WO2020216371A1 - Inhibiteur d'egfr et son utilisation - Google Patents

Inhibiteur d'egfr et son utilisation Download PDF

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Publication number
WO2020216371A1
WO2020216371A1 PCT/CN2020/086871 CN2020086871W WO2020216371A1 WO 2020216371 A1 WO2020216371 A1 WO 2020216371A1 CN 2020086871 W CN2020086871 W CN 2020086871W WO 2020216371 A1 WO2020216371 A1 WO 2020216371A1
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amino
compound
pharmaceutically acceptable
reaction
formula
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PCT/CN2020/086871
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English (en)
Chinese (zh)
Inventor
刘磊
谷晓辉
刘扬
诸舜伟
薛黎婷
于晓虹
张国宝
唐任宏
任晋生
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江苏先声药业有限公司
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Priority to CN202080006242.5A priority Critical patent/CN113166103B/zh
Publication of WO2020216371A1 publication Critical patent/WO2020216371A1/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
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • 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

Definitions

  • the present invention relates to a fourth-generation (T790M/C797S mutation) EGFR kinase inhibitor and its medical application, and specifically discloses a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • EGFR Epithelial growth factor Receptor
  • EGF epithelial growth factor
  • EGFR belongs to the ErbB receptor family, which includes EGFR (ErbB-1), HER2/c-neu (ErbB-2), HER 3 (ErbB-3), and HER 4 (ErbB-4).
  • EGFR is also called HER1, ErbB1.
  • EGFR is widely distributed on the surface of mammalian epithelial cells, fibroblasts, glial cells, keratinocytes and other cells. The EGFR signaling pathway plays an important role in the physiological processes of cell growth, proliferation and differentiation.
  • EGFR is divided into three regions: extracellular ligand binding region, transmembrane region and intracellular kinase region.
  • extracellular ligand binding region When EGFR is bound by the corresponding ligand, it will induce the formation of homotypic or heterodimers, thereby activating the intracellular tyrosine kinase pathway, making it autophosphorylate, and guiding downstream phosphorylation, including MAPK, Akt and JNK Pathway to induce cell proliferation.
  • EGFR tyrosine kinase inhibitors (Tyrosine Kinase Inhibitor, TKI) block tumors by blocking the binding of endogenous ATP to the intracellular kinase region, thereby inhibiting receptor phosphorylation and the activation of downstream signal transduction molecules Proliferation of cells.
  • TKI Tyrosine Kinase Inhibitor
  • the present invention provides the compound represented by formula (I), its stereoisomer, racemate, and mutual Mmutomers, isotopic labels, nitrogen oxides or pharmaceutically acceptable salts thereof,
  • Y is selected from O, S, C(O), C(R 1 R 2 ) or NR 1 ;
  • Z is selected from or
  • R 1 and R 2 are the same or different, independently selected from H, C 1-6 alkoxy, C 1-6 alkylamino, C 2-12 dialkylamino, C 1-6 alkyl, C 3 -6 cycloalkyl, or R 1 and R 2 are connected to form a 4-7 membered ring;
  • M and P are the same or different, and are independently selected from N or C;
  • Ring A is selected from the following groups that are unsubstituted or optionally substituted with one, two or more R 3 : phenyl, 5-6 membered heteroaryl, 5-7 membered heterocycloalkyl; X, Q, W is the same or different, and is independently selected from N or CR 3 ;
  • Each Ra is the same or different, and is independently selected from H, halogen, CN, NH 2 , OH, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 heteroalkyl, C 3- 6 Heterocycloalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 2-8 dialkylamino;
  • Ar is selected from the following groups that are unsubstituted or optionally substituted with one, two or more R 4 : C 6-10 aryl, 5-10 membered heteroaryl,
  • Each R 4 is the same or different and is independently selected from the following groups: H, halogen, CN, NO 2 , unsubstituted or optionally substituted with one, two or more R: OH, NH 2 , aldehyde group , C 3-6 cycloalkyloxy, C 3-6 heterocycloalkyloxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-16 cycloalkyl , C 3-6 cycloalkenyl, C 4-6 cycloalkynyl, C 1-6 heteroalkyl and 3-15 membered heterocyclic group,
  • R' is selected from H, halogen, CN, OH, NH 2 , Me, Et, Pr, iPr, tBu, OMe, CF 3 , CHF 2 , CH 2 F, cyclopropyl and CH 2 CF 3 ;
  • L is selected from O, S, NR 5, carbonyl, unsubstituted or optionally substituted with one, two or more R substituents of the following groups: C 0- 4 is an alkylene group, a C 3-6 cycloalkylene Group, C 3-6 heterocycloalkylene (wherein, the S contains its possible valence, such as thioether, sulfoxide or sulfone), R 5 is selected from H or C 1-3 alkyl;
  • R 6 is selected from the group consisting of H, halogen, CN, OH, NO 2 , unsubstituted or optionally substituted with one, two or more R groups: NH 2 , C 1-6 alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-14 cycloalkyl, C 3-6 cycloalkenyl, C 4-6 cycloalkynyl, phenyl and 3-14 membered hetero Ring base.
  • Y is selected from NR 1 .
  • Z is selected from
  • R 1 and R 2 are independently selected from H or C 1-6 alkyl.
  • R 1 and R 2 are independently selected from H or C 1-3 alkyl.
  • R 1 and R 2 are independently selected from H, methyl or isopropyl.
  • Y is selected from NH.
  • Z is selected from or
  • M and P are independently selected from C.
  • X and Q are independently selected from CH or N.
  • Q is selected from CH.
  • W is selected from N or CR 3
  • R 3 is selected from the H, halogen, CN, unsubstituted or optionally substituted with one, two or more of the following R a substituents group: OH, C 1- 4 alkyl or C 3-6 cycloalkyl.
  • W is selected from N or CR 3
  • R 3 is selected from the H, halogen, unsubstituted or optionally substituted with one, two or more of the following R a substituents group: OH, C 1-4 alkyl or C 3-6 cycloalkyl group, said R a is selected from halogen, CN or C 1-4 alkyl.
  • W is selected from N or CR 3
  • said R 3 is selected from halogen, cyclopropyl, methoxy, trifluoromethyl.
