WO2022060094A1 - 피리미도 피리미디논 화합물 및 그를 포함하는 약제학적 조성물 - Google Patents

피리미도 피리미디논 화합물 및 그를 포함하는 약제학적 조성물 Download PDF

Info

Publication number
WO2022060094A1
WO2022060094A1 PCT/KR2021/012616 KR2021012616W WO2022060094A1 WO 2022060094 A1 WO2022060094 A1 WO 2022060094A1 KR 2021012616 W KR2021012616 W KR 2021012616W WO 2022060094 A1 WO2022060094 A1 WO 2022060094A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
compound
benzamide
pyridin
oxo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2021/012616
Other languages
English (en)
French (fr)
Korean (ko)
Inventor
박영준
박성준
유혜빈
송현남
윤시은
박소진
김준우
윤성일
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Axceso Biopharma Co Ltd
Original Assignee
Axceso Biopharma Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Axceso Biopharma Co Ltd filed Critical Axceso Biopharma Co Ltd
Priority to IL300920A priority Critical patent/IL300920A/en
Priority to EP21869716.7A priority patent/EP4215533B1/en
Priority to US18/245,395 priority patent/US12590098B2/en
Priority to JP2023515773A priority patent/JP7824667B2/ja
Priority to CN202180063334.1A priority patent/CN116137815B/zh
Priority to MX2023003087A priority patent/MX2023003087A/es
Priority to AU2021344164A priority patent/AU2021344164A1/en
Priority to CA3190461A priority patent/CA3190461A1/en
Priority to BR112023004179A priority patent/BR112023004179A2/pt
Publication of WO2022060094A1 publication Critical patent/WO2022060094A1/ko
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a pyrimido pyrimidinone compound and a pharmaceutical composition comprising the same, and more particularly, to a pyrimido pyrimidinone compound having an effect of inhibiting PD-L1 expression and a pharmaceutical composition comprising the same as an active ingredient it's about
  • PD-1 Programmed death-1, CD279
  • CD274 Programmed death-Ligand 1
  • PD-L2 Programmed death-ligand 2, CD273
  • PD-1 and PD-L1/2 interactions downregulate immune responses in infections, tumors, or autoimmune diseases (Keir Me, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu. Rev. Immunol. 2008; 26).
  • Blocking the PD-1/PD-L1 interaction with antibodies to PD-1 and PD-L1 has been shown to restore and enhance T cell activation in many systems.
  • cancer patients such as melanoma, non-small cell lung cancer, and renal cancer
  • the binding inhibition therapy of PD-1/PD-L1 using a monoclonal antibody, etc. are known.
  • ⁇ v ⁇ 3-integrin-targeted PD-L1 expression in cancer cells and regulation of immune anticancer response ⁇ 3-integrin-depleted tumor cell transplantation dramatically reduced the growth of primary tumors, and the result was attributed to decreased PD-L1 expression. It was found that inhibition of ⁇ 3-integrin can increase the efficacy of melanoma immunotherapy (Proc Natl Acad Sci USA., 2019 Oct 1, 116(40), 20141-20150). It is known that retinoblastoma protein RB, known as a tumor suppressor, exhibits anticancer efficacy by inhibiting PD-L1 expression by inhibiting NF-kB activity.
  • curcumin and apigenin showed growth inhibitory effects on melanoma cells.
  • apigenin significantly inhibited IFN- ⁇ -induced PD-L1 expression.
  • the expression of PD-L1 induced by IFN- ⁇ in the lung cancer cell line A549 pretreated with EGCG and green tea extract (GTE) is reduced by 40 to 80%.
  • Regorafenib was the most potent among about 20 drugs that reduced the cell surface PD-L1 expression level by more than 50%. It was identified as an effective drug.
  • the drug strongly promotes anti-tumor efficacy when combined with IFN- ⁇ or immune checkpoint blockers (ICB) in cells and in vivo, and strongly inhibits JAK1/2-STAT1 and MAPK signaling followed by induction by IFN- ⁇ It is known to decrease PD-L1 and IDO1 expression (Clin Cancer Res., 2019 Jul 15, 25(14), 4530-4541).
  • 3,4-dihydropyrimido[4,5-d]pyrimidin-2-one derivatives as protein kinase inhibitors are Abl, BCR-Abl, Bmx, c-Raf, Csk, Fes, FGFR, Flt3, Ikk, IR , JNK, Lck, Mkk, PKC, PKD, Rsk, SAPK, Syk, Trk, RTK, Src, EGFR, IGF, Mek, Ros, are known as inhibitors of Tie2 kinase activity, but the effect of this derivative on PD-L1 There is no mention of In addition, it is known that the 3-phenyl-dihydropyrimido[4,5-d]pyrimidinone derivative exhibits inhibitory activity of 1 to 5nM (IC 50 ) on Src kinase, but also mentions the effect on PD-L1 not (International Patent Publication No. WO 2005/011597).
  • One object of the present invention is to provide a compound of formula (I) or a pharmaceutically acceptable salt thereof, which exhibits an effect of inhibiting PD-L1 expression.
  • Another object of the present invention is to provide a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • One embodiment of the present invention relates to a pyrimido pyrimidinone compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.
  • R 1 is a C 5 -C 15 aryl group, a C 5 -C 15 heteroaryl group, a C 3 -C 10 cycloalkyl group, or a C 3 -C 10 heterocycloalkyl group,
  • R 2 is hydrogen, a C 1 -C 4 alkyl group or a C 1 -C 4 alkoxy group
  • R 3 is hydrogen, halogen, C 1 -C 4 alkyl group or C 1 -C 4 alkoxy group
