WO2020001351A1 - Inhibiteur r-egf, son procédé de préparation et son utilisation - Google Patents

Inhibiteur r-egf, son procédé de préparation et son utilisation Download PDF

Info

Publication number
WO2020001351A1
WO2020001351A1 PCT/CN2019/091972 CN2019091972W WO2020001351A1 WO 2020001351 A1 WO2020001351 A1 WO 2020001351A1 CN 2019091972 W CN2019091972 W CN 2019091972W WO 2020001351 A1 WO2020001351 A1 WO 2020001351A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
cycloalkyl
halogen
amino
cancer
Prior art date
Application number
PCT/CN2019/091972
Other languages
English (en)
Chinese (zh)
Inventor
龚彦春
孟磊
郭其润
刘永强
Original Assignee
江苏威凯尔医药科技有限公司
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
Priority claimed from CN201910519558.3A external-priority patent/CN110642838B/zh
Application filed by 江苏威凯尔医药科技有限公司 filed Critical 江苏威凯尔医药科技有限公司
Publication of WO2020001351A1 publication Critical patent/WO2020001351A1/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—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
    • 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
    • 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
    • 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
    • C07D401/14—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 three or more hetero rings

Definitions

  • the present application belongs to the technical field of medicine, and particularly relates to a 2-aminopyrimidine derivative and use thereof for preparing an antitumor drug.
  • Epidermal growth factor receptor (EpidermalRowthFactorReceptor, EGFR) is a transmembrane receptor protein with tyrosine kinase activity widely distributed on human tissue cell membranes, and is a member of the erbB receptor family of tyrosine kinases.
  • EGFR ligand epidermal growth factor
  • EGFR forms a homodimer on the cell membrane, or forms a heterodimer with other receptors in the family (such as erbB2, erbB3, or erbB4) to activate and cause Phosphorylation of key tyrosine residues in EGFR cells activates the kinase domain and further activates multiple downstream signaling pathways within the cell.
  • These intracellular signaling pathways play important roles in cell proliferation, survival, and anti-apoptosis.
  • the tyrosine kinase domain of EGFR can be mutated, resulting in the activation of constitutive signals. This active signaling pathway plays a vital role in the growth, survival and migration of tumor cells.
  • the most common activating mutations are an in-frame deletion mutation in exon 19 and a missense mutation in the 858 codon (L858R). Lung cancer with EGFR mutations is highly sensitive to EGFR tyrosine kinase inhibitors (TKIs) (Science [2004] No. 304, 1497-500).
  • tyrosine kinase inhibitors that target EGFR (such as Gefitinib, erlotinib) and other drugs have achieved great success in the clinical treatment of non-small cell lung cancer (New England Journal of Medicine [2004] No. 350, 2129-39; The Lancet Oncology [2012] No. 13 Volume 3, 239-46).
  • TKI inhibitors often face relapse problems due to the development of resistance.
  • the most common drug resistance mechanism is the second mutation of T790M in EGFR, which is present in about 50% of patients with drug-resistant tumors (PLOS Medicine [2005] No. 2, 1-11).
  • Second-generation EGFR irreversible inhibitors such as Canertinib and Afatinib can overcome drug resistance, but these molecules have poor selectivity for EGFR T790M mutants, and their inhibitory effect on wild-type EGFR is relatively low. Strong, lower tolerated doses in the body.
  • CN105503827A and CN106187915A disclose compounds that selectively inhibit the EGFR T790M mutant.
  • the compounds of the present invention are different from their structures, and the compounds of the present invention are generally superior to CN105503827A in their EGFR kinase and cell inhibitory activity and selectivity to EGFR wild-type / mutant And CN106187915A patent.
  • An object of the present invention is to provide a 2-aminopyrimidine EGFR inhibitor which is highly selective for EGFR mutation and has higher safety.
