WO2017088746A1 - 新的表皮生长因子受体抑制剂及其应用 - Google Patents

新的表皮生长因子受体抑制剂及其应用 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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French (fr)
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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/zh

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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.

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Abstract

如下式所示的表皮生长因子受体抑制剂、含有该抑制剂的药物组合物，以及所述抑制剂或药物组合物作为癌症预防和/或治疗药物的用途，其中所述基团具有如说明书相同的定义。所述化合物表现出良好的EGFR抑制活性，尤其是针对突变的EGFR，有望成为对抗EGFR突变导致耐药的肿瘤具有特异疗效且副作用较小的药物。

Description

新的表皮生长因子受体抑制剂及其应用 技术领域
本发明属于医药化学领域，具体涉及一类新的表皮生长因子受体抑制剂、含有该抑制剂的药物组合物，以及所述抑制剂或药物组合物作为癌症治疗药物的用途。
背景技术
表皮生长因子受体(Epidermal Growth Factor Receptor,EGFR)是原癌基因C-erbB-1的表达产物，为EGFR家族成员之一。EGFR家族包括EGFR(HER-1)、ERBB2(HER-2)、ERBB3(HER-3)和ERBB4(HER-4)四个成员。已表明EGFR过表达或突变一般会引发肿瘤。EGFR突变导致EGFR的持续活化，自分泌环的作用增强，受体下调机制破坏，异常信号传导通路激活，在肿瘤的演进中起着重要作用。
针对EGFR采用EGFR-酪氨酸激酶抑制剂(EGFR-TKI)治疗已经成为非小细胞肺癌治疗领域里的金标准。不过，临床使用发现，多数患者会在吉非替尼、厄洛替尼等EGFR-TKI抑制剂治疗后6-12个月发生不同程度的耐药现象，进而导致药物的疗效显著降低，肿瘤进展。研究显示EGFR-TKI耐药性的产生与EGFR基因的二次突变有关，其中最常见的突变是EGFR基因20号外显子第790位点的突变，即T790M基因突变。由于甲硫氨酸比苏氨酸空间占位大，因此形成空间位阻，改变了EGFR激酶区ATP的亲和性，导致EGFR-TKI小分子药物不能有效阻断EGFR活化信号，导致耐药性的产生。同时，第一代EGFR抑制剂缺乏野生型EGFR与突变型EGFR的选择性，普遍存在皮疹、腹泻等副作用，影响患者依从性。
因此，开发对因EGFR二次突变产生耐药的肿瘤患者有效的药物，特别是开发能进一步提高对野生型EGFR与突变型EGFR选择性，增强疗效，降低副作用的药物，将具有良好的应用前景。
发明内容
本发明的目的是提供通式I的表皮生长因子抑制剂或其药学可接受的盐、异构体、溶剂合物、结晶或前药，该类化合物表现出良好的EGFR抑制活性，尤其是针对突变的EGFR，
Figure PCTCN2016106862-appb-000001
本发明的另一个目的是提供通式II的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，以所述通式II的化合物为关键中间体，制备通式I的化合物，反应条件温和，收率和纯度较高，
Figure PCTCN2016106862-appb-000002
本发明的第三个目的是提供通式III的化合物或其盐，以所述通式III的化合物为关键中间体，制备通式I的化合物，反应步骤少，条件温和，收率和纯度较高，
Figure PCTCN2016106862-appb-000003
本发明的第四个目的是提供制备本发明的通式I、II或III的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药的方法。
本发明的第五个目的是提供包含本发明的通式I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药和药学可接受的载体的药物组合物以及包含本发明的通式I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药和另一种肿瘤抑制剂的药物组合物。
本发明的第六个目的是提供本发明的通式I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药以及本发明的药物组合物治疗和/或预防癌症的方法及其在制备用于治疗和/或预防癌症的药物中的应用。
针对上述发明目的，本发明提供以下技术方案：
第一方面，本发明提供通式I所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，
Figure PCTCN2016106862-appb-000004
其中，
环A为C4-C8含氮杂环基，其任选被一个或多个卤素、氧代、烷基、环烷基、卤代烷基、烷氧基、卤代烷氧基、硝基、氰基、羟基、氨基、单烷基氨基、二烷基氨基、氨基烷基、单烷基氨基烷基、二烷基氨基烷基、羟基烷基、烷氧基烷基、烷基酰基、氨基酰基、单烷基氨基酰基、二烷基氨基酰基、芳基、杂芳基和杂环烷基取代，当取代基有两个以上时，相邻的两个取代基可以与它们连接的原子一起构成取代或未取代的环烷基、杂环烷基、芳基、杂芳基，或连接在同一个原子上的两个取代基可以与它们共同连接的原子形成取代或未取代的环烷基、杂环烷基；
X1、X2、X3和X4各自独立选自C(R1)和N；
R1、R2a、R2b、R3a、R3b和R3c各自独立地选自氢、卤素、烷基、环烷基、卤代烷基、烷氧基、卤代烷氧基、硝基、氰基、羟基、氨基、单烷基氨基、二烷基氨基、氨基烷基、单烷基氨基烷基、二烷基氨基烷基、羟基烷基、烷氧基烷基、烷基酰基、氨基酰基、单烷基氨基酰基和二烷基氨基酰基；
R4、R5和R6各自独立地选自氢、卤素、氰基、烷基、烷氧基和环烷基，所述的烷基、烷氧基和环烷基任选被一个或多个卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氨基、单烷基氨基、二烷基氨基、羟基、氨基烷基、单烷基氨基烷基、二烷基氨基烷基或羟基烷基取代；
R7选自氢、烷基、环烷基和卤代烷基；和
R8选自氢、烷基和环烷基，所述的烷基和环烷基任选被一个或多个卤素、烷基、卤代烷基、烷氧基、氨基、单烷基氨基、二烷基氨基或羟基取代；或
R7、R8及其连接的N原子一起构成含氮杂环烷基，所述的含氮杂环烷基任选被一个或多个卤素、烷基、卤代烷基、烷氧基、氨基、单烷基氨基、二烷基氨基、羟基、氨基烷基、单烷基氨基烷基、二烷基氨基烷基或羟基烷基取代。
第二方面，本发明提供通式II的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，
Figure PCTCN2016106862-appb-000005
其中环A、X1、X2、X3、X4、R2a、R2b、R3a、R3b、R3c、R7和R8具有通式I中的定义。
第三方面，本发明提供通式III的化合物或其药学可接受的盐，
Figure PCTCN2016106862-appb-000006
其中环A、X1、X2、X3、X4、R2a、R2b具有通式I中的定义，M为卤素。
在一些实施方案中，本发明提供通式I、II或III所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中环A为C4-C8含氮杂单环烷基，其任选被一个或多个卤素、氧代、烷基、环烷基、卤代烷基、烷氧基、卤代烷氧基、硝基、氰基、羟基、氨基、单烷基氨基、二烷基氨基、氨基烷基、单烷基氨基烷基、二烷基氨基烷基、羟基烷基、烷氧基烷基、烷基酰基、氨基酰基、单烷基氨基酰基、二烷基氨基酰基、芳基、杂芳基和杂环烷基取代，当取代基有两个以上时，相邻的两个取代基可以与它们连接的原子一起构成取代或未取代的环烷基、杂环烷基、芳基、杂芳基，或连接在同一个原子上的两个取代基可以与它们共同连接的原子形成取代或未取代的环烷基、杂环烷基。
在一些实施方案中，本发明提供通式I、II或III所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中环A为只含有一个氮原子的C4-C8含氮杂单环烷基，其任选被一个或多个卤素、氧代、烷基、环烷基、卤代烷基、烷氧基、卤代烷氧基、硝基、氰基、羟基、氨基、单烷基氨基、二烷基氨基、氨基烷基、单烷基氨基烷基、二烷基氨基烷基、羟基烷基、烷氧基烷基、烷基酰基、氨基酰基、单烷基氨基酰基、二烷基氨基酰基、芳基、杂芳基和杂环烷基取代，当取代基有两个以上时，相邻的两个取代基可以与它们连接的原子一起构成取代或未取代的环烷基、杂环烷基、芳基、杂芳基，或连接在同一个原子上的两个取代基可以与它们共同连接的原子形成取代或未取代的环烷基、杂环烷基。
在一些优选的实施方案中，本发明提供通式I、II或III所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中环A为
Figure PCTCN2016106862-appb-000007
n选自1、2、3、4、5和6，m选自1、2、3和4，Ra选自氢、C1-6烷基、C3-8环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、硝基、氰基、羟基、氨基、单C1-6烷基氨基、二C1-6烷基氨基、氨基C1-6烷基、单C1-6烷基氨基C1-6烷基、二C1-6烷基氨基C1-6烷基、羟基C1-6烷基、C1-6烷氧基C1-6烷基、C1-6烷基酰基、氨基酰基、单C1-6烷基氨基酰基、二C1-6烷基氨基酰基、C6-10芳基、C5-10杂芳基和C3-8杂环烷基，当m选自2、3和4时，相邻两个碳原子上的两个Ra可以与它们所连接的碳原子一起构成C3-8环烷基或C3-8杂环烷基，或同一个碳原子上的两个Ra可以与它们共同连接的碳原子一起构成C3-8环烷基或C3-8杂环烷基。
在一些优选的实施方案中，本发明提供通式I、II或III所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中环A为
Figure PCTCN2016106862-appb-000008
n选自1、2、3和4，m选自1、2、3和4，Ra选自氢、C1-3烷基、C3-6环烷基、卤代C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、硝基、氰基、羟基、氨基、单C1-3烷基氨基、二C1-3烷基氨基、氨基C1-3烷基、单C1-3烷基氨基C1-3烷基、二C1-3烷基氨基C1-3烷基、羟基C1-3烷基、C1-3烷氧基C1-3烷基、C1-3烷基酰基、氨基酰基、单C1-3烷基氨基酰基、二C1-3烷基氨基酰基、C6-10芳基、C5-10杂芳基和C3-6杂环烷基，当m选自2、3和4时，相邻两个碳原子上的两个Ra可以与它们所连接的碳原子一起构成C3-6环烷基或C3-6杂环烷基，或同一个碳原子上的两个Ra可以与它们共同连接的碳原子一起构成C3-6环烷基或C3-6杂环烷基。
在另一些实施方案中，本发明提供通式I、II或III所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中环A为含有两个氮原子的C4-C8含氮杂单环烷基，其任选被一个或多个卤素、氧代、烷基、环烷基、卤代烷基、烷氧基、卤代烷氧基、硝基、氰基、羟基、氨基、单烷基氨基、二烷基氨基、氨基烷基、单烷基氨基烷基、二烷基氨基烷基、羟基烷基、烷氧基烷基、烷基酰基、氨基酰基、单烷基氨基酰基、二烷基氨基酰基、芳基、杂芳基和杂环烷基取代，当取代基有两个以上时，相邻的两个取代基可以与它们连接的原子一起构成取代或未取代的环烷基、杂环烷基、芳基、杂芳基，或连接在同一个原子上的两个取代基可以与它们共同连接的原子形成取代或未取代的环烷基、杂环烷基。
在一些优选的实施方案中，本发明提供通式I、II或III所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中环A为
Figure PCTCN2016106862-appb-000009
m选自1、2、3和4，p选自0、1和2，q选自0、1和2，Ra选自氢、C1-6烷基、C3-8环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、硝基、氰基、羟基、氨基、单C1-6烷基氨基、二C1-6烷基氨基、氨基C1-6烷基、单C1-6烷基氨基C1-6烷基、二C1-6烷基氨基C1-6烷基、羟基C1-6烷基、C1-6烷氧基C1-6烷基、C1-6烷基酰基、氨基酰基、单C1-6烷基氨基酰基、二C1-6烷基氨基酰基、C6-10芳基、C5-10杂芳基和C3-8杂环烷基，当m选自2、3和4时，相邻两个原子上的两个Ra可以与它们所连接的原子一起构成C3-8环烷基或C3-8杂环烷基，或同一个原子上的两个Ra可以与它们共同连接的原子一起构成C3-8环烷基或C3-8杂环烷基。
