CN103052641B - Novel condensed ring Hete rocyclic derivatives as c Met inhibitor - Google Patents

Novel condensed ring Hete rocyclic derivatives as c Met inhibitor Download PDF

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CN103052641B
CN103052641B CN201180005362.4A CN201180005362A CN103052641B CN 103052641 B CN103052641 B CN 103052641B CN 201180005362 A CN201180005362 A CN 201180005362A CN 103052641 B CN103052641 B CN 103052641B
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fluoro
phenyl
alkyl
base
compound
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CN103052641A (en
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胡邵京
王飞
龙伟
沈晓燕
谭芬来
王印祥
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Zhejiang Beta Pharma Inc
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Zhejiang Beta Pharma Inc
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Abstract

The present invention relates to a kind of novel condensed ring quinazoline derivant (shown in formula I) as c Met inhibitor and synthesis thereof and the application for the treatment of c Met regulation disorder.Especially, the present invention relates to a kind of fused heterocyclic derivative as c Met inhibitor and synthetic method thereof and the application for the treatment of c Met regulation disorder

Description

Novel condensed ring Hete rocyclic derivatives as c-Met inhibitor
Technical field
The present invention relates to a series of novel condensed ring quinazoline derivant as c-Met inhibitor and preparation method thereof and its The purposes for the treatment of c-Met regulation imbalance.Especially, the present invention relates to the fused ring heterocycle derivant as c-Met inhibitor and Preparation method treats the purposes of c-Met regulation imbalance with it.
Background technology
Because the profit potential that the disease that new molecular targeted agent therapy is relevant to signal transduction pathway produces, make to be correlated with Personnel must have sizable interest to the research of these paths under normal condition and pathological state.
Receptor tyrosine kinase (RTKs) is the tyrosine residue autophosphorylation in activated cell matter and the egg of C-end The key enzyme of the signal transduction pathway of white matter domain.This will produce binding site, and this binding site is to raise downstream egg The signal of white matter and a large amount of cellular events related to including growing, breeding and survive subsequently is propagated.The most general The kinase signal breaking away from regulation is the pathological state of diversification, moves back including immunology, diseases associated with inflammation, cardiovascular disease and nerve The property changed disease.Known receptor tyrosine kinase includes 20 families, and a lot of receptor tyrosine kinase is relevant to cancer (Blume-Jensen P et al,2001.Nature 411355-365).C-Met is the subtribe of receptor tyrosine kinase, should Receptor tyrosine kinase (RTKs) includes protein and its chicken homoreceptor that macrophage stimulating protein receptor (Ron) is relevant (Sea).Endogenic ligand is growth and motion gene hepatocyte growth factor (HGF is also known as invasin).C-Met and The expression of HGF is interrelated, although their expression is typically limited to the cell tissue of epithelial cell and mesenchymal origin.On the contrary, Tumor cell is usually expressed in the c-Met of activation.
Now, have more and more derive from zooscopy and cancer patient, convincing evidence shows: pernicious swollen In the development of tumor and progress, HGF-Met signal has played important function, and especially relevant with the malignant tumor of invasion type.Very In many cancer patients, c-Met and HGF is relative to surrounding tissue high expressed, and their expression is the best to patient's prognosis relevant, (Jiang,W et al.1999Crit.Rev.Oncol.-hematol.,29,209-248.).Swashing of c-Met kinase domain Site mutation of living relates to sporadic and genetic emulsus renal carcinoma section (Danilkovitch-Miagkova, A et al 2002.1J.Clin.Invest.109,863-867) .c-Met is the labelling of cancer and malignant tumor, and c-Met-HGF letter Number conduction depressant drug may improve the progression of disease of associated cancer.
Summary of the invention
Know that a kind of novel condensed ring quinazoline derivant is effective inhibitor of c-Met, it is an object of the invention to carry For a kind of new compound that can suppress c-Met activity.Shown in the general structure of this compound such as formula (I):
Or they pharmaceutically acceptable salts, hydrate, solvate or prodrug,
Wherein,
A is the ring of 5-18 unit；
R1Independently selected from hydrogen, halogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C2-8Thiazolinyl, replacement Or unsubstituted C2-8Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted miscellaneous Cycloalkyl, C1-8Alkanoyl, C1-8Alkoxy carbonyl, C1-8Alkylsulfinyl, C1-8Alkyl sulphonyl, aryl sulfonyl, cyano group, Nitro, hydroxyl, amido, carboxyl, oxo base, aminoacyl, C1-8Alkoxyl, C2-8Alkenyloxy group, C2-8Alkynyloxy group, C1-8Alkylthio group, N-(C1-8Alkyl) aminoacyl, N, N-bis-(C1-8Alkyl) aminoacyl, C1-8Alkanoic acid ester group, C1-8Alkyl amide, C3-8Alkynyl amide Base, N-(C1-8Alkyl) amino-sulfonyl or N, N-bis-(C1-8Alkyl) amino-sulfonyl；
M is the integer of 0-3；
A1And A2Independently selected from :=N-or=C (R2)-；
A3It is selected from :=N-,=C (H)-or=C (CN)-；
X is selected from NR20、CHR21, O or S；Described R20And R21Independently selected from H or Cl-8Alkyl；
R2Selected from-H, halogen, trichloromethyl ,-CN ,-NO2、-NH2、-OR5、-NR5R6、-S(O)0-2R5、-SO2NR5R6、- CO2R5、-C(O)NR5R6、-N(R3)SO2R5、-N(R5)C(O)R6、-N(R5)CO2R6、-C(O)R5Or it is substituted or unsubstituted rudimentary Alkyl；
N is the integer of 0-4；
Z is selected from NR3R4Or the group shown in formula (II):
R3Independently selected from hydrogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C2-8Thiazolinyl, replacement or do not take The C in generation2-8Alkynyl, substituted or unsubstituted C1-8Alkanoyl, substituted or unsubstituted C1-8Alkoxy carbonyl, C1-8Alkyl thionyl Base, C1-8Alkyl sulphonyl, aryl sulfonyl, cyano group, nitro, hydroxyl, amido, carboxyl, oxo base, aminoacyl, C1-8Alcoxyl Base, C2-8Alkenyloxy group, C2-8Alkynyloxy group, C1-8Alkylthio group, N-(C1-8Alkyl) aminoacyl, N, N-bis-(C1-8Alkyl) aminoacyl, C1-8Alkanoic acid ester group, C1-8Alkyl amide, C3-8Alkynyl amide base, N-(C1-8Alkyl) amino-sulfonyl or N, N-bis-(C1-8Alkyl) ammonia Base sulfonyl；
Another embodiment, R4Selected from the group shown in formula (III):
B1It is
Q1It is C (R5)2；
B2It is NHQ2；
Q2Selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycle alkane Base, substituted or unsubstituted C1-8Alkylaryl, substituted or unsubstituted C1-8Alkyl heterocycle aryl or substituted or unsubstituted C1-8 Base Heterocyclylalkyl；
B1And B2Form the 5-10 substituted or unsubstituted heterocyclic aryl of unit or substituted or unsubstituted Heterocyclylalkyl together；
R5And R6Independently selected from hydrogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C2-8Thiazolinyl, replacement or Unsubstituted C2-8Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycle Alkyl, C1-8Alkanoyl, C1-8Alkoxy carbonyl, C1-8Alkylsulfinyl, C1-8Alkyl sulphonyl, aryl sulfonyl, cyano group, nitre Base, hydroxyl, amido, carboxyl, oxo base, aminoacyl, C1-8Alkoxyl, C2-8Alkenyloxy group, C2-8Alkynyloxy group, C1-8Alkylthio group, N- (C1-8Alkyl) aminoacyl, N, N-bis-(C1-8Alkyl) aminoacyl, substituted or unsubstituted C1-8Alkylaryl, replacement or not Substituted C1-8Alkyl heterocycle aryl or substituted or unsubstituted C1-8Alkyl cycloheteroalkyl, and pharmaceutically acceptable salt；
Another more excellent embodiment, A ring comprises 0-6 the hetero atom selected from O, S or N further.
One more excellent embodiment, R1Selected from hydrogen, halogen, C1-8Alkyl, C2-8Thiazolinyl, C2-8Alkynyl, aryl, heterocyclic aryl, Heterocyclylalkyl (heterocyclyl), (halogen)1-3(C1-8) alkyl, hydroxyl (C1-8) alkyl, C1-4Alkoxyl (C1-8) alkyl, cyanogen Base (C1-8) alkyl, amido (C1-8) alkyl, aryl (C1-8) alkyl, heterocyclic aryl (C1-8) alkyl, Heterocyclylalkyl (C1-8) alkyl, (halogen)1-3(C2-8) thiazolinyl, hydroxyl (C2-8) thiazolinyl, C1-4Alkoxyl (C2-8) thiazolinyl, cyano group (C2-8) thiazolinyl, amido (C2-8) alkene Base, aryl (C2-8) thiazolinyl, heterocyclic aryl (C2-8) thiazolinyl, Heterocyclylalkyl (C2-8) thiazolinyl, (halogen)1-3(C2-8) alkynyl, hydroxyl (C2-8) alkynyl, C1-4Alkoxyl (C2-8) alkynyl, cyano group (C2-8) alkynyl, amido (C2-8) alkynyl, aryl (C2-8) alkynyl, heterocycle virtue Base (C2-8) alkynyl, Heterocyclylalkyl (C2-8) alkynyl, C1-8Alkanoyl, aryl (C1-8) alkanoyl, heterocyclic aryl (C1-8) alkanoyl, Heterocyclylalkyl (C1-8) alkanoyl, C1-8Alkoxy carbonyl, aryl (C1-8) alkoxy carbonyl, heterocyclic aryl (C1-8) alkoxyl carbonyl Base, Heterocyclylalkyl (C1-8) alkoxy carbonyl, C1-8Alkylsulfinyl, C1-8Alkyl sulphonyl, aryl sulfonyl, aryl (C1-8) Alkyl sulphonyl, heterocyclic aryl (C1-8) alkyl sulphonyl, Heterocyclylalkyl (C1-8) alkyl sulphonyl, aryl, heterocyclic aryl, heterocycle Alkyl, cyano group, nitro, hydroxyl, amido, carboxyl, oxo base, aminoacyl, C1-8Alkoxyl, C2-8Alkenyloxy group, C2-8Alkynyloxy group, C1-8Alkylthio group, N-(C1-8Alkyl) aminoacyl, N, N-bis-(C1-8Alkyl) aminoacyl, C1-8Alkanoic acid ester group, C1-8Alkane amide Base, C3-8Alkynyl amide base, N-(C1-8Alkyl) amino-sulfonyl and N, N-bis-(C1-8Alkyl) amino-sulfonyl.
Another more excellent embodiment, above-mentioned R1On amido, amido (C1-8) alkyl, amido (C2-8) thiazolinyl or amido (C2-8) alkynyl by two independently selected from hydrogen, C1-8Alkyl, C2-8Thiazolinyl or C2-8The substituent group of alkynyl replaces.
Another more excellent embodiment, above-mentioned R1On any aryl, heterocyclic aryl or Heterocyclylalkyl can be at random by 1-3 Individual independently selected from halogen, trifluoromethyl, cyano group, nitro, hydroxyl, amido, carboxyl, aminoacyl, (C1-8) alkyl, (C2-8) alkene Base, (C2-8) alkynyl or (C1-8) alkoxyl substituent group replace.
Another more excellent embodiment, R3Independently selected from hydrogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C2-8Thiazolinyl, substituted or unsubstituted C2-8Alkynyl, C1-8Alkanoyl, C1-8Alkoxy carbonyl, C1-8Alkylsulfinyl, C1-8Alkyl Sulfonyl, aryl sulfonyl, cyano group, nitro, hydroxyl, amido, carboxyl, oxo base, aminoacyl, C1-8Alkoxyl, C2-8Alkene oxygen Base, C2-8Alkynyloxy group, C1-8Alkylthio group, N-(C1-8Alkyl) aminoacyl, N, N-bis-(C1-8Alkyl) aminoacyl, C1-8Alkanoic acid ester Base, C1-8Alkyl amide, C3-8Alkynyl amide base, N-(C1-8Alkyl) amino-sulfonyl and N, N-bis-(C1-8Alkyl) amino-sulfonyl.
Another more excellent embodiment, R4Selected from the compound shown in formula (IV):
Wherein,
Q3Selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycle alkane Base, substituted or unsubstituted C1-8Alkylaryl, substituted or unsubstituted C1-8Alkyl heterocycle aryl, substituted or unsubstituted C1-8 Alkyl cycloheteroalkyl.
Another more excellent embodiment, R7And R8Independently selected from hydrogen, halogen, substituted or unsubstituted C1-8Alkyl, replacement or Unsubstituted C2-8Thiazolinyl, substituted or unsubstituted C2-8Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle virtue Base, substituted or unsubstituted Heterocyclylalkyl, C1-8Alkanoyl, C1-8Alkoxy carbonyl, C1-8Alkylsulfinyl, C1-8Alkyl sulfonyl Base, aryl sulfonyl, cyano group, nitro, hydroxyl, amido, carboxyl, oxo base, aminoacyl, C1-8Alkoxyl, C2-8Alkenyloxy group, C2-8Alkynyloxy group, C1-8Alkylthio group, N-(C1-8Alkyl) aminoacyl, N, N-bis-(C1-8Alkyl) aminoacyl, C1-8Alkanoic acid ester group, C1-8Alkyl amide, C3-8Alkynyl amide base, N-(C1-8Alkyl) amino-sulfonyl and N, N-bis-(C1-8Alkyl) amino-sulfonyl, replacement Or unsubstituted C1-8Alkylaryl, substituted or unsubstituted C1-8Alkyl heterocycle aryl, substituted or unsubstituted C1-8Alkyl heterocycle Alkyl.
Another more excellent embodiment, R3Independently selected from hydrogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C2-8Thiazolinyl, substituted or unsubstituted C2-8Alkynyl, C1-8Alkanoyl, C1-8Alkoxy carbonyl, C1-8Alkylsulfinyl, C1-8Alkyl Sulfonyl, aryl sulfo group, cyano group, nitro, hydroxyl, amido, carboxyl, oxo base, aminoacyl, C1-8Alkoxyl, C2-8Alkenyloxy group, C2-8Alkynyloxy group, C1-8Alkylthio group, N-(C1-8Alkyl) aminoacyl, N, N-bis-(C1-8Alkyl) aminoacyl, C1-8Alkanoic acid ester group, C1-8Alkyl amide, C3-8Alkynyl amide base, N-(C1-8Alkyl) amino-sulfonyl and N, N-bis-(C1-8Alkyl) amino-sulfonyl.
Another more excellent embodiment, R4Selected from the compound shown in formula (V):
Wherein,
Q3Selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycle alkane Base, substituted or unsubstituted C1-8Alkylaryl, substituted or unsubstituted C1-8Alkyl heterocycle aryl, substituted or unsubstituted C1-8 Alkyl cycloheteroalkyl.
X1Selected from NR8Or CR7R8。
R7And R8Independently selected from hydrogen, halogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C2-8Thiazolinyl, take Generation or unsubstituted C2-8Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted Heterocyclylalkyl, C1-8Alkanoyl, C1-8Alkoxy carbonyl, C1-8Alkylsulfinyl, C1-8Alkyl sulphonyl, aryl sulfonyl, cyanogen Base, nitro, hydroxyl, amido, carboxyl, oxo base, aminoacyl, C1-8Alkoxyl, C2-8Alkenyloxy group, C2-8Alkynyloxy group, C1-8Alkane sulfur Base, N-(C1-8Alkyl) aminoacyl, N, N-bis-(C1-8Alkyl) aminoacyl, C1-8Alkanoic acid ester group, C1-8Alkyl amide, C3-8Alkynes Amide groups, N-(C1-8Alkyl) amino-sulfonyl and N, N-bis-(C1-8Alkyl) amino-sulfonyl, substituted or unsubstituted C1-8Alkyl Aryl, substituted or unsubstituted C1-8Alkyl heterocycle aryl, substituted or unsubstituted C1-8Alkyl cycloheteroalkyl.
Another more excellent embodiment, R3Independently selected from hydrogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C2-8Thiazolinyl, substituted or unsubstituted C2-8Alkynyl, C1-8Alkanoyl, C1-8Alkoxy carbonyl, C1-8Alkylsulfinyl, C1-8Alkyl Sulfonyl, aryl sulfonyl, cyano group, nitro, hydroxyl, amido, carboxyl, oxo base, aminoacyl, C1-8Alkoxyl, C2-8Alkene oxygen Base, C2-8Alkynyloxy group, C1-8Alkylthio group, N-(C1-8Alkyl) aminoacyl, N, N-bis-(C1-8Alkyl) aminoacyl, C1-8Alkanoic acid ester Base, C1-8Alkyl amide, C3-8Alkynyl amide base, N-(C1-8Alkyl) amino-sulfonyl and N, N-bis-(C1-8Alkyl) amino-sulfonyl.
Another more excellent embodiment, R4Selected from the compound shown in formula (VI):
Wherein,
Q3Selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycle alkane Base, substituted or unsubstituted C1-8Alkylaryl, substituted or unsubstituted C1-8Alkyl heterocycle aryl, substituted or unsubstituted C1-8 Alkyl cycloheteroalkyl.
R7And R8Independently selected from hydrogen, halogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C2-8Thiazolinyl, take Generation or unsubstituted C2-8Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted Heterocyclylalkyl, C1-8Alkanoyl, C1-8Alkoxy carbonyl, C1-8Alkylsulfinyl, C1-8Alkyl sulphonyl, aryl sulfonyl, cyanogen Base, nitro, hydroxyl, amido, carboxyl, oxo base, aminoacyl, C1-8Alkoxyl, C2-8Alkenyloxy group, C2-8Alkynyloxy group, C1-8Alkane sulfur Base, N-(C1-8Alkyl) aminoacyl, N, N-bis-(C1-8Alkyl) aminoacyl, C1-8Alkanoic acid ester group, C1-8Alkyl amide, C3-8Alkynes Amide groups, N-(C1-8Alkyl) amino-sulfonyl and N, N-bis-(C1-8Alkyl) amino-sulfonyl, C1-8Alkanoic acid ester group, C1-8Alkane amide Base, C3-8Alkynyl amide base, N-(C1-8Alkyl) amino-sulfonyl, N, N-bis-(C1-8Alkyl) amino-sulfonyl, substituted or unsubstituted C1-8Alkylaryl, substituted or unsubstituted C1-8Alkyl heterocycle aryl, substituted or unsubstituted C1-8Alkyl cycloheteroalkyl.
Another more excellent embodiment, R4Selected from the compound shown in formula (VII):
Wherein,
Q3Selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycle alkane Base, substituted or unsubstituted C1-8Alkylaryl, substituted or unsubstituted C1-8Alkyl heterocycle aryl, substituted or unsubstituted C1-8 Alkyl cycloheteroalkyl.
R7、R8And R11Independently selected from hydrogen, halogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C2-8Alkene Base, substituted or unsubstituted C2-8Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, replacement or do not take The Heterocyclylalkyl in generation, C1-8Alkanoyl, C1-8Alkoxy carbonyl, C1-8Alkylsulfinyl, C1-8Alkyl sulphonyl, arylsulfonyl Base, cyano group, nitro, hydroxyl, amido, carboxyl, oxo base, aminoacyl, C1-8Alkoxyl, C2-8Alkenyloxy group, C2-8Alkynyloxy group, C1-8 Alkylthio group, N-(C1-8Alkyl) aminoacyl, N, N-bis-(C1-8Alkyl) aminoacyl, C1-8Alkanoic acid ester group, C1-8Alkyl amide, C3-8Alkynyl amide base, N-(C1-8Alkyl) amino-sulfonyl and N, N-bis-(C1-8Alkyl) amino-sulfonyl, substituted or unsubstituted C1-8Alkylaryl, substituted or unsubstituted C1-8Alkyl heterocycle aryl, substituted or unsubstituted C1-8Alkyl cycloheteroalkyl.
