WO2024000763A1 - Inhibiteur covalent g9a/glp, son procédé de préparation et son utilisation - Google Patents

Inhibiteur covalent g9a/glp, son procédé de préparation et son utilisation Download PDF

Info

Publication number
WO2024000763A1
WO2024000763A1 PCT/CN2022/113518 CN2022113518W WO2024000763A1 WO 2024000763 A1 WO2024000763 A1 WO 2024000763A1 CN 2022113518 W CN2022113518 W CN 2022113518W WO 2024000763 A1 WO2024000763 A1 WO 2024000763A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
alkyl
glp
groups
Prior art date
Application number
PCT/CN2022/113518
Other languages
English (en)
Chinese (zh)
Inventor
王元相
王军舰
冯宗博
杨春菊
刘培庆
Original Assignee
中山大学
广州中大南沙科技创新产业园有限公司
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 中山大学, 广州中大南沙科技创新产业园有限公司 filed Critical 中山大学
Publication of WO2024000763A1 publication Critical patent/WO2024000763A1/fr

Links

Images

Classifications

    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the invention relates to the field of medicine, and in particular to a G9a/GLP covalent inhibitor and its preparation method and application.
  • Histone methyltransferase G9a (KMT1C or EHMT2) and GLP (KMT1D or EHMT1) are a type of closely related methyltransferases.
  • the SET domain of GLP has 80% sequence homology with G9a; GLP can also form heterodimers with G9a to jointly exert physiological functions.
  • G9a/GLP can also dimethylate the lysine 373 residue of the tumor suppressor gene p53, causing p53 transcriptional inactivation and increasing cancer cell proliferation.
  • G9a/GLP GLP has been shown to be involved in many physiological and pathological processes in the body and is overexpressed in various human cancers including leukemia, prostate cancer, hepatocellular carcinoma and lung cancer. Therefore, in recent years, G9a/GLP has become a popular target for research on multiple diseases.
  • G9a/GLP inhibitors generally suffer from low efficacy, and there are currently no candidate compounds that have entered the clinical research stage. Therefore, there is an urgent need to develop inhibitors with new modes of action to solve this problem.
  • all reported G9a/GLP inhibitors are non-covalent reversible inhibitors (Cao H, Li L, Yang D, et al. Recent progress in histone methyltransferase (G9a) inhibitors as anticancer agents. Eur J Med Chem.2019;179:537-546.), no covalent inhibitors have been reported. When covalent inhibitors bind to the target protein, they can form covalent bonds with the electrophilic amino acid residues on the target protein near the binding site.
  • covalent inhibitors have a longer action time. It has a series of advantages such as long life, strong efficacy and low dosage.
  • electrophilic cysteine residues G9a-Cys1098, GLP-1186
  • G9a-Cys1098, GLP-1186 electrophilic cysteine residues
  • the purpose of the present invention is to overcome the lack of G9a/GLP covalent inhibitors and provide a G9a/GLP covalent inhibitor.
  • the G9a/GLP covalent inhibitor provided by the invention has good specificity, strong drug effect, and high selectivity for histone methyltransferase G9a/GLP, and can be used to prepare drugs that inhibit G9a/GLP, prevent and/or treat tumors or Cancer drugs.
  • Another object of the present invention is to provide a method for preparing the above-mentioned G9a/GLP covalent inhibitor.
  • Another object of the present invention is to provide the use of the above-mentioned G9a/GLP covalent inhibitor in the preparation of drugs that inhibit G9a/GLP.
  • the present invention provides the following technical solutions:
  • a G9a/GLP covalent inhibitor which is a compound with a structure shown in formula (I) and its salt:
  • n 1 , n 2 , n 3 and n 4 are independently selected from integers from 0 to 2;
  • n 5 is an integer from 0 to 4.
  • X is CH or N
  • R 1 is selected from hydrogen, C 1 -C 6 alkyl and its deuterated products, C 3 -C 6 cycloalkyl, C 3 -C 6 heterocycloalkyl; the alkyl and its deuterated products and cycloalkyl are any Optionally selected by halogen, cyano, hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkyl, amino, C 1 -C 6 alkylamino, bis C 1 -C 6 alkylamino, 4-12 membered heterocyclic group substituted by one or more groups;
  • R 3 is selected from hydrogen, trifluoromethyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 Heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted C 5 -C 6 heteroaryl; the substitution means that at least 1 position is substituted by the following substituents: halogen, cyano, amino, Nitro, hydroxyl, trifluoromethyl, methylthio, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, C 1 -C 6 alkylamino, C 3 -C 8 heterocyclyl; C 3 -C 8 cycloalkoxy group, C 3 -C 8 cycloalkylamino group, aryl group, C 5 -C 6 heteroary
