WO2017088746A1 - Nouvel inhibiteur de récepteur du facteur de croissance épidermique et son application - Google Patents

Nouvel inhibiteur de récepteur du facteur de croissance épidermique et son application Download PDF

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WO2017088746A1
WO2017088746A1 PCT/CN2016/106862 CN2016106862W WO2017088746A1 WO 2017088746 A1 WO2017088746 A1 WO 2017088746A1 CN 2016106862 W CN2016106862 W CN 2016106862W WO 2017088746 A1 WO2017088746 A1 WO 2017088746A1
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alkyl
group
amino
alkylamino
cycloalkyl
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PCT/CN2016/106862
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Chinese (zh)
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王勇
张小猛
赵立文
王小伟
韩璐薇
戴雪娟
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南京圣和药业股份有限公司
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Publication of WO2017088746A1 publication Critical patent/WO2017088746A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medical chemistry, and in particular relates to a novel class of epidermal growth factor receptor inhibitors, a pharmaceutical composition containing the same, and the use of the inhibitor or pharmaceutical composition as a therapeutic drug for cancer.
  • the Epidermal Growth Factor Receptor is an expression product of the proto-oncogene C-erbB-1 and is a member of the EGFR family.
  • the EGFR family includes four members, EGFR (HER-1), ERBB2 (HER-2), ERBB3 (HER-3), and ERBB4 (HER-4).
  • Overexpression or mutation of EGFR has been shown to generally trigger tumors.
  • EGFR mutations lead to sustained activation of EGFR, enhanced autocrine loops, disruption of receptor down-regulation, activation of abnormal signaling pathways, and play an important role in tumor progression.
  • EGFR-tyrosine kinase inhibitor for EGFR has become the gold standard in the field of non-small cell lung cancer treatment.
  • clinical use has found that most patients will have different degrees of drug resistance 6-12 months after treatment with EGFR-TKI inhibitors such as gefitinib and erlotinib, resulting in a significant reduction in drug efficacy and tumor progression.
  • EGFR-TKI inhibitors such as gefitinib and erlotinib
  • methionine has a larger space occupying than threonine, it forms steric hindrance and changes the affinity of ATP in EGFR kinase domain, which leads to EGFR-TKI small molecule drug can not effectively block EGFR activation signal, leading to drug resistance.
  • the production At the same time, the first generation of EGFR inhibitors lacked the selectivity of wild-type EGFR and mutant EGFR, and generally had side effects such as rash and diarrhea, which affected patient compliance.
  • Another object of the present invention is to provide a compound of the formula II or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, which is prepared by using the compound of the formula II as a key intermediate.
  • Compound I mild reaction conditions, high yield and purity,
  • a third object of the present invention is to provide a compound of the formula III or a salt thereof, which is a key intermediate of the compound of the formula III, which has a small number of reaction steps, mild conditions, and a relatively good yield and purity. high,
  • a fourth object of the present invention is to provide a process for the preparation of a compound of the formula I, II or III of the present invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof.
  • a fifth object of the present invention is to provide a pharmaceutical composition comprising a compound of the formula I of the present invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier, and a pharmaceutical composition comprising the same
  • a pharmaceutical composition of a compound of formula I of the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and another tumor suppressor is provided.
  • a sixth object of the present invention is to provide a compound of the formula I of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a pharmaceutical composition of the present invention for treating and/or preventing cancer Methods and their use in the preparation of a medicament for the treatment and/or prevention of cancer.
  • the present invention provides the following technical solutions:
  • the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,
  • Ring A is a C 4 -C 8 nitrogen-containing heterocyclic group optionally substituted by one or more halogen, oxo, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano , hydroxy, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, alkyl acyl, amino acyl, a monoalkylaminoacyl group, a dialkylaminoacyl group, an aryl group, a heteroaryl group, and a heterocycloalkyl group.
  • two adjacent substituents may be substituted together with the atoms to which they are attached.
  • an unsubstituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl group, or two substituents attached to the same atom may form a substituted or unsubstituted cycloalkyl group with the atoms to which they are attached.
  • X 1 , X 2 , X 3 and X 4 are each independently selected from C(R 1 ) and N;
  • R 1 , R 2a , R 2b , R 3a , R 3b and R 3c are each independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, Hydroxy, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, alkyl acyl, amino acyl, single An alkylamino acyl group and a dialkylamino acyl group;
  • R 4 , R 5 and R 6 are each independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, alkoxy and cycloalkyl, said alkyl, alkoxy and cycloalkyl optionally being one or more Halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, monoalkylamino, dialkylamino, hydroxy, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or hydroxy Alkyl substitution
  • R 7 is selected from the group consisting of hydrogen, alkyl, cycloalkyl and haloalkyl
  • R 8 is selected from the group consisting of hydrogen, alkyl and cycloalkyl, optionally substituted by one or more halogen, alkyl, haloalkyl, alkoxy, amino, monoalkylamino, dioxane Substituted by a base or a hydroxy group; or
  • the present invention provides a compound of Formula II, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,
  • Rings A, X 1 , X 2 , X 3 , X 4 , R 2a , R 2b , R 3a , R 3b , R 3c , R 7 and R 8 have the definitions in Formula I.
  • the present invention provides a compound of Formula III or a pharmaceutically acceptable salt thereof,
  • Rings A, X 1 , X 2 , X 3 , X 4 , R 2a , R 2b have the definitions in Formula I, and M is a halogen.
  • the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is C 4 -C 8 a nitrogen-containing heteromonocycloalkyl group optionally substituted by one or more of halogen, oxo, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano, hydroxy, amino, singly Alkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, alkylacyl, aminoacyl, monoalkylaminoacyl, a dialkylamino acyl group, an aryl group, a heteroaryl group and a heterocycloalkyl group.
  • Ring A is C 4 -C 8 a nitrogen-containing heteromonocycloalkyl group optionally substitute
  • two adjacent substituents may form a substituted or unsubstituted naphthenic ring together with the atoms to which they are attached.
  • a heterocyclic alkyl group, an aryl group, a heteroaryl group, or two substituents bonded to the same atom may form a substituted or unsubstituted cycloalkyl group or a heterocycloalkyl group with the atoms to which they are attached.
  • the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is a nitrogen atom only C 4 -C 8 nitrogen-containing heteromonocycloalkyl optionally substituted by one or more halogen, oxo, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyano , hydroxy, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, alkyl acyl, amino acyl, a monoalkylaminoacyl group, a dialkylaminoacyl group, an aryl group, a heteroaryl group, and a heterocycloalkyl group.
  • Ring A is a nitrogen atom only C 4 -C 8 nitrogen-containing hetero
  • two adjacent substituents may be substituted together with the atoms to which they are attached.
  • an unsubstituted cycloalkyl, heterocycloalkyl, aryl, heteroaryl group, or two substituents attached to the same atom may form a substituted or unsubstituted cycloalkyl group with the atoms to which they are attached. Cycloalkyl.