R9And R10Independently selected from substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C2-8Thiazolinyl, replacement or not Substituted C2-8Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycle alkane Base, C1-8Alkanoyl, C1-8Alkoxy carbonyl, C1-8Alkylsulfinyl, (C1-8) alkyl sulphonyl, aryl sulfonyl.
Another more excellent embodiment, A is 6-18 ring.
Another more excellent embodiment, A is 5-8 ring.
Another more excellent embodiment, A is 5 or 12 rings.
Another more excellent embodiment, A is 12 yuan of heterocycles.
Another more excellent embodiment, A is the 12 yuan of heterocycles comprising 1,2,3 or 4 oxygen atoms.
Another more excellent embodiment, A is the 12 yuan of heterocycles comprising 4 oxygen atoms.
Another more excellent embodiment, A is
Another more excellent embodiment, RlSelected from hydrogen, halogen, substituted or unsubstituted C1-5Alkyl, substituted or unsubstituted C2-5Thiazolinyl, substituted or unsubstituted C2-5Alkynyl, C1-5Alkanoyl, C1-5Alkoxy carbonyl, C1-5Alkylsulfinyl, C1-5Alkyl Sulfonyl, Cl-5Alkoxyl, C2-5Alkenyloxy group, C2-5Alkynyloxy group, C1-5Alkylthio group, N-(C1-5Alkyl) amino-sulfonyl, N, N-bis- (C1-5Alkyl) amino-sulfonyl, Cl-5Alkanoic acid ester group, Cl-5Alkyl amide, C3-6Alkynyl amide base, N-(C1-5Alkyl) amino-sulfonyl Or N, N-bis-(C1-5Alkyl) amino-sulfonyl.
Another more excellent embodiment, RlSelected from hydrogen, halogen, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle Aryl, substituted or unsubstituted Heterocyclylalkyl, aryl sulfonyl, cyano group, nitro, hydroxyl, amido, carboxyl, oxo base or amino Acyl group.
Another more excellent embodiment, RlSelected from hydrogen or halogen.
Another more excellent embodiment, RlIt is hydrogen.
Another more excellent embodiment, m is the integer of 0-2.
Another more excellent embodiment, m is 0.
Another more excellent embodiment, A2It is=N-.
Another more excellent embodiment, A1It is=C (R2)-, A2It is=N-.
Another more excellent embodiment, A1It is=CH-, A2It is=N-.
Another more excellent embodiment, A1And A2It is=C (R2)-。
Another more excellent embodiment, A1And A2It is=CH-.
Another more excellent embodiment, A3Selected from=N-or=C (H)-.
Another more excellent embodiment, X is selected from NR20Or CHR21, R20And R21Independently selected from H or Cl-3Alkyl.
Another more excellent embodiment, X is selected from NR20Or CHR21, R20And R21It is H.
Another more excellent embodiment, X is selected from oxygen or sulfur.
Another more excellent embodiment, X is oxygen.
Another more excellent embodiment, R2Selected from-H, halogen, trihalomethyl ,-CN ,-NO2Or-NH2。
Another more excellent embodiment, R2Selected from-H or halogen.
Another more excellent embodiment, R2Selected from fluorine or hydrogen.
Another more excellent embodiment, R2Selected from-OR5、-NR5R6、-S(O)0-2R5、-SO2NR5R6、-CO2R5、-C(O) NR5R6、-N(R3)SO2R5、-N(R5)C(O)R6、-N(R5)CO2R6Or-C (O) R5。
Another more excellent embodiment, R2Selected from substituted low alkyl group ,-CN ,-NO2Or-NH2。
Another more excellent embodiment, R3Selected from substituted or unsubstituted C1-5Alkyl, substituted or unsubstituted C2-5Thiazolinyl, take Generation or unsubstituted C2-5Alkynyl, C1-5Alkanoyl, substituted or unsubstituted C1-5Alkoxy carbonyl, C1-5Alkylsulfinyl, C1-5 Alkyl sulphonyl, Cl-5Alkoxyl, C2-5Alkenyloxy group, C2-5Alkynyloxy group, C1-5Alkylthio group, N-(C1-5Alkyl) amino-sulfonyl, N, N- Two (C1-5Alkyl) amino-sulfonyl, Cl-5Alkanoic acid ester group, Cl-5Alkyl amide, C3-6Alkynyl amide base, N-(C1-5Alkyl) aminosulfonyl Base or N, N-bis-(C1-5Alkyl) amino-sulfonyl.
Another more excellent embodiment, R3Selected from substituted or unsubstituted C1-3Alkyl, substituted or unsubstituted C2-3Thiazolinyl, take Generation or unsubstituted C2-3Alkynyl, C1-3Alkanoyl, substituted or unsubstituted C1-3Alkoxy carbonyl, C1-3Alkylsulfinyl, C1-3 Alkyl sulphonyl, Cl-3Alkoxyl, C2-3Alkenyloxy group, C2-3Alkynyloxy group, C1-3Alkylthio group, N-(C1-3Alkyl) amino-sulfonyl, N, N- Two (C1-3Alkyl) amino-sulfonyl, Cl-3Alkanoic acid ester group, Cl-3Alkyl amide, N-(C1-3Alkyl) amino-sulfonyl, C4-6Alkynyl amide Base or N, N-bis-(C1-3Alkyl) amino-sulfonyl.
Another more excellent embodiment, R3Selected from substituted or unsubstituted C1-3Alkoxy carbonyl, C1-3Alkylsulfinyl, C1-3Alkyl sulphonyl, Cl-3Alkoxyl, C2-3Alkenyloxy group, C2-3Alkynyloxy group or C1-3Alkylthio group.
Another more excellent embodiment, R3It is hydrogen.
Another more excellent embodiment, Q1It is CH2。
Another more excellent embodiment, Q2It is substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl or replacement Or unsubstituted Heterocyclylalkyl.
Another more excellent embodiment, Q2Selected from halogenophenyl.
Another more excellent embodiment, Q2It it is difluorophenyl.
Another more excellent embodiment, Q2Selected from substituted or unsubstituted C1-5Alkylaryl, substituted or unsubstituted C1-5Alkane Base heterocyclic aryl or substituted or unsubstituted C1-5Alkyl cycloheteroalkyl.
Another more excellent embodiment, B1And B2Together formed 5-10 unit substituted or unsubstituted heterocyclic aryl, replace or not Substituted Heterocyclylalkyl.
Another more excellent embodiment, Q3Selected from substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic aryl.
Another more excellent embodiment, Q3Selected from substituted or unsubstituted phenyl.
Another more excellent embodiment, Q3Selected from phenyl or halogenophenyl.
Another more excellent embodiment, Q3Selected from difluorophenyl.
Another more excellent embodiment, X1Selected from NR8。
Another more excellent embodiment, X1Selected from NC1-6Alkyl.
Another more excellent embodiment, X1It is NCH3。
Another more excellent embodiment, R7、R8And R11Independently selected from hydrogen, halogen or substituted or unsubstituted C1-8Alkyl.
Another more excellent embodiment, R7、R8And R11Independently selected from substituted or unsubstituted C2-5Thiazolinyl, replacement or do not take The C in generation2-5Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted Heterocyclylalkyl, C1-5Alkanoyl, C1-5Alkoxy carbonyl, N-(C1-5Alkyl) aminoacyl, N, N bis-(C1-5Alkyl) aminoacyl, C1-5Alkanoic acid ester Base, aryl sulfonyl, cyano group, nitro, hydroxyl, amido, carboxyl, oxo base, aminoacyl, C1-5Alkoxyl, C2-5Alkenyloxy group, C2-5Alkynyloxy group, C1-5Alkylthio group, C1-5Alkyl amide, C3-5Alkynyl amide base, N-(C1-5Alkyl) amino-sulfonyl, N, N-bis-(C1-5 Alkyl) amino-sulfonyl, substituted or unsubstituted C1-5Alkylaryl, substituted or unsubstituted C1-5Alkyl heterocycle aryl, or take Generation or unsubstituted C1-5Alkyl cycloheteroalkyl.
Another more excellent embodiment, R7、R8And R11It is hydrogen.
Another more excellent embodiment, R7It is C1-6Alkyl.
Another more excellent embodiment, R7It is-CH3。
Another more excellent embodiment, R7Selected from phenyl or halogenophenyl.
Another more excellent embodiment, R7Selected from difluorophenyl.
Another more excellent embodiment, R8It is hydrogen.
Another more excellent embodiment, R5And R6Independently selected from hydrogen, substituted or unsubstituted C1-6Alkyl, replacement or unsubstituted C2-6Thiazolinyl or substituted or unsubstituted C2-6Alkynyl.
Another more excellent embodiment, R5And R6It is hydrogen.
Another more excellent embodiment, R5And R6Independently selected from C1-5Alkanoyl, C1-5Alkoxy carbonyl, C1-5Alkyl thionyl Base or C1-5Alkyl sulphonyl.
Another more excellent embodiment, R5And R6Independently selected from cyano group, nitro, hydroxyl, amido, carboxyl, oxo base or amino Acyl group.
Another more excellent embodiment, R5And R6Independently selected from cyano group, nitro, hydroxyl or amido.
Another more excellent embodiment, R9And R10Independently selected from substituted or unsubstituted C1-6Alkyl or replacement or unsubstituted C6-12Aryl.
Another more excellent embodiment, R9And R10Independently selected from halo C6-12Aryl or unsubstituted C1-6Alkyl.
Another more excellent embodiment, R9And R10Independently selected from methyl or halogenophenyl.
Another more excellent embodiment, R9And R10Independently selected from methyl or difluorophenyl.
The following compound that the present invention provides, can make reader be more fully understood that the compound that the present invention is contained:
5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyrido-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14-six Hydrogen
-6,9,12,15-four oxygen-1,3-diaza-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide；
1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyrido-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14-six Hydrogen
-6,9,12,15-four oxygen-1,3-diaza-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide；
Cyclopropyl-1,1-dicarboxylic acids [the fluoro-4-of 3-(7,8,10,11,13,14-hexahydro-6,9,12,15-four oxygen-1,3-two Azepine-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide (4-fluoro-phenyl)-amide；
3-(4-fluoro-phenyl)-2-oxo-imidazol quinoline-1-carboxylic acid [the fluoro-4-of 3-(7,8,10,11,13,14-hexahydro-6,9, 12,15-tetra-oxygen
-1,3-diaza-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide；
2-(4-fluoro-phenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1 h-pyrazole-4-carboxylic acid [3-fluorine
-4-(7,8,10,11,13,14-hexahydro-6,9,12,15-four oxygen-1,3-diaza-cyclododecane [b] naphthalene-4-oxygen Base)-phenyl]-amide；
2-(4-fluoro-phenyl amino)-5-[5-(7,8,10,11,13,14-hexahydro-6,9,12,15-four oxygen-1,3-phenodiazine Miscellaneous-cyclododecane [b] naphthalene-4-epoxide)-pyridine-2-base]-3-methyl-3H-pyrimidin-4-one；
5-[5-([1,3] dioxy [4,5-g] quinazoline-8-epoxide)-pyridine-2-base]-2-(4-fluoro-phenyl amino)-3- Methyl-3H-pyrimidin-4-one；
5-[5-(2,2-bis-fluoro-[1,3] dioxy [4,5-g] quinazoline-8-epoxide)-pyridine-2-base]-2-(4-fluoro-phenyl Amino)-3-methyl-3H-pyrimidin-4-one；
5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyrido-3-carboxylic acid [4-([1,3] dioxy [4,5-g] quinazoline- 8-epoxide)-3-fluoro-phenyl]-amide；
5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyrido-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14-six Hydrogen-6,9,12,15-four oxygen-1-azepine-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide；
1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyrido-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14-six Hydrogen-6,9,12,15-four oxygen-1-azepine-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide；
2-(4-fluoro-phenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1 h-pyrazole-4-carboxylic acid [the fluoro-4-of 3-(7,8, 10,11,13,14-hexahydro-6,9,12,15-four oxygen-1-azepine-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide；
Cyclopropyl-1,1-dicarboxylic acids [the fluoro-4-of 3-(7,8,10,11,13,14-hexahydro-6,9,12,15-four oxygen-1-azepine- Cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide (4-fluoro-phenyl)-amide；
3-(4-fluoro-phenyl)-2-oxo-imidazol quinoline-1-carboxylic acid [the fluoro-4-of 3-(7,8,10,11,13,14-hexahydro-6,9, 12,15-tetra-oxygen-1-azepine-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide
5-[5-(2,2-bis-fluoro-[1,3] dioxy [4,5-g] quinazoline-8-epoxide)-pyridine-2-base]-2-(2-fluoro-phenyl Amino)-3-methyl-3H-pyrimidin-4-one；
5-[5-(2,2-bis-fluoro-[1,3] dioxy [4,5-g] quinazoline-8-epoxide)-pyridine-2-base]-2-(phenylamino Base)-3-methyl-3H-pyrimidin-4-one；
5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyrido-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14-six Hydrogen-6,9,12,15-four oxygen-1-azepine-cyclododecane [b] naphthalene-4-amino)-phenyl]-amide；
5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyrido-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14-six Hydrogen-6,9,12,15-four oxygen-1-azepine-cyclododecane [b] naphthalene-4-sulfydryl)-phenyl]-amide；
3-methyl-2-phenyl amino-5-[5-(2,5,7,10-tetra-oxygen-14,16-diaza-three ring [9.8.0.013,18] Nonadecane-1 (11), 12,14,16,18-five thiazolinyl-17-epoxide)-pyridine-2-base]-3H-pyrimidin-4-one；
5-[5-([8,9] dihydro-7H-6,10-dioxy-1,3-diaza-cycloheptane [b] naphthalene-4-epoxide)-pyridine-2- Base]-2-(4-fluoro-phenyl amino)-3-methyl-3H-pyrimidin-4-one；
2-(4-fluoro-phenyl amino)-3-methyl-5-[5-(9-methyl-8,9,10,11-tetrahydrochysene-7H-6,12-dioxy-1, 3,9-tri-azepines-cyclononane [b] naphthalene-4-epoxide)-pyridine-2-base]-3H-pyrimidin-4-one；
2-(4-fluoro-phenyl amino)-3-methyl-5-[5-(7,8,10,11-tetrahydrochysene-6,9,12-three oxygen-1,3-diaza- Cyclononane [b] naphthalene-4-epoxide)-pyridine-2-base]-3H-pyrimidin-4-one；
5-[5-(8,9-dihydro-7H-6,10-dioxy-1-azepine-cycloheptane [b] naphthalene-4-epoxide)-pyridine-2-base]-2- (4-fluoro-phenyl amino)-3-methyl-3H-pyrimidin-4-one；
2-(4-fluoro-phenyl amino)-3-methyl-5-[5-(9-methyl-8,9,10,11-tetrahydrochysene-7H-6,12-dioxy-1, 9-diaza-cyclononane [b] naphthalene-4-epoxide)-pyridine-2-base]-3H-pyrimidin-4-one；
2-(4-fluoro-phenyl amino)-3-methyl-5-[5-(7,8,10,11-tetrahydrochysene-6,9,12-three oxygen-1-azepine-ring nonyl Alkane [b] naphthalene-4-epoxide)-pyridine-2-base]-3H-pyrimidin-4-one；
3-methyl-2-phenyl amino-5-[5-(2,5,7,10-tetra-oxygen-14-azepine-three ring [9.8.0.013,18] 19 Alkane-1 (11), 12,14,16,18-five thiazolinyl-17-epoxide)-pyridine-2-base]-3H-pyrimidin-4-one；
5-[5-(2,2-bis-fluoro-[1,3] dioxy [4,5-g] quinoline-8-epoxide)-pyridine-2-base]-2-(2-fluoro-phenyl ammonia Base)-3-methyl-3H-pyrimidin-4-one；
5-[5-(2,2-bis-fluoro-[1,3] dioxy [4,5-g] quinoline-8-epoxide)-pyridine-2-base]-2-(phenyl amino)- 3-methyl-3H-pyrimidin-4-one；
5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyrido-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14-six Hydrogen-6,9,12,15-four oxygen-1,3-diaza-cyclododecane [b] naphthalene-4-amino)-phenyl]-amide；
5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyrido-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14-six Hydrogen-6,9,12,15-four oxygen-1,3-diaza-cyclododecane [b] naphthalene-4-sulfydryl)-phenyl]-amide；
5-[5-(2,5,8,11,14,17-six oxygen-21-azepine-three ring [16.8.0.020,25] hexacosane-1 (18), 19,21,23,25-five thiazolinyl-24-epoxide)-pyridine-2-base]-3-methyl-2-phenyl amino-3H-pyrimidin-4-one.
On the other hand, present invention also offers a kind of pharmaceutical composition: comprise at least one above-claimed cpd and pharmaceutically Acceptable excipient.Term " pharmaceutically acceptable excipient " refers to be applied at least one chemical combination of the present invention arbitrarily Present invention also offers the optimal technical scheme of technique scheme:
Described compound is 0.0001-10:1 with the weight ratio of described excipient.
Invention further provides at least one compound shown in aforementioned pharmaceutical compositions and formula (I) prepares medicine Application.
Present invention also offers the optimal technical scheme of above-mentioned application:
Prepared medicine is for treatment or prophylaxis of cancer, cancer metastasis, cardiovascular disease, immunologic derangement or visual disorders Purposes.
Prepared medicine is used for delaying or prophylaxis of cancer, cancer metastasis, cardiovascular disease, immunologic derangement or visual disorders The purposes of disease progression.
Prepared medicine is used for treating or delay cancer, cancer metastasis, cardiovascular disease, immunologic derangement or visual disorders Disease progression or the purposes of morbidity.
The invention provides compound shown in formula (I) be used for treating cancer, prophylaxis of cancer transfer, treatment cardiovascular disease, Immunologic derangement or the purposes of visual disorders.
As preferably, at least one compound shown in formula (I) is as the application of c-Met inhibitor.
The invention provides compound or its pharmaceutically acceptable salt shown in a kind of formula (I), be used for treating protein kinase The purposes of Active Regulation disease.
As preferably, described protein kinase is KDR, Tie-2, Flt3, FGFR3, AbI, Aurora A, c-Src, IGF- IR, ALK, c-MET, RON, PAKl, PAK2 or TAKl.
As preferably, described protein kinase activity regulation disease is cancer.
As preferably, described cancer is that solid tumor, sarcoma, fibrosarcoma, osteoma, malignant melanoma, retina are female thin Born of the same parents' tumor, rhabdomyosarcoma, glioblastoma multiforme, neuroblastoma, monster, hematopoietic malignancies or malignant ascite.
Present invention also offers compound shown in formula (I) or its pharmaceutically acceptable salt purposes as medicine.
As preferably, described medicine is used for treating cancer.
As preferably, described medicine is used for treating cancer.Described cancer is selected from pulmonary carcinoma, breast carcinoma, colorectal cancer, renal carcinoma, pancreas Adenocarcinoma, head cancer, neck cancer, heritability Papillary Renal Cell Carcinoma, child's hepatocarcinoma and gastric cancer.