  • Another object of the present invention is to provide the use of the EGFR inhibitor in the preparation of a medicament for preventing or treating an epidermal growth factor receptor (EGFR) kinase-related disease.
  • EGFR epidermal growth factor receptor
  • R 1 is selected from C 1 -C 8 alkyl or C 3 -C 8 cycloalkyl, optionally further selected from one or more selected from halogen, hydroxyl, C 1 -C 8 alkyl, C 1 -C 8 Alkoxy, halogen-substituted C 1 -C 8 alkoxy, C 3 -C 8 cycloalkyl or C 3 -C 8 cycloalkoxy substituted by a substituent;
  • R 2 is selected from hydrogen, deuterium, halogen, cyano, nitro, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 3 -C 8 cycloalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, trifluoromethyl, difluoromethyl or trifluoromethoxy;
  • R 3 is selected from C 1 -C 8 alkyl or C 3 -C 8 cycloalkyl, optionally further selected from one or more of halogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, Halogen-substituted C 1 -C 8 alkoxy, C 3 -C 8 cycloalkyl, or C 3 -C 8 cycloalkoxy;
  • X is N or CH
  • R 4 is selected from hydrogen, halogen, cyano, nitro, C 1 -C 8 alkyl, halo C 1 -C 8 alkyl, -C (O) R 5 , -C (O) NR 5 R 6 , -OR 5 , -NR 5 R 6 , -NR 5 C (O) R 6 , -NR 7 (CH 2 ) m NR 5 R 6 , -NC (O) R 7 (CH 2 ) m NR 5 R 6 , -NR 7 (CH 2 ) m NR 5 C (O) R 6 , -NR 7 (CH 2 ) m OR 6 , -NC (O) R 7 (CH 2 ) m OR 6 , -O (CH 2 ) m NR 5 R 6 or -O (CH 2 ) m NR 5 C (O) R 6 ;
  • R 5 , R 6 and R 7 are each independently selected from hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, wherein C 1 -C 8 alkyl or C 3 -C 8 cycloalkyl is optional Is further substituted with one or more selected from halogen, hydroxy, -NR 8 R 9 , C 1 -C 8 alkyl, C 1 -C 8 alkoxy, halogen substituted C 1 -C 8 alkoxy, C 3 -C 8 cycloalkyl or C 3 -C 8 cycloalkoxy substituents;
  • R 5 , R 6 and R 7 may independently form a 4-10 membered heterocyclic group
  • n 1, 2, 3 or 4;
  • R 8 and R 9 are each independently selected from hydrogen, C 1 -C 8 alkyl or C 3 -C 8 cycloalkyl.
  • R 1 is selected from C 1 -C 8 alkyl or C 3 -C 8 cycloalkyl, optionally further substituted with one or more substituents selected from halogen or hydroxyl;
  • R 2 is selected from hydrogen, deuterium, halogen or methyl
  • R 3 is selected from C 1 -C 8 alkyl or C 3 -C 8 cycloalkyl, optionally further substituted with one or more substituents selected from halogen;
  • X is N or CH
  • R 4 is selected from hydrogen, halogen, cyano, nitro, C 1 -C 8 alkyl, -NR 5 R 6 or -NR 7 (CH 2 ) m NR 5 R 6 ;
  • R 5 , R 6 and R 7 are each independently selected from hydrogen, C 1 -C 8 alkyl or C 3 -C 8 cycloalkyl;
  • R 5 , R 6 and R 7 may independently form a 4-10 membered heterocyclic group
  • n 1, 2, 3 or 4.
  • the compound of formula (I) is characterized in that:
  • R 1 is selected from C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl, optionally further substituted by one or more substituents selected from halogen;
  • R 2 is selected from hydrogen, deuterium, halogen or methyl
  • R 3 is selected from C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl
  • X is N or CH
  • R 4 is selected from -NR 5 R 6 or -NR 7 (CH 2 ) m NR 5 R 6 ;
  • R 5 , R 6 and R 7 are each independently selected from hydrogen, C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl;
  • R 5 , R 6 , and R 7 may independently form a 6-8 membered heterocyclic group
  • n 1, 2 or 3.
  • the compound of formula (I) is characterized in that:
  • R 1 is selected from methyl, ethyl, difluoromethyl, n-propyl, isopropyl or trifluoroethyl;
  • R 2 is selected from hydrogen, deuterium, F, Cl, Br or methyl
  • R 3 is selected from methyl, ethyl, n-propyl, isopropyl or cyclopropyl;
  • X is N or CH
  • R 4 is -NR 7 (CH 2 ) m NR 5 R 6 ;
  • R 5 , R 6 and R 7 are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl or cyclopropyl;
  • R 5 , R 6 , and R 7 may independently form a 6-membered heterocyclic group
  • n 1, 2 or 3.
  • a particularly preferred compound of the general formula (I) or a pharmaceutically acceptable salt thereof includes the following:
