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WO2025239662A1 - Composés induisant la dégradation de plk1 pour conjugué agent de dégradation-anticorps - Google Patents

Composés induisant la dégradation de plk1 pour conjugué agent de dégradation-anticorps

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Publication number
WO2025239662A1
WO2025239662A1 PCT/KR2025/006502 KR2025006502W WO2025239662A1 WO 2025239662 A1 WO2025239662 A1 WO 2025239662A1 KR 2025006502 W KR2025006502 W KR 2025006502W WO 2025239662 A1 WO2025239662 A1 WO 2025239662A1
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Prior art keywords
amino
mmol
mixture
methyl
synthesis
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PCT/KR2025/006502
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English (en)
Korean (ko)
Inventor
류지훈
류수희
김성훈
민임숙
강금영
노솔희
이준규
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Uppthera Inc
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Uppthera Inc
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Publication of WO2025239662A1 publication Critical patent/WO2025239662A1/fr
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Classifications

    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems

Definitions

  • the present invention relates to a PLK1 degradation-inducing compound that can be utilized in a degrading drug-antibody conjugate, a method for producing the same, and a use thereof.
  • ADCs Antibody-drug conjugates
  • ADCs are emerging as a precision anticancer therapeutic platform that utilizes tumor-specific antibodies to selectively deliver highly toxic drugs, thereby selectively killing tumor cells and minimizing side effects on normal cells.
  • One key factor influencing the therapeutic efficacy of these ADCs is the selection of the cytotoxic drug used as the payload. Since the payload must exert toxicity after intracellular delivery and effectively block tumor cell growth, factors such as the target of action, timing of action within the cell cycle, and enzymatic specificity are crucial factors in payload selection.
  • DAC Degrader-Antibody Conjugate
  • TPD targeted protein degradation
  • PROTAC Proteolysis-Targeting Chimera
  • Polo-like kinase 1 is a key regulator of the cell cycle and is overexpressed in tumor cells, making it a key anticancer target in various cancers.
  • small-molecule PLK1 inhibitors have failed to achieve sufficient pharmacological efficacy at clinically required concentrations when administered alone or have raised clinical toxicity issues, leading to commercialization failure. Therefore, recent research has focused on developing event-driven, PROTAC-based anticancer agents that target PLK1 and are expected to exhibit sustained efficacy even at low concentrations, moving beyond the occupancy-driven mechanism of traditional inhibitors.
  • the literature [Mu, Xupeng, et al. Biochemical and biophysical research communications 521.4 (2020): 833-839.] confirmed PLK1 degradation ability and anticancer efficacy in a compound implemented as a PROTAC modality of a PLK1 inhibitor of the dihydropteridone analogue series.
  • the linker moiety of the PROTAC compound does not contain a modifiable functional group (amine group, hydroxyl group, etc.) that can be attached to an ADC linker, making it inappropriate to consider as a compound candidate that can be utilized as a payload in DAC.
  • PROTAC compounds based on dihydropteridone analogs, some of which utilize a PROTAC linker containing a functional group capable of modifying an antibody.
  • these compounds utilize a thalidomide-like moiety, which is structurally susceptible to in vivo hydrolysis. Furthermore, they only disclose the selective degradation of PLK1, without addressing the payload's key function of potent cytotoxicity.
  • PROTAC compound For a PROTAC compound to be utilized as a DAC payload that induces PLK1 degradation, it is considered that it must satisfy special conditions, such as maintaining PLK1 degradation efficacy, possessing a chemical structure that allows stable conjugation to an ADC linker connected to an antibody, and exhibiting potent cytotoxicity when delivered into tumor cells.
  • special conditions such as maintaining PLK1 degradation efficacy, possessing a chemical structure that allows stable conjugation to an ADC linker connected to an antibody, and exhibiting potent cytotoxicity when delivered into tumor cells.
  • special conditions such as maintaining PLK1 degradation efficacy, possessing a chemical structure that allows stable conjugation to an ADC linker connected to an antibody, and exhibiting potent cytotoxicity when delivered into tumor cells.
  • special conditions such as maintaining PLK1 degradation efficacy, possessing a chemical structure that allows stable conjugation to an ADC linker connected to an antibody, and exhibiting potent cytotoxicity when delivered into tumor cells.
  • the purpose of the present invention is to provide a novel PLK1 protein degradation-inducing compound that can be usefully utilized in DAC (Degrader-Antibody Conjugate).
  • Another object of the present invention is to provide a method for producing and using the PLK1 protein degradation-inducing compound.
  • the present invention provides a novel PROTAC compound for inducing PLK1 degradation based on dihydropteridone and glutarimide analogues, which has excellent cytotoxicity as a DAC payload, a method for preparing the same, and a use thereof.
