WO2023082052A1 - Composé de 2-aminopyrimidine cyclique et son application - Google Patents

Composé de 2-aminopyrimidine cyclique et son application Download PDF

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WO2023082052A1
WO2023082052A1 PCT/CN2021/129582 CN2021129582W WO2023082052A1 WO 2023082052 A1 WO2023082052 A1 WO 2023082052A1 CN 2021129582 W CN2021129582 W CN 2021129582W WO 2023082052 A1 WO2023082052 A1 WO 2023082052A1
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substituted
unsubstituted
cyclic
alkyl
cycloalkyl
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PCT/CN2021/129582
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Chinese (zh)
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丁克
丁健
陈灏
谢华
陆小云
张弢
任小梅
童林江
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暨南大学
中国科学院上海药物研究所
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Priority to PCT/CN2021/129582 priority Critical patent/WO2023082052A1/fr
Publication of WO2023082052A1 publication Critical patent/WO2023082052A1/fr

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    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention relates to the field of chemistry and medicine, in particular to a cyclic 2-aminopyrimidine compound and its application.
  • Continuous proliferation is one of the most important characteristics of tumor cells.
  • the continuous development and proliferation of tumor cells can destroy the structure and function of tissues and organs, leading to the death of patients due to organ failure.
  • cell proliferation is strictly regulated by cell proliferation signals, but tumor cells can escape the regulation of proliferation signals through a series of mutations. Therefore, blocking the relevant mechanisms of tumor cells through drugs is an important means of tumor treatment.
  • the receptor tyrosine kinase represented by EGFR is the key protein that receives growth factor proliferation signal.
  • Tumor cells can fix the protein in its active conformation through the mutation of EGFR, so that it can continuously activate downstream signaling pathways related to proliferation without relying on exogenous ligands.
  • EGFR mutations In patients with non-small cell lung cancer, about 20% of patients have EGFR mutations and show EGFR mutation-dependent tumor cell proliferation, most of which are deletion mutations of exon 19 (19deletion mutation) and exon 21.
  • a point mutation (L858R) in the daughter is the receptor tyrosine kinase represented by EGFR.
  • EGFR inhibitory therapy has greatly improved the survival period of patients with non-small cell lung cancer. Taking gefitinib as an example, its use has increased the survival period of patients from less than 10 months of traditional chemotherapy to nearly 30 months. The above evidence shows that EGFR is a reliable and effective drug target.
  • the EGFR kinase inhibitors gefitinib and erlotinib which were launched in 2003 and 2004, will develop drug resistance after a period of medication, which is reflected in the decline in the sensitivity of tumor cells to drugs.
  • One of the main reasons (about 25%) is the second point mutation (T790M) in the kinase region of EGFR.
  • the mutation hinders the binding of drugs through amino acids with increased steric hindrance, reducing the binding ability of drugs to EGFR , on the other hand, it enhances the interaction between the kinase and the substrate ATP, thereby inactivating the competitive tyrosine kinase inhibitors.
  • the inhibitor osimertinib which was launched in 2015, effectively overcomes the drug resistance problem of the T790M point mutation by introducing covalent interactions. It was first approved as a second-line drug for the treatment of patients who developed drug resistance after using gefitinib. At the same time, further studies have shown that when osimertinib is used as a first-line drug, it can achieve better results than traditional EGFR therapy and can effectively target patients with brain metastases. Therefore, covalently bound EGFR inhibitors represented by osimertinib will become the first choice for patients with non-small cell lung cancer in the foreseeable future.
  • osimertinib also produces drug resistance.
  • C797S third point mutation
  • the present invention provides a kind of cyclic 2-aminopyrimidine compounds, which can effectively inhibit EGFR protein kinase drug-resistant mutants (such as EGFR L858R/T790M , EGFR L858R/T790M/C797S , EGFR 19del/T790M/ C797S ) activity.