  • Another aspect of the present invention provides a method for preparing a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:
  • a compound of formula (II) and a compound of formula (III) undergo a substitution reaction in the presence of a metal catalyst to obtain a compound of formula (IV), and a reduction reaction to obtain a compound of general formula (V), and a condensation reaction to obtain a compound of formula (I), wherein R 1 , R 2 , R 3 , R 4 , X are as defined for a compound of formula (I).
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective dose of the aforementioned compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the aforementioned compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition is prepared for treating EGFR mutants, especially L858R, EGFR mutant, T790M EGFR mutants and deletion of exon 19 activate mutants for the treatment of disease-mediated diseases.
  • the aforementioned compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition is prepared for treating a disease mediated by EGFR mutant activity alone or in part. Application in therapeutic drugs.
  • Another aspect of the present invention provides the aforementioned compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the use of the aforementioned pharmaceutical composition in the preparation of a medicament for treating cancer.
  • the cancer is selected from the group consisting of ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, and non-Hodgkin cancer.
  • C 1 -C 8 alkyl refers to a straight-chain alkyl group and a branched alkyl group including 1 to 8 carbon atoms.
  • the alkyl group refers to a saturated aliphatic hydrocarbon group, such as methyl, ethyl, n- Propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2 -Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-tris Methylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl
  • cycloalkyl refers to a saturated monocyclic hydrocarbon substituent
  • C 3 -C 8 alkylcycloalkyl refers to a monocyclic cycloalkyl including 3 to 8 carbon atoms, for example, a monocyclic cycloalkyl
  • Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein one or more ring atoms are selected from nitrogen, oxygen, or S (O) r (where r is an integer of 0, Heteroatoms of 1, 2), but excluding the ring part of -OO-, -OS- or -SS-, the remaining ring atoms are carbon.
  • S (O) r where r is an integer of 0, Heteroatoms of 1, 2
  • 4-10 membered heterocyclyl refers to a cyclic group containing 4 to 10 ring atoms.
  • Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
  • Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
  • alkenyl refers to an alkyl group as defined above, which is composed of at least two carbon atoms and at least one carbon-carbon double bond
  • C 2 -C 8 alkenyl refers to a straight chain containing 2 to 8 carbons. Or containing branched alkenyl. Examples are vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.
  • alkynyl refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon triple bond
  • C 2 -C 8 alkenyl refers to a straight-chain or Contains branched alkynyl. For example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl and the like.
  • alkoxy means -O- (alkyl), wherein alkyl is as defined above.
  • C 3 -C 8 alkoxy refers to an alkyloxy group containing 1 to 8 carbons. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, and the like.
  • cycloalkoxy refers to -O- (unsubstituted cycloalkyl), wherein the definition of cycloalkyl is as described above.
  • C 3 -C 8 cycloalkoxy refers to a cycloalkyloxy group containing 3-8 carbons. Non-limiting examples include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy Wait.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or a physiologically pharmaceutically acceptable salt or prodrug thereof with other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients. ⁇ ⁇ Shape agent.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and then exerts the biological activity.