在一些优选的实施方案中，本发明提供通式I、II或III所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中环A为
Figure PCTCN2016106862-appb-000010
m选自1、2、3和4，p选自0、1和2，q选自0、1和2，Ra选自氢、C1-3烷基、C3-6环烷基、卤代C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、硝基、氰基、羟基、氨基、单C1-3烷基氨基、二C1-3烷基氨基、氨基C1-3 烷基、单C1-3烷基氨基C1-3烷基、二C1-3烷基氨基C1-3烷基、羟基C1-3烷基、C1-3烷氧基C1-3烷基、C1-3烷基酰基、氨基酰基、单C1-3烷基氨基酰基、二C1-3烷基氨基酰基、C6-10芳基、C5-10杂芳基和C3-6杂环烷基，当m选自2、3和4时，相邻两个原子上的两个Ra可以与它们所连接的原子一起构成C3-6环烷基或C3-6杂环烷基，或同一个原子上的两个Ra可以与它们共同连接的原子一起构成C3-6环烷基或C3-6杂环烷基。
在另一些实施方案中，本发明提供通式I、II或III所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中环A为含有一个氮原子和一个氧原子的C4-C8含氮杂单环烷基，其任选被一个或多个卤素、氧代、烷基、环烷基、卤代烷基、烷氧基、卤代烷氧基、硝基、氰基、羟基、氨基、单烷基氨基、二烷基氨基、氨基烷基、单烷基氨基烷基、二烷基氨基烷基、羟基烷基、烷氧基烷基、烷基酰基、氨基酰基、单烷基氨基酰基、二烷基氨基酰基、芳基、杂芳基和杂环烷基取代，当取代基有两个以上时，相邻的两个取代基可以与它们连接的原子一起构成取代或未取代的环烷基、杂环烷基、芳基、杂芳基，或连接在同一个原子上的两个取代基可以与它们共同连接的原子形成取代或未取代的环烷基、杂环烷基。
在一些优选的实施方案中，本发明提供通式I、II或III所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中环A为
Figure PCTCN2016106862-appb-000011
m选自1、2、3和4，p选自0、1和2，q选自0、1和2，Ra选自氢、C1-6烷基、C3-8环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、硝基、氰基、羟基、氨基、单C1-6烷基氨基、二C1-6烷基氨基、氨基C1-6烷基、单C1-6烷基氨基C1-6烷基、二C1-6烷基氨基C1-6烷基、羟基C1-6烷基、C1-6烷氧基C1-6烷基、C1-6烷基酰基、氨基酰基、单C1-6烷基氨基酰基、二C1-6烷基氨基酰基、C6-10芳基、C5-10杂芳基和C3-8杂环烷基，当m选自2、3和4时，相邻两个原子上的两个Ra可以与它们所连接的原子一起构成C3-8环烷基或C3-8杂环烷基，或同一个原子上的两个Ra可以与它们共同连接的原子一起构成C3-8环烷基或C3-8杂环烷基。
在一些优选的实施方案中，本发明提供通式I、II或III所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中环A为
Figure PCTCN2016106862-appb-000012
m选自1、2、3和4，p选自0、1和2，q选自0、1和2，Ra选自氢、C1-3烷基、C3-6环烷基、卤代C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、硝基、氰基、羟基、氨基、单C1-3烷基氨基、二C1-3烷基氨基、氨基C1-3烷基、单C1-3烷基氨基C1-3烷基、二C1-3烷基氨基C1-3烷基、羟基C1-3烷基、C1-3烷氧基C1-3烷基、C1-3烷基酰基、氨基酰基、单C1-3烷基氨基酰基、二C1-3烷基氨基酰基、C6-10芳基、C5-10杂芳基和C3-6杂环烷基，当m选自2、3和4时，相邻两个原子上的两个Ra可以与它们所连接的原子一起构成C3-6环烷基或C3-6杂环烷基，或同一个原子上的两个Ra可以与它们共同连接的原子一起构成C3-6环烷基或C3-6杂环烷基。在一些实施方案中，本发明提供通式I、 II或III所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中环A为含有一个氮原子和一个硫原子的C4-C8含氮杂单环烷基，其任选被一个或多个卤素、氧代、烷基、环烷基、卤代烷基、烷氧基、卤代烷氧基、硝基、氰基、羟基、氨基、单烷基氨基、二烷基氨基、氨基烷基、单烷基氨基烷基、二烷基氨基烷基、羟基烷基、烷氧基烷基、烷基酰基、氨基酰基、单烷基氨基酰基、二烷基氨基酰基、芳基、杂芳基和杂环烷基取代，当取代基有两个以上时，相邻的两个取代基可以与它们连接的原子一起构成取代或未取代的环烷基、杂环烷基、芳基、杂芳基，或连接在同一个原子上的两个取代基可以与它们共同连接的原子形成取代或未取代的环烷基、杂环烷基。
在一些实施方案中，本发明提供通式I、II或III所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中X1、X2、X3和X4均为C(R1)。
在一些具体的实施方案中，本发明提供以下通式Ia、IIa和IIIa所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，
Figure PCTCN2016106862-appb-000013
其中环A、R1、R2a、R2b、R3a、R3b、R3c、R4、R5、R6、R7、R8和M具有以上通式I、II和III中的定义，n选自1、2、3和4的整数。
在另一些实施方案中，本发明提供通式I、II或III所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中X1、X2、X3和X4中至少有一个为N。
在另一些实施方案中，本发明提供通式I、II或III所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中X1、X2、X3和X4中有两个为N。
在另一些实施方案中，本发明提供通式I、II或III所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中X1、X2、X3和X4中有三个为N。
在另一些实施方案中，本发明提供通式I、II或III所示的化合物或其药学可接受的盐、 异构体、溶剂合物、结晶或前药，其中X1、X2、X3和X4均为N。
在一些实施方案中，本发明提供通式I、II或III所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中R1、R2a和R2b各自独立地选自氢、卤素、C1-6烷基、C3-8环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、硝基、氰基、羟基、氨基、单C1-6烷基氨基、二C1-6烷基氨基、氨基C1-6烷基、单C1-6烷基氨基C1-6烷基、二C1-6烷基氨基C1-6烷基、羟基C1-6烷基、C1-6烷氧基C1-6烷基、C1-6烷基酰基、氨基酰基、单C1-6烷基氨基酰基和二C1-6烷基氨基酰基。
在一些优选的实施方案中，本发明提供通式I、II或III所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中各R1、R2a和R2b各自独立地独立地选自氢、卤素、C1-3烷基、C3-6环烷基、卤代C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、硝基、氰基、羟基、氨基、单C1-3烷基氨基、二C1-3烷基氨基、氨基C1-3烷基、单C1-3烷基氨基C1-6烷基、二C1-3烷基氨基C1-3烷基、羟基C1-3烷基、C1-3烷氧基C1-3烷基、C1-3烷基酰基、氨基酰基、单C1-3烷基氨基酰基和二C1-3烷基氨基酰基。
在另一些优选的实施方案中，本发明提供通式I、II或III所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中R1、R2a和R2b各自独立地选自氢、氟、氯、溴、碘、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、三氟甲基、三氟乙基、二氟甲基、二氟乙基、甲氧基、乙氧基、丙氧基、三氟甲基氧基、硝基、氰基、羟基、氨基、甲氨基、乙氨基、丙氨基、异丙基氨基、二甲氨基、二乙氨基、二丙氨基、二异丙氨基、N-甲基-N-乙基氨基、N-甲基-N-丙基氨基、N-甲基-N-异丙基氨基、N-乙基-N-丙基氨基、N-乙基-N-异丙基氨基、N-丙基-N-异丙基氨基、氨基甲基、氨基乙基、氨基丙基、甲氨基甲基、甲氨基乙基、乙氨基甲基、乙氨基乙基、二甲氨基甲基、二甲氨基乙基、二乙氨基甲基、二乙氨基乙基、羟甲基、羟乙基、甲氧基甲基、乙氧基甲基、丙氧基甲基、甲氧基乙基和乙氧基乙基。
在另一些优选的实施方案中，本发明提供通式I、II或III所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中R1、R2a和R2b各自独立地选自氢、氟、氯、溴、甲基、乙基、丙基、异丙基、三氟甲基、三氟乙基、甲氧基、乙氧基、羟基、氨基、甲氨基、乙氨基、丙氨基、二甲氨基、二乙氨基、氨基甲基、氨基乙基、氨基丙基、甲氨基甲基、甲氨基乙基、乙氨基甲基、乙氨基乙基、二甲氨基甲基、二乙氨基甲基、羟甲基和羟乙基。
在一些优选的实施方案中，本发明提供通式I或II所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中R3a、R3b和R3c各自独立地选自氢、卤素、C1-6烷基、C3-8环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、硝基、氰基、羟基、氨基、单C1-6烷基氨基、二C1-6烷基氨基、氨基C1-6烷基、单C1-6烷基氨基C1-6烷基、二C1-6烷基氨基C1-6烷基、羟基C1-6烷基、C1-6烷氧基C1-6烷基、C1-6烷基酰基、氨基酰基、单C1-6烷基氨基酰基和二C1-6烷基氨基酰基。
在另一些优选的实施方案中，本发明提供通式I或II所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中各R3a、R3b和R3c各自独立地选自氢、卤素、C1-3烷基、C3-6环烷基、卤代C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、硝基、氰基、羟基、氨基、单C1-3烷基氨基、二C1-3烷基氨基、氨基C1-3烷基、单C1-3烷基氨基C1-6烷基、二C1-3烷基氨基C1-3烷基、羟基C1-3烷基、C1-3烷氧基C1-3烷基、C1-3烷基酰基、氨基酰基、单C1-3烷基氨基酰基和二C1-3烷基氨基酰基。
在另一些优选的实施方案中，本发明提供通式I或II所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中R3a、R3b和R3c各自独立地选自氢、氟、氯、溴、碘、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基、三氟甲基、三氟乙基、二氟甲基、二氟乙基、甲氧基、乙氧基、丙氧基、三氟甲基氧基、硝基、氰基、羟基、氨基、甲氨基、乙氨基、丙氨基、异丙基氨基、二甲氨基、二乙氨基、二丙氨基、二异丙氨基、N-甲基-N-乙基氨基、N-甲基-N-丙基氨基、N-甲基-N-异丙基氨基、N-乙基-N-丙基氨基、N-乙基-N-异丙基氨基、N-丙基-N-异丙基氨基、氨基甲基、氨基乙基、氨基丙基、甲氨基甲基、甲氨基乙基、乙氨基甲基、乙氨基乙基、二甲氨基甲基、二甲氨基乙基、二乙氨基甲基、二乙氨基乙基、羟甲基、羟乙基、甲氧基甲基、乙氧基甲基、丙氧基甲基、甲氧基乙基和乙氧基乙基。
在另一些优选的实施方案中，本发明提供通式I或II所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中R3a、R3b和R3c各自独立地选自氢、氟、氯、溴、甲基、乙基、丙基、异丙基、三氟甲基、三氟乙基、甲氧基、乙氧基、羟基、氨基、甲氨基、乙氨基、丙氨基、二甲氨基、二乙氨基、氨基甲基、氨基乙基、氨基丙基、甲氨基甲基、甲氨基乙基、乙氨基甲基、乙氨基乙基、二甲氨基甲基、二乙氨基甲基、羟甲基和羟乙基。
在一些实施方案中，本发明提供通式I或II所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中R7选自氢、C1-6烷基、C3-6环烷基和卤代C1-6烷基。
