient or carrier. .
  • the "safe and effective amount” refers to: 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, and course of treatment of the subject to be treated.
  • “Pharmaceutically acceptable excipients or carriers” refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity . "Compatibility” here means that each component of the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
  • Examples of pharmacologically acceptable excipients or carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose,
  • the compound of the present invention when administered, it can be administered orally, rectally, parenterally (intravenous, intramuscular, or subcutaneous), or locally.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glycty
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microcapsules with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain 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.
  • the dosage form of the compound of the present invention for topical administration includes ointment, powder, patch, propellant and inhalant.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment.
  • the dosage is usually 1 to 1000 mg, preferably 10 to 500 mg.
  • the specific dosage should also consider factors such as the route of administration and the patient's health status, which are all within the skill range of a skilled physician.
  • the melting point was measured with an X-4 melting point instrument, and the thermometer was not calibrated; 1 H-NMR was recorded with a Varian Mercury400 nuclear magnetic resonance instrument, and the chemical shift was expressed in ⁇ (ppm); the unspecified silica gel for separation was 200-300 mesh , The ratio of eluent is volume ratio.
  • ACN stands for acetonitrile
  • Ar stands for argon
  • (Boc) 2 O stands for di-tert-butyl dicarbonate
  • CDCl 3 stands for deuterated chloroform
  • CD 3 OD stands for deuterated methanol
  • DCM stands for two Methyl chloride
  • DIPEA stands for diisopropylethylamine
  • Diox or Dioxane stands for 1,4-dioxane
  • DMAP stands for 4-dimethylaminopyridine
  • DMF stands for dimethylformamide
  • DMSO stands for dimethyl sulfoxide
  • EA stands for ethyl acetate
  • h stands for hours
  • K 2 CO 3 stands for potassium carbonate
  • KI stands for potassium iodide
  • K 3 PO 4 stands for potassium phosphate
  • LC-MS stands for liquid phase-mass spectrometry
  • LDA stands for lithium diisopropylamide
  • the target compound 2-28 was obtained.
  • Example 30 Using different raw materials, according to the similar synthesis method in Example 30, the target compounds 31-34 were obtained.
  • Example 35 Using different raw materials, according to the similar synthesis method in Example 35, the target compounds 36 and 37 were obtained.
  • the in vitro inhibitory activity of the compound of the present invention on Aurora kinase activity was determined by the Caliper Mobility Shift method.
  • the compound was diluted gradually starting from 10 ⁇ M to obtain a total of 10 concentrations.
  • the enzyme and kinase reaction solution (20 mM HEPES, pH 7.5, 0.01% Triton X-100)
  • the compound with gradient dilution was added.
  • After a certain period of time add the stop solution to stop.
  • use Caliper to read the conversion rate, convert it to the inhibition rate, calculate the IC 50 value, use the solvent blank without added medicine as the negative control, and LY-3295668 as the positive control.
  • the results of the above compounds are listed in Table 4.
  • Inoculate tumor cells in logarithmic growth phase human small cell lung cancer H69 cells
  • a 384-well culture plate 4 ⁇ 10 3 cells per well, add 50 ⁇ L of medium to each well, culture in an incubator at 37°C and 5% CO 2 overnight. After the cells adhere to the wall, the appropriate concentration of test compound and positive control drug are added respectively, and five different concentrations of samples are configured.
  • the blank group is used as the negative control group, and the cells are cultured in an incubator for another 72 hours. Then, add 50 ⁇ L CTL plus to each well, and evaluate the number of cells by measuring the content of ATP in the cells. GRAPHPAD was used for fitting, and IC 50 was calculated. The results are listed in Table 4.
  • the above data shows that in the compound of formula (1), compared with the control drug LY-3295668, the compound of the present invention has stronger Aurora kinase activity and anti-cell proliferation activity.
  • the R 3 group is changed from Me to a larger group Or replaced by a strong electron withdrawing group, such as CF 3 , and/or, when W is
  • the compound has very strong Aurora-A kinase activity, and at the same time, the Aurora-B kinase activity and the anti-proliferation activity of H1975 cells are greatly improved.
  • Human lung cancer H69 cells are routinely cultured in a 1640 medium containing 10% fetal bovine serum in a 37°C, 5% CO 2 incubator. After passage, when the cells reach the required amount, the cells are collected. 1 ⁇ 10 7 H69 cells were injected into the right back of each nude mouse. After the tumor grew to 150 mm 3 , the animals were randomly divided into groups to start the administration. Respectively 1) solvent control group, 8 animals; 2) LY-3295668 group, compound 1, compound 5, and compound 6 groups, each with 8 animals. The solvent control group was intragastrically administered with 0.5% CMC-Na twice a day; the LY-3295668 group, compound 1, compound 5, and compound 6 groups were intragastrically administered with 0.5% CMC-Na suspension twice a day. The tumor volume was measured every Tuesday and Thursday, and the body weight of the mice was measured. Nude mice were sacrificed on the 21st day of administration. The test results are shown in Table 5 below.