  • 6-bromo-2-methoxypyridin-3-amine (12.00 g, 59.10 mmol), acetic anhydride (48.67 g, 466.90 mmol) were sequentially added to the four-necked flask, and the reaction was terminated at 20 ° C for 1 h.
  • the reaction solution was added with water (240 ml) and stirred for 1 h, a brown precipitate was precipitated, filtered with suction, and the filter cake was dried to obtain 9.80 g of a brown solid with a yield of 68%.
  • Step 4 Synthesis of N- (6-bromo-2-methoxy-5-nitro-pyridin-3-yl) acetamide
  • N- (6-bromo-2-methoxypyridin-3-yl) acetamide (6.80 g, 27.74 mmol) and trifluoroacetic anhydride (68 ml) were sequentially added to the four-necked flask, and the temperature was lowered to 0 ° C.
  • fuming nitric acid (2.00 g, 28.58 mmol) was added dropwise, and the reaction was terminated for 0.5 h.
  • the reaction solution was slowly poured into ice water (500 g) and stirred for 1 h. An off-white precipitate was precipitated, filtered with suction, and the filter cake was dried to obtain 7.60 g of a yellow solid with a yield of 94%.
  • 1 H NMR 400 MHz, DMSO-d 6 ) 9.12 (s, 1H), 4.06 (s, 3H), 2.16 (s, 3H).
  • Step 5 Synthesis of N- (6-((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitro-pyridin-3-yl) acetamide
  • N- (6-bromo-2-methoxy-5-nitro-pyridin-3-yl) acetamide (5.60 g, 19.30 mmol), N, N, N ' -Trimethylethylenediamine (2.96g, 28.96mmol), acetonitrile (168ml), warmed to 80 ° C, and the reaction was terminated in 1h.
  • the solvent was distilled off under reduced pressure at 50 ° C, EA (70 ml) was slurried, suction filtered, washed with EA (20 ml), and the filter cake was dried to obtain 5.40 g of a yellow powder with a yield of 72%.
  • Step 6 N 2 - (2- (dimethylamino) ethyl) -6-methoxy-2 -N - Synthesis of methyl 3-nitropyridine-2,5-diamine
  • Step 8 Synthesis of 2- (isopropylsulfonyl) -3-nitropyridine
  • Step 9 Synthesis of 2- (isopropylsulfonyl) pyridin-3-amine
  • Step 10 Synthesis of 2,5-dichloro-N- (2- (isopropylsulfonyl) pyridin-3-yl) pyrimidin-4-amine
  • reaction solution was slowly poured into a solution of acetic acid (8g) in ice-water (720ml) to quench, precipitate was precipitated, and isopropyl ether (360ml) was added to beat and disperse for 0.5h, suction-filtered, and the filter cake was dried to obtain 27.00g of a yellowish solid
  • the yield was 86.4%.
  • Step 11 5-chloro-N 2- (6-((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitro-pyridin-3-yl) Synthesis of -N 4- (2- (isopropylsulfonyl) pyridin-3-yl) pyrimidine-2,4-diamine
  • Step 12 N 5 - (5- chloro-4 - ((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) -N 2 - (2- (dimethylamino ) Ethyl) -6-methoxy-N 2 -methylpyridine 2,3,5-triamine
  • Step 13 N- (5-((5-chloro-4-((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -2-((2- Synthesis of (dimethylamino) ethyl) (meth) amino) -6-methoxypyridin-3-yl) acrylamide
  • reaction solution was quenched by adding 5% NaHCO 3 (100 ml), and extracted by adding EA (50 ml x 5).
  • the organic phases were combined, concentrated, and subjected to crude column chromatography to obtain a brown-yellow solid 0.14 g with a yield of 10%.
  • Step 4 Synthesis of N- (6-chloro-2- (difluoromethoxy) pyridin-3-yl) acetamide
  • 6-chloro-2- (difluoromethoxy) pyridine-3-amine 34.20 g, 175.77 mmol
  • acetic anhydride 171 g, 1.67 mol
  • the reaction solution was added with water (800 ml) and stirred for 1 h.
  • a brown precipitate was precipitated, extracted with DCM (200 ml x 3), washed once with 100 ml of water, and the combined organic phases were concentrated to give 28.60 g of a yellow solid with a yield of 69%.
  • Step 5 Synthesis of N- (6-chloro-2- (difluoromethoxy) -5-nitro-pyridin-3-yl) acetamide
  • N- (6-chloro-2- (difluoromethoxy) pyridin-3-yl) acetamide (22.60 g, 95.52 mmol), and trifluoroacetic anhydride (113 ml) were sequentially added to the four-necked flask.
  • the reaction solution was slowly poured into ice-water (1000 ml) and stirred for 1 h, extracted with methyl tert-ether (300 ml x 3), the organic phases were combined, concentrated, and column chromatography gave 3.40 g of a brown solid with a yield of 13%.