  • R 4 is selected from hydrogen, halogen, cyano, hydroxyl, methoxy or trifluoromethoxy;
  • R 5 is selected from substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 heterocycloalkyl, substituted or Unsubstituted aryl, substituted or unsubstituted C 5 -C 6 heteroaryl, substituted or unsubstituted C 1 -C 6 alkoxy, substituted or unsubstituted C 1 -C 6 alkylamino, substituted or unsubstituted Substituted C 3 -C 8 cycloalkyloxy group, substituted or unsubstituted C 3 -C 8 cycloalkylamino group, substituted or unsubstituted C 3 -C 8 cycloalkylamino group, the substitution means at least 1 The position is substituted by the following substituents: halogen, cyano, amino, nitro, hydroxyl,
  • R b and R c are independently selected from hydrogen or R d ;
  • R d is selected from substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 4-12 membered heterocyclyl;
  • R a and R b together with the carbon atoms to which they are connected form a 3-5-membered heterocyclyl group or a substituted 3-5-membered heterocyclyl group containing 0 or 1 additional heteroatom;
  • Y is selected from halogen.
  • the present invention uses quinazoline and quinoline as the drug skeleton.
  • Quinazoline and quinoline have good drug properties
  • the skeleton inhibitor has a cysteine residue near the binding pocket where it interacts with G9a.
  • the direction and distance are suitable for adding an electrophilic active group, that is, a covalent warhead, which can undergo an electrophilic addition reaction with the cysteine residue near the binding pocket to form a covalent bond, thereby achieving a long-lasting inhibitory effect
  • the G9a/GLP covalent inhibitor obtained after specific substitutions has good specificity, strong efficacy, and high selectivity for histone methyltransferase G9a/GLP, and can be used to prepare G9a inhibitors.
  • /GLP drugs drugs to prevent and/or treat tumors or cancer.
  • n 1 is 0 or 1.
  • n 2 is 0 or 1.
  • n 3 is 1.
  • n 4 is an integer from 0 to 3.
  • R1 is selected from hydrogen or C1 - C6 alkyl.
  • R 2 is selected from
  • R d are one or more -JT groups;
  • the substituents in the substituted 3-5-membered heterocyclic groups in R a and R b are one or more -J 1 -T 1 groups;
  • J is selected from a bond or substituted C 1 -C 6 alkylene
  • T is selected from hydrogen, halogen, cyano, hydroxyl, -NR f R g , -C(O)R f , -OR f , -C(O)OR f , -C(O)NR f R g , -NR f C(O)R g , -NR h C(O)NR f R g , -NR f C(O)OR h or R i ;
  • R f , R g , and Rh h are each independently selected from hydrogen or R j , and R j is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6- cycloalkyl, 4-12-membered heterocyclyl, 5- or 6-membered heteroaryl, aryl, R j is substituted by one or more -J 1 -T 1 groups;
  • R f and R g together with the N atoms to which they are connected form a 4-12-membered heterocyclyl group containing 0 or 1 additional heteroatom, and the 4-12-membered heterocyclyl group is replaced by one or more -J 1 -T 1 group substitution;
  • R i is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4-12 membered heterocyclyl, 5-10 membered heterocyclic group
  • Aryl, aryl, R i is substituted by one or more -J 1 -T 1 groups;
  • J 1 is selected from a bond or substituted C 1 -C 6 alkylene
  • T 1 is selected from hydrogen, halogen, cyano, hydroxyl, -NR k R l , -C(O)R k , -OR k , -C(O)OR k , -C(O)NR k R l , - NR k C(O)R l , -NR o C(O)NR k R l , -NR k C(O)OR o or R p ;
  • R k , R l , and R o are each independently selected from hydrogen or R q , and R q is selected from the following substituted groups: C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkyne Base, C 3 -C 6 cycloalkyl group, 4-12 membered heterocyclyl group, 5-membered or 6-membered heteroaryl group, aryl group;
  • R k and R l together with the N atom to which they are connected form a 4-12 membered heterocyclyl group containing 0 or 1 additional heteroatom, and the heterocyclyl group is optionally selected from halogen, hydroxyl, oxo, C 1 -C 6 alkyl, OR x , -NR x R y , -C(O)R x , -O(CH 2 ) n OR x is substituted by one or more groups;
  • R p is selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 4-12 membered heterocyclyl, 5 to 6 membered heterocyclic group Aryl, aryl;
  • R x and R y are each independently selected from hydrogen or R z , and R z is selected from the following groups or substituted groups: C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 Alkynyl, C 3 -C 6 cycloalkyl, 4-12-membered heterocyclyl, aryl, 5- or 6-membered heteroaryl; Rz is replaced by halogen, hydroxyl, 5- or 6-membered arylheteroyl, aryl or one or more substituted 5- or 6-membered heteroaryl groups,