  • the present invention provides a novel compound represented by the following chemical formula I:
  • R 1 is methyl, ethyl, isopropyl or cyclopentyl
  • R 2 is methyl or ethyl
  • R 3 is CH, CF, COCH 3 or N;
  • R 4 is H, F, OH, CH 3 , OCH 3 , OCH 2 CH 2 OH, OCH(CH 3 ) 2 OC(CH3) 3 or O-cyclopentyl;
  • ULM is a moiety represented by the following chemical formula II-1 or II-2 ⁇ wherein, within the moiety represents a covalent bond connecting to L 1 ⁇ ,
  • U 1 is a single bond, -NH-, -O- or -N(CH 3 )-;
  • U 2 is CH, CD or N [wherein D is deuterium];
  • U 3 and U 4 are each independently CH or N;
  • U 5 and U 6 are each independently H, F, CH 3 , OH or OCH 3 .
  • L 1 is a single bond, NH, NHCH 2 , NHCH 2 CH 2 , NHCO or NCO;
  • L 2 and L 4 are each independently cyclohexyl, piperidinyl, piperazinyl, cyclobutyl, azetidinyl, 7-azaspiro[3.5]nonyl, 2,7-diazaspiro[3.5]nonyl, hydroxypiperidinyl, 2-azaspiro[3.3]heptane, spiro[3.3]heptane, 2-azaspiro[3.3]heptane, 2-azaspiro[3.3]heptane, pyrrolidine
  • L 5 represents a covalent bond connecting to L 4 ⁇ .
  • the compound represented by the above chemical formula I is a bispecific compound implementing a PROTAC (Proteolysis targeting chimera) modality.
  • the compound is characterized by having a structure in which a moiety (PTM) that binds to the target protein PLK1 and an E3 ubiquitin ligase binding moiety (ULM) are connected by a linker molecule.
  • PTM moiety
  • ULM E3 ubiquitin ligase binding moiety
  • the compound can effectively induce inhibition and degradation of the PLK1 protein by the ubiquitin-proteasome system (UPS) in the cell by positioning the PLK1 protein and E3 ubiquitin ligase in close proximity and inducing artificial ubiquitination of the PLK1 protein.
  • UPS ubiquitin-proteasome system
  • the PLK-1 protein is an enzyme encoded by the polo-like kinase 1 (PLK1) gene.
  • the sequence of the PLK-1 protein is known in the biotechnology field, and can be referred to, for example, in the literature [NCBI Reference Sequence NP_005021.].
  • the structure of the PLK1 protein includes an N-terminal serine/threonine kinase domain and a C-terminal repeat of the polo-box domain (PBD), the phosphorylation of which is directly related to the enzymatic activity of PLK1.
  • the PLK1 protein plays an essential role in mitotic processes in tumor cells, primarily in the G2/M phase cell cycle transition, spindle formation, chromosome alignment, and segregation. It is specifically overexpressed in tumor cells. Due to these biological characteristics, inhibition of PLK1 function can induce cell cycle arrest and apoptosis. Therefore, utilizing PLK1 degraders as payloads in degrader-antibody conjugates (DACs) can be expected to have significant anticancer effects.
  • DACs degrader-antibody conjugates
  • the PLK1 binding moiety may be, for example, a moiety having a dihydropteridone-based analog structure, and the definitions of the substituents are as described above.
  • the PTM may be selected from the group consisting of the following moieties, but is not limited thereto.
  • E3 ubiquitin ligase is a protein that promotes ubiquitin transfer to a target substrate protein, and the ULM moiety described above in the compound of the present invention can bind to CRBN, i.e., Cereblon E3 ubiquitin ligase.
  • CRBN forms an E3 ubiquitin ligase complex together with DDB1, Cul4A, and ROC1, wherein CRBN is a substrate recognition subunit of the complex.
  • ULM may be selected from the group consisting of the following moieties, but is not limited thereto.
  • the ULM moiety is an E3 ubiquitin ligase binding moiety of the glutarimide family, which offers several important chemical and functional advantages over conventional IMiDs (e.g., thalidomide, lenalidomide, and pomalidomide) in PROTAC design.
  • IMiDs e.g., thalidomide, lenalidomide, and pomalidomide
  • the IMiD family of moieties has a two-ring structure consisting of a phthalimide ring and a glutarimide ring, and the phthalimide moiety is vulnerable to degradation by reactive oxygen species (ROS).
  • ROS reactive oxygen species
  • IMiDs recruit specific substrates (e.g., IKZF1, IKZF3, CK1 ⁇ , etc.) after binding to CRBN, and this substrate selectivity can sensitively vary depending on the drug structure, which can lead to unexpected off-target degradation.
  • IMiDs have limited substitution of the phthalimide ring, and structural modifications can sensitively affect the degradation function.
  • IMiDs were originally developed as immunomodulatory drugs, so there is a possibility that immune-related side effects may be raised.