  • Step 7 6- (difluoromethoxy) -N 2 - (2- (dimethylamino) ethyl) 2 -N - Synthesis of methyl 3-nitropyridine-2,5-diamine
  • Step 8 5-Chloro -N 2 - (2- (difluoromethoxy) -6 - ((2- (dimethylamino) ethyl) (methyl) amino) -5-nitro-pyridin-3 -Yl) -N 4- (2- (isopropylsulfonyl) pyridin-3-yl) pyrimidine-2,4-diamine
  • reaction solution was cooled to 25-35 ° C, water (20 ml) was added to quench the reaction, and DCM (20 ml x 2) was added for extraction.
  • the organic phases were combined, washed with saturated brine (10 ml), and the organic phase was concentrated.
  • the crude column chromatography yielded Brownish yellow solid 0.25g, yield 25%, directly into the next step.
  • Step 9 N 5 - (5- chloro-4- (2- (isopropylsulfonyl) pyridin-3-ylamino) pyrimidin-2-yl) -6- (difluoromethoxy) -N 2 - Synthesis of (2- (dimethylamino) ethyl) -N2-methylpyridin-2-yl) 2,3,5-triamine
  • Step 10 N- (5- (5-chloro-4- (2- (isopropylsulfonyl) pyridin-3-ylamino) pyrimidin-2-ylamino) -6- (difluoromethoxy)- Synthesis of 2-((2- (dimethylamino) ethyl) (meth) amino) pyridin-3-yl) acrylamide
  • reaction solution was quenched by adding 5% NaHCO 3 (15 ml), and extracted by adding DCM (10 ml x 2).
  • the organic phases were combined, concentrated, and subjected to crude column chromatography. A scrape was obtained to obtain 0.052 g of an off-white solid with a yield of 52%.
  • Step 1 Synthesis of 6- (N, N, N'-trimethylethylenediamino) -5-nitro-3-amino-2- (2,2,2-trifluoroethoxy) with reference to Example 4 ) Pyridine.
  • Step 2 Synthesis of sodium cyclopropane sulfonate
  • Step 4 Synthesis of 2- (cyclopropylsulfonyl) pyridine-3-amine
  • Step 5 Synthesis of 2,5-dichloro-N- (2- (cyclopropylsulfonyl) pyridin-3-yl) pyrimidin-4-amine
  • Step 6 5-Chloro-N 4- (2- (cyclopropylsulfonyl) pyridin-3-yl) -N 2- (6-((2- (dimethylamino) ethyl) (methyl) Synthesis of Amino) -5-nitro-2- (2,2,2-trifluoroethoxy) pyridin-3-yl) pyrimidine-2,4-diamine
  • Step 7 N 5 - (5- chloro-4 - ((2- (cyclopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) -N 2 - (2- (dimethylamino ) Ethyl) -N 2 -methyl-6- (2,2,2-trifluoroethoxy) pyridine-2,3,5-triamine
  • Step 8 N- (5-((5-chloro-4-((2- (cyclopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -2-((2- Synthesis of (dimethylamino) ethyl) (methyl) amino) -6- (2,2,2-trifluoroethoxy) pyridin-3-yl) acrylamide
  • reaction solution was quenched by adding 5% NaHCO 3 (30 ml), and extracted by adding DCM (20 ml x 2).
  • Step 1 Synthesis of N- (6-bromo-2-difluoromethoxy-5-nitropyridin-3-yl) acetamide with reference to Example 5.
  • Step 2 Synthesis of N- (2- (difluoromethoxy) -6- (4-methylpiperazin-1-yl) -5-nitro-pyridin-3-yl) acetamide
  • Step 3 Synthesis of 2- (difluoromethoxy) -6- (4-methylpiperazin-1-yl) -5-nitro-pyridine-3-amine
  • Step 4 5-Chloro -N 2 - (2- (difluoromethoxy) -6- (4-methylpiperazin-l-yl) -5-nitro - pyridin-3-yl) -N 4 Synthesis of-(2- (isopropylsulfonyl) pyridin-3-yl) pyrimidine-2,4-diamine
  • Step 5 N 2- (5-amino-2- (difluoromethoxy) -6- (4-methylpiperazin-1-yl) pyridin-3-yl) -5-chloro-N 4- ( Synthesis of 2- (isopropylsulfonyl) pyridin-3-yl) pyrimidine-2,4-diamine
  • Step 6 N- (5-((5-chloro-4-((2- (isopropylsulfonyl) pyridin-3-yl) amino) pyrimidin-2-yl) amino) -6- (difluoromethyl Synthesis of oxy) -2- (4-methylpiperazin-1-yl) pyridin-3-yl) acrylamide
  • N 2- (5-amino-2- (difluoromethoxy) -6- (4-methylpiperazin-1-yl) pyridin-3-yl) -5 was sequentially added to a four-necked flask.
  • the ⁇ - 33 p-ATP isotope test method was used to test the inhibitory effect of the compound on the kinases EGFR (WT), EGFR (T790M / L858R), and IGF1R, and the compound's half inhibitory concentration of the enzyme's inhibitory activity, IC 50 , was obtained.
  • the drug AZD-9291 is prepared by referring to the method in patent WO2013014448A1.
  • the compound was dissolved to a specific concentration with 100% DMSO, and then it was gradient diluted to a different concentration of the test sample (DMSO solution) using an automatic sampling device.
