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WO2017143842A1 - Composé diaminopyrimidine substitué et composition comprenant ce composé et utilisation associée - Google Patents

Composé diaminopyrimidine substitué et composition comprenant ce composé et utilisation associée Download PDF

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Publication number
WO2017143842A1
WO2017143842A1 PCT/CN2016/110913 CN2016110913W WO2017143842A1 WO 2017143842 A1 WO2017143842 A1 WO 2017143842A1 CN 2016110913 W CN2016110913 W CN 2016110913W WO 2017143842 A1 WO2017143842 A1 WO 2017143842A1
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Prior art keywords
compound
substituted
acid
pharmaceutically acceptable
diaminopyrimidine
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Chinese (zh)
Inventor
王义汉
李焕银
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Shenzhen Targetrx Inc
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Shenzhen Targetrx Inc
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention belongs to the field of medical technology, and in particular to substituted diaminopyrimidine compounds and compositions comprising the same and uses thereof.
  • Epidermal growth factor receptors are members of the ErbB receptor family, and the ErbB receptor family is the four closely related receptor tyrosine kinases EGFR (ErbB-1), HER2/c-neu (ErbB-2), a subfamily of Her3 (ErbB-3) and Her4 (ErbB-4).
  • EGFR is a cell surface receptor for members of the epidermal growth factor family (EGF family) of the extracellular protein ligand. Mutations that affect EGFR expression or activity may result in cancer. It has been reported that EGFR is unregulated in most solid tumors such as lung cancer, breast cancer and brain tumors. It is estimated that 30% of epithelial cancers are associated with mutations, amplification or dysregulation of EGFR or family members.
  • Treatments for inhibition of EGFR have been developed based on drugs or small molecule inhibitor drugs such as gefitinib and erlotinib.
  • gefitinib and erlotinib are beneficial for 10% to 40% of patients.
  • acquired resistance to gefitinib or erlotinib after a period of treatment has become a major clinical problem.
  • T790M which is the "guard" of EGFR.
  • these T790Ms targeting EGFR inhibitors also have relative inhibitory activity against wild-type EGFR, which limits clinical applications. Therefore, it is necessary to further develop more effective types of EGFR inhibitors that only target mutant proteins rather than wild-type proteins.
  • gefitinib, erlotinib and other EGFR inhibitors have achieved remarkable results in the treatment of advanced NSCLC with EGFR mutation, but subsequently found that EGFR-TKI is primary resistant in the treatment of NSCLC. Or secondary resistance, we are facing new challenges in the treatment of advanced NSCLC, and then carry out new exploration and find countermeasures.
  • the present invention discloses a substituted diaminopyrimidine compound and a composition comprising the same and use thereof, which have better EGFR kinase inhibitory activity and/or have better pharmacodynamics/pharmacokinetics Kinetic properties that can be used to treat, prevent, and alleviate diseases mediated by EGFR kinases.
  • a substituted diaminopyrimidine compound such as a diaminopyrimidine compound represented by formula (I), or a crystalline form thereof, a pharmaceutically acceptable salt, a hydrate or a solvent compound,
  • R 1a , R 1b , R 1c , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6 , R 7 , R 8 , R 9a , R 9b , R 9c , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17a and R 17b are each independently hydrogen, deuterium, halogen or trifluoromethyl;
  • R 11 is a trifluoromethyl group.
  • the compound is selected from the group consisting of the compounds or pharmaceutically acceptable salts thereof:
  • the first route is as follows: a 2,4-dihalopyrimidine compound and m-N-Boc aniline are reacted under basic conditions to produce a 2-halopyrimidine compound, and the 2-halopyrimidine compound is protected by Boc to obtain an amino compound.
  • amino compound is reacted with deuterated or undeuterated acrylic acid, or deuterated or undeuterated acryloyl halide to obtain an amide compound VI;
  • the phenolic compound is reacted with an alkyl halide under basic conditions to obtain an alkoxy compound,
  • the alkoxy compound is substituted under basic conditions, 4-F is substituted with a fatty amine to obtain a nitro compound, the nitro compound is reduced to an aniline, and the aniline is reacted with the 2-halopyrimidine compound to obtain a formula (1).