  • W is selected from N or CR 3
  • said R 3 is selected from Br, Cl, cyclopropyl, methoxy, trifluoromethyl.
  • ring A is selected from unsubstituted or optionally substituted with one, two or more R 3 substituents of the following groups: phenyl, 5-6 membered heteroaryl.
  • At least one of X, Q, M, and P is N.
  • R 3 is selected from H, halogen, OH, NH 2 , CN, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, ethynyl, vinyl, methoxy, trifluoro methyl.
  • R 3 is selected from H, halogen, OH, NH 2 , CN, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, ethynyl, vinyl.
  • R 3 is selected from OH, ethynyl, vinyl, methoxy.
  • Ar is selected from the following groups unsubstituted or optionally substituted with one, two or more R 4 : phenyl, benzo 5-6 membered ring, 5-6 membered azaaryl, 6 membered Azaaryl and 5-membered ring.
  • Ar is selected from the following groups unsubstituted or optionally substituted with one, two or more R 4 : phenyl, benzo 5-membered ring, 5-6 membered azaaryl, 6-membered aza Aryl and 5-membered ring.
  • Ar is selected from the following groups that are unsubstituted or optionally substituted with one, two or more R 4 :
  • Ar is selected from the following groups that are unsubstituted or optionally substituted with one, two or more R 4 :
  • Ar is selected from:
  • Ar is selected from:
  • R 4 is selected from H, methoxy, ethoxy, propoxy, isopropoxy, methyl, ethyl, propyl, isopropyl, halogen, CN, ethynyl, vinyl, halogen Substituted C 1-4 alkoxy, C 3-6 epoxyalkyloxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl.
  • R 4 is selected from methoxy, ethoxy, methyl, ethyl, halogen, vinyl, halogenated C 1-4 alkoxy, C 3-6 epoxyalkyloxy, C 3- 6 cycloalkyl, acetyl, 1-hydroxyethyl, methoxyethyl.
  • L is selected from carbonyl, C 0 alkylene, CH 2 , NH.
  • L is selected from carbonyl or CH 2 .
  • L is selected from a carbonyl group or a C 0 alkylene group.
  • R 6 is selected from the group consisting of H, halogen, CN, OH, NO 2 , unsubstituted or optionally substituted by one, two or more R groups: NH 2 , C 1-6 alkyl,
  • R 6 is selected from the following groups which are unsubstituted or optionally substituted with one, two or more R: C 1-6 alkyl,
  • R 6 is selected from the group consisting of H, halogen, CN, OH, NO 2 , unsubstituted or optionally substituted by one, two or more R groups: NH 2 , C 1-6 alkyl,
  • R 6 is selected from H, CN, OH, NO 2 , NHR, NR 2 ,
  • R 6 is selected from H, CN, OH, NO 2 , NHR, NR 2 ,
  • R 6 is selected from
  • Ar is selected from 5-10 membered heteroaryl groups that are unsubstituted or optionally substituted with one, two or more R 4 , or Ar is selected from:
  • R 7 , R 8 , R 9 , R 10 and R 4 have the same definition, and R 7 and R 8 are not hydrogen at the same time; or R 7 , R 10 and R 4 have the same definition, and R 9 and R 8 are connected to form A 4-7 membered ring; or R 8 , R 9 and R 4 have the same definition, and R 7 and R 10 are connected to form a 4-7 membered ring; or R 7 , R 8 , R 9 and R 4 have the same definition, R 10 is selected from CN, NO 2 , OH, C 2-6 alkynyloxy, C 3-6 cycloalkenyloxy, C 4-6 cycloalkynyloxy, unsubstituted or optionally by one, two or The following groups substituted with more R: NH 2 , aldehyde group, C 2-6 alkenyl, C 2-6 alkynyl, C 3-16 cycloalkyl, C 3-6 cycloalkenyl, C 4-6 Cyclo
  • Ar is selected from 5-10 membered heteroaryl groups that are unsubstituted or optionally substituted with one, two or more R 4 , or Ar is selected from:
  • R 7 , R 8 , R 9 , R 10 and R 4 have the same definition, and R 7 and R 10 are not hydrogen at the same time; or R 7 , R 10 and R 4 have the same definition, and R 9 and R 8 are connected to form A 4-7 membered ring; or R 8 , R 9 and R 4 have the same definition, and R 7 and R 10 are connected to form a 4-7 membered ring; or R 7 , R 8 , R 9 and R 4 have the same definition, R 10 is selected from CN, NO 2 , OH, C 2-6 alkynyloxy, C 3-6 cycloalkenyloxy, C 4-6 cycloalkynyloxy, unsubstituted or optionally by one, two or The following groups substituted with more R: NH 2 , aldehyde group, C 2-6 alkenyl, C 2-6 alkynyl, C 3-16 cycloalkyl, C 3-6 cycloalkenyl, C 4-6 Cyclo
  • Z is selected from When, X, Q, and W is at least one N; 3 is selected from unsubstituted or optionally substituted with one, two or more of the substituents R a, or W is selected from the group CR 3, and R: C 2-3 Alkenyl, C 2-3 alkynyl.
  • the compound represented by formula (I), its stereoisomers, racemates, tautomers, isotope markers, nitrogen oxides or pharmaceutically acceptable salts thereof are selected from those of formula (II)
  • rings A, Ar, L, R 3 , R 6 , X, and Z are as defined above.
  • R 3 is selected from halogen, cyclopropyl, trifluoromethyl, methoxy
  • X is selected from CH or N;
  • Ring A is selected from
  • Ar is selected from the following groups that are unsubstituted or optionally substituted with one, two or more R 4 :
  • R 4 is selected from H, methoxy, ethoxy, propoxy, isopropoxy, methyl, ethyl, propyl, isopropyl, halogen, CN, ethynyl, vinyl, halogenated C 1 -4 alkoxy, C 3-6 epoxyalkyloxy, C 3-6 cycloalkyloxy, C 3-6 cycloalkyl;
  • L and R 6 are as described above.