  • the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is n is selected from 1, 2, 3, 4, 5 and 6, m is selected from 1, 2, 3 and 4, and R a is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, halogen C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, nitro, cyano, hydroxy, amino, mono C 1-6 alkylamino, di C 1-6 alkyl Amino group, amino C 1-6 alkyl group, mono C 1-6 alkylamino C 1-6 alkyl group, di C 1-6 alkylamino C 1-6 alkyl group, hydroxy C 1-6 alkyl group, C 1 -6 alkoxy C 1-6 alkyl, C 1-6 alkyl acyl, amino acyl, mono C 1-6 alkylamino
  • the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is n is selected from 1, 2, 3 and 4, m is selected from 1, 2, 3 and 4, and R a is selected from the group consisting of hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, halogenated C 1-3 alkane , C 1-3 alkoxy, halo C 1-3 alkoxy, nitro, cyano, hydroxy, amino, mono C 1-3 alkylamino, di C 1-3 alkylamino, amino C 1-3 alkyl, mono C 1-3 alkylamino C 1-3 alkyl, di C 1-3 alkylamino C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy a group C 1-3 alkyl, C 1-3 alkyl acyl, amino acyl, mono C 1-3 alkylamino acyl, di C
  • the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is two nitrogens A C 4 -C 8 nitrogen-containing heteromonocycloalkyl group of an atom optionally substituted by one or more halogen, oxo, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, nitro, cyanide Base, hydroxy, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, alkyl acyl, amino acyl a monoalkylaminoacyl group, a dialkylaminoacyl group, an aryl group, a heteroaryl group, and a heterocycloalkyl group.
  • Ring A is two nitrogens
  • two adjacent substituents may be bonded together with the atoms to which they are attached.
  • a substituted or unsubstituted cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or two substituents bonded to the same atom may form a substituted or unsubstituted cycloalkyl group with an atom to which they are attached, Heterocycloalkyl.
  • the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is m is selected from 1, 2, 3 and 4, p is selected from 0, 1 and 2, q is selected from 0, 1 and 2, and R a is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, halo-C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, nitro, cyano, hydroxy, amino, mono-C 1-6 alkylamino, di C 1- 6 alkylamino group, amino C 1-6 alkyl group, mono C 1-6 alkylamino C 1-6 alkyl group, di C 1-6 alkylamino C 1-6 alkyl group, hydroxy C 1-6 alkyl group , C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl acyl, amino acyl, mono C 1-6
  • the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is m is selected from 1, 2, 3 and 4, p is selected from 0, 1 and 2, q is selected from 0, 1 and 2, and R a is selected from the group consisting of hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, Halogen C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, nitro, cyano, hydroxy, amino, mono C 1-3 alkylamino, di C 1- 3 alkylamino group, amino C 1-3 alkyl group, mono C 1-3 alkylamino C 1-3 alkyl group, di C 1-3 alkylamino C 1-3 alkyl group, hydroxy C 1-3 alkyl group , C 1-3 alkoxy C 1-3 alkyl, C 1-3 alkyl acyl, amino acyl, mono C 1-3 alkyla
  • the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is a nitrogen atom And a C 4 -C 8 nitrogen-containing heteromonocycloalkyl group having one oxygen atom, optionally substituted by one or more halogen, oxo, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, nitrate Base, cyano, hydroxy, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, alkyl acyl , aminoacyl, monoalkylaminoacyl, dialkylaminoacyl, aryl, heteroaryl and heterocycloalkyl substituted, when two or more substituents are present, two adjacent substituents may be attached there
  • the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is m is selected from 1, 2, 3 and 4, p is selected from 0, 1 and 2, q is selected from 0, 1 and 2, and R a is selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, Halogen C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, nitro, cyano, hydroxy, amino, mono C 1-6 alkylamino, di C 1- 6 alkylamino group, amino C 1-6 alkyl group, mono C 1-6 alkylamino C 1-6 alkyl group, di C 1-6 alkylamino C 1-6 alkyl group, hydroxy C 1-6 alkyl group , C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl acyl, amino acyl, mono C 1-6 alkyla
  • the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is m is selected from 1, 2, 3 and 4, p is selected from 0, 1 and 2, q is selected from 0, 1 and 2, and R a is selected from the group consisting of hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, Halogen C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, nitro, cyano, hydroxy, amino, mono C 1-3 alkylamino, di C 1- 3 alkylamino group, amino C 1-3 alkyl group, mono C 1-3 alkylamino C 1-3 alkyl group, di C 1-3 alkylamino C 1-3 alkyl group, hydroxy C 1-3 alkyl group , C 1-3 alkoxy C 1-3 alkyl, C 1-3 alkyl acyl, amino acyl, mono C 1-3 alkyla
  • the present invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein Ring A is a nitrogen atom and a C 4 -C 8 nitrogen-containing heteromonocycloalkyl group of a sulfur atom optionally substituted by one or more halogen, oxo, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, nitro , cyano, hydroxy, amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, alkyl acyl, Aminoacyl, monoalkylaminoacyl, dialkylaminoacyl, aryl, heteroaryl and heterocycloalkyl substituted, when two or more substituents are present, the two adjacent substituents may be
  • the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein X 1 , X 2 , X 3 And X 4 are both C(R 1 ).
  • the invention provides a compound of formula Ia, IIa, and IIIa, or a pharmaceutically acceptable salt, isomer, solvate, crystal, or prodrug thereof,
  • Rings A, R 1 , R 2a , R 2b , R 3a , R 3b , R 3c , R 4 , R 5 , R 6 , R 7 , R 8 and M have the definitions of Formulas I, II and III above , n is selected from integers of 1, 2, 3 and 4.
  • the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein X 1 , X 2 , X At least one of 3 and X 4 is N.
  • the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein X 1 , X 2 , X Two of 3 and X 4 are N.
  • the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein X 1 , X 2 , X Three of 3 and X 4 are N.
  • the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein X 1 , X 2 , X 3 and X 4 are both N.
  • the present invention of general formula I, II or III compound or a pharmaceutically acceptable salt, isomer, solvate, crystallization or prodrug thereof, wherein R 1, R 2a and R 2b Each is independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 3-8 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy , nitro, cyano, hydroxy, amino, mono C 1-6 alkylamino, di C 1-6 alkylamino, amino C 1-6 alkyl, mono C 1-6 alkylamino C 1-6 alkane Base, di-C 1-6 alkylamino C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl acyl, amino acyl, Mono C 1-6 alkylamino acyl and di C 1-6 alkylamino acyl.