在一些优选的实施方案中，本发明提供通式I或II所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中R7选自氢、C1-3烷基、C3-6环烷基和卤代C1-3烷基。
在一些优选的实施方案中，本发明提供通式I或II所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中R7选自氢、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基和三氟甲基。
在一些优选的实施方案中，本发明提供通式I或II所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中R7为甲基。
在一些实施方案中，本发明提供通式I或II所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中R8选自氢、C1-6烷基和C3-6环烷基，所述的C1-6烷基和C3-6环烷基任选被一个或多个卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、氨基、单C1-6烷基氨基、二C1-6烷基氨基或羟基取代。
在一些优选的实施方案中，本发明提供通式I或II所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中R8选自氢、C1-3烷基和C3-6环烷基，所述的C1-3烷基和C3-6环烷基任选被一个或多个卤素、C1-3烷基、卤代C1-3烷基、C1-3烷氧基、氨基、单C1-3烷基氨基、二C1-3烷基氨基或羟基取代。
在一些优选的实施方案中，本发明提供通式I或II所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中R8选自氢、C1-3烷基和C3-6环烷基，所述的C1-3烷基和C3-6环烷基任选被一个或多个卤素、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、三氟乙基、甲氧基、乙氧基、丙氧基、异丙基氧基、氨基、甲氨基、乙氨基、丙氨基、二甲氨基、二乙胺基、二丙氨基、甲基乙基氨基、甲基丙基氨基、乙基丙基氨基或羟基取代。
在一些优选的实施方案中，本发明提供通式I或II所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中R8选自氢、甲基、乙基和丙基，所述的甲基、乙基和丙基任选被一个或多个氨基、甲氨基、乙氨基、丙氨基、二甲氨基、二乙胺基、二丙氨基、甲基乙基氨基、甲基丙基氨基或乙基丙基氨基取代。
在一些优选的实施方案中，本发明提供通式I或II所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中R8为被二甲氨基取代的乙基。
在另一些实施方案中，本发明提供通式I或II所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中R7、R8及其连接的N构成四至八元氮杂环烷基，所述的四至八元氮杂环烷基任选被一个或多个卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、氨基、单C1-6烷基氨基、二C1-6烷基氨基、羟基、氨基C1-6烷基、单C1-6烷基氨基C1-6烷基、二C1-6烷基氨基C1-6烷基或羟基烷基取代。
在一些优选的实施方案中，本发明提供通式I或II所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中R7、R8及其连接的N构成四至八元氮杂环烷基，所述的四至八元氮杂环烷基任选被一个或多个卤素、C1-3烷基、卤代C1-3烷基、C1-3烷氧基、氨基、单C1-3烷基氨基、二C1-3烷基氨基、羟基、氨基C1-3烷基、单C1-3烷基氨基C1-3烷基、二C1-3烷基氨基C1-3烷基或羟基烷基取代。
在一些优选的实施方案中，本发明提供通式I或II所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中R7、R8及其连接的N构成五至六元氮杂环烷基，所述的五至六元氮杂环烷基任选被一个或多个卤素、C1-3烷基、卤代C1-3烷基、C1-3烷氧基、氨基、单C1-3烷基氨基、二C1-3烷基氨基、羟基、氨基C1-3烷基、单C1-3烷基氨基C1-3烷基、二C1-3烷基氨基C1-3烷基或羟基烷基取代。
在一些实施方案中，本发明提供通式I所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中R4、R5和R6各自独立地选自氢、卤素、氰基、C1-6烷基、C1-6烷氧基、C3-8环烷基，所述的C1-6烷基、C1-6烷氧基和环烷基任选被一个或多个卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、单C1-6烷基氨基、二C1-6烷基氨基、羟 基、氨基C1-6烷基、单C1-6烷基氨基C1-6烷基、二C1-6烷基氨基C1-6烷基和羟基C1-6烷基取代。
在一些优选的实施方案中，本发明提供通式I所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中R4、R5和R6各自独立地选自氢、卤素、氰基、C1-3烷基、C1-3烷氧基、C3-6环烷基，所述的C1-3烷基、C1-3烷氧基和C3-6环烷基任选被一个或多个卤素、C1-3烷基、卤代C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、氨基、单C1-3烷基氨基、二C1-3烷基氨基、羟基、氨基C1-3烷基、单C1-3烷基氨基C1-3烷基、二C1-3烷基氨基C1-3烷基或羟基C1-3烷基取代。
在一些优选的实施方案中，本发明提供通式I所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中R4、R5和R6均为氢。
在一些实施方案中，本发明提供通式III所示的化合物或其药学可接受的盐，其中M选自氟、氯、溴和碘。
在一些优选的实施方案中，本发明提供通式III所示的化合物或其药学可接受的盐，其中M选自氯、溴和碘。
在一些具体的实施方案中，本发明提供通式I所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中
环A为
Figure PCTCN2016106862-appb-000014
n选自1、2、3和4；
m选自1、2、3和4；
Ra选自氢、C1-3烷基、C3-6环烷基、卤代C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、硝基、氰基、羟基、氨基、单C1-3烷基氨基、二C1-3烷基氨基、氨基C1-3烷基、单C1-3烷基氨基C1-3烷基、二C1-3烷基氨基C1-3烷基、羟基C1-3烷基、C1-3烷氧基C1-3烷基、C1-3烷基酰基、氨基酰基、单C1-3烷基氨基酰基、二C1-3烷基氨基酰基、C6-10芳基、C5-10杂芳基和C3-6杂环烷基，当m选自2、3和4时，相邻两个碳原子上的两个Ra可以与它们所连接的碳原子一起构成C3-6环烷基或C3-6杂环烷基，或同一个碳原子上的两个Ra可以与它们共同连接的碳原子一起构成C3-6环烷基或C3-6杂环烷基；
X1、X2、X3和X4各自独立选自C(R1)和N；
R1、R2a、R2b、R3a、R3b和R3c各自独立地选自氢、卤素、C1-3烷基、卤代C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、硝基、氰基、羟基、氨基、单C1-3烷基氨基、二C1-3烷基氨基、氨基C1-3烷基、单C1-3烷基氨基C1-6烷基、二C1-3烷基氨基C1-3烷基、羟基C1-3烷基、C1-3烷氧基C1-3烷基、C1-3烷基酰基、氨基酰基、单C1-3烷基氨基酰基和二C1-3烷基氨基酰基；
R4、R5和R6均为氢；
R7为甲基；
R8为被二甲氨基取代的乙基。
在另一些具体的实施方案中，本发明提供通式I所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中
环A为
Figure PCTCN2016106862-appb-000015
m选自1、2、3和4；
p选自0、1和2；
q选自0、1和2；Ra选自氢、C1-3烷基、C3-6环烷基、卤代C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、硝基、氰基、羟基、氨基、单C1-3烷基氨基、二C1-3烷基氨基、氨基C1-3烷基、单C1-3烷基氨基C1-3烷基、二C1-3烷基氨基C1-3烷基、羟基C1-3烷基、C1-3烷氧基C1-3烷基、C1-3烷基酰基、氨基酰基、单C1-3烷基氨基酰基、二C1-3烷基氨基酰基、C6-10芳基、C5-10杂芳基和C3-6杂环烷基，当m选自2、3和4时，相邻两个原子上的两个Ra可以与它们所连接的原子一起构成C3-6环烷基或C3-6杂环烷基，或同一个原子上的两个Ra可以与它们共同连接的原子一起构成C3-6环烷基或C3-6杂环烷基；
X1、X2、X3和X4各自独立选自C(R1)和N；
R1、R2a、R2b、R3a、R3b和R3c各自独立地选自氢、卤素、C1-3烷基、卤代C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、硝基、氰基、羟基、氨基、单C1-3烷基氨基、二C1-3烷基氨基、氨基C1-3烷基、单C1-3烷基氨基C1-6烷基、二C1-3烷基氨基C1-3烷基、羟基C1-3烷基、C1-3烷氧基C1-3烷基、C1-3烷基酰基、氨基酰基、单C1-3烷基氨基酰基和二C1-3烷基氨基酰基；
R4、R5和R6均为氢；
R7为甲基；
R8为被二甲氨基取代的乙基。
在另一些具体的实施方案中，本发明提供通式I所示的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中
环A为
Figure PCTCN2016106862-appb-000016
m选自1、2、3和4；
p选自0、1和2；
q选自0、1和2；Ra选自氢、C1-3烷基、C3-6环烷基、卤代C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、硝基、氰基、羟基、氨基、单C1-3烷基氨基、二C1-3烷基氨基、氨基C1-3烷基、单C1-3烷基氨基C1-3烷基、二C1-3烷基氨基C1-3烷基、羟基C1-3烷基、C1-3烷氧基C1-3烷基、C1-3烷基酰基、氨基酰基、单C1-3烷基氨基酰基、二C1-3烷基氨基酰基、C6-10芳基、C5-10杂芳基和C3-6杂环烷基，当m选自2、3和4时，相邻两个原子上的两个Ra可以与它们 所连接的原子一起构成C3-6环烷基或C3-6杂环烷基，或同一个原子上的两个Ra可以与它们共同连接的原子一起构成C3-6环烷基或C3-6杂环烷基；
X1、X2、X3和X4各自独立选自C(R1)和N；
R1、R2a、R2b、R3a、R3b和R3c各自独立地选自氢、卤素、C1-3烷基、卤代C1-3烷基、C1-3烷氧基、卤代C1-3烷氧基、硝基、氰基、羟基、氨基、单C1-3烷基氨基、二C1-3烷基氨基、氨基C1-3烷基、单C1-3烷基氨基C1-6烷基、二C1-3烷基氨基C1-3烷基、羟基C1-3烷基、C1-3烷氧基C1-3烷基、C1-3烷基酰基、氨基酰基、单C1-3烷基氨基酰基和二C1-3烷基氨基酰基；
R4、R5和R6均为氢；
R7为甲基；
R8为被二甲氨基取代的乙基。
在一些具体的实施方案中，本发明提供了以下化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药：
Figure PCTCN2016106862-appb-000017
Figure PCTCN2016106862-appb-000018
在另一些具体的实施方案中，本发明提供了以下化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药：
Figure PCTCN2016106862-appb-000019
Figure PCTCN2016106862-appb-000020
Figure PCTCN2016106862-appb-000021
第四方面，本发明提供本发明的通式I、II和III的化合物的制备方法，包括如下步骤：
Figure PCTCN2016106862-appb-000022
A)式1的原料和式2的原料发生亲核反应制得式III的中间体；
B)式III的中间体与式3的原料反应制得式4的中间体；
C)式4的中间体经过亲核反应制得式5的中间体；
D)式5的中间体经过还原反应制得式II的中间体；
E)式II的中间体与式6的原料反应制得式I的化合物。
上述环A、X1、X2、X3、X4、R2a、R2b、R3a、R3b、R3c、R4、R5、R6、R7、R8和M具有通式I、II、III中的定义。
在一些实施方案中，本发明提供制备本发明的通式I的化合物的制备方法，所述方法包括使用本发明的通式II的化合物。