  • EGFR protein kinase drug-resistant mutants such as EGFR L858R/T790M , EGFR L858R/T790M/C797S , EGFR 19del/T790M/ C797S
  • R1 is selected from: hydrogen, hydroxyl, carbonyl, aryl, heteroaryl, sulfonyl, phosphorus oxy, substituted or unsubstituted alkyl or cycloalkyl, substituted or unsubstituted N, S, O hetero Atomic alkyl or cycloalkyl, the substituents are independently selected from halogen, alkyl, cycloalkyl, alkyl containing N, S, O, cycloalkyl containing N, S, O, hydroxyl, cyanide group, amino group, ester group, amido group, aryl group, aryl group containing N, S, O, sulfonyl group;
  • R 2 , R 3 , R 5 , R 6 , and R 13 are each independently selected from: hydrogen, halogen, cyano, nitro, trifluoromethyl, substituted or unsubstituted C 1 -C 6 alkyl, substituted or Unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 1 -C 6 alkoxy, or substituted or unsubstituted C 3 -C 6 cycloalkoxy, wherein the substituents are independently selected from halogen, alkyl, cycloalkyl, alkyl containing N, S, O, C 3 -C 6 cycloalkyl containing N, S, O, hydroxyl, cyano, amino, ester, amido, Aryl, aryl containing N, S, O, sulfonyl;
  • R 4 is selected from: substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted cycloalkyl containing N, S, O, said Substituents include C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 epoxyalkyl, amino, ester, cyano, amido, thioamide; R 4 also includes -(CH 2 ) m NR 8 R 9 , -(CH 2 ) m OCR 7 R 8 R 9 or -(CH 2 ) m CR 7 R 8 R 9 ; wherein, m is selected from: 0, 1, 2, 3 or 4;
  • R 7 is selected from: hydrogen or C 1 -C 3 alkyl
  • R 8 and R 9 are independently selected from: hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, or R 8 , R 9 and the N or C connected to them together form a substituted or unsubstituted heteroatom-containing Monocyclic, condensed, spiro or bridged rings;
  • L is selected from: substituted or unsubstituted straight-chain C 2 -C 8 alkyl, substituted or unsubstituted straight-chain C 2 -C 8 alkenyl, wherein one or more of the alkyl and alkenyl groups are The methyl group can be independently replaced by O, S and NR 14 , wherein one or more S, N or C in the straight chain can form a substituted or unsubstituted heteroatom-containing single ring, condensed ring, Spiro ring or bridged ring, the substituents are independently selected from halogen, alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, hydroxyl, cyano, amino, ester, amido, aryl, heteroaryl group, sulfonyl group;
  • R 14 is selected from: hydrogen, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, alkyl containing N, S, O, cycloalkyl containing N, S, O, hydroxyl, cyano, amino , ester group, amido group, aryl group, aryl group containing N, S, O, sulfonyl group.
  • the cyclic 2-aminopyrimidine compound is:
  • n is selected from 3 to 10;
  • the cyclic 2-aminopyrimidine compound is:
  • n 1 and n 2 are selected from 1 to 6;
  • the cyclic 2-aminopyrimidine compound is:
  • n 1 and n 2 are selected from 1 to 6;
  • Ring A is selected from aryl, C 3 -C 6 cycloalkyl, C 3 -C 6 epoxyalkyl, aryl containing N, S, O;
  • R 1 is S(O) 2 R 12
  • R 12 is selected from: hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted or unsubstituted C 3 - C 6 cycloalkyl, substituted or unsubstituted C 3 -C 6 epoxyalkyl.
  • R is selected from hydrogen, halogen, haloarene, cyano, trifluoromethyl
  • R 3 is selected from hydrogen, trifluoromethyl, halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted Substituted alkyl containing N, S, O, substituted or unsubstituted C 3 ⁇ C 6 cycloalkyl containing N, S, O;
  • the R is selected from:
  • the cyclic 2-aminopyrimidine compound is selected from one of the following:
  • the present invention also provides the application of the cyclic 2-aminopyrimidine compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule.
  • the tumor is a malignant tumor with EGFR gene mutation.
  • the tumor is a malignant tumor with EGFR L858R/T790M/C797S or EGFR 19del/T790M/C797S mutation.
  • the tumor is: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, gastrointestinal glioma, leukemia, histiocytic lymphoma, nasopharyngeal cancer, head and neck cancer, colon cancer, rectal cancer, or glioma.
  • the invention also provides a pharmaceutical composition for preventing and treating tumors.