  • a substituted diaminopyrimidine compound
  • the second reaction scheme is as follows: an alkoxy compound is reacted with an N-Boc-protected piperazine compound under basic conditions to obtain XI, a nitro group is reduced to an amine group to form a compound XII, and a 2-halopyrimidine compound VI
  • the reaction results in a docking compound XIII which is decarboxylated under acidic conditions to give the piperazine compound XIV and is reacted with an acid anhydride to give a substituted diaminopyrimidine compound of the formula (1).
  • the cerium isotope content of cerium in the deuterated position is at least 0.015%, preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, more preferably greater than the natural strontium isotope content. More than 95%, more preferably more than 99%.
  • the strontium isotope content of strontium at each metamorphic position is at least greater than the natural strontium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, and even more preferably greater than 75%. More preferably greater than 95%, more preferably greater than 99%.
  • the yttrium isotope content of each of the R 9a , R 9b , R 9c , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17a and R 17b is at least 5%, preferably More than 10%, more preferably more than 15%, more preferably more than 20%, more preferably more than 25%, more preferably more than 30%, more preferably more than 35%, more preferably more than 40%, more preferably More than 45%, more preferably more than 50%, more preferably more than 55%, more preferably more than 60%, more preferably more than 65%, more preferably more than 70%, more preferably more than 75%, more preferably more than 80%
  • the two Rs contain ruthenium, more preferably three R ⁇ , more preferably four R ⁇ , more preferably five R ⁇ , more preferably six R ⁇ , more preferably seven R ⁇ , preferably eight R ⁇ , more preferably nine R ⁇ , more preferably ten R ⁇ , more preferably eleven R ⁇ , more preferably twelve R ⁇ , More preferably, thirteen R ⁇ , more preferably fourteen R ⁇ , more preferably fifteen R
  • the solvent used in the first scheme or the second reaction scheme is dichloromethane, dichloroethane, ethyl acetate, methyl acetate, isopropyl acetate, n-hexane, n-heptane, petroleum.
  • Ether n-butanol, ethanol, isobutanol, tert-butanol, isopropanol, n-propanol, n-pentanol, isoamyl alcohol, acetone, acetonitrile, n-hexane, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, 1
  • 4-dioxane ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide
  • 4-dioxane ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide
  • 4-dioxane ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, N,N-dimethylformamide, N,
  • the base used in the first scheme or the second reaction scheme is potassium carbonate, sodium carbonate, sodium hydrogencarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, diisopropylethylamine, At least one of 4-N,N-lutidine or pyridine;
  • the acid used in the first scheme or the second reaction scheme is trifluoroacetic acid, acetic acid, concentrated hydrochloric acid, dilute hydrochloric acid, concentrated sulfuric acid, dilute sulfuric acid, concentrated nitric acid, dilute nitric acid, hydrochloric acid dioxane solution, hydrochloric acid ethanol solution, p-toluene At least one of a sulfonic acid or a benzenesulfonic acid.
  • the above reaction temperature is from -30 ° C to 200 ° C, more preferably from -10 ° C to 100 ° C.
  • reaction time is from 0 to 48 h, more preferably from 0 to 24 h, still more preferably from 0 to 6 h.
  • a pharmaceutically acceptable carrier is hydrated with a compound described in the first aspect of the invention, or a crystalline form thereof, a pharmaceutically acceptable salt, a prodrug, a stereoisomer, an isotope variant
  • the solvates or solvates are mixed to form a pharmaceutical composition.
  • the present invention also discloses a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a substituted diaminopyrimidine compound as described above, or a crystalline form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof, A pharmaceutical composition of a stereoisomer, prodrug or isotopic variation.
  • the invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein.
  • isotopes which may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, respectively. , 31 P, 32 P, 35 S, 18 F and 36 Cl. a compound, or an enantiomer, a diastereomer, an isomer, or a pharmaceutically acceptable salt or solvate of the present invention, wherein an isotope or other isotopic atom containing the above compound is within the scope of the present invention .