在一些实施方案中，本发明提供制备本发明的通式I的化合物的制备方法，所述方法包括使用本发明的通式III的化合物。
第五方面，本发明提供药物组合物，其包含本发明通式I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药和药学可接受的载体。
在一些实施方案中，本发明提供药物组合物，其包含本发明通式I的化合物、异构体、溶剂合物、结晶或前药，还包含选自下列组成的一种或多种化合物：吉非替尼、厄洛替尼、拉帕替尼、阿法替尼、凡德他尼、卡奈替尼、阿帕替尼、达卡替尼(dacomitinib)、培利替尼(pelitinib)、WZ4002、AG-490、AZD8931、AZD9291等。
可以将本发明通式I的化合物、异构体、溶剂合物、结晶或前药与药学上可接受的载体混合制备成药物制剂，以适合于经口或胃肠外给药。给药方法包括，但不限于皮内、肌内、腹膜内、静脉内、皮下、鼻内和经口途径。所述制剂可以通过任何途径施用，例如通过输注或推注，通过经上皮或皮肤粘膜(例如口腔粘膜或直肠等)吸收的途径施用。给药可以是全身的或局部的。经口施用制剂的实例包括固体或液体剂型，具体而言，包括片剂、丸剂、粒剂、粉剂、胶囊剂、糖浆、乳剂、混悬剂等。所述制剂可通过本领域已知的方法制备，且包含药物制剂领域常规使用的载体。
第六方面，本发明提供本发明通式I的化合物、异构体、溶剂合物、结晶或前药或本发明的药物组合物治疗和/或预防肿瘤的方法和在制备治疗和/或预防肿瘤药物中的应用，包括向肿瘤易发人群或肿瘤患者施用本发明通式I的化合物、异构体、溶剂合物、结晶或前药或者包含本发明通式I的化合物、异构体、溶剂合物、结晶或前药的药物组合物，以有效降低肿瘤发生率、延长肿瘤患者生命。
在一些实施方案中，本发明提供本发明的通式I的化合物、异构体、溶剂合物、结晶或前药或本发明的药物组合物治疗具有抗药性的肿瘤的方法，包括向具有抗药性的肿瘤患者施用治疗有效量的本发明通式I的化合物、异构体、溶剂合物、结晶或前药或者包含本发明通式I的化合物、异构体、溶剂合物、结晶或前药的药物组合物。
在另一些实施方案中，本发明提供本发明的通式I的化合物、异构体、溶剂合物、结晶或前药或本发明的药物组合物在制备治疗具有抗药性的肿瘤的药物中的应用。所述具有抗药性的肿瘤可以是对多种药物具有抗药性的肿瘤，优选对EGFR抑制剂抗药的肿瘤，例如对第一、第二、第三代EGFR抑制剂，例如对吉非替尼、厄洛替尼和拉帕替尼具有抗药性的肿瘤。所述肿瘤包括但不限于实体瘤，优选为肺癌、头颈部肿瘤、结直肠癌、膀胱癌、胰腺癌、乳腺癌、***癌、胃癌、口腔癌、肝癌、卵巢癌。更优选地，所述肿瘤为非小细胞肺癌。在一些实施方案中，本发明提供本发明的通式I的化合物、异构体、溶剂合物、结晶或前药治疗具有抗药性的肿瘤的方法，其中所述肿瘤携带EGFR突变基因。在一个实施方案中，所述肿瘤携带的EGFR突变基因是第20号外显子存在T790M突变。在另一个实施方案中，所述肿瘤携带的EGFR突变基因是第21号外显子存在L858R突变和/或缺失/***突变。在另一个实施方案中，所述肿瘤携带的EGFR突变基因是T790M和L858R双重突变。在另一些实施方案中，本发明提供用于***的本发明的通式I的化合物、异构体、溶剂合物、结晶或 前药或本发明的药物组合物，其中***作用表现在突出的疗效，高度的选择性和/或较少的副作用。在再一些实施方案中，本发明提供本发明的通式I的化合物、异构体、溶剂合物、结晶或前药或本发明的药物组合物***的方法，所述方法包括给予需要其的患者治疗有效量的本发明的通式I的化合物、异构体、溶剂合物、结晶或前药或本发明的药物组合物，所产生的***方面的作用表现在突出的疗效，高度的选择性和/或较少的副作用。
术语定义
除非另外定义，本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同的含义。
本发明的“异构体”包括顺式或反式构型的顺反异构体，也包括手性碳产生的对映异构体和非对映异构体。
本发明的“药学可接受的盐”是指本发明所述的化合物与酸形成的药学上可接受的盐，所述的酸可选自：磷酸、硫酸、盐酸、氢溴酸、柠檬酸、马来酸、丙二酸、扁桃酸、琥珀酸、富马酸、醋酸、乳酸、硝酸、磺酸、对甲苯磺酸、苹果酸、甲烷磺酸等。
本发明的“溶剂合物”是指通过与溶剂分子配位形成固态或液态的配合物的本发明化合物的形式。水合物是溶剂合物的特殊形式，其中与水发生配位。在本发明范围内，溶剂合物优选是水合物。
本发明的“结晶”是指本发明所述的化合物形成的各种固体形态，包括晶型、无定形。
本发明的“前药”是指在生物体的生理条件下，由于与酶、胃酸等反应而转化成本发明的化合物，即通过酶的氧化、还原、水解等转化成本发明的化合物和/或通过胃酸等的水解反应等转化成本发明的化合物的化合物。
本发明的“药物组合物”是指包含任何一种本文所述的化合物，包括异构体、前药、溶剂合物、药学上可接受的盐或其化学的保护形式，和一种或多种药学上可接受载体的混合物。
本发明的“在制备用于治疗和/或预防肿瘤的药物中的应用”是指可以抑制肿瘤的生长、发展和/或转移，主要向所需要的人或动物给予治疗有效剂量的本发明的化合物以抑制、减慢或逆转受治疗者肿瘤的生长、发展或扩散。
术语“烷基”是指直链或支链的饱和烃基，优选6个碳原子以下的烃基。烷基的实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、2,2-甲基丁基和2,3-二甲基丁基。术语“C1-6烷基”是指含有1-6个碳原子的直链或支链的饱和烃基。术语“C1-3烷基”是指含有1-3个碳原子的直链或支链的饱和烃基。
本发明的“环烷基”是指环状的饱和的、部分饱和的烃基，优选12个碳原子以下的环烷基，进一步优选8个碳原子以下的环烷基，更进一步优选6个碳原子以下的环烷基。环烷基的实施例包括环丙基、环丁基、环戊基、环己基、环庚基。本发明的“C3-8环烷基”是指含有3-8个碳原子的环状的饱和烃基。
本发明的“烷氧基”是指-O-烷基。
本发明的“氧代”是指O＝，例如碳原子被氧代基团取代形成
Figure PCTCN2016106862-appb-000023
硫原子被一个氧代基团取代形成
Figure PCTCN2016106862-appb-000024
硫原子被两个氧代基团取代形成
Figure PCTCN2016106862-appb-000025
本发明的“卤素”是指氟、氯、溴、碘。
本发明的“卤代烷基”是指至少被一个卤素原子取代的烷基。
本发明的“卤代烷氧基”是指至少被一个卤素取代的烷氧基，优选为至少被一个卤素取代的C1-6烷氧基，进一步优选为至少被一个卤素取代的C1-3烷氧基，合适的卤代C1-3烷氧基为氯甲氧基、氟甲氧基、二氯甲氧基、二氟甲氧基、三氯甲氧基、三氟甲氧基；二氯乙氧基、二氟乙氧基、三氯乙氧基、三氟乙氧基。
本发明的“单烷基氨基”是指-NH-烷基，优选为-NH-C1-6烷基，进一步优选为-NH-C1-3烷基。
本发明的“二烷基氨基”是指-N-(烷基)(烷基)，优选为-N-(C1-6烷基)(C1-6烷基)，进一步优选为-N-(C1-3烷基)(C1-3烷基)。
本发明的“氨基烷基”是指-烷基-NH2。
本发明的“单烷基氨基烷基”是指-烷基-NH-烷基。
本发明的“二烷基氨基烷基”是指-烷基-N-(烷基)(烷基)。
本发明的“羟基烷基”是指-烷基-OH。
本发明的“烷基酰基”是指-C(O)-烷基。
本发明的“氨基酰基”是指-C(O)-NH2。
本发明的“单烷基氨基酰基”是指-C(O)-NH-烷基。
本发明的“二烷基氨基酰基”是指-C(O)-N-(烷基)(烷基)。
本发明的“杂环烷基”是指取代或未取代的至少含有一个杂原子的饱和的、部分饱和的环状烷基，所述的杂原子选自N、O、S。
本发明的“芳基”是指可以包含单环或多稠环例如二环或三环的芳香环的芳香系，其中至少稠合的环的一部分形成共轭的芳香系，其含有5至50个碳原子，优选约6至约14个碳原子。合适的芳基包括但不限于苯基、萘基、联苯基、蒽基、四氢萘基、芴基、茚满基、亚联苯基和苊基。本发明的“C6-C10芳基”是指含有6-10个碳原子的芳香系。
本发明的“杂芳基”是指芳族单环或多稠环如二环或三环的至少有一个碳原子被杂原子替代的芳香性基团，所述的杂原子为O、S、N。合适的杂芳基包括但不限于咪唑基、苯并咪唑基、咪唑并吡啶基、喹唑啉酮基、吡咯基、咪唑酮基、呋喃基、噻吩基、吡唑基、噁唑基、噻唑基、异噁唑基、异噻唑基、噁二唑基、***基等。本发明的“C5-C10杂芳基”是指含有5-10个原子的杂芳基。
本发明的“C4-C8含氮杂环基”是指含有至少一个氮原子的取代或未取代的饱和、部分饱和 和完全不饱和的总环原子数为4、5、6、7或8的杂环基团，例如C4含氮杂环基是指取代或未取代的饱和、部分饱和和完全不饱和的总环原子数为4的含氮杂环基团。本发明的“C4-C8含氮杂单环烷基”是指含有至少一个氮原子的取代或未取代的饱和、部分饱和和完全不饱和的总环原子数为4、5、6、7或8的单杂环烷基，合适的例子包括但不限于取代或未取代的氮杂环丁基、氮杂环戊基、氮杂环己基、氮杂环庚基、氮杂环辛基、氮氧杂环戊基、氮氧杂环己基、氮氧杂环庚基、氮氧杂环辛基、氮硫杂环戊基、氮硫杂环己基、氮硫杂环庚基、氮硫杂环辛基、二氮杂环戊基、二氮杂环己基、二氮杂环庚基或二氮杂环辛基；以及取代或未取代的含氮杂芳基，例如取代或未取代的吡啶基、咪唑基、吡唑基、吡咯基、哒嗪基、嘧啶基、吡嗪基，其中所述取代基选自烷基、氧代、环烷基、羟基、羟烷基、烷氧基、氨基、单烷基氨基、双烷基氨基、酰氨基、烷基酰氨基、芳基酰氨基、杂芳基酰氨基、卤素、卤代烷基、卤代烷氧基。本文中，所述C4-C8含氮杂环基与吲哚环构成氮杂环并吲哚结构，例如，合适的氮杂环并吲哚结构包括但不限于
Figure PCTCN2016106862-appb-000026
Figure PCTCN2016106862-appb-000027
Figure PCTCN2016106862-appb-000028
等。
具体实施方式
下面代表性的实施例是为了更好地说明本发明，而非用于限制本发明的保护范围。
实施例1 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(2,3-二氢-1H-吡咯并[1,2-a]-吲哚-9-基)嘧啶-2-基)氨基)苯基)烯丙酰胺的合成
Figure PCTCN2016106862-appb-000029
步骤a 1-(3-溴丙基)-1H-吲哚的合成
Figure PCTCN2016106862-appb-000030
在100ml反应瓶中，依次加入NaH(60％含量,1.23g,30.73mmol)和DMF(10ml)，室温搅拌5min后冷却至0-4℃，缓慢加入10mL溶解有吲哚(3g,25.61mmol)的DMF溶液，加毕，升至室温反应20min制得吲哚活化溶液。
另取250ml反应瓶，加入1,3-二溴丙烷(15.51g,76.82mmol)和DMF(50ml)。0-4℃下缓慢滴加上述制得的吲哚活化溶液，滴毕，室温下反应0.5h。反应结束后，加入水(100ml)淬灭反 应，乙酸乙酯萃取，合并乙酸乙酯层，无水硫酸钠干燥，过滤，浓缩，柱层析纯化得标题化合物。
ESI-Ms m/z:239.1[M+H]。
步骤b 1-(3-碘丙基)-1H-吲哚的合成
Figure PCTCN2016106862-appb-000031
在250ml反应瓶中，依次加入步骤a所得物1-(3-溴丙基)-1H-吲哚(4.72g,19.83mmol)、碘化钠(13.39g,89.93mmol)和乙腈(100ml)，回流过夜。反应结束后，加水，乙酸乙酯萃取，合并乙酸乙酯层，无水硫酸钠干燥，过滤，浓缩干燥得标题物，直接用于下一步。
ESI-Ms m/z:286.1[M+H]。
步骤c 2,3-二氢吡咯并[1,2-a]吲哚的合成
Figure PCTCN2016106862-appb-000032
在250ml三颈瓶中，依次加入步骤b所得物1-(3-碘丙基)-1H-吲哚(5.44g,19.83mmol)、磷酸钾(8.4g，39.67mmol)、四三苯基磷钯(2.3g,1.98mmol)和1,4-二氧六环(80ml)，氩气保护，回流过夜反应。反应结束后，加水淬灭反应，乙酸乙酯萃取，合并乙酸乙酯层，无水硫酸钠干燥，过滤，浓缩，柱层析纯化得标题化合物。
ESI-Ms m/z:158.1[M+H]。
步骤d 9-(2-氯嘧啶-4-基)-2,3-二氢吡咯并[1,2-a]吲哚的合成
Figure PCTCN2016106862-appb-000033
在100ml反应瓶中，依次加入三氯化铝(2.18g,16.35mmol)、乙二醇二甲醚(50ml)、2,4-二氯嘧啶(2.44g,16.35mmol)和步骤c所得物2,3-二氢吡咯并[1,2-a]吲哚(2.57g,16.35mmol)，回流反应2h。反应结束后，反应液冷却至室温，过滤，滤饼水洗，干燥后得标题物。
ESI-Ms m/z:270.4[M+H]。
步骤e N-(4-氟-2-甲氧基-5-硝基苯基)-4-(2,3-二氢吡咯并[1,2-a]吲哚-9-基)-嘧啶-2-胺的合成
Figure PCTCN2016106862-appb-000034