As preferably, at least the one of the present invention offer of the administration dose therapeutically effective needing this treatment Plant compound or its pharmaceutically acceptable salt.
On the other hand, the invention provides a kind of compound for treating the disorderly patient of c-Met tyrosine kinase regulation.
Term " halogen " (halo) or " halogen " (halogen), unless there are other clear and definite implications, refer to fluorine, chlorine, bromine or Iodine.More preferably, fluorine, chlorine and bromine are referred to.
Herein, unless there are other clear and definite implications, term " alkyl " includes straight chain, side chain or looped saturated singly-bound Hydrocarbon group.Such as, alkyl includes methyl, ethyl, propyl group, isopropyl, cyclopropyl, normal-butyl, isobutyl group, sec-butyl, tertiary fourth Base, cyclobutyl, n-pentyl, 3-(2-methyl) butyl, 2-amyl group, 2-methyl butyl, neopentyl, cyclopenta, n-base, 2-are Base, 2-methyl amyl and cyclohexyl.Alkoxyl is derived from the oxygen ether form of straight chain, side chain or cyclic alkyl described above. Similarly, thiazolinyl and alkynyl include straight chain, side chain or cyclic olefin and alkynes.
Term " hydroxy alkyl " refer to alkyl chain end connect a hydroxyl, molecular formula be the group of HO-alkyl.Term " aminoalkyl " refers to by the alkyl (e.g. ,-alkyl-NH that be instead of by an amido2).Term " alkyl amine group " refers to by alkyl The amido (e.g. ,-NH-alkyl) that instead of.Term " dialkyl amino " refers to by two identical or different alkyl substituted Amido (e.g. ,-N-(alkyl)2)。
Herein, term " aryl ", unless there are other clear and definite implications, refer to unsubstituted or substituted aromatic group, such as benzene Base, naphthyl and anthryl.Term " aroyl " refers to-C (O)-aryl.
Herein, term " Heterocyclylalkyl " (heterocyclyl), unless there are other clear and definite implications, refer to unsubstituted or Substituted 3 to 8 yuan of stable monocycle saturated rings systems, this system is by carbon atom and 1 to 3 hetero atom groups selected from N, O or S Become, and N or S hetero atom can also be oxidized, and N hetero atom can also be the miscellaneous nitrogen of quaternary ammonium salt.Heterocyclylalkyl can connect On any hetero atom that can produce rock-steady structure or carbon atom.Such as, Heterocyclylalkyl, include but not limited to, azetidin Alkyl, pyrrolidinyl, piperidyl, piperazinyl, oxopiperazinyl, oxo-piperidine base, oxo azatropylidene base, azatropylidene base, tetrahydrochysene Furyl, dioxolane base, imidazolidine base, tetrahydro-thiazoles base, tetrahydrochysene oxazolyl, THP trtrahydropyranyl, morpholinyl, thiomorpholine Base, thiamorpholinyl sulfoxide base, thiomorpholine sulfone and di azoly.
Herein, term " heterocyclic aryl ", unless there are other clear and definite implications, refer to unsubstituted or substituted stable 5 Unit or 6 yuan of monocyclic aromatic ring system, or unsubstituted or substituted 9 yuan or 10 yuan of fused benzo ring heteroaryl perfume (or spice) loop systems or dicyclo heteroaryl fragrant Loop systems, described fused benzo ring heteroaryl perfume (or spice) loop systems or dicyclo heteroaryl perfume (or spice) loop systems are selected from N, O or S by carbon atom and 1 to 4 Hetero atom forms, and N or S hetero atom can also be oxidized, and N hetero atom can also be the miscellaneous nitrogen of quaternary ammonium salt.Heterocyclic aryl Can be connected on any hetero atom that can produce rock-steady structure or carbon atom.Such as, heterocyclic aryl, include but not limited to, Thienyl, furyl, imidazole radicals, isoxazolyl, oxazolyl, pyrazolyl, pyrrole radicals, thiazolyl, thiadiazolyl group, triazolyl, pyrrole Piperidinyl, pyridazinyl, indyl, azaindole base, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxa are disliked Oxazolyl, benzoxazolyl, benzopyrazoles base, benzothiazolyl, diazosulfide base, benzotriazole adenyl, quinolyl or Isoquinolyl.
Term " aryl alkyl " refers to the alkyl replaced by one or more aryl.
Term " aryl alkenyl " or " aromatic yl polysulfide yl " include the alkenyl or alkynyl replaced by one or more aryl.Similar , term " heterocyclic aryl alkyl ", " heterocyclic aryl thiazolinyl " or " heterocyclic aryl alkynyl " refers to by one or more heterocyclic aryls Substituted alkyl, alkenyl or alkynyl；" hetercycloalkylalkyl " (heterocyclylalkyl), " Heterocyclylalkyl thiazolinyl " Or " heterocycloalkylalkinyl " (heterocyclylalkynyl) refers to by one or more miscellaneous (heterocyclylalkenyl) The alkyl of cycloalkyl substituted, alkenyl or alkynyl.
Term " carbonyl " refers to C (O).
No matter when, term " alkyl " or " aryl " or occur in the prefix root in substituent group (such as aralkyl, dioxane Base amido), they all should be by above-mentioned limited interpretation " alkyl " and " aryl ".The specified quantity of carbon atom is (such as Cl-C6, Cl-6) refer to The carbon number of independent moieties or the carbon number of the moieties as the prefix root appearance of relatively large-substituent group.
Herein, term " compositions " includes the product containing certain amount of specific components, also include any directly or Product containing certain amount of specific components indirectly.Correspondingly, pharmaceutical composition includes carrying as the present invention of active component The compound of confession.The method being prepared as this compound is also the part of the present invention.Further, some crystalline substances of compound Shape exists with polymorph, and these polymorphs are also included within protection scope of the present invention.It addition, some compounds and water (such as hydrate) or ordinary organic solvents etc. form solvate, and such solvate is also contained in protection scope of the present invention In.
The compound that the present invention provides can also exist as a pharmaceutically acceptable salt form.Medicinal application aspect, this The salt of the compound that invention provides refers to nontoxic pharmaceutically acceptable salt.The form of pharmaceutically acceptable salt includes pharmacy Upper acceptable acid/anion or alkali/cationic salts.Pharmaceutically acceptable acid/anion salt typically with basic nitrogen with inorganic Presented in acid or organic acid protonation.Typical organic or inorganic acid includes hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfur Acid, nitric acid, phosphoric acid, acetic acid, propanoic acid, glycolic, lactic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, Benzoic acid, mandelic acid, methanesulfonic acid, ethylenehydrinsulfonic acid, benzenesulfonic acid, oxalic acid, flutter acid, 2-LOMAR PWA EINECS 246-676-2, p-methyl benzenesulfonic acid, hexamethylene ammonia sulphur Acid, salicylic acid, saccharinic acid or trifluoroacetic acid.Pharmaceutically acceptable alkali/cationic salts, includes but not limited to, aluminium salt, calcium salt, Villaumite, choline, diethanolamine salt, ethylenediamine salt, lithium salts, magnesium salt, potassium salt, sodium salt and zinc salt.
The prodrug of the compound that the present invention provides comprises within the scope of the present invention.Under normal circumstances, described Prodrug is the functional derivatives of the compound that the present invention provides, it is easy to change into required compound in vivo. Herein, the term administering that the Therapeutic Method that the present invention provides relates to " though including by compound disclosed by the invention or the present invention So the openest but this compound can be converted into compound disclosed by the invention after using, various uncomfortable or disorderly described in treatment Disorderly.The conventional program selecting and preparing suitable prodrugs derivant, such as " prodrug design " is had described in books (Design of Prodrugs,ed.H.Bundgaard,Elsevier,1985)。
Herein, the definition of the variable of ad-hoc location in any substituent group or molecule, independent of the definition of its place molecule. It is appreciated that in the present invention, it is contemplated that chemical stability and the method provided according to prior art and the present invention are closed relatively easily Becoming, those of ordinary skill in the art can be to select substituent group and the mode of replacement of compound.
Compound of the present invention may contain one or more asymmetric centers, and may thus produce/occur different Structure body and optical isomer.The present invention includes all possible isomer and racemic mixture thereof, simple mapping through disassembling Isomer, all possible geometric isomer and pharmaceutically acceptable salt thereof.
Above-mentioned formula (I) the most definitely defines the stereochemical structure of a certain position of this compound.The present invention includes formula (I) shownization All stereoisomers of compound and pharmaceutically acceptable salt thereof.Further, the mixture of stereoisomer and isolating Specific stereoisomer be also included in the present invention.It will appreciated by the skilled person that and prepare this compounds Building-up process in, or during using racemization or epimerization, the product that this process prepares can be three-dimensional different The mixture of structure body.
When compound shown in formula (I) exists isomer, unless specifically stated otherwise, the present invention includes any possible isomer With its pharmaceutically acceptable salt, and their mixture.
When shown in formula (I) there is solvate or polymorphic in compound and pharmaceutically acceptable salt thereof, unless especially Statement, the present invention includes any possible solvate and polymorphic.The type of solvent forming solvate is not to limit especially Fixed, as long as this solvent is that pharmacologically acceptable is the most permissible.The solvent that such as water, ethanol, propanol, acetone etc. are similar to is all Permissible.
Term " pharmaceutically acceptable salt " refers to from the salt that pharmaceutically acceptable nontoxic alkali or processed with acid are standby.When this When the compound of bright offer is acid, can be from pharmaceutically acceptable nontoxic alkali, including inorganic base and organic base, prepare its phase The salt answered.From the salt that inorganic base is derivative include aluminum, ammonium, calcium, copper (ic and ous), ferrum, ferrous iron, lithium, magnesium, manganese (ic and ous), potassium, The salt of sodium, zinc etc.In particular it is preferred to the salt of ammonium, calcium, magnesium, potassium and sodium.Pharmaceutically acceptable can be derivatized to the nontoxic of salt Organic base includes primary amine, secondary amine and tertiary amine, also includes cyclammonium and containing the amine of substituent group, as naturally and synthesis containing substituent group Amine.Other pharmaceutically acceptable non-toxic organic alkali of salt can be become, including ion exchange resin and arginine, Radix Betae Alkali, caffeine, choline, N', N'-Dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylamino-ethanol, ethanol Amine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, Kazakhstan amine, 2-aminopropane., bad ammonia Acid, methyl glucose osamine, morpholine, piperazine, piperidines, many polyimide resins, procaine, purine, theobromine, triethylamine, trimethylamine, three Propylamine, trometamol etc..
When the compound that the present invention provides is alkali, can from pharmaceutically acceptable nontoxic acid, including mineral acid and Organic acid, prepares its corresponding salt.Such acid includes, e.g., and acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, second sulphur Acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, almond Acid, methanesulfonic acid, mucic acid, nitric acid, flutter acid, pantothenic acid, phosphoric acid, succinic acid, sulphuric acid, tartaric acid, p-methyl benzenesulfonic acid etc..More preferably, lemon Lemon acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulphuric acid acid and tartaric acid.More preferably, formic acid and hydrochloric acid.Shown in formula (I) Compound is as the application of medicine, more preferably, uses certain purity, and such as purity at least 60%, proper purity is at least 75%, specially suitable purity at least 98% (% weight ratio).
The pharmaceutical composition that the present invention provides includes that compound (or its pharmaceutically acceptable salt) shown in formula (I) is as living Property component, a kind of pharmaceutically acceptable excipient and other optional therapeutic component or adjuvant.Although optimal activity group Divide administering mode to depend on specific main body, main nature and coincident with severity degree of condition, but the pharmaceutical composition of the present invention includes Be suitable to oral cavity, pharmaceutical composition that rectum, local and parenteral (including subcutaneous administration, intramuscular injection, intravenously administrable) use.This Bright pharmaceutical composition can exist and any preparation method well known in the art with any dosage form well known in the art easily Prepare.
It practice, according to conventional pharmaceutical compounding technique, compound shown in formula (I) of the present invention, or prodrug, or metabolism Thing, or pharmaceutically acceptable salt, can be mixed into pharmaceutical composition as active component with pharmaceutical carrier.Described medicine carries Body can depend on, to take various form, the administering mode wanting to use, and such as, oral or injection (includes that vein is noted Penetrate).Therefore, the pharmaceutical composition of the present invention can exist with any dosage form of any one predetermined active ingredient doses, Such as capsule, cachet or tablet.Further, the pharmaceutical composition of the present invention uses powder, granule, solution, aqueous suspension Liquid, on-aqueous liquid, emulsion oil-in-water, or water-in-oil emulsion form.It addition, except above-mentioned common dosage form, shown in formula (I) Compound or its pharmaceutically acceptable salt, it is also possible to by the way of controlled release and/or conveying equipment is used.The medicine of the present invention Compositions can be prepared with the pharmaceutical methods on any pharmacopedics.Generally, this method includes making active component The step associated with the carrier constituting one or more necessary component.Generally, described pharmaceutical composition is via activity group Point being closely mixed to prepare through unify with liquid-carrier or the solid carrier of fine segmentation or both mixture.It addition, should Product can be prepared as required outward appearance easily.
Therefore, the pharmaceutical composition of the present invention includes compound shown in pharmaceutically acceptable carrier and formula (I), or its medicine Acceptable salt on.Compound shown in formula (I), or its pharmaceutically acceptable salt, one or more have treatment with other The drug combination of the compound of activity is also included within the pharmaceutical composition of the present invention.
The present invention use pharmaceutical carrier it may be that such as, solid carrier, liquid-carrier or carrier gas.Solid carrier, Include but not limited to, lactose, Gypsum Fibrosum powder, sucrose, Pulvis Talci, gelatin, agar, pectin, arabic gum, magnesium stearate, stearic acid. Liquid-carrier, includes but not limited to, syrup, Oleum Arachidis hypogaeae semen, olive oil and water.Carrier gas, includes but not limited to, carbon dioxide and Nitrogen.When preparing drug oral preparation, it is possible to use the medium on any convenient pharmacopedics.Such as, water, ethylene glycol, oils, Alcohols, flavour enhancer, preservative, coloring agent etc. can be used for liquid preparation such as suspending agent, elixir and the solution being administered orally；And carrier, As starch based, saccharide, microcrystalline Cellulose, diluent, granulating agent, lubricant, binding agent, disintegrating agent etc. can be used for the solid that is administered orally Preparation such as powder, capsule and tablet.In view of being prone to use, oral formulations first-selection tablet and capsule.Alternatively, tablet coating Water formulation or the non-aqueous formulation technology of standard can be used.
Tablet containing the compounds of this invention or pharmaceutical composition can be compressed or molded, it is alternatively possible to one Tablet made together by individual or multiple helper component or accessory drugs.Active component with can with free-pouring form such as powder or granule, With lubricant, inert diluent, surface activity or dispersant, in suitable machine, compression can be prepared by compression Sheet.Soak compound or the pharmaceutical composition of powder by a kind of inert liquid diluent, then in suitable machine, pass through Molding can prepare molding sheet.More preferably, each tablet contains the active component of about 0.05mg to 5g, each flat assists agent or glue Wafer contains the active component of about 0.05mg to 5g.Such as, mankind's formula of oral may comprise the about 0.5mg activity to about 5g Component, with the auxiliary Material cladding of suitable and convenient metering, this auxiliary material accounts for the 5% to 95% of pharmaceutical composition total amount. Unit dosage forms generally comprises the active component of about 1 milligram to about 2 grams, it is typical that 25 milligrams, 50 milligrams, 100 milligrams, 200 millis Gram, 300 milligrams, 400 milligrams, 500 milligrams, 600 milligrams, 800 milligrams, or 1000 milligrams.
The present invention provide the pharmaceutical composition being applicable to parenteral administration, active component can be added to the water be prepared as water-soluble Liquid or suspension.Suitable surfactant such as hydroxypropyl cellulose can be comprised.At glycerol, liquid polyethylene glycol, and Mixture in oil, it is also possible to prepare dispersion.Further, preservative is possible to prevent the growth of microorganism being harmful to, therefore It is also contained in the pharmaceutical composition of the present invention.
The pharmaceutical composition that the present invention provides is applicable to injection and uses, including aseptic aqueous solution or dispersion.Further Ground, above-mentioned sterile solution or dispersion can be to be first prepared as the form of sterilized powder.In any case, final injection form must Must be aseptic, and for ease of injection, it is necessary to it is easy to flowing.Additionally, the preparation of described pharmaceutical composition and storing Cheng Bixu is stable.Therefore, best antimicrobial, such as antibacterial and the pollution of fungus.Carrier can be solvent or disperse medium, example As, water, ethanol, polyhydric alcohol (such as glycerol, propylene glycol, liquid polyethylene glycol), vegetable oil, and suitably mixture.
The present invention provide drug regimen, can use with suitable exemplary dosage form, such as, aerosol, Emulsion, ointment, Washing liquid, dusting, or other similar dosage forms.Further, the pharmaceutical composition that the present invention provides can be at transdermal administration equipment In use in an appropriate form.Utilize compound shown in formula (I) of the present invention, or its pharmaceutically acceptable salt, by routine Processing method, can prepare these preparations.As an example, Emulsion or ointment by adding hydrophilic material and water (the two Total amount is about 5wt% to the 10wt% of compound), prepare Emulsion or the ointment with desired consistency.
The pharmaceutical composition that the present invention provides, can with solid as carrier, be applicable to the form of rectally, unit dose Suppository be most typical dosage form.Suitably adjuvant includes cocoa butter commonly used in the art and other materials.Suppository can facilitate Ground preparation, first pharmaceutical composition mix with the adjuvant of softening or fusing, then cool down with mould molding and prepare.
In addition to adjuvant component mentioned above, above-mentioned pharmaceutical formulation can also include, suitable, one or more additional Adjuvant component, as diluent, buffer agent, flavoring agent, binding agent, surfactant, thickening agent, lubricant, preservative (include Antioxidant) etc..Further, other accessory drugs can also include regulating drug and the isotonic penetrating agent of blood.Include Compound shown in formula (I), or the pharmaceutical composition of its pharmaceutically acceptable salt, can be prepared as the shape of powder or concentrated solution Formula.
Generally, treating above-mentioned shown situation or discomfort, the dosage level of medicine is about 0.01mg/kg body every day Heavily arrive 150mg/kg body weight, or each patient 0.5mg to 7g every day.Such as, inflammation, tumor, psoriasis, allergy/asthma, exempt from The disease of epidemic disease system and discomfort, the disease of central nervous system (CNS) and discomfort, effectively the article dose level for the treatment of is every day 0.01mg/kg body weight is to 50mg/kg body weight, or each patient 0.5mg to 3.5g every day.
However, it will be understood that the concrete dosage level of any given patient will depend upon which many factors, including age, body Weight, general health, sex, diet, administration time, route of administration, excretion rate, the situation of drug combination and connect subject The order of severity of specified disease.
In order to make foregoing become apparent from, clearly, the present invention is further illustrated below.