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Abstract

本发明公开了一类新型吡啶类化合物及其制备方法和用途。具体地，本发明公开了式（1）所示的化合物及其制备方法，以及式（1）化合物及其药学上可接受的盐或酯作为极光激酶（Aurora Kinase）抑制剂在抗肿瘤药物制备中的用途。

Description

新型极光激酶抑制剂及其用途
本申请要求申请日为2019年12月3日的中国专利申请CN201911256773.5的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属涉及药物化学领域，更具体而言，涉及具有极光激酶(Aurora Kinase)抑制作用的新化合物，及其制备方法和该类化合物在抗肿瘤药物制备中的用途。
背景技术
极光激酶(Aurora kinase)是一类苏氨酸/丝氨酸蛋白激酶，在中心体复制、两极纺锤体形成、染色体重排和染色体检查点监测等重要的有丝分裂事件中发挥着至关重要的作用[Cancer Metastasis Rev.,2003,22,451]。目前已知人类细胞中存在3种结构和功能高度相关的Aurora激酶亚型：Aurora-A、Aurora-B和Aurora-C。Aurora-A在分裂前期位于中心体周围、中期位于纺锤体附近的微管、后期和末期位于极性微管上。它主要负责中心体的复制和分离、双极纺锤体聚集、有丝分裂的进入和退出、对中心体的成熟和纺锤体的装配起着重要的作用[Nat.Rev.Cancer,2005,5,42]。Aurora-B在有丝分裂早期位于染色体的着丝粒区域，分裂后期则从着丝粒移到微管。Aurora-B调控着丝粒的功能、染色体排列和分离、纺锤体检测点、胞质分裂[Mol.Cancer Ther.,2009,8,2046-2056]。Aurora-C特异性的在睾丸中高水平表达，可能在雄性动物中起到特殊的作用[Proc Natl Acad Sci USA,2002,99(24):15440-15445.]。
编码Aurora-A的基因定位于20q13.2，该区域在许多肿瘤中普遍存在扩增，如乳腺癌、结肠癌、卵巢癌和甲状腺癌等。在细胞中过表达Aurora-A导致细胞显示诸如中心体扩增、非整倍体、染色体不稳定、端粒延长等多种癌细胞特征[J.Cell Sci.,2007,120,2987]。过表达Aurora-A，或者与TPX-2共表达，诱发染色体不稳定。此外，Aurora-A还会干扰重要的肿瘤抑制因子及促凋亡蛋白例如p53的功能。其中Aurora-A磷酸化Ser215干扰p53的正常功能，磷酸化p53的Ser315位点引起p53的降解。
Aurora-B位于17p13.1，与Aurora-A不同，这一区域在除了脑胶质瘤以外的很多癌症中并没有明显的扩增[J.Clin.Pathol.,2007,60(2):218-221]。然而，Aurora-B的mRNA和蛋白质在增殖迅速的细胞，例如很多肿瘤中存在过度表达，例如结肠癌、口腔癌、非小细胞肺癌。因此，肿瘤细胞通过不同的方式上调Aurora家族蛋白的表达。染色体过客 蛋白复合物(CPC)是调控有丝分裂的重要复合物，Aurora-B是其核心成员。Aurora-B磷酸化的主要底物包括：INCENP、CENP-A、Survivin等，Aurora-B通过磷酸化其底物，调节有丝分裂。除了有丝分裂外，Aurora-B过度表达还能增强致癌基因ras信号转导通路。
Aurora激酶独特的药理作用机制以及与恶性肿瘤的关系，使得它成为抗肿瘤药物研究的重要靶点，而其抑制剂也被认为是具有良好开发前景的新型抗肿瘤药物。LY-3295668是一个含吡啶主环的Aurora-A激酶抑制剂[WO2016077161]，现在处于临床1期阶段。LY-3295668的结构式如下：
Figure PCTCN2020133235-appb-000001
然而LY-3295668和其它的Aurora-A激酶抑制剂都有一些缺点，比如Aurora激酶活性不够高，口服吸收性质较差，体内抗肿瘤活性也有待提高。因此针对现有Aurora激酶抑制剂存在的问题，找到具有更强体外活性和体内活性的新型Aurora抑制剂具有重要的意义。
发明内容
本发明旨在提供结构如式(1)所示的新型Aurora Kinase抑制剂，或其各光学异构体、各晶型、药学上可接受的盐或酯：
Figure PCTCN2020133235-appb-000002
式(1)中：
“*”表示手性中心；
L为CH 2或CO；
R 1和R 2独立为H、卤素、CN、C1-C3烷基、C3-C6环烷基、C1-C3烷氧基、卤素取代C1-C3烷基、卤素取代C1-C3烷氧基；
R 3为C2-C3烷基、C3-C6环烷基、卤素取代C1-C3烷基、-(C1-C3)烷基-OH、-(C1-C3)烷基-(C1-C3)烷氧基、-(C1-C3)烷基-CN或-(C1-C3)烷基-NR 5R 6，其中R 5和R 6独立为H或C1-C3烷基，或R 5和R 6共N原子形成4-7元杂环烷基；
R 4为H或F；
W为
Figure PCTCN2020133235-appb-000003
其中R 7为H、C1-C3烷基或C3-C6环烷基。
在另一优先例中，其中所述式(1)中，
Figure PCTCN2020133235-appb-000004
为
Figure PCTCN2020133235-appb-000005
Figure PCTCN2020133235-appb-000006
在另一优先例中，其中所述式(1)中，R 3为下列基团：Et、 n-Pr、 i-Pr、
Figure PCTCN2020133235-appb-000007
CH 2F、CHF 2、CF 3、CH 2OH、CH 2OMe、CH 2OEt、CH 2CN、
Figure PCTCN2020133235-appb-000008
Figure PCTCN2020133235-appb-000009
在另一优先例中，其中所述式(1)中，W为下列基团：