  • R x , R y and the N atom to which they are connected together form a 4-12 membered heterocyclyl group containing 0 or 1 additional heteroatom;
  • R 3 is selected from hydrogen, aryl, C 1 -C 6 alkyl, C 3 -C 8 heterocycloalkyl or C 1 -C 6 alkyl substituted by C 3 -C 8 heterocycloalkyl base.
  • R 5 is selected from C 1 -C 6 alkyl or C 3 -C 8 heterocycloalkyl.
  • the G9a/GLP covalent inhibitor is the structure shown in the following numbering and its salt:
  • the salts in the present invention are pharmaceutically acceptable salts.
  • the salt is a hydrochloride, a hydrobromide, a nitrate, a methyl nitrate, a sulfate, a hydrogen sulfate, an aminosulfate, a phosphate, an acetate, a glycolate, or a phenyl ethyl salt.
  • the preparation method of the above-mentioned G9a/GLP covalent inhibitor includes the following steps:
  • the compound represented by formula (1) and acid undergo a condensation reaction under the conditions of a condensing agent and an organic base to obtain a compound with a structure represented by formula (I).
  • the molar ratio of the compound represented by formula (1) to acid, condensing agent and organic base is 1:(1.2 ⁇ 1.5):(1.2 ⁇ 1.4):(2 ⁇ 3).
  • the acid is propionic acid, acrylic acid, methacrylic acid, 2-butenoic acid, 2-butynoic acid, chloroacetic acid, cyanoacetic acid, 1-cyano-1-cyclopropanecarboxylic acid or (E)- One or more of 4-(dimethylamino)but-2-enoic acid.
  • the condensing agent is acid chloride.
  • the organic base is DIPEA.
  • the solvent is ultradry methylene chloride.
  • the reaction temperature of the condensation reaction is 0°C to room temperature (for example, 0°C to 26°C), and the reaction time is 1 to 2 hours.
  • the compound represented by formula (1) is prepared by the following process: the compound represented by formula (2) and the compound represented by formula (3) undergo a substitution reaction in the presence of basic substances and solvents to generate formula (4) The intermediate shown in formula (4) then undergoes a substitution reaction with methylamine under heating conditions to obtain the compound shown in formula (1);
  • the molar ratio of the compound represented by the formula (2) to the compound represented by the formula (3) and the basic substance is 1:(1.5 ⁇ 2):(2.5 ⁇ 3).
  • the alkaline substance is K 2 CO 3 .
  • the solvent is N,N-dimethylformamide.
  • the reaction temperature for the substitution reaction between the compound represented by formula (2) and the compound represented by formula (3) is 0°C to room temperature (for example, 0°C to 26°C), and the reaction time is 3 to 4 hours.
  • the conditions for the substitution reaction between the intermediate represented by formula (4) and methylamine are: methylamine solution is the solvent, the reaction temperature is 120°C, and the reaction time is 8 hours.
  • G9a/GLP covalent inhibitors can inhibit the expression of G9a/GLP, prevent and/or treat abnormal cell proliferation, morphological changes, and hypermotility related to G9a/GLP, and can treat and/or prevent tumor growth. and transfer.
  • the drug is a drug for preventing and/or treating diseases involving abnormal cell proliferation, morphological changes, and hypermotility related to G9a/GLP.
  • the drug is a drug for treating and/or preventing tumor growth and metastasis.
  • the tumor is one or more of cancer or benign tumors.
  • the cancer can be pancreatic cancer, breast cancer, lung cancer, bone cancer, stomach cancer, skin cancer, head and neck cancer, uterine cancer, ovarian cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, brain cancer, pituitary gland cancer Adenomas, epidermoid carcinoma, T-cell lymphoma, chronic and acute leukemia, colorectal cancer, kidney cancer, esophageal cancer, breast cancer, cervical cancer, bladder cancer, fibrosarcoma, esophageal cancer, bladder cancer, hematopoietic system cancer, lymphoma , medulloblastoma, medulloblastoma, rectal adenocarcinoma, colon cancer, liver cancer, adenoid cystic carcinoma, prostate cancer, head and neck squamous cell carcinoma, brain cancer, hepatocellular carcinoma, melanoma, oligodendro
  • the present invention has the following advantages and effects:
  • the G9a/GLP covalent inhibitor provided by the invention has good specificity, strong drug effect, and high selectivity for histone methyltransferase G9a/GLP, and can be used to prepare drugs that inhibit G9a/GLP, prevent and/or treat tumors or Cancer drugs.