  • R 7 , R 8 , R 9 , R 10 and R 4 have the same definition
  • R 7 , R 8 , R 9 have the same definition as R 4
  • R 10 is selected from CN, NO 2 , OH, C 2-6 alkynyloxy, C 3-6 cycloalkenyloxy, C 4- 6 cycloalkynyloxy, unsubstituted or optionally substituted with one, two or more R groups: NH 2 , aldehyde group, C 2-6 alkenyl, C 2-6 alkynyl, C 3 -16 cycloalkyl, C 3-6 cycloalkenyl, C 4-6 cycloalkynyl and 3-15 membered heterocyclic group;
  • R 7 , R 8 , R 10 and R 4 have the same definition, and R 9 is selected from CN, NO 2 , OH, C 2-6 alkynyloxy, C 3-6 cycloalkenyloxy, C 4-6 Cycloalkynyloxy, unsubstituted or optionally substituted with one, two or more R groups: NH 2 , aldehyde group, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 6 cycloalkenyl, C 4-6 cycloalkynyl, C 1-6 azaalkyl and 3 to 4, 7 to 16 membered heterocyclic group;
  • R 7 , R 8 , R 9 , R 10 and R 4 have the same definition, and R 7 and R 10 are not hydrogen at the same time;
  • Y, Z, M, P, ring A, X, Q, W, L, R 6 are as defined above.
  • the compound represented by formula (I), its stereoisomers, racemates, tautomers, isotope markers, nitrogen oxides or pharmaceutically acceptable salts thereof are selected from those of formula (IV)
  • R 3 , R 6 , R 9 and R 10 are as defined above.
  • R 3 is selected from halogen.
  • R 9 and R 10 are independently selected from methoxy, ethoxy, methyl, ethyl or vinyl.
  • R 6 is selected from
  • the compound of formula (I) is selected from the following compounds or a pharmaceutically acceptable salt thereof:
  • the salt is trifluoroacetate.
  • the salt is a one-molecular salt, a two-molecular salt or a multi-molecular salt.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by formula (I), its stereoisomers, racemates, tautomers, isotope markers, nitrogen oxides or the like At least one of pharmaceutically acceptable salts, and pharmaceutically acceptable excipients.
  • the present invention also provides at least one of the compound represented by formula (I), its stereoisomer, racemate, tautomer, isotope label, nitrogen oxide or its pharmaceutically acceptable salt Application in preparing medicine for treating cancer.
  • the cancer is lung cancer.
  • the cancer is non-small cell lung cancer, glioblastoma, pancreatic cancer, head and neck cancer, breast cancer, colorectal cancer, epithelial cancer, ovarian cancer, prostate cancer, adenocarcinoma or squamous cell carcinoma.
  • the present invention also provides at least one of the compound represented by formula (I), its stereoisomer, racemate, tautomer, isotope label, nitrogen oxide, or a pharmaceutically acceptable salt thereof Application in the preparation of drugs for treating diseases caused by EGFR mutations.
  • the present invention also provides at least one of the compound represented by formula (I), its stereoisomer, racemate, tautomer, isotope label, nitrogen oxide, pharmaceutically acceptable salt or pharmaceutical composition
  • the present invention also provides at least one of the compound represented by formula (I), its stereoisomer, racemate, tautomer, isotope label, nitrogen oxide, pharmaceutically acceptable salt or pharmaceutical composition A use in preventing or treating diseases caused by EGFR mutations.
  • the present invention relates to a compound represented by formula (I), its stereoisomers, racemates, tautomers, isotope markers, nitrogen oxides, pharmaceutically acceptable compounds for preventing or treating diseases caused by EGFR mutations Salt or pharmaceutical composition.
  • the present invention also relates to a method for preventing or treating diseases caused by EGFR mutations, the method comprising administering to a patient a therapeutically effective dose containing the compound of formula (I) of the present invention, its stereoisomers, racemates, and tautomers Pharmaceutical preparations of isomers, isotope labels, nitrogen oxides, pharmaceutically acceptable salts or pharmaceutical compositions.
  • the EGFR mutation is one, two or more mutations selected from the following: (1) Del19; (2) T790M; (3) C797S; (4) L858R.
  • the present invention also provides a method for treating cancer, which comprises: administering at least one of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof to an individual in need.
  • halogen refers to F, Cl, Br and I. In other words, F, Cl, Br, and I can be described as “halogen" in this specification.
  • halo should be understood to include monohalogenation, dihalogenation and polyhalogenation.
  • haloalkoxy should be understood to include monohaloalkoxy, dihaloalkoxy and polyhaloalkoxy.
  • halo C 1-4 alkoxy should be understood to include monohaloalkoxy, dihaloalkoxy and polyhaloalkoxy, which have 1 to 4 carbon atoms.
  • halogenated C 1- 4 alkoxy is to be understood as preferably meaning to include monohaloalkyl and polyhaloalkyl-alkoxy group having 3 or 4 carbon atoms.
  • halogenated C 1-4 alkoxy group is, for example, trifluoromethoxy, trichloromethoxy, tribromomethoxy, 2,2,2-trifluoroethoxy, 2,2,2 -Trichloroethoxy, 2,2,2-tribromoethoxy, 4-chlorobutoxy, 3-bromopropoxy, pentafluoroethoxy or pentachloroethoxy.
  • alkyl should be understood to mean a saturated monovalent hydrocarbon group having a straight or branched chain.
  • C 1-6 alkyl should be understood to mean a linear or branched saturated monovalent hydrocarbon group, which has 1 to 6 carbon atoms.
  • C 1-6 alkyl is understood to preferably mean a linear or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Group, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, 1,2-dimethylbutyl, etc. or their isomers.
  • the group has 1, 2 or 3 carbon atoms ("C 1-3 alkyl”), such
  • alkylene should be understood to mean a saturated divalent hydrocarbon group having a straight or branched chain.
  • C 0-4 alkylene group should be understood to mean a linear or branched saturated divalent hydrocarbon group, which has 0 to 4 carbon atoms.
  • C 0 alkylene group should be understood as a bond, that is, having 0 carbon atoms.
  • alkenyl should be understood to mean a linear or branched monovalent hydrocarbon group containing one, two or more double bonds.
  • C 2-6 alkenyl should be understood to mean a linear or branched monovalent hydrocarbon group containing one, two or more double bonds and having 2 to 6 carbon atoms.
  • C 2-6 alkenyl should be understood to preferably mean a linear or branched monovalent hydrocarbon group containing one, two or more double bonds and having 2, 3, 4, 5 or 6 carbon atoms, in particular Is 2 or 3 carbon atoms (“C 2-3 alkenyl”), and it should be understood that where the alkenyl group contains more than one double bond, the double bonds may be separated from each other or conjugated.