Figure PCTCN2020133235-appb-000010
Figure PCTCN2020133235-appb-000011
在各种不同实施方式中，本发明代表性化合物具有以下结构之一：
Figure PCTCN2020133235-appb-000012
Figure PCTCN2020133235-appb-000013
本发明的另一个目的是提供了一种药物组合物，它含有药理上可接受的赋形剂或载 体，以及本发明的式(1)合物、或其各光学异构体、各晶型、药学上可接受的盐或酯作为活性成分。
本发明的再一个目的提供了本发明的上述化合物、或其各光学异构体、各晶型、药学上可接受盐或酯用于制备治疗Aurora相关的疾病、特别是抗肿瘤药物中的应用。
化合物的合成
下面具体地描述本发明式(1)化合物的制备方法，但这些具体方法不对本发明构成任何限制。
以上说明的式(1)化合物可使用标准的合成技术或公知的技术与文中结合的方法来合成。此外，在此提到的溶剂，温度和其他反应条件可以改变。用于表1化合物的合成的起始物料可以由合成或从商业来源上获得，如，但不限于Aldrich Chemical Co.(Milwaukee，Wis.)或Sigma Chemical Co.(St.Louis，Mo.)。本文所述的化合物和其他具有不同取代基的有关化合物可使用公知的技术和原料来合成，包括发现于March，ADVANCED ORGANIC CHEMISTRY 4 th Ed.，(Wiley 1992)；Carey和Sundberg，ADVANCED ORGANIC CHEMISTRY 4 th Ed.，Vols.A和B(Plenum 2000，2001)，Green和Wuts，PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd Ed.，(Wiley 1999)中的方法。化合物制备的一般方法可通过使用适当的试剂和在此提供的分子式中引入不同基团的条件来改变。
一方面，本文所述的式(1)化合物根据工艺中公知的方法。然而方法的条件，例如反应物、溶剂、碱、所用化合物的量、反应温度、反应所需时间等不限于下面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。一方面，本发明还提供了一种所述的式(1)所示化合物的制备方法，其采用下列方法A、方法B或方法C制备：
方法A包含下列步骤：首先化合物A在催化剂下被氢化还原成化合物B，化合物B和片段S1在碱性条件下生成化合物C，化合物C在碱性条件下与片段S2对接生成化合物D，化合物D和片段S3在碱性条件以及金属钯催化剂和配体存在下反应生成化合物E，化合物E在酸性或碱性条件下进行酯水解反应得到目标化合物(1a)。
Figure PCTCN2020133235-appb-000014
上述反应方程式中，R 1、R 2、R 3、R 4、L和W的定义如前所述，X为I、Br、Cl、OTf或OH等基团。
方法B包含下列步骤：首先化合物B在适当条件下上Boc保护得到化合物F，化合物F在碱性条件下与片段S2反应得到化合物G，化合物G在金属钯催化剂和配体存在下与片段S3反应生成化合物H，化合物H在酸性条件下脱去Boc保护得到化合物I，化合物I在碱性条件下与片段S1反应生成化合物J，化合物J在酸性或碱性条件下酯水解反应得到目标化合物(1b)。
Figure PCTCN2020133235-appb-000015
上述反应方程式中，R 1、R 2、R 3、R 4、L和W的定义如前所述，X为I、Br、Cl、OTf或OH等基团。
方法C包含下列步骤：首先化合物G在酸性条件下脱去Boc保护得到化合物K，化合物K与片段S1缩合得到化合物L，化合物L在金属钯催化剂和配体存在下与片段S3反应生成化合物M，化合物M在酸性或碱性条件下酯水解反应得到目标化合物(1c)。
Figure PCTCN2020133235-appb-000016
上述反应方程式中，R 1、R 2、R 3、R 4、L和W的定义如前所述，X为I、Br、Cl、OTf或OH等基团。
化合物的进一步形式
本专利说明书，包括附随的权利要求书中，前述的取代基具有下述含义：
“卤素”(或卤代基)是指氟、氯、溴或碘。在基团名前面出现的术语“卤代”表示该基团是部分或全部卤代，也就是说，以任意组合的方式被F，Cl，Br,或I取代，优选被F或Cl取代。“C1-3烷基”是指含有1至3个碳原子的直链或支链烷基。“C2-3烷基”是指含有2至3个碳原子的直链或支链烷基。“C1-3卤代烷基”是指如上定义的C1-3烷基中含有一个或多个卤素原子取代基。“C3-6环烷基”是指含有3至6个碳原子的非芳族环基团。“C1-3烷氧基”是指C1-3烷基-O-基团，通过氧与母体部分键接。-(C1-C3)烷基-OH，-(C1-C3)烷基-(C1-C3)烷氧基、-(C1-C3)烷基-CN和-(C1-C3)烷基-NR 5R 6是指由上述定义的C1-C3烷基分别和OH，(C1-C3)烷氧基，CN和NR 5R 6基团连接形成的基团，并通过(C1-C3)烷基与母体部分键接。“4-7元杂环烷基”是指含有4至7个环原子的非芳族饱环基团。
术语“药学上可接受的盐”指一种化合物的存在形式，该形式不会引起对给药有机体的重要的刺激，且不会使化合物的生物活性和性质消失。本发明化合物的盐指有机化学领域中所使用的惯用的盐，例如能够列举在具有羧基时的该羧基的碱添加盐、或者具有胺基或碱性杂环基时该胺基或碱性杂环基的酸添加盐的盐类。
作为该碱添加盐，可以列举例如钠盐、钾盐等碱金属盐；例如钙盐、镁盐等碱土金属盐；例如铵盐；例如三甲胺盐、三乙胺盐、二环己胺盐、乙醇胺盐、二乙醇胺盐、三乙醇胺盐、普鲁卡因盐、N,N’-二苄基亚乙基二胺盐、葡甲胺、精氨酸、赖氨酸等有机胺盐等。
作为该碱添加盐，可以列举例如盐酸盐、硫酸盐、硝酸、磷酸盐等无机酸盐；例如乙酸盐、甲酸盐、马来酸盐、富马酸盐、柠檬酸盐、草酸盐、抗坏血酸盐等有机酸盐；例如甲磺酸盐、苯环酸盐、对甲苯磺酸盐等磺酸盐等。