在250ml反应瓶中，加入步骤d所得9-(2-氯嘧啶-4-基)-2,3-二氢吡咯并[1,2-a]吲哚(2.69g，10mmol)、4-氟-2-甲氧基-5-硝基苯胺(1.86g，10mmol)和对甲苯磺酸(1.71g，10mmol)，加入50mL仲丁醇溶解，110℃反应2h，反应结束后，冷却至室温，过滤，仲丁醇洗涤，干燥得标题化合物。
ESI-Ms m/z:420.4[M+H]。
步骤f N-(4-((2-(二甲基氨基)乙基)(甲基)氨基)-2-甲氧基-5-硝基苯基)-4-(2,3-二氢吡咯并[1,2-a]吲哚-9-基)-嘧啶-2-胺的合成
Figure PCTCN2016106862-appb-000035
在50ml反应瓶中，依次加入步骤e所得物N-(4-氟-2-甲氧基-5-硝基苯基)-4-(2,3-二氢吡咯并[1,2-a]吲哚-9-基)-嘧啶-2-胺(2.5g，6mmol)、N,N,N’-三甲基乙二胺(0.61g，6mmol)、二异丙基乙胺(2.3g，18mmol)和10ml二氧六环，110℃回流反应3h，反应结束后，浓缩，柱层析纯化得标题化合物。
ESI-Ms m/z:502.4[M+H]。
步骤g N-(4-((2-(二甲基氨基)乙基)(甲基)氨基)-2-甲氧基-5-氨基苯基)-4-(2,3-二氢吡咯并[1,2-a]吲哚-9-基)-嘧啶-2-胺的合成
Figure PCTCN2016106862-appb-000036
在50ml反应瓶中，依次加入步骤f所得物N-(4-((2-(二甲基氨基)乙基)(甲基)氨基)-2-甲氧基-5-硝基苯基)-4-(2,3-二氢吡咯并[1,2-a]吲哚-9-基)-嘧啶-2-胺(2.5g，5mmol)、10％Pd-C(20mg)和30ml甲醇，在1个标准大气压下，氢气还原1h，反应结束后，过滤，浓缩得标题化合物，直接用于下一步。
ESI-Ms m/z:472.6[M+H]。
步骤h N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((5-甲基-4-(2,3-二氢-1H-吡咯并[1,2-a]-吲哚-9-基)嘧啶-2-基)氨基)苯基)烯丙酰胺的合成
Figure PCTCN2016106862-appb-000037
在150ml单口瓶中，加入步骤g所得物N-(4-((2-(二甲基氨基)乙基)(甲基)氨基)-2-甲氧基-5-氨基苯基)-4-(2,3-二氢吡咯并[1,2-a]吲哚-9-基)-嘧啶-2-胺(2g，4.2mmol)、二异丙基乙胺(0.53g，4.2mmol)和20ml无水二氯甲烷，溶解后缓慢加入5ml溶解有烯丙基酰氯(0.37g，4.2mmol)的二氯甲烷溶液，反应10min，反应结束后，浓缩，柱层析纯化得标题化合物。1H NMR(300MHz,DMSO-d6):δ10.17(s,1H),8.69(s,1H),8.28-8.25(d,2H),8.02(s,1H),7.37-7.35(d,1H),7.15-6.97(m,4H),6.44-6.35(m,1H),6.21-6.15(m,1H)，5.74-5.70(d,1H),4.1-4.10(t,2H),3.81(s,3H),3.35(s,1H),3.30-3.25(t,1H),2.90(s,2H),2.73(s,3H),2.60-2.56(m,2H),2.33(s,2H),2.22(s,6H)。
ESI-Ms m/z:526.4[M+H]。
实施例2 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(6,7,8,9-四氢吡啶并[1,2-a]吲哚-10-基)-嘧啶-2-基)氨基)苯基)烯丙酰胺的合成
Figure PCTCN2016106862-appb-000038
步骤a 1-(4-溴丁基)-1H-吲哚的合成
Figure PCTCN2016106862-appb-000039
在100mL反应瓶中，依次加入NaH(60％含量,1.23g,30.73mmol)、DMF(10mL)，室温搅拌5min后冷却至0-4℃，缓慢加入10mL溶解有吲哚(3g,25.61mmol)的DMF溶液，加毕，升至室温反应20min制得吲哚活化溶液。
另取250mL反应瓶，加入1,4-二溴丁烷(16.59g,76.82mmol)、DMF(50mL)。0-4℃下缓慢滴加上述制得的吲哚活化溶液，滴毕，室温下反应0.5h。反应结束后，加入水(100mL)淬灭，乙酸乙酯萃取，合并乙酸乙酯层，无水硫酸钠干燥，过滤，浓缩，柱层析纯化得标题化合物。
ESI-Ms m/z:252.1[M+H]。
步骤b 1-(4-碘丁基)-1H-吲哚的合成
Figure PCTCN2016106862-appb-000040
在250mL反应瓶中，依次加入步骤a所得物1-(4-溴丁基)-1H-吲哚(5g,19.83mmol)、碘化钠(13.39g,89.93mmol)、乙腈(100mL)，回流过夜。反应结束后，加水，乙酸乙酯萃取，合并乙酸乙酯层，无水硫酸钠干燥，过滤，浓缩干燥得标题物，直接用于下一步。
ESI-Ms m/z:300.0[M+H]。
步骤c 6,7,8,9-四氢吡啶并[1,2-a]吲哚的合成
Figure PCTCN2016106862-appb-000041
在250mL三颈瓶中，依次加入步骤b所得物1-(4-碘丁基)-1H-吲哚(5.93g,按19.83mmol)、磷酸钾(8.4g，39.67mmol)、四三苯基磷钯(2.3g,1.98mmol)、1,4-二氧六环(80mL)，氩气保护，回流过夜反应。反应结束后，加水淬灭反应，乙酸乙酯萃取，合并乙酸乙酯层，无水硫酸钠干燥，过滤，浓缩，柱层析纯化得标题化合物。
ESI-Ms m/z:172.1[M+H]。
步骤d 10-(2-氯嘧啶-4-基)-6,7,8,9-四氢吡啶并[1,2-a]吲哚的合成
Figure PCTCN2016106862-appb-000042
在100mL反应瓶中，依次加入三氯化铝(2.18g,16.35mmol)、乙二醇二甲醚(50mL)、2,4-二氯嘧啶(2.44g,16.35mmol)、步骤c所得物6,7,8,9-四氢吡啶并[1,2-a]吲哚(2.8g,16.35mmol)，回流反应2h。反应结束后，反应液冷却至室温，过滤，滤饼水洗，干燥后得标题物。
ESI-Ms m/z:284.1[M+H]。
步骤e N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(6,7,8,9-四氢吡啶并[1,2-a]吲哚-10-基)嘧啶-2-基)氨基)苯基)烯丙酰胺的合成
Figure PCTCN2016106862-appb-000043
以步骤d所得物10-(2-氯嘧啶-4-基)-6,7,8,9-四氢吡啶并[1,2-a]吲哚、4-氟-2-甲氧基-5-硝基苯胺，N,N,N’-三甲基乙二胺、烯丙基酰氯为原料，按照实施例1步骤e、f、g和h的方法制得标题化合物。
1H NMR(300MHz,DMSO-d6)δ10.20(s,1H),8.65(s,1H),8.34(d,1H),8.11(s,1H),8.06(d,1H),7.43(d,1H),7.19-7.03(m,3H),6.98(s,1H),6.57-6.41(m,1H),6.28-6.15(m,1H),5.82-5.71(m,1H),4.09(t,2H),3.84(s,3H),3.18(t,2H),3.06-2.92(m,2H),2.66(s,3H),2.47-2.40(m,2H),2.27(s,6H),2.08-1.96(m,2H),1.87-1.74(m,2H)。
ESI-Ms m/z:540.3[M+H]。
实施例3 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((5-甲基-4-(6,7,8,9-四氢吡啶并[1,2-a]吲哚-10-基)嘧啶-2-基)氨基)苯基)烯丙酰胺的合成
Figure PCTCN2016106862-appb-000044
步骤a 10-(2-氯-5-甲基嘧啶-4-基)-6,7,8,9-四氢吡啶并[1,2-a]吲哚的合成
Figure PCTCN2016106862-appb-000045
以实施例2步骤c所得物6,7,8,9-四氢吡啶并[1,2-a]吲哚和5-甲基-2,4-二氯嘧啶为原料，按照实施例2步骤d的方法制得标题化合物。
步骤b N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((5-甲基-4-(6,7,8,9-四氢吡啶并[1,2-a]吲哚-10-基)嘧啶-2-基)氨基)苯基)烯丙酰胺的合成
Figure PCTCN2016106862-appb-000046
以步骤a所得物10-(2-氯-5-甲基嘧啶-4-基)-6,7,8,9-四氢吡啶并[1,2-a]吲哚、4-氟-2-甲氧基-5-硝基苯胺、N,N,N’-三甲基乙二胺和烯丙基酰氯为原料，按照实施例1步骤e、f、g和h的方法制得标题化合物。
1H NMR(300MHz,DMSO-d6)δ10.02(s,1H),δ8.84(s,1H),8.33(s,1H),7.77(s,1H),7.42(d,1H),7.26(d,1H),7.10-7.13(m,1H),7.04-7.07(m,1H),6.95(s,1H),6.34-6.39(m,1H),6.19-6.22(m,1H),5.73(d,1H),4.11(t,2H),3.83(s,3H),2.99(s,2H),2.83(t,2H),2.67(s,3H),2.25(t,2H),2.17(s,6H),2.07(s,3H),2.04(m,2H),1.79(m,2H)。
ESI-Ms m/z:554.3[M+H]。
实施例4 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(6,7,8,9-四氢吡啶并[1,2-a]-5-氟吲哚-10-基)嘧啶-2-基)氨基)苯基)烯丙酰胺的合成
Figure PCTCN2016106862-appb-000047
以4-氟-2-甲氧基-5-硝基苯胺、2,4-二氯嘧啶、5-氟吲哚、1,4-二溴丁烷、N,N,N’-三甲基乙二胺、烯丙基酰氯为原料，按照实施例1的方法制得标题化合物。
1H NMR(300MHz,DMSO-d6):δ9.62(s,1H),9.42(s,1H),8.3-8.27(d,2H),7.87(s,1H),7.49(d,1H),7.14(d,1H),7.06(s,2H),6.71-6.63(m,1H),6.22-6.16(m,1H)5.73(d,1H),4.13(s,2H),3.84(s,3H),3.32(s,4H),3.22-3.20(t,2H),2.83 (s,6H),2.64(s,3H),2.02(s,2H),1.85(s,2H)。
ESI-Ms m/z:558.4[M+H]。
实施例5 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-((2,3-二氢-1H-吡咯并[1,2-a]-5-氟吲哚-9-基)-5-氯-嘧啶-2-基)氨基)苯基)烯丙酰胺的合成
Figure PCTCN2016106862-appb-000048
以4-氟-2-甲氧基-5-硝基苯胺、2,4,5-三氯嘧啶、5-氟吲哚、1,3-二溴丙烷、N,N,N’-三甲基乙二胺、烯丙基酰氯为原料，按照实施例1的方法制得标题化合物。
1H NMR(300MHz,DMSO-d6)δ：9.99(s,1H),8.48(s,1H),8.42(s,2H),7.41-7.34(m,2H),6.98-6.91(m,2H),6.44–6.39(m,1H),6.17(m,1H),5.61(d,1H),4.14(t,2H),3.82(s,3H),3.16–3.11(m,2H),2.91-2.87(m,2H),2.68(s,3H),2.57–2.54(m,2H),2.39–2.35(m,2H),2.23(s,6H).
ESI-Ms m/z:578.2[M+H]。
实施例6 N-(2–((2–(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5–((4-(2,3-二氢-1H-吡咯并[1,2-a]-5-氟吲哚-9-基)嘧啶-2-基)氨基)苯基)烯丙酰胺的合成
Figure PCTCN2016106862-appb-000049
以4-氟-2-甲氧基-5-硝基苯胺、2,4-二氯嘧啶、5-氟吲哚、1，3-二溴丙烷、N,N,N’-三甲基乙二胺、烯丙基酰氯为原料，按照实施例1的方法制得标题化合物。
1H NMR(300MHz,DMSO-d6)δ10.07(s,1H),8.65(s,1H),8.25(d,1H),8.05–8.02(m,1H),7.36-7.34(m,2H),7.01(s,1H),6.90–6.97(m,2H),6.36-6.34(m,1H),6.17-6.15(m,1H),5.69-5.67(d,1H),4.13(t,2H),3.79(s,3H),2.89–2.88(t,2H),2.73(s,3H),2.62–2.60(t,2H),2.51–2.50(t,2H),2.32-2.30(t,2H),2.21(s,6H).