Detailed description of the invention
The invention provides a kind of new compound, as c-Met activity inhibitor.The knot of the compound that the present invention provides Shown in structure formula such as formula (I):
Wherein,
A is 5-18 ring；
R1Independently selected from hydrogen, halogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C2-8Thiazolinyl, replacement Or unsubstituted C2-8Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted miscellaneous Cycloalkyl, C1-8Alkanoyl, C1-8Alkoxy carbonyl, C1-8Alkylsulfinyl, C1-8Alkyl sulphonyl, aryl sulfonyl, cyano group, Nitro, hydroxyl, amido, carboxyl, oxo base, aminoacyl, C1-8Alkoxyl, C2-8Alkenyloxy group, C2-8Alkynyloxy group, C1-8Alkylthio group, N-(C1-8Alkyl) aminoacyl, N, N-bis-(C1-8Alkyl) aminoacyl, C1-8Alkanoic acid ester group, C1-8Alkyl amide, C3-8Alkynyl amide Base, N-(C1-8Alkyl) amino-sulfonyl or N, N-bis-(C1-8Alkyl) amino-sulfonyl；
M is the integer of 0-3；
A1And A2Independently selected from :=N-or=C (R2)-；
A3It is selected from :=N-,=C (H)-or=C (CN)-；
X is selected from NR20、CHR21, O or S；Described R20And R21Independently selected from H or Cl-8Alkyl；
R2Selected from-H, halogen, trihalomethyl ,-CN ,-NO2、-NH2、-OR5、-NR5R6、-S(O)0-2R5、-SO2NR5R6、- CO2R5、-C(O)NR5R6、-N(R3)SO2R5、-N(R5)C(O)R6、-N(R5)CO2R6、-C(O)R5Or any substituted lower alkyl Base；
N is the integer of 0-4；
Z is selected from NR3R4Or the group shown in formula (II):
R3Independently selected from hydrogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C2-8Thiazolinyl, replacement or do not take The C in generation2-8Alkynyl, C1-8Alkanoyl, C1-8Alkoxy carbonyl, C1-8Alkylsulfinyl, C1-8Alkyl sulphonyl, aryl sulfonyl, Cyano group, nitro, hydroxyl, amido, carboxyl, oxo base, aminoacyl, C1-8Alkoxyl, C2-8Alkenyloxy group, C2-8Alkynyloxy group, C1-8Alkane Sulfenyl, N-(C1-8Alkyl) aminoacyl, N, N-bis-(C1-8Alkyl) aminoacyl, C1-8Alkanoic acid ester group, C1-8Alkyl amide, C3-8 Alkynyl amide base, N-(C1-8Alkyl) amino-sulfonyl or N, N-bis-(C1-8Alkyl) amino-sulfonyl；
R4Selected from the group shown in formula (III):
B1It is
Q1It is C (R5)2；
B2It is NHQ2；
Q2Selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycle alkane Base, substituted or unsubstituted C1-8Alkylaryl, substituted or unsubstituted C1-8Alkyl heterocycle aryl or substituted or unsubstituted C1-8 Alkyl cycloheteroalkyl；
Or, B1And B2Form the 5-10 substituted or unsubstituted heterocyclic aryl of unit or substituted or unsubstituted heterocycle alkane together Base；
R5And R6Independently selected from hydrogen, halogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C2-8Thiazolinyl, take Generation or unsubstituted C2-8Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted Heterocyclylalkyl, C1-8Alkanoyl, C1-8Alkoxy carbonyl, C1-8Alkylsulfinyl, C1-8Alkyl sulphonyl, aryl sulfonyl, cyanogen Base, nitro, hydroxyl, amido, carboxyl, oxo base, aminoacyl, C1-8Alkoxyl, C2-8Alkenyloxy group, C2-8Alkynyloxy group, C1-8Alkane sulfur Base, N-(C1-8Alkyl) aminoacyl, N, N-bis-(C1-8Alkyl) aminoacyl, C1-8Alkanoic acid ester group, C1-8Alkyl amide, C3-8Alkynes Amide groups, N-(C1-8Alkyl) amino-sulfonyl, N, N-bis-(C1-8Alkyl) amino-sulfonyl, substituted or unsubstituted C1-8Alkyl Aryl, substituted or unsubstituted C1-8Alkyl heterocycle aryl or substituted or unsubstituted C1-8Alkyl cycloheteroalkyl, and they medicines Acceptable salt on.
One more excellent detailed description of the invention, A ring farther includes 0 to 6 hetero atoms selected from O, S and N.
One more excellent detailed description of the invention, R1Selected from hydrogen, halogen, C1-8Alkyl, C2-8Thiazolinyl, C2-8Alkynyl, aryl, heterocycle Aryl, Heterocyclylalkyl, (ring)1-3(C1-8) alkyl, hydroxyl, (C1-8) alkyl, C1-4Alkoxyl (C1-8) alkyl, cyano group (C1-8) alkane Base, amido (C1-8) alkyl, aryl (C1-8) alkyl, heterocyclic aryl (C1-8) alkyl, Heterocyclylalkyl (C1-8) alkyl, (ring)1-3 (C2-8) thiazolinyl, hydroxyl (C2-8) thiazolinyl, (C1-4) alkoxyl (C2-8) thiazolinyl, cyano group (C2-8) thiazolinyl, amido (C2-8) thiazolinyl, aryl (C2-8) thiazolinyl, heterocyclic aryl (C2-8) thiazolinyl, Heterocyclylalkyl (C2-8) thiazolinyl, (ring)1-3(C2-8) alkynyl, hydroxyl (C2-8) alkynyl, (C1-4) alkoxyl (C2-8) alkynyl, cyano group (C2-8) alkynyl, amido (C2-8) alkynyl, aryl (C2-8) alkynyl, heterocyclic aryl (C2-8) Alkynyl, Heterocyclylalkyl (C2-8) alkynyl, C1-8Alkanoyl, aryl (C1-8)(C1-8) alkanoyl, heterocyclic aryl (C1-8) alkanoyl, miscellaneous Cycloalkyl (C1-8) alkanoyl, C1-8Alkoxy carbonyl, aryl (C1-8) alkoxy carbonyl, heterocyclic aryl (C1-8) alkoxy carbonyl, Heterocyclylalkyl (C1-8) alkoxy carbonyl, C1-8Alkylsulfinyl, C1-8Alkyl sulphonyl, aryl sulfonyl, aryl (C1-8) virtue Base sulfonyl, heterocyclic aryl (C1-8) aryl sulfonyl, Heterocyclylalkyl (C1-8) aryl sulfonyl, aryl, heterocyclic aryl, heterocycle alkane Base, cyano group, nitro, hydroxyl, amido, carboxyl, oxo base, aminoacyl, C1-8Alkoxyl, C2-8Alkenyloxy group, C2-8Alkynyloxy group, C1-8 Alkylthio group, N-(C1-8Alkyl) aminoacyl, N, N-bis-(C1-8Alkyl) aminoacyl, C1-8Alkanoic acid ester group, C1-8Alkyl amide, C3-8Alkynyl amide base, N-(C1-8Alkyl) amino-sulfonyl or N, N-bis-(C1-8Alkyl) amino-sulfonyl；
Another more excellent detailed description of the invention, above-mentioned RlOn amido, amido (C1-8) alkyl, amido (C2-8) thiazolinyl or amine Base (C2-8) alkynyl by two independently selected from hydrogen, (C1-8) alkyl, (C2-8) thiazolinyl or (C2-8) alkynyl substituted.
Another more excellent detailed description of the invention, any aryl, heterocyclic aryl or Heterocyclylalkyl can optionally comprise 1 to 3 Individual independently selected from halogen, trifluoromethyl, cyano group, nitro, hydroxyl, amido, carboxyl, acyl methylamino, (C1-8) alkyl, (C2-8) alkene Base, (C2-8) alkynyl or (C1-8) alkoxyl replacement.
Another more excellent detailed description of the invention, R3Independently selected from hydrogen, substituted or unsubstituted C1-8Alkyl, replacement or not Substituted C2-8Thiazolinyl, substituted or unsubstituted C2-8Alkynyl, C1-8Alkanoyl, C1-8Alkoxy carbonyl, C1-8Alkylsulfinyl, C1-8Alkyl sulphonyl, aryl sulfonyl, cyano group, nitro, hydroxyl, amido, carboxyl, oxo base, aminoacyl, C1-8Alkoxyl, C2-8Alkenyloxy group, C2-8Alkynyloxy group, C1-8Alkylthio group, N-(C1-8Alkyl) aminoacyl, N, N-bis-(C1-8Alkyl) aminoacyl, C1-8 Alkanoic acid ester group, C1-8Alkyl amide, C3-8Alkynyl amide base, N-(C1-8Alkyl) amino-sulfonyl or N, N-bis-(C1-8Alkyl) amino sulphur Acyl group；
Another more excellent detailed description of the invention, R4Selected from the group shown in formula (IV):
Wherein,
Q3Selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycle alkane Base, substituted or unsubstituted alkylaryl, substituted or unsubstituted C1-8Alkyl heterocycle aryl or substituted or unsubstituted C1-8Alkane Base Heterocyclylalkyl；
R7、R8Independently selected from hydrogen, halogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C2-8Thiazolinyl, take Generation or unsubstituted C2-8Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted Heterocyclylalkyl, C1-8Alkanoyl, C1-8Alkoxy carbonyl, C1-8Alkylsulfinyl, C1-8Alkyl sulphonyl, aryl sulfonyl, cyanogen Base, nitro, hydroxyl, amido, carboxyl, oxo base, aminoacyl, C1-8Alkoxyl, C2-8Alkenyloxy group, C2-8Alkynyloxy group, C1-8Alkane sulfur Base, N-(C1-8Alkyl) aminoacyl, N, N-bis-(C1-8Alkyl) aminoacyl, C1-8Alkanoic acid ester group, C1-8Alkyl amide, C3-8Alkynes Amide groups, N-(C1-8Alkyl) amino-sulfonyl, N, N-bis-(C1-8Alkyl) amino-sulfonyl, substituted or unsubstituted C1-8Alkyl Aryl, substituted or unsubstituted C1-8Alkyl heterocycle aryl or substituted or unsubstituted C1-8Alkyl cycloheteroalkyl.
Another more excellent detailed description of the invention, R3Independently selected from hydrogen, substituted or unsubstituted C1-8Alkyl, replacement or not Substituted C2-8Thiazolinyl, substituted or unsubstituted C2-8Alkynyl, C1-8Alkanoyl, C1-8Alkoxy carbonyl, C1-8Alkylsulfinyl, C1-8Alkyl sulphonyl, aryl sulfonyl, cyano group, nitro, hydroxyl, amido, carboxyl, oxo base, aminoacyl, C1-8Alkoxyl, C2-8Alkenyloxy group, C2-8Alkynyloxy group, C1-8Alkylthio group, N-(C1-8Alkyl) aminoacyl, N, N-bis-(C1-8Alkyl) aminoacyl, C1-8 Alkanoic acid ester group, C1-8Alkyl amide, C3-8Alkynyl amide base, N-(C1-8Alkyl) amino-sulfonyl or N, N-bis-(C1-8Alkyl) amino sulphur Acyl group；
Another more excellent detailed description of the invention, R4Selected from the group shown in formula (V):
Wherein,
Q3Selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycle alkane Base, substituted or unsubstituted C1-8Alkylaryl, substituted or unsubstituted C1-8Alkyl heterocycle aryl or substituted or unsubstituted C1-8 Alkyl cycloheteroalkyl；
X1Selected from NR8Or CR7R8；
R7、R8Independently selected from hydrogen, halogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C2-8Thiazolinyl, take Generation or unsubstituted C2-8Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted Heterocyclylalkyl, C1-8Alkanoyl, C1-8Alkoxy carbonyl, C1-8Alkylsulfinyl, C1-8Alkyl sulphonyl, aryl sulfonyl, cyanogen Base, nitro, hydroxyl, amido, carboxyl, oxo base, aminoacyl, C1-8Alkoxyl, C2-8Alkenyloxy group, C2-8Alkynyloxy group, C1-8Alkane sulfur Base, N-(C1-8Alkyl) aminoacyl, N, N-bis-(C1-8Alkyl) aminoacyl, C1-8Alkanoic acid ester group, C1-8Alkyl amide, C3-8Alkynes Amide groups, N-(C1-8Alkyl) amino-sulfonyl, N, N-bis-(C1-8Alkyl) amino-sulfonyl, substituted or unsubstituted C1-8Alkyl Aryl, substituted or unsubstituted C1-8Alkyl heterocycle aryl or substituted or unsubstituted C1-8Alkyl cycloheteroalkyl.
Another more excellent detailed description of the invention, R3Independently selected from hydrogen, substituted or unsubstituted C1-8Alkyl, replacement or not Substituted C2-8Thiazolinyl, substituted or unsubstituted C2-8Alkynyl, C1-8Alkanoyl, C1-8Alkoxy carbonyl, C1-8Alkylsulfinyl, C1-8Alkyl sulphonyl, aryl sulfonyl, cyano group, nitro, hydroxyl, amido, carboxyl, oxo base, aminoacyl, C1-8Alkoxyl, C2-8Alkenyloxy group, C2-8Alkynyloxy group, C1-8Alkylthio group, N-(C1-8Alkyl) aminoacyl, N, N-bis-(C1-8Alkyl) aminoacyl, C1-8 Alkanoic acid ester group, C1-8Alkyl amide, C3-8Alkynyl amide base, N-(C1-8Alkyl) amino-sulfonyl or N, N-bis-(C1-8Alkyl) amino sulphur Acyl group；
Another more excellent detailed description of the invention, R4Selected from the group shown in formula (VI):
Wherein,
Q3Selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycle alkane Base, substituted or unsubstituted C1-8Alkylaryl, substituted or unsubstituted C1-8Alkyl heterocycle aryl, substituted or unsubstituted C1-8 Alkyl cycloheteroalkyl.
R7、R8Independently selected from hydrogen, halogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C2-8Thiazolinyl, take Generation or unsubstituted C2-8Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted Heterocyclylalkyl, C1-8Alkanoyl, C1-8Alkoxy carbonyl, C1-8Alkylsulfinyl, C1-8Alkyl sulphonyl, aryl sulfonyl, cyanogen Base, nitro, hydroxyl, amido, carboxyl, oxo base, aminoacyl, C1-8Alkoxyl, C2-8Alkenyloxy group, C2-8Alkynyloxy group, C1-8Alkane sulfur Base, N-(C1-8Alkyl) aminoacyl, N, N-bis-(C1-8Alkyl) aminoacyl, C1-8Alkanoic acid ester group, C1-8Alkyl amide, C3-8Alkynes Amide groups, N-(C1-8Alkyl) amino-sulfonyl, N, N-bis-(C1-8Alkyl) amino-sulfonyl, substituted or unsubstituted C1-8Alkyl Aryl, substituted or unsubstituted C1-8Alkyl heterocycle aryl or substituted or unsubstituted C1-8Alkyl cycloheteroalkyl.
Another more excellent detailed description of the invention, R4Selected from the group shown in formula (VII):
Wherein,
Q3Selected from substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycle alkane Base, substituted or unsubstituted C1-8Alkylaryl, substituted or unsubstituted C1-8Alkyl heterocycle aryl, substituted or unsubstituted C1-8 Alkyl cycloheteroalkyl.
R7、R8And R11Independently selected from hydrogen, halogen, substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C2-8Alkene Base, substituted or unsubstituted C2-8Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, replacement or do not take The Heterocyclylalkyl in generation, C1-8Alkanoyl, C1-8Alkoxy carbonyl, C1-8Alkylsulfinyl, C1-8Alkyl sulphonyl, arylsulfonyl Base, cyano group, nitro, hydroxyl, amido, carboxyl, oxo base, aminoacyl, C1-8Alkoxyl, C2-8Alkenyloxy group, C2-8Alkynyloxy group, C1-8 Alkylthio group, N-(C1-8Alkyl) aminoacyl, N, N-bis-(C1-8Alkyl) aminoacyl, C1-8Alkanoic acid ester group, C1-8Alkyl amide, C3-8Alkynyl amide base, N-(C1-8Alkyl) amino-sulfonyl, N, N-bis-(C1-8Alkyl) amino-sulfonyl, substituted or unsubstituted C1-8 Alkylaryl, substituted or unsubstituted C1-8Alkyl heterocycle aryl or substituted or unsubstituted C1-8Alkyl cycloheteroalkyl.
R9And R10Independently selected from substituted or unsubstituted C1-8Alkyl, substituted or unsubstituted C2-8Thiazolinyl, replacement or not Substituted C2-8Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted heterocycle alkane Base, C1-8Alkanoyl, C1-8Alkoxy carbonyl, C1-8Alkylsulfinyl, C1-8Alkyl sulphonyl or aryl sulfonyl；
Another more excellent embodiment, A is 6-18 ring.
Another more excellent embodiment, A is 5-8 ring.
Another more excellent embodiment, A is 5 or 12 rings.
Another more excellent embodiment, A is 12 yuan of heterocycles.
Another more excellent embodiment, A is the 12 yuan of heterocycles comprising 1,2,3 or 4 oxygen atoms.
Another more excellent embodiment, A is the 12 yuan of heterocycles comprising 4 oxygen atoms.
Another more excellent embodiment, A is
Another more excellent embodiment, RlSelected from hydrogen, halogen, substituted or unsubstituted C1-5Alkyl, substituted or unsubstituted C2-5Thiazolinyl, substituted or unsubstituted C2-5Alkynyl, C1-5Alkanoyl, C1-5Alkoxy carbonyl, C1-5Alkylsulfinyl, C1-5Alkyl Sulfonyl, Cl-5Alkoxyl, C2-5Alkenyloxy group, C2-5Alkynyloxy group, C1-5Alkylthio group, N-(C1-5Alkyl) amino-sulfonyl, N, N-bis- (C1-5Alkyl) amino-sulfonyl, Cl-5Alkanoic acid ester group, Cl-5Alkyl amide, C3-6Alkynyl amide base, N-(C1-5Alkyl) amino-sulfonyl Or N, N-bis-(C1-5Alkyl) amino-sulfonyl.
Another more excellent embodiment, RlSelected from hydrogen, halogen, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle Aryl, substituted or unsubstituted Heterocyclylalkyl, aryl sulfonyl, cyano group, nitro, hydroxyl, amido, carboxyl, oxo base or amino Acyl group.
Another more excellent embodiment, RlSelected from hydrogen or halogen.
Another more excellent embodiment, RlIt is hydrogen.
Another more excellent embodiment, m is the integer of 0-2.
Another more excellent embodiment, m is 0.
Another more excellent embodiment, A2It is=N-.
Another more excellent embodiment, A1It is=C (R2)-, A2It is=N-.
Another more excellent embodiment, A1It is=CH-, A2It is=N-.
Another more excellent embodiment, A1And A2It is=C (R2)-。
Another more excellent embodiment, A1And A2It is=CH-.
Another more excellent embodiment, A3Selected from=N-or=C (H)-.
Another more excellent embodiment, X is selected from NR20Or CHR21, R20And R21Independently selected from H or Cl-3Alkyl.
Another more excellent embodiment, X is selected from NR20Or CHR21, R20And R21It is H.
Another more excellent embodiment, X is selected from oxygen or sulfur.
Another more excellent embodiment, X is oxygen.
Another more excellent embodiment, R2Selected from-H, halogen, trihalomethyl ,-CN ,-NO2Or-NH2。
Another more excellent embodiment, R2Selected from-H or halogen.
Another more excellent embodiment, R2Selected from fluorine or hydrogen.
