WO2015014283A1 - Inhibiteur de protéine tyrosine kinase et application associée - Google Patents

Inhibiteur de protéine tyrosine kinase et application associée Download PDF

Info

Publication number
WO2015014283A1
WO2015014283A1 PCT/CN2014/083284 CN2014083284W WO2015014283A1 WO 2015014283 A1 WO2015014283 A1 WO 2015014283A1 CN 2014083284 W CN2014083284 W CN 2014083284W WO 2015014283 A1 WO2015014283 A1 WO 2015014283A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
fluorenyl
hydrogen
amino
methyl
Prior art date
Application number
PCT/CN2014/083284
Other languages
English (en)
Chinese (zh)
Inventor
王勇
赵立文
陈宏雁
王德忠
刘阳
毕胜
高毅平
张迪
张仓
Original Assignee
南京圣和药业股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 南京圣和药业股份有限公司 filed Critical 南京圣和药业股份有限公司
Publication of WO2015014283A1 publication Critical patent/WO2015014283A1/fr

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present invention belongs to the field of chemical medicine, and particularly relates to a compound having a protein tyrosine kinase inhibitory activity or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a pharmaceutical composition containing the same And the use of these compounds or compositions in the preparation of a medicament. Background technique
  • Protein tyrosine kinases are a class of kinases that catalyze the transfer of ⁇ -phosphates on ATP to protein tyrosine residues, which are activated by catalyzing the phosphorylation of phenolic hydroxyl groups on various protein tyrosine residues.
  • a proteinase system that functions as a functional protein.
  • Protein tyrosine kinases (PTKs) play an important role in the signal transduction pathways in cells, regulating a series of physiological and biochemical processes such as cell growth, differentiation and death. Abnormal expression of a protein tyrosine kinase can lead to disturbances in cell proliferation regulation, which in turn leads to tumorigenesis.
  • Tyrosine kinase inhibitors act as competitive inhibitors of adenosine triphosphate (ATP) binding to tyrosine kinases, competitively bind to tyrosine kinases, block tyrosine kinase activity, and inhibit cell proliferation.
  • ATP adenosine triphosphate
  • BCR-ABL chronic myeloid leukemia
  • BCR-ABL protein tyrosine kinase plays an important role in cell signal transduction and transformation, and promotes CML through phosphorylation and the like. Mature granulocytes infinite proliferation. BCR-ABL is not expressed in normal cells and has become an ideal drug target for the treatment of CML.
  • Imatinib is the first protein-targeted therapeutic protein tyrosine kinase inhibitor that competitively inhibits the binding site of adenosine triphosphate (ATP) to thymidine kinase (TK) receptors (such as KIT) and blocks TK phosphorylation. It inhibits signal transduction and inhibits kinase-related KIT mutations and wild-type KIT, and has therapeutic effects on various types of cancer.
  • ATP adenosine triphosphate
  • TK thymidine kinase receptors
  • Imatinib inhibits BCR-ABL tyrosine kinase at the cellular level in vitro and in vivo, selectively inhibits BCR-ABL-positive cell line cells and Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) and acute lymphoid
  • Ph+ Philadelphia chromosome-positive
  • CML chronic myeloid leukemia
  • imatinib also inhibits the receptor tyrosine kinase of platelet-derived growth factor (PDGF) and the receptor tyrosine kinase c-Kit of stem cell factor (SCF), thereby inhibiting mediated by PDGF and stem cell factors.
  • PDGF platelet-derived growth factor
  • SCF stem cell factor
  • CML chronic myeloid leukemia
  • GIST malignant gastrointestinal stromal tumor
  • GIST CD117-positive gastrointestinal stromal tumors
  • imatinib has opened a new era of tumor molecular targeting.
  • taking imatinib for a long time will cause drug resistance and cause the disease to recur.
  • the problem of drug resistance has become increasingly prominent.
  • the main reason for acquired tolerance is due to point mutations in BCR-ABL that result in the inability of imatinib to bind to BCR-ABL.
  • hundreds of BCR-ABL point mutations have been found to be associated with imatinib resistance, with 15 to 20% of imatinib-tolerant patients having a T315I mutation.
  • R 2 is selected from the group consisting of hydrogen, fluorenyl, decyloxy, halofluorenyl, halodecyloxy, -OH, -NH 2 , halogen, and CN;
  • R 3 is selected from the group consisting of hydrogen, fluorenyl, halofluorenyl, halogen, aminoacyl, monodecylaminoacyl, bis-decylaminoacyl and cyano;
  • R4 is selected from the group consisting of hydrogen, fluorenyl, -OH, hydroxydecyl, halofluorenyl;
  • X is selected from N and C(R 5 ), wherein R 5 is selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, acylamino, decylamido, aryl amide, heteroaryl amide, sulfonate
  • R 5 is selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, acylamino, decylamido, aryl amide, heteroaryl amide, sulfonate
  • An acylamino group, a decylsulfonylamino group, an arylsulfonylamino group, a heteroarylsulfonylamino group, or a carbon atom to which R 5 is bonded to form C( 0)
  • Y is selected from the group consisting of N, H and C(R6), wherein Re is selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, acylamino, decylamido, aryl amide, heteroaryl amide, sulfonate
  • An amide group, a mercaptosulfonylamino group, an arylsulfonylamino group, a heteroarylsulfonylamino group, the amino group, a monodecylamino group, a bis-decylamino group, an acylamino group, a decylamino group, an aryl amide group, a heteroarylamino group, a sulfonylamino group, a decylsulfonylamino group, an arylsulfonylamino group, a heteroarylsulfonylamino group may
  • Another object of the invention is to provide a process for the preparation of a compound of formula I according to the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof.