  • the alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)- But-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z) -Pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-ene Group, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3- Alkenyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-eny
  • alkynyl should be understood to mean a linear or branched monovalent hydrocarbon group, which contains one, two or more triple bonds.
  • C 2-6 alkynyl should be understood to mean a linear or branched monovalent hydrocarbon group containing one, two or more triple bonds and having 2 to 6 carbon atoms.
  • C 2-6 alkynyl should be understood to preferably mean a linear or branched monovalent hydrocarbon group containing one, two or more triple bonds and having 2, 3, 4, 5 or 6 carbon atoms, Especially 2 or 3 carbon atoms ("C 2-3 alkynyl").
  • the alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl , Pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, Hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl , 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpentyl -4-ynyl, 2-methylpent-3-yn
  • alkylamino should be understood to mean an amino group substituted by an alkyl group.
  • C 1-6 alkylamino should be understood to mean an amino group substituted by an alkyl group, which has 1 to 6 carbon atoms.
  • the alkylamino group is, for example, N-methylamino, N-ethylamino, N-propylamino, N-isopropylamino, N-butylamino, N-isobutylamino, N-sec-butyl Amino and so on.
  • dialkylamino should be understood to mean an amino group substituted by two alkyl groups, the two alkyl groups being the same or different.
  • C2-12 dialkylamino should be understood to mean an amino group substituted by two alkyl groups, the two alkyl groups being the same or different and having 2-12 carbon atoms.
  • the alkylamino group is, for example, N,N-dimethylamino, N,N-diethylamino, N,N-methylethylamino, N,N-methylpropylamino, and the like.
  • heteroalkyl by itself or in combination with another term means a stable linear or branched hydrocarbon radical or combination thereof, consisting of a certain number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from O, N, and S, wherein nitrogen and sulfur atoms are optionally oxidized, and nitrogen heteroatoms are optionally quaternized.
  • heteroatom or heteroatom group can be located in any internal position of the heterohydrocarbyl group, including the position where the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkoxy Group) belongs to the customary expression and refers to those alkyl groups connected to the rest of the molecule through an oxygen atom, amino or sulfur atom, respectively.
  • the two heteroatoms can be continuous, for example -CH2-NH-OCH3.
  • cycloalkenyl should be understood to include any stable cyclic or polycyclic hydrocarbon group containing one or more unsaturated carbon-carbon double bonds at any position of the ring, which may be mono- or poly-substituted Yes, it can be one price, two price or multiple price.
  • C 3-6 cycloalkenyl should be understood to include any stable cyclic or polycyclic hydrocarbon group containing one or more unsaturated carbon-carbon double bonds at any position of the ring, which may be single
  • the substituted or multi-substituted may be monovalent, divalent or multivalent, and have 3 to 6 carbon atoms.
  • the cycloalkenyl group is, for example, cyclopentenyl or cyclohexenyl.
  • cycloalkynyl should be understood to include any stable cyclic or polycyclic hydrocarbon group containing one or more carbon-carbon triple bonds at any position of the ring, which may be monosubstituted or polysubstituted, and may It is one price, two price or multiple price.
  • the cycloalkynyl group is, for example, cyclopentynyl or cyclohexynyl.
  • Ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl.
  • the so-called ring includes single ring, double ring, spiro ring, parallel ring or bridged ring.
  • the number of atoms in the ring is generally defined as the number of ring members. For example, "4 to 7 membered ring” refers to a surrounding arrangement of 4 to 7 atoms.
  • the term "5- to 7-membered heterocycloalkyl” includes pyridyl and piperidinyl, but does not include phenyl.
  • the term "ring” also includes a ring system containing at least one ring, each of which independently meets the above definition.
  • C 3-6 cycloalkyl should be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring, which has 3 to 6 carbon atoms.
  • the C 3-6 cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • C 3-16 cycloalkyl should be understood to mean a saturated monovalent monocyclic, bicyclic or polycyclic hydrocarbon ring, including monocyclic, bicyclic, spiro, fused or bridged rings, which has 3-16 carbon atom.
  • C 3-6 heterocycloalkyloxy should be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring with 3 to 6 carbon atoms, which contains at least one N, O or S atom, and The oxygen atom is connected outside the ring, and then connected to other groups through the oxygen atom, such as epoxypropyloxy, epoxybutyloxy, epoxypentyloxy or epoxyhexyloxy.
  • 3-15 membered heterocyclic group means a saturated or unsaturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5 heteroatoms independently selected from N, O and S, preferably “3-10 membered Heterocyclyl".
  • 3-10 membered heterocyclic group means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5, preferably 1-3 heteroatoms selected from N, O and S.
  • the heterocyclic group may be connected to the rest of the molecule through any one of the carbon atoms or the nitrogen atom (if present).
  • the heterocyclic group may include but is not limited to: 4-membered ring, such as azetidinyl, oxetanyl; 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl Or trithiaalkyl; or 7-membered ring, such as diazeppanyl.
  • 4-membered ring such as azetidinyl, oxetanyl
  • 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidinyl, pyrazolidinyl, pyrrol
  • the heterocyclic group may be benzo-fused.
  • the heterocyclic group may be bicyclic, such as but not limited to a 5, 5-membered ring, such as hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a 5, 6-membered bicyclic ring, such as hexahydropyrrole And [1,2-a]pyrazine-2(1H)-yl ring.
  • the ring containing nitrogen atoms may be partially unsaturated, that is, it may contain one or more double bonds, such as but not limited to 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadi Azinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as but not limited to dihydroisoquinolinyl.
  • the heterocyclic group is non-aromatic.
  • C 5-10 aryl should be understood to preferably mean a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring with 5-10 carbon atoms, especially a ring with 6 carbon atoms (“C6 aryl”), such as phenyl, or a ring with 9 carbon atoms (“C9 aryl”), such as indanyl or indenyl, or a ring with 10 carbon atoms (“C10 aryl Group”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.
  • C6 aryl a ring with 6 carbon atoms
  • C9 aryl such as indanyl or indenyl
  • C10 aryl Group a ring with 10 carbon atoms
  • 5-6 membered heteroaryl should be understood to include a monovalent monocyclic aromatic ring system having 5-6 ring atoms and containing 1-3 heteroatoms independently selected from N, O and S
  • it can be selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl , Thio-4H-pyrazolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.