  • the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein each R 1 , R 2a And R 2b are each independently independently selected from the group consisting of hydrogen, halogen, C 1-3 alkyl, C 3-6 cycloalkyl, halo C 1-3 alkyl, C 1-3 alkoxy, halo C 1 -3 alkoxy, nitro, cyano, hydroxy, amino, mono C 1-3 alkyl amino, di C 1-3 alkyl amino, amino C 1-3 alkyl, mono C 1-3 alkyl amino C 1-6 alkyl, di C 1-3 alkylamino C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy C 1-3 alkyl, C 1-3 alkyl An acyl group, an aminoacyl group, a mono C 1-3 alkylamino acyl group and a di C 1-3 alkylamino
  • the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R 1 , R 2a And R 2b are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trifluoromethyl , trifluoroethyl, difluoromethyl, difluoroethyl, methoxy, ethoxy, propoxy, trifluoromethyloxy, nitro, cyano, hydroxy, amino, methylamino, ethylamino , propylamino, isopropylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, N-methyl
  • the invention provides a compound of Formula I, II or III, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R 1 , R 2a And R 2b are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, hydroxy, amino , methylamino, ethylamino, propylamino, dimethylamino, diethylamino, aminomethyl, aminoethyl, aminopropyl, methylaminomethyl, methylaminoethyl, ethylaminomethyl, ethylaminoethyl, Dimethylaminomethyl, diethylaminomethyl, hydroxymethyl and hydroxyethyl.
  • R 1 , R 2a And R 2b are each independently selected from the group consisting of
  • the invention provides a compound of Formula I or II, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R 3a , R 3b and R 3c Each is independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 3-8 cycloalkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy , nitro, cyano, hydroxy, amino, mono C 1-6 alkylamino, di C 1-6 alkylamino, amino C 1-6 alkyl, mono C 1-6 alkylamino C 1-6 alkane Base, di-C 1-6 alkylamino C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl acyl, amino acyl, Mono C 1-6 alkylamino acyl and di C 1-6 alkylamino acyl.
  • the present invention provides a compound of Formula I or II, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein each R 3a , R 3b and R 3c are each independently selected from the group consisting of hydrogen, halogen, C 1-3 alkyl, C 3-6 cycloalkyl, halo C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkane Oxy, nitro, cyano, hydroxy, amino, mono C 1-3 alkylamino, di C 1-3 alkylamino, amino C 1-3 alkyl, mono C 1-3 alkylamino C 1- 6 alkyl, di C 1-3 alkyl amino C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy C 1-3 alkyl, C 1-3 alkyl group, an amino group An acyl group, a mono C 1-3 alkylamino acyl group and a di C 1-3 alkyla
  • the invention provides a compound of Formula I or II, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R 3a , R 3b and R 3c are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trifluoromethyl, tri Fluoroethyl, difluoromethyl, difluoroethyl, methoxy, ethoxy, propoxy, trifluoromethyloxy, nitro, cyano, hydroxy, amino, methylamino, ethylamino, propyl Amino, isopropylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, N-methyl-N
  • the invention provides a compound of Formula I or II, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R 3a , R 3b and R 3c are each independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, hydroxy, amino, A Amino, ethylamino, propylamino, dimethylamino, diethylamino, aminomethyl, aminoethyl, aminopropyl, methylaminomethyl, methylaminoethyl, ethylaminomethyl, ethylaminoethyl, dimethyl Aminomethyl, diethylaminomethyl, hydroxymethyl and hydroxyethyl.
  • R 3a , R 3b and R 3c are each independently selected from the group consisting of hydrogen,
  • the invention provides a compound of Formula I or II, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R 7 is selected from the group consisting of hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl and halogenated C 1-6 alkyl.
  • the present invention provides Formula I or II compound as shown or a pharmaceutically acceptable salt, isomer, solvate, crystallization or prodrug thereof, wherein R 7 is selected from hydrogen, C 1 a -3 alkyl group, a C 3-6 cycloalkyl group, and a halogenated C 1-3 alkyl group.
  • the present invention provides Formula I or II compound as shown or a pharmaceutically acceptable salt, isomer, solvate, crystallization or prodrug thereof, wherein R 7 is selected from hydrogen, methyl , ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and trifluoromethyl.
  • the present invention provides Formula I or II compound as shown or a pharmaceutically acceptable salt, isomer, solvate, crystallization or prodrug thereof, wherein R 7 is methyl.
  • the present invention provides a formula I or II compound represented by or a pharmaceutically acceptable salt, isomer, solvate, crystallization or prodrug thereof, wherein R 8 is selected from hydrogen, C 1-6 An alkyl group and a C 3-6 cycloalkyl group, said C 1-6 alkyl group and a C 3-6 cycloalkyl group optionally being one or more halogen, C 1-6 alkyl, halogenated C 1-6 Alkyl, C 1-6 alkoxy, amino, mono C 1-6 alkylamino, di C 1-6 alkylamino or hydroxy substituted.
  • R 8 is selected from hydrogen, C 1-6 An alkyl group and a C 3-6 cycloalkyl group, said C 1-6 alkyl group and a C 3-6 cycloalkyl group optionally being one or more halogen, C 1-6 alkyl, halogenated C 1-6 Alkyl, C 1-6 alkoxy, amino, mono C 1-6 alkylamino, di C
  • the present invention provides a formula I or II or a compound represented by the pharmaceutically acceptable salts, isomers, solvates, crystalline or prodrug thereof, wherein R 8 is selected from hydrogen, C 1 a -3 alkyl group and a C 3-6 cycloalkyl group, said C 1-3 alkyl group and a C 3-6 cycloalkyl group optionally being one or more halogen, C 1-3 alkyl group, halogenated C 1 a -3 alkyl group, a C 1-3 alkoxy group, an amino group, a mono C 1-3 alkylamino group, a di C 1-3 alkylamino group or a hydroxy group.
  • the present invention provides a formula I or II compound represented by or a pharmaceutically acceptable salt, isomer, solvate, crystallization or prodrug thereof, wherein R 8 is selected from hydrogen, C 1 -3 alkyl and C 3-6 cycloalkyl, said C 1-3 alkyl and C 3-6 cycloalkyl optionally being one or more halogen, methyl, ethyl, propyl, isopropyl Base, trifluoromethyl, difluoromethyl, trifluoroethyl, methoxy, ethoxy, propoxy, isopropyloxy, amino, methylamino, ethylamino, propylamino, dimethylamino, Diethylamine, dipropylamino, methylethylamino, methylpropylamino, ethylpropylamino or hydroxy substituted.
  • R 8 is selected from hydrogen, C 1 -3 alkyl and C 3-6 cycloalkyl, said
  • the present invention provides a formula I or II compound represented by or a pharmaceutically acceptable salt, isomer, solvate, crystallization or prodrug thereof, wherein R 8 is selected from hydrogen, methyl , ethyl and propyl, said methyl, ethyl and propyl optionally being one or more amino, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, A Substituted by ethylamino, methylpropylamino or ethylpropylamino.
  • the present invention provides a formula I or II compound represented by or a pharmaceutically acceptable salt, isomer, solvate, crystallization or prodrug thereof, wherein R 8 is substituted with dimethylamino Ethyl.