  • R 4 is a C 1 -C 4 alkyl group, a C 1 -C 4 haloalkyl group, or an unsubstituted C 5 -C 15 aryl group or C 5 -C 15 heteroaryl group substituted with a C 5 -C 15 heteroaryl group It is an aryl group.
  • the C 5 -C 15 aryl group includes both an aromatic group and a partially reduced derivative thereof.
  • the aromatic group is a simple or fused cyclic type having 5 to 15 carbon atoms.
  • Representative examples of the aryl group include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, and the like.
  • the C 5 -C 15 heteroaryl group includes both a heteroaromatic group and a partially reduced derivative thereof.
  • the heteroaromatic group is a simple or fused cyclic type consisting of 5 to 15 carbon atoms, and includes at least one oxygen, sulfur or nitrogen.
  • Examples of representative heteroaryl groups include pyridinyl, furanyl, thiophenyl, indolyl, quinolinyl, imidazolinyl, oxazolyl ( oxazolyl), dihydrooxazolyl, thiazolyl, and the like, but are not limited thereto.
  • a C 3 -C 10 cycloalkyl group refers to a simple or fused cyclic hydrocarbon consisting of 3 to 10 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. are included, but limited thereto it's not going to be
  • a C 3 -C 10 heterocycloalkyl group refers to a functional group in which at least one of the ring carbons of a simple or fused cyclic hydrocarbon consisting of 3 to 10 carbon atoms is substituted with oxygen, sulfur or nitrogen, for example, thiazolidinyl, oxiranyl, and the like.
  • C 1 -C 4 Alkyl group refers to a linear or branched monovalent hydrocarbon having 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl , i-butyl, t-butyl, and the like are included, but are not limited thereto.
  • the C 1 -C 4 alkoxy group refers to a straight-chain or branched alkoxy group having 1 to 4 carbon atoms, and includes, but is not limited to, methoxy, ethoxy, n-propanoxy, and the like.
  • a C 1 -C 4 haloalkyl group refers to a straight-chain or branched hydrocarbon having 1 to 4 carbon atoms substituted with one or more halogens selected from the group consisting of fluorine, chlorine, bromine and iodine, for example, trifluoromethyl, trichloromethyl, trifluoroethyl, and the like.
  • the compound of formula (I) is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 1 is phenyl unsubstituted or substituted with halogen or hydroxy
  • R 2 is a C 1 -C 4 alkyl group
  • R 3 is hydrogen, halogen, C 1 -C 4 alkyl group or C 1 -C 4 alkoxy group
  • R 4 is a C 1 -C 4 alkyl group, a C 1 -C 4 haloalkyl group, phenyl unsubstituted or substituted with alkyldihydrooxazolyl, or alkylthiazolyl.
  • Alkyldihydrooxazolyl as used herein means a dihydrooxazole group substituted with one or more C 1 -C 4 alkyl groups, and includes, but is not limited to, dimethyldihydrooxazolyl.
  • Alkylthiazolyl as used herein means a thiazolyl group substituted with one or more C 1 -C 4 alkyl groups, and includes, but is not limited to, t-butylthiazolyl.
  • the compound of formula (I) is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 1 is phenyl, fluorophenyl or hydroxyphenyl
  • R 2 is methyl
  • R 3 is hydrogen, chloro, bromo, methyl or methoxy
  • R 4 is trifluoromethylphenyl, t-butylphenyl, dimethyldihydrooxazolylphenyl or t-butylthiazolyl.
  • Pharmaceutically acceptable salts herein may include both non-toxic inorganic acid salts and organic acid salts, for example, hydrochloride, phosphate, sulfate, nitrate, tartrate, methanesulfonate, p-toluenesulfonate, acetate, tri Fluoroacetate, citrate, maleate, succinate, oxalate, benzoate, tartrate, fumarate, manderate, propionate, citrate, lactate, glycolate, gluconate, galacturate, glutamate , glutarate, glucurate, aspartate, ascorbate, carbonate, vanillic acid, hydroiodic acid, malate, malonate, and the like.
  • organic acid salts for example, hydrochloride, phosphate, sulfate, nitrate, tartrate, methanesulfonate, p-toluenesulfonate, acetate, tri Fluoroacetate, citrate,
  • Representative compounds of the compounds of the present invention are selected from the following groups.
  • a method for preparing the compound of Formula I of the present invention is shown in Scheme 1 below.
  • the method described in the following scheme is merely an example of the method typically used in the present invention, and the order of unit operations, reaction reagents, reaction conditions, etc. may be freely changed depending on the case.
  • Scheme 1 shows a four-step preparation process for preparing a compound of Formula I using a compound of Formula II and a compound of Formula III as starting materials.
  • a compound of formula (IV) is obtained by reacting a compound of formula (II) with a compound of formula (III).
  • the compound of formula IV is obtained by amination reaction in the presence of an organic base.
  • organic base triethylamine, N,N-diisopropylethylamine (DIPEA), etc.
  • DIPEA diethylamine
  • the reducing agent is sodium borohydride (sodium borohydride, NaBH 4 ), sodium cyanoborohydride Ride (NaCNBH 3 ), sodium triacetoxy borohydride (Na(CH 3 COO) 3 BH), and the like may be used.