应理解药学上可接受的盐的参考包括溶剂添加形式或结晶形式，尤其是溶剂化物或 多晶型。溶剂化物含有化学计量或非化学计量的溶剂，且是在与药学上可接受溶剂如水，乙醇等，结晶化过程中选择性形成的。当溶剂是水时形成水合物，或当溶剂是乙醇时形成醇化物。式(1)化合物的溶剂化物按照本文所述的方法，很方便的制得或形成。举例说明，式(1)化合物的水合物从水/有机溶剂的混合溶剂中重结晶而方便的制得，使用的有机溶剂包括但不限于，二氧杂环乙烷，四氢呋喃，乙醇或甲醇。此外，在此提到的化合物能够以非溶剂化和溶剂化形式存在。总之，对于在此提供的化合物和方法为目的，溶剂化形式被认为相当于非溶剂化形式。
在其他具体实施例中，式(1)化合物被制备成不同的形式，包括但不限于，无定形，粉碎形和毫微-粒度形式。此外，式(1)化合物包括结晶型，也可以作为多晶型。多晶型包括化合物的相同元素组成的不同晶格排列。多晶型通常有不同的X-射线衍射图、红外光谱、熔点、密度、硬度、晶型、光和电的性质、稳定性和溶解性。不同的因素如重结晶溶剂，结晶速率和贮存温度可能引起单一晶型为主导。
在另一个方面，式(1)化合物有一个或多个立体中心，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式出现。可以存在的不对称中心，取决于分子上各种取代基的性质。每个这种不对称中心将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。
治疗用途
文中描述的化合物或组合物通常可用于抑制Aurora激酶，因此可用于治疗与Aurora激酶活性相关的一种或多种病症。因此，在某些实施方式中，本发明提供了用于治疗Aurora激酶介导的病症的方法，所述方法包括向有需要的患者施用本发明化合物、或其药学上可接受的组合物的步骤。
可用本发明化合物治疗的癌症包括但不限于，血液恶性肿瘤(白血病、淋巴瘤、骨髓瘤包括多发性骨髓瘤、骨髓异常增生综合症和骨髓增生姓综合症)和实体瘤(癌例如前列腺、乳腺、肺、结肠、胰腺、肾、卵巢以及软组织癌和骨肉瘤，以及间质瘤)等。
给药途径
本发明的化合物及其药学上可接受的盐可制成各种制剂，其中包含安全、有效量范围内的本发明化合物或其药学上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全、有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。化合 物的安全、有效量根据治疗对象的年龄、病情、疗程等具体情况来确定。
“药学上可以接受的赋形剂或载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能与本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药理上可以接受的赋形剂或载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2020133235-appb-000017
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
施用本发明化合物时，可以口服、直肠、肠胃外(静脉内、肌肉内或皮下)、局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～1000mg，优选10～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
在下面的说明中将会详细阐述上述化合物、方法、药物组合物的各个具体方面、特性和优势，使本发明的内容变得十分明了。在此应理解，下述的详细说明及实例描述了具体的实施例，仅用于参考。在阅读了本发明的说明内容后，本领域的技术人员可对本发明作各种改动或修改，这些等价形势同样落于本申请所限定的范围。
所有实施例中，熔点用X-4熔点仪测定，温度计未校正； 1H-NMR用Varian Mercury400核磁共振仪记录，化学位移以δ(ppm)表示；分离用硅胶未说明均为200-300目，洗脱液的配比均为体积比。
本发明采用下述缩略词：ACN代表乙腈；Ar代表氩气；(Boc) 2O代表二叔丁基二碳酸酯；CDCl 3代表氘代氯仿；CD 3OD代表氘代甲醇；DCM代表二氯甲烷；DIPEA代表二异丙基乙基胺；Diox或Dioxane代表1,4-二氧六环；DMAP代表4-二甲氨基吡啶；DMF代表二甲基甲酰胺；DMSO代表二甲基亚砜；EA代表乙酸乙酯；h代表小时；K 2CO 3代表碳酸钾；KI代表碘化钾；K 3PO 4代表磷酸钾；LC-MS代表液相-质谱；LDA 代表二异丙基氨基锂；LiOH代表氢氧化锂；mL代表毫升；MeOH代表甲醇；min代表分钟；MS代表质谱；NMR代表核磁共振；Pd 2(dba) 3代表三(二亚苄基丙酮)二钯；PE代表石油醚；PtO 2代表二氧化铂；THF代表四氢呋喃；Xantphos代表4,5-双二苯基膦-9,9-二甲基氧杂蒽。
具体实施方式
实施例1 1-(3-氯-2-氟苄基)-4-((3-氟-6-(噻唑-2-基氨基)吡啶-2-基)甲基)-2-(三氟甲基)哌啶-4-羧酸(化合物1)的合成
Figure PCTCN2020133235-appb-000018
2-(三氟甲基)哌啶-4-羧酸甲酯(1-A):
500mL单口瓶中加入2-三氟甲基吡啶-4-甲酸甲酯(5g,24.374mmol)、HOAc(100mL)和PtO 2(0.5g)，体系H 2置换三次后升温至60℃，接氢气袋剧烈搅拌反应1～3天。LC-MS监测反应完成后，体系降至室温，硅藻土助滤，滤液浓缩。残留物加入EA(100mL)，室温下缓慢倒入饱和碳酸氢钠溶液(50mL)，搅拌，分液，水相再用EA(25mL*2)萃取，合并有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液浓缩得淡棕色油状产物(4.8g,收率93％)，ESI-MS m/z:212.0[M+H] +。
1-(3-氯-2-氟苄基)-2-(三氟甲基)哌啶-4-羧酸甲酯(1-B):