  • isotopically-labeled compounds of the present invention such as the radioisotopes of 3 H and 14 C, are also among them, useful in tissue distribution experiments of drugs and substrates. ⁇ , ie 3 H and carbon-14, ie 14 C, are easier to prepare and detect and are preferred in isotopes.
  • Isotopically labeled compounds can be prepared in a conventional manner by substituting a readily available isotopically labeled reagent with a non-isotopic reagent using the protocol of the examples.
  • it further comprises other therapeutic agents, which are drugs for cancer, cell proliferative diseases, inflammation, infection, immune diseases, organ transplantation, viral diseases, cardiovascular diseases or metabolic diseases. .
  • compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 10 to 1000 mg of the compound of the invention per agent.
  • the "one dose" is a capsule or tablet.
  • the present invention also discloses the use of a substituted diaminopyrimidine compound as described above, or a crystalline form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof, for the preparation of a therapeutic, prophylactic and mitigating mediated by a protein kinase A pharmaceutical composition of the disease.
  • the compound of the present invention has excellent inhibitory activity against protein kinase (Kinase), particularly against EGFR kinase, the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, Hydrates or solvates, as well as pharmaceutical compositions containing the compounds of the invention as the main active ingredient, are useful for the treatment, prevention, and alleviation of diseases mediated by protein kinases, particularly against EGFR kinases.
  • the compounds of the invention are useful in the treatment of diseases such as cancer, cell proliferative diseases, inflammation, infections, immune diseases, organ transplants, viral diseases, cardiovascular diseases or metabolic diseases.
  • the substituted diaminopyrimidine compound disclosed in the present invention and the composition comprising the same have excellent inhibition to EGFR kinase, and have better pharmacokinetic parameter characteristics, and can increase the drug concentration of the compound in the animal, Improving drug efficacy and safety; the substituted diaminopyrimidine compounds disclosed herein and compositions comprising the same are useful for the treatment, prevention, and alleviation of diseases mediated by protein kinases, particularly EGFR kinases.
  • Step 1 Preparation of 3-(2-chloro-5-trifluoromethyl)pyrimidine-4-aminophenyl tert-butyl ester (Compound 3);
  • Step 2 Preparation of 3-(2-chloro-5-trifluoromethyl)pyrimidine-4-aminophenyl acrylamide (Compound 5);
  • Acetone (30 mL) was added to a 100 mL vial, and 5-fluoro-2-nitrophenol (2.0 g, 12.7 mmol), anhydrous potassium carbonate (3.5 g, 25.4 mmol), and deuterated iodomethane (2.4) were sequentially added with stirring. g, 16.5 mmol), warmed to 60 ° C and stirred for 2 h. The mixture was cooled to room temperature, and the residue was evaporated. EtOAcjjjjjjjjjjjj .
  • Step 4 Preparation of 1-[4-(3-d 3 -methoxy-4-nitrophenyl)]acetylpiperazine (Compound 9);
  • N,N-dimethylformamide (4 mL) was added to a 25 mL single-necked flask, and 4-fluoro-2-d3-methoxynitrobenzene (0.4 g, 2.3 mmol) and anhydrous potassium carbonate were added sequentially with stirring. 0.64g, 4.6mmol), 1- acetyl-piperazine (0.38g, 3.0mmol), the reaction mixture was warmed to 80 °C, the reaction overnight under N 2 phenol. After cooling to room temperature, water (20 mL) was added, and ethyl acetate (30 mL) was evaporated. The yield was 77.0%.