  • the present invention provides a compound of general formula I or II, or a pharmaceutically acceptable salt thereof shown, isomer, solvate, crystallization or prodrug thereof, wherein R 7, R 8 and connected N constitutes a four to eight membered azacycloalkyl group, and the four to eight membered azacycloalkyl group is optionally substituted by one or more halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1- 6 alkoxy, amino, mono C 1-6 alkylamino, di C 1-6 alkylamino, hydroxy, amino C 1-6 alkyl, mono C 1-6 alkylamino C 1-6 alkyl, Di-C 1-6 alkylamino C 1-6 alkyl or hydroxyalkyl substituted.
  • the present invention provides a compound of Formula I or II, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R 7 , R 8 and their linkages N constitutes a four to eight membered azacycloalkyl group, and the four to eight membered azacycloalkyl group is optionally substituted by one or more halogen, C 1-3 alkyl, halo C 1-3 alkyl, C 1 -3 alkoxy, amino, mono C 1-3 alkylamino, di C 1-3 alkylamino, hydroxy, amino C 1-3 alkyl, mono C 1-3 alkylamino C 1-3 alkyl , a di-C 1-3 alkylamino C 1-3 alkyl group or a hydroxyalkyl group.
  • the present invention provides a compound of Formula I or II, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R 7 , R 8 and their linkages N-constituting five to six yuan azacycloalkyl, said azacycloalkyl five to six yuan optionally substituted with one or more halo, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, amino, mono C 1-3 alkylamino, di C 1-3 alkylamino, hydroxy, amino C 1-3 alkyl, mono C 1-3 alkylamino C 1-3 Alkyl, di-C 1-3 alkylamino C 1-3 alkyl or hydroxyalkyl substituted.
  • the invention provides a compound of Formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R 4 , R 5 and R 6 are each independently selected From hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, said C 1-6 alkyl, C 1-6 alkoxy and ring
  • the alkyl group is optionally selected from one or more of halogen, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, amino, mono C 1 -6 alkylamino, di C 1-6 alkylamino, hydroxy, amino C 1-6 alkyl, mono C 1-6 alkylamino C 1-6 alkyl, di C 1-6 alkylamino C 1 -6 alkyl and hydroxy C 1-6 alkyl substituted.
  • the invention provides a compound of Formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R 4 , R 5 and R 6 are each independently Is selected from the group consisting of hydrogen, halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl optionally substituted with one or more halo, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, a C 1-3 alkoxy group, halo , amino, mono C 1-3 alkylamino, di C 1-3 alkylamino, hydroxy, amino C 1-3 alkyl, mono C 1-3 alkylamino C 1-3 alkyl, di C 1- 3 alkylamino C 1-3 alkyl or hydroxy C 1-3 alkyl substituted.
  • R 4 , R 5 and R 6 are each
  • the invention provides a compound of Formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein R 4 , R 5 and R 6 are hydrogen.
  • the invention provides a compound of Formula III, or a pharmaceutically acceptable salt thereof, wherein M is selected from the group consisting of fluorine, chlorine, bromine, and iodine.
  • the invention provides a compound of Formula III, or a pharmaceutically acceptable salt thereof, wherein M is selected from the group consisting of chlorine, bromine, and iodine.
  • the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein
  • n is selected from 1, 2, 3 and 4;
  • n is selected from 1, 2, 3 and 4;
  • R a is selected from the group consisting of hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, nitro , cyano, hydroxy, amino, mono C 1-3 alkylamino, di C 1-3 alkylamino, amino C 1-3 alkyl, mono C 1-3 alkylamino C 1-3 alkyl, two C 1-3 alkylamino C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy C 1-3 alkyl, C 1-3 alkyl acyl, amino acyl, mono C 1 -3 alkylaminoacyl, di C 1-3 alkylamino acyl, C 6-10 aryl, C 5-10 heteroaryl and C 3-6 heterocycloalkyl, when m is selected from 2, 3 and 4 When two R a groups of two adjacent carbon atoms may form a C 3-6 cycloalkyl
  • X 1 , X 2 , X 3 and X 4 are each independently selected from C(R 1 ) and N;
  • R 1 , R 2a , R 2b , R 3a , R 3b and R 3c are each independently selected from the group consisting of hydrogen, halogen, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, Halogen C 1-3 alkoxy, nitro, cyano, hydroxy, amino, mono C 1-3 alkylamino, di C 1-3 alkylamino, amino C 1-3 alkyl, mono C 1- 3 alkylamino C 1-6 alkyl, di C 1-3 alkylamino C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy C 1-3 alkyl, C 1 a -3 alkyl acyl group, an amino acyl group, a mono C 1-3 alkylamino acyl group and a di C 1-3 alkylamino acyl group;
  • R 4 , R 5 and R 6 are all hydrogen
  • R 7 is a methyl group
  • R 8 is an ethyl group substituted by dimethylamino.
  • the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein
  • n is selected from 1, 2, 3 and 4;
  • p is selected from 0, 1, and 2;
  • R a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogen C 1-3 alkoxy, nitro, cyano, hydroxy, amino, mono C 1-3 alkylamino, di C 1-3 alkylamino, amino C 1-3 alkyl, mono C 1-3 alkyl C 1-3 alkyl amino, di C 1-3 alkyl amino C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy C 1-3 alkyl, C 1-3 alkoxy Alkanoyl group, aminoacyl group, mono C 1-3 alkylamino acyl group, di C 1-3 alkylamino acyl group, C 6-10 aryl group, C 5-10 heteroaryl group and C 3-6 heterocycloalkyl group, When m is selected from 2, 3 and 4, two R a on two adjacent atoms may together with the atom to
  • X 1 , X 2 , X 3 and X 4 are each independently selected from C(R 1 ) and N;
  • R 1 , R 2a , R 2b , R 3a , R 3b and R 3c are each independently selected from the group consisting of hydrogen, halogen, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, Halogen C 1-3 alkoxy, nitro, cyano, hydroxy, amino, mono C 1-3 alkylamino, di C 1-3 alkylamino, amino C 1-3 alkyl, mono C 1- 3 alkylamino C 1-6 alkyl, di C 1-3 alkylamino C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy C 1-3 alkyl, C 1 a -3 alkyl acyl group, an amino acyl group, a mono C 1-3 alkylamino acyl group and a di C 1-3 alkylamino acyl group;
  • R 4 , R 5 and R 6 are all hydrogen
  • R 7 is a methyl group
  • R 8 is an ethyl group substituted by dimethylamino.