  • a further object of the present invention is to provide a composition comprising a compound of formula I of the present invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier, and a composition comprising the same A composition of a compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof and another protein tyrosine kinase inhibitor.
  • a further object of the present invention is to provide a compound of the formula I according to the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystallization or prodrug thereof, for treating and/or preventing a tumor, and the method of the invention Use of a compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof for the manufacture of a medicament for the treatment and/or prevention of a tumor.
  • the present invention provides a compound of formula I or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,
  • R 2 is selected from the group consisting of hydrogen, fluorenyl, decyloxy, halofluorenyl, halodecyloxy, -OH, -NH 2 , halogen, and CN;
  • R 3 is selected from the group consisting of hydrogen, fluorenyl, halofluorenyl, halogen, aminoacyl, monodecylaminoacyl, bis-decylaminoacyl and cyano;
  • R4 is selected from the group consisting of hydrogen, fluorenyl, -OH, hydroxydecyl, halofluorenyl;
  • X is selected from N and C(R 5 ), wherein R 5 is selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, acylamino, decylamido, aryl amide, heteroaryl amide, sulfonate
  • R 5 is selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, acylamino, decylamido, aryl amide, heteroaryl amide, sulfonate
  • An acylamino group, a decylsulfonylamino group, an arylsulfonylamino group, a heteroarylsulfonylamino group, or a carbon atom to which R 5 is bonded to form C( 0)
  • Y is selected from the group consisting of N, H and C(R6), wherein Re is selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, acylamino, decylamido, aryl amide, heteroaryl amide, sulfonate
  • X is N and Y is N, indicating a double bond.
  • X is N
  • Y is CCRe
  • X is C(R 5 )
  • Y is N, represents a double bond, and is selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, acylamino, hydrazine Amino group, aryl amido group, heteroaryl amido group, sulfonylamino group, decylsulfonylamino group, arylsulfonylamino group, heteroarylsulfonylamino group, said amino group, monodecylamino group, biguanide Alkylamino, amido, decylamido, arylamido, heteroarylamino, sulfonylamino, decylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino can be one or more Halogen, sulfhydryl, amino, cyano substitute
  • X is C(R 5 )
  • Y is C(R6)
  • said R 5 , Re are each independently selected from hydrogen, amino, monodecylamino , bis-decylamino, amido, decyl amido, aryl amide, heteroaryl amide, sulfonylamino, decyl sulfonylamino, aryl sulfonylamino, heteroaryl sulfonylamino, said Amino, monodecylamino, bis-decylamino, amido, decanoylamino, aryl amido, heteroarylamino, sulfonylamino, decylsulfonylamino, arylsulfonylamino, heteroaryl
  • the sulfonylamino group may be substituted by one or more halogen, thiol, amino, cyan
  • 1 is selected from the group consisting of hydrogen, d- 6 fluorenyl, d- 6 methoxy, halo d- 6 fluorenyl, halo d. 6 decyloxy, -OH, - NH 2 , halogen and CN;
  • R 2 is selected from the group consisting of hydrogen, d. 6 fluorenyl, d. 6 decyloxy, halo C fluorenyl, halogenated d. 6 decyloxy, -OH, -NH 2 , halogen And CN;
  • R 3 is selected from the group consisting of hydrogen, d. 6 fluorenyl, halogenated d.
  • 1 is selected from the group consisting of hydrogen, d- 4 thiol, d- 4 methoxy, halo C 14 Sulfhydryl, halogenated d. 4 methoxy, -OH, -NH 2 , halogen and CN;
  • R 2 is selected from hydrogen, d. 4 fluorenyl, d. 4 decyloxy, halogenated C 14 fluorenyl, halogen Substituting CM methoxy, -OH, -NH 2 , halogen and CN;
  • R 3 is selected from the group consisting of hydrogen, d. 4 fluorenyl, halogenated d.
  • R 4 fluorenyl, halogen, aminoacyl, mono C 14 mercaptoaminoacyl, A double C 14 mercaptoamino acyl group and a cyano group; and R 4 is selected from the group consisting of hydrogen, C 14 fluorenyl, -OH, hydroxy. 14 fluorenyl, halogenated C 14 fluorenyl.
  • 1 ⁇ is selected from hydrogen, alkyl with d_ 3, d_ 3 embankment group, d_ 3 alkyl with halo, haloalkyl d. 3 embankment group, -OH, -NH 2 , halogen and CN;
  • R 2 is selected from the group consisting of hydrogen, d. 3 fluorenyl, d. 3 decyloxy, halo Cw fluorenyl, halogenated d. 3 decyloxy, -OH, -NH 2 , halogen And CN;
  • R 3 is selected from the group consisting of hydrogen, d. 3 fluorenyl, halogenated d.
  • the present invention provides a compound of the formula la or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,
  • R 2 is selected from the group consisting of hydrogen, fluorenyl, decyloxy, halofluorenyl, halodecyloxy, -OH, -NH 2 , halogen, and CN;
  • R 3 is selected from the group consisting of hydrogen, fluorenyl, halofluorenyl, halogen, aminoacyl, monodecylaminoacyl, bis-decylaminoacyl and cyano;
  • R4 is selected from the group consisting of hydrogen, fluorenyl, -OH, hydroxydecyl, halofluorenyl;
  • X is selected from N and C(R 5 ), wherein R 5 is selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, acylamino, decylamido, aryl amide, heteroaryl amide, sulfonate
  • R 5 is selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, acylamino, decylamido, aryl amide, heteroaryl amide, sulfonate
  • An acylamino group, a decylsulfonylamino group, an arylsulfonylamino group, a heteroarylsulfonylamino group, or a carbon atom to which R 5 is bonded to form C( 0)
  • Y is selected from the group consisting of N, H and C(R6), wherein Re is selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, acylamino, decylamido, aryl amide, heteroaryl amide, sulfonate
  • An amide group, a mercaptosulfonylamino group, an arylsulfonylamino group, a heteroarylsulfonylamino group, the amino group, a monodecylamino group, a bis-decylamino group, an acylamino group, a decylamino group, an aryl amide group, a heteroarylamino group, a sulfonylamino group, a decylsulfonylamino group, an arylsulfonylamino group, a heteroarylsulfonylamino group may