250mL单口瓶中加入1-A(4.8g,22.729mmol)，2-氟-3-氯溴苄(5.59g,25.0mmol)，K 2CO 3(9.41g,68.2mmol)，KI(200mg)和ACN(100mL)，Ar保护下升至回流搅拌反应20h。LC/MS检测反应完全，体系加入EA(50mL)/水(100mL)，搅拌，分液，水相再用 EA(50mL)萃取，合并有机相用饱和氯化钠溶液洗涤，浓缩，残留物柱层析纯化(EA/PE＝0/20 to 1/20)得无色油状物(4.3g,收率53.5％)，ESI-MS m/z:354.0[M+H] +。
4-((6-溴-3-氟吡啶-2-基)甲基)-1-(3-氯-2-氟苄基)-2-(三氟甲基)哌啶-4-羧酸甲酯(1-C):
250mL三口瓶中加入1-B(4.3g,12.156mmol)和无水THF(86mL)，Ar保护下降温至-60℃，后缓慢滴加LDA(9.1mL,2M in THF,18.2mmol)，滴加过程中保持温度低于-45℃，滴毕，混合液在-50±10℃搅拌2h。再在-60±10℃下滴加6-溴-2-(溴甲基)-3-氟吡啶(3.923g,14.587mmol)的THF(20mL)溶液，滴毕，-60±10℃搅拌1h，后缓慢升至室温反应1h。TLC(EA/PE＝1/10)和LC-MS监测反应完成后，加氯化铵溶液(50mL)淬灭，EA(50mL*2)萃取，合并有机相用饱和氯化钠溶液(50mL*2)洗涤，浓缩，残留物柱层析纯化(EA/PE＝1/20 to 1/10)得淡棕色液体(5.12g,收率77.9％)，ESI-MS m/z:541.1/543.1[M+H] +。
1-(3-氯-2-氟苄基)-4-((3-氟-6-(噻唑-2-基氨基)吡啶-2-基)甲基)-2-(三氟甲基)哌啶-4-羧酸甲酯(1-D):
250mL单口瓶中加入1-C(2g,3.697mmol)，2-氨基噻唑(444mg,4.44mmol),无水K 3PO 4(1.96g,9.243mmol)，Xantphos(214mg,0.37mmol)和Dioxane(50mL)，Ar置换保护后加入Pd 2(dba) 3(174mg,0.19mmol)，Ar保护下升温至回流反应12h。LC-MS监测反应完成后，体系降至室温，过滤，滤液浓缩至干，残留物经柱层析纯化(DCM/MeOH＝100/1to 40/1)得棕色油状物(1.62g,收率78.1％)，ESI-MS m/z:561.1[M+H] +。
1-(3-氯-2-氟苄基)-4-((3-氟-6-(噻唑-2-基氨基)吡啶-2-基)甲基)-2-(三氟甲基)哌啶-4-羧酸(1):
100mL单口瓶中加入1-D(1.62g,2.888mmol)，水(32mL)，浓HCl(32mL)，105℃回流反应20h。LC/MS监测反应完全后，将反应液减压浓缩至干，残留物加ACN(30mL)室温打浆，抽滤，滤饼用ACN(5mL*2)洗涤，干燥，得类白色固体产物(622mg，收率39.4％)。
1H NMR(400MHz,CD 3OD)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),7.28(dd,J＝4.4,1.7Hz,1H),7.26-7.20(m,1H),7.17(dd,J＝8.9,3.1Hz,1H),4.92-4.85(m,1H),4.47(d,J＝13.8Hz,1H),4.26(dd,J＝40.5,13.7Hz,2H),3.51-3.33(m,2H),3.23-3.17(m,1H),2.39(dd,J＝15.1,9.1Hz,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] +.
通过手性分离的方法，可以得到化合物1的四个不同的光学异构体，结构式如下:
Figure PCTCN2020133235-appb-000019
实施例2-28 化合物2-28的合成：
采用不同原料，根据实施例1中类似的合成方法得到目标化合物2-28。
表1
Figure PCTCN2020133235-appb-000020
Figure PCTCN2020133235-appb-000021
Figure PCTCN2020133235-appb-000022
Figure PCTCN2020133235-appb-000023
Figure PCTCN2020133235-appb-000024
实施例29 1-(3-氯-2-氟苄基)-2-乙基-4-((3-氟-6-(噻唑-2-基氨基)吡啶-2-基)甲基)哌啶-4-羧酸(化合物29)的合成
Figure PCTCN2020133235-appb-000025
以2-羟甲基吡啶-4-羧酸甲酯为原料,采用实施例1中的合成方法得到中间体2-(3-氯-2-氟苄基)-5-((3-氟-6-(噻唑-2-基氨基)吡啶-2-基)甲基)-7-氧杂-2-氮杂双环[3.3.1]壬基-6-酮(29-D)。
1-(3-氯-2-氟苄基)-2-乙基-4-((3-氟-6-(噻唑-2-基氨基)吡啶-2-基)甲基)哌啶-4-羧酸(29):
10ml单口瓶中加入29-D(25mg,0.051mmol)，THF(2mL)和H 2O(1mL)，室温下加入LiOH.H 2O(10.7mg，0.25mmol)，室温搅拌2h，LC-MS监测反应完成后，混合液Flash纯化得产物(18mg,收率69.3％)。
1H NMR(400MHz,CDCl 3)δ:7.82(t,J＝8.9Hz,1H),7.75(t,J＝7.8Hz,1H),7.61(d,J＝4.4Hz,1H),7.52(t,J＝6.9Hz,1H),7.41(d,J＝7.9Hz,1H),7.32(d,J＝4.3Hz,1H),7.22(dd,J＝8.9,3.0Hz,1H),4.85-4.75(m,2H),4.47(d,J＝13.6Hz,1H),4.23(d,J＝11.4Hz,1H), 4.01(d,J＝12.0Hz,1H),3.83-3.62(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] +.