  • Figure 1 shows the mass spectrum verification of covalent binding of G9a to compound 14.
  • Figure 2(A) shows the predicted binding mode of compound 14 and G9a protein
  • Figure 2(B) shows the predicted binding mode of compound 14 and GLP protein
  • Figure 3 shows the methylation inhibition elution experiment of compounds 14 and 26;
  • Figure 4 shows that compounds 14 and 26 inhibit the clonogenesis of MDA-MB-231 and PANC1;
  • Figure 5 shows the methylation inhibition experiments of compounds 14 and 26.
  • Figure 6 shows the in vivo anti-tumor activity experiment of compound 14.
  • the present invention will be further explained below with reference to the examples and drawings, but the examples do not limit the invention in any way.
  • the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in this technical field.
  • Step 1 Add compound 14a (300mg, 0.84mmol) into the reaction bottle, add DMF solvent to dissolve it, add 1-methylpiperidine-4-amino (158.11ul, 1.26mmol) and slowly add K at 0°C. 2 CO 3 (348.29mg, 2.52mmol), then stirred at room temperature, TLC detected the reaction progress, the 3h reaction was completed, extracted with ethyl acetate, the organic layer was washed with brine, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and vortexed The solvent was dried, and the crude product was separated and purified by column chromatography to obtain compound 14b.
  • Step 2 Add the product from the previous step (200 mg, 0.46 mmol) into a sealed tube, add methylamine solution (3 ml), and heat at 120°C overnight. After the reaction is completed, spin the solvent dry, extract with ethyl acetate, and use saline for the organic layer. Wash, combine the organic phases, dry with anhydrous sodium sulfate, then filter and spin dry the solvent. No purification is required. Directly proceed to the next reaction.
  • the final target products prepared in Examples 1 to 25 are respectively designated as compounds 1 to 15.
  • Compound 26 was prepared by the following process: replacing acryloyl chloride with an equal molar amount of propionyl chloride, and the remaining required raw materials, reagents and preparation methods were the same as in Example 14 to obtain a white solid.
  • the experimental method is as follows: G9a protein is incubated with compound 14, and then electrospray time-of-flight mass spectrometry is used for verification.
  • the known amino acid sequence and mass spectrum of G9a protein the molecular weight of G9a is 59.62KD, after incubation of compound and protein G9a,
  • the mass spectrometry data shows that compared with the G9a protein blank mass spectrometry data, the small molecule processed spectrum has a new peak near 59.62KD.
  • the molecular weight is equal to the molecular weight of the G9a protein and Compound 14 complex.
  • the C-2 position of the compounds represented by formula (I) all contain electrophilic active groups, that is, covalent warheads, so they can all undergo Michael addition reactions with cysteine residues near the binding pocket of the target protein. Generate covalent bonds to achieve the purpose of covalent binding.
  • the experimental method is as follows: After the MDA-MB-231 cell density reaches about 90% and the cells are in good condition, the cells are digested and counted, then seeded into a six-well plate at a density of 120,000/well, and placed in an incubator for overnight culture. On the second day after seeding the plate, compound 14 and non-covalent control compound 26 were added into the wells at a final concentration of 10 ⁇ M, and a well containing the same DMSO as the 10 ⁇ M well was set as a control, and the culture was continued for 48 h. Take out the six-well plate, remove the culture medium, and wash it twice with PBS. Collect the cells treated for 48 hours and freeze them at -80°C.
  • the experimental method is as follows: Prepare 1x detection buffer (modified Tris buffer). Compound serial dilutions: Transfer compounds to assay plates via Echo in 100% DMSO.
  • Prepare enzyme solution Prepare enzyme solution in 1x Assay Buffer.
  • Prepare substrate mix solution Prepare substrate mix solution in 1x Assay Buffer, transfer 5 ⁇ L of enzyme solution to assay plate or for low control transfer 5 ⁇ L of 1x Assay Buffer, incubate at room temperature for 15 minutes, add to each well Start the reaction with 5 ⁇ L of substrate mixed solution, and incubate G9a for 60 minutes at room temperature. Then prepare 1x Alphalisa buffer and prepare acceptor and donor bead mixed solution in 1x Alphalisa buffer.