  • the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, wherein
  • n is selected from 1, 2, 3 and 4;
  • p is selected from 0, 1, and 2;
  • R a is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl, halogenated C 1-3 alkyl, C 1-3 alkoxy, halogen C 1-3 alkoxy, nitro, cyano, hydroxy, amino, mono C 1-3 alkylamino, di C 1-3 alkylamino, amino C 1-3 alkyl, mono C 1-3 alkyl Amino C 1-3 alkyl, di C 1-3 alkylamino C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy C 1-3 alkyl, C 1-3 alkane an acyl group, an amino group, a mono C 1-3 alkyl amino group, a di C 1-3 alkyl amino group, C 6-10 aryl, C 5-10 heteroaryl, and C 3-6 heterocycloalkyl, When m is selected from 2, 3 and 4, two R a on two adjacent atoms may form a C 3-6 cycloalkyl, When m is selected from 2,
  • X 1 , X 2 , X 3 and X 4 are each independently selected from C(R 1 ) and N;
  • R 1 , R 2a , R 2b , R 3a , R 3b and R 3c are each independently selected from the group consisting of hydrogen, halogen, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, Halogen C 1-3 alkoxy, nitro, cyano, hydroxy, amino, mono C 1-3 alkylamino, di C 1-3 alkylamino, amino C 1-3 alkyl, mono C 1- 3 alkylamino C 1-6 alkyl, di C 1-3 alkylamino C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy C 1-3 alkyl, C 1 a -3 alkyl acyl group, an amino acyl group, a mono C 1-3 alkylamino acyl group and a di C 1-3 alkylamino acyl group;
  • R 4 , R 5 and R 6 are all hydrogen
  • R 7 is a methyl group
  • R 8 is an ethyl group substituted by dimethylamino.
  • the invention provides the following compounds, or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof:
  • the invention provides the following compounds, or pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs thereof:
  • the invention provides a process for the preparation of a compound of formula I, II and III of the invention, comprising the steps of:
  • the invention provides a process for the preparation of a compound of formula I of the invention, which process comprises the use of a compound of formula II of the invention.
  • the invention provides a process for the preparation of a compound of formula I of the invention, which process comprises the use of a compound of formula III of the invention.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I of the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound, isomer, solvate, crystal or prodrug of Formula I of the invention, further comprising one or more compounds selected from the group consisting of: Gefitinib, erlotinib, lapatinib, afatinib, vandetanib, carnitinib, apatinib, dacomitinib, pelitinib , WZ4002, AG-490, AZD8931, AZD9291 and so on.
  • the compound, isomer, solvate, crystal or prodrug of the formula I of the present invention may be admixed with a pharmaceutically acceptable carrier to prepare a pharmaceutical preparation suitable for oral or parenteral administration.
  • Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes.
  • the formulation may be administered by any route, for example by infusion or bolus injection, by a route of absorption through the epithelium or skin mucosa (e.g., oral mucosa or rectum, etc.). Administration can be systemic or topical.
  • orally administered preparations include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like.
  • the formulation can be prepared by methods known in the art and comprises a carrier conventionally used in the field of pharmaceutical formulations.
  • the present invention provides a method of treating and/or preventing a tumor of a compound, isomer, solvate, crystal or prodrug of the present invention or a pharmaceutical composition of the present invention, and in the preparation of a treatment and/or prevention Use in a tumor drug, comprising administering to a tumor-prone population or a tumor patient a compound, isomer, solvate, crystal or prodrug of the formula I of the invention or a compound, isomer comprising the formula I of the invention, A pharmaceutical composition of a solvate, crystal or prodrug to effectively reduce the incidence of tumors and prolong the life of a tumor patient.
  • the invention provides a method of treating a tumor having resistance to a compound, a isomer, a solvate, a crystal or a prodrug of the invention, or a pharmaceutical composition of the invention, comprising A pharmaceutically acceptable tumor patient is administered a therapeutically effective amount of a compound, isomer, solvate, crystal or prodrug of the formula I according to the invention or a compound, isomer, solvate, crystal or pre-compound comprising the formula I of the invention Pharmaceutical composition of the drug.
  • the invention provides a compound, isomer, solvate, crystal or prodrug of the invention, or a pharmaceutical composition of the invention, in the manufacture of a medicament for treating a tumor having drug resistance application.
  • the drug-resistant tumor may be a tumor resistant to a plurality of drugs, preferably a tumor resistant to an EGFR inhibitor, for example, to a first, second, and third generation EGFR inhibitor, such as gefitinib. , erlotinib and lapatinib have drug-resistant tumors.
  • Such tumors include, but are not limited to, solid tumors, preferably lung cancer, head and neck tumors, colorectal cancer, bladder cancer, pancreatic cancer, breast cancer, prostate cancer, gastric cancer, oral cancer, liver cancer, ovarian cancer. More preferably, the tumor is non-small cell lung cancer.
  • the invention provides a method of treating a tumor having resistance to a compound, isomer, solvate, crystal or prodrug of Formula I of the invention, wherein the tumor carries an EGFR mutated gene.
  • the EGFR mutated gene carried by the tumor is a T790M mutation in exon 20.
  • the EGFR mutated gene carried by the tumor is a L858R mutation and/or a deletion/insertion mutation in exon 21.
  • the EGFR mutated gene carried by the tumor is a T790M and L858R double mutation.
  • the invention provides a compound, isomer, solvate, crystal or a compound of the formula I of the invention for use in treating a tumor A prodrug or a pharmaceutical composition of the invention wherein the therapeutic effect of the tumor is manifested in a prominent therapeutic effect, a high degree of selectivity and/or less side effects.
  • the present invention provides a method of treating a tumor of a compound, isomer, solvate, crystal or prodrug of the present invention or a pharmaceutical composition of the present invention, the method comprising administering it A therapeutically effective amount of a compound, isomer, solvate, crystal or prodrug of the present invention or a pharmaceutical composition of the present invention, which produces a therapeutic effect in the treatment of a tumor, which is highly effective. Selectivity and / or fewer side effects.
  • “Isomers” of the present invention include cis-trans isomers of the cis or trans configuration, as well as enantiomers and diastereomers derived from chiral carbons.
  • the "pharmaceutically acceptable salt” of the present invention means a pharmaceutically acceptable salt formed by the compound of the present invention and an acid, and the acid may be selected from the group consisting of phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, Maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid and the like.
  • Crystal as used in the present invention refers to various solid forms formed by the compounds of the present invention, including crystalline forms and amorphous forms.
  • the "prodrug” of the present invention refers to a compound which is converted into a compound of the present invention by a reaction with an enzyme, gastric acid or the like under physiological conditions of a living body, that is, a compound which is converted into the invention by oxidation, reduction, hydrolysis or the like of the enzyme and/or A compound which is converted into a compound of the invention by a hydrolysis reaction such as gastric acid or the like.
  • a "pharmaceutical composition” is meant to comprise any one of the compounds described herein, including isomers, prodrugs, solvates, pharmaceutically acceptable salts or chemically protected forms thereof, and one or more A mixture of pharmaceutically acceptable carriers.
  • the "application in the preparation of a medicament for treating and/or preventing a tumor” of the present invention means that the growth, development and/or metastasis of a tumor can be inhibited, and a therapeutically effective dose of the present invention is mainly administered to a human or animal in need thereof.
  • a compound inhibits, slows or reverses the growth, progression or spread of a tumor in a subject.
  • alkyl refers to a straight or branched saturated hydrocarbon group, preferably a hydrocarbon group of 6 or less carbon atoms.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 2,2-Methylbutyl and 2,3-dimethylbutyl.
  • C 1-6 alkyl refers to a straight or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms.