Another more excellent embodiment, R2Selected from-OR5、-NR5R6、-S(O)0-2R5、-SO2NR5R6、-CO2R5、-C(O) NR5R6、-N(R3)SO2R5、-N(R5)C(O)R6、-N(R5)CO2R6Or-C (O) R5。
Another more excellent embodiment, R2Selected from substituted low alkyl group ,-CN ,-NO2Or-NH2。
Another more excellent embodiment, R3Selected from substituted or unsubstituted C1-5Alkyl, substituted or unsubstituted C2-5Thiazolinyl, take Generation or unsubstituted C2-5Alkynyl, C1-5Alkanoyl, substituted or unsubstituted C1-5Alkoxy carbonyl, C1-5Alkylsulfinyl, C1-5 Alkyl sulphonyl, Cl-5Alkoxyl, C2-5Alkenyloxy group, C2-5Alkynyloxy group, C1-5Alkylthio group, N-(C1-5Alkyl) amino-sulfonyl, N, N- Two (C1-5Alkyl) amino-sulfonyl, Cl-5Alkanoic acid ester group, Cl-5Alkyl amide, C3-6Alkynyl amide base, N-(C1-5Alkyl) aminosulfonyl Base or N, N-bis-(C1-5Alkyl) amino-sulfonyl.
Another more excellent embodiment, R3Selected from substituted or unsubstituted C1-3Alkyl, substituted or unsubstituted C2-3Thiazolinyl, take Generation or unsubstituted C2-3Alkynyl, C1-3Alkanoyl, substituted or unsubstituted C1-3Alkoxy carbonyl, C1-3Alkylsulfinyl, C1-3 Alkyl sulphonyl, Cl-3Alkoxyl, C2-3Alkenyloxy group, C2-3Alkynyloxy group, C1-3Alkylthio group, N-(C1-3Alkyl) amino-sulfonyl, N, N- Two (C1-3Alkyl) amino-sulfonyl, Cl-3Alkanoic acid ester group, Cl-3Alkyl amide, N-(C1-3Alkyl) amino-sulfonyl, C4-6Alkynyl amide Base or N, N-bis-(C1-3Alkyl) amino-sulfonyl.
Another more excellent embodiment, R3Selected from substituted or unsubstituted C1-3Alkoxy carbonyl, C1-3Alkylsulfinyl, C1-3Alkyl sulphonyl, Cl-3Alkoxyl, C2-3Alkenyloxy group, C2-3Alkynyloxy group or C1-3Alkylthio group.
Another more excellent embodiment, R3It is hydrogen.
Another more excellent embodiment, Q1It is CH2。
Another more excellent embodiment, Q2It is substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl or replacement Or unsubstituted Heterocyclylalkyl.
Another more excellent embodiment, Q2Selected from halogenophenyl.
Another more excellent embodiment, Q2It it is difluorophenyl.
Another more excellent embodiment, Q2Selected from substituted or unsubstituted C1-5Alkylaryl, substituted or unsubstituted C1-5Alkane Base heterocyclic aryl or substituted or unsubstituted C1-5Alkyl cycloheteroalkyl.
Another more excellent embodiment, B1And B2Together formed 5-10 unit substituted or unsubstituted heterocyclic aryl, replace or not Substituted Heterocyclylalkyl.
Another more excellent embodiment, Q3Selected from substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic aryl.
Another more excellent embodiment, Q3Selected from substituted or unsubstituted phenyl.
Another more excellent embodiment, Q3Selected from phenyl or halogenophenyl.
Another more excellent embodiment, Q3Selected from difluorophenyl.
Another more excellent embodiment, X1Selected from NR8。
Another more excellent embodiment, X1Selected from NC1-6Alkyl.
Another more excellent embodiment, X1It is NCH3。
Another more excellent embodiment, R7、R8And R11Independently selected from hydrogen, halogen or substituted or unsubstituted C1-8Alkyl.
Another more excellent embodiment, R7、R8And R11Independently selected from substituted or unsubstituted C2-5Thiazolinyl, replacement or do not take The C in generation2-5Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic aryl, substituted or unsubstituted Heterocyclylalkyl, C1-5Alkanoyl, C1-5Alkoxy carbonyl, N-(C1-5Alkyl) aminoacyl, N, N bis-(C1-5Alkyl) aminoacyl, C1-5Alkanoic acid ester Base, aryl sulfonyl, cyano group, nitro, hydroxyl, amido, carboxyl, oxo base, aminoacyl, C1-5Alkoxyl, C2-5Alkenyloxy group, C2-5Alkynyloxy group, C1-5Alkylthio group, C1-5Alkyl amide, C3-5Alkynyl amide base, N-(C1-5Alkyl) amino-sulfonyl, N, N-bis-(C1-5 Alkyl) amino-sulfonyl, substituted or unsubstituted C1-5Alkylaryl, substituted or unsubstituted C1-5Alkyl heterocycle aryl, or take Generation or unsubstituted C1-5Alkyl cycloheteroalkyl.
Another more excellent embodiment, R7、R8And R11It is hydrogen.
Another more excellent embodiment, R7It is C1-6Alkyl.
Another more excellent embodiment, R7It is-CH3。
Another more excellent embodiment, R7Selected from phenyl or halogenophenyl.
Another more excellent embodiment, R7Selected from difluorophenyl.
Another more excellent embodiment, R8It is hydrogen.
Another more excellent embodiment, R5And R6Independently selected from hydrogen, substituted or unsubstituted C1-6Alkyl, replacement or unsubstituted C2-6Thiazolinyl or substituted or unsubstituted C2-6Alkynyl.
Another more excellent embodiment, R5And R6It is hydrogen.
Another more excellent embodiment, R5And R6Independently selected from C1-5Alkanoyl, C1-5Alkoxy carbonyl, C1-5Alkyl thionyl Base or C1-5Alkyl sulphonyl.
Another more excellent embodiment, R5And R6Independently selected from cyano group, nitro, hydroxyl, amido, carboxyl, oxo base or amino Acyl group.
Another more excellent embodiment, R5And R6Independently selected from cyano group, nitro, hydroxyl or amido.
Another more excellent embodiment, R9And R10Independently selected from substituted or unsubstituted C1-6Alkyl or replacement or unsubstituted C6-12Aryl.
Another more excellent embodiment, R9And R10Independently selected from halo C6-12Aryl or unsubstituted C1-6Alkyl.
Another more excellent embodiment, R9And R10Independently selected from methyl or halogenophenyl.
Another more excellent embodiment, R9And R10Independently selected from methyl or difluorophenyl.
Compound shown in formula (I) is the tyrosine kinase activity inhibitor including the mankind for mammal, and, they It is useful for treating and/or prevent various disease and discomfort.Especially, disclosed compound is inhibitors of kinases, especially Be, but be not limited only to, c-Met, KDR, Tie-2, FLT3, FGFR3, AbI, Aurora A, c-Src, IGF-IR, ALK, RON, PAK1, PAK2 and TAK1, and can be used for treating proliferative disease, e.g., but it is not limited only to, cancer.Due to MET and RON kinases Be proved to during EMT play a role, the compound shown in formula (I) treatment and/or prevention relate to the various diseases of EMT with The most moderate is useful, and such as, treatment is by the uncomfortable discomfort caused of EMT.
Specifically, the compound shown in formula (I) that the present invention provides is useful when treating kinds cancer, including, But be not limited only to, solid tumor, sarcoma, fibrosarcoma, osteoma, malignant melanoma, retinoblastoma, rhabdomyosarcoma, Glioblastoma multiforme, neuroblastoma, teratocarcinoma, hematopoietic malignancies, malignant ascite.More specifically, cancer, include but Be not limited to, pulmonary carcinoma, bladder cancer, cancer of pancreas, renal carcinoma, gastric cancer, breast carcinoma, colon cancer, carcinoma of prostate (including Bone tumour), hepatocyte Cancer, ovarian cancer, esophageal squamous cell carcinoma, melanoma, primary cutaneous type, Inflammatory myofibroblastic tumor, glue Matter blastoma.
Another more excellent detailed description of the invention, the pharmaceutical composition that the present invention provides includes the formula of dose therapeutically effective
(I) compound shown in, or its pharmaceutically acceptable salt, and pharmaceutically acceptable adjuvant.The present invention also provides for The method that treatment protein kinase activity is disorderly, including the drug regimen mentioned above using dose therapeutically effective to patient Thing.
The following compound that the present invention provides, can make reader be more fully understood that the compound that the present invention is contained:
1) 5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyrido-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14- Hexahydro
-6,9,12,15-four oxygen-1,3-diaza-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide；
2) 1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyrido-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14- Hexahydro-6,9,12,15-four oxygen-1,3-diaza-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide；
3) cyclopropyl-1,1-dicarboxylic acids [the fluoro-4-of 3-(7,8,10,11,13,14-hexahydro-6,9,12,15-four oxygen-1,3- Diaza-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide (4-fluoro-phenyl)-amide；
4) 3-(4-fluoro-phenyl)-2-oxo-imidazol quinoline-1-carboxylic acid [the fluoro-4-of 3-(7,8,10,11,13,14-hexahydro-6, 9,12,15-tetra-oxygen-1,3-diaza-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide；
5) 2-(4-fluoro-phenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1 h-pyrazole-4-carboxylic acid [the fluoro-4-of 3-(7, 8,10,11,13,14-hexahydro-6,9,12,15-four oxygen-1,3-diaza-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-acyl Amine；
6) 2-(4-fluoro-phenyl amino)-5-[5-(7,8,10,11,13,14-hexahydro-6,9,12,15-four oxygen-1,3-two Azepine-cyclododecane [b] naphthalene-4-epoxide)-pyridine-2-base]-3-methyl-3H-pyrimidin-4-one；
7) 5-[5-([1,3] dioxy [4,5-g] quinazoline-8-epoxide)-pyridine-2-base]-2-(4-fluoro-phenyl amino)- 3-methyl-3H-pyrimidin-4-one；
8) 5-[5-(2,2-bis-fluoro-[1,3] dioxy [4,5-g] quinazoline-8-epoxide)-pyridine-2-base]-2-(the fluoro-benzene of 4- Base amino)-3-methyl-3H-pyrimidin-4-one；
9) 5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyrido-3-carboxylic acid [4-([1,3] dioxy [4,5-g] quinoline azoles Quinoline-8-epoxide)-3-fluoro-phenyl]-amide；
10) 5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyrido-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14- Hexahydro-6,9,12,15-four oxygen-1-azepine-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide；
11) 1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyrido-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14- Hexahydro-6,9,12,15-four oxygen-1-azepine-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide；
12) 2-(4-fluoro-phenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1 h-pyrazole-4-carboxylic acid [the fluoro-4-of 3-(7, 8,10,11,13,14-hexahydro-6,9,12,15-four oxygen-1-azepine-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide；
13) cyclopropyl-1,1-dicarboxylic acids [the fluoro-4-of 3-(7,8,10,11,13,14-hexahydro-6,9,12,15-four oxygen-1-nitrogen Miscellaneous-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide (4-fluoro-phenyl)-amide；
14) 3-(4-fluoro-phenyl)-2-oxo-imidazol quinoline-1-carboxylic acid [the fluoro-4-of 3-(7,8,10,11,13,14-hexahydro-6, 9,12,15-tetra-oxygen-1-azepine-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide
15) (2-is fluoro-for-2-for 5-[5-(2,2-bis-fluoro-[1,3] dioxy [4,5-g] quinazoline-8-epoxide)-pyridine-2-base] Phenyl amino)-3-methyl-3H-pyrimidin-4-one；
16) 5-[5-(2,2-bis-fluoro-[1,3] dioxy [4,5-g] quinazoline-8-epoxide)-pyridine-2-base]-2-(phenylamino Base)-3-methyl-3H-pyrimidin-4-one；
17) 5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyrido-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14- Hexahydro-6,9,12,15-four oxygen-1-azepine-cyclododecane [b] naphthalene-4-amino)-phenyl]-amide；
18) 5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyrido-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14- Hexahydro-6,9,12,15-four oxygen-1-azepine-cyclododecane [b] naphthalene-4-sulfydryl)-phenyl]-amide；
19) 3-methyl-2-phenyl amino-5-[5-(2,5,7,10-tetra-oxygen-14,16-diaza-three ring [9.8.0.013, 18] nonadecane-1 (11), 12,14,16,18-five thiazolinyl-17-epoxide)-pyridine-2-base]-3H-pyrimidin-4-one；
20) 5-[5-([8,9] dihydro-7H-6,10-dioxy-1,3-diaza-cycloheptane [b] naphthalene-4-epoxide)-pyridine- 2-yl]-2-(4-fluoro-phenyl amino)-3-methyl-3H-pyrimidin-4-one；
21) 2-(4-fluoro-phenyl amino)-3-methyl-5-[5-(9-methyl-8,9,10,11-tetrahydrochysene-7H-6,12-dioxy- 1,3,9-tri-azepines-cyclononane [b] naphthalene-4-epoxide)-pyridine-2-base]-3H-pyrimidin-4-one；
22) 2-(4-fluoro-phenyl amino)-3-methyl-5-[5-(7,8,10,11-tetrahydrochysene-6,9,12-three oxygen-1,3-phenodiazine Miscellaneous-cyclononane [b] naphthalene-4-epoxide)-pyridine-2-base]-3H-pyrimidin-4-one；
23) 5-[5-(8,9-dihydro-7H-6,10-dioxy-1-azepine-cycloheptane [b] naphthalene-4-epoxide)-pyridine-2-base]- 2-(4-fluoro-phenyl amino)-3-methyl-3H-pyrimidin-4-one；
24) 2-(4-fluoro-phenyl amino)-3-methyl-5-[5-(9-methyl-8,9,10,11-tetrahydrochysene-7H-6,12-dioxy- 1,9-diaza-cyclononane [b] naphthalene-4-epoxide)-pyridine-2-base]-3H-pyrimidin-4-one；
25) 2-(4-fluoro-phenyl amino)-3-methyl-5-[5-(7,8,10,11-tetrahydrochysene-6,9,12-three oxygen-1-azepine- Cyclononane [b] naphthalene-4-epoxide)-pyridine-2-base]-3H-pyrimidin-4-one；
26) 3-methyl-2-phenyl amino-5-[5-(2,5,7,10-tetra-oxygen-14-azepine-three ring [9.8.0.013,18] ten Nine alkane
-1 (11), 12,14,16,18-five thiazolinyl-17-epoxide)-pyridine-2-base]-3H-pyrimidin-4-one；
27) 5-[5-(2,2-bis-fluoro-[1,3] dioxy [4,5-g] quinoline-8-epoxide)-pyridine-2-base]-2-(the fluoro-benzene of 2- Base amino)-3-methyl-3H-pyrimidin-4-one；
28) 5-[5-(2,2-bis-fluoro-[1,3] dioxy [4,5-g] quinoline-8-epoxide)-pyridine-2-base]-2-(phenylamino Base)-3-methyl-3H-pyrimidin-4-one；
29) 5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyrido-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14- Hexahydro-6,9,12,15-four oxygen-1,3-diaza-cyclododecane [b] naphthalene-4-amino)-phenyl]-amide；
30) 5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyrido-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14- Hexahydro-6,9,12,15-four oxygen-1,3-diaza-cyclododecane [b] naphthalene-4-sulfydryl)-phenyl]-amide；
31) 5-[5-(2,5,8,11,14,17-six oxygen-21-azepine-three ring [16.8.0.020,25] hexacosane-1 (18), 19,21,23,25-five thiazolinyl-24-epoxide)-pyridine-2-base]-3-methyl-2-phenyl amino-3H-pyrimidin-4-one.
As definition herein, term " main body " refers to a kind of animal, preferably refers to mammal, most preferably refers to People, this " main body " refers to treat always, the object of observation or experiment.Herein, term " dose therapeutically effective " refer to researcher, Reactive compound that veterinary, doctor or other clinicians seek or pharmaceutical composition, for animals or humans tissue system Biology or the response magnitude of medicine, alleviate including the symptom connecing subject disease or discomfort.
As definition herein, term " substituted " (substitued) or " substituent group " (substituent), including many Individual substituent group (such as phenylalanyl, aryl, Heterocyclylalkyl, heterocyclic aryl), usually 1 to 5 substituent groups, are preferably 1 to 3 Individual substituent group, best 1 to 2 substituent groups.
The compound of the present invention may contain asymmetric carbon atom.Those of ordinary skill in the art understands, diastereomer Mixture, differences based on its physicochemical properties, can be separated into single diastereoisomer, such as, chromatography or point One step crystallizing.Mixture of enantiomers, by reacting with suitable optically active compound (such as ethanol), is converted into non-by enantiomer Mixture of enantiomers thus separate, be then peeled off non-enantiomer mixture, and single for gained diastereomer changed (such as water Solve) it is the purest enantiomer.All such isomers, are this including non-enantiomer mixture and pure enantiomer A bright part.
Generally, the compound that the present invention provides can synthesize according to the general synthetic route that scheme 1 describes, but The compound that the present invention provides is not limited in using this route to synthesize.More specifically, what scheme 1 described is quinazoline Compounds, the synthetic method of quinolines.Example subsequently further illustrates described general synthetic route, in order to Those of ordinary skill in the art can prepare, use the present invention to provide quinazoline or quinoline compound.
Scheme 1 summarises the general synthetic route of the compound that the present invention provides, and such as, the Z in formula (I) is NR3R4。
Scheme 1
4-chloro-6,7-Dimethoxy-quinazolin (1a) or 4-chloro-6,7-Dimethoxy-quinolin (1b) commercially available or The method conventional by those of ordinary skill in the art prepares.In " step 1 " of scheme 1,1a or 1b and phenyl amines 2a, phenols , there is trialkylamine or the condition of basic carbonate (such as, triethylamine, potassium carbonate) in 2b or the nucleophilic displacement of fluorine of thiophenols 2c Under, can easily complete.
In " step 2 " of scheme 1, start with suitable reagent and step process, 6 of intermediate 3 and 7 from " step 1 " Methyl protection group on position all can remove.Such as, process 1 hour with Boron tribromide at 0 DEG C, then process 4 hours under room temperature.
In " step 3 " of scheme 1, with suitable reagent such as 5 (leaving group R9Tosylate, bromide ion or iodine from Son), under conditions of depositing trialkylamine or basic carbonate (such as, triethylamine, potassium carbonate), processing diphenols intermediate 4 can Prepare fused ring heterocycle compound.The selection of solvent and reaction temperature is critically important to high yield.Generally preferable solvent is DMF Or DMSO.
In " step 4 " of scheme 1, nitro reduction can be completed by hydrogenation using palladium carbon as catalyst.Additionally, nitro is also Former can also use zinc powder or iron powder.
The final step of scheme 1, aniline 7 and suitably acid or its corresponding acid chloride 8 in the basic conditions as triethylamine, Diisopropylethylamine, carries out coupling and prepares end-product amide 9.Aniline and sour 8 couplings, need to use coupling reagent, as HOBt, DCC。
Scheme 2
One substitutes the synthetic route of key intermediate 7 as shown in scheme 2.10 with phenyl amines 11a, phenols 11b or thiophenol 11c coupling produces corresponding key intermediate 7, the chloro-quinazoline of fused ring compound 4-(10a), 4-chlorine-quinoline (10b), phenyl amines 11a, phenols 11b or thiophenols 11c are commercially available, or pass through various according to known references preparation or those skilled in the art Known method is prepared easily.