  • the reaction solution was subjected to ion exchange filtration system to remove unreacted ATP and ADP plasma generated by the reaction, and then measured the 33 P isotope radiation in the substrate.
  • the inhibitory effect of different concentrations of compounds on kinase activity was calculated based on the amount of kinase added to the inhibitor system at different concentrations, and the IC 50 was inhibited by graphpad prism fitting.
  • the compound of the present invention has better EGFR (L858R / T790M) mutant kinase inhibitory activity.
  • Examples 1, 2, 3, 5, 7, 9, 12, 13, 14, The compounds of 15, 16, and 18 have better selectivity for EGFR (L858R / T790M) mutant kinase compared to the positive control.
  • the compounds of Examples 7, 8, 9, and 11 have significant relative IGF1R compared to the positive control.
  • Kinase has the advantage of selectivity, and the risk of side effects of elevated blood glucose caused by off-target is smaller.
  • the MTT method was used to test the cell activity of the compound on Hcc827, and the inhibitory concentration IC 50 of the compound's inhibitory cell proliferation activity was obtained.
  • Hcc827 cell line was cultured under the condition of RPMI-1640 + 10% FBS.
  • a 96-well cell culture plate was inoculated with 100 ⁇ L of a suspension of Hcc827 cells in logarithmic growth phase with a density of 5 ⁇ 10 4 / ml.
  • the culture plate was cultured in an incubator for 24 hours to attach the cells (37 ° C, 5% CO 2 ).
  • Each compound has been dissolved in DMSO to prepare a 10 mM stock solution, which is diluted 400 times the target concentration with DMSO and diluted to 2 times the target concentration with serum-free medium to maintain the DMSO concentration in the drug solution at 0.5. %.
  • DMSO fetal sulfate
  • 100 ⁇ L / well of each concentration of drug solution was sequentially added. Three replicates were set for each concentration, and a blank control and a negative control were set. The culture was continued at 37 ° C and 5% CO 2 for 72 hours.
  • the MTT method was used to test the cell activity of the compound on NCI-H1975, and the IC 50 value of the half-inhibition concentration of the compound to inhibit cell proliferation activity was obtained.
  • NCI-H1975 cell line was cultured under the condition of RPMI-1640 + 10% FBS, and 100 ⁇ L of NCI-H1975 cell suspension in logarithmic growth phase was inoculated in a 96-well cell culture plate with a density of 5X 10 4 / ml, the culture plate was cultured in an incubator for 24 hours to make the cells adhere (37 ° C, 5% CO 2 ).
  • Terminate the culture add 20 ⁇ L of MTT solution (5mg / ml) to each well, continue to incubate at 37 ° C, 5% CO 2 for 4 h, discard the medium, add DMSO 150 ⁇ L / well, shake at room temperature for 10 min, and measure the OD at a wavelength of 490 nM Value, and calculated IC 50 value by Graphpad Prism data processing.
  • MTT solution 5mg / ml
  • A431 cell line was cultured under the conditions of DMEM + 10% FBS.
  • a 96-well cell culture plate was inoculated with 100 ⁇ L of A431 cell suspension in logarithmic growth phase, with a density of 5 ⁇ 10 4 / ml. The plate was cultured in an incubator for 24 hours to make the cells adhere (37 ° C, 5% CO 2 ). .
  • Each compound has been dissolved in DMSO to prepare a 10 mM stock solution, which is diluted 400 times the target concentration with DMSO and diluted to 2 times the target concentration with serum-free medium to maintain the DMSO concentration in the drug solution at 0.5. %.
  • DMSO fetal sulfate
  • 100 ⁇ L / well of each concentration of drug solution was sequentially added. Three replicates were set for each concentration, and a blank control and a negative control were set. The culture was continued at 37 ° C and 5% CO 2 for 72 hours.
  • the compound-positive drug of the present invention has a better inhibitory activity on H1975 (EGFR-T790M / L858R) cells, and the control-positive drug has a significant selectivity for suppressing mutant cell lines.