  • C 1-3 alkyl means a straight or branched saturated hydrocarbon group having 1 to 3 carbon atoms.
  • the "cycloalkyl group” of the present invention means a cyclic saturated, partially saturated hydrocarbon group, preferably a cycloalkyl group of 12 or less carbon atoms, more preferably a cycloalkyl group of 8 or less carbon atoms, still more preferably 6 carbon atoms.
  • the following cycloalkyl group examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.
  • the "C 3-8 cycloalkyl group” of the present invention means a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms.
  • alkoxy group of the present invention means an -O-alkyl group.
  • the sulfur atom is replaced by an oxo group
  • the sulfur atom is replaced by two oxo groups
  • halogen of the present invention means fluorine, chlorine, bromine or iodine.
  • haloalkoxy group of the present invention means an alkoxy group substituted with at least one halogen, preferably a C 1-6 alkoxy group substituted with at least one halogen, and further preferably a C 1-3 alkane substituted with at least one halogen.
  • Oxyl, a suitable halogenated C 1-3 alkoxy group is chloromethoxy, fluoromethoxy, dichloromethoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy; Chloroethoxy, difluoroethoxy, trichloroethoxy, trifluoroethoxy.
  • the "monoalkylamino group” of the present invention means -NH-alkyl group, preferably -NH-C 1-6 alkyl group, and more preferably -NH-C 1-3 alkyl group.
  • dialkylamino group means -N-(alkyl)(alkyl), preferably -N-(C 1-6 alkyl)(C 1-6 alkyl), further preferably -N -(C 1-3 alkyl) (C 1-3 alkyl).
  • aminoalkyl group of the present invention means -alkyl-NH 2 .
  • the "monoalkylaminoalkyl group" of the present invention means an -alkyl-NH-alkyl group.
  • dialkylaminoalkyl group of the present invention means -alkyl-N-(alkyl)(alkyl).
  • hydroxyalkyl group of the present invention means -alkyl-OH.
  • alkyl acyl group of the present invention means a -C(O)-alkyl group.
  • the "monoalkylaminoacyl" of the present invention means -C(O)-NH-alkyl.
  • dialkylaminoacyl group of the present invention means -C(O)-N-(alkyl)(alkyl).
  • heterocycloalkyl group of the present invention means a substituted or unsubstituted saturated, partially saturated cyclic alkyl group containing at least one hetero atom selected from N, O, and S.
  • the "aryl group” of the present invention means an aromatic system which may contain a monocyclic or polycondensed ring such as a bicyclic or tricyclic aromatic ring, wherein at least a part of the fused ring forms a conjugated aromatic system containing 5 to 50 One carbon atom, preferably from about 6 to about 14 carbon atoms.
  • Suitable aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, anthracenyl, tetrahydronaphthyl, anthracenyl, indanyl, biphenylene, and anthracenyl.
  • the "C 6 -C 10 aryl group” of the present invention means an aromatic system having 6 to 10 carbon atoms.
  • heteroaryl of the present invention means an aromatic monocyclic or polycondensed ring such as an aromatic group in which at least one carbon atom of a bicyclic or tricyclic ring is replaced by a hetero atom, and the hetero atom is O, S, N.
  • Suitable heteroaryl groups include, but are not limited to, imidazolyl, benzimidazolyl, imidazopyridyl, quinazolinone, pyrrolyl, imidazolidinyl, furyl, thienyl, pyrazolyl, oxazolyl, thiazole Base, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl and the like.
  • the "C 5 -C 10 heteroaryl group” of the present invention means a heteroaryl group having 5 to 10 atoms.
  • the "C 4 -C 8 nitrogen-containing heterocyclic group” of the present invention means a substituted or unsubstituted saturated, partially saturated and fully unsaturated total ring atom number of 4, 5, 6, 7 or containing at least one nitrogen atom.
  • the heterocyclic group of 8, for example, a C 4 nitrogen-containing heterocyclic group means a substituted or unsubstituted saturated, partially saturated and fully unsaturated total nitrogen-containing heterocyclic group having 4 ring atoms.
  • the "C 4 -C 8 nitrogen-containing heteromonocycloalkyl group” of the present invention means a substituted or unsubstituted saturated, partially saturated and fully unsaturated total ring atom number of 4, 5, 6, containing at least one nitrogen atom.
  • Suitable heterocycloalkyl groups of 7 or 8 include, but are not limited to, substituted or unsubstituted azetidinyl, azacyclopentyl, azacyclohexyl, azepanyl, azacyclooctyl , azacyclopentyl, azacyclohexyl, aziridine, azacyclooctyl, azathiolanyl, azathioheptyl, azathioheptyl, a nitrogen sulfur a heterocyclic octyl group, a diazacyclopentyl group, a diazacyclohexyl group, a diazepanyl group or a diazacyclooctyl group; and a substituted or unsubstituted nitrogen-containing heteroaryl group, for example, substituted or unsubstituted Pyridyl, imidazolyl, pyrazolyl, pyrrolyl, pyrida
  • the obtained product of the step b was sequentially added 1-(3-iodopropyl)-1H-indole (5.44 g, 19.83 mmol), potassium phosphate (8.4 g, 39.67 mmol), tetratriphenylphosphine.
  • Palladium (2.3 g, 1.98 mmol) and 1,4-dioxane (80 ml) were argon-protected and refluxed overnight. After the reaction was completed, the mixture was evaporated.
  • step d 9-(2-chloropyrimidin-4-yl)-2,3-dihydropyrrolo[1,2-a]indole
  • step 2 In a 100 ml reaction flask, aluminum trichloride (2.18 g, 16.35 mmol), ethylene glycol dimethyl ether (50 ml), 2,4-dichloropyrimidine (2.44 g, 16.35 mmol) and step 2 were successively added. 3-Dihydropyrrolo[1,2-a]indole (2.57 g, 16.35 mmol), refluxed for 2 h. After completion of the reaction, the reaction solution was cooled to room temperature, filtered, and the filter cake was washed with water and dried to give the title compound.
  • step e In a 50 ml reaction flask, the resulting product of step e was sequentially added N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(2,3-dihydropyrrolo[1,2-a ⁇ -9-yl)-pyrimidine-2-amine (2.5 g, 6 mmol), N,N,N'-trimethylethylenediamine (0.61 g, 6 mmol), diisopropylethylamine (2.3 g , 18 mmol), and 10 ml of dioxane, refluxing at 110 ° C for 3 h. After completion of the reaction, concentration and purification by column chromatography
  • step N was added N-(4-((2-(dimethylamino)ethyl))(methyl)amino)-2-methoxy-5-nitrophenyl) 4-(2,3-dihydropyrrolo[1,2-a]indol-9-yl)-pyrimidin-2-amine (2.5 g, 5 mmol), 10% Pd-C (20 mg) and 30 mL methanol Hydrogen was reduced for 1 h at 1 standard atmosphere. After the reaction was completed, it was filtered and concentrated to give the title compound.