  • the compound's inhibitory effect on cell activity was tested using cell viability assay.
  • the experimental method is as follows: until the cell density reaches about 90% and the cells are in good condition, digest the cells, count them, and inoculate them into a 96-well plate at a concentration of 1500 cells/100 ⁇ L per well. , put in the incubator overnight. Observe whether the cell status is good the next day. If it is good, prepare the drug first, dilute the compound in equal proportions with complete culture medium, and then add three duplicate wells of each concentration into the wells, 50 ⁇ L per well, and return the plate to the incubator. Continue culturing for 96h.
  • the inhibitory activity of the non-covalent control compound on Panc-1 cells is 14.78 ⁇ 0.07 ⁇ m
  • the inhibitory activity on Mda-mb-231 cells is 9.734 ⁇ 0.04 ⁇ m
  • the inhibitory activity of the covalent compound 14 on Panc-1 cells is 2.68 ⁇ 0.15 ⁇ m
  • the inhibitory activity against Mda-mb-231 cells is 2.88 ⁇ 0.64 ⁇ m.
  • compound 14 has a more significant medicinal effect, which can also prove that compound 14 and G9a achieve covalent binding. .
  • the experimental method is as follows: After digesting and counting MDA-MB-231 and PANC-1 cells, they were seeded into a six-well plate at a density of 1200 cells/well and 800 cells/well respectively, and placed in an incubator to culture overnight. On the second day after seeding the plate, compound 14 and its non-covalent control compound 26 were added into the wells at final concentrations of 1.25, 2.5, and 5 ⁇ M, and a well containing the same DMSO as the 5 ⁇ M well was set as a control. Each treatment setting Make 3 multiple wells, put the plate back into the incubator and continue culturing for 15 days. Change the complete medium every three days, and add corresponding concentrations of compound 14 and non-covalent control compound 26.
  • the size of the cell clones in the control group has grown to the size visible to the naked eye.
  • the culture medium is removed, washed three times with PBS, and 800 ⁇ L of 4% paraformaldehyde is added to each well and fixed for 15 minutes. Remove the fixative, wash 3 times with PBS, add 800 ⁇ L of crystal violet dye to each well, and stain in the dark for 30 minutes. Recover the crystal violet dye solution, wash away the excess dye solution with ultrapure water, and place the 6-well plate in a fume hood to dry. Use a printer to scan the 6-well plate, and use Image J to count the number of cell clones.
  • the experimental method is as follows: After the MDA-MB-231 cell density reaches about 90% and the cells are in good condition, the cells are digested and counted, then seeded into a six-well plate at a density of 120,000/well, and placed in an incubator for overnight culture. On the 2nd, 3rd, 4th, and 5th days of the seeding plate, compound 14 was added into the wells at a final concentration of 10 ⁇ M, and the drug was allowed to act for 96h, 72h, 48h, and 24h respectively, and the same well containing DMSO as the 10 ⁇ M well was set as a control. . On the 6th day after plating, take out the six-well plate, remove the culture medium, and wash gently twice with PBS.
  • the control group (recorded as Vehicle) was given drug cosolvent, and the experimental group (recorded as 14-2mg/kg) was given 2mg/kg of compound 14.
  • the covalent inhibitor 14 can significantly inhibit the growth of PANC-1 subcutaneous transplanted tumors without obvious toxicity to the major organs of mice.
  • AlphaLISA and HTRF methods were used to further investigate the inhibitory effect of compound 14 on multiple other histone-modifying enzymes at the molecular level to determine the selectivity of the compound against histone-modifying enzymes.
  • AlphaLISA technology was used to detect the molecular-level inhibitory activities of compounds against histone-modifying enzymes PRMT1, PRMT4, and PRMT5. Selectivity to EZH2, MLL1, MLL4, DNMT1 was assessed using the HTRF assay.
  • Table 2 Compound 14 has inhibitory activity against G9a enzyme.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne un inhibiteur covalent G9a/GLP, son procédé de préparation et son utilisation. L'inhibiteur covalent G9a/GLP est un composé ayant une structure telle que représentée dans la formule (I) et un sel de celui-ci :
PCT/CN2022/113518 2022-06-27 2022-08-19 Inhibiteur covalent g9a/glp, son procédé de préparation et son utilisation WO2024000763A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210738401.1A CN115160294B (zh) 2022-06-27 2022-06-27 一种G9a/GLP共价抑制剂及其制备方法及应用
CN202210738401.1 2022-06-27