  • the glutarimide-based moiety used in the ULM moiety of the present invention is chemically more stable, and thus exhibits superior in vivo metabolic stability, which may be advantageous for improving the pharmacokinetic (PK) profile. Furthermore, it can be designed to recruit CRBN while minimizing off-target substrates, thereby inducing more precise target degradation. Furthermore, N-alkyl substitution or C-position modification is relatively flexible. Therefore, as a DAC payload, it has the advantage of ensuring controllable linker attachment sites and structural diversity while minimizing immune-activating side effects.
  • the linker is a group that connects a PLK1 binding moiety (PTM) and an E3 ubiquitin ligase binding moiety (ULM), thereby allowing the E3 ubiquitin ligase protein targeted by the ULM moiety and the PLK1 protein targeted by the PTM moiety to interact with each other within an appropriate physical distance, thereby inducing ubiquitination of the target PLK1 protein.
  • PTM PLK1 binding moiety
  • ULM E3 ubiquitin ligase binding moiety
  • the linker may be, for example, the following moiety, and the definition of the substituent is as described above.
  • the above linker has a six-membered ring form in which L 2 and L 5 are connected in a para-linked form, thereby imparting rigidity to the entire linker molecule.
  • L 2 in the linker can be selected from the group consisting of the following moieties.
  • L 4 in the linker can be selected from the group consisting of the following moieties.
  • the linker may be selected from the group consisting of the following moieties, but is not limited thereto.
  • the compound represented by formula I is ULM , and R 4 may be a compound other than OCH 2 CH 2 OH.
  • the compound represented by formula I is selected from the group consisting of the following compounds.
  • the compounds of the present invention may include, in addition to compounds explicitly represented by Formula I, tautomers, optical isomers (including racemic mixtures), specific enantiomers or enantiomerically enriched mixtures thereof.
  • the compound of the present invention may be in the form of a salt thereof, preferably a pharmaceutically acceptable salt, in addition to the compound explicitly represented by Chemical Formula I.
  • the pharmaceutically acceptable salt refers to any organic or inorganic acid addition salt having a concentration that is relatively non-toxic and harmless to the patient and has an effective effect, and the side effects caused by the salt do not diminish the beneficial effects of the compound represented by Chemical Formula I.
  • the compounds of the present invention may exist in the form of chimeric molecules conjugated to a functional macromolecule via an additional chemical linker to the compound explicitly represented by Formula I.
  • the macromolecule may be a biomolecule comprising a nucleic acid, an aptamer, a carbohydrate, a peptide or a fragment thereof, or an antibody or a fragment thereof.
  • the compounds of the present invention can be prepared by synthetic methods known in the field of organic chemistry or by modification techniques apparent to those skilled in the art, for example, by the following reaction schemes 1 to 3.
  • each step may comprise one or multiple synthetic steps.
  • Isolation and purification of the product can be accomplished by standard procedures known to those skilled in the art of organic chemistry.
  • the compound represented by Chemical Formula I of the present invention can induce PLK1 protein degradation.
  • a luciferase assay experiment comparing the PLK1 protein level with that of a control cell line that was not treated with the compound confirmed the effect of inducing degradation of the target protein (Experimental Example 1; Table 2).
  • the compound represented by Chemical Formula I of the present invention exhibits a potent cancer cell killing effect through PLK1 protein degradation.
  • the compound represented by Chemical Formula I of the present invention exhibits a potent cancer cell killing effect through PLK1 protein degradation.
  • As a result of an experiment measuring the apoptotic effect after treating PLK1-expressing cancer cells with the example compound of the present invention it was confirmed that the compound effectively exhibits a cell killing effect in various cancer cells (Experimental Example 2; Tables 3 and 4).
  • the compounds of the present invention were found to have excellent anti-cancer cell killing effects in a cell killing experiment conducted on lung cancer cell lines (H69, H526) (Table 4). Furthermore, in an experiment measuring the anti-cancer cell killing effects on various cancers, including chronic myelogenous leukemia (K562), Hodgkin's lymphoma (L540), acute monocytic leukemia (THP-1), anaplastic large cell lymphoma (Karpas 299), breast cancer (MCF-7, MDA-MB-468, SK-BR-3), ovarian cancer (SKOV-3), gastric cancer (N87), non-small cell lung cancer (Calu-6), and multiple myeloma (MM1.S), effective anti-cancer cell killing effects were confirmed (Table 5).
  • K562 chronic myelogenous leukemia
  • L540 Hodgkin's lymphoma
  • THP-1 acute monocytic leukemia
  • Karpas 299 anaplastic large cell lymphoma
  • MCF-7
  • the compound of the present invention exhibits potent cancer cell killing effects, it can be utilized as a payload for antibody-drug conjugates (ADCs).
  • ADCs enable the delivery of cancer-specific cytotoxic payloads, thereby achieving maximum efficacy in cancer cells while minimizing undesirable effects in non-cancerous cells. Therefore, a degrader-antibody conjugate (DAC) utilizing the PROTAC of the present invention can be a useful strategy for significantly improving the cell permeability and bioavailability shortcomings of PROTAC compounds while also enhancing tissue and cell-type selectivity.