实施例30 1-(2,3-二氟苄基)-2-乙基-4-((3-氟-6-(噻唑-2-基氨基)吡啶-2-基)甲基)哌啶-4-羧酸(化合物30)的合成
Figure PCTCN2020133235-appb-000026
1-(叔丁基)4-甲基2-乙基哌啶-1,4-二羧酸酯(30-A):
250mL单口瓶中加入2-乙基哌啶-4-甲酸甲酯(8.94g,52.24mmol)，DIPEA(20.3g,156.72mmol)，DMAP(638mg,5.224mmol)和ACN(100mL)，室温下滴加Boc 2O(14.82g,67.92mmol)的ACN(30mL)溶液。滴毕，体系r.t.搅拌3h，LC-MS检测反应完成后，反应液减压浓缩，残留物经柱层析纯化(EA/PE＝1/20 to 1/10)得无色液体产物(13.5g,收率95％)，ESI-MS m/z:272.0[M+H] +。
1-(叔丁基)4-甲基4-((6-溴-3-氟吡啶-2-基)甲基)-2-乙基哌啶-1,4-二羧酸(30-B):
500mL三口瓶中加入30-A(10.5g,38.9mmol)，和无水THF(200mL)，Ar保护下降温至-60℃，后缓慢滴加LDA(29.2mL,2M in THF,58,4mmol)，滴加过程中保持温度低于-50℃，滴毕，混合液在-60±10℃搅拌1.5h。再在-60±10℃下滴加6-溴-2-(溴甲基)-3-氟吡啶(12.55g,46.68mmol)的THF(50mL)溶液，滴毕，-60±10℃搅拌1h，后缓慢升至室温反应1h。TLC(EA/PE＝1/5)和LC-MS监测反应完成后，加氯化铵溶液(100mL)淬灭，EA(100mL*2)萃取，合并有机相用饱和氯化钠溶液(100mL*2)洗涤，浓缩，残留物经柱层析纯化(EA/PE＝1/20 to 1/10)得黄色液体产物(12.87g,收率72％)，ESI-MS m/z:459.0/461.0[M+H] +。
1-(叔丁基)4-甲基2-乙基-4-((3-氟-6-(噻唑-2-基氨基)吡啶-2-基)甲基)哌啶-1,4-二羧酸 酯(30-C):
250mL单口瓶中加入30-B(6.2g,13.5mmol)，2-氨基噻唑(1.35g,13.5mmol)，无水磷酸钾(7.2g,34.0mmol)，Xantphos(780mg,1.35mmol)和Dioxane(100mL)，Ar置换保护后加入Pd 2(dba) 3(617mg,0.675mmol)，Ar保护下升温至回流反应5h。LC-MS监测反应完成后，体系减压浓缩，残留物经柱层析纯化(DCM/MeOH＝40/0 to 40/1)得棕色固体(5.23g,收率81％)，ESI-MS m/z:479.2[M+H] +。
2-乙基-4-((3-氟-6-(噻唑-2-基氨基)吡啶-2-基)甲基)哌啶-4-羧酸甲酯二盐酸盐(30-D):
100mL单口瓶中加入30-C(5g,10.46mmol)，DCM(20mL)和HCl/Dioxane(26mL,4M,104mmol)，室温下搅拌20h。LC-MS检测反应完成后，反应液浓缩，残留物加入EA(30mL)室温搅拌30min，过滤，无水Na 2SO 4干燥，得黄色固体产物(4.8g,收率100％)，ESI-MS m/z:379.2[M+H] +。
1-(2,3-二氟苄基)-2-乙基-4-((3-氟-6-(噻唑-2-基氨基)吡啶-2-基)甲基)哌啶-4-羧酸甲酯(30-E):
100mL单口瓶中加入30-D(413mg,0.92mmol)，1-(溴甲基)-2,3-二氟苯(226mg,1.1mmol)，K 2CO 3(632mg,4.58mmol)，KI(20mg)和ACN(10mL)，于r.t.反应约2h。LC/MS检测反应完全，加水(100mL)析出固体，抽滤，滤饼以水(20mLx2)洗2次后加PE(50mL)打浆，抽滤，滤饼以PE(20mL*2)洗，晾干得产物(295mg,收率64％)，ESI-MS m/z:505.1[M+H] +。
1-(2,3-二氟苄基)-2-乙基-4-((3-氟-6-(噻唑-2-基氨基)吡啶-2-基)甲基)哌啶-4-羧酸(30):
100mL单口瓶中加入30-E(295mg,0.585mmol)，水(5mL)，浓HCl(5mL)，105℃回流反应约20h。LC/MS监测反应完全后，将反应液减压浓缩至干，残留物加ACN(30mL)室温打浆，抽滤，滤饼用ACN(5mL*2)洗涤，晾干得淡黄色粉末状产物(118mg，收率41％)。
1H NMR(400MHz,DMSO-d 6)δ:11.31(s,1H),9.15(s,1H),7.85-7.72(m,2H),7.59-7.45(m,1H),7.33-7.19(m,2H),7.05-6.92(m,2H),4.75(d,J＝13.4Hz,1H),4.26-4.10(m,1H),3.24-3.06(m,2H),2.96-2.73(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] +.