ESI-Ms m/z:544.4[M+H]。
实施例7 N–(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(3,4-二氢-1H-[1,4]噁嗪并[4,3-a]吲哚-10-基)嘧啶-2-基)氨基)苯基)烯丙酰胺的合成
Figure PCTCN2016106862-appb-000050
步骤a 2-羟甲基吲哚的合成
Figure PCTCN2016106862-appb-000051
在100ml反应瓶中，依次加入四氢铝锂(902.63mg,23.78mmol)、THF(30ml)，室温搅拌 5min后冰浴，缓慢加入吲哚-2-羧酸乙酯(3g,15.86mmol)，加毕，升至室温反应2h。反应结束后，将体系冷却至0℃，然后将20ml THF以及1.7ml 20％KOH加入其中，搅拌10min后过滤，用20ml THF洗涤滤饼，滤液用饱和NaCl(10ml)洗一次，无水硫酸钠干燥，过滤，浓缩干燥得标题物2.3g，直接用于下一步。
ESI-Ms m/z:148.1[M+H]。
步骤b 3,4-二氢-1H-[1,4]噁嗪并[4,3-a]吲哚的合成
Figure PCTCN2016106862-appb-000052
在500ml反应瓶中，依次加入步骤a所得2-羟甲基吲哚(300mg,2.04mmol)，KOH(285.91mg,5.10mmol)、CH2Cl2(160ml)，冰浴冷却至0℃左右，氮气保护，搅拌10min后。将40mL溶有Diphenyl(vinyl)sulfonium trifluoromethanesulfonate(888.86mg,2.45mmol)的CH2Cl2溶液滴加入上述反应体系中，加毕，升至室温反应。当TLC监测原料消失后，反应结束后，加水淬灭反应，乙酸乙酯萃取，合并乙酸乙酯层，无水硫酸钠干燥，过滤，浓缩，柱层析纯化得标题物300mg。
ESI-Ms m/z:174.1[M+H]。
步骤c N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(3,4-二氢-1H-[1,4]噁嗪并[4,3-a]吲哚-10-基)嘧啶-2-基)氨基)苯基)烯丙酰胺的合成
Figure PCTCN2016106862-appb-000053
以4-氟-2-甲氧基-5-硝基苯胺、2,4-二氯嘧啶、步骤b所得3,4-二氢-1H-[1,4]噁嗪并[4,3-a]吲哚、N,N,N’-三甲基乙二胺、烯丙基酰氯为原料，按照实施例1的方法制得标题化合物。
1H NMR(300MHz,DMSO-d6)δ10.04(s,1H),8.61(s,1H),8.35(d,1H),8.06(d,1H),8.03(s,1H),7.50-7.49(d,1H),7.24–7.19(m,2H),7.12-7.11(d,1H),7.00(s,1H),6.45(s,1H),6.22–6.19(d,1H),5.73-5.71(d,1H),5.07(s,2H),4.16–4.14(t,2H),4.06–4.04(t,2H),3.81(s,3H),2.96(s,2H),2.70(s,3H),2.30(s,6H),2.35(m,2H).
ESI-Ms m/z:542.2[M+H]。
实施例8 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(6,7,8,9-四氢吡啶并[1,2-a]-7-氯吲哚-10-基)嘧啶-2-基)氨基)苯基)烯丙酰胺的合成
Figure PCTCN2016106862-appb-000054
以4-氟-2-甲氧基-5-硝基苯胺、2,4-二氯嘧啶、7-氯吲哚、1，4-二溴丁烷、N,N,N’-三甲基乙二胺、烯丙基酰氯为原料，按照实施例1的方法制得标题化合物。
1H NMR(300MHz,DMSO-d6)δ：10.04(s,1H),8.69(s,1H),8.38–8.36(d,1H),8.26(s,1H),8.00(s,2H),7.14–7.12(m,1H),7.03–6.98(m,2H),6.43–6.35(m,1H),6.17–6.16(d,1H),5.71–5.70(d,1H),4.66–4.62(m,2H),3.34–3.21(m,3H),2.90–2.86(m,3H),2.70(s,4H),2.33–2.31(m,2H),2.20(s,6H),2.20–2.19(m,2H),1.78–1.76(m,2H),
ESI-Ms m/z:575.2[M+H]。
实施例9 N-(5-((4-(1,1-二甲基-2,3-二氢-1H-吡咯并[1,2-a]吲哚-9-基)嘧啶-2-基)氨基)-2-((2-(二甲氨基)乙基)(甲基)氨基)-4-甲氧基苯基)丙烯酰胺的合成
Figure PCTCN2016106862-appb-000055
以4-氟-2-甲氧基-5-硝基苯胺、2,4-二氯嘧啶、1,3-二溴-3-甲基丁烷、吲哚、N,N,N’-三甲基乙二胺、烯丙基酰氯为原料，按照实施例1的方法制得标题化合物。
1H NMR(300MHz,DMSO-d6)δ10.00(s,1H),8.58(s,1H),8.36–8.58(m,1H),7.91–7.96(m,2H),7.35–7.40(m,1H),7.09–7.40(m,4H),6.36–6.45(m,1H),6.18–6.23(m,1H),5.71–5.74(m,1H)4.12–4.19(m,2H),3.80(s,3H),2.93(s,2H),2.69(s,3H),2.37–2.44(m,2H),2.28(s,6H),1.56(s,2H),1.37(s,6H).
ESI-Ms m/z:554.3[M+H]。
实施例10 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(6,7,8,9-四氢吡啶并[1,2-a]吲哚-10-基)-5-氯-嘧啶-2-基)氨基)苯基)烯丙酰胺的合成
Figure PCTCN2016106862-appb-000056
以实施例2步骤c所得物6,7,8,9-四氢吡啶并[1,2-a]吲哚、4-氟-2-甲氧基-5-硝基苯胺、2,4,5-三氯嘧啶、N,N,N’-三甲基乙二胺、烯丙基酰氯为原料，按照实施例1的方法制得标题化合物。
1H NMR(300MHz,DMSO-d6)δ：9.63(s,1H),9.47(s,1H),8.3–8.30(d,2H),7.85(s,1H),7.5(d,1H),7.12(d,1H),7.04(s,2H),6.72–6.61(m,1H),6.23–6.15(m,1H)，5.7,5(d,1H),4.12(s,2H),3.86(s,3H),3.34(s,4H),3.20–3.17(t,2H),2.86(s,6H),2.66(s,3H),2.01(s,2H),1.86(s,2H).
ESI-Ms m/z:575.2[M+H]。
实施例11 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(6,7,8,9-四氢吡啶并[1,2-a]-5-甲氧基-吲哚-10-基)嘧啶-2-基)氨基)苯基)烯丙酰胺的合成
Figure PCTCN2016106862-appb-000057
以4-氟-2-甲氧基-5-硝基苯胺、2,4-二氯嘧啶、5-甲氧基吲哚、1,4-二溴丁烷、N,N,N’-三 甲基乙二胺、烯丙基酰氯为原料，按照实施例1的方法制得标题化合物。
1H NMR(300MHz,DMSO-d6)δ：10.02(s,1H),9.53(s,1H),8.40–8.45(d,2H),7.92(s,1H),7.52(d,1H),7.18(d,1H),7.10(s,2H),6.76–6.70(m,1H),6.28–6.20(m,1H)5.72(d,1H),4.12(s,2H),3.85(s,3H),3.72(s,3H),3.32(s,4H),3.21–3.19(t,2H),2.83(s,6H),2.65(s,3H),2.02(s,2H),1.86(s,2H).
ESI-Ms m/z:570.4[M+H]。
实施例12 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基-4-甲氧基-5-((4-(1,1a,2,8b-四氢环丙基[3,4]吡咯并[1,2-a]吲哚-8-基)嘧啶-2-基)氨基)苯基)丙烯酰胺的合成
Figure PCTCN2016106862-appb-000058
步骤a 1-烯丙基-1H-吲哚-2-甲醛的合成：
Figure PCTCN2016106862-appb-000059
在100mL双口瓶中，加入25ml无水DMF，冷却至0-5℃，缓慢加入662mg NaH，搅拌10min。将10mL溶有2g 1H-吲哚-2-甲醛的无水DMF溶液缓慢滴入上述反应液中，气泡产生，溶液颜色变为暗黑色，持续搅拌15min，然后缓慢加入5mL溶有1.82g 3-溴丙烯的无水DMF溶液，室温反应3h，加入50mL水，3X 60ml乙酸乙酯萃取，浓缩，干燥，柱层析得标题物2.0g。
ESI-Ms m/z:186.0[M+H]
步骤b：N-((1-丙烯基-1H-吲哚-2-基)甲烯基)-4-甲基苯磺酰肼的合成：
Figure PCTCN2016106862-appb-000060
在100mL单口瓶中，依次加入步骤a所得1-烯丙基-1H-吲哚-2-甲醛(1.85g,10mmol)、对甲基苯磺酰肼(1.86g、10mmol)、50mL甲醇，油浴85℃回流反应2h。浓缩得标题粗产物3.6g，直接用于下一步。
步骤c：1,1a,2,8b-四氢环丙基[3,4]吡咯并[1,2-a]吲哚的合成：
Figure PCTCN2016106862-appb-000061
在250mL三口瓶中，加入步骤b所得N-((1-丙烯基-1H-吲哚-2-基)甲烯基)-4-甲基苯磺酰肼(2.2g,6.23mmol)、碳酸钾(1.29g、9.35mmol)、60ml二氧六环，油浴100℃回流反应12h。过滤，浓缩，加入50ml水，3X 40ml乙醇萃取，30ml水洗，浓缩，柱层析得1.0g标题产物， 直接用于下一步。
步骤d：N-(2-((2-(二甲基氨基)乙基)(甲基)氨基-4-甲氧基-5-((4(1,1a,2,8b-四氢环丙基[3,4]吡咯并[1,2-a]吲哚-8-基)嘧啶-2-基)氨基)苯基)丙烯酰胺的合成
Figure PCTCN2016106862-appb-000062
以4-氟-2-甲氧基-5-硝基苯胺、2,4-二氯嘧啶、步骤c所得1,1a,2,8b-四氢环丙基[3,4]吡咯并[1,2-a]吲哚、N,N,N’-三甲基乙二胺和烯丙基酰氯为原料，按照实施例1合成方法制得标题化合物。
1H-NMR(300MHz,DMSO-d6)δ:10.03(s,1H),8.70(s,1H),8.32-8.33(d,1H),8.24-8.26(d,1H),8.01(s,1H),7.21-7.28(m,2H),7.10-7.13(m,1H),7.03-7.06(m,2H),6.41-6.47(m,1H),6.20-6.23(d,1H),5.74-5.76(d,1H),4.19-4.28(m,2H),3.86(s,3H),2.97(s,2H),2.95(s,2H),2.74(s,3H),2.29-2.5(m,8H),1.44-1.45(m,1H),0.70-0.71(m,1H)。
ESI-Ms m/z:537.9[M+H]
实施例13 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(6-氧代-6,7,8,9-四氢吡啶并[1,2-a]吲哚-10-基)-嘧啶-2-基)氨基)苯基)烯丙酰胺的合成
Figure PCTCN2016106862-appb-000063
ESI-Ms m/z:554.4[M+H]
实施例14 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(6-氟-6,7,8,9-四氢吡啶并[1,2-a]吲哚-10-基)-嘧啶-2-基)氨基)苯基)烯丙酰胺的合成
Figure PCTCN2016106862-appb-000064
ESI-Ms m/z:558.3[M+H]
实施例15 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(9-氟-6,7,8,9-四氢吡啶并[1,2-a]吲哚-10-基)-嘧啶-2-基)氨基)苯基)烯丙酰胺的合成
Figure PCTCN2016106862-appb-000065
ESI-Ms m/z:558.5[M+H]
实施例16 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(9,9-二氟-6,7,8,9-四氢吡啶并[1,2-a]吲哚-10-基)-嘧啶-2-基)氨基)苯基)烯丙酰胺的合成
Figure PCTCN2016106862-appb-000066
ESI-Ms m/z:575.3[M+H]
实施例17 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1,2-二氢氮杂环丁二烯并[1,2-a]吲哚-8-基)-嘧啶-2-基)氨基)苯基)烯丙酰胺的合成
Figure PCTCN2016106862-appb-000067
ESI-Ms m/z:511.6[M+H]
实施例18 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-氟-2,3-二氢-1H-吡咯并[1,2-a]-吲哚-9-基)嘧啶-2-基)氨基)苯基)烯丙酰胺的合成
Figure PCTCN2016106862-appb-000068
ESI-Ms m/z:543.8[M+H]
实施例19 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(2-氧代-1,2-二氢氮杂环丁二烯并[1,2-a]吲哚-8-基)-嘧啶-2-基)氨基)苯基)烯丙酰胺的合成
Figure PCTCN2016106862-appb-000069
ESI-Ms m/z:525.4[M+H]
实施例20 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1,1-二氧代-3,4-二氢-2H-[1,2]噻嗪[2,3-a]吲哚-5-基)嘧啶-2-基)氨基)苯基)烯丙酰胺的合成
Figure PCTCN2016106862-appb-000070
ESI-Ms m/z:590.4[M+H]
实施例21 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(2,3-二甲基-1,2,3,4-四氢吡嗪[1,2-a]吲哚-10-基)嘧啶-2-基)氨基)苯基)烯丙酰胺的合成
Figure PCTCN2016106862-appb-000071
ESI-Ms m/z:569.5[M+H]
实施例22 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(1-氧代-1,2,3,4-四氢吡嗪[1,2-a]吲哚-10-基)嘧啶-2-基)氨基)苯基)烯丙酰胺的合成
Figure PCTCN2016106862-appb-000072
ESI-Ms m/z:555.7[M+H]
实施例23 N-(2-((2-(二甲基氨基)乙基)(甲基)氨基)-4-甲氧基-5-((4-(2-甲基-1,2,3,4-四氢吡嗪[1,2-a]吲哚-10-基)嘧啶-2-基)氨基)苯基)烯丙酰胺的合成
Figure PCTCN2016106862-appb-000073
ESI-Ms m/z:554.8[M+H]
实验例1体外激酶活性评价
1实验材料
1.1酶
EGFRWT激酶，购于Carna公司；
EGFRT790M/L858R激酶，购于Invitrogen公司。
1.2试剂
三磷酸腺苷(ATP)，购于Sigma公司；
缩氨酸(Peptide FAM-P22)，购于GL Biochem公司；
乙二胺四乙酸(EDTA)，购于Sigma公司。
1.3仪器
Caliper EZ reader微流控芯片仪器，购于Caliper Life Sciences,Inc.