Landscapes

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

Abstract

Font l'objet de la présente invention un dérivé de 2-aminopyrimidine ayant une structure de formule (I), une composition pharmaceutique contenant ledit composé de formule (I) et ses utilisations pour la préparation d'un récepteur de facteur de croissance épidermique (R-EGF) de kinase pour la prévention ou le traitement de maladies y relatives, notamment les utilisations pour la prévention ou le traitement de cancers en rapport avec le R-EGF.
PCT/CN2019/091972 2018-06-27 2019-06-20 Inhibiteur r-egf, son procédé de préparation et son utilisation WO2020001351A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201810704813.7 2018-06-27
CN201810704813 2018-06-27
CN201910519558.3A CN110642838B (zh) 2018-06-27 2019-06-17 Egfr抑制剂及其制备和应用
CN201910519558.3 2019-06-17

Publications (1)

Publication Number Publication Date
WO2020001351A1 true WO2020001351A1 (fr) 2020-01-02

Family

ID=68986204

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/091972 WO2020001351A1 (fr) 2018-06-27 2019-06-20 Inhibiteur r-egf, son procédé de préparation et son utilisation

Country Status (1)

Country Link
WO (1) WO2020001351A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022101184A1 (fr) 2020-11-11 2022-05-19 Bayer Aktiengesellschaft Dérivés de n-[2-({4-[3-(anilino)-4-oxo-4,5,6,7-tétrahydro-1h-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl)oxy)éthyl]prop-2-énamide et composés similaires utilisés en tant qu'inhibiteurs d'egfr pour le traitement du cancer
WO2023213882A1 (fr) 2022-05-04 2023-11-09 Bayer Aktiengesellschaft Inhibiteurs irréversibles de mutegfr
WO2024028316A1 (fr) 2022-08-02 2024-02-08 Bayer Aktiengesellschaft Dérivés de 1h-pyrrolo[3,2-b]pyridine en tant qu'inhibiteurs irréversibles de mutant egfr pour le traitement du cancer

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011140338A1 (fr) * 2010-05-05 2011-11-10 Gatekeeper Pharmaceuticals, Inc. Composés modulant l'activité des récepteurs egfr et méthodes pour traiter ou prévenir des troubles à l'aide de ceux-ci
CN105503827A (zh) * 2014-10-11 2016-04-20 上海翰森生物医药科技有限公司 Egfr抑制剂及其制备方法和用途
CN106187915A (zh) * 2015-05-27 2016-12-07 上海翰森生物医药科技有限公司 具有alk与egfr双重活性的抑制剂及其制备方法和应用
CN106883213A (zh) * 2015-12-15 2017-06-23 合肥中科普瑞昇生物医药科技有限公司 一种新型egfr和alk激酶的双重抑制剂

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011140338A1 (fr) * 2010-05-05 2011-11-10 Gatekeeper Pharmaceuticals, Inc. Composés modulant l'activité des récepteurs egfr et méthodes pour traiter ou prévenir des troubles à l'aide de ceux-ci
CN105503827A (zh) * 2014-10-11 2016-04-20 上海翰森生物医药科技有限公司 Egfr抑制剂及其制备方法和用途
CN106187915A (zh) * 2015-05-27 2016-12-07 上海翰森生物医药科技有限公司 具有alk与egfr双重活性的抑制剂及其制备方法和应用
CN106883213A (zh) * 2015-12-15 2017-06-23 合肥中科普瑞昇生物医药科技有限公司 一种新型egfr和alk激酶的双重抑制剂