  • reaction solvent acetonitrile, tetrahydrofuran, 1,4-dioxane, chloroform, dichloromethane, 1,2-dichloroethane, dimethylformamide, dimethylacetamide, methyl alcohol, ethyl alcohol, etc. It can be used, and the reaction temperature is preferably -10 ⁇ 25 °C.
  • the heterocyclic urea formation reaction may be performed in the presence of an organic base.
  • organic base triethylamine, N,N-diisopropylethylamine (DIPEA), and the like may be used.
  • reaction solvent acetonitrile, tetrahydrofuran, 1,4-dioxane, etc. may be used, and the reaction temperature is preferably -10 to 100°C.
  • the sulfone group of the compound of formula (V) is oxidized to obtain a sulfone compound of formula (VI) having a sulfone group.
  • the oxidation reaction may be performed using oxone, meta-chloroperoxybenzoic acid (mCPBA), or the like as an oxidizing agent.
  • mCPBA meta-chloroperoxybenzoic acid
  • reaction solvent dichloromethane, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, 1,4-dioxane, water, etc.
  • reaction temperature is preferably -10 to 100°C. .
  • the compound of formula (I) is obtained by substituting an amine compound of formula (VII) with the compound of formula (VI).
  • reaction solvent acetonitrile, tetrahydrofuran, 1,4-dioxane, chloroform, dichloromethane, 1,2-dichloroethane, ethyl acetate, dimethylformamide, methyl alcohol, ethyl alcohol, etc.
  • an organic base or an inorganic base such as triethylamine, N,N-diisopropylethylamine, and pyridine may be used together, or an organic acid such as trifluoroacetic acid may be used together as needed, and the reaction
  • the temperature is 50 to 150°C, more preferably 80°C to 100°C.
  • the compound of formula (II) and compound of formula (III) may be prepared and used according to a known method or may be used by obtaining a commercially available product.
  • the compound of Formula II is obtained by reacting ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate with an amine compound of Formula XIII to obtain a compound of Formula VIII, , the compound of formula VIII is reduced by using a reducing agent such as lithium aluminum hydride (LiAlH 4 ) to obtain a compound of formula IX, and then the alcohol group of the compound of formula IX is thionyl chloride (SOCl 2 ), etc. It can be prepared by halogenation or by oxidation reaction using manganese dioxide (MnO 2 ) to aldehyde.
  • a reducing agent such as lithium aluminum hydride (LiAlH 4 )
  • SiAlH 4 lithium aluminum hydride
  • SOCl 2 thionyl chloride
  • R 3 and R 4 are as defined in Formula I, and Y is halogen or hydroxy.
  • Y is chloro, bromine, iodine or hydroxy, in particular chloro or hydroxy.
  • the compound of Formula III is prepared by reacting a compound of Formula X with a compound of Formula XI in the presence of an organic base such as DIPEA or a coupling agent to obtain a compound of Formula XII, It can be prepared by reducing the nitro group of the compound to an amine group.
  • the reduction reaction may be performed using a combination of potassium t-butoxide and bis(pinacolato)diboron, or hydrogen gas under a palladium carbon catalyst.
  • the compound of Formula III can be prepared by reacting a diamine pyridine compound of Formula X' with a compound of Formula XI in the presence of an organic base such as DIPEA or a coupling agent, as shown in Scheme 4 above. .
  • the compound of Formula I or a pharmaceutically acceptable salt thereof according to the present invention exhibits excellent PD-L1 expression inhibitory activity (Test Example 1).
  • the present invention provides an agent for inhibiting programmed death-ligand 1 (PD-L1) comprising the compound of Formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. It relates to a pharmaceutical composition, specifically, a pharmaceutical composition for the treatment or prevention of cancer.
  • PD-L1 programmed death-ligand 1
  • the compound of Formula I or a pharmaceutically acceptable salt thereof induces an anticancer effect through activation of immune cells by inhibiting the expression of PD-L1, thereby causing colon cancer, lung cancer, breast cancer, gastric cancer , cervical cancer, bladder cancer, blood cancer, or non-Hodgkin's lymphoma.
  • the pharmaceutical composition according to the present invention may be administered orally (eg, ingestion or inhalation) or parenterally (eg, injection, deposition, implantation, suppository), and the injection is administered, for example, intravenously , may be subcutaneous injection, intramuscular injection or intraperitoneal injection.
  • the pharmaceutical composition according to the present invention can be administered as a tablet, capsule, granule, fine subtilae, powder, sublingual tablet, suppository, ointment, injection, emulsion, suspension, syrup, spray, etc., depending on the route of administration. can be formulated.
  • the various types of the pharmaceutical composition according to the present invention can be prepared by known techniques using a pharmaceutically acceptable carrier commonly used for each formulation.
  • Examples of pharmaceutically acceptable carriers include excipients, binders, disintegrating agents, lubricants, preservatives, antioxidants, isotonic agents, buffers, coating agents, sweetening agents, solubilizing agents, bases, dispersing agents, wetting agents , suspending agents, stabilizing agents, coloring agents, and the like.