2实验方法
2.1准备1×激酶基础缓冲液和终止缓冲液
1×激酶基础缓冲液(对于EGFRWT)：50mM HEPES，pH7.5，0.0015％Brij-35，10mM MgCl2，10mM MnCl2，2mM DTT；
1×激酶基础缓冲液(对于EGFRT790M/L858R)：50mM HEPES，pH7.5，0.0015％Brij-35，10mM MgCl2，2mM DTT；
终止缓冲液：100mM HEPES，pH7.5，0.0015％Brij-35，0.2％Coating Reagent#3，50mM EDTA。
2.2准备化合物
用100％DMSO将本发明的化合物分别溶解至10mM，再用完全培养基稀释至50μM，然后用含0.1％DMSO的完全培养基稀释至5μM后，依次3倍稀释，共10个浓度(对于EGFRWT)；
用100％DMSO将本发明的化合物分别溶解至10mM，再用完全培养基稀释至50μM，然后用含0.1％DMSO的完全培养基稀释至1μM后，依次3倍稀释，共10个浓度(对于EGFRT790M/L858R)；
在空的孔中加入100μl 100％DMSO用于配制有激酶无化合物对照组和无激酶无化合物对照组；
标记以上所用96孔板为来源板。
2.3准备中间板
从来源板中转移10μl溶液到新的96孔板中，作为中间板，在中间板每孔中加入90μl 1×激酶缓冲液，振荡混匀10min。
2.4准备实验板
从96孔中间板中，每孔转移5μl溶液到384孔板中。
2.5激酶反应
2.5.1.准备2.5×激酶溶液：将EGFRWT激酶和EGFRT790M/L858R激酶原液分别加入1×基础缓冲液中，配制成2.5×激酶溶液；
2.5.2.准备2.5×缩氨酸溶液：将FAM标记的缩氨酸和ATP加到1×基础缓冲液中，配制成2.5×缩氨酸溶液；
2.5.3.转移10μl 2.5×激酶溶液到384孔实验板中，室温孵育10min；
2.5.4.转移10μl 2.5×缩氨酸溶液到384孔实验板中，在28℃条件下孵育一段时间，加入25μl终止缓冲液终止反应。
同时设置无激酶无化合物对照组(包含DMSO、1×基础缓冲液和2.5×缩氨酸溶液和有激酶无化合物对照组(包括DMSO、2.5×激酶溶液和2.5×缩氨酸溶液)。
2.5.5.Caliper仪器读数、拟合曲线，计算抑制率
在Caliper仪器上读取数据，并从Caliper程序中获得conversion数据，根据以下公式计算抑制率：
抑制率％＝(max-com)/(max-min)×100计算抑制率，其中“max”代表有激酶无化合物对照组，“com”代表受试化合物组，“min”代表无激酶无化合物对照组。
2.5.6.采用Graphpad 5.0数据处理软件计算IC50值。结果见表1。
表1
Figure PCTCN2016106862-appb-000074
Figure PCTCN2016106862-appb-000075
从实验结果可知，本发明的化合物对突变型EGFR激酶，例如EGFRL858R/T790M激酶具有良好的抑制活性，IC50值小于1nM，对野生型EGFR激酶影响小，具有较好的选择性。
实验例2体外细胞活性评价
2.实验材料
1.1细胞和阳性对照药
实验用细胞株NCI-H1975(EGFR双突变细胞，具有L858R和T790M突变)和A431(EGFR野生型细胞)，购自于ATCC。
使用阿斯利康公司生产的已上市高效选择性、不可逆性EGFR突变体抑制剂AZD9291作为阳性对照药，合成方法参见PCT/GB2012/051783(专利号WO 2013/014448)说明书实施例28，并通过氢谱和质谱确认。
1.2试剂
Cell Titer-Glo luminescent cell viability assay，购自于Promega公司；
RPMI1640 medium，购自于Invitrogen公司；
DMEM medium，购自于Invitrogen公司；
胎牛血清，购自于Invitrogen公司；
DMSO，购自于Sigma公司；
NCI-H1975细胞培养于含10％灭活的胎牛血清(GIBCO)的RPMI1640培养基中，含青霉素100IU/mL和链霉素100μg/mL；
A431细胞培养于含10％灭活的胎牛血清(GIBCO)的DMEM培养基中，含青霉素100IU/mL和链霉素100μg/mL。
2实验方法
2.1实验过程(CTG assay)
将对数生长期的NCI-H1975细胞和A431细胞消化后，吹打成单细胞悬液，接种于96孔培养板，每孔培养基100μL，每个细胞株各种3块96孔板，其中NCI-H1975细胞每孔接种3X 103个细胞，A431细胞每孔接种4X 103个细胞。将接种后的NCI-H1975细胞和A431细胞在5％CO2培养箱中培养16-24小时，待细胞贴壁后，按以下浓度要求加入受试化合物(化合物在NCI-H1975细胞上的最高测试浓度为4μM，3倍稀释，共9个浓度；在A431细胞上的最高测试浓度为10μM，3倍稀释，共9个浓度)，在培养箱中再培养72小时。同时设置空白对照组(只有培养基，不加细胞和DMSO溶液)和DMSO对照组(培养基中加入细胞和0.5％的DMSO溶液)。加入100μL的CTG溶液，避光振荡2min，孵育10min。
2.2读数，计算IC50值
将培养板放入
Figure PCTCN2016106862-appb-000076
多模式微孔板检测仪读板，记录luminescence读值结果，并按照以下公式计算抑制率：
抑制剂(％)＝(1-(RLUcom-RLUblank)/(RLUDMSO–RLUblank))×100％，
其中RLUcom表示受试化合物组的吸光值，RLUblank表示空白对照组的吸光值，RLUDMSO表示DMSO对照组的吸光值，
利用XLFit曲线拟合软件绘制药效抑制率曲线并计算IC50值，结果见表2。
表2
Figure PCTCN2016106862-appb-000077
体外细胞实验结果表明，本发明的化合物对双突变型细胞(NCI-H1975)的抑制作用较好，且对EGFR野生型细胞(A431)的抑制小，选择性与AZD9291相似或明显优于AZD9291。已知目前上市的EGFR抑制剂的主要副作用之一为皮疹、腹泻等，这些都与野生型的EGFR被抑制，选择性差有关。因此，本发明的化合物有望成为对抗EGFR突变导致耐药的肿瘤具有特异疗效且副作用较小的药物。
实验例3血糖影响检测
1实验材料
1.1化合物
将本发明的化合物用25mM的枸橼酸-枸橼酸钠缓冲液(pH4.5)溶解，配制成浓度为1.25mg/mL的澄清溶液，设为受试化合物组；以25mM的枸橼酸-枸橼酸钠缓冲液(pH4.5)设为溶媒对照组；
1.2动物
雌性BALB/C小鼠，每组各5只，体重18-22g，上海西普尔-必凯实验动物有限公司提供。 受试小鼠实验前给予2～4天的环境适应期，给药前禁食8-12h。
2实验方法
2.1小鼠禁食但可自由饮水12小时；
2.2取步骤2.1中的小鼠5只，灌胃(intragastric administration,I.G.)给予本发明的化合物25mg/kg；
2.3于灌胃后0min，15min，30min，1h，2h眼眶采血，使用罗氏卓越型血糖仪检测动物血糖值A，根据公式AUC＝[(A15min+A0)×7.5]+[(A30min+A15min)×7.5]+[(A60min+A30min)×15]+[(A120min+A60min)×30]计算AUC值，并根据公式AUC增长％＝[(AUC化合物－AUC溶媒)/AUC溶媒]×100％计算出AUC增长率，其中“A0”代表灌胃后0min的血糖值，“A15min”代表灌胃15min后的血糖值，“A30min”代表灌胃30min后的血糖值，“A60min”代表灌胃60min后的血糖值，“A120min”代表灌胃120min后的血糖值，“AUC化合物”代表受试化合物的AUC值，“AUC溶媒”代表溶媒对照组的AUC值，结果见表3。
表3
Figure PCTCN2016106862-appb-000078
已知EGFR抑制剂可能会导致在体高血糖以及受损的胰岛素信号传导等副作用。根据实验报道，AZD9291和Clovis Oncology公司的Rociletinib(CO1686)对血糖会有一定程度的升高副作用(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)。本发明的以上实验结果表明，本发明的化合物 对血糖影响较小，有望克服现有的EGFR抑制剂具有的高血糖副作用，从而有助于降低不良反应和提高患者依从性。
实验例4药物代谢实验
1实验材料
1.1化合物
将本发明的化合物配制成口服和注射两种给药配方。其中，口服药物配方为25mM的枸橼酸-枸橼酸钠缓冲液(pH4.5)溶解，制成1.25mg/mL澄清溶液；尾静脉注射药物配方为枸橼酸-枸橼酸钠缓冲液(pH4.5)与生理盐水体积比为1：1的混合溶液，制成0.2mg/mL溶液。
1.2动物
雌性BALB/C小鼠，每组各5只，体重18-22g，上海西普尔-必凯实验动物有限公司提供。受试小鼠实验前给予2～4天的环境适应期，给药前禁食8-12h，给药2h后给水，4h后给食。
1.3试剂
甲醇(色谱纯)：Spectrum公司生产；
乙腈(色谱纯)：Spectrum公司生产；
其余试剂均为市售分析纯。
1.4仪器
美国AB公司API 4500型三重四级杆液质联用仪，配有电喷雾离子源(ESI)，LC-30AD双泵；SIL-30AC自动进样器；CTO-30AC柱温箱；DGU-20A3R脱气机；Analyst QS A01.01色谱工作站；Milli-Q超纯水器(Millipore Inc)；Qilinbeier Vortex-5振荡器；HITACHI CF16RⅩⅡ台式高速冷冻离心机。
2实验方法
2.1小鼠禁食但可自由饮水12小时后，采取0时刻空白血浆；
2.2取步骤2.1中的小鼠5只，灌胃(intragastric administration,I.G.)给予本发明化合物25mg/kg；
取步骤2.1中的小鼠5只，尾静脉(Intravenousadministration,I.V.)给予本发明的化合物2mg/kg；
2.3于灌胃后5min，15min，30min，1h，2h，4h，10h，24h，从眼底静脉丛连续取血置于分布有肝素的EP管中，8000rpm/min离心5min后取上层血浆，-20℃冻存，待LC-MS/MS分析；
于尾静脉注射给药后5min，15min，30min，1h，2h，4h，10h，24h，从眼底静脉丛连续取血置于分布有肝素的EP管中，8000rpm/min离心5min后取上层血浆，-20℃冻存，待LC-MS/MS分析；
2.4根据步骤2.3所得的血药浓度-时间数据，采用WinNonlin软件求算药代动力学参数，见表4。
表4
Figure PCTCN2016106862-appb-000079
本发明的化合物具有较好的药代动力学数据，应具有较好的临床应用前景。
尽管以上已经对本发明作了详细描述，但是本领域技术人员理解，在不偏离本发明的精神和范围的前提下可以对本发明进行各种修改和改变。本发明的权利范围并不限于上文所作的详细描述，而应归属于权利要求书。