实施例31-34 化合物31-34的合成：
采用不同原料，根据实施例30中类似的合成方法得到目标化合物31-34。
表2
Figure PCTCN2020133235-appb-000027
Figure PCTCN2020133235-appb-000028
实施例35 1-(3-氯-2-氟苯甲酰基)-4-((3-氟-6-(噻唑-2-基氨基)吡啶-2-基)甲基)-2-(三氟甲基)哌啶-4-羧酸(化合物35)的合成
Figure PCTCN2020133235-appb-000029
1-(叔丁基)4-甲基2-(三氟甲基)哌啶-1,4-二羧酸酯(35-A):
250mL单口瓶中加入2-(三氟甲基)哌啶-4-甲酸甲酯(2.11g,10mmol)，DIPEA(3.87g,30mmol)，DMAP(244mg,24mmol)和CAN(50mL)，室温下滴加Boc 2O(3.27g,15mmol)的ACN(30mL)溶液，滴毕，体系升至回流搅拌3h。LC-MS监测反应完成后，反应液减压浓缩，残留物经柱层析纯化(EA/PE＝1/20 to 1/10)得无色液体产物(2.3g,收率74％)，ESI-MS m/z:312.0[M+H] +。
1-(叔丁基)4-甲基4-((6-溴-3-氟吡啶-2-基)甲基)-2-(三氟甲基)哌啶-1,4-二羧酸(35-B):
250mL三口瓶中加入35-A(2.2g,7.07mmol)和无水THF(50mL)，Ar保护下降温至-60℃，后缓慢滴加LDA(5.3mL,2M in THF,10.6mmol)，滴加过程中保持温度低于-50℃，滴毕，混合液在-60±10℃搅拌1.5h。然后在-60±10℃下滴加6-溴-2-(溴甲基)-3-氟吡啶(2.09g,7.777mmol)的THF(50mL)溶液，滴毕，-60±10℃搅拌1h，后缓慢升至室温反应1h。TLC(EA/PE＝1/5)和LC-MS监测反应完成后，加氯化铵溶液(100mL)淬灭，EA(100mL*2)萃取，合并有机相用饱和氯化钠溶液(100mL*2)洗涤，浓缩，残留物经柱层析纯化(EA/PE＝1/20 to 1/10)得黄色液体产物(2.58g,收率73％)，ESI-MS m/z:499.0/501.0[M+H] +。
4-((6-溴-3-氟吡啶-2-基)甲基)-2-(三氟甲基)哌啶-4-羧酸甲酯二盐酸盐(35-C):
100mL单口瓶中加入35-B(2.5g,5.01mmol)，DCM(25mL)和HCl/Dioxane(12.5mL,4M,50mmol)，室温下搅拌20h。LC-MS监测反应完成后，反应液浓缩，残留物加入EA(10mL)室温搅拌30min，过滤，无水Na 2SO 4干燥，得黄色固体产物(1.68g,收率71％)，ESI-MS m/z:399.0/401.0[M+H] +。
4-((6-溴-3-氟吡啶-2-基)甲基)-1-(3-氯-2-氟苯甲酰基)-2-(三氟甲基)哌啶-4-羧酸甲酯(35-D):
100mL单口瓶中加入35-C(1.68g,3.56mmol)，DMF(30mL)，DIPEA(2.3g,17.8mmol)，EDCI(1.023g,5.34mmol)，HOBt(721mmol,5.34mmol)和3-氯-2-氟苯甲酸(746mg,4.27mmol)，Ar保护下50℃下搅拌反应20h。LC-MS监测反应完成后，体系加入EA(50mL)和H 2O(50mL)，搅拌，分液，有机相浓缩至干，残留物经柱层析纯化(EA/PE＝1/20 to 1/10)得产物(1.4g,收率71％)，ESI-MS m/z:555.0/557.0[M+H] +。
1-(3-氯-2-氟苯甲酰基)-4-((3-氟-6-(噻唑-2-基氨基)吡啶-2-基)甲基)-2-(三氟甲基)哌啶-4-羧酸甲酯(35-E):
250mL单口瓶中加入35-D(200mg,0.36mmol)，2-氨基噻唑(36mg,0.36mmol)，无水K 2CO 3(124g,0.9mmol)，Xantphos(42mg,0.072mmol)和Dioxane(10mL)，Ar置换保护后加入Pd 2(dba) 3(33mg,0.036mmol)，Ar保护下升温至回流反应5h。LC-MS监测 反应完成后，体系减压浓缩，残留物柱层析纯化(DCM/MeOH＝40/0 to 40/1)得棕色固体(126mg,收率61％)，ESI-MS m/z:575.1[M+H] +。
1-(3-氯-2-氟苯甲酰基)-4-((3-氟-6-(噻唑-2-基氨基)吡啶-2-基)甲基)-2-(三氟甲基)哌啶-4-羧酸(35):
100mL单口瓶中加入35-E(120mg,0.208mmol)，THF(5mL)，水(2mL)和LiOH.H 2O(88mg,2.1mmol)，Ar保护下升至50℃反应约5h。LC/MS监测反应完全后，将反应液调至pH＝4～5，减压浓缩，残留物过Flash纯化得淡黄色粉末状产物(28mg,收率24％)。
1H NMR(400MHz,CD 3OD)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＝8.9,3.0Hz,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] +.