Scheme 3
Another substitutes the synthetic route of end-product shown in preparation formula (I) as shown in Scheme 3,10 and phenyl amines 12a, phenols 12b or thiophenols 12c coupling prepares the compound shown in corresponding formula (I).The chloro-quinazoline of fused ring compound 4-(10a), 4- Chlorine-quinoline (10b), aniline 12a, phenols 12b or thiophenol 12c be commercially available, or according to known references preparation or this area Technical staff is prepared easily by various known methods
In order to prepare the pharmaceutical composition that the present invention provides, the one or more compound or its salt conducts shown in formula (I) Active component, mixes according to field of medicaments routine complex technique with pharmaceutically acceptable carrier, and this carrier can be taked Various forms, depend on the method for application (such as oral or injection) of prepared medicine.Pharmaceutically acceptable carrier exists Known in the art, American Medical Association and Great Britain's medicine and pharmacology can publish " pharmaceutic adjuvant handbook " (The Handbook of Pharmaceutical Excipients) describe some pharmaceutically acceptable carriers, to of the present inventionization The preparation process of the pharmaceutically acceptable carrier that compound may use has carried out some explanations.Sensitivity in protection molecular structure Group or reactive group are probably necessity and/or favourable.The sensitive base of method protection of protection protection group that can be conventional Group or reactive group, these methods are at " protection group in organic chemistry " (Protective Groups in Organic Chemistry, ed.J.F.W.McOmie, Plenum Press, 1973) and " protection group in organic synthesis " In (T.W.Greene&P.G.M.Wuts, John Wiley&Sons, 1991) the most on the books, protection group can be in later step Techniques well known is used to remove easily.
Use any method that compound can be transported to target spot (such as cancerous cell), executing of reactive compound can be realized With.These methods include that oral route, rectal delivery, duodenal administration approach, parenteral injection (include that vein is noted Penetrate, subcutaneous injection, intramuscular injection, intravascular injection or transfusion), topical etc., certainly, the amount of application of reactive compound, rely on Subject main body, the judgement of the painful order of severity, method of application and prescriber is connect in.But, effective dose Scope at about 0.001 milligram to about 300 milligrams (more preferably, from about 0.01 milligram to about 100 milligram；More preferably, from about 0.1 Milligram to about 30 milligrams), possible dosage about 0.001 mg/kg/day to 300 mg/kg/day (more preferably, from About 0.01 mg/kg/day is to about 100 mg/kg/day；More preferably, from about 0.1 mg/kg/day to about 30 milligram/thousand Gram/day).
Such as, this pharmaceutical composition is applicable to peroral dosage form, such as tablet, capsule, pill, powder, slow release formulation, solution Agent or suspending agent；It is applicable to parenteral injection type, such as sterile solution, suspending agent or Emulsion；Or Topical dosage forms, such as ointment Or ointment；Or forms for rectal administration such as suppository.It is accurate that this pharmaceutical composition is applicable to the form single administration with unit dosage forms Dosage.Described pharmaceutical composition includes that conventional pharmaceutical carrier or excipient and the present invention are provided as the chemical combination of active component Thing.Furthermore it is also possible to include other medical or medicinal reagent, carrier or accessory drugss etc..
Typical parenteral form of medication, the solution formed in aseptic aqueous solution including reactive compound or suspension, example Such as aqueous solution of propylene glycol or glucose solution.Dosage form is suitably buffered it is possible if desired to make.
The pharmaceutical carrier being suitable for includes inert diluent or filler, water and various organic solvent.If it is required, this medicine group Compound can also comprise supplementary element such as spice, binding agent, excipient etc..The multiple auxiliary materials that oral tablet can contain, as with Citric acid associated with the silicate of various disintegrating agents such as starch, alginic acid and some complexity, and bonding agent such as sucrose, gelatin and I Uncle's natural gum.Additionally, it is useful that lubricant such as magnesium stearate, sodium lauryl sulphate and Pulvis Talci may often be such that film-making.
The solid constituent that type is similar, it is also possible to for soft, the filling of hard capsule.Therefore, first-selected material includes lactose Or milk sugar and the Polyethylene Glycol of super high molecular weight.If it is required, the water slurry of oral administration or elixir, active ingredient therein Thing can be combined various sweeting agent or flavoring agent, coloring agent or food coloring, and, if it is desired, emulsifying agent can also be combined Or flotation reagents and diluent such as water, ethanol, propylene glycol, glycerol or combinations thereof.
The compound that the present invention provides is likely to the mammal being applied to beyond the mankind.It is administered to the dosage of mammal Depend on animal species and connecing subject disease or disorder.This compound may soak with capsule, pill, tablet or liquid Thoroughly etc. mode is administered to animal.This compound is likely in the way of injection or implantation be administered to animal.Veterinary according to standard Practice, prepares above-mentioned formula in a conventional manner.As the therapeutic compound of a kind of replacement, may execute together with animal feed With.Therefore, in order to mix with intact animal's feedstuff, feed additive or the premix material of concentration can be prepared.
One example of the use present invention is: a main body, and this main body needs to treat EGF-R ELISA
(EGFR) tyrosine kinase or the tyrosine kinase mediated obstacle of vascular endothelial growth factor receptor (VEGFR), control Treatment method includes any of above compound to treatment administered therapeutically effective amount or pharmaceutical composition.Preferably embodiment party Formula, is used for treating cancer, such as the brain cancer, pulmonary carcinoma, squamous cell cancer, bladder cancer, gastric cancer, cancer of pancreas, breast carcinoma, head cancer, neck Cancer, esophageal carcinoma, carcinoma of prostate, colorectal carcinoma, gynecological cancer or thyroid carcinoma.
Detailed description of the invention
The following examples are used for being more fully understood that the present invention.Unless stated otherwise, otherwise, all of part and percentage ratio Being by weight calculation, all of temperature is all degree Celsius.
Embodiment employs following abbreviations:
ATP: adenosine triphosphate；
DMF:N, dinethylformamide；
DMSO: dimethyl sulfoxide；
EtOAc: ethyl acetate；
GSR: glutathion-s-transferring enzyme；
Crk, CT10: chicken tumor disease poison 10；
Min: minute；
H: hour；
H: hour；
Rt: room temperature；
SDS: sodium lauryl sulphate；
SDS-PAGE: alkyl sodium sulfate polyacrylamide gel electrophoresis gel；
TLC: thin layer chromatography.
Embodiment 1
5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyrido-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14-six Hydrogen-6,9,12,15-four oxygen-1,3-diaza-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide (9a)
Step 1:4-(4-amino-2-methyl-phenoxy group)-7,8,10,11,13,14-hexahydro-6,9,12,15-four oxygen-1, 3-diaza-cyclododecane [b] naphthalene
The 4-fluoro-phenol of amino-2-(1.53 grams, 12.0mmol) is dissolved in the nothing of 60%NaH (774mg, 19.3mmol) In water dimethylformamide (30 milliliters).Then, mixed at room temperature stirs a few minutes, adds 4-chloro-7,8,10,11,13,14-six Hydrogen-6,9,12,15-tetra-oxygen-1, DMF (40ml) suspension of 3-diaza-cyclododecane [b] naphthalene (2.08g, 6.7mmol), instead Answer and stir 1-2 hour under mixture room temperature, then dilute with EtOAc and use NaHCO3With 3 times in saturated solution, wash 1 time, salt Wash 1 time, then use Na2SO4Being dried, the vacuum drying of gained concentrated solution obtains crude product (2.68g ,-100%), it is not necessary to purification, directly Connect and react for next step.
1H-NMR(400MHz,DMSO):8.58(s,1H),7.80(s,1H),7.50(s,1H),7.04(t,1H),6.50 (dd,2H),5.40(br s,2H),4.35(s,4H),3.87(d,4H),3.62(s,4H).
LC/MS theoretical value (M+H)+401.4, measured value 402.5.
Step 2:5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyrido-3-carboxylic acid [the fluoro-4-of 3-(7,8,10,11,13, 14-hexahydro-6,9,12,15-four oxygen-1,3-diaza-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide
Under nitrogen protection and ice bath temperature, by HATU (15.65g, 41.2mmol) and i-Pr2NEt(18mL,104mmol) Join 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid 8d (J.Med.Chem.2008,51,5330 5341) In dry DMF (56mL) suspension of (8.0g, 34.3mmol).Mixture is stirred for after becoming settled solution 5 minutes.The slowest Slow add in this solution 4-(4-amino-2-methyl-phenoxy group)-7,8,10,11,13,14-hexahydro-6,9,12,15-four oxygen- 1,3-diaza-cyclododecane [b] naphthalene 7a (7.9g, 32.5mmol).After stirring 3 hours under room temperature, pour the water-soluble of 1N HCl into In liquid.Formed and filter after solid, then with distilled water wash, and be dried.Gained thick product silica gel column chromatography, with the methanol of 1-5% Dichloromethane, obtains light yellow solid 9a (5.9g, 40%), fusing point 188-190 DEG C.HPLC is further purified to obtain purity The product of 97%.
1H NMR(400MHz,DMSO)δ13.13(s,1H),12.68(br s,1H),8.62(m,2H),7.97-8.12 (m,2H),8.04-7.99(m,2H),7.78(m,1H),7.69(m,2H),7.42(d,2H),7.21(m,2H)；4.35(s, 4H),3.87(d,4H),3.62(s,4H)。
LC/MS theoretical value (M+H)+617.6, measured value 617.5.
Embodiment 2
1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyrido-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14-six Hydrogen-6,9,12,15-four oxygen-1,3-diaza-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide)
Use 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (J.Med.Chem.2008,51,5330- 5341) 5-(4-fluorophenyl)-4-oxo-Isosorbide-5-Nitrae-dihydro-pyrido-3-carboxylic acid is replaced, according to step same as in Example 1 and bar Part prepares target compound.
LC/MS theoretical value (M+H)+617.6, measured value 617.5.
Embodiment 3
Cyclopropyl-1,1-dicarboxylic acids [the fluoro-4-of 3-(7,8,10,11,13,14-hexahydro-6,9,12,15-four oxygen-1,3-two Azepine-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide (4-fluoro-phenyl)-amide
Use 1-(4-fluoro-phenyl aminoacyl)-cyclopropyl-carboxylic acid (J.Med.Chem.2008,51,5330-5341) generation For 5-(4-fluorophenyl)-4-oxo-Isosorbide-5-Nitrae-dihydro-pyrido-3-carboxylic acid, prepare with condition according to step same as in Example 1 Target compound.
1H NMR(400MHz,DMSO)δ10.33(s,1H),10.08(s,1H),8.56(m,1H),7.82(m,2H), 7.69(m,2H),7.28-7.51(m,3H),7.19(m,2H),4.35(s,4H),3.87(d,4H),3.62(s,4H),1.47 (s,4H)。
LC/MS theoretical value (M+H)+607.6, measured value 607.7.
Embodiment 4
3-(4-fluoro-phenyl)-2-oxo-imidazol quinoline-1-carboxylic acid [the fluoro-4-of 3-(7,8,10,11,13,14-hexahydro-6,9, 12,15-tetra-oxygen-1,3-diaza-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide
Use 3-(4-fluoro-phenyl)-2-oxo-1-imidazoles-1-carboxylic acid (J.Med.Chem.2008,51,5330-5341) Replace 5-(4-fluorophenyl)-4-oxo-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid, prepare with condition according to step same as in Example 3 Target compound.
LC/MS theoretical value (M+H)+608.6, measured value 608.8.
Embodiment 5
2-(4-fluoro-phenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1 h-pyrazole-4-carboxylic acid [the fluoro-4-of 3-(7,8, 10,11,13,14-hexahydro-6,9,12,15-four oxygen-1,3-diaza-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide
Use 2-(4-fluoro-phenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1 h-pyrazole-4-carboxylic acid (J.Med.Chem.2008,51,5330-5341) replaces 5-(4-fluorophenyl)-4-oxo-Isosorbide-5-Nitrae-dihydro-pyrido-3-carboxylic acid, presses Target compound is prepared according to step same as in Example 2 and condition.
1H NMR(400MHz,DMSO)δ10.93(s,1H),8.59(s,1H),7.96(d,1H),7.82(s,1H),7.69 (m,2H),7.28-7.51(m,4H),7.19(m,1H),4.35(s,4H),3.87(d,4H),3.62(s,4H),3.47(s, 3H),2.71(s,3H)。
LC/MS theoretical value (M+H)+634.6, measured value 634.8.
Embodiment 6
2-(4-fluoro-phenyl amino)-5-[5-(7,8,10,11,13,14-hexahydro-6,9,12,15-four oxygen-1,3-phenodiazine Miscellaneous-cyclododecane [b] naphthalene-4-epoxide)-pyridine-2-base]-3-methyl-3H-pyrimidin-4-one
By 2-(4-fluoro-phenyl amino)-5-(5-Hydroxy-pyridine-2-base)-3-methyl-3H-pyrimidin-4-one (2.18g, 7mmol) it is dissolved in the anhydrous dimethyl formamide (30 milliliters) of 60%NaH (774mg, 19.3mmol).Then, mixed at room temperature Stirring a few minutes, add chloro-7,8,10,11,13,14-hexahydro-6 of 4-, 9,12,15 four oxygen-1,3-diaza-cyclododecane The DMF suspension (40ml) of [b] naphthalene (2.08g, 6.7mmol), stirs 1-2 hour under reactant mixture room temperature, then uses EtOAc Dilute and use NaHCO3With 3 times in saturated solution, washing 1 time, salt is washed 1 time, then uses Na2SO4It is dried, gained concentrated solution vacuum It is dried to obtain crude product and is further purified, obtaining product (3.68g, 90%).
1H-NMR(400MHz,DMSO):9.18(s,1H),8.60(m,3H),8.45(d,1H),7.84(s,1H),7.82 (m,1H),7.55(m,3H),7.21(m,2H),4.35(s,4H),3.87(d,4H),3.62(s,4H)。
LC/MS theoretical value (M+H)+587.6, measured value 587.9.
Embodiment 7
5-[5-([1,3] dioxy [4,5-g] quinazoline-8-epoxide)-pyridine-2-base]-2-(4-fluoro-phenyl amino)-3- Methyl-3H-pyrimidin-4-one
By 2-(4-fluoro-phenyl amino)-5-(5-Hydroxy-pyridine-2-base)-3-methyl-3H-pyrimidin-4-one (2.18g, 7mmol) it is dissolved in the anhydrous dimethyl formamide (30 milliliters) of 60%NaH (774mg, 19.3mmol).Mixed at room temperature stirs After a few minutes, the DMF (40ml) adding the 8-chloro-[1,3] dioxy [4,5-g] quinazoline (2.08g, 6.7mmol) being dried suspends Liquid, stirs 1-2 hour under reactant mixture room temperature, then dilutes with EtOAc and use NaHCO3With 3 times in saturated solution, wash 1 Secondary, salt is washed 1 time, then uses Na2SO4Being dried, the vacuum drying of gained concentrated solution obtains crude product and is further purified, and obtains product (3.68g, 90%).
1H-NMR(400MHz,DMSO):9.18(s,1H),8.60(m,3H),8.45(d,1H),7.84(s,1H),7.82 (m,1H),7.55(m,3H),7.21(m,2H),4.15(s,2H)。
LC/MS theoretical value (M+H)+485.4, measured value 485.9.
Embodiment 8
5-[5-(2,2-bis-fluoro-([1,3] dioxy [4,5-g] quinazoline-8-epoxide)-pyridine-2-base]-2-(the fluoro-benzene of 4- Base amino)-3-methyl-3H-pyrimidin-4-one
By 2-(4-fluoro-phenyl amino)-5-(5-Hydroxy-pyridine-2-base)-3-methyl-3H-pyrimidin-4-one (2.18g, 7mmol) it is dissolved in the anhydrous dimethyl formamide (30 milliliters) of 60%NaH (774mg, 19.3mmol).Then, mixed at room temperature Stirring a few minutes, add chloro-7,8,10,11,13,14-hexahydro-6 of 4-, 9,12,15 four oxygen-1,3-diaza-cyclododecane Stir 1-2 hour under DMF (40ml) the suspension reactant mixture room temperature of [b] naphthalene (2.08g, 6.7mmol), then use EtOAc Dilute and use NaHCO3With 3 times in saturated solution, washing 1 time, salt is washed 1 time, then uses Na2SO4It is dried, gained concentrated solution vacuum It is dried to obtain crude product and is further purified, obtaining product (3.68g, 90%).
1H-NMR(400MHz,DMSO):9.18(s,1H),8.70(m,3H),8.55(d,1H),7.84(s,1H),7.82 (m,1H),7.55(m,3H),7.21(m,2H)。
LC/MS theoretical value (M+H)+521.4, measured value 521.6.
Embodiment 9
5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyrido-3-carboxylic acid [4-([1,3] dioxy [4,5-g] quinazoline- 8-epoxide)-3-fluoro-phenyl]-amide
By 2-(4-fluoro-phenyl amino)-5-(5-Hydroxy-pyridine-2-base)-3-methyl-3H-pyrimidin-4-one (2.18g, 7mmol) it is dissolved in the anhydrous dimethyl formamide (30 milliliters) of 60%NaH (774mg, 19.3mmol).Then, mixed at room temperature Stirring a few minutes, add chloro-7,8,10,11,13,14-hexahydro-6 of 4-, 9,12,15-tetra-oxygen-1,3-diaza-cyclododecane DMF (40ml) suspension of [b] naphthalene (2.08g, 6.7mmol), stirs 1-2 hour under reactant mixture room temperature, then uses EtOAc Dilute and use NaHCO3With 3 times in saturated solution, washing 1 time, salt is washed 1 time, then uses Na2SO4It is dried, gained concentrated solution vacuum It is dried to obtain crude product and is further purified, obtaining product (3.68g, 90%).
1H NMR(400MHz,DMSO)δ13.43(s,1H),12.98(br s,1H),8.82(m,2H),7.97-8.12 (m,2H),8.04-7.99(m,2H),7.78(m,1H),7.69(m,2H),7.42(d,2H),7.21(m,2H)；4.65(s, 4H)。
LC/MS theoretical value (M+H)+515.4, measured value 515.5.
Embodiment 10
5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyrido-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14-six Hydrogen-6,9,12,15-four oxygen-1-azepine-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide
Step 1:1-(3-nitro-6,7,9,10,12,13-hexahydro-5,8,11,14-four oxygen-benzo ring dodecane-2- Base)-ethyl ketone
By 1-(6,7,9,10,12,13-hexahydro-5,8,11,14-four oxygen-benzo ring dodecane-2-base)-ethyl ketone (200mmol, 51.3g) is dissolved in DCM (750ml) and is cooled to 0 DEG C.After 20 minutes, by nitric acid (90%, 300mmol, 14ml) It is added dropwise in the reactant liquor after cooling.Then, at 0 DEG C, sulphuric acid (96.2%, 300mmol, 8.75ml) is added dropwise over In reactant liquor, 40 minutes used times.It addition, again nitric acid (200mmol, 9.4ml) is added dropwise in reactant liquor, 20 minutes used times. Reactant mixture 300ml water dilutes and washes (3X 200ml), then uses NaHCO3Saturated solution washing (4X 200ml, or Person is until neutral).Organic layer Na2SO4It is dried and concentrates.Crude mixture DMF is recrystallized to give 22.5g nitrification product. DMF layer concentrates and obtains 8.75g product with re-crystallizing in ethyl acetate is another.Ethyl acetate layer concentrates and uses silica column purification, eluent 20%EtOAc/ n-hexane, obtains other 4.75g product.Total recovery 36g, (about 60%).