  • X is N and Y is N, indicating a double bond.
  • X is N
  • Y is C(R6)
  • the ring containing X, Y is formed with the pyridine ring to which it is fused and the ethynyl group to which the pyridine ring is attached.
  • R6 is selected from the group consisting of hydrogen, acylamino, decylamido, arylamido, heteroaryl Amido, sulfonylamino, decylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, said acylamino, decylamido, aryl amide, heteroaryl amide, sulfonyl
  • the amino group, mercaptosulfonylamino group, arylsulfonylamino group, heteroarylsulfonylamino group may be substituted by one or more halogen, sulfhydryl, amino, cyano groups.
  • X is N
  • Y is C(R6)
  • the ring containing X, Y is formed with the pyridine ring to which it is fused and the ethynyl group to which the pyridine ring is attached.
  • R6 is selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, acylamino, hydrazine Amino group, aryl amido group, heteroaryl amido group, sulfonylamino group, decylsulfonylamino group, arylsulfonylamino group, heteroarylsulfonylamino group, said amino group, monodecylamino group, biguanide Alkylamino, amido, decylamido, arylamido, heteroarylamino, sulfonylamino, decylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino can be one or more Halogen, sulfhydryl, amino, cyano substituted.
  • X is C(R 5 )
  • Y is N, represents a double bond
  • said R 5 is selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, amido , mercaptoamido, aryl amido, heteroaryl amido, sulfonylamino, decylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, said amino group, monodecylamino group, Bis-nonylamino, acylamino, decylamido, aryl amide, heteroaryl amide, sulfonylamino, decyl sulfonylamino, aryl sulfonylamino, heteroaryl sulfonylamino can be one or Multiple halogen, sulfhydryl, amino, cyano substituted
  • X is C(R 5 )
  • Y is C(R6)
  • said R 5 , Re are each independently selected from hydrogen, amino, monodecylamino , bis-decylamino, amido, decyl amido, aryl amide, heteroaryl amide, sulfonylamino, decyl sulfonylamino, aryl sulfonylamino, heteroaryl sulfonylamino, said Amino, monodecylamino, bis-decylamino, amido, decanoylamino, aryl amido, heteroarylamino, sulfonylamino, decylsulfonylamino, arylsulfonylamino, heteroaryl
  • the sulfonylamino group may be substituted by one or more halogen, thiol, amino, cyan
  • 1 is selected from the group consisting of hydrogen, d- 6 fluorenyl, d- 6 methoxy, halo d- 6 fluorenyl, halo d. 6 decyloxy, -OH, - NH 2 , halogen and CN;
  • R 2 is selected from the group consisting of hydrogen, d. 6 fluorenyl, d. 6 decyloxy, halo C fluorenyl, halogenated d. 6 decyloxy, -OH, -NH 2 , halogen And CN;
  • R 3 is selected from the group consisting of hydrogen, d. 6 fluorenyl, halogenated d.
  • R4 is selected from hydrogen.
  • 1 ⁇ is selected from hydrogen, alkyl with d_ 3, d_ 3 embankment group, d_ 3 alkyl with halo, haloalkyl group embankment d 3, -OH,. - NH 2 , halogen and CN;
  • R 2 is selected from the group consisting of hydrogen, d. 3 fluorenyl, d. 3 decyloxy, halo Cw fluorenyl, halogenated d. 3 decyloxy, -OH, -NH 2 , halogen and CN;
  • R 3 is selected from the group consisting of hydrogen, d. 3 fluorenyl, halogenated d.
  • R 4 is selected from hydrogen, d_ 3 alkyl with, -OH, Cw alkyl with hydroxyl, C ⁇ alkyl with halo.
  • the present invention provides a compound of the formula I-a or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,
  • R 2 is selected from the group consisting of hydrogen, fluorenyl, decyloxy, halofluorenyl, halodecyloxy, -OH, -NH 2 , halogen, and CN;
  • R 3 is selected from the group consisting of hydrogen, fluorenyl, halofluorenyl, halogen, aminoacyl, monodecylaminoacyl, bis-decylaminoacyl and cyano;
  • R4 is selected from the group consisting of hydrogen, fluorenyl, -OH, hydroxydecyl, halofluorenyl;
  • R6 is selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, amido, decylamino, arylamido, heteroarylamino, sulfonylamino, decylsulfonylamino, arylsulfonyl Amino, heteroarylsulfonylamino, said amino, monodecylamino, bis-decylamino, acylamino, decylamido, aryl amide, heteroaryl amide, sulfonylamino, decyl sulfonate
  • the acylamino, arylsulfonylamino, heteroarylsulfonylamino group may be substituted by one or more halogen, thiol, amino, cyano; provided that the compound is not the following:
  • the present invention provides a compound of the formula Ib or a pharmaceutically acceptable salt, isomer, solvate thereof,
  • R 2 is selected from the group consisting of hydrogen, fluorenyl, decyloxy, halofluorenyl, halodecyloxy, -OH, -NH 2 , halogen, and CN;
  • R 3 is selected from the group consisting of hydrogen, fluorenyl, halofluorenyl, halogen, aminoacyl, monodecylaminoacyl, bis-decylaminoacyl and cyano;
  • R4 is selected from the group consisting of hydrogen, fluorenyl, -OH, hydroxydecyl, halofluorenyl;
  • Y is selected from N and H;
  • R 5 is selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, acylamino, decyl amido, aryl amide, heteroaryl amide, sulfonylamino, decyl sulfonylamino, aryl sulfonate
  • the present invention provides a compound of the formula Ia-a or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,
  • R 2 is selected from the group consisting of hydrogen, fluorenyl, decyloxy, halofluorenyl, halodecyloxy, -OH, -NH 2 , halogen, and CN;
  • R 3 is selected from the group consisting of hydrogen, fluorenyl, halodecyl, halogen, aminoacyl, monodecylaminoacyl, bis-decylaminoacyl and cyanide Base
  • R4 is selected from the group consisting of hydrogen, fluorenyl, -OH, hydroxydecyl, halofluorenyl;
  • R6 is selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, amido, decylamino, arylamido, heteroarylamino, sulfonylamino, decylsulfonylamino, arylsulfonyl Amino, heteroarylsulfonylamino, said amino, monodecylamino, bis-decylamino, acylamino, decylamido, aryl amide, heteroaryl amide, sulfonylamino, decyl sulfonate
  • the acylamino, arylsulfonylamino, heteroarylsulfonylamino group may be substituted by one or more halogen, sulfhydryl, amino, cyano groups.