  • Step 5 Preparation of 1-[4-(3-d 3 -methoxy-4-aminophenyl)]acetylpiperazine (Compound 10);
  • Step 6 Preparation of N- (3- (2- (4- acetyl-piperazin-1-yl) 2-d 3 - methoxyphenoxy) -5-trifluoromethyl-pyrimidin -4-yl) phenyl Acrylamide (Compound 11)
  • Step 2 Preparation of N-(3-(2-(4-d 3 -acetylpiperazin-1-yl) 2-methoxyanilino)-5-trifluoromethylpyrimidin-4-amino)benzene Acrylamide (compound 15)
  • Triethylamine (2 mL) was slowly added dropwise to trifluoroacetic acid, and deuterated acetic anhydride (0.1 mL) was slowly added dropwise, and the reaction was stirred for 10 minutes in an ice water bath. After completion of the reaction, water (10 mL) was added to quench the reaction, and the mixture was separated. The organic layer was washed with EtOAc EtOAc EtOAc.
  • this example uses 2,4,6-d 3 -3-N-Boc-aniline instead of 3-N-Boc-aniline to obtain the target product (Compound 30) 80 mg.
  • the yield was 37%.
  • the difference is that N-(3-d 3 -methoxy-nitrophenyl)-2,2,3,3, 5,5,6,6-d is used in this example. 8 -acetylpiperazine was used in place of N-acetylpiperazine to obtain 150 mg of the target product (Compound 34) in a yield of 41.9%.
  • N-(3-d 3 -methoxy-nitro-2,6-d2-phenyl)-d 3 -acetyl-2,2 is used in this example.
  • 3,3,5,5,6,6-d 8 -piperazine instead of N-(3-d 3 -methoxy-nitro-2,6-d 2 -phenyl)-2,2,3, 3,5,5,6,6-d 8 -acetylpiperazine, 190 mg of the target product (Compound 40) was never obtained, and the yield was 54.8%.
  • the biological evaluation of the compounds was carried out by evaluating the compounds of the invention in a number of tests to determine their biological activity. For example, the ability of a compound of the invention to inhibit a variety of protein kinases of interest can be tested. Some of the compounds tested showed potent inhibitory activity against EGFR kinase. Furthermore, anti-proliferative activity in some of these compounds was screened in human A431 skin cancer cells and human NCI-H1975 and HCC827 lung cancer cell lines, and the activity was demonstrated to be in the range of 1-50 nM. The cytotoxic or growth inhibitory effects of the compounds on the tumor cells of interest were evaluated.
  • Test compounds were dissolved in DMSO to make a 20 mM stock solution. The solution was diluted in DMSO to a final concentration of 100 times the dilution. Dilute to 10 times the final concentration of the dilution solution with the buffer.
  • EGFR and EGFR [T790M/L858R] kinase assay After buffer preparation, the enzyme was mixed with different concentrations of pre-diluted compounds for 10 minutes, each double well. The corresponding substrate and ATP were added and reacted at room temperature for 20 minutes (in which a negative positive control was set). After the reaction is completed, the detection reagent is added, and after incubation at room temperature for 30 minutes, the machine is detected and data is collected. Data analysis and mapping according to Graphpad 5.0 software.
  • EGFR [d746-750] Kinase Assay: After the buffer was prepared, the mixed solution of the enzyme and the antibody was mixed with the different concentrations of the compound prepared by pre-dilution for 10 minutes, and the concentration was doubled. Kinase tracer 199 was added and incubated for 60 minutes at room temperature (where a negative positive control was set). After the reaction is completed, the machine is tested, the data is collected, and the analysis and mapping are performed according to the following formula.
  • IC50 [(ABS test-ABS start)/(ABS control-ABS start)]x100
  • Example 9 >60 ⁇ 10
  • the substituted diaminopyrimidines of Examples 1 to 9 exhibited relatively low inhibitory activity (IC 50 greater than 60) and EGFR L858R/T790M mutants (associated with EGFR WT). It is resistant to commercially available EGFR inhibitors) and exhibits excellent inhibitory activity (IC 50 less than 10), indicating that the compounds of the present invention have a strong selective inhibitory ability against EGFR.
  • Cell lines skin cancer cells A431; lung cancer cells HCC827; all cultured in RPMI1640 medium containing 10% fetal bovine serum, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin.
  • test compound preparation The test compound was dissolved in DMSO to prepare a 20 mM stock solution and stored at -20 °C. The solution was diluted to a final concentration of 200 times with a DMSO gradient. When the drug is added, it is diluted with a cell culture medium to a 4-fold final concentration of the working solution.