  • DAC degrader-antibody conjugate
  • the invention provides a pharmaceutical composition comprising a PROTAC compound of the invention, wherein the PROTAC compound is conjugated to an antibody or an antigen-binding fragment thereof via an additional linker.
  • the additional linker may be covalently linked to a functional group, such as an amine group, of an ULM of the PROTAC compound or an internal linker of the PROTAC compound.
  • the additional linker is a cleavable or non-cleavable linker.
  • the present disclosure provides an antibody-drug conjugate comprising an antibody and an antigen-binding fragment thereof and a PROTAC of the present invention, wherein the PROTAC compound is conjugated to the antibody or antigen-binding fragment thereof via a linker.
  • the PROTAC of the present invention eliminates rather than inhibits the target protein, it exhibits superior therapeutic efficacy compared to the small molecule PLK1 inhibitor from which it is derived. Accordingly, the PROTAC of the present invention, particularly when conjugated to a DAC payload, can be utilized for the treatment of PLK1-associated disorders or conditions in which abnormal expression of the PLK1 protein is involved in the onset and/or progression of the disease.
  • a PLK1-related protein-related disease refers to any disease or condition that can be treated, alleviated, delayed, inhibited, or prevented by inducing degradation or inhibiting the activity of the PLK1 protein, such as cancer.
  • the cancer includes all types of cancer that can exhibit preventive or therapeutic efficacy due to inhibition of the activity of the PLK1 protein.
  • the cancer may be a solid cancer or a blood cancer, and may be at least one selected from the group consisting of squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous cell carcinoma of the lung, peritoneal cancer, skin cancer, cutaneous or intraocular melanoma, rectal cancer, anal cancer, esophageal cancer, small intestine cancer, endocrine cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, chronic or acute leukemia, lymphocytic lymphoma, hepatocellular carcinoma, gastric cancer, stomach cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, large intestine cancer, endometrial or uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, head and neck cancer, brain
  • the pharmaceutical composition of the present invention can be formulated through a conventional method in the field of pharmaceutical science, and can be administered orally or parenterally depending on the intended method, and the dosage can be determined by taking into consideration the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of the disease.
  • the compounds of the present invention can be used to degrade PLK1 protein in a sample by treating the sample in vivo or in vitro.
  • the sample may be a cell, cell culture, or a bodily fluid or tissue of a mammal, including a human.
  • the method can be used for diagnostic or therapeutic purposes.
  • the present invention provides a method for preventing or treating a PLK1 protein-related disease, comprising administering to a patient a therapeutically effective amount of a compound represented by Chemical Formula I, preferably conjugated to a payload of DAC.
  • the PLK1 protein-related disease includes cancer.
  • novel PLK1 degradation-inducing compound of the present invention has a high cell killing effect on various cancers, and thus can be usefully utilized as a payload conjugated to a degrader-antibody conjugate (DAC) for PLK1-related diseases.
  • DAC degrader-antibody conjugate
  • LCMS data were recorded on a Shimadzu LC-20AD system equipped with an electron spray ionization (ESI) LCMS 2020 or an Agilent Single Quad system (1260).
  • ESI electron spray ionization
  • acetonitrile solvent B
  • 0.025% NH 3 ⁇ H 2 O in water (solvent A) and acetonitrile (solvent B) were used as mobile phases.
  • HALO C18 (3.0X30mm, 5um, 5.0um), XPtC-C18 (2.1X30mm, 5.0um), or Kinetex EVO C13 (2.1*30mm, 5.0um) columns were used.
  • HPLC was performed using a Shimadzu model-LC-20AB/AD system or an Agilent 1260 II LC, with 0.04% TFA in water (solvent A) and 0.02% TFA in acetonitrile (solvent B) as mobile phases.
  • the columns used were Kinetex C18 (4.6X50mm, 5um), HALO C18 (3.0X100mm, 2.7um), or Unison UK C18 (4.6X150mm, 3.0um).
  • SFC was performed on a SHIMADZU LC-30ADsf with mobile phases of CO2 (solvent A) and 0.05% DEA in isopropanol (solvent B) or 0.05% DEA in ethanol and ACN (solvent B).
  • the columns used were Chiralpak IK-3 50 ⁇ 4.6 mm, 3 ⁇ m or Chiralpak AD-3 50 ⁇ 4.6 mm, 3 ⁇ m or (S,S)Whelk-O1 50 ⁇ 4.6 mm, 3.5 ⁇ m.
  • Step 3 Synthesis of 4-(((R)-8-cyclopentyl-5,7-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-((1r,4R)-4-(4-(((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)methyl)piperidin-1-yl)cyclohexyl)-3-(2-hydroxyethoxy)benzamide (Compound 3)
  • 2,5-Difluoro-4-nitrobenzoic acid (5 g, 24.62 mmol) was added to a solution of KOH (13.81 g, 46.18 mmol) in H 2 O (100 mL), and the resulting mixture was stirred at 80 °C for 5 h.