  • a pharmaceutical composition comprising an active ingredient and a pharmaceutically acceptable carrier, the active ingredient including the above-mentioned cyclic 2-aminopyrimidine compound or a pharmaceutically acceptable salt thereof or a stereoisomer or a prodrug thereof molecular.
  • the present invention has the following beneficial effects:
  • the cyclic 2-aminopyrimidine compounds of the present invention or their pharmaceutically acceptable salts or their stereoisomers or their prodrug molecules can inhibit EGFR family proteases, thereby inhibiting various tumor cells growth. Compared with wild-type cancer cells, the compound of the present invention has higher selectivity for mutant cancer cells.
  • the compound of the present invention can especially effectively inhibit the activity of EGFR protein kinase drug-resistant mutants (such as EGFR T790M and EGFR T790M/C797S ), and can selectively act on EGFR L858R/T790M , EGFR 19del and EGFR L858R/T790M/C797S lung cancer cells, It can overcome the clinical drug resistance of non-small cell lung cancer and other tumor patients induced by the existing third-generation selective EGFR T790M small molecule inhibitors Osimertinib (AZD9291), Olmutinib (HM6171), Rociletinib (CO-1686).
  • EGFR protein kinase drug-resistant mutants such as EGFR T790M and EGFR T790M/C797S
  • the compound of the present invention can be used to prepare antineoplastic drugs, and can overcome the drug resistance induced by existing drugs such as gefitinib, erlotinib, especially Osimertinib (AZD9291), and is a novel class of drugs that can overcome existing drugs.
  • the protein kinase inhibitor that is resistant to EGFR tyrosine kinase inhibitors and has selectivity and good pharmacokinetic properties can be used for treating hyperproliferative diseases such as tumors of humans and other mammals.
  • any variable eg, R1 , R2, etc.
  • its definition at each occurrence is independent of its definition at each other occurrence.
  • combinations of substituents and variables are permissible only if such combinations render the compounds stable.
  • a line drawn from a substituent into a ring system indicates that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic it means that such bonds are only to any suitable carbon atoms of adjacent rings. It is understood that one of ordinary skill in the art can select substituents and substitution patterns of the compounds of the present invention to provide compounds that are chemically stable and can be readily synthesized from readily available starting materials by skill in the art and by methods set forth below. If a substituent is itself substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, so long as the structure is stabilized.
  • alkyl used herein refers to a saturated chain alkyl
  • chain alkyl refers to a linear or branched alkyl, such as C 1 ⁇ C 4 alkyl refers to a group having 1 to 4 carbon atoms Saturated straight-chain or branched alkyl, wherein examples of straight-chain alkyl include but not limited to ethyl, n-propyl, etc., examples of branched-chain alkyl include but not limited to isopropyl, tert-butyl, etc.;
  • cycloalkyl refers to an alkyl group with a ring structure, such as C 3 to C 4 cycloalkyl refers to an alkyl group with a ring structure having 3 to 4 carbon atoms, examples include but are not limited to cyclopropyl , Cyclobutyl, methyl substituted cyclopropyl, etc.
  • alkoxy means a straight chain or branched chain alkyl group containing an oxygen atom at the end, examples include but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and the like.
  • Halo or "halo” as used herein means chlorine, fluorine, bromine and iodine.
  • the present invention provides a compound of formula 1, its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule,
  • R 1 , R 2 , R 3 , R 4 , X, Y and L are as defined above.
  • the present invention includes the free form of the compound of formula 1, as well as its pharmaceutically acceptable salts and stereoisomers.
  • Some specific exemplary compounds herein are protonated salts of amine compounds.
  • the term "free form” refers to the amine compound in non-salt form.
  • the inclusion of pharmaceutically acceptable salts includes not only the exemplary salts of the specific compounds described herein, but also all typical pharmaceutically acceptable salts of the free form of the compounds of formula 1 .
  • the free form of a particular salt of the compound may be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with an appropriate dilute aqueous base, such as dilute aqueous NaOH, dilute potassium carbonate, dilute ammonia and dilute aqueous sodium bicarbonate.
  • the free forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms for the purposes of the invention.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from compounds of the present invention that contain a basic or acidic moiety by conventional chemical methods.