  • heterocyclic groups or heteroaryl groups include all possible isomeric forms thereof, such as positional isomers. Therefore, for some illustrative non-limiting examples, pyridinyl or pyridinylene includes pyridin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, pyridin-4-yl And pyridin-4-yl; thienyl or thienylene includes thiophen-2-yl, thiophen-2-yl, thiophen-3-yl and thiophen-3-yl.
  • the number of heteroatoms or heteroatom groups is respectively Choose from 1, 2, or 3.
  • aryl refers to a single all-carbon aromatic ring or a polycyclic fused all-carbocyclic ring system in which at least one of the rings is aromatic.
  • an aryl group has 6 to 20 ring carbon atoms, 6 to 14 ring carbon atoms, or 6 to 12 ring carbon atoms.
  • Aryl includes phenyl.
  • Aryl groups also include polycyclic fused ring systems having about 9 to 20 carbon atoms (for example, ring systems containing 2, 3, or 4 rings), in which at least one ring is aromatic, and in which other rings may be Aromatic or non-aromatic (ie, carbocyclic).
  • Such a polycyclic fused ring system is optionally substituted with one or more (e.g. 1, 2, or 3) oxo groups on any carbocyclic moiety of the polycyclic fused ring system.
  • the rings of a polycyclic fused ring system can be connected to each other through fused, spiro, and bridging bonds.
  • the atom range refers to the total ring (cyclic) atoms of the aryl group.
  • a 6-membered aryl group will include phenyl
  • a 10-membered aryl group will include naphthyl and 1,2,3,4-tetrahydronaphthyl.
  • aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthryl and the like.
  • heteroaryl refers to a single aromatic ring having at least one atom other than carbon in the ring, wherein the atom is selected from oxygen, nitrogen, and sulfur; the term also includes polyatomic rings having at least one such aromatic ring.
  • a ring fused ring system which is described further below. Therefore, the term includes a single aromatic ring of about 1 to 6 ring carbon atoms and about 1 to 4 ring heteroatoms selected from oxygen, nitrogen, and sulfur in the ring. Sulfur and nitrogen atoms can also exist in oxidized form, provided that the ring is aromatic.
  • Such rings include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl.
  • the term also includes polycyclic fused ring systems (for example, ring systems containing 2, 3, or 4 rings) in which a heteroaryl group as defined above is fused with one or more rings selected from the following to form a polycyclic ring system.
  • Ring condensed ring system heteroaryl (to form, for example, naphthyridinyl such as 1,8-naphthyridinyl), heterocycloalkyl (to form, for example, 1,2,3,4-tetrahydronaphthyridinyl such as 1, 2,3,4-tetrahydro-1,8-naphthyridinyl), cycloalkyl (to form, for example, 5,6,7,8-tetrahydroquinolinyl) and aryl (to form, for example, indazolyl) .
  • heteroaryl to form, for example, naphthyridinyl such as 1,8-naphthyridinyl
  • heterocycloalkyl
  • a heteroaryl group (a single aromatic ring or a polycyclic fused ring system) has about 1-20 ring carbon atoms and about 1-6 ring heteroatoms.
  • Such a polycyclic fused ring system may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocyclic or heterocyclic portion of the fused ring.
  • the rings of a polycyclic fused ring system can be connected to each other through fused, spiro, and bridging bonds. It should be understood that the individual rings of a polycyclic fused ring system can be connected in any order relative to each other.
  • the point of attachment of the polycyclic fused ring system can be at any position of the polycyclic fused ring system (including heteroaryl, heterocycle, Aryl or carbocyclic moieties) and at any suitable atom (including carbon atoms and heteroatoms, such as nitrogen) of the polycyclic fused ring system.
  • heteroaryl groups include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, thiazolyl, furyl , Oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalinyl, quinazolinyl, 5,6,7 , 8-Tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl and thiaindenyl (thianaphthenyl).
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and can include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues, and There is no excessive toxicity, irritation, allergic reaction or other problems or functions, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable salts” means those salts that retain the biological effectiveness and properties of the parent compound. Such salts include: (1) Formation of salts with acids, obtained by the reaction of the free base of the parent compound with inorganic or organic acids. Inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, and sulfurous acid And perchloric acid, etc., organic acids include acetic acid, trifluoroacetic acid, propionic acid, acrylic acid, caproic acid, cyclopentane propionic acid, glycolic acid, pyruvic acid, oxalic acid, (D) or (L) malic acid, fumaric acid , Maleic acid, benzoic acid, hydroxybenzoic acid, ⁇ -hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid,
  • the acidic protons present in the parent compound are replaced by metal ions or the salts formed by coordination with organic bases.
  • metals are alkali metal ions, alkaline earth metal ions or aluminum ions, and organic bases such as ethanolamine, diethanolamine, tri Ethanolamine, tromethamine, N-methylglucamine, etc.
  • the "pharmaceutically acceptable salt" of the present invention includes but is not limited to trifluoroacetate, and the number of molecules of the salt includes but is not limited to one molecule of salt or two molecule of salt.
  • tapped keys and virtual keys are used Express the absolute configuration of a three-dimensional center, using Represents the relative configuration of a three-dimensional center.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, they include E, Z geometric isomers. Likewise, all tautomeric forms are included within the scope of the present invention.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, non- Enantiomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomeric enriched mixtures, all of them
  • the mixtures are all within the scope of the present invention.
  • Substituents such as alkyl may have additional asymmetric carbon atoms. All these isomers and their mixtures are included in the scope of the present invention.
  • optically active (R)- and (S)-isomers and (D)- and (L)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one wants to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated, and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • the molecule when the molecule contains a basic group (such as an amino group) or an acidic functional group (such as a carboxylic acid), it forms a diastereomeric salt with a suitable optically active acid or base, and then passes through a method known in the art The conventional method is used for resolution, and then the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which uses a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of aminomethyl from amines). Acid salt).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium, iodine-125, and C-14. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • “Pharmaceutical composition” refers to mixing one or more of the compounds of the present invention or a pharmaceutically acceptable salt thereof with other chemical ingredients, such as pharmaceutically acceptable excipients.