  • the pharmaceutical composition according to the present invention varies depending on the form of the drug, but contains the compound of the present invention or a pharmaceutically acceptable salt thereof in an amount of about 0.01 to 95% by weight.
  • the specific dosage of the pharmaceutical composition of the present invention may vary depending on the type of mammal, including the human being, to be treated, weight, sex, degree of disease, judgment of a doctor, and the like.
  • a doctor preferably, in the case of oral administration, 0.01 to 50 mg of the active ingredient per kg of body weight is administered per day, and in the case of parenteral administration, 0.01 to 10 mg of the active ingredient per kg of body weight is administered per day.
  • the total daily dose may be administered at one time or divided into several doses depending on the severity of the disease, the judgment of the doctor, and the like.
  • the compound of the present invention has an effect of inhibiting PD-L1 expression, it can be effectively used in a pharmaceutical composition for treating or preventing cancer.
  • 1 is a graph showing the change in tumor volume with time after administration of the Example compound to mice induced with cancer with B16F10 cells.
  • FIG. 2 is a graph showing the weight of tumors extracted from mice after administration of Example compound to mice induced with cancer with B16F10 cells.
  • FIG. 3 shows the results of measuring the degree of inhibition of PD-L1 expression in tumors extracted from mice after administration of the Example compound to mice induced with cancer with B16F10 cells through Western-blot.
  • Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (10.00 g, 42.98 mmol) was dissolved in 100 mL of tetrahydrofuran, triethylamine (7.37 mL, 52.86 mmol) and methylamine 40% After adding the solution (3.54 g, 45.55 mmol), the mixture was stirred at 20 ⁇ 25 °C for 16 hours. Upon completion of the reaction, the precipitated salt was filtered, the solvent was removed under reduced pressure, and saturated sodium hydrogen carbonate solution and ethyl acetate were added to the concentrated residue, followed by extraction.
  • 6-Methyl-5-nitropyridin-3-amine X-1 (1.00 g, 6.53 mmol) was dissolved in 50 mL of dichloromethane and cooled to 0°C. After adding 3-(trifluoromethyl)benzoyl chloride XI-1 (0.97 mL, 6.52 mmol) and N,N-diisopropylethylamine (3.33 mL, 19.59 mmol) to the reaction solution, 1 stirred for hours. When the reaction was completed, dichloromethane, distilled water, and brine were sequentially extracted.
  • N-(6-methyl-5-nitropyridin-3-yl)-3-(trifluoromethyl)benzamide XII-1 obtained above (1.16 g, 3.57 mmol) was dissolved in 50 mL of methyl alcohol, 0.32 g of 10% palladium carbon was added, and the mixture was stirred under a hydrogen atmosphere for 3 hours. Upon completion of the reaction, the reaction mixture was filtered through celite, washed with methanol, and then concentrated under reduced pressure to obtain 1.04 g (99%) of the title compound.
  • 3-(t-butyl)benzoic acid (0.6 g, 3.37 mmol) was suspended in 20 mL of dichloromethane, then oxalyl chloride (0.58 mL, 6.73 mmol) and 1 to 2 drops of dimethylformamide in a catalytic amount were added at room temperature. was stirred for 3 hours. After completion of the reaction, the reaction solvent was concentrated under reduced pressure to obtain 3-(t-butyl)benzoyl chloride XI-2 (0.67 g, Quant) without purification.
  • 6-Methyl-5-nitropyridin-3-amine X-1 (0.90 g, 5.88 mmol) was dissolved in 50 mL of dichloromethane and 3-(t-butyl)benzoyl chloride XI-2 obtained above at 0°C (1.15 g, 5.88 mmol) and N,N-diisopropylethylamine (3.07 mL, 17.63 mmol) were added, followed by stirring at 20 to 25°C for 1 hour. When the reaction was completed, dichloromethane, distilled water, and brine were sequentially extracted.
  • 2-Methoxy-3,5-dinitropyridine (0.55 g, 2.76 mmol) was dissolved in 20 mL of ethyl alcohol, 6N hydrochloric acid (4.00 mL) and iron (1.30 g) were added, and the mixture was heated to reflux for 1 hour. .
  • the mixture was cooled to 20-25 °C, neutralized with 5M sodium hydroxide solution, and the reaction mixture was filtered through Celite. The filtered solution was concentrated under reduced pressure, dissolved in ethyl acetate, extracted once with water, and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2-methoxypyridine-3,5-diamine X'-1 (0.21 g, 55%).
  • 6-Methyl-5-nitropyridin-3-amine X-1 (1.00 g, 6.52 mmol) was dissolved in 50 mL of dichloromethane, cooled to 0 °C, and N,N-diisopropylethylamine (3.41) mL, 19.59 mmol) and 4-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)benzoyl chloride XI-3 (1.55 g, 6.52 mmol) were added and stirred for 2 hours. When the reaction was completed, dichloromethane, distilled water, and brine were sequentially extracted.