  • the salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base with a stoichiometric amount or excess of the desired salt form of an inorganic or organic acid in a suitable solvent or combination of solvents.
  • salts of acidic compounds are formed by reaction with an appropriate inorganic or organic base.
  • pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts of the compounds of the present invention formed by reacting a basic compound of the present invention with an inorganic or organic acid.
  • conventional nontoxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like, as well as organic acids such as acetic, propionic, succinic, glycolic, hard Fatty acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetyl Salts prepared from oxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid,
  • salts refer to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Particular preference is given to ammonium, calcium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as amino acid, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethyl Diamine, N-Ethylmorpholine, N-Ethylpiperidine, Glucosamine, Glucosamine, Histidine, Hydroxocobalamin, Isopropylamine, Lysine, Methylglucamine, Morpholine, Piperazine , piperidine, quack, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.
  • the compounds with the structure of formula 1 and the pharmaceutically acceptable salts thereof provided by the present invention can be used for treating transitional proliferative diseases or symptoms such as human or other mammalian tumors.
  • transitional proliferative diseases or symptoms such as human or other mammalian tumors.
  • Drug metabolites and prodrugs metabolites of the compounds involved in the present invention and their pharmaceutically acceptable salts, and prodrugs that can be transformed into structures of the compounds involved in the present invention and their pharmaceutically acceptable salts in vivo, It is also included in the claims of this application.
  • composition also provides a pharmaceutical composition, which contains active ingredients in a safe and effective amount range, and a pharmaceutically acceptable carrier.
  • active ingredient in the present invention refers to the compound of formula 1 or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule in this invention.
  • active ingredients and pharmaceutical compositions described in the present invention can be used as EGFR protease inhibitors. In another preferred embodiment, it is used for preparing drugs for preventing and/or treating tumors.
  • a cyclic 2-aminopyrimidine compound with a novel structure is provided.
  • the compounds can effectively inhibit the action of drug-resistant mutants of EGFR protein kinase, and can be used to prepare antitumor drugs.
  • This type of compound can overcome the drug resistance induced by existing drugs such as gefitinib, erlotinib, especially osimertinib (AZD9291), has selectivity for wild-type EGFR, and has good pharmacokinetics nature.
  • the synthetic route is as follows:
  • 6-Methoxy-1H-indole (1 g, 6.79 mmol) was dissolved in 25 mL of dry dichloromethane, and the system was replaced with argon, then placed in an ice bath and cooled to 0°C.
  • a 3 mol/L methylmagnesium bromide ether solution (3.4 mL, 10.18 mmol) was added dropwise to the solution.
  • 2,4,5-trichloropyrimidine (1.25 g, 6.79 mmol) was dissolved in another 25 mL of dry dichloromethane, and the solution was added dropwise to the reaction system.
  • the reaction was quenched with 30 mL of saturated sodium bicarbonate solution, the mixture was passed through a celite filter cake and extracted with ethyl acetate, the organic phase was washed twice with saturated brine, dried and concentrated.
  • 6-(5-amino-2-morpholinephenoxy)hexanol (0.2g, 0.67mmol)
  • 3-(2,5-dichloropyrimidin-4-yl)-1-(ethylsulfonyl) -1H-indol-6-ol (0.25g, 0.67mmol)
  • Step 6 2 5 -Chloro-1 1 -(ethylsulfonyl)-4 4 -morpholine-1 1 H-5,12-dioxa-3-aza-1(3,6)-indole - Preparation of 2(4,2)-pyrimidine-4(1,3)-benzocyclododecane (HC57866)
  • the synthesis method refers to Example 1, and the intermediate (7) is replaced by 5-bromopentan-1-ol.
  • the synthesis method refers to Example 1, and the intermediate (7) is replaced by 7-bromoheptan-1-ol.
  • the synthesis method refers to Example 1, and the intermediate (7) is replaced by 8-bromooctan-1-ol.
  • the synthesis method refers to Example 1, and the intermediate (6) is replaced by 2,4-difluoro-5-nitrophenol.
  • the synthesis method refers to Example 1, and the intermediate (6) is replaced by 4-chloro-2-fluoro-5-nitrophenol.