  • Solution 1 (Methyl 5-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-fluoro-4-nitrobenzoate (2.3 g, 6.16 mmol) in THF (23 mL) and MeOH (11.5 mL).
  • the fixed bed (named FLR 1 , volume 1 mL) was packed with a granular catalyst (Pt/C (1.37 g, 1% purity)).
  • the H 2 pressure regulator was adjusted to 1.5 Mpa, and the H 2 flow rate (H 2 , 10 sccm).
  • the solution 1 was pumped by pump 1 (S 1 , P1, 0.4 mL/min) and flowed into reactor 1 (FLR 1 , SS, Fixed bed, 6.350 (1/4") mm, 1.0 mL, 50.0 °C).
  • the reaction mixture was The mixture was continuously collected from the reactor into a storage container. The peak of the target mass was confirmed by LCMS. The mixture was concentrated under reduced pressure to obtain the title compound (2.2 g, crude) as a yellow solid.
  • MS(M+H) + 344.3
  • Step 7 Synthesis of 4-(((R)-8-cyclopentyl-5,7-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-((1r,4R)-4-(4-(((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)methyl)piperidin-1-yl)cyclohexyl)-2-fluoro-5-(2-hydroxyethoxy)benzamide (Compound 9)
  • Step 8 Synthesis of 4-(((R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-((1r,4R)-4-(4-(((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)methyl)piperidin-1-yl)cyclohexyl)-3-(2-hydroxyethoxy)benzamide (Compound 10)
  • Step 8 Synthesis of N-((1r,4R)-4-(4-(((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)methyl)piperidin-1-yl)cyclohexyl)-4-(((R)-8-ethyl-5,7-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-3-methoxybenzamide (Compound 11)
  • Step 7 Synthesis of benzyl ((1r,4r)-4-(4-(((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)methyl)piperidin-1-yl)cyclohexyl)carbamate (11C)
  • Step 9 Synthesis of 4-(((R)-7,8-diethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-((1r,4R)-4-(4-(((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)methyl)piperidin-1-yl)cyclohexyl)-3-methoxybenzamide (Compound 12)
  • Step 8 Synthesis of benzyl ((1r,4r)-4-(4-(((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)methyl)piperidin-1-yl)cyclohexyl)carbamate (15)
  • the target mass peak (67%) was identified by LCMS.
  • the suspension was extracted with DCM (50 mL ⁇ 2).
  • the combined organic layer was washed with brine (50 mL ⁇ 2), dried over Na 2 SO 4 , and filtered.
  • the filtrate was concentrated under reduced pressure.
  • the mixture was filtered.
  • the filter cake was dried under reduced pressure to obtain the product (1.3 g).
  • the filtrate was concentrated under reduced pressure.
  • Solution 1 Reg 1 : Methyl 3-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-nitrobenzoate (3.98 g, 11.20 mmol) in MeOH (19.9 mL) and THF (19.9 mL).
  • Solution 1 was pumped by Pump 1 (S 1 , P1, 0.4 mL/min) and flowed into Reactor 1 (FLR 1 , SS, Fixed bed, 6.350 (1/4") mm, 1.0 mL, 50.0 °C).
  • the fixed bed (Fixed bed, named FLR 1 , volume 5 mL) was completely packed with granular catalyst Pt/C (1.5 g, 1% purity).
  • the H 2 pressure controller was adjusted to 1.5 MPa, and the H 2 flow rate was (WuXi-EHS, 10 mL/min).
  • the mixture was concentrated under reduced pressure to obtain the title compound (3.3 g, crude) as a yellow oil.
  • the residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25 mm*10 um; mobile phase: [H 2 O (0.1% TFA)-ACN]; gradient: 0%-28% B over 15.0 min), and the eluate was lyophilized.
  • the resulting suspension was extracted with EtOAc (10 mL x 3), the combined organic layers were dried over Na 2 SO 4 , filtered, the filtrate was concentrated under reduced pressure, and the residue was lyophilized.
  • Step 6 5-(((R)-8-cyclopentyl-5,7-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-((1r,4R)-4-(4-(((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)methyl)piperidin-1-yl)cyclohexyl)-4-(2-hydroxyethoxy)picolinamide (Compound 19)
  • the combined organic layer was washed with water (50 mL), dried over Na 2 SO 4 , and It was filtered. The filtrate was concentrated under reduced pressure.
  • the product was diluted with water (300 mL) and the pH was adjusted to ⁇ 2 with 15% H 2 SO 4 .
  • the suspension was filtered.
  • the filter cake was washed with water (50 mL) and dried under reduced pressure.
  • the product was diluted with DCM (150 mL) and stirred at 20 °C for 0.5 h.
  • the suspension was filtered, and the filter cake was washed with DCM (20 mL).
  • the filtrate was concentrated under reduced pressure to give the title compound (17.47 g, 79.34 mmol, 41.67% yield) as a red solid.