  • the purpose of the pharmaceutical composition is to facilitate the process of administration to animals.
  • “Pharmaceutically acceptable excipients” refer to inactive ingredients in a pharmaceutical composition that do not cause significant irritation to the organism and do not interfere with the biological activity and properties of the administered compound, such as but not limited to: calcium carbonate, calcium phosphate , Various sugars (such as lactose, mannitol, etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylic acid polymer or methacrylic acid polymer, gel, water, polyethylene glycol, Propylene glycol, ethylene glycol, castor oil or hydrogenated castor oil or polyethoxylated hydrogenated castor oil, sesame oil, corn oil, peanut oil, etc.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, implementation methods formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • Figure 1 is a graph of the tumor growth curve of the PC9-EGFR-Del19/T790M/C797S subcutaneous tumor model in Test Example 5 (in vivo efficacy study);
  • Fig. 2 is a graph showing changes in body weight of PC9-EGFR-Del19/T790M/C797S subcutaneous tumor model mice in Test Example 5 (in vivo efficacy study).
  • reaction solution was stirred and reacted at -78°C for 30 minutes, then A solution of hexachloroethane (1.2 g, 5.06 mmol) in tetrahydrofuran (10 mL) was slowly added to the reaction solution. After the addition, the mixture was stirred and reacted at -78°C for 2.5 hours until the reaction was complete. The reaction was quenched with saturated aqueous ammonium chloride solution (10 mL), the mixture was extracted with ethyl acetate (50 mL ⁇ 3), the organic phases were combined and dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure.
  • reaction solution was cooled to room temperature and added to a mixture of water (10 mL) and ethyl acetate (30 mL). After the two phases were separated, the aqueous phase was extracted with ethyl acetate (30 mL ⁇ 3). The organic phases were combined and dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure.
  • reaction solution was heated to 100°C under the protection of argon, and the reaction was stirred for 4 hours until the reaction was complete.
  • Example 1 Purification to obtain the target compound (6-((5-bromo-2-((5-ethyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl )-2-(oxetan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide trifluoroacetate (4) (35mg , Yield: 12%), traits: gray solid.
  • Example 6 (6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidine-1- (Yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine sulfide trifluoroacetate (compound 6)
  • dichloropyrimidin-4-yl) amino) quinoxalin-5-yl) dimethyl phosphine sulfide (8-11) (70.0 mg, 0.18 mmol) and 5-methyl-1-(tetrahydro- 2H-pyran-4-yl)-1H-pyrazole-4-amine (8-5) (65.5mg, 0.36mmol) was dissolved in isopropanol (3mL), and then trifluoroacetic acid (205.2mg, 1.8 mmol); The reaction solution was heated to 100°C and stirred for 24 hours. After the completion of the reaction, the reaction solution was cooled to room temperature, and then concentrated under reduced pressure.
  • tert-butyl 4-(3-(benzyloxy)cyclobutyl)piperazine-1-carboxylate 9-7) (6.0g, 17.34mmol) in trifluoroacetic acid (20mL) at room temperature, The reaction solution was stirred and reacted at 80°C for 6 hours. LCMS detected that the reaction was complete. The reaction mixture was concentrated to obtain a crude product. The crude product was dissolved in dichloromethane (5mL) and triethylamine (5.25g, 52.02mmol) and di-tert-butyl dicarbonate (7.56g, 34.68mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. Compound 4 was detected by LCMS.
  • tert-butyl 4-(3-hydroxycyclobutyl)piperazine-1-carboxylate (9-8) (3.0g, 11.71mmol) in dichloromethane (50 mL) and add triethylamine ( 3.5g, 35.13mmol), then methylsulfonyl chloride (2.6mg, 23.43mmol) was added.
  • the reaction solution was stirred and reacted at room temperature for 10 hours.
  • 2-bromo-1-fluoro-3-methoxy-4-nitrobenzene (10-7) (600mg, 2.39mmol), 1-methyl-4-(piperidin-4-yl)piper Pyrazine (485.2 mg, 2.65 mmol) and potassium carbonate (999.25 mg, 7.18 mmol) were added to N,N-dimethylformamide (20 mL), and the reaction system was heated to 60° C. under an argon atmosphere and stirred overnight.
  • the reaction system was heated to 100°C under an argon atmosphere and stirred for 4 hours.
  • the reaction solution was concentrated under reduced pressure and spin-dried.
  • reaction liquid was filtered, and the filtrate was decompressed to obtain the target product 5-ethyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2,2 -Trifluoroethoxy)pyridine-3-amine (11-10) (60mg, yield: 80%), properties: brown solid.
  • the reaction solution was cooled to room temperature, and then concentrated under reduced pressure.
  • the residue was purified by HPLC (eluent gradient reference example 1) to obtain the target compound (6-((5-bromo-2- ((5-Ethyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2,2-trifluoroethoxy)pyridine-3 -Yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide-trifluoroacetate (11) (30mg, yield: 19%), properties: yellow solid.
  • Example 14 (6-((5-Bromo-2-((3-ethyl-2-fluoro-6-methoxy-4-(4-(4-methylpiperazin-1-yl)piper (Pyridin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) quinoxalin-5-yl) dimethyl phosphine oxide trifluoroacetate (Compound 15)
  • the remaining steps refer to the synthesis method of Example 2 to obtain the target compound (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(1-methylpiperidine- 4-yl)-1,4-diazepan-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide trifluoroacetate (17), traits: yellow solid.
  • Benzyl 4-((3-hydroxypropyl)amino)piperidine-1-carboxylate (18-2) (4.0g, 13.68mmol and triethylamine (6.91g, 68.40mmol)) were dissolved in tetrahydrofuran ( 60mL), add N,N'-carbonyldiimidazole (2.66g, 16.42mmol), react at room temperature for 5 hours and add DBU (1,8-diazabicycloundec-7-ene) (2.08g, 13.68 mmol), heated at 70°C for half an hour, and after the reaction was completed, it was reduced to room temperature, and ethyl acetate (100ml) and water (100ml) were added for extraction and separation.
  • reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium chloride solution, the organic phase was dried and filtered with anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain the crude target product 2-chloro-6 -Methoxy-3-methyl-5-nitropyridine (30-2) and 2-chloro-6-methoxy-5-methyl-3-nitropyridine (30-2a) mixture (338mg , Yield: 69%), traits: yellow solid.