  • the synthesis method refers to Example 1, and the intermediate (6) is replaced by 4-methyl-2-fluoro-5-nitrophenol.
  • the synthesis method refers to Example 8, and the intermediate (12) is replaced by cyclopropylboronic acid.
  • the synthesis method refers to Example 8, the intermediate (12) is 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxolane alkanes instead.
  • the synthesis method refers to Example 8, the intermediate (12) is 4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-di Oxybenzaldehyde instead.
  • the synthetic method refers to Example 8, the intermediate (12) is 2-(3,3-dimethyl-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2 -Dioxolane instead.
  • the synthetic method refers to Example 8, the intermediate (12) is 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxane Pentane instead.
  • the synthetic route is as follows:
  • the synthesis method refers to Example 1, step 4, 6-bromohexan-1-ol is replaced by 5-bromopentene.
  • Step 3 4-(6-(allyloxy)-1-(ethylsulfonyl)-1H-indol-3-yl)-5-chloro-N-(4-morpholine-3-(pentyl Preparation of -4-ene-1-acyloxy)phenyl)pyrimidin-2-amine (17)
  • the synthesis method refers to Example 1, step 5, intermediates 5 and 8 are replaced by intermediates 15 and 16, respectively.
  • Step 3 -2 5 -chloro- 1 1- (ethylsulfonyl)-4 4 -morpholinyl-1 1 H-5,12-dioxa-3-aza-1(3,6 Preparation of )-indole-2(4,2)-pyrimidine-4(1,3)-benzocyclododecane-9-ene (HC614)
  • step 4 morpholine was replaced by 1-methyl-4-(piperidin-4-yl)piperazine.
  • the synthetic method refers to Example 1, and in step 4, morpholine is replaced by 1-methylpiperazine.
  • Example 1 for the synthesis method, the intermediate (6) was replaced by 4-trifluoromethyl-2-fluoro-5-nitrophenol.
  • step 2 is omitted, and intermediate (6) is replaced by 2-fluoro-4-methyl-5-nitrophenol.
  • the synthesis method refers to Example 14, and the raw material 5-bromopentene in step 2 is replaced by 6-bromohexene.
  • the synthesis method refers to Example 14, and the raw material 5-bromopentene in step 2 is replaced by 4-bromobutene. .
  • the synthesis method refers to Example 19, the raw material 19 in Step 1 is replaced by 3-(2-(benzyloxy)ethoxy)propan-1-ol.
  • the synthesis method refers to Example 19, and the raw material 19 in step 1 is replaced by 2-(2-(benzyloxy)ethoxy)ethan-1-ol.
  • the synthesis method refers to Example 19, and the raw material 19 in step 1 is replaced by 4-(2-(benzyloxy)ethoxy)butanol.
  • the synthesis method refers to Example 19, and the raw material 19 in Step 1 is replaced by 1,4-cyclohexanedimethanol.
  • EGFR (WT) is the wild-type epidermal growth factor receptor
  • EGFR (T790M) is the epidermal growth factor receptor with the 790th amino acid mutated from threonine to methionine
  • EGFR (L858R) is the epidermal growth factor receptor with the 790th amino acid mutation The 858th amino acid is mutated from leucine to arginine epidermal growth factor receptor
  • EGFR (L861Q) is the epidermal growth factor receptor with the 861st amino acid mutation from leucine to glutamine
  • EGFR ( L858R/T790M) is an epidermal growth factor receptor with a double mutation of amino acid 858 from leucine to glutamine and amino acid 790 from threonine to methionine.
  • EGFR (L858R/T790M/C797S) has a mutation of amino acid 858 from leucine to glutamine, amino acid 790 from threonine to methionine, and amino acid 797 from cysteine Triple mutant epidermal growth factor receptor mutated to serine.
  • EGFR (19del/T790M/C797S) is a triple-mutated epidermis in which exon 19 is partially deleted, amino acid 790 is mutated from threonine to methionine, and amino acid 797 is mutated from cysteine to serine growth factor receptors.
  • Enzyme-Linked Immunosorbent Assay Enzyme-Linked Immunosorbent Assay, ELISA.
  • EGFR WT was purchased from Eurofins
  • EGFR 19del/T790M/C797S kinase was purchased from BPS Bioscience.