  • the product was diluted with water (80 mL), and the pH was adjusted to 8 with saturated NaHCO 3 .
  • the suspension was filtered, and the filter cake was washed with water (50 mL) and DCM (50 mL).
  • the filter cake was collected to obtain product A.
  • the filtrate was extracted with DCM (30 mL x 3), and the mixed organic layer was dried over Na 2 SO 4 It was filtered.
  • the filtrate was concentrated under reduced pressure to obtain product B.
  • Product A and product B were mixed to obtain the title compound (4.03 g, 17.21 mmol, 39.48% yield) as a yellow solid.
  • the filter cake was dried under reduced pressure.
  • the filter cake was washed with DCM (10 mL) and water (10 mL), and then dried under reduced pressure to obtain 5-amino-4-(4-nitrophenyl)-5-oxopentanoic acid-4-d (1.94 g, crude) as a yellow solid.
  • the filtrate was extracted with DCM (50 mL x 3) and EtOAc (20 mL x 3). The mixed organic layer was dried over Na 2 SO 4 It was filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (1.43 g, crude) as a yellow solid.
  • Product A was purified by prep-HPLC (column: Waters Xbridge C18 150*25mm*5um; mobile phase: [H 2 O (10mM NH 4 HCO 3 ) - ACN]; gradient: 1%-15% B over 15.0 min), and the eluate was lyophilized to obtain (R)-3-(4-aminophenyl)piperidine-2,6-dione-3-d (0.1 g, 467.77 ⁇ mol, 10.48% yield, 96% purity) as a white solid.
  • Step 7 Synthesis of benzyl ((1R,4r)-4-(4-(((4-((R)-2,6-dioxopiperidin-3-yl-3-d)phenyl)amino)methyl)piperidin-1-yl)cyclohexyl)carbamate (11)
  • the peak of the target mass was confirmed by LCMS.
  • the mixture was concentrated under reduced pressure.
  • the product was purified by prep-HPLC (column: Phenomenex Luna C18 150*25 mm*10um; mobile phase: [H 2 O (0.1% TFA) - ACN]; gradient: 3%-33% B over 15.0 min).
  • the eluate was lyophilized to obtain the title compound as a yellow solid (63 mg, 97.27 ⁇ mol, 60.92% yield, TFA salt).
  • Step 9 Synthesis of 4-(((R)-8-cyclopentyl-5,7-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-((1R,4R)-4-(4-(((4-((R)-2,6-dioxopiperidin-3-yl-3-d)phenyl)amino)methyl)piperidin-1-yl)cyclohexyl)-3-methoxybenzamide (Compound 20)
  • the filtrate was purified by prep-HPLC (column: Waters Xbridge C18 150*25 mm*5um; mobile phase: [H 2 O (10 mM NH 4 HCO 3 ) - ACN]; gradient: 33% - 63% B over 15.0 min), and the eluate was lyophilized to obtain product A (20.7 mg, 89% purity).
  • Product A (5.2 mg) was delivered.
  • the residue (14.5 mg) was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [H 2 O (0.225% FA) - ACN]; gradient: 8%-38% B over 10.0 min), and the eluate was lyophilized.
  • the product was diluted with water (50 mL) at 0 °C, and the pH was adjusted to 9 with saturated Na 2 CO 3 .
  • the filtrate was concentrated under reduced pressure to obtain the title compound (1.6 g, crude) as a yellow solid.
  • Step 6 4-(((R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-((1r,4R)-4-(4-(((6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)amino)methyl)piperidin-1-yl)cyclohexyl)-3-methoxybenzamide (Compound 22)
  • the target mass peak (72%) was identified by LCMS.
  • the mixture was diluted with H 2 O (20 mL) and extracted with EtOAc (10 mL x 3). The mixed organic layer was washed with brine (20 mL), dried over Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (5 g SepaFlash® silica flash column, eluent of 0–100% EtOAc/Commercial hexanes gradient @ 100 mL/min) to give the title compound (45 mg, 84.32 ⁇ mol, 16.98% yield) as a yellow solid.
  • MS (M+H) + 534.2
  • Step 1 Synthesis of benzyl ((1r,4r)-4-(4-(((4-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)methyl)piperidin-1-yl)cyclohexyl)carbamate (3)
  • 1,4-dioxa-8-azaspiro[4.5]decan-8-amine 0.3 g, 1.10 mmol, TFA salt
  • the resulting mixture was stirred at 20 °C for 1 h.
  • the peak of the target mass (41%) was confirmed by LCMS.
  • the mixture was diluted with H 2 O (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layer was washed with brine (100 mL), dried over Na 2 SO 4 , and filtered. The filtrate was concentrated under reduced pressure.
  • Solution 1 4-(2,6-Dibenzyloxy-3-pyridyl)-3-fluoro-aniline (1.6 g, 4.00 mmol) in THF (30 mL).
  • the fixed bed (named FLR 1 , volume 1 mL) was packed with a granular catalyst (Pd(OH) 2 /Al 2 O 3 (1.12 g, 399.56 ⁇ mol, 5% purity)).