  • 6-Methyl-5-nitropyridin-3-amine X-1 (1.00 g, 6.52 mmol) was dissolved in 60 mL of tetrahydrofuran, cooled to 0 °C, and N,N-diisopropylethylamine (3.41) mL, 19.59 mmol) and 3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)benzoylchloride XI-4 (1.55 g, 6.52 mmol) were added and stirred for 2 hours. When the reaction was completed, dichloromethane, distilled water, and brine were sequentially extracted.
  • reaction solvent was concentrated under reduced pressure, sequentially extracted using ethyl acetate, water, and brine, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • concentrated residue was purified by column chromatography to obtain 0.70 g (70%) of the title compound.
  • Test Example 1 PD-L1 expression inhibition activity analysis
  • the PD-L1 promoter gene region is a promoter-reporter construct for measuring gene transcriptional activity.
  • pGL4.14-[luc2/Hygro] vector promega, Madison, Wis.
  • PCR polymerase chain reaction
  • electrophoresis was performed on an agarose gel to isolate the promoter region DNA.
  • the pGL4.14-[luc2/Hygro] vector containing firefly luciferase as a reporter gene was treated with the same restriction enzyme and then isolated by agarose gel electrophoresis and gel extraction.
  • the purely isolated PD-L1 promoter gene region and pGL4.14-[luc2/Hygro] vector were reacted with In-fusion DNA ligase (Takara) at 50° C. for 1 hour, and then E. coli (E. coli) was transformed to prepare a promoter-reporter construct into which the PCSK9 promoter was inserted, which was named pGL4.14-PD-L1.
  • A549 cells were transiently transfected with the PD-L1 promoter-reporter construct as follows, and then the luciferase activity of the cell extract was measured.
  • DNA-lipofectamine complex was prepared according to the manufacturer's protocol using 0.1 ⁇ g of promoter-reporter construct plasmid and lipofectamine 2000 reagent (Invitrogen). In the process of forming a complex between DNA and Lipofectamine 2000, opti-MEM medium (Invitrogen) was used. For A549 cells, 2.5 ⁇ 10 5 cells (1 ml) per well were prepared in a 12-well plate by checking the number of cells immediately before adding DNA. After carefully mixing the DNA-lipofectamine complex with A549 cells, it was reacted in an incubator at 37° C. for 6 hours.
  • the task of finding the transfected cells was carried out, and the PD-L1-transfected A549 cells could be found through the luciferase test. This was named A549 pGL4.14-PD-L1 cell line and the experiment was carried out.
  • IFN ⁇ 50 ng/ml
  • PD-L1 expression conditions were established using EGF and IFN ⁇ , which are known to induce PD-L1 in Beas-2B cells, a human normal lung epithelial cell line.
  • EGF EGF
  • IFN ⁇ IFN ⁇
  • Beas-2B cells a human normal lung epithelial cell line.
  • RNA level when EGF was treated at concentrations of 25, 50, and 100 ng/ml, activation of PD-L1 was not seen, and it was confirmed that only IFN ⁇ increased PD-L1.
  • the mRNA level of PD-L1 increased 2 hours after IFN ⁇ was treated with 50 ng/ml, and finally, the mRNA level increased most clearly 4 hours after IFN ⁇ was treated with 50 ng/ml.
  • the A549 pGL4.14-PD-L1 cell line was treated with the pyrimido pyrimidinone derivatives of Example at concentrations of 0.1 ⁇ M and 1.0 ⁇ M, respectively, and the inhibition rate of PD-L1 expression was evaluated using a luminometer.
  • GS9973 Entospletinib
  • the PD-L1 expression inhibition rate was calculated by Equation 1 below.
  • PD-L1 expression inhibition rate (%) 100-[(A/B) ⁇ 100]
  • A is a value with drug treatment
  • B is a value without drug treatment
  • the pyrimido pyrimidinone compound according to the present invention has superior PD-L1 expression inhibitory activity compared to GS9973 (Entospletinib), and this PD-L1 expression inhibitory activity is concentration-dependent.
  • Test Example 2 In vivo efficacy evaluation of PD-L1 expression inhibitors
  • a disease model was prepared by injecting melanoma melanoma B16F10 cells subcutaneously in the dorsal region of the mouse at 1 ⁇ 10 6 cells/100 ⁇ l per 6-week-old male C57BL/6 mouse. The next day after the disease model production was made the first day of administration, and as shown in Table 2 below, it was orally administered once a day for 14 days, and tumors were excised on the 15th day of the start of the test. Tumor volume change and tumor size were measured.
  • G1 Normal control M 8 1 to 8 - G2 I-8 M 8 9 to 16 10 G3 I-9 M 8 17 to 24 10 G4 I-2 M 8 25 to 32 20 G5 I-3 M 8 33 to 40 20
  • the protein was confirmed with the ChemiDoc TM imaging system (Bio-rad) using a chemiluminescence (ECL) kit (elpis biotec, EBP-1073). The results are shown in FIG. 3 .
  • NCI-H358 (NSCLC) cell line was aliquoted at 6 ⁇ 10 5 cells/ml. After 24 hours, NCI-H358 (NSCLC) cell line was treated with IFN- ⁇ (20 ng/ml) to overexpress PD-L1, and 24 hours later, the compound was further treated with 1 ⁇ M and 10 ⁇ M, respectively. After 24 hours, the protein was identified with a ChemiDoc TM imaging system (Bio-rad) using a chemiluminescence (ECL) kit (elpis biotec, EBP-1073). The results of Western-blot analysis are shown in FIG. 4 .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
PCT/KR2021/012616 2020-09-16 2021-09-15 피리미도 피리미디논 화합물 및 그를 포함하는 약제학적 조성물 Ceased WO2022060094A1 (ko)