  • the [1,5-a]pyridine-7-ethynyl group is selected from the group consisting of hydrogen, acylamino, decylamido, aryl amide, heteroaryl amide, sulfonylamino, decyl sulfonate
  • the sulfonylamino, heteroarylsulfonylamino group may be substituted by one or more halogen, thiol, amino, cyano groups.
  • the present invention provides a compound of the formula I-a' or a pharmaceutically acceptable salt, isomer, solvate, crystal or former thereof
  • R 2 is selected from the group consisting of hydrogen, fluorenyl, decyloxy, halofluorenyl, halodecyloxy, -OH, -NH 2 , halogen, and CN;
  • R 3 is selected from the group consisting of hydrogen, fluorenyl, halofluorenyl, halogen, aminoacyl, monodecylaminoacyl, bis-decylaminoacyl and cyano;
  • R4 is selected from the group consisting of hydrogen, fluorenyl, -OH, hydroxydecyl, halofluorenyl;
  • R6 is selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, amido, decylamino, arylamido, heteroarylamino, sulfonylamino, decylsulfonylamino, arylsulfonyl Amino, heteroarylsulfonylamino, said amino, monodecylamino, bis-decylamino, acylamino, decylamido, aryl amide, heteroaryl amide, sulfonylamino, decyl sulfonate
  • the acylamino, arylsulfonylamino, heteroarylsulfonylamino group may be substituted by one or more halogen, sulfhydryl, amino, cyano groups.
  • the present invention provides a compound of Formula Ia" or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,
  • R 2 is selected from the group consisting of hydrogen, fluorenyl, decyloxy, halofluorenyl, halodecyloxy, -OH, -NH 2 , halogen, and CN;
  • R 3 is selected from the group consisting of hydrogen, fluorenyl, halodecyl, halogen, aminoacyl, monodecylaminoacyl, bis-decylaminoacyl and cyanide
  • R4 is selected from the group consisting of hydrogen, fluorenyl, -OH, hydroxydecyl, halofluorenyl;
  • R6 is selected from the group consisting of hydrogen, monodecylamino, bis-decylamino, acylamino, decylamido, aryl amide, heteroaryl amide, sulfonylamino, decyl sulfonylamino, aryl sulfonylamino, Heteroarylsulfonylamino, said amido, decylamido, arylamido, heteroarylamino, sulfonylamino, decylsulfonylamino, arylsulfonylamino, heteroarylsulfonyl
  • the amino group may be substituted by one or more halogen, thiol, amino, cyano;
  • the present invention provides a compound of the formula I-b' or a pharmaceutically acceptable salt, isomer, solvate, crystal or former thereof
  • R 2 is selected from the group consisting of hydrogen, fluorenyl, decyloxy, halodecyl, halodecyloxy, -OH, -H 2 halogen, and CN;
  • R 3 is selected from the group consisting of hydrogen, fluorenyl, halodecyl, halogen, aminoacyl, monodecylaminoacyl, bis-decylaminoacyl and cyanide
  • R4 is selected from the group consisting of hydrogen, fluorenyl, -OH, hydroxydecyl, halofluorenyl;
  • Y is selected from N and H;
  • R 5 is selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, acylamino, decyl amido, aryl amide, heteroaryl amide, sulfonylamino, decyl sulfonylamino, aryl sulfonate
  • An acylamino group, a heteroarylsulfonylamino group, or a carbon atom to which R 5 forms a C( 0)
  • said amino group, monodecylamino group, bis-decylamino group, amido group, decylamino group, aromatic Alkylamino, heteroarylamino, sulfonylamino, decylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino may be substituted by one or more halogen, thiol, amino, cyano;
  • the present invention provides a compound of formula I-b" or a pharmaceutically acceptable salt, isomer, solvate, crystal or
  • R 2 is selected from the group consisting of hydrogen, fluorenyl, decyloxy, halofluorenyl, halodecyloxy, -OH, -NH 2 , halogen, and CN;
  • R 3 is selected from the group consisting of hydrogen, fluorenyl, halodecyl, halogen, aminoacyl, monodecylaminoacyl, bis-decylaminoacyl and cyanide
  • R4 is selected from the group consisting of hydrogen, fluorenyl, -OH, hydroxydecyl, halofluorenyl;
  • Y is selected from N and H;
  • R 5 is selected from the group consisting of hydrogen, amino, monodecylamino, bis-decylamino, acylamino, decyl amido, aryl amide, heteroaryl amide, sulfonylamino, decyl sulfonylamino, aryl sulfonate
  • An acylamino group, a heteroarylsulfonylamino group, or a carbon atom to which R 5 forms a C( 0)
  • said amino group, monodecylamino group, bis-decylamino group, amido group, decylamino group, aromatic Alkylamino, heteroarylamino, sulfonylamino, decylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino may be substituted by one or more halogen, thiol, amino, cyano;
  • the present invention provides a compound of the formula Ia-a', or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof,
  • R 2 is selected from the group consisting of hydrogen, fluorenyl, decyloxy, halofluorenyl, halodecyloxy, -OH, -NH 2 , halogen, and CN;
  • R 3 is selected from the group consisting of hydrogen, fluorenyl, halofluorenyl, halogen, aminoacyl, monodecylaminoacyl, bis-decylaminoacyl and cyano;
  • R4 is selected from the group consisting of hydrogen, fluorenyl, -OH, hydroxydecyl, halofluorenyl;
  • R6 is selected from the group consisting of hydrogen, acylamino, decylamido, aryl amide, heteroaryl amide, sulfonylamino, decyl sulfonylamino, aryl sulfonylamino, heteroaryl sulfonylamino, said Amido, decyl amido, aryl amide, heteroaryl amide, sulfonylamino, decyl sulfonylamino, aryl sulfonylamino, heteroaryl sulfonylamino can be one or more halogen, hydrazine Substituted, amino, cyano substituted.
  • 1 is selected from the group consisting of hydrogen, fluorenyl, halofluorenyl, halogen and CN.
  • R 2 is selected from the group consisting of hydrogen, fluorenyl, halo fluorenyl, halogen and CN.
  • R 2 is selected from the group consisting of methyl, ethyl, propyl and isopropyl.
  • R 3 is selected from the group consisting of hydrogen, d- 6 fluorenyl, halo d- 6 fluorenyl, halogen, aminoacyl, mono d- 6 fluorenylamino, di d 6 decylamino acyl and cyano .
  • R 3 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoroethyl, halogen and methylamino.