  • the H 2 pressure controller was adjusted to 1 MPa, and the H 2 flow rate (H 2 , 10 sccm) was set.
  • Solution 1 was pumped by pump 1 (S 1 , P1, 0.4 mL/min) and flowed into reactor 1 (FLR 1 , SS, Fixed bed, 6.350 (1/4") mm, 1.0 mL, 50.0 °C).
  • the reaction mixture was continuously collected from the reactor into a storage vessel. The peak of the desired mass was identified by LCMS.
  • the reaction mixture was concentrated under reduced pressure. The residue was triturated with MTBE (10 mL) at 20 °C for 5 min to obtain the title compound (0.62 g, 2.43 mmol, 60.75% yield, 87% purity) as a pale pink solid.
  • MS(M+H) + 223.0
  • Solution 1 4-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methylaniline (1.6 g, 4.04 mmol) in THF (30 mL).
  • the fixed bed (named FLR 1 , volume 1 mL) was packed with a granular catalyst (Pd(OH) 2 /Al 2 O 3 (1.13 g, 403.55 ⁇ mol, 5% purity)).
  • the H 2 pressure regulator was adjusted to 1 MPa, and the H 2 flow rate (H 2 , 10 sccm) was adjusted.
  • Solution 1 was pumped by pump 1 (S 1 , P1, 0.4 mL/min) and flowed into reactor 1 (FLR 1 , SS, Fixed bed, 6.350 (1/4") mm, 1.0 mL, 50.0 °C).
  • the reaction mixture was continuously collected from the reactor into a storage vessel. The peak of the desired mass was identified by LCMS.
  • the reaction mixture was concentrated under reduced pressure. The residue was triturated with MTBE (10 mL) at 20 °C for 5 min to obtain the title compound (0.42 g, 1.69 mmol, 41.96% yield, 88% purity) as a green solid.
  • MS (M+H) + 219.0
  • Example 36 Synthesis of 4-(((R)-8-cyclopentyl-5,7-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-(4-((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)-[1,4'-bipiperidin]-1'-yl)-3-methoxybenzamide (Compound 36)
  • Example 37 Synthesis of 4-(((R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-((1r,4R)-4-(4-(2-((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)ethyl)piperidin-1-yl)cyclohexyl)-3-methoxybenzamide (Compound 37)
  • Step 3 Synthesis of 4-(((R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-((1r,4R)-4-(4-(2-((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)ethyl)piperidin-1-yl)cyclohexyl)-3-methoxybenzamide (Compound 37)
  • Solution 1 tert-Butyl (2',6'-bis(benzyloxy)-[3,3'-bipyridin]-6-yl)carbamate (500 mg, 1.03 mmol) in THF (10 mL) and i-PrOH (10 mL).
  • the fixed bed (named FLR 1 , volume 5 mL) was packed with a granular catalyst (1% Pd/C, WXC1030, 1.7 g).
  • the H 2 pressure regulator was adjusted to 0.5 MPa, and the flow rate (H 2 , WuXi-EHS, 30 mL/min).
  • solution 1 was pumped by pump 1 (S 1 , P1, 0.30 mL/min) and flowed into reactor 1 (FLR 1 , SS, fixed bed, 6.350 (1/4'') mm, 5 mL, 50 °C; residence time 3.3 min).
  • the reaction mixture was then collected from the reactor.
  • the peak of the target mass was identified by LCMS.
  • the mixture was filtered, and the filter cake was washed with THF (200 mL).
  • the filtrate was concentrated under reduced pressure.
  • the mixture was filtered, and the filter cake was dried under reduced pressure to obtain the title compound (160 mg, 524.03 ⁇ mol, 50.68% yield) as a pale yellow solid.
  • MS (M+H) + 306.2
  • the target mass peak (42%) was identified by LCMS.
  • the mixture was extracted with DCM (25 mL ⁇ 2).
  • the combined organic layers were washed with brine (20 mL ⁇ 2), dried over anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated under reduced pressure.
  • Example 40 Synthesis of 4-(((R)-8-cyclopentyl-5,7-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-(4-(2-((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)ethyl)-[1,4'-bipiperidin]-1'-yl)-3-methoxybenzamide (Compound 40)
  • the suspension was extracted with DCM (30 mL ⁇ 2), and the combined organic layer was washed with brine (30 mL ⁇ 2), dried over anhydrous Na 2 SO 4 , and filtered.
  • the filtrate was concentrated under reduced pressure.
  • the residue was purified by prep-HPLC (column: Phenomenex Luna C18 150 x 25 mm x 10 ⁇ m; mobile phase: [H 2 O (0.1% TFA) - ACN]; gradient: 15% - 45% B over 15.0 min; column Temp: 30 °C).
  • the eluate was lyophilized to obtain the title compound (400 mg, 929.07 ⁇ mol, 62.52% yield) as a yellow solid.