Priority Applications (9)

Application Number Priority Date Filing Date Title
IL300920A IL300920A (en) 2020-09-16 2021-09-15 A pyrimidopyrimidinane compound and a pharmaceutical composition comprising it
EP21869716.7A EP4215533B1 (en) 2020-09-16 2021-09-15 Pyrimidopyrimidinone compound and pharmaceutical composition comprising same
US18/245,395 US12590098B2 (en) 2020-09-16 2021-09-15 Pyrimido pyrimidinone compound and pharmaceutical composition comprising the same
JP2023515773A JP7824667B2 (ja) 2020-09-16 2021-09-15 ピリミドピリミジノン化合物及びそれを含む薬剤学的組成物
CN202180063334.1A CN116137815B (zh) 2020-09-16 2021-09-15 嘧啶并嘧啶酮化合物及包含其的药物组合物
MX2023003087A MX2023003087A (es) 2020-09-16 2021-09-15 Compuesto de pirimido pirimidinona y composicion farmaceutica que comprenden el mismo.
AU2021344164A AU2021344164A1 (en) 2020-09-16 2021-09-15 Pyrimidopyrimidinone compound and pharmaceutical composition comprising same
CA3190461A CA3190461A1 (en) 2020-09-16 2021-09-15 Pyrimido pyrimidinone compound and pharmaceutical composition comprising the same
BR112023004179A BR112023004179A2 (pt) 2020-09-16 2021-09-15 Composto de pirimido pirimidinona e composição farmacêutica compreendendo o mesmo