1H NMR(400MHz,DMSO)δ7.82(s,1H),7.61(s,1H),4.35(s,4H),3.87(d,4H),3.62 (s,4H),2.71(s,3H)。
LC/MS theoretical value (M+H)+312.3, measured value 312.5
Step 2:1-(3-amino-6,7,9,10,12,13-hexahydro-5,8,11,14-four oxygen-benzo ring dodecane-2- Base)-ethyl ketone
Iron powder (477mmol, 27g), ammonium acetate (500mmol, 31g), 1-(3-nitro-6,7,9,10,12,13-hexahydro- 5,8,11,14-tetra-oxygen-benzo ring dodecane-2-base)-ethyl ketone (120mmol, 36g), toluene (500ml) and water (500ml) Mixture backflow is overnight or until reaction is complete.Mixture filters through kieselguhr, and washs by ethyl acetate.Organic layer is washed And NaCl saturated solution washes, and use Na2SO4It is dried and is concentrated to give product, yield 90%.
1H NMR(400MHz,DMSO)δ7.82(s,1H),7.61(s,1H),5.45(s,2H),4.35(s,4H),3.87 (d,4H),3.62(s,4H),2.71(s,3H)。
LC/MS theoretical value (M+H)+282.3, measured value 282.5.
Step 3:7,8,10,11,13,14-hexahydro-1H-6,9,12,15-four oxygen-1-azepine-cyclododecane [b] naphthalene-4- Ketone
1-(3-amino-6,7,9,10,12,13-hexahydro-5,8,11,14-four oxygen-benzo ring dodecane-2-base)-ethyl ketone In the DME solution (700ml) of (108mmol, 29.3g), add Feldalat NM (432mmol, 23.35g).Gained mixture stirring 30 Minute.Entering Ethyl formate (540mmol, 44ml), this mixture is stirred overnight.(with LC/MS monitoring reaction, if unreacted is complete Entirely, in addition it is also necessary to add Feldalat NM).After reaction completely, mixture washing (40ml) is also acidified to neutrality with 1M HC1.It is heavy to filter Shallow lake thing is also washed, be vacuum dried to obtain 22g (72%) 7,8,10,11,13,14-hexahydro-1H-6,9,12,15-tetra-oxygen-1-azepine- Cyclododecane [b] naphthalene-4-ketone.
1H NMR(400MHz,DMSO)δ8.58(s,1H),7.52(s,1H),7.22(s,1H),7.12(m,1H),4.35 (s,4H),3.87(d,4H),3.62(s,4H)。
LC/MS theoretical value (M+H)+292.3, measured value 292.5.
Step 4:4-(2-fluoro-4-nitro-phenoxy)-7,8,10,11,13,14-hexahydro-6,9,12,15-four oxygen-1-nitrogen Miscellaneous-cyclododecane [b] naphthalene
Equipped with the round-bottomed flask of magnetic stirring apparatus adds 7,8,10,11,13,14-hexahydro-1H-6,9,12,15- Four oxygen-1-azepines-cyclododecane [b] naphthalene-4-ketone (12.2g, 43.3mmol, 1.0eq), acetonitrile (150ml), DMF (150ml) and Cesium carbonate (28.2g, 86.5mmol, 2.0eq).Stir 30 minutes, then, 10 minutes used times under gained mixture room temperature, add 1,2-fluoro-4-nitro-benzene (7.57g, 47.6mmoL, 1.1eq).After 2 hours, react 75%, removed acetonitrile and DMF, so After pour in frozen water.Solid filters, is dried, and further chromatographic column (purchased from Biotage company) excessively.Eluent is 1:3 acetic acid Ethyl ester/normal hexane.Remove solvent, obtain light green solid 4-(2-fluoro-4-nitro-phenoxy)-7,8,10,11,13,14-six Hydrogen-6,9,12,15-tetra-oxygen-1-azepines-cyclododecane [b] naphthalene (7.4g, yield 41%).
1H-NMR(400MHz,DMSO):8.58(s,1H),7.80(s,1H),7.50(s,1H),7.04(t,1H),6.88 (m,1H),6.50(m,2H),4.35(s,4H),3.87(d,4H),3.62(s,4H)。
LC/MS theoretical value (M+H)+431.4, measured value 431.5.
Step 5:4-(the fluoro-phenoxy group of 4-amino-2-)-7,8,10,11,13,14-hexahydro-6,9,12,15-four oxygen-1-nitrogen Miscellaneous-cyclododecane [b] naphthalene
By 4-(2-fluoro-4-nitro-phenoxy)-7,8,10,11,13,14-hexahydro-6,9,12,15-four oxygen-1-azepine- Cyclododecane [b] naphthalene (0.800g, 1.6mmol, 1.0eq.), DMF (50ml), EtoAc (50ml), MeOH (50ml), TEA (5ml) and 10%Pd/C (200mg) puts in hydrogenation reaction kettle, under 35psi pressure, hydrogenated over night.It is filtered to remove Pd, then Remove solvent, obtain yellow solid 4-(the fluoro-phenoxy group of 4-amino-2-)-7,8,10,11,13,14-hexahydro-6,9,12,15-tetra- Oxygen-1-azepine-cyclododecane [b] naphthalene (0.78g, yield 99%).
1H-NMR(400MHz,DMSO):8.58(s,1H),7.80(s,1H),7.50(s,1H),7.04(t,1H),6.88 (m,1H),6.50(m,2H),5.40(br s,2H),4.35(s,4H),3.87(d,4H),3.62(s,4H)。
LC/MS theoretical value (M+H)+401.4, measured value 401.5.
Step 6:5-(4-fluoro-phenyl l)-4-oxo-1,4-dihydro-pyrido-3-carboxylic acid [the fluoro-4-of 3-(7,8,10,11, 13,14-hexahydro-6,9,12,15-four oxygen-1-azepine-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide
By 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid 8d (J.Med.Chem.2008,51,5330- 5341) suspension, then under the protection of nitrogen, ice bath temperature are formed during (8.0g, 34.3mmol) adds dry DMF (56mL) Lower addition HATU (15.65g, 41.2mmol) and i-Pr2NEt(18mL,104mmol).After stirring 5 minutes, mixture becomes clarification, It is slowly added into 4-(the fluoro-phenoxy group of 4-amino-2-)-7,8,10,11,13,14-hexahydro-6,9,12,15-four oxygen-1-azepine-ring Dodecane [b] naphthalene 7a (7.9g, 32.5mmol).After stirring 3 hours under reactant mixture room temperature, pour in 1NHCl.Filter and formed Solid, with distilled water wash, and be dried.Thick product silica gel chromatography is purified, the CH of eluent 1-5%MeOH2Cl2Solution, Obtain light yellow solid 9a (5.9g, 40%), fusing point: 188-190 DEG C.HPLC purity after purification is 97%.
1H NMR(400MHz,DMSO)δ13.13(s,1H),12.68(br s,1H),8.62(m,2H),7.97-8.12 (m,2H),8.04-7.99(m,2H),7.78(m,1H),7.69(m,2H),7.42(d,2H),7.21(m,2H)；6.89(m, 1H),4.35(s,4H),3.87(d,4H),3.62(s,4H)。
LC/MS theoretical value (M+H)+616.6, measured value 616.5.
Embodiment 11
1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyrido-3-carboxylic acid [3-fluoro-4-(7,8,10,11,13,14-six Hydrogen-6,9,12,15-four oxygen-1-azepine-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide
5-(4-fluorophenyl)-4-oxo-1,4-is replaced with 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid Dihydro-pyrido-3-carboxylic acid, the step described according to embodiment 6 and condition prepare target compound.
LC/MS theoretical value (M+H)+616.6, measured value 616.5.
Embodiment 12
2-(4-fluoro-phenyl)-1,5 dimethyl-3-oxo-2,3-dihydro-1 h-pyrazole-4-carboxylic acid [the fluoro-4-of 3-(7,8, 10,11,13,14-hexahydro-6,9,12,15-four oxygen-1-azepine-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide
5-(4-fluorobenzene is replaced with 2-(4-fluoro-phenyl)-1,5-dimethyl-3-oxo-2,3 dihydro-1 h-pyrazole-4-carboxylic acid Base)-4-oxo-Isosorbide-5-Nitrae-dihydro-pyrido-3-carboxylic acid, the step described according to embodiment 6 and condition prepare target compound.
1H NMR(400MHz,DMSO)δ10.93(s,1H),8.59(s,1H),7.96(d,1H),7.82(s,1H),7.69 (m,2H),7.28-7.51(m,4H),7.19(m,1H),6.46(m,1H),4.35(s,4H),3.87(d,4H),3.62(s, 4H),3.47(s,3H),2.71(s,3H)。
LC/MS theoretical value (M+H)+633.6, measured value 633.8.
Embodiment 13
Cyclopropyl-1,1-dicarboxylic acids [the fluoro-4-of 3-(7,8,10,11,13,14-hexahydro-6,9,12,15-four oxygen-1-azepine- Cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide (4-fluoro-phenyl)-amide
5-(4-fluorophenyl)-4-oxo-1,4-dihydro-pyrrole is replaced with 1-(4-fluoro-phenyl aminoacyl)-cyclopropane-carboxylic acid Pyridine-3-carboxylic acid, the step described according to embodiment 6 and condition prepare target compound.
1H NMR(400MHz,DMSO)δ10.33(s,1H),10.08(s,1H),8.56(m,1H),7.82(m,2H), 7.69(m,2H),7.28-7.51(m,3H),7.19(m,2H),6.88(m,1H),4.35(s,4H),3.87(d,4H),3.62 (s,4H),1.47(s,4H)。
LC/MS theoretical value (M+H)+606.6, measured value 606.7.
Embodiment 14
3-(4-fluoro-phenyl)-2-oxo-imidazol quinoline-1-carboxylic acid [the fluoro-4-of 3-(7,8,10,11,13,14-hexahydro-6,9, 12,15-tetra-oxygen-1-azepine-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide
With 3-(4-fluoro-phenyl)-2-oxo-imidazolidin-1-carboxylic acid replace 5-(4-fluorophenyl)-4-oxo-1,4-dihydro- Pyridine-3-carboxylic acid, the step described according to embodiment 6 and condition prepare target compound.
LC/MS theoretical value (M+H)+607.6, measured value 607.7.
Pharmacological testing
Tests below shows, some compound of the present invention restrained effectively intracellular c-Met phosphorylation and internal The activity of c-Met, in some heteroplastic transplantation model, shows the anti-tumor activity relevant to dosage.
Biological Detection
The kinase domain (from 966 glycine to 1390 serine, NCBI NM_000245) of people c-Met is cloned ArriveOn (Invitrogen, Carlsbad, CA) carrier.UseSystem (Invitrogen) will His-c-Met kinase domain is transcribed on baculovirus DNA.SF9 cell infection recombinant baculovirus.Infected cell from The heart is enriched with and collects cell grain and is stored in-80 DEG C.Buffer A (40mM tri-(methylol) aminomethane (being abbreviated as Tris), The sodium chloride of PH7.5,500mM, 20% glycerol, and 10mM imidazoles) cell lysis.Cell pyrolysis liquid homogenate is centrifugal.Supernatant is used Nickel-nitrilotriacetic acid (Ni-NTA) resin is hatched and upper prop.Protein buffer B (buffer A adds 0.3M imidazoles) eluting, contains The eluent having c-Met segment pools together, and is then charged intoPost (Amershan Bioscience, Piscataway, NJ), with buffer C (40mMTris, PH7.5,250mM sodium chloride, 10% glycerol) eluting.
NCI-H460Met (pY1349 sudden change) the cellular level ELISA that hepatocyte growth factor (HGF) stimulates tests NCI- H460 cell (purchased from ATCC) is training in containing 10% hyclone (FBS) at RPMI RPMI-1640 (Invitrogen company) Supporting, in tiling to (70% merge before) 96 hole flat undersides, density is that every hole 80 μ L contain about 20 altogether, and then 000 cell, is somebody's turn to do Cell cultivates couveuse (5%CO at cell2, 95% relative humidity (RH) and 37 DEG C) and overnight incubation, it is allowed to be adsorbed onto on flat board. The next morning, with the low serum free culture system liquid (RSM) of 2 times of volumes, (RPMI RPMI-1640 adds 0.5% hyclone (FBS)) cell is cleaned.After removing last cleanout fluid, each hole of cell plates adds the RSM of 80 μ L.Cell plates are at cell Cultivate and couveuse is hatched 2.5 hours, then, add the compound demarcating dosage.This compound is first dissolved in 100%DMSO In, concentration is 10mM, is then diluted to 100 μMs with the RSM containing 2%DMSO.Subsequently, serial dilution (1:3) arrives to 100 μMs The scope of 0.005 μM.Cell is according to dosage administered, and adds 20 compound solutions standby for μ L, makes DMSO final concentration of 0.4%, and Final compound concentration dosage range is made to be 20 to 0.001 μM.After adding each group of compound, it is shaken gently for cell mixing plate, so After be placed on cell cultivate couveuse hatch 30 minutes.After medicine effect, every hole adds 20 μ L hepatocyte growth factors (HGF), (except negative control hole (MIN wells), this hole is with the 20 low serum of μ L for final concentration of 100ng/mL low serum free culture system liquid Culture fluid) stimulate cell.After hatching 10 minutes in cell cultivates couveuse, remove liquid, add 50 phosphoric acid ice-cold for μ L Enzyme I and II and the Meso Scale of protease inhibitor (Sigma, St.Louis, MO)(MSD, Gaithersburg, Maryland) IX lysis buffer (IX Lysis Buffer, 150mM NaCl, 20mM Tris, PH7.5,1mM EDTA, 1mM ethylene glycol tetraacetic andX-100), cell lysis.After lysis at room temperature 30min, turn Move pyrolysis product and utilizeMultiple spot 96 orifice plate capture signal.
Table 1
Met phosphorylation 4 spot plate BSA (the IX Tris lavation buffer solutions of 30 mg/ml Block A) closes, then Wash once with Tris lavation buffer solution.After room temperature captures 2 hours, fromPyrolysis product is removed on plate, and by this plate IX Tris lavation buffer solution washs.After removing stain, anti-total Met antibody (detection antibody of 25 μ L5nM sulfur labellingsSystem Standby: IX Tris lavation buffer solution be aided with 10mg/mL BSA and 0.1% sealer D-R ()) addThe hole of plate In.After room temperature captures 1 hour, wash with IX Tris lavation buffer solutionPlate hole, is subsequently adding 150 μ L IX readings bufferings Liquid T (with surfactant,).After adding readings buffer, immediately with SECTOR 6000Imager enzyme mark Microwell plate analyzed by instrument." maximum ", the interval percentage of " minimum " value difference is accounted for by 10 dose points and corresponding response value Rate matching quadruplex parameters, calculates relative IC50 value with MSD unit of activity.The minimum notable ratio (Minimum of this detection method Significant Ratio) it is 2.06.The IC50 of the compound of all mensuration is both less than 0.2 μM (as shown in table 1).Such as, real Executing in example 1, average (N=6) IC50 value (50% inhibition concentration) is 0.0352 μM, shows that compound can suppress in cell effectively C-Met phosphorylation.
Targeted inhibition experiment in c-Met body
SL14 cell (deriving from PHS, overexpression human Hepatocyte Growth's factor (HGF) and mankind c-Met) is containing The growth medium (the Eagle culture medium of Dulbecco's improvement, auxiliary) of 10% calf serum is cultivated and amplification.Collect cell And wash twice with phosphate buffer, 2X106Cell and BD MatrigelTMmatrix(BD Bioscience, Franklin, NJ) equal-volume mixing, inject nude mice oxter (nude mouse, derives from Harlan, Indianapolis, IN) after 8 days, compound (by 10% Radix Acaciae senegalis, or 1% carboxymethyl cellulose/0.5% sodium lauryl sulphate/0.05% Defoamer is constituted, a kind of suspension) it is applied to animal by gastric infusion, dosage is 50mg/kg, and animal was put to death after 2 hours, receives Collection tumor freezer storage.
Freezing tumor motar-pastel is pulverized.The tissue pulverized is transferred to containing Lysing Matrix D beads (MP Biomedicals, Solon, OH) and 600 μ L lysis buffers (RIPA buffer, containing 50mM Tris-HCl, PH7.4,150mM NaCl, 1%NP-40,0.5% oxycholic acid sodium, 0.1%SDS, derive from Boston Bioproducts) In test tube.WithCell Disrupter (MP Biomedicals) destroys tissue and cell lysis.With No. 20 syringe needles Lysate is transferred in a clean test tube.Protein concentration is measured by Bradford method.Tumor lysis is placed in Phosphor-Met elisa plate (fluorescent screen), c-Met phosphorylation level assay method is with the ELISA side of H460 cellular level Method.When dosage is 50mg/kg, in the SL14 body of all mensuration compounds, suppression ratio is equal to or more than 50%.Such as, embodiment 1 gained compound is effective inhibitor of c-Met phosphorylation, ED50 value (intra-tumor c-Met be suppressed 50% dosage 2.9mg/ Kg) show that it is inhibitor in an effective c-Met body.
Transplanted tumor model
Human glioma cell U87MG, Human Gastric carcinoma cell MKN45, human non-small cell lung cancer cell H441 and the mankind Renal cell carcinoma cell Caki-1 is amplified cultivation, collects, and is subcutaneously injected into the nearly back, flank portion of nude mouse.Testization Compound is prepared with suitable excipient, and tumor forms (after implanting 7-21 days) gastric infusion afterwards.In therapeutic process, measure weekly two Secondary gross tumor volume is to determine tumor response.By comparison therapy group and blank group, measure gross tumor volume suppression ratio (%, life Long suppression), measure body weight and test as general toxicity.In these models, embodiment 1 compound demonstrates outstanding dose-dependant Property anti-tumor activity.Such as, dosage 30 mg/kg (oral (PO), every day twice (BID) × 35), embodiment 1 compound pair The suppression ratio of U87MG tumor growth is 59%.Dosage 60 mg/kg (PO, BID × 35), the suppression to U87MG tumor growth Rate is 82%.Dosage 120 mg/kg (PO, BID × 35), the suppression ratio to U87MG tumor growth is 92%
In the Tumor Xenograft Models relevant to c-Met, c-Met overexpression is many human tumors, including pulmonary carcinoma, Breast carcinoma, colon cancer, gastric cancer, renal carcinoma, cancer of pancreas, the common feature of head and neck cancer (1,2).The sudden change of c-Met kinase domain activates For tumor inducement, such as heritability Papillary Renal Cell Carcinoma, child's hepatocarcinoma, gastric cancer (3-7).The c-Met inhibitor table of Pfizer Bright to many human tumors, including U87MG, GTL16, H441, Caki-1 and PC3 (8), there is therapeutic effect.
1.Christinsen,JG.,Burrows,J.,and Salgia,R.Cancer Letters 225:1-26, 2005.
2.Birchmeier,C,Birchmeier,W.,Gherardi,E.,and Vande Woude,GF.Nat Rev MoI Cell Biol 4:915-925,2003.
3.Di Renzo,MF.,Olivero,M.,Martone,T.Et al.Oncogene 19:1547-1555,2000.
4.Lee,JH.,Han,SU,Cho,H.et al.Oncogene 19:4947-4953,2000.
5.Ma,PC,Kijima,T.,Maulik,G.et al.Cancer Res 63:6272-6281,2003.6.Park, WS.,Dong,SM.,Kim,SY.et al.Cancer Res 59:307-310,1999.
7.Schmidt,L.,Duh,FM.,Chen,F.,et al.Nat Genet 16:68-73,1997.
8.Zou,HY.,Li,Qiuhua.,Lee,JH.,et al.Cancer Res 67:4408-4417,2007.