Publications (1)

Publication Number Publication Date
WO2024000763A1 true WO2024000763A1 (fr) 2024-01-04

Family

ID=83487315

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/113518 WO2024000763A1 (fr) 2022-06-27 2022-08-19 Inhibiteur covalent g9a/glp, son procédé de préparation et son utilisation

Country Status (2)

Country Link
CN (1) CN115160294B (fr)
WO (1) WO2024000763A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106536509A (zh) * 2014-06-16 2017-03-22 基础应用医学研究基金会 作为组蛋白甲基转移酶和dna甲基转移酶的双重抑制剂的新型化合物
US20200010454A1 (en) * 2017-01-26 2020-01-09 Araxes Pharma Llc Substituted quinazoline and quinazolinone compounds and methods of use thereof
CN113248481A (zh) * 2021-04-19 2021-08-13 中山大学 Ezh2共价不可逆抑制剂、制备方法及其用途

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007011618A1 (fr) * 2005-07-15 2007-01-25 Schering Corporation Derivees de quinazoline utiles pour le traitement du cancer
WO2009036057A1 (fr) * 2007-09-10 2009-03-19 Curis, Inc. Agents antiprolifératifs contenant une fraction de liaison au zinc
EP2300456A1 (fr) * 2008-05-22 2011-03-30 Allergan, Inc. Composés bicycliques ayant une activité sur le récepteur cxcr4
TWI629266B (zh) * 2012-12-28 2018-07-11 藍印藥品公司 纖維母細胞生長因子受體之抑制劑
US9284272B2 (en) * 2014-03-28 2016-03-15 Abbvie Inc. Inhibitors of histone methyltransferase G9a
US20190322643A1 (en) * 2016-06-29 2019-10-24 Georgia State University Research Foundation, Inc. Histone deacetylase and histone methyltransferase inhibitors and methods of making and use of the same
CN106518849B (zh) * 2016-10-27 2019-08-16 上海人类基因组研究中心 喹唑啉类化合物及其制备方法和用途
GB201700814D0 (en) * 2017-01-17 2017-03-01 Liverpool School Tropical Medicine Compounds
US10703748B2 (en) * 2017-10-31 2020-07-07 Samumed, Llc Diazanaphthalen-3-yl carboxamides and preparation and use thereof
WO2019243236A1 (fr) * 2018-06-18 2019-12-26 Fundación Para La Investigación Médica Aplicada Nouvelles combinaisons de médicaments anticancéreux
CN111875582B (zh) * 2019-10-12 2021-06-01 深圳贝瑞生物医药科技有限公司 一种喹啉异羟肟酸衍生物及其制备方法和应用
CN112480078B (zh) * 2020-11-10 2022-01-04 清华大学深圳国际研究生院 一种喹唑啉异羟肟酸衍生物及其制备方法与应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106536509A (zh) * 2014-06-16 2017-03-22 基础应用医学研究基金会 作为组蛋白甲基转移酶和dna甲基转移酶的双重抑制剂的新型化合物
US20200010454A1 (en) * 2017-01-26 2020-01-09 Araxes Pharma Llc Substituted quinazoline and quinazolinone compounds and methods of use thereof
CN113248481A (zh) * 2021-04-19 2021-08-13 中山大学 Ezh2共价不可逆抑制剂、制备方法及其用途