  • step g was added N-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-aminophenyl)-4 -(2,3-dihydropyrrolo[1,2-a]indol-9-yl)-pyrimidin-2-amine (2 g, 4.2 mmol), diisopropylethylamine (0.53 g, 4.2 mmol)
  • 20 ml of anhydrous dichloromethane was added, and 5 ml of a solution of allylic acid chloride (0.37 g, 4.2 mmol) in methylene chloride was added slowly, and the mixture was reacted for 10 min.
  • step b In a 250 mL three-necked flask, the obtained product of step b was added 1-(4-iodobutyl)-1H-indole (5.93 g, 19.83 mmol), potassium phosphate (8.4 g, 39.67 mmol), tetratriphenyl. Palladium phosphate (2.3 g, 1.98 mmol), 1,4-dioxane (80 mL), argon-protected, refluxed overnight. After the reaction was completed, the mixture was evaporated.
  • step c In a 100 mL reaction flask, aluminum trichloride (2.18 g, 16.35 mmol), ethylene glycol dimethyl ether (50 mL), 2,4-dichloropyrimidine (2.44 g, 16.35 mmol), and the obtained product of step c were successively added. , 7,8,9-tetrahydropyrido[1,2-a]indole (2.8 g, 16.35 mmol), refluxed for 2 h. After completion of the reaction, the reaction solution was cooled to room temperature, filtered, and the filter cake was washed with water and dried to give the title compound.
  • the product obtained in the step d is 10-(2-chloropyrimidin-4-yl)-6,7,8,9-tetrahydropyrido[1,2-a]indole, 4-fluoro-2-methoxy- 5-Nitroaniline, N,N,N'-trimethylethylenediamine and allyl chloride were used as starting materials, and the title compound was obtained according to the following procedure:
  • Step b N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((5-methyl-4-(6,7,8) Synthesis of 9-tetrahydropyrido[1,2-a]indol-10-ylpyrimidin-2-yl)amino)phenyl)propanamide
  • the product obtained in the step a is 10-(2-chloro-5-methylpyrimidin-4-yl)-6,7,8,9-tetrahydropyrido[1,2-a]indole, 4-fluoro-2. -Methoxy-5-nitroaniline, N,N,N'-trimethylethylenediamine and allyl chloride as starting materials, the title compound was obtained according to the procedure of Example 1, Steps e, f, g and h .
  • Step c N-(2-((2-(Dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3,4-dihydro-1H-[ Synthesis of 1,4]oxazino[4,3-a]indole-10-ylpyrimidin-2-yl)amino)phenyl)propanamide
  • Step b Synthesis of N-((1-propenyl-1H-indol-2-yl)methenyl)-4-methylbenzenesulfonylhydrazide:
  • Step c Synthesis of 1,1,2,8b-tetrahydrocyclopropyl[3,4]pyrrolo[1,2-a]indole:
  • N-((1-propenyl-1H-indol-2-yl)methenyl)-4-methylbenzenesulfonyl hydrazide (2.2 g, 6.23 mmol) obtained in step b was added, and carbonic acid was added.
  • Potassium (1.29 g, 9.35 mmol) and 60 ml of dioxane were refluxed in an oil bath at 100 ° C for 12 h. Filtration, concentration, addition of 50 ml of water, extraction with 3X 40 ml of ethanol, washing with 30 ml of water, concentration and column chromatography to give 1.0 g of the title product. Used directly in the next step.
  • Step d N-(2-((2-(Dimethylamino)ethyl)(methyl)amino-4-methoxy-5-((4(1,1a,2,8b-tetrahydrocyclo)) Synthesis of propyl[3,4]pyrrolo[1,2-a]indole-8-yl)pyrimidin-2-yl)amino)phenyl)acrylamide
  • EGFR WT kinase purchased from Carna Corporation
  • EGFR T790M/L858R kinase was purchased from Invitrogen.
  • ATP Adenosine triphosphate
  • Peptide FAM-P22 purchased from GL Biochem
  • Ethylenediaminetetraacetic acid was purchased from Sigma.
  • Caliper EZ reader microfluidic chip instrument purchased from Caliper Life Sciences, Inc.
  • 1 ⁇ kinase base buffer (for EGFR WT ): 50 mM HEPES, pH 7.5, 0.0015% Brij-35, 10 mM MgCl 2 , 10 mM MnCl 2 , 2 mM DTT;
  • 1 ⁇ kinase base buffer for EGFR T790M/L858R : 50 mM HEPES, pH 7.5, 0.0015% Brij-35, 10 mM MgCl 2 , 2 mM DTT;
  • Stop buffer 100 mM HEPES, pH 7.5, 0.0015% Brij-35, 0.2% Coating Reagent #3, 50 mM EDTA.
  • the compounds of the present invention were separately dissolved in 10 mM with 100% DMSO, diluted to 50 ⁇ M with complete medium, and then diluted to 5 ⁇ M with complete medium containing 0.1% DMSO, followed by 3-fold dilution for a total of 10 concentrations (for EGFR WT );
  • the compound of the present invention was separately dissolved to 10 mM with 100% DMSO, diluted to 50 ⁇ M with complete medium, and then diluted to 1 ⁇ M with complete medium containing 0.1% DMSO, and then diluted 3 times in total for 10 concentrations (for EGFR T790M/L858R );
  • the 96-well plate used above was labeled as the source plate.
  • 10 ⁇ l of the solution was transferred from the source plate into a new 96-well plate as an intermediate plate, and 90 ⁇ l of 1 ⁇ kinase buffer was added to each well of the intermediate plate, and vortexed and mixed for 10 minutes.
  • a non-kinase-free compound control group (containing DMSO, 1 ⁇ basal buffer and 2.5 ⁇ peptide solution, and a kinase-free compound control group (including DMSO, 2.5 ⁇ kinase solution, and 2.5 ⁇ peptide solution) was also provided.
  • Inhibition rate % (max-com)/(max-min) ⁇ 100 Calculate the inhibition rate, where “max” represents a kinase-free compound control group, “com” represents a test compound group, and “min” represents a kinase-free compound. Control group.
  • the compound of the present invention has a good inhibitory activity against a mutant EGFR kinase such as EGFR L858R/T790M kinase, and has an IC 50 value of less than 1 nM, and has a small effect on wild-type EGFR kinase and has good selectivity.
  • a mutant EGFR kinase such as EGFR L858R/T790M kinase
  • the experimental cell line NCI-H1975 (EGFR double mutant cells with L858R and T790M mutations) and A431 (EGFR wild type cells) were purchased from ATCC.
  • RPMI1640 medium purchased from Invitrogen
  • DMEM medium purchased from Invitrogen
  • Fetal bovine serum purchased from Invitrogen;
  • NCI-H1975 cells were cultured in RPMI1640 medium containing 10% inactivated fetal bovine serum (GIBCO), containing penicillin 100 IU/mL and streptomycin 100 ⁇ g/mL;
  • GEBCO inactivated fetal bovine serum
  • A431 cells were cultured in DMEM medium containing 10% inactivated fetal bovine serum (GIBCO) containing penicillin 100 IU/mL and streptomycin 100 ⁇ g/mL.