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR20200119100 2020-09-16
KR10-2020-0119100 2020-09-16

Publications (1)

Publication Number Publication Date
WO2022060094A1 true WO2022060094A1 (ko) 2022-03-24

Family

ID=80777269

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2021/012616 Ceased WO2022060094A1 (ko) 2020-09-16 2021-09-15 피리미도 피리미디논 화합물 및 그를 포함하는 약제학적 조성물

Country Status (11)

Country Link
US (1) US12590098B2 (https=)
EP (1) EP4215533B1 (https=)
JP (1) JP7824667B2 (https=)
KR (1) KR102673031B1 (https=)
CN (1) CN116137815B (https=)
AU (1) AU2021344164A1 (https=)
BR (1) BR112023004179A2 (https=)
CA (1) CA3190461A1 (https=)
IL (1) IL300920A (https=)
MX (1) MX2023003087A (https=)
WO (1) WO2022060094A1 (https=)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005011597A2 (en) 2003-07-29 2005-02-10 Irm Llc Compounds and compositions as protein kinase inhibitors
KR100853975B1 (ko) * 2004-08-31 2008-08-25 에프. 호프만-라 로슈 아게 3-페닐 디히드로피리미도[4,5-ｄ]피리미디논의 아미드유도체, 이의 제조 방법 및 약제로서의 용도
KR20160040301A (ko) * 2013-08-23 2016-04-12 갈라파고스 엔.브이. 증식성 질환의 치료를 위한 １ｈ― 피라졸로［3,4―ｂ］피리딘의 유도체 및 그의 약학 조성물
WO2018009544A1 (en) * 2016-07-05 2018-01-11 The Broad Institute, Inc. Bicyclic urea kinase inhibitors and uses thereof

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UY29439A1 (es) * 2005-03-25 2006-10-02 Glaxo Group Ltd Nuevos compuestos
RU2007147917A (ru) * 2005-06-10 2009-07-20 Айрм Ллк (Bm) Соединения, поддерживающие плюрипотентность эмбриональных стволовых клеток
EP2455382B1 (en) 2005-12-13 2016-10-26 Incyte Holdings Corporation Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as Janus kinase inhibitors
KR102591947B1 (ko) * 2018-04-19 2023-10-25 길리애드 사이언시즈, 인코포레이티드 Pd-1/pd-l1 억제제
KR102382613B1 (ko) * 2020-01-15 2022-04-06 한국과학기술연구원 단백질 키나아제 저해 활성을 갖는 7-아미노-3,4-디히드로피리미도피리미딘-2-온 유도체 및 이를 포함하는 치료용 약학 조성물

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005011597A2 (en) 2003-07-29 2005-02-10 Irm Llc Compounds and compositions as protein kinase inhibitors
KR100853975B1 (ko) * 2004-08-31 2008-08-25 에프. 호프만-라 로슈 아게 3-페닐 디히드로피리미도[4,5-ｄ]피리미디논의 아미드유도체, 이의 제조 방법 및 약제로서의 용도
KR20160040301A (ko) * 2013-08-23 2016-04-12 갈라파고스 엔.브이. 증식성 질환의 치료를 위한 １ｈ― 피라졸로［3,4―ｂ］피리딘의 유도체 및 그의 약학 조성물
WO2018009544A1 (en) * 2016-07-05 2018-01-11 The Broad Institute, Inc. Bicyclic urea kinase inhibitors and uses thereof

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CHO HANNA, SHIN INJAE, JU EUNHYE, CHOI SEUNGHYE, HUR WOOYOUNG, KIM HAELEE, HONG EUNMI, KIM NAM DOO, CHOI HWAN GEUN, GRAY NATHANAEL: "First SAR Study for Overriding NRAS Mutant Driven Acute Myeloid Leukemia", JOURNAL OF MEDICINAL CHEMISTRY, vol. 61, no. 18, 27 September 2018 (2018-09-27), US , pages 8353 - 8373, XP055829016, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.8b00882 *
CLIN CANCER RES., vol. 25, no. 14, 15 July 2019 (2019-07-15), pages 4530 - 4541
KEIR MEBUTTE MJFREEMAN GJ ET AL.: "PD-1 and its ligands in tolerance and immunity", ANNU. REV. IMMUNOL., 2008, pages 26
PROC NATL ACAD SCI USA., vol. 116, no. 40, 1 October 2019 (2019-10-01), pages 20141 - 20150
See also references of EP4215533A4