  • R4 is selected from the group consisting of hydrogen, d- 6 fluorenyl, -OH, hydroxy d- 6 fluorenyl, halo d- 6 fluorenyl. In a more preferred embodiment of the invention, R4 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, -OH, hydroxymethyl, hydroxyethyl, hydroxypropyl, trifluoromethyl, trifluoro Ethyl.
  • R 5 is selected from the group consisting of amino, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, dipropylamino, methylethylamino, methylpropyl Amino, ethylpropylamino, formylamino, acetylamino, propionylamino, cyclopropylamido, cyclobutylamido, trifluoroacetamido, methanesulfonylamino, ethanesulfonyl
  • Re is selected from amino, mono d_ 6 alkyl with an amino group, bis d_ 6 alkyl with an amino group, formylamino, acetylamino, propionylamino, amido cyclopropyl, cyclobutyl amido , benzoylamino, trifluoroacetamido, methanesulfonylamino, ethanesulfonylamino, benzenesulfonylamino.
  • Re is selected from the group consisting of amino, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, dipropylamino, methylethylamino, methylpropyl Amino, ethylpropylamino, formylamino, acetylamino, propionylamino, cyclopropylamido, cyclobutylamido, trifluoroacetamido, methanesulfonylamino, ethanesulfonylamino.
  • the present invention provides the following specific compounds:
  • the invention provides a process for the preparation of a compound of the formula of the invention.
  • the preparation of the compound of formula I comprises the following steps:
  • Ri, R 2 , R 3 , R6, X, Y have the meanings in the formula I, and M is selected from the group consisting of chlorine, bromine and iodine.
  • the method for preparing the compound of the formula I-a comprises the following steps:
  • an intermediate of formula 9 is prepared by conventional thiolation, acylation or sulfonylation to give the intermediate of formula 10
  • Ri R 2 R 3 and R 4 have the meanings in the formula Ib, and M is selected from the group consisting of chlorine, bromine and iodine.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof.
  • the invention provides a compound of the invention, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug thereof, and a compound comprising the same, or a pharmaceutically acceptable salt, isomer thereof , solvate, crystal or former
  • a pharmaceutical composition of the medicament for use in the treatment or prevention of cancer including solid tumors and various forms of leukemia, including leukemia resistant to other therapies.
  • the invention provides a pharmaceutical composition comprising a compound, isomer, solvate, crystal or prodrug of the invention, further comprising one or more selected from the group consisting of: tyrosine protease Inhibitors, EGFR inhibitors, VEGFR inhibitors, BCR-ABL inhibitors, c-kit inhibitors, c-Met inhibitors, Raf inhibitors, MEK inhibitors, histone deacetylase inhibitors, VEGF antibodies, EGF antibodies , HIV protein kinase inhibitors, HMG-CoA reductase inhibitors, and the like.
  • tyrosine protease Inhibitors EGFR inhibitors, VEGFR inhibitors, BCR-ABL inhibitors, c-kit inhibitors, c-Met inhibitors, Raf inhibitors, MEK inhibitors, histone deacetylase inhibitors, VEGF antibodies, EGF antibodies , HIV protein kinase inhibitors, HMG-CoA reductase inhibitors, and the like.
  • the compound, isomer, solvate, crystal or prodrug of the present invention may be mixed with a pharmaceutically acceptable carrier, diluent or excipient 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 preparation 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 formulations may be prepared by methods known in the art and comprise carriers, diluents or excipients conventionally employed in the field of pharmaceutical formulations.
  • the present invention provides a method for treating and/or preventing a tumor of a compound, an isomer, a solvate, a crystal or a prodrug of the present invention or a pharmaceutical composition of the present invention and in the preparation of a medicament for preventing and/or treating cancer
  • a compound, isomer, solvate, crystal or prodrug of the invention or a compound, isomer, solvate, crystal or prodrug of the invention to a tumor-prone population or tumor patient
  • the pharmaceutical composition is effective for reducing the incidence of tumors and prolonging the life of tumor patients.
  • the invention provides a method for treating and/or preventing a tumor comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of a compound, isomer, solvate, crystallization of the invention Or a prodrug or a pharmaceutical composition of the invention.
  • the compounds, isomers, solvates, crystals or prodrugs of the invention or pharmaceutical compositions of the invention may be administered to a mammal in need thereof to inhibit tumor growth, progression and/or metastasis, including solid tumors
  • tumor growth, progression and/or metastasis including solid tumors
  • solid tumors for example, breast cancer, colon cancer, gastric cancer, pancreatic cancer, central nervous system tumors and head and neck cancer, and various forms of leukemia, including leukemia and other cancers that are resistant to other treatments such as imatinib or other kinase inhibitors,
  • the kinase is inhibited by a compound or composition of the invention.
  • the "mercapto" of the present invention means a linear, branched or cyclic saturated hydrocarbon group, preferably a d- 6 fluorenyl group.
  • a suitable d- 6 fluorenyl group includes, but is not limited to, a methyl group, an ethyl group, a n-propyl group.
  • Base isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, cyclopentyl, cyclohexyl, n-hexyl.
  • a fluorenyl group in the present invention includes a substituted or unsubstituted fluorenyl group which may be optionally substituted with one or more groups selected from the group consisting of an anthracenyl group, a decyloxy group, an aryloxy group, Anthracene amino, arylamino, halogen, hydroxy, amino, nitro, cyano, decyl acyl, amino acyl, Amidinoyl, sulfonyl, sulfinyl, decyl, aryl or heteroaryl.