The compound that the present invention provides, preferably as pharmaceutical composition, is used by various modes.Most preferably, described medicine Compositions is by Orally administered.This pharmaceutical composition and preparation process are known technology, such as, Lei Mingdun in the art (REMINGTON): " pharmaceutical science and put into practice " (THE SCIENCE AND PRACTICE OF PHARMACY, A.Gennaro, et al,eds.,19thed.,Mack Publishing Co.,1995).Shown in formula (I), compound is at relatively wide administration model It is all effective for enclosing interior.
Such as, the dosage of every day normally about 1 milligram to about 200 milligrams (every TDD), preferably, every TDD 1 Milligram is to 150 milligrams, preferably, and every TDD 1 milligram to 50 milligrams.In some cases, dosage level is less than above-mentioned model The lower limit enclosed is possible or enough, and in other cases, heavy dose remains available.Above-mentioned dosage range not with Any mode limits the scope of the invention.This will be understood by, the actual application dosage of the compound that the present invention provides To be determined according to correlation circumstance by doctor, including the condition for the treatment of, the selection of method of application, the actual compound used and compound Thing, age, body weight, the reaction of given patient and the order of severity of patient symptom.

Claims (66)

1. the compound of the regulation c-Met kinase activity shown in formula (I),
Or they pharmaceutically acceptable salts,
Wherein,
A is the ring of 5-18 unit, and containing 0-6 oxygen atom or nitrogen-atoms；
R1Independently selected from hydrogen, halogen or C1-8Alkyl；
M is the integer of 0-3；
A1And A2Independently selected from :=N-or=C (H)-；
R2Selected from-H, halogen or trihalomethyl；Wherein,
N is the integer of 0-4；
A3It is selected from :=N-or=C (H)-；
X is selected from NR20, O or S；Described R20Selected from H or Cl-8Alkyl；
Z is selected from NR3R4Or the group shown in formula (II):
R3Independently selected from hydrogen or C1-8Alkyl；
R9And R10Independently selected from C1-8Alkyl, phenyl or halogenophenyl；
R4Selected from formula (III), formula (IV), formula (V), formula (VI) or the group shown in formula (VII):
Wherein,
B1It is
Q1It is C (R5)2；Wherein
R5Selected from hydrogen or C1-8Alkyl；
B2It is NHQ2；
Q2Selected from halogenophenyl；
Q3Selected from phenyl or halogenophenyl；
X1Selected from NR8；
R7Selected from hydrogen, C1-8Alkyl, phenyl or halogenophenyl；
R8Selected from hydrogen or C1-8Alkyl；
R11Selected from hydrogen or C1-8Alkyl.
Compound the most according to claim 1, it is characterised in that A is 6-18 ring, and containing 0-6 oxygen atom or nitrogen Atom.
Compound the most according to claim 1, it is characterised in that A is 5-8 ring, and former containing 0-6 oxygen atom or nitrogen Son.
Compound the most according to claim 1, it is characterised in that A is 5 or 12 rings, and containing 0-6 oxygen atom or nitrogen Atom.
Compound the most according to claim 1, it is characterised in that A is 12 yuan of heterocycles, and containing 0-6 oxygen atom or nitrogen Atom.
Compound the most according to claim 5, it is characterised in that described 12 yuan of heterocycles comprise 1,2,3 or 4 oxygen atoms.
Compound the most according to claim 5, it is characterised in that described 12 yuan of heterocycles comprise 4 oxygen atoms.
Compound the most according to claim 1, it is characterised in that described A is
9. according to the compound described in claim 1-8 any one claim, it is characterised in that described RlSelected from hydrogen, halogen or C1-5Alkyl.
10. according to the compound described in claim 1-8 any one claim, it is characterised in that described RlSelected from hydrogen or halogen Element.
11. according to the compound described in claim 1-8 any one claim, it is characterised in that described RlIt is hydrogen.
12. according to the compound described in claim 1-8 any one claim, it is characterised in that described m is the integer of 0-2.
13. according to the compound described in claim 1-8 any one claim, it is characterised in that described m is 0.
14. according to the compound described in claim 1-8 any one claim, it is characterised in that described A2It is=N-.
15. according to the compound described in claim 1-8 any one claim, it is characterised in that described A1It is=CH-, A2It is =N-.
16. according to the compound described in claim 1-8 any one claim, it is characterised in that described A1And A2Be= CH-。
17. according to the compound described in claim 1-8 any one claim, it is characterised in that described A3Selected from=N-or= C(H)-。
18. according to the compound described in claim 1-8 any one claim, it is characterised in that described X is selected from NR20, R20Choosing From H or Cl-3Alkyl.
19. according to the compound described in claim 1-8 any one claim, it is characterised in that described X is selected from NR20, R20For H。
20. according to the compound described in claim 1-8 any one claim, it is characterised in that described X is selected from oxygen or sulfur.
21. according to the compound described in claim 1-8 any one claim, it is characterised in that described X is oxygen.
22. according to the compound described in claim 1-8 any one claim, it is characterised in that described R2Selected from-H, halogen Or trihalomethyl.
23. according to the compound described in claim 1-8 any one claim, it is characterised in that described R2Selected from-H or halogen Element.
24. according to the compound described in claim 1-8 any one claim, it is characterised in that described R2Selected from fluorine or hydrogen.
25. according to the compound described in claim 1-8 any one claim, it is characterised in that described R3Selected from C1-5Alkyl.
26. according to the compound described in claim 1-8 any one claim, it is characterised in that described R3Selected from C1-3Alkyl.
27. according to the compound described in claim 1-8 any one claim, it is characterised in that described R3It is hydrogen.
28. according to the compound described in claim 1-8 any one claim, it is characterised in that described Q1It is CH2。
29. according to the compound described in claim 1-8 any one claim, it is characterised in that described Q2Selected from halogeno-benzene Base.
30. according to the compound described in claim 1-8 any one claim, it is characterised in that described Q2It it is difluorophenyl.
31. according to the compound described in claim 1-8 any one claim, it is characterised in that described Q3Selected from phenyl or halogen For phenyl.
32. according to the compound described in claim 1-8 any one claim, it is characterised in that described Q3Selected from fluorobenzene Base.
33. according to the compound described in claim 1-8 any one claim, it is characterised in that described X1Selected from NC1-6Alkane Base.
34. according to the compound described in claim 1-8 any one claim, it is characterised in that described X1It is NCH3。
35. according to the compound described in claim 1-8 any one claim, it is characterised in that described R7、R8And R11Independent Ground is selected from hydrogen or C1-8Alkyl.
36. according to the compound described in claim 1-8 any one claim, it is characterised in that described R7、R8And R11It is hydrogen.
37. according to the compound described in claim 1-8 any one claim, it is characterised in that described R7It is C1-6Alkyl.
38. according to the compound described in claim 1-8 any one claim, it is characterised in that described R7It is-CH3。
39. according to the compound described in claim 1-8 any one claim, it is characterised in that described R7Selected from phenyl or halogen For phenyl.
40. according to the compound described in claim 1-8 any one claim, it is characterised in that described R7Selected from fluorobenzene Base.
41. according to the compound described in claim 1-8 any one claim, it is characterised in that described R8It is hydrogen.
42. according to the compound described in claim 1-8 any one claim, it is characterised in that described R5Selected from hydrogen or C1-6 Alkyl.
43. according to the compound described in claim 1-8 any one claim, it is characterised in that described R5For hydrogen.
44. according to the compound described in claim 1-8 any one claim, it is characterised in that described R9And R10Independently Selected from methyl or halogenophenyl.
45. according to the compound described in claim 1-8 any one claim, it is characterised in that described R9And R10Independently Selected from methyl or difluorophenyl.
46. compounds being selected from following structure:
● 5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyrido-3-carboxylic acid [the fluoro-4-of 3-(7,8,10,11,13,14-hexahydro- 6,9,12,15-tetra-oxygen-1,3-diaza-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide；
● 1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyrido-3-carboxylic acid [the fluoro-4-of 3-(7,8,10,11,13,14-hexahydro- 6,9,12,15-tetra-oxygen-1,3-diaza-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide；
● cyclopropyl-1,1-dicarboxylic acids [the fluoro-4-of 3-(7,8,10,11,13,14-hexahydro-6,9,12,15-four oxygen-1,3-phenodiazine Miscellaneous-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide (4-fluoro-phenyl)-amide；
● 3-(4-fluoro-phenyl)-2-oxo-imidazol quinoline-1-carboxylic acid [the fluoro-4-of 3-(7,8,10,11,13,14-hexahydro-6,9,12, 15-tetra-oxygen-1,3-diaza-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide；
● 2-(4-fluoro-phenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1 h-pyrazole-4-carboxylic acid [the fluoro-4-of 3-(7,8,10, 11,13,14-hexahydro-6,9,12,15-four oxygen-1,3-diaza-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide；
● 2-(4-fluoro-phenyl amino)-5-[5-(7,8,10,11,13,14-hexahydro-6,9,12,15-four oxygen-1,3-diaza- Cyclododecane [b] naphthalene-4-epoxide)-pyridine-2-base]-3-methyl-3H-pyrimidin-4-one；
● 5-[5-([1,3] dioxy [4,5-g] quinazoline-8-epoxide)-pyridine-2-base]-2-(4-fluoro-phenyl amino)-3-first Base-3H-pyrimidin-4-one；
● 5-[5-(2,2-bis-fluoro-[1,3] dioxy [4,5-g] quinazoline-8-epoxide)-pyridine-2-base]-2-(4-fluoro-phenyl ammonia Base)-3-methyl-3H-pyrimidin-4-one；
● 5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyrido-3-carboxylic acid [4-([1,3] dioxy [4,5-g] quinazoline-8- Epoxide)-3-fluoro-phenyl]-amide；
● 5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyrido-3-carboxylic acid [the fluoro-4-of 3-(7,8,10,11,13,14-hexahydro- 6,9,12,15-tetra-oxygen-1-azepine-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide；
● 1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyrido-3-carboxylic acid [the fluoro-4-of 3-(7,8,10,11,13,14-hexahydro- 6,9,12,15-tetra-oxygen-1-azepine-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide；
● 2-(4-fluoro-phenyl)-1,5-dimethyl-3-oxo-2,3-dihydro-1 h-pyrazole-4-carboxylic acid [the fluoro-4-of 3-(7,8,10, 11,13,14-hexahydro-6,9,12,15-four oxygen-1-azepine-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide；
● cyclopropyl-1,1-dicarboxylic acids [the fluoro-4-of 3-(7,8,10,11,13,14-hexahydro-6,9,12,15-four oxygen-1-azepine-ring Dodecane [b] naphthalene-4-epoxide)-phenyl]-amide (4-fluoro-phenyl)-amide；
● 3-(4-fluoro-phenyl)-2-oxo-imidazol quinoline-1-carboxylic acid [the fluoro-4-of 3-(7,8,10,11,13,14-hexahydro-6,9,12, 15-tetra-oxygen-1-azepine-cyclododecane [b] naphthalene-4-epoxide)-phenyl]-amide
● 5-[5-(2,2-bis-fluoro-[1,3] dioxy [4,5-g] quinazoline-8-epoxide)-pyridine-2-base]-2-(2-fluoro-phenyl ammonia Base)-3-methyl-3H-pyrimidin-4-one；
● 5-[5-(2,2-bis-fluoro-[1,3] dioxy [4,5-g] quinazoline-8-epoxide)-pyridine-2-base]-2-(phenyl amino)- 3-methyl-3H-pyrimidin-4-one；
● 5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyrido-3-carboxylic acid [the fluoro-4-of 3-(7,8,10,11,13,14-hexahydro- 6,9,12,15-tetra-oxygen-1-azepine-cyclododecane [b] naphthalene-4-amino)-phenyl]-amide；
● 5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyrido-3-carboxylic acid [the fluoro-4-of 3-(7,8,10,11,13,14-hexahydro- 6,9,12,15-tetra-oxygen-1-azepine-cyclododecane [b] naphthalene-4-sulfydryl)-phenyl]-amide；
● 3-methyl-2-phenyl amino-5-[5-(2,5,7,10-tetra-oxygen-14,16-diaza-three ring [9.8.0.013,18] ten Nine alkane-1 (11), 12,14,16,18-five thiazolinyl-17-epoxide)-pyridine-2-base]-3H-pyrimidin-4-one；
● 5-[5-([8,9] dihydro-7H-6,10-dioxy-1,3-diaza-cycloheptane [b] naphthalene-4-epoxide)-pyridine-2-base]- 2-(4-fluoro-phenyl amino)-3-methyl-3H-pyrimidin-4-one；
● 2-(4-fluoro-phenyl amino)-3-methyl-5-[5-(9-methyl-8,9,10,11-tetrahydrochysene-7H-6,12-dioxy-1,3, 9-tri-azepines-cyclononane [b] naphthalene-4-epoxide)-pyridine-2-base]-3H-pyrimidin-4-one；
● 2-(4-fluoro-phenyl amino)-3-methyl-5-[5-(7,8,10,11-tetrahydrochysene-6,9,12-three oxygen-1,3-diaza-ring Nonane [b] naphthalene-4-epoxide)-pyridine-2-base]-3H-pyrimidin-4-one；
● 5-[5-(8,9-dihydro-7H-6,10-dioxy-1-azepine-cycloheptane [b] naphthalene-4-epoxide)-pyridine-2-base]-2-(4- Fluoro-phenyl amino)-3-methyl-3H-pyrimidin-4-one；
● 2-(4-fluoro-phenyl amino)-3-methyl-5-[5-(9-methyl-8,9,10,11-tetrahydrochysene-7H-6,12-dioxy-1,9- Diaza-cyclononane [b] naphthalene-4-epoxide)-pyridine-2-base]-3H-pyrimidin-4-one；
● 2-(4-fluoro-phenyl amino)-3-methyl-5-[5-(7,8,10,11-tetrahydrochysene-6,9,12-three oxygen-1-azepine-cyclononane [b] naphthalene-4-epoxide)-pyridine-2-base]-3H-pyrimidin-4-one；
● 3-methyl-2-phenyl amino-5-[5-(2,5,7,10-tetra-oxygen-14-azepine-three ring [9.8.0.013,18] nonadecane- 1 (11), 12,14,16,18-five thiazolinyl-17-epoxide)-pyridine-2-base]-3H-pyrimidin-4-one；
● 5-[5-(2,2-bis-fluoro-[1,3] dioxy [4,5-g] quinoline-8-epoxide)-pyridine-2-base]-2-(2-fluoro-phenyl ammonia Base)-3-methyl-3H-pyrimidin-4-one；
● 5-[5-(2,2-bis-fluoro-[1,3] dioxy [4,5-g] quinoline-8-epoxide)-pyridine-2-base]-2-(phenyl amino)-3- Methyl-3H-pyrimidin-4-one；
● 5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyrido-3-carboxylic acid [the fluoro-4-of 3-(7,8,10,11,13,14-hexahydro- 6,9,12,15-tetra-oxygen-1,3-diaza-cyclododecane [b] naphthalene-4-amino)-phenyl]-amide；
● 5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyrido-3-carboxylic acid [the fluoro-4-of 3-(7,8,10,11,13,14-hexahydro- 6,9,12,15-tetra-oxygen-1,3-diaza-cyclododecane [b] naphthalene-4-sulfydryl)-phenyl]-amide；
● 5-[5-(2,5,8,11,14,17-six oxygen-21-azepine-three ring [16.8.0.020,25] hexacosane-1 (18), 19, 21,23,25-five thiazolinyl-24-epoxide)-pyridine-2-base]-3-methyl-2-phenyl amino-3H-pyrimidin-4-one.
47. 1 kinds of pharmaceutical compositions, comprise at least one compound described in any one of claim 1-46 and at least one medicine Acceptable adjuvant on.
48. pharmaceutical compositions according to claim 47, it is characterised in that described compound and the weight ratio of described adjuvant For 0.0001-10.
Pharmaceutical composition described in 49. claim 47 or 48 prepares the application of medicine.
50. application preparing medicine according to claim 49, for treatment or prophylaxis of cancer, cancer metastasis, cardiovascular Disease, immunologic derangement or visual disorders.
51. application preparing medicine according to claim 49, are used for delaying or prophylaxis of cancer, cancer metastasis, cardiovascular The disease progression of disease, immunologic derangement or visual disorders.
52. application preparing medicine according to claim 49, are used for treating or delay cancer, cancer metastasis, cardiovascular The disease progression of disease, immunologic derangement or visual disorders or morbidity.
At least one compound described in 53. any one of claim 1-46 prepares the application of medicine.
54. application preparing medicine according to claim 53, for treatment or prophylaxis of cancer, cancer metastasis, cardiovascular Disease, immunologic derangement or visual disorders.
55. application preparing medicine according to claim 53, are used for delaying or prophylaxis of cancer, cancer metastasis, cardiovascular The disease progression of disease, immunologic derangement or visual disorders.
56. application preparing medicine according to claim 53, are used for treating or delay cancer, cancer metastasis, cardiovascular The disease progression of disease, immunologic derangement or visual disorders or morbidity.
57. application preparing medicine according to claim 53, as c-Met inhibitor.
58. according to the application preparing medicine described in claim 49 or 53, for treating protein kinase activity regulation disorder Disease.
59. application preparing medicine according to claim 58, it is characterised in that described protein kinase is KDR, Tie-2, Flt3, FGFR3, AbI, Aurora A, c-Src, IGF-IR, ALK, c-MET, RON, PAKl, PAK2 or TAKl.
60. application preparing medicine according to claim 58, it is characterised in that described protein kinase activity regulation disorder Disease be cancer.
61. application preparing medicine according to claim 60, it is characterised in that described cancer is solid tumor, hemopoietic evil Property tumor or malignant ascite.
62. application preparing medicine according to claim 61, it is characterised in that described solid tumor is sarcoma, osteoma, evil Property melanoma, retinoblastoma, glioblastoma multiforme, neuroblastoma or teratoma.
63. application preparing medicine according to claim 62, it is characterised in that described sarcoma is fibrosarcoma or band Myosarcoma.
At least one compound or its pharmaceutically acceptable salt described in 64. any one of claim 1-46 prepare answering of medicine With.
65. application preparing medicine according to claim 64, are used for treating cancer.
66. application preparing medicine according to claim 65, it is characterised in that described cancer selected from pulmonary carcinoma, breast carcinoma, Colorectal cancer, renal carcinoma, cancer of pancreas, head cancer, neck cancer, heritability Papillary Renal Cell Carcinoma, child's hepatocarcinoma and gastric cancer.
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PCT/CN2011/077169 WO2012006960A1 (en) 2010-07-14 2011-07-14 NOVEL FUSED HETEROCYCLIC DERIVATIVES USEFUL AS c-MET TYROSINE KINASE INHIBITORS

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001072758A1 (en) * 2000-03-28 2001-10-04 Wyeth Tricyclic protein kinase inhibitors
CN1534026A (en) * 2002-03-28 2004-10-06 �Ϳ���ҽҩ��˾ Condensed quinazoline derirative used as tyrosine kinase inhibitor
WO2007075567A1 (en) * 2005-12-21 2007-07-05 Janssen Pharmaceutica, N.V. Triazolopyridazines as tyrosine kinase modulators

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001072758A1 (en) * 2000-03-28 2001-10-04 Wyeth Tricyclic protein kinase inhibitors
CN1534026A (en) * 2002-03-28 2004-10-06 �Ϳ���ҽҩ��˾ Condensed quinazoline derirative used as tyrosine kinase inhibitor
WO2007075567A1 (en) * 2005-12-21 2007-07-05 Janssen Pharmaceutica, N.V. Triazolopyridazines as tyrosine kinase modulators

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