Claims (10)

  1. 通式I的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，
    Figure PCTCN2016106862-appb-100001
    其中：
    环A为C4-C8含氮杂环基，其任选被一个或多个卤素、氧代、烷基、环烷基、卤代烷基、烷氧基、卤代烷氧基、硝基、氰基、羟基、氨基、单烷基氨基、二烷基氨基、氨基烷基、单烷基氨基烷基、二烷基氨基烷基、羟基烷基、烷氧基烷基、烷基酰基、氨基酰基、单烷基氨基酰基、二烷基氨基酰基、芳基、杂芳基和杂环烷基取代，当取代基有两个以上时，相邻的两个取代基可以与它们连接的原子一起构成取代或未取代的环烷基、杂环烷基、芳基、杂芳基，或连接在同一个原子上的两个取代基可以与它们共同连接的原子形成取代或未取代的环烷基、杂环烷基；
    X1、X2、X3和X4各自独立选自C(R1)和N；
    R1、R2a、R2b、R3a、R3b和R3c各自独立地选自氢、卤素、烷基、环烷基、卤代烷基、烷氧基、卤代烷氧基、硝基、氰基、羟基、氨基、单烷基氨基、二烷基氨基、氨基烷基、单烷基氨基烷基、二烷基氨基烷基、羟基烷基、烷氧基烷基、烷基酰基、氨基酰基、单烷基氨基酰基和二烷基氨基酰基；
    R4、R5和R6各自独立地选自氢、卤素、氰基、烷基、烷氧基和环烷基，所述的烷基、烷氧基和环烷基任选被一个或多个卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、氨基、单烷基氨基、二烷基氨基、羟基、氨基烷基、单烷基氨基烷基、二烷基氨基烷基或羟基烷基取代；
    R7选自氢、烷基、环烷基和卤代烷基；和
    R8选自氢、烷基和环烷基，所述的烷基和环烷基任选被一个或多个卤素、烷基、卤代烷基、烷氧基、氨基、单烷基氨基、二烷基氨基或羟基取代；或
    R7、R8及其连接的N原子一起构成含氮杂环烷基，所述的含氮杂环烷基任选被一个或多个卤素、烷基、卤代烷基、烷氧基、氨基、单烷基氨基、二烷基氨基、羟基、氨基烷基、单烷基氨基烷基、二烷基氨基烷基或羟基烷基取代。
  2. 根据权利要求1的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中：
    环A为只含有一个氮原子的C4-C8含氮杂单环烷基，其任选被一个或多个卤素、氧代、 烷基、环烷基、卤代烷基、烷氧基、卤代烷氧基、硝基、氰基、羟基、氨基、单烷基氨基、二烷基氨基、氨基烷基、单烷基氨基烷基、二烷基氨基烷基、羟基烷基、烷氧基烷基、烷基酰基、氨基酰基、单烷基氨基酰基、二烷基氨基酰基、芳基、杂芳基和杂环烷基取代，当取代基有两个以上时，相邻的两个取代基可以与它们连接的原子一起构成取代或未取代的环烷基、杂环烷基、芳基、杂芳基，或连接在同一个原子上的两个取代基可以与它们共同连接的原子形成取代或未取代的环烷基、杂环烷基；
    优选地，
    环A为
    Figure PCTCN2016106862-appb-100002
    n选自1、2、3、4、5和6，m选自1、2、3和4，Ra选自氢、C1-6烷基、C3-8环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、硝基、氰基、羟基、氨基、单C1-6烷基氨基、二C1-6烷基氨基、氨基C1-6烷基、单C1-6烷基氨基C1-6烷基、二C1-6烷基氨基C1-6烷基、羟基C1-6烷基、C1-6烷氧基C1-6烷基、C1-6烷基酰基、氨基酰基、单C1-6烷基氨基酰基、二C1-6烷基氨基酰基、C6-10芳基、C5-10杂芳基和C3-8杂环烷基，当m选自2、3和4时，相邻两个碳原子上的两个Ra可以与它们所连接的碳原子一起构成C3-8环烷基或C3-8杂环烷基，或同一个碳原子上的两个Ra可以与它们共同连接的碳原子一起构成C3-8环烷基或C3-8杂环烷基。
  3. 根据权利要求1的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中：
    环A为含有两个氮原子的C4-C8含氮杂单环烷基，其任选被一个或多个卤素、氧代、烷基、环烷基、卤代烷基、烷氧基、卤代烷氧基、硝基、氰基、羟基、氨基、单烷基氨基、二烷基氨基、氨基烷基、单烷基氨基烷基、二烷基氨基烷基、羟基烷基、烷氧基烷基、烷基酰基、氨基酰基、单烷基氨基酰基、二烷基氨基酰基、芳基、杂芳基和杂环烷基取代，当取代基有两个以上时，相邻的两个取代基可以与它们连接的原子一起构成取代或未取代的环烷基、杂环烷基、芳基、杂芳基，或连接在同一个原子上的两个取代基可以与它们共同连接的原子形成取代或未取代的环烷基、杂环烷基；
    优选地，
    环A为
    Figure PCTCN2016106862-appb-100003
    m选自1、2、3和4，p选自0、1和2，q选自0、1和2，Ra选自氢、C1-6烷基、C3-8环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、硝基、氰基、羟基、氨基、单C1-6烷基氨基、二C1-6烷基氨基、氨基C1-6烷基、单C1-6烷基氨基C1-6烷基、二C1-6烷基氨基C1-6烷基、羟基C1-6烷基、C1-6烷氧基C1-6烷基、C1-6烷基酰基、氨基酰基、单C1-6烷基氨基酰基、二C1-6烷基氨基酰基、C6-10芳基、C5-10杂芳基和C3-8杂环烷基，当m选自2、3和4时，相邻两个原子上的两个Ra可以与它们所连接的原子一起构成C3-8环烷基或C3-8杂 环烷基，或同一个原子上的两个Ra可以与它们共同连接的原子一起构成C3-8环烷基或C3-8杂环烷基。
  4. 根据权利要求1的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中：
    环A为含有一个氮原子和一个氧原子的C4-C8含氮杂单环烷基，其任选被一个或多个卤素、氧代、烷基、环烷基、卤代烷基、烷氧基、卤代烷氧基、硝基、氰基、羟基、氨基、单烷基氨基、二烷基氨基、氨基烷基、单烷基氨基烷基、二烷基氨基烷基、羟基烷基、烷氧基烷基、烷基酰基、氨基酰基、单烷基氨基酰基、二烷基氨基酰基、芳基、杂芳基和杂环烷基取代，当取代基有两个以上时，相邻的两个取代基可以与它们连接的原子一起构成取代或未取代的环烷基、杂环烷基、芳基、杂芳基，或连接在同一个原子上的两个取代基可以与它们共同连接的原子形成取代或未取代的环烷基、杂环烷基；
    优选地，
    环A为
    Figure PCTCN2016106862-appb-100004
    m选自1、2、3和4，p选自0、1和2，q选自0、1和2，Ra选自氢、C1-6烷基、C3-8环烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、硝基、氰基、羟基、氨基、单C1-6烷基氨基、二C1-6烷基氨基、氨基C1-6烷基、单C1-6烷基氨基C1-6烷基、二C1-6烷基氨基C1-6烷基、羟基C1-6烷基、C1-6烷氧基C1-6烷基、C1-6烷基酰基、氨基酰基、单C1-6烷基氨基酰基、二C1-6烷基氨基酰基、C6-10芳基、C5-10杂芳基和C3-8杂环烷基，当m选自2、3和4时，相邻两个原子上的两个Ra可以与它们所连接的原子一起构成C3-8环烷基或C3-8杂环烷基，或同一个原子上的两个Ra可以与它们共同连接的原子一起构成C3-8环烷基或C3-8杂环烷基。
  5. 根据权利要求1-4之任一项的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，其中：
    X1、X2、X3和X4各自独立选自C(R1)和N；和
    R1、R1a、R1b、R2a、R2b、R3a、R3b和R3c各自独立地选自氢、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、硝基、氰基、羟基、氨基、单C1-6烷基氨基、二C1-6烷基氨基、氨基C1-6烷基、单C1-6烷基氨基C1-6烷基、二C1-6烷基氨基C1-6烷基、羟基C1-6烷基、C1-6烷氧基C1-6烷基、C1-6烷基酰基、氨基酰基、单C1-6烷基氨基酰基和二C1-6烷基氨基酰基；
    R7选自氢、C1-6烷基、C3-6环烷基和卤代C1-6烷基；优选地，Ra选自氢、甲基、乙基、丙基、异丙基、环丙基、环丁基、环戊基、环己基和三氟甲基；和
    R8选自氢、C1-6烷基和C3-6环烷基，所述的C1-6烷基和C3-6环烷基任选被一个或多个卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、氨基、单C1-6烷基氨基、二C1-6烷基氨基或羟基 取代；优选地，Rb选自氢、C1-3烷基和C3-6环烷基，所述的C1-3烷基和C3-6环烷基任选被一个或多个卤素、甲基、乙基、丙基、异丙基、三氟甲基、二氟甲基、三氟乙基、甲氧基、乙氧基、丙氧基、异丙基氧基、氨基、甲氨基、乙氨基、丙氨基、二甲氨基、二乙胺基、二丙氨基、甲基乙基氨基、甲基丙基氨基、乙基丙基氨基或羟基取代；和
    R4、R5和R6各自独立地选自氢、卤素、氰基、C1-6烷基、C1-6烷氧基、C3-8环烷基，所述的C1-6烷基、C1-6烷氧基和环烷基任选被一个或多个卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、氨基、单C1-6烷基氨基、二C1-6烷基氨基、羟基、氨基C1-6烷基、单C1-6烷基氨基C1-6烷基、二C1-6烷基氨基C1-6烷基和羟基C1-6烷基取代。
  6. 根据权利要求1的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药，所述化合物为以下化合物：
    Figure PCTCN2016106862-appb-100005
    Figure PCTCN2016106862-appb-100006
  7. 一种药物组合物，其包含权利要求1-6之任一项的化合物或其药学可接受的盐、异构体、溶剂合物、结晶或前药和药学可接受的载体。
  8. 权利要求1-6之任一项的化合物或权利要求7的组合物在制备用于治疗和/或预防肿瘤的药物中的应用，优选地，所述肿瘤为具有抗药性的肿瘤，更优选地，所述肿瘤为对EGFR抑制剂具有抗药性的肿瘤。
  9. 通式II的化合物或其药学可接受的盐，
    Figure PCTCN2016106862-appb-100007
    其中环A、X1、X2、X3、X4、R2a、R2b、R3a、R3b、R3c、R7和R8具有权利要求1-5中的定义。
  10. 通式III的化合物或其药学可接受的盐，
    Figure PCTCN2016106862-appb-100008
    其中环A、X1、X2、X3、X4、R2a、R2b具有权利要求1-5中的定义，M为卤素。
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