  • Firing group of the present invention means alkyl with -0-, preferably d_ 6 alkyl with -0-, more preferably alkyl with -0- d_ 3, d_ 3 alkyl with a suitable -0- methoxy , ethoxy, propoxy, isopropoxy.
  • halogen of the present invention means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • halogenated fluorenyl group of the present invention means a fluorenyl group substituted with at least one halogen, preferably a halogenated d- 6 fluorenyl group, further preferably a halogenated Cw fluorenyl group, and a suitable halogenated d 3 fluorenyl group is a chloromethyl group. , fluoromethyl, dichloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, chloroethyl, fluoroethyl, dichloroethyl, difluoroethyl, trichloroethyl, trifluoro Ethyl.
  • Embankment haloalkoxy group of the present invention means at least one halogen substituted embankment group, preferably at least one halogen substituted embankment d_ 6 group, more preferably a halogeno group d_ 3 embankment, a suitable halide Generation d_ 3 methoxy is chloromethoxy, fluoromethoxy, dichloromethoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy; dichloroethoxy, difluoroethyl Oxy, trichloroethoxy, trifluoroethoxy.
  • the "amido" of the present invention means HC(0)-H-.
  • the "mercaptoamido" of the present invention means fluorenyl-C(0)-H-, preferably d- 6 fluorenyl-C(0)-H-, and more preferably Ci -3 fluorenyl-C(0) - H -.
  • heteroarylamino group of the present invention means a heteroaryl group -C(0)-H-.
  • the "sulfonylamino group" of the present invention means HS(0) 2 -NH -.
  • the "mercaptosulfonylamino group" of the present invention means fluorenyl-S(0) 2 - H -, preferably d_ 6 fluorenyl-S(0) 2 - H - , more preferably . 3 fluorenyl-S ( 0) 2 -NH -.
  • heteroarylsulfonylamino of the present invention means heteroaryl-S(0) 2 -H-.
  • the "aryl group” of the present invention means an aromatic hydrocarbon group containing one or more benzene rings. Suitable aryl groups include phenyl, naphthyl.
  • the "heteroaryl” of the present invention means an aromatic group in which at least one carbon atom of the aryl group is replaced by a hetero atom. The heteroatoms are 0, S, N.
  • the "solvate” of the present invention means, in a conventional sense, a solute (e.g., an active compound, a salt of an active compound) and a solvent.
  • a solute e.g., an active compound, a salt of an active compound
  • Solvent refers to a solvent known or readily determinable by those skilled in the art. In the case of water, the solvate is generally referred to as a hydrate such as a monohydrate, a dihydrate, a trihydrate or the like.
  • Crystalline of the present invention means various solid forms formed by the compounds of the present invention, including crystalline forms and amorphous forms.
  • the "isomer” of the present invention refers to an isomer of the cis or trans configuration of the compound. Accordingly, the invention includes each cis isomer or trans isomer substantially free of other isomers and mixtures of such isomers.
  • 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 a compound of the invention by oxidation, reduction, hydrolysis or the like of the enzyme. And/or a compound which converts to the compound of the invention by a hydrolysis reaction such as gastric acid or the like.
  • the "pharmaceutically acceptable salt” of the present invention means a pharmaceutically acceptable salt formed by the compound of the present invention and an acid, Acids include, but are not limited to, 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, and the like.
  • the "pharmaceutically acceptable carrier” of the present invention means a carrier which does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound, and includes a solvent, a diluent or other excipients, a dispersing agent, a surface. Active agents, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, and the like. Unless any conventional carrier medium is incompatible with the compounds of the invention.
  • Some examples which may be used as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, And cellulose and cellulose acetate; malt, gelatin, and the like.
  • Excipient refers to an inert substance that is added to a pharmaceutical composition to further facilitate administration of the compound.
  • Excipients may include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycol.
  • 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 the tumor can be inhibited, and the therapeutically effective dose is mainly administered to a human or animal in need thereof.
  • the compounds of the invention inhibit, slow or reverse the growth, progression or spread of a tumor in a subject.
  • the compound of the present invention refers to all the compounds of the formula of the present invention, including the formula I, the formula Ia, the formula Ia, the formula Ib, the formula Ia-a, the formula I-a', the formula Ia", A compound of the formula I-b', formula Ib" and formula Ia-a' and specific compounds. detailed description
  • Step 5 3-Trimethylsilylethynyl-4-methyl-N-[4-((4-methylpiperazin-1-yl)methyl);-3-trifluoromethylbenzene Preparation of benzamide
  • the reaction product of the reaction of the step 5 (1.59 g, 3.3 mmol), potassium carbonate (1.82 g, 13.2 mmol), 20 ml of methanol was mixed in the reactor, and the mixture was stirred at room temperature for 3 hours under an inert gas atmosphere.
  • Step 7 3-((2-Methylamino-7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N -[4-((4-methylpiperazine)
  • DIPEA diisopropylethylamine
  • 6 mL of DMF 6 drops were added to the sealed tube. After argon gas was purged for 5 minutes, it was sealed and stirred at 80 ° C overnight. The reactants were placed in a 10 mL sealed tube, DMF was added to half volume, and argon gas was purged for 5 minutes, sealed, and stirred at 80 ° C overnight. The next day, the reaction mixture was washed twice with aqueous ammonia, and the mixture was combined with ethyl acetate.