实施例36和37 化合物36和37的合成：
采用不同原料，根据实施例35中类似的合成方法得到目标化合物36和37。
表3
Figure PCTCN2020133235-appb-000030
实施例38 Aurora激酶抑制活性的测试
本发明化合物对于Aurora激酶活性在体外的抑制活性测定通过Caliper Mobility Shift方法测定。化合物从10μM开始进行梯度稀释，总共得到10个浓度。将酶和激酶反应液(20mM HEPES,pH 7.5,0.01％Triton X-100)混合后，加入梯度稀释的化合物。在室温孵育10分钟，让化合物和酶充分结合。然后加入FAM标记的多肽作为底物在25℃进行激酶反应，一定时间后，加入终止液终止。然后采用Caliper读取转化率，换算成抑制率， 计算IC 50值，以不加药的溶剂空白作为阴性对照，以LY-3295668作为阳性对照。上述各化合物的结果列于表4中。
实施例39 H69细胞抗增殖活性的测试
把对数生长期的肿瘤细胞(人小细胞肺癌H69细胞)接种于384孔培养板；每孔4×10 3个细胞，每孔加入培养基50μL，37℃，5％CO 2培养箱中培养过夜。待细胞贴壁后，分别加入适当浓度的受试化合物和阳性对照药物，配置五种不同浓度的样品，以空白组为阴性对照组，在培养箱中再培养72h。然后，每孔加入50μL CTL plus,通过测量细胞中ATP的含量评价细胞的数量。用GRAPHPAD进行拟合，计算IC 50，结果列于表4中。
表4.本发明部分化合物对Aurora激酶活性和对H69细胞的抗增殖活性
Figure PCTCN2020133235-appb-000031
以上数据说明式(1)化合物中，和对照药物LY-3295668相比，本发明化合物具有更强的Aurora激酶活性和抗细胞增殖活性，当R 3基团从Me改变成一个比较大的基团或者强吸电子基团所取代，比如CF 3，和/或者，当W是
Figure PCTCN2020133235-appb-000032
基团时，化合物具有极强的Aurora-A激酶活性，同时Aurora-B激酶活性和H1975细胞抗增殖活性得到大 幅提高。
实施例40 小鼠体内抗肿瘤活性评价
人肺癌H69细胞用含10％胎牛血清的1640培养基于37℃、5％CO 2培养箱中常规培养，传代后，待细胞达到所需量时，收集细胞。将1×10 7个H69细胞注射入每只裸小鼠右侧背部，待肿瘤生长至150mm 3后，将动物随机分组开始给药。分别为1)溶剂对照组，8只；2)LY-3295668组、化合物1组、化合物5组和化合物6组，每组8只。溶剂对照组每天两次灌胃0.5％CMC-Na；LY-3295668组、化合物1组、化合物5组和化合物6组每天两次灌胃化合物0.5％CMC-Na悬浮液。每周二、四测定肿瘤体积，测量小鼠体重，于给药第21天处死裸小鼠，试验结果见下表5。
表5.化合物对人非小细胞肺腺癌NCI-H69裸小鼠移植瘤的实验治疗作用
化合物 剂量(mg/kg) 给药方案 抗肿瘤作用
1 20 bid*21 29％退缩
5 20 bid*21 9％退缩
6 20 bid*21 30％退缩
LY-3295668 20 bid*21 15％退缩
从上表5可以看出，化合物1、化合物6和阳性对照LY-3295668相比，体内抗肿瘤活性明显增强，说明式(1)化合物中，当R 3基团从Me改变成适当大小的基团所取代，比如CF 3或-CH 2OMe，和/或者，当W是
Figure PCTCN2020133235-appb-000033
基团时，化合物的体内抗肿瘤活性得到大幅提高。

Claims (8)

  1. 一种结构如式(1)所示的化合物或其各光学异构体、各晶型、药学上可接受的盐或酯：
    Figure PCTCN2020133235-appb-100001
    式(1)中：
    “*”表示手性中心；
    L为CH 2或CO；
    R 1和R 2独立为H、卤素、CN、C1-C3烷基、C3-C6环烷基、C1-C3烷氧基、卤素取代C1-C3烷基、卤素取代C1-C3烷氧基；
    R 3为C2-C3烷基、C3-C6环烷基、卤素取代C1-C3烷基、-(C1-C3)烷基-OH、-(C1-C3)烷基-(C1-C3)烷氧基、-(C1-C3)烷基-CN或-(C1-C3)烷基-NR 5R 6，其中R 5和R 6独立为H或C1-C3烷基，或R 5和R 6共N原子形成4-7元杂环烷基；
    R 4为H或F；
    W为
    Figure PCTCN2020133235-appb-100002
    其中R 7为H、C1-C3烷基或C3-C6环烷基。
  2. 如权利要求1所述的化合物，其中所述式(1)中，
    Figure PCTCN2020133235-appb-100003
    为
    Figure PCTCN2020133235-appb-100004
    Figure PCTCN2020133235-appb-100005
    Figure PCTCN2020133235-appb-100006
  3. 如权利要求1或2所述的化合物，其中所述式(1)中，R 3为下列基团：Et、 n-Pr、 i-Pr、
    Figure PCTCN2020133235-appb-100007
    CH 2F、CHF 2、CF 3、CH 2OH、CH 2OMe、CH 2OEt、CH 2CN、
    Figure PCTCN2020133235-appb-100008
    Figure PCTCN2020133235-appb-100009
  4. 如权利要求1-3中任一项所述的化合物，其中所述式(1)中，W为下列基团：
    Figure PCTCN2020133235-appb-100010
    Figure PCTCN2020133235-appb-100011
  5. 如权利要求1-4中任一项所述的化合物，或其一种药学上可接受的盐或酯，其中所述化合物具有以下结构之一：
    Figure PCTCN2020133235-appb-100012
    Figure PCTCN2020133235-appb-100013
    Figure PCTCN2020133235-appb-100014
  6. 以权利要求1-5中任一项所述的化合物、或其各光学异构体、各晶型、药学上可接受的盐或酯作为有效成分的极光激酶抑制剂。
  7. 一种药物组合物，其包含如权利要求1-5中任一项所述的化合物、其各光学异构体、各晶型、药学上可接受的盐或酯作为活性成分，并含有可药用载体或稀释剂。
  8. 一种如权利要求1-5中任一项所述的化合物、或其各光学异构体、各晶型、药学上可接受的盐或酯作为极光激酶抑制剂在抗肿瘤药物制备中的用途。
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