  • Example 11 The remaining steps refer to the synthesis method of Example 11 to obtain the target compound (6-((5-bromo-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazine- 1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide trifluoroacetate (30), properties : Yellow solid.
  • 2,3,6-Trichloropyridine (37-1) (2g, 11mmol) was dissolved in a mixture of concentrated sulfuric acid (10mL) and fuming nitric acid (12.4mL) at room temperature, and the reaction was stirred at 100°C for 12 hours . After the reaction was completed, the reaction mixture was poured into ice water (50 mL), the mixture was filtered, and the filter cake was dried to obtain the target product 2,3,6-trichloro-5-nitropyridine (37-2) (1.43 g, yield : 58%), traits: white solid.
  • potassium vinyl trifluoroborate was replaced with methylboronic acid to obtain the target compound (6-((5-bromo-2-((5-methyl-6-(4-(4-methyl Piperazine-1-yl)piperidin-1-yl)-2-(2,2,2-trifluoroethoxy)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoxaline -5-yl) dimethyl phosphine oxide trifluoroacetate (60), properties: yellow solid.
  • potassium vinyl fluoroborate was replaced with potassium cyclopropyl fluoroborate to obtain the target compound (6-((5-bromo-2-((5-cyclopropyl-6-(4- (4-Methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2,2-trifluoroethoxy)pyridin-3-yl)amino)pyrimidin-4-yl)amino )
  • reaction solution is cooled to room temperature, and then 10mL of water is added, extracted with ethyl acetate (20mL X 3), the organic phases are combined, washed with saturated brine and dried with anhydrous sodium sulfate to obtain the crude compound, which is purified by preparation plate ((2-Aminonaphthalene-1-yl)dimethylphosphine oxide (88-3) (60mg, brown solid.)
  • Example 26 (6-((5-bromo-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidine-1- (Pyridine-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethyl phosphine sulfide trifluoroacetate (compound 89)
  • the reaction solution was heated to 100°C under an argon atmosphere and stirred for 16 hours.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified by HPLC (eluent gradient reference example 1) to obtain the target compound (6-((5-bromo-2-((2-methoxy- 5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoxaline-5 -Yl) dimethyl phosphine sulfide trifluoroacetate (89) (15 mg, yield: 13.4%), properties: yellow solid.
  • reaction solution was added to an aqueous sodium bicarbonate solution, the mixture was extracted with dichloromethane (50mL 2), the organic phase was dried and filtered with anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain the crude target product 4- (4-Methyl-1,4-diazaheptan-1-yl)piperidine-1-carboxylic acid benzyl ester (90-2) (4.2 g, yield: 99%), properties: colorless oily liquid.
  • reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude target product 5-ethyl-2-methoxy-4-(4-(4-methyl-1,4-homopiperazin-1-yl)piperidine -1-yl)aniline (90-6) (65mg, yield: 70.7%), properties: brown oily liquid.
  • the reaction solution was cooled to room temperature, and then concentrated under reduced pressure.
  • the residue was purified by high performance liquid chromatography (eluent gradient: the same as in Example 1) to obtain the target compound (6-((5-bromo-2) -((5-Ethyl-2-methoxy-4-(4-(4-methyl-1,4-homopiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidine -4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide trifluoroacetate (90) (13.2mg, yield: 18.9%), properties: yellow solid.
  • the reaction solution was basified with 2M aqueous sodium hydroxide and saturated aqueous potassium carbonate solution, the mixture was extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure.
  • reaction solution is filtered to remove the palladium-carbon catalyst, and the filtrate is concentrated under reduced pressure to obtain the crude target product 6-(4-(dimethylamino)piperidin-1-yl)-2-methoxy-5-methyl Pyridin-3-amine (92-4) and 2-(4-(dimethylamino)piperidin-1-yl)-6-methoxy-5-methylpyridin-3-amine (92-4a) (213mg, yield: 60%), properties: brown oily liquid.
  • N,N-dimethylpiperidin-4-amine was replaced with N-methylpiperazine to obtain the target compound (6-((5-bromo-2-((2-methyl Oxy-5-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethyl oxide Phosphine trifluoroacetate (93), properties: yellow solid.
  • N,N-dimethylpiperidin-4-amine was replaced with 1,4-diazabicyclo[3.2.2]nonane, and the target compound (6-((2- ((6-(1,4-Diazabicyclo[3.2.2]non-4-yl)-2-methoxy-5-methylpyridin-3-yl)amino)-5-bromopyrimidine- 4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide trifluoroacetate (compound 94), properties: yellow solid.
  • the reaction solution was cooled to room temperature, and then concentrated under reduced pressure.
  • the residue was purified by high performance liquid chromatography (eluent gradient reference example 1) to obtain the target compound (3-((5-bromo-2- ((5-Ethyl-2-methoxy-6-(4-(4-methyl-1,4-homopiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino )Pyrimidine-4-yl)amino)quinolin-4-yl)dimethylphosphine oxide trifluoroacetate (98) (3.2 mg, yield: 3.6%, properties: yellow solid.
  • N-(5-bromo-2-chloropyrimidin-4-yl)-5-(isopropylsulfonyl)quinoxaline-6-amine (101-3) (150mg, 0.339mmol)
  • 5- Ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (6-10) (225mg, 0.678mmol)
  • 1N dilute hydrochloric acid 0.067ml, 0.067mmol
  • ethylene glycol monomethyl ether 5mL
  • reaction solution was cooled to room temperature, and the solution was directly purified by high performance liquid chromatography (eluent gradient refer to Example 1) to obtain the pure target product 5-bromo-N 2 -(5-ethyl-2) -Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-N 4 -(5-(isopropylsulfonyl)quinoxaline- 6-yl)pyrimidine-2,4-diamine trifluoroacetate (101) 5.5 mg, yield: 20%, properties: yellow solid.
  • Example 40 (6-((5-bromo-2-((6-(4-(dimethylamino)piperidin-1-yl)-5-ethyl-2-methoxypyridin-3-yl )Amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide trifluoroacetate (compound 104)

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Abstract

La présente invention concerne un inhibiteur de kinase EGFR de quatrième génération (mutation T790M/C797S) et son utilisation médicale, et concerne en particulier un composé représenté par la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci. Le composé selon la présente invention a un bon effet thérapeutique sur des maladies provoquées par des mutations anormales de l'EGFR Del19/T790M/C797S et L858R/T790M/C797S.