Also Published As

Publication number Publication date
EP4215533B1 (en) 2026-02-11
CN116137815A (zh) 2023-05-19
BR112023004179A2 (pt) 2023-04-11
US20230348474A1 (en) 2023-11-02
JP7824667B2 (ja) 2026-03-05
KR20220036895A (ko) 2022-03-23
EP4215533A4 (en) 2024-12-18
IL300920A (en) 2023-04-01
JP2023541052A (ja) 2023-09-27
CN116137815B (zh) 2025-08-19
KR102673031B1 (ko) 2024-06-07
CA3190461A1 (en) 2022-03-24
MX2023003087A (es) 2023-04-14
AU2021344164A9 (en) 2024-03-21
AU2021344164A1 (en) 2023-05-04
US12590098B2 (en) 2026-03-31
EP4215533A1 (en) 2023-07-26

Similar Documents

Publication Publication Date Title
WO2021158071A1 (ko) Kras 돌연변이와 관련된 암의 예방 또는 치료용 약학 조성물
WO2019190259A1 (ko) 상피세포 성장인자 수용체 돌연변이 저해 효과를 갖는 신규 설폰아마이드 유도체
WO2021256861A1 (ko) 신규한 산 분비 억제제 및 이의 용도
WO2019231271A1 (en) Heterocyclic derivatives and use thereof
WO2012115479A2 (en) Diaminopyrimidine derivatives and processes for the preparation thereof
WO2018004258A1 (ko) 신규한 헤테로시클릭 유도체 화합물 및 이의 용도
WO2017188720A2 (en) Quinazoline derivative or its salt and pharmaceutical composition comprising the same
WO2023287128A1 (ko) 인다졸일 벤즈이미다졸 유도체 또는 이의 약학적으로 허용가능한 염 및 이의 용도
WO2024215130A1 (en) Novel gspt1 degrader and use thereof
WO2022060094A1 (ko) 피리미도 피리미디논 화합물 및 그를 포함하는 약제학적 조성물
WO2025034034A1 (ko) 신규한 화합물, 및 이를 포함하는 암 또는 종양의 예방 또는 치료용 약학적 조성물
WO2010032986A2 (ko) 신규 5-(4-아미노페닐)-이소퀴놀린 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 raf 키나제의 과활성에 의해 유발되는 질환의 예방 또는 치료용 조성물
WO2024080792A1 (en) Novel heterobicyclic compound for inhibiting yap-tead interaction and pharmaceutical composition comprising same
WO2024029877A1 (ko) A3 아데노신 수용체 작용제로서의 신규한 퓨린 유도체 화합물
WO2023038481A1 (ko) Stat3 저해제로서 헤테로아릴 유도체 화합물 및 이의 용도
WO2021235813A1 (ko) Ron 돌연변이와 관련된 췌장암 예방 또는 치료용 약학 조성물 및 이를 이용한 방법
WO2018021762A1 (ko) 신규 화합물, 이의 제조방법 및 이를 포함하는 약학 조성물
WO2021256900A1 (ko) 신규한 옥소피리다지닐-페닐-카르보노하이드라조노일 디시아나이드 화합물 및 이의 용도
WO2014038881A2 (ko) 피리돈 유도체를 포함하는 단백질 키나제 억제제
WO2020080742A1 (en) Novel (isopropyl-triazolyl)pyridinyl-substituted benzooxazinone or benzothiazinone derivatives and use thereof
WO2022203332A1 (en) Novel indoleamine 2,3-dioxygenase inhibitors, processes for the preparation thereof and pharmaceutical compositions comprising the same
WO2015034213A1 (ko) 피롤로피리다진 유도체를 포함하는 단백질 키나제 억제제
WO2021145641A1 (ko) 혈관생성 저해 효과를 가지는 n-페닐벤조티아졸-2-아민 화합물 및 그를 포함하는 약제학적 조성물
WO2021107590A1 (ko) 신규한 트리아졸로피리딘 유도체 및 이를 포함하는 약학 조성물
WO2025014314A1 (en) Novel heterocyclic compounds and pharmaceutical composition comprising the same as dna polymerase theta inhibitors for the prevention or treatment of cancer

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21869716

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3190461

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 300920

Country of ref document: IL

ENP Entry into the national phase

Ref document number: 2023515773

Country of ref document: JP

Kind code of ref document: A

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112023004179

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 112023004179

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20230306

WWE Wipo information: entry into national phase

Ref document number: 202317027317

Country of ref document: IN

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2021869716

Country of ref document: EP

Effective date: 20230417

ENP Entry into the national phase

Ref document number: 2021344164

Country of ref document: AU

Date of ref document: 20210915

Kind code of ref document: A

WWG Wipo information: grant in national office

Ref document number: 202180063334.1

Country of ref document: CN

WWG Wipo information: grant in national office

Ref document number: 2021869716

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 18245395

Country of ref document: US