  • GEBCO inactivated fetal bovine serum
  • NCI-H1975 cells and A431 cells After digesting NCI-H1975 cells and A431 cells in logarithmic growth phase, they were blown into single cell suspensions, seeded in 96-well culture plates, 100 ⁇ L per well medium, and each cell line was composed of 3 96-well plates. NCI-H1975 cells were seeded with 3 ⁇ 10 3 cells per well, and A431 cells were seeded with 4 ⁇ 10 3 cells per well. The inoculated NCI-H1975 cells and A431 cells were cultured in a 5% CO 2 incubator for 16-24 hours. After the cells were attached, the test compound was added at the following concentration (the highest test of the compound on NCI-H1975 cells).
  • the concentration was 4 ⁇ M, 3 fold dilution, a total of 9 concentrations; the highest test concentration on A431 cells was 10 ⁇ M, 3 fold dilution, a total of 9 concentrations), and cultured for an additional 72 hours in an incubator.
  • a blank control group only medium, no cell and DMSO solution
  • a DMSO control group cells and 0.5% DMSO solution were added to the medium.
  • Add 100 ⁇ L of CTG solution shake it for 2 min in the dark, and incubate for 10 min.
  • the multi-mode microplate reader reads the plate, records the luminescence reading results, and calculates the inhibition rate according to the following formula:
  • Inhibitor (%) (1-(RLU com - RLU blank ) / (RLU DMSO - RLU blank )) ⁇ 100%,
  • RLU com represents the absorbance of the test compound group
  • RLU blank represents the absorbance of the blank control group
  • RLU DMSO represents the absorbance of the DMSO control group
  • the XEFFit curve fitting software was used to plot the pharmacodynamic inhibition rate curve and calculate the IC 50 value. The results are shown in Table 2.
  • the compounds of the present invention have a better inhibitory effect on double mutant cells (NCI-H1975), and have less inhibition on EGFR wild type cells (A431), and the selectivity is similar to or significantly superior to AZD9291.
  • One of the major side effects of currently marketed EGFR inhibitors is rash, diarrhea, etc., which are associated with inhibition of wild-type EGFR and poor selectivity. Therefore, the compound of the present invention is expected to be a drug having a specific therapeutic effect against a tumor resistant to EGFR mutation and having a small side effect.
  • the compound of the present invention was dissolved in 25 mM sodium citrate-sodium citrate buffer (pH 4.5) to prepare a clear solution having a concentration of 1.25 mg/mL, and was set as a test compound group; 25 mM citric acid was used.
  • - sodium citrate buffer (pH 4.5) was set as a vehicle control group;
  • mice Female BALB/C mice, 5 in each group, weighing 18-22 g, were provided by Shanghai Xipuer-Beikai Experimental Animal Co., Ltd. The test mice were given an environmental adaptation period of 2 to 4 days before the experiment, and fasted for 8-12 hours before administration.
  • intragastric administration administration of the compound of the invention 25mg / kg;
  • AUC [(A 15min +A 0 ) ⁇ 7.5]+[(A 30min + A 15min ) ⁇ 7.5]+[(A 60min +A 30min ) ⁇ 15]+[(A 120min +A 60min ) ⁇ 30]
  • AUC value and increase % [(AUC compound- AUC solvent ) according to the formula AUC/ AUC solvent ] ⁇ 100% calculated the AUC growth rate, where “A 0 ” represents the blood glucose level at 0 min after gavage, “A 15 min ” represents the blood glucose level after 15 min, and “A 30 min ” represents the blood glucose after 30 min.
  • EGFR inhibitors may cause side effects such as hyperglycemia and impaired insulin signaling.
  • AZD9291 and Clociletinib (CO1686) of Clovis Oncology have a certain degree of side effects on blood glucose (Management of hyperglycemia from epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) targeting T790M-mediated resistance, Jeryl Villadolid , et al. Translational Lung Cancer Research (2015), 4(5), 576-583).
  • EGFR epidermal growth factor receptor
  • TKIs tyrosine kinase inhibitors
  • the compounds of the invention are formulated into either oral and injectable formulations.
  • the oral drug formulation was dissolved in 25 mM sodium citrate-sodium citrate buffer (pH 4.5) to prepare a 1.25 mg/mL clear solution; the tail vein injection drug formulation was citrate-sodium citrate buffer solution.
  • a mixed solution of (pH 4.5) and physiological saline volume ratio of 1:1 was prepared into a 0.2 mg/mL solution.
  • mice Female BALB/C mice, 5 in each group, weighing 18-22 g, were provided by Shanghai Xipuer-Beikai Experimental Animal Co., Ltd. The test mice were given an environmental adaptation period of 2 to 4 days before the experiment, and were fasted for 8-12 hours before administration, and given water for 2 hours after administration, and fed after 4 hours.
  • Acetonitrile (chromatographically pure): produced by Spectrum;
  • intragastric administration administration of the compound of the invention 25mg / kg;
  • mice in step 2.1 the intravenous vein (Intravenous administration, I.V.) administered the compound of the invention 2mg / kg;
  • the compounds of the invention have good pharmacokinetic data and should have good clinical application prospects.

Abstract

La présente invention concerne un inhibiteur de récepteur du facteur de croissance épidermique tel que représenté dans la formule suivante, une composition pharmaceutique contenant l'inhibiteur de récepteur, et une utilisation de l'inhibiteur ou de la composition pharmaceutique comme médicament pour la prévention et/ou le traitement des cancers. Les groupes sont définis dans la description. Le composé présente une bonne activité d'inhibition d'EGFR, en particulier pour un EGFR muté, étant ainsi supposé être un médicament contre des tumeurs résistants, présentant une résistance aux médicaments due à des mutations de l'EGFR ; présente un effet curatif spécifique et moins d'effets secondaires.
PCT/CN2016/106862 2015-11-23 2016-11-23 Nouvel inhibiteur de récepteur du facteur de croissance épidermique et son application WO2017088746A1 (fr)

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CN110818690B (zh) * 2016-07-26 2021-08-10 深圳市塔吉瑞生物医药有限公司 用于抑制蛋白酪氨酸激酶活性的氨基嘧啶类化合物
CN107663208B (zh) * 2016-07-27 2021-10-15 南京圣和药业股份有限公司 一种新型egfr激酶抑制剂的药用盐及其制备方法与用途
CN109705117A (zh) * 2017-10-25 2019-05-03 南京圣和药业股份有限公司 三环类化合物、其制备方法及用途
CN109705118B (zh) * 2017-10-25 2021-12-28 南京圣和药业股份有限公司 三环类egfr激酶抑制剂的制备方法
CN108191861B (zh) * 2018-03-01 2020-10-02 天津大学 N-[5-(嘧啶-2-氨基)-2,4-二取代苯基]-反式-2,4-戊二烯酰胺
CN113544132A (zh) * 2019-03-12 2021-10-22 默克专利有限公司 用于有机电致发光器件的材料

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