  • the main experimental steps are as follows: Enzyme reaction substrate Poly(Glu,Tyr) 4:1 was diluted to 20 ⁇ g/mL with potassium ion-free PBS (10mM sodium phosphate buffer, 150mM NaCl, pH 7.2-7.4), and reacted at 37°C for 12 -16h coated microtiter plates.
  • reaction buffer 50mM HEPES pH7.4, 50mM MgCl 2 , 0.5mM MnCl 2 , 0.2mM Na 3 VO 4 , 1mM DTT
  • test compound or solvent control 50mM MgCl 2 , 0.5mM MnCl 2 , 0.2mM Na 3 VO 4 , 1mM DTT
  • reaction buffer 50mM HEPES pH7.4, 50mM MgCl 2 , 0.5mM MnCl 2 , 0.2mM Na 3 VO 4 , 1mM DTT
  • IgG labeled with horseradish peroxidase was added and reacted on a shaking table at 37°C for 0.5h. After washing the plate again, add 2 mg/mL OPD color developing solution, and react in the dark at 25°C for 1-10 min. The reaction was terminated by adding 2M H 2 SO 4 , and detected with an adjustable wavelength microplate microplate reader SPECTRAMAX 190 with a wavelength of 492 nm. IC50 values were obtained from inhibition curve analysis.
  • Table 1 Listed in Table 1 are the compound numbers (corresponding to the compound numbers in the above examples) and the detection results of the compounds' inhibitory activities on various kinases.
  • the cyclic 2-aminopyrimidine compounds of the present invention can inhibit the EGFR triple mutant protease, thereby inhibiting the growth of various tumor cells.
  • the compound of the present invention can especially effectively and selectively inhibit the activity of EGFR protein kinase drug-resistant mutant (EGFR 19del/T790M/C797S ), can selectively act on EGFR L858R/T790M and EGFR 19del/T790M/C797S lung cancer cells, and can overcome the existing Clinical drug resistance in patients with non-small cell lung cancer and other tumors induced by third-generation selective EGFR T790M small molecule inhibitors Osimertinib (AZD9291), Olmutinib (HM6171), Rociletinib (CO-1686).

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Abstract

L'invention concerne un composé de 2-aminopyrimidine cyclique ayant une structure représentée par la formule (1), ou un sel pharmaceutiquement acceptable ou un stéréoisomère ou une molécule de promédicament de celui-ci, et une application de celui-ci. Le composé de l'invention peut inhiber efficacement l'activité de mutants pharmacorésistants de la protéine kinase EGFR (tels que EGFRT790M et EGFR19del/T790M/C797S), et peut surmonter la pharmacorésistance clinique chez des patients tumoraux atteints d'un cancer du poumon non à petites cellules, etc., induite par des inhibiteurs à petites molécules EGFR T790M sélectifs de troisième génération existants tels que l'Osimertinib (AZD9291), l'Olmutinib (HM6171) et le Rocilétinib (CO-1686).
PCT/CN2021/129582 2021-11-09 2021-11-09 Composé de 2-aminopyrimidine cyclique et son application WO2023082052A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110214138A (zh) * 2017-01-26 2019-09-06 韩美药品株式会社 嘧啶化合物及其药物用途
WO2020211853A1 (fr) * 2019-04-18 2020-10-22 华东理工大学 Nouvel inhibiteur de la mutation triple de l'egfr et utilisation associée
WO2020233669A1 (fr) * 2019-05-22 2020-11-26 上海翰森生物医药科技有限公司 Inhibiteur contenant un dérivé d'indole, son procédé de préparation et son utilisation

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Publication number Priority date Publication date Assignee Title
CN110214138A (zh) * 2017-01-26 2019-09-06 韩美药品株式会社 嘧啶化合物及其药物用途
WO2020211853A1 (fr) * 2019-04-18 2020-10-22 华东理工大学 Nouvel inhibiteur de la mutation triple de l'egfr et utilisation associée
WO2020233669A1 (fr) * 2019-05-22 2020-11-26 上海翰森生物医药科技有限公司 Inhibiteur contenant un dérivé d'indole, son procédé de préparation et son utilisation

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