  • DIPEA diisopropylethylamine
  • Step 1 Preparation of 2-amino-6-bromo-7-methyl-[1,2,4]triazolo[1,5-a]pyridine Starting from 2-amino-4-methyl-5-bromopyridine, the title compound was obtained according to Step 1 and Step 2 of Example 1.
  • IH MR 300 MHz, DMSO-d6) ⁇ : 10.52 (s, IH), 8.87 (s, IH), 8.22 (s, IH), 8.16 (s, IH), 8.07 (d, IH), 7.92 (d , IH), 7.72 (d, IH), 7.53 (d, IH), 7.48 (s, IH), 3.58 (s, 2H), 3.31 (s, 3H), 3.08 (s, 3H), 2.88 (s, 3H), 2.58 (s, 3H), 2.37 (m, 8H), 2.18 (s, 3H).
  • Step 1 Preparation of 2-methylamino-8-methyl-6-bromo-[1,2,4]triazolo[1,5-a]pyridine
  • 2-amino-3-methyl-5-bromopyridine the title compound was obtained according to the procedure 1H MR (300 MHz, OMSO-d 6 ) ⁇ : 8.83-8.79 (m, IH), 7.43 (s, IH), 6.53-6.52 (m, IH), 3.32 (s,
  • Step 2 3-((2-Amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N-[ Preparation of 4-((4-methylpiperazin-1-yl;)methyl; )-3-trifluoromethylphenyl]benzamide
  • Step 2 3-((2-Methylamino-5-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl Preparation of -N-[4-((4-methylpiperazin-1-yl;)methyl;)-3-trifluoromethylphenyl]benzamide
  • Step 2 3-((2-Amino-8-carbamoyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N -[4-((4-Methylpiperazin-1-yl;)methyl;)-3-trifluoromethylphenyl]benzamide
  • Step 2 3-((2-Amino-7-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethynyl)-4-methyl-N-[ Preparation of 4-((4-methylpiperazin-1-yl;)methyl; )-3-trifluoromethylphenyl]benzamide
  • the title compound was prepared by the procedure of Step 1 and Step 2 using 2-amino-4-bromopyridine as the starting material.
  • the title compound was prepared by the procedure of Step 1 to Step 3 using 2-amino-3-bromopyridine as a starting material.
  • Step 2 3-((2-Methylamino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)ethynyl)-4-methyl-N-[4-( Preparation of (4-methylpiperazin-1-yl)methyl; )--trifluoromethylphenyl]benzamide
  • Step 4 3-((2-(2,2,2-Trifluoroacetamideamino)imidazo[1,2-a]pyrazin-7-yl)ethynyl)-4-methyl-N-[4 -((4-methylpiperazin-1-yl;)methyl; )-3-trifluoromethylphenyl]benzamide
  • IH MR 300 MHz, DMS0-d6) ⁇ : 10.84 (s, IH), 10.54 (s, IH), 8.90 (d, IH), 8.22 (d, IH), 8.21 (d, IH), 8.07 (d , IH), 7.98 (d, IH), 7.97 (s, IH), 7.71 (d, IH), 7.55 (s, IH), 7.27 (dd, IH), 3.58 (s, 2H), 2.60 (s, 3H), 2.41 (m, 8H), 2.19 (s, 3H), 2.16 (s, 3H).
  • the product obtained in the first step was 2-cyclopropylformylamino-6-bromo-[1,2,4]triazolo[1,5-a]pyridine and the product obtained in Step 6 of Example 1 was 3-ethynyl- 4-methyl-N-[4-(4-methylpiperazin-1-ylmethyl)-3-trifluoromethylphenyl]benzamide as raw material, according to The target compound was obtained by the method of Step 7 of Example 1.
  • each compound was dissolved in DMSO to 10 mM, diluted to 50 ⁇ M with complete medium, and then diluted to ⁇ with complete medium containing 0.1% DMSO, sequentially diluted 10 times, total 10 Concentration.
  • ⁇ 562 leukemia cells purchased from the United States ATCC company
  • DMSO Dimethyl sulfoxide
  • IMEM medium (IMEM medium), purchased from Gibco, USA;
  • Penicillin/streptomycin (Pen/Strep), purchased from Gibco, USA;
  • Fetal bovine serun purchased from Gibco, USA;
  • 0.25% containing EDTA trypsin (0.25% Trypsin-EDTA), purchased from Gibco, USA;
  • centrifuge tube 50 mL centrifuge tube (50 mL centrifuge tube), purchased from Coming, USA;
  • PBS Phosphate Buffered Saline
  • the compound of the present invention has a strong inhibitory activity on the IC 5Q value of leukemia cells at the nM level (Jia HY, et al. ZD 6474 inhibits Src kinase leading to apoptosis of imatinib- Resistant K562 cells. Leuk Res (2009), doi: 10.1016/j.leukres.2009.03.033) Studies have shown that the IC 50 value of imatinib for K562 cells is 280 nM, H Luo et al (H Luo, et al.
  • HH -GV-678 a novel selective inhibitor of Bcr-Abl, outperforms imatinib and effectively overrides imatinib resistance.
  • imatinib IC 5 on K562 cells The value is 296 nM.
  • the combination of the present invention It has comparable and even better effects to imatinib.
  • This experiment tested the inhibition of ABL (T3151) kinase activity by the compounds prepared in the examples of the present invention, using imatinib as a control.
  • Imatinib was prepared by the method described in Chinese Patent No. CN1043531C and identified by hydrogen spectroscopy and mass spectrometry.
  • ABL (T3151) tyrosine kinase activity was tested using a commercially available human ABL T315I mutant enzyme (Human ABL1 (T315I), active, Cat. No. #14-522, Millipore, USA).
  • Kinase activity assays were performed according to the manufacturer's instructions.
  • the Peptide substrate was Abltide (EAIYAAPFAKKK;), which was purchased from Millipore, USA.
  • Ion exchange chromatography paper P81 (ion exchange filter paper) was purchased from Whatman Company, UK. [ ⁇ -33 ⁇ ] ATP was purchased from Perkin Elmer.
  • the compound of the present invention and imatinib were serially diluted 3 times from ⁇ , respectively, for a total of 10 concentrations (50.8 pM, 152.0 pM, 457.0 pM, 1.37 nM, 4.12 nM, 12.3 nM, 37.0 nM, 111.0 nM, 333.0 nM). And 1.0 ⁇ ).
  • 5.0 ⁇ Abltide was added to each well, followed by human T315I mutant enzyme.
  • [ ⁇ - 33 ⁇ ] ⁇ was added at room temperature, and the final concentration was ⁇ . ⁇ , and the reaction was carried out for 120 minutes.
  • a 20 ⁇ l aliquot was transferred to a P81 ion exchange chromatography paper. The chromatography paper was then washed thoroughly 3 times with a 0.75% phosphoric acid solution and once with acetone.
  • a gamma- 33 ⁇ radioactivity assay was performed. The experimental results are shown in Table 2.
  • the compound of the present invention has not only a very good effect on leukemia cells without mutation, but also a significant inhibition of the T315I mutant enzyme, and thus is a broad-spectrum BCR-ABL inhibitor.
  • TKI tyrosine kinase inhibitor