PCT/CN2020/086871 2019-04-26 2020-04-24 Inhibiteur d'egfr et son utilisation WO2020216371A1 (fr)

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Cited By (16)

* Cited by examiner, † Cited by third party
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WO2021104441A1 (fr) * 2019-11-29 2021-06-03 江苏先声药业有限公司 Composé polyaromatique utilisé en tant qu'inhibiteur de kinase egfr
CN113717156A (zh) * 2020-05-25 2021-11-30 南京红云生物科技有限公司 Egfr抑制剂、其制备方法及用途
WO2021244502A1 (fr) * 2020-06-03 2021-12-09 江苏先声药业有限公司 Composé polyaryle et son utilisation
WO2021249324A1 (fr) * 2020-06-08 2021-12-16 南京红云生物科技有限公司 Composé d'alcényle pyrimidine, procédé de préparation associé et son application
WO2022100688A1 (fr) * 2020-11-13 2022-05-19 南京红云生物科技有限公司 Modulateur de kinase hpk1, son procédé de préparation et son utilisation
WO2022171123A1 (fr) * 2021-02-10 2022-08-18 Beigene, Ltd. Agents de dégradation d'egfr et procédés d'utilisation
CN115073364A (zh) * 2022-06-20 2022-09-20 上海毕得医药科技股份有限公司 一种6-硝基吡啶-3-醇的制备方法
WO2022211573A1 (fr) * 2021-04-01 2022-10-06 주식회사 테라펙스 Dérivé de pyrimidine ayant une activité inhibitrice de protéine kinase, et composition pharmaceutique thérapeutique le comprenant
CN115536699A (zh) * 2022-12-01 2022-12-30 北京鑫开元医药科技有限公司 一种新型EGFR-TKIs、制备方法、药物组合物及其应用
WO2023020600A1 (fr) * 2021-08-19 2023-02-23 贝达药业股份有限公司 Forme saline et forme cristalline d'un inhibiteur de l'egfr, et composition et utilisation associées
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WO2023061433A1 (fr) * 2021-10-14 2023-04-20 齐鲁制药有限公司 Polymorphe d'inhibiteur d'egfr
WO2023061434A1 (fr) * 2021-10-14 2023-04-20 齐鲁制药有限公司 Utilisation d'un composé tricyclique
WO2023071314A1 (fr) * 2021-10-29 2023-05-04 中国药科大学 Synthèse, procédé de préparation et utilisation d'un composé inhibiteur à double cible de shp2 et de cdk4/6
WO2023138607A1 (fr) * 2022-01-18 2023-07-27 Beigene , Ltd. Dégradation d'egfr par conjugaison d'inhibiteurs d'egfr avec un ligand de ligase e3 et procédés d'utilisation
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AU2020385527B2 (en) * 2019-11-21 2023-04-13 Tyk Medicines, Inc. Compound used as EGFR kinase inhibitor and use thereof
WO2021104441A1 (fr) * 2019-11-29 2021-06-03 江苏先声药业有限公司 Composé polyaromatique utilisé en tant qu'inhibiteur de kinase egfr
CN113717156A (zh) * 2020-05-25 2021-11-30 南京红云生物科技有限公司 Egfr抑制剂、其制备方法及用途
WO2021238827A1 (fr) * 2020-05-25 2021-12-02 南京红云生物科技有限公司 Inhibiteur d'egfr, son procédé de préparation et son utilisation
CN113717156B (zh) * 2020-05-25 2023-05-09 南京红云生物科技有限公司 Egfr抑制剂、其制备方法及用途
WO2021244502A1 (fr) * 2020-06-03 2021-12-09 江苏先声药业有限公司 Composé polyaryle et son utilisation
WO2021249324A1 (fr) * 2020-06-08 2021-12-16 南京红云生物科技有限公司 Composé d'alcényle pyrimidine, procédé de préparation associé et son application
WO2022100688A1 (fr) * 2020-11-13 2022-05-19 南京红云生物科技有限公司 Modulateur de kinase hpk1, son procédé de préparation et son utilisation
WO2022171123A1 (fr) * 2021-02-10 2022-08-18 Beigene, Ltd. Agents de dégradation d'egfr et procédés d'utilisation
WO2022211573A1 (fr) * 2021-04-01 2022-10-06 주식회사 테라펙스 Dérivé de pyrimidine ayant une activité inhibitrice de protéine kinase, et composition pharmaceutique thérapeutique le comprenant
WO2023020600A1 (fr) * 2021-08-19 2023-02-23 贝达药业股份有限公司 Forme saline et forme cristalline d'un inhibiteur de l'egfr, et composition et utilisation associées
WO2023061433A1 (fr) * 2021-10-14 2023-04-20 齐鲁制药有限公司 Polymorphe d'inhibiteur d'egfr
WO2023061434A1 (fr) * 2021-10-14 2023-04-20 齐鲁制药有限公司 Utilisation d'un composé tricyclique
WO2023071314A1 (fr) * 2021-10-29 2023-05-04 中国药科大学 Synthèse, procédé de préparation et utilisation d'un composé inhibiteur à double cible de shp2 et de cdk4/6
WO2023138607A1 (fr) * 2022-01-18 2023-07-27 Beigene , Ltd. Dégradation d'egfr par conjugaison d'inhibiteurs d'egfr avec un ligand de ligase e3 et procédés d'utilisation
CN115073364A (zh) * 2022-06-20 2022-09-20 上海毕得医药科技股份有限公司 一种6-硝基吡啶-3-醇的制备方法
CN115073364B (zh) * 2022-06-20 2024-04-05 上海毕得医药科技股份有限公司 一种6-硝基吡啶-3-醇的制备方法
WO2024046405A1 (fr) * 2022-09-01 2024-03-07 齐鲁制药有限公司 Utilisation d'inhibiteur de kinase egfr
CN115536699A (zh) * 2022-12-01 2022-12-30 北京鑫开元医药科技有限公司 一种新型EGFR-TKIs、制备方法、药物组合物及其应用

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