  • MTS cell viability assay Trypsin digested logarithmic growth phase cells, inoculate 150 ⁇ l in 96-well plates at an optimized density, and add 4 ⁇ l of compound 50 ⁇ l/well diluted in the medium 24 hours later (see Table 2. for concentration settings). A well of the same volume of 0.5% DMSO was added as a control. After the cells were cultured for 72 hours, MTS was assayed for cell viability. The specific method is as follows: adherent cells, the medium is discarded, and a mixture containing 20 ⁇ l of MTS and 100 ⁇ l of the medium is added to each well. OD490 was detected after being placed in an incubator for 1-4 hours, with the OD650 value as a reference. The GraphPad Prism software produces a dose-effect curve and calculates the IC 50 . The results are shown in Table 2.
  • Example number Skin cancer cell IC 50 (nM) Lung cancer cell IC 50 (nM) Example 1 >1000 ⁇ 60
  • Example 2 >1000 ⁇ 60
  • Example 3 >1000 ⁇ 60
  • Example 4 >1000 ⁇ 60
  • Example 5 >1000 ⁇ 60
  • Example 6 >1000 ⁇ 60
  • Example 7 >1000 ⁇ 60
  • Example 8 >1000 ⁇ 60
  • Example 9 >1000 ⁇ 60
  • the compound of the present invention has an inhibitory effect on the proliferation of cancer cells in vitro; wherein the inhibition of proliferation of lung cancer cells in vitro is stronger than that of skin cancer cells in vitro.
  • Rats were fed a standard diet and given water. Fasting began 16 hours before the test.
  • the drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the eyelids at a time point of 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration.
  • Rats were briefly anesthetized after inhalation of ether, and 300 ⁇ L of blood samples were collected from the eyelids in test tubes. There was 30 ⁇ L of 1% heparin salt solution in the test tube. The tubes were dried overnight at 60 ° C before use. After the blood sample collection was completed at a later time point, the rats were anesthetized with ether and sacrificed.
  • Plasma samples were centrifuged at 5000 rpm for 5 minutes at 4 ° C to separate plasma from red blood cells. Pipette 100 ⁇ L of plasma into a clean plastic centrifuge tube to indicate the name and time point of the compound. Plasma was stored at -80 °C prior to analysis. The concentration of the compound of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.
  • the experimental results show that the compound of the present invention has better pharmacokinetics in animals relative to the control compound, and thus has better pharmacodynamics and therapeutic effects.
  • Microsomal experiments human liver microsomes: 0.5 mg/mL, Xenotech; rat liver microsomes: 0.5 mg/mL, Xenotech; coenzyme (NADPH/NADH): 1 mM, Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer Agent (pH 7.4).
  • Preparation of stock solution A certain amount of the powder of the compound example was accurately weighed and dissolved to 5 mM with DMSO, respectively.
  • phosphate buffer 100 mM, pH 7.4.
  • the pH was adjusted to 7.4, diluted 5 times with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer (100 mM) containing 100 mM potassium phosphate, 3.3 mM magnesium chloride, and a pH of 7.4.
  • NADPH regeneration system containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U/mL G-6-PD, 3.3 mM magnesium chloride was prepared and placed on wet ice before use.
  • Formulation stop solution acetonitrile solution containing 50 ng/mL propranolol hydrochloride and 200 ng/mL tolbutamide (internal standard). Take 25057.5 ⁇ L of phosphate buffer (pH 7.4) into a 50 mL centrifuge tube, add 812.5 ⁇ L of human liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL. 25057.5 ⁇ L of phosphate buffer (pH 7.4) was taken into a 50 mL centrifuge tube, and 812.5 ⁇ L of SD rat liver microsomes were added and mixed to obtain a liver microsome dilution having a protein concentration of 0.625 mg/mL.
  • the corresponding compound had a reaction concentration of 1 ⁇ M and a protein concentration of 0.5 mg/mL.