Abstract

La présente invention concerne les domaines de la chimie et de la médecine, et porte sur un composé ayant une activité inhibitrice de protéine tyrosine kinase et sur un sel, des isomères, des solvates, des cristaux ou des promédicaments associés pharmaceutiquement acceptables. La présente invention concerne en outre un procédé de préparation du composé selon la présente invention, une composition pharmaceutique comprenant le composé selon la présente invention ou un sel, des isomères, des solvates, des cristaux ou des promédicaments associés pharmaceutiquement acceptables, et une application du composé et de la composition selon la présente invention dans des médicaments destinés à traiter ou à prévenir des tumeurs.
PCT/CN2014/083284 2013-07-31 2014-07-30 Inhibiteur de protéine tyrosine kinase et application associée WO2015014283A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201310329248.8A CN104341416B (zh) 2013-07-31 2013-07-31 蛋白酪氨酸激酶抑制剂及其应用
CN201310329248.8 2013-07-31

Publications (1)

Publication Number Publication Date
WO2015014283A1 true WO2015014283A1 (fr) 2015-02-05

Family

ID=52431006

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2014/083284 WO2015014283A1 (fr) 2013-07-31 2014-07-30 Inhibiteur de protéine tyrosine kinase et application associée

Country Status (3)

Country Link
CN (1) CN104341416B (fr)
TW (1) TWI546304B (fr)
WO (1) WO2015014283A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019043635A1 (fr) 2017-09-01 2019-03-07 Richter Gedeon Nyrt. Composés inhibiteurs de l'activité de d-amino acide oxydase
WO2020121263A1 (fr) 2018-12-14 2020-06-18 Yuhan Corporation Triazolopyridin-3-ones ou leurs sels et compositions pharmaceutiques les comprenant

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106749278B (zh) * 2016-12-29 2019-03-26 天津国际生物医药联合研究院 三氮唑类化合物的制备及其应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007075869A2 (fr) * 2005-12-23 2007-07-05 Ariad Pharmaceuticals, Inc. Composes heteroaryles bicycliques
WO2012139027A1 (fr) * 2011-04-07 2012-10-11 Ariad Pharmaceuticals, Inc. Procédés et compositions pour le traitement de maladies neurodégénératives
WO2013101281A1 (fr) * 2011-04-07 2013-07-04 Ariad Pharmaceuticals, Inc. Procédés et compositions pour le traitement de la maladie de parkinson
CN103421005A (zh) * 2012-05-16 2013-12-04 上海医药集团股份有限公司 具有抗肿瘤活性的乙炔衍生物
CN103848829A (zh) * 2012-11-28 2014-06-11 南京圣和药业有限公司 杂芳基炔烃化合物及其应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2477723C2 (ru) * 2011-06-16 2013-03-20 Общество С Ограниченной Ответственностью "Фьюжн Фарма" Ингибиторы протеинкиназ (варианты), их применение для лечения онкологических заболеваний и фармацевтическая композиция на их основе

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007075869A2 (fr) * 2005-12-23 2007-07-05 Ariad Pharmaceuticals, Inc. Composes heteroaryles bicycliques
WO2012139027A1 (fr) * 2011-04-07 2012-10-11 Ariad Pharmaceuticals, Inc. Procédés et compositions pour le traitement de maladies neurodégénératives
WO2013101281A1 (fr) * 2011-04-07 2013-07-04 Ariad Pharmaceuticals, Inc. Procédés et compositions pour le traitement de la maladie de parkinson
CN103421005A (zh) * 2012-05-16 2013-12-04 上海医药集团股份有限公司 具有抗肿瘤活性的乙炔衍生物
CN103848829A (zh) * 2012-11-28 2014-06-11 南京圣和药业有限公司 杂芳基炔烃化合物及其应用

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019043635A1 (fr) 2017-09-01 2019-03-07 Richter Gedeon Nyrt. Composés inhibiteurs de l'activité de d-amino acide oxydase
WO2020121263A1 (fr) 2018-12-14 2020-06-18 Yuhan Corporation Triazolopyridin-3-ones ou leurs sels et compositions pharmaceutiques les comprenant

Also Published As

Publication number Publication date
TW201504239A (zh) 2015-02-01
CN104341416B (zh) 2017-03-29
TWI546304B (zh) 2016-08-21
CN104341416A (zh) 2015-02-11

Similar Documents

Publication Publication Date Title
USRE48731E1 (en) Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
JP6869947B2 (ja) 置換キナゾリン化合物ならびにそのｇ１２ｃ変異ｋｒａｓ、ｈｒａｓおよび／またはｎｒａｓタンパク質の阻害剤としての使用
ES2415863T3 (es) Heterociclos sustituidos como inhibidores de Janus Quinasas
JP6035423B2 (ja) 新規な縮合ピリミジン化合物又はその塩
JP6496301B2 (ja) Ｒａｓ／ｒａｆ／ｍｅｋ／ｅｒｋ経路およびｐｉ３ｋ／ａｋｔ／ｐｔｅｎ／ｍｔｏｒ経路の二重阻害剤としてのキナゾリンおよびアザキナゾリン
EP3600287B1 (fr) Inhibiteurs de réseaux de kinase et leurs utilisations
US20150119392A1 (en) Raf inhibitor compounds
WO2015158310A1 (fr) Inhibiteur de tyrosine kinase et ses utilisations
JP2015520186A (ja) 増殖性疾患の治療にキナーゼ阻害剤として有用なジヒドロナフチリジン及び関連化合物
TW201245161A (en) 1-(arylmethyl)quinazoline-2,4(1H,3H)-diones as PARP inhibitors and the use thereof
WO2014082578A1 (fr) Composé de type hétéroarylalcyne et ses applications
WO2014040549A1 (fr) Composé cyclique hétéroaromatique alcynylique et son application
TWI523856B (zh) BCR-ABL kinase inhibitor and its application
WO2014135028A1 (fr) Composé de pyridopyrimidine ou de pyrimidopyrimidine, procédé de préparation, composition pharmaceutique et utilisation de celui-ci
KR20170045748A (ko) 증식성 질병의 치료를 위한 조성물 및 방법
TW201840564A (zh) 稠合的四環或五環二氫二氮呯幷哢唑酮的鹽的結晶形式及其用途
TW200916458A (en) Heterocyclic compounds and methods of use thereof
WO2017088746A1 (fr) Nouvel inhibiteur de récepteur du facteur de croissance épidermique et son application
ES2709003T3 (es) Compuestos de 5-(piridin-2-il-amino)-pirazina-2-carbonitrilo y su uso terapéutico
KR20200041954A (ko) 화합물, 이의 약제학적 조성물, 및 이의 용도 및 응용
WO2019080723A1 (fr) Dérivé de pyridone polysubstitué, son procédé de préparation et son utilisation médicale
TWI546304B (zh) Protein tyrosine kinase inhibitors and their use
WO2020221209A1 (fr) Inhibiteur de cd73, son procédé de préparation et son utilisation
WO2020077944A1 (fr) Dérivé de purine, son procédé de préparation et son utilisation
WO2016115869A1 (fr) Nouvel inhibiteur de la kinase flt3 et utilisation de ce dernier

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14832906

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14832906

Country of ref document: EP

Kind code of ref document: A1