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CAO, HAO ET AL.: ""Recent Progress in Histone Methyltransferase (G9a) Inhibitors as Anticancer Agents"", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 179, 28 June 2019 (2019-06-28), pages 537 - 546, XP085772612, DOI: 10.1016/j.ejmech.2019.06.072 *
LIU, FENG ET AL.: ""Optimization of Cellular Activity of G9a Inhibitors 7-Aminoalkoxy-quinazolines"", JOURNAL OF MEDICINAL CHEMISTRY, vol. 54, 22 July 2011 (2011-07-22), pages 6139 - 6150, XP002702500, DOI: 10.1021/jm200903z *

Also Published As

Publication number Publication date
CN115160294A (zh) 2022-10-11
CN115160294B (zh) 2023-09-29

Similar Documents

Publication Publication Date Title
JP5596139B2 (ja) 二置換フタラジンヘッジホッグ経路アンタゴニスト
ES2928773T3 (es) Inhibidores de proteína cinasas para fomentar la regeneración hepática o reducir o prevenir la muerte de hepatocitos
CN114057771B (zh) 大环化合物及其制备方法和应用
KR101335746B1 (ko) 이치환된 프탈라진 헷지호그 경로 길항제
WO2014040549A1 (fr) Composé cyclique hétéroaromatique alcynylique et son application
WO2018095398A1 (fr) Composé pyrimido[5,4-b]indolizine ou pyrimido[5,4-b]pyrrolizine, son procédé de préparation et son utilisation
WO2021088265A1 (fr) Composé d'imidazopyridine, composition pharmaceutique contenant le composé, procédé de préparation correspondant et utilisation associée
CN107056755B (zh) 五元杂环酰胺类wnt通路抑制剂
CN105705493A (zh) 喹唑啉衍生物、其制备方法、药物组合物和应用
WO2020135507A1 (fr) Dérivé d'anilinopyrimidine polysubstitué, son procédé de préparation et son application
CN107739368B (zh) N-取代-5-（（4-取代嘧啶-2-基）氨基）吲哚类衍生物及其制备方法和用途
WO2024000763A1 (fr) Inhibiteur covalent g9a/glp, son procédé de préparation et son utilisation
WO2023236820A1 (fr) Dérivé d'imidazole à cycle condensé aromatique à six chaînons, son procédé de préparation et son utilisation
CN109081818B (zh) 新型吲哚胺2,3-双加氧化酶抑制剂
CN110885332A (zh) 一种PDEδ蛋白降解靶向嵌合体及其制备方法和应用
CN109988120A (zh) 一种吲哚胺-2,3-双加氧酶抑制剂及其制备方法和用途
CN109734677A (zh) 抑制组蛋白赖氨酸甲基转移酶nsd2的小分子化合物及其应用
JP2021512930A (ja) ジオキシノキノリン系化合物、その調製方法および使用
CN108727370A (zh) 一类羟基取代的四氢-β-咔啉类小分子有机化合物及其衍生物和医药用途
AU2018278283B2 (en) Pyridoquinazoline derivatives useful as protein kinase inhibitors
CN115490689A (zh) 不可逆krasg12c抑制剂的制备及其应用
CN108383837B (zh) 一种氨基取代四氢吡啶并嘧啶类化合物或其可用盐及其制备方法与应用
CN104945414A (zh) 苯并硫杂蒽类衍生物及其制备方法与应用
CN102827160B (zh) PI3K或PI3K/m-TOR通路抑制剂及其在药学中的用途
CN108610333A (zh) 诱导MDM2自我降解E3泛素连接酶二聚体酰胺类小分子PROTACs

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: 22948854

Country of ref document: EP

Kind code of ref document: A1