  • 100 ⁇ L of the reaction solution was taken at 10, 30, and 90 min, respectively, and added to the stopper, and the reaction was terminated by vortexing for 3 min.
  • the plate was centrifuged at 5000 x g for 10 min at 4 °C.
  • 100 ⁇ L of the supernatant was taken into a 96-well plate to which 100 ⁇ L of distilled water was previously added, mixed, and sample analysis was performed by LC-MS/MS.
  • the deuterated diaminopyrimidines of Examples 1 to 9 can improve metabolic stability by comparison with the undeuterated compound CO-1686.

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Abstract

La présente invention concerne un composé diaminopyrimidine substitué, une composition le comprenant et une utilisation associée. Ce composé diaminopyrimidine substitué est un composé diaminopyrimidine représenté par la formule (I), ou une forme cristalline, un sel pharmaceutiquement acceptable, un promédicament, un stéréoisomère, un hydrate ou un solvate de ce composé. Le composé diaminopyrimidine substitué et la composition comprenant ce composé selon la présente invention présentent une excellente activité inhibitrice sur les kinases EGFR avec des paramètres pharmacocinétiques améliorés et peuvent augmenter la concentration médicamenteuse du composé chez l'animal de façon à améliorer l'efficacité et la sécurité d'un médicament.
PCT/CN2016/110913 2016-02-23 2016-12-20 Composé diaminopyrimidine substitué et composition comprenant ce composé et utilisation associée Ceased WO2017143842A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020140054A1 (fr) 2018-12-28 2020-07-02 Spv Therapeutics Inc. Inhibiteurs de kinase cycline-dépendants
RU2820555C2 (ru) * 2018-12-27 2024-06-05 Хинова Фармасьютикалс Инк. Ингибитор fak и комбинации лекарственных средств с ним

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106146406A (zh) * 2016-02-23 2016-11-23 深圳市塔吉瑞生物医药有限公司 一种取代的二氨基嘧啶类化合物及包含该化合物的组合物及其用途
CN107344925B (zh) * 2016-05-04 2022-11-11 正大天晴药业集团股份有限公司 氘代二苯基氨基-三氟甲基嘧啶化合物
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CN110204529A (zh) * 2018-02-28 2019-09-06 朱允涛 一种氘代的三嗪类化合物的制备方法和用途
EP3792257B1 (fr) 2018-05-07 2024-07-17 Hinova Pharmaceuticals Inc. Composé de défactinib deutéré et son utilisation
BR112021012682A2 (pt) * 2018-12-27 2021-09-08 Hinova Pharmaceuticals Inc. Inibidor de fak e combinação de fármaco do mesmo
EP4349339A4 (fr) * 2021-05-25 2025-05-14 Hinova Pharmaceuticals Inc. Composition pharmaceutique pour le traitement du cancer et son utilisation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103269704A (zh) * 2010-11-01 2013-08-28 西建阿维拉米斯研究公司 杂环化合物和其用途
CN106146406A (zh) * 2016-02-23 2016-11-23 深圳市塔吉瑞生物医药有限公司 一种取代的二氨基嘧啶类化合物及包含该化合物的组合物及其用途

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX356753B (es) * 2012-03-15 2018-06-12 Celgene Avilomics Res Inc Formas solidas de un inhibidor de cinasa del receptor del factor de crecimiento epidermico.
NO2718543T3 (fr) * 2014-02-04 2018-01-06

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103269704A (zh) * 2010-11-01 2013-08-28 西建阿维拉米斯研究公司 杂环化合物和其用途
CN106146406A (zh) * 2016-02-23 2016-11-23 深圳市塔吉瑞生物医药有限公司 一种取代的二氨基嘧啶类化合物及包含该化合物的组合物及其用途

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2820555C2 (ru) * 2018-12-27 2024-06-05 Хинова Фармасьютикалс Инк. Ингибитор fak и комбинации лекарственных средств с ним
WO2020140054A1 (fr) 2018-12-28 2020-07-02 Spv Therapeutics Inc. Inhibiteurs de kinase cycline-dépendants

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