  • MS(M+H) + 431.3
  • the mixture was stirred at 20 °C for 1 h. After that, NaBH 3 CN (80 mg, 1.27 mmol) was added at 0 °C, and the suspension was stirred at 20 °C for 15 h. The peak of the target mass (39%) was confirmed by LCMS.
  • the reaction mixture was diluted with H 2 O (10 mL) and DCM (25 mL), and then NaHCO 3 (sat. aq, 20 mL) was added to adjust the pH to 9.
  • the mixture was extracted with DCM (25 mL ⁇ 2).
  • the mixed organic layer was washed with brine (20 mL ⁇ 2), dried over Na 2 SO 4 , and filtered. The filtrate was concentrated under reduced pressure.
  • Step 7 Synthesis of 4-(((R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-(1'-(2-((6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)amino)ethyl)-[1,4'-bipiperidin]-4-yl)-3-methoxybenzamide (Compound 44)
  • the mixture was stirred at 20 °C for 1 h. After that, NaBH(OAc) 3 (123.31 mg, 581.80 ⁇ mol), HOAc (8.73 mg, 145.45 ⁇ mol, 8.33 ⁇ L) were added at 0 °C, and the mixture was stirred at 20 °C for 15 h. The peak of the target mass was confirmed by LCMS.
  • Example 48 Synthesis of 4-(((R)-8-cyclopentyl-5,7-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-((1r,4R)-4-(4-(2-((4-((2,6-dioxopiperidin-3-yl)amino)phenyl)amino)ethyl)piperazin-1-yl)cyclohexyl)-3-methoxybenzamide (Compound 48)
  • the reaction mixture was stirred at 20 °C for 1 h. Afterwards, NaBH(OAc) 3 (400 mg, 1.89 mmol) was added at 0 °C and the mixture was stirred at 20 °C for 15 h. By LCMS The target mass peak (35%) was identified.
  • Example 50 Synthesis of 4-(((R)-8-cyclopentyl-5,7-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-((1r,4R)-4-((4-((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)piperidin-1-yl)methyl)cyclohexyl)-3-methoxybenzamide (Compound 50)
  • Step 5 Synthesis of 4-(((R)-8-cyclopentyl-5,7-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-((1r,4R)-4-((4-((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)piperidin-1-yl)methyl)cyclohexyl)-3-methoxybenzamide (Compound 50)
  • Example 51 Synthesis of 4-(((R)-8-cyclopentyl-5,7-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-(4-((4-((4-(2,6-dioxopiperidin-3-yl)phenyl)amino)piperidin-1-yl)methyl)piperidin-1-yl)-3-methoxybenzamide (Compound 51)

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Abstract

La présente invention concerne de nouveaux composés induisant la dégradation de PLK1 pour un conjugué agent de dégradation-anticorps, leur procédé de préparation et leur utilisation. Les nouveaux composés induisant la dégradation de PLK1, selon la présente invention, sont conçus pour présenter une structure de groupe fonctionnel pouvant être conjuguée à des anticorps et analogues tout en présentant un fort effet cytotoxique sur divers carcinomes, et peuvent ainsi être efficacement utilisés en tant que médicament de charge utile conjugué à un conjugué agent de dégradation-anticorps (DAC) anticancéreux.
PCT/KR2025/006502 2024-05-13 2025-05-13 Composés induisant la dégradation de plk1 pour conjugué agent de dégradation-anticorps Pending WO2025239662A1 (fr)

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KR20240062291 2024-05-13
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106543185A (zh) * 2016-11-10 2017-03-29 吉林大学 一种靶向泛素化降解plk1和brd4蛋白的化合物及其应用
CN109879877A (zh) * 2019-03-04 2019-06-14 吉林大学 一种可降解plk1和brd4蛋白的化合物及其应用
KR20210122162A (ko) * 2020-03-27 2021-10-08 (주) 업테라 Plk1 선택적 분해 유도 화합물
WO2023277583A1 (fr) * 2021-06-30 2023-01-05 (주) 업테라 Nouveau composé induisant la dégradation de la protéine plx1
KR20230024250A (ko) * 2021-08-10 2023-02-20 (주) 업테라 신규 plk1 분해 유도 화합물

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106543185A (zh) * 2016-11-10 2017-03-29 吉林大学 一种靶向泛素化降解plk1和brd4蛋白的化合物及其应用
CN109879877A (zh) * 2019-03-04 2019-06-14 吉林大学 一种可降解plk1和brd4蛋白的化合物及其应用
KR20210122162A (ko) * 2020-03-27 2021-10-08 (주) 업테라 Plk1 선택적 분해 유도 화합물
WO2023277583A1 (fr) * 2021-06-30 2023-01-05 (주) 업테라 Nouveau composé induisant la dégradation de la protéine plx1
KR20230024250A (ko) * 2021-08-10 2023-02-20 (주) 업테라 신규 plk1 분해 유도 화합물

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