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JANG, JAEBONG ET AL.: "Discovery of a Potent Dual ALK and EGFR T790M Inhibitor", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 136, 3 May 2017 (2017-05-03), pages 497 - 510, XP055600972, ISSN: 0223-5234, DOI: 10.1016/j.ejmech.2017.04.079 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022101184A1 (fr) 2020-11-11 2022-05-19 Bayer Aktiengesellschaft Dérivés de n-[2-({4-[3-(anilino)-4-oxo-4,5,6,7-tétrahydro-1h-pyrrolo[3,2-c]pyridin-2-yl]pyridin-3-yl)oxy)éthyl]prop-2-énamide et composés similaires utilisés en tant qu'inhibiteurs d'egfr pour le traitement du cancer
WO2023213882A1 (fr) 2022-05-04 2023-11-09 Bayer Aktiengesellschaft Inhibiteurs irréversibles de mutegfr
WO2024028316A1 (fr) 2022-08-02 2024-02-08 Bayer Aktiengesellschaft Dérivés de 1h-pyrrolo[3,2-b]pyridine en tant qu'inhibiteurs irréversibles de mutant egfr pour le traitement du cancer

Similar Documents

Publication Publication Date Title
WO2018045957A1 (fr) Inhibiteur de cdk4/6, son procédé de préparation et son application
JP5740409B2 (ja) キナーゼ阻害剤
CN106883213B (zh) 一种egfr和alk激酶的双重抑制剂
JP6606561B2 (ja) ピリミドピロール類化合物、その調製方法、医薬用組成物及びその応用
CN112552294B (zh) 含哌嗪杂环类衍生物抑制剂、其制备方法和应用
JP2020510642A (ja) ｏ−アミノヘテロアリールアルキニル基含有化合物およびその製造方法と用途
EA036453B1 (ru) Замещенные производные 2-анилинпиримидина в качестве модуляторов egfr
WO2016026445A1 (fr) Composés indazole utilisés comme inhibiteurs de la fgfr kinase, préparation et utilisation associées
JP2016525509A (ja) プロテインチロシンキナーゼモジュレーター及び使用方法
WO2014025128A1 (fr) Dérivé de n2,n4-bis(4-(pipérazine-1-yl)phényl)pirimidine-2,4-diamine ou sel pharmaceutiquement acceptable de celui-ci, et composition contenant celle-ci en tant que substance active pour prévenir ou traiter un cancer
WO2020001351A1 (fr) Inhibiteur r-egf, son procédé de préparation et son utilisation
CN111196814B (zh) 芳环连二噁烷并喹唑啉或喹啉类化合物、组合物及其应用
WO2019233459A1 (fr) Inhibiteur du récepteur de facteur de croissance épidermique humain, procédé de préparation correspondant et utilisation associée
WO2020001350A1 (fr) Inhibiteur r-egf, son procédé de préparation et son utilisation
JP2020523348A (ja) プロテインキナーゼ阻害剤としてのアミノチアゾール化合物
ES2709003T3 (es) Compuestos de 5-(piridin-2-il-amino)-pirazina-2-carbonitrilo y su uso terapéutico
CN109311852A (zh) 作为egfr抑制剂的苯胺嘧啶化合物的结晶
WO2021129561A1 (fr) Composé de pyridine à substitution cyano et composé de pyrimidine à substitution cyano, et leur procédé de préparation et leur utilisation
CA3090876C (fr) Compose de dioxazoline, son procede de preparation et ses applications
WO2020221209A1 (fr) Inhibiteur de cd73, son procédé de préparation et son utilisation
WO2023024545A1 (fr) Inhibiteur de fgfr4 et composition, et leurs utilisations pour la préparation d'un médicament
Yan et al. Discovery of novel 2, 4-diarylaminopyrimidine derivatives as potent and selective epidermal growth factor receptor (EGFR) inhibitors against L858R/T790M resistance mutation
CN115322158A (zh) 作为krasg12c蛋白抑制剂的取代喹唑啉类化合物
CN110642838B (zh) Egfr抑制剂及其制备和应用
WO2022007841A1 (fr) Inhibiteur de l'egfr, procédé de préparation associé, et application pharmaceutique associée

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: 19827317

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC, EPO FORM 1205A DATED 07.05.2021

122 Ep: pct application non-entry in european phase

Ref document number: 19827317

Country of ref document: EP

Kind code of ref document: A1