CN106496107A - VEGFR inhibitor 2 and preparation method thereof - Google Patents

VEGFR inhibitor 2 and preparation method thereof Download PDF

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Publication number
CN106496107A
CN106496107A CN201610793266.5A CN201610793266A CN106496107A CN 106496107 A CN106496107 A CN 106496107A CN 201610793266 A CN201610793266 A CN 201610793266A CN 106496107 A CN106496107 A CN 106496107A
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alkyl
group
represent
aryl
halo
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叶天健
陆修伟
郁光亮
刘婷
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Zhejiang Yongning Pharmaceutical Co Ltd
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Zhejiang Yongning Pharmaceutical Co Ltd
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Abstract

The present invention provides a kind of compound of Formula I as VEGFR inhibitor 2 and preparation method thereof and the application in the medicine for disease caused by treating by persistence angiogenesis is prepared.

Description

VEGFR-2 inhibitor and preparation method thereof
Technical field
The present invention relates to medicinal chemistry art, and in particular to VEGFR-2 inhibitor and its production and use.
Background technology
Persistence angiogenesis can be the inducement of various diseases, for example hemangioma, fibrohemangioma, pernicious renal necrosis, Embolic microangiopathy syndromes, hepatocarcinoma, gastrointestinal stromal tumor etc., or may result in the deterioration of above-mentioned disease.
Persistence angiogenesis are by VEGF (vascular endothelial growth Factor, VEGF) induced by its receptor, for making VEGF play the effect, VEGF must be bound to receptor, and induce cheese Propylhomoserin phosphorylation.
Directly or indirectly suppress vegf receptor lure to draw and treat these diseases and other pathologic for being induced by VEGF The such as tumor vessel production of angiogenesis and vascular permeability disease.For example, as it is known that the available soluble recepter of the growth of tumor and The antibody of anti-vegf is suppressing.
Used as the major receptors of VEGF, VEGFR-2 is mainly expressed in chrotoplast in intravascular, can with VEGF-A and VEGF-C combines, stimulating endothelial cell propagation, increase vascular permeability and new vascular generation.Many caused by VEGF in The change of chrotoplast physiology or pathology is mainly mediated by VEGFR-2, for example propagation, migration, survival and the change of permeability Small molecule class angiogenesis inhibitor Deng targeting VEGFR-2 is by acting in VEGFR-2 intracellular kinase activities area ATP-binding site, competitive inhibition ATP and receptor binding suppress VEGFR-2 autophosphorylations, so as to blocking VEGF/VEGFR Signal path.
From for pharmacy angle, research and development are directed to the small molecular protein kinase inhibitor of VEGFR-2 for treatment and blood vessel The relevant disease of growth is very valuable, has disclosed various inhibitors, such as quinazoline derivant, benzo in this area The kinase inhibition such as thiazole, but this area still needs the new protease inhibitor of exploitation.
Content of the invention
It is an object of the invention to provide a kind of new compound, the pharmaceutical composition comprising the compound, and will The compound or compositionss are used for the disease mediated by treatment by abnormal VEGFR2.
The present invention relates to a kind of compound of Formula I：
Wherein A is representedOrN represents 1 or 2；
X represents halogen or hydrogen；
R1Represent at one or more position on ring optional, same or different by halogen, cyano group, C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkyl, halo C1-6Alkoxyl, or by group-OR3、-SR4、-SOR4、-SO2R4Substituted aryl Or heteroaryl, or by group-COOR5、-CONR6R7、-NHR15、-SR4、-SOR4、-SO2R4、-SCN、-PO(OR8)(OR9)、- CH=CH-COR10Or-C ≡ C-R10The nitrogenous aromatic heterocycle for replacing or not being substituted；
R2Represent at one or more position optional on phenyl ring, identical or different selected from hydrogen, halogen, cyanogen Base, hydroxyl, C1-6Alkoxyl, halo C1-6Alkoxyl, C2-6Thiazolinyl, cyano group-C3-6Cycloalkyl, cyano group-C1-6Alkyl, aryl-C1-6 Alkoxyl, aryloxy, C1-6Alkyl, halo-C1-6Alkyl or group-SO2R4、OR3、-R3Or-PO (OR8)(OR9)；Or, R2C is formed together with two carbon atoms of arbitrary neighborhood on phenyl ring4-6Ring, the ring are optional comprising nitrogen-atoms, oxygen atom or sulfur Atom, and optional at one or more position, identical or different by halogen, cyano group, C1-6Alkyl, halo- C1-6Alkyl, aryl or by group-OR3、-SR4、-SOR4Or-SO2R4Replace；
R3Represent hydrogen, C1-12Alkyl, halo-C1-6Alkyl, C3-6Cycloalkyl or halo-C3-6Cycloalkyl, or represent which The middle C for inserting one or more oxygen1-12Alkyl, or represent group-(CH2)mNR6R7、-CH2CN or-CH2CF3；
M represents 1,2 or 3；
R4Representation hydroxy, C1-6Alkyl, aryl, heteroaryl represent group-NR6R7；
R5Represent hydrogen or represent optionally by the C of one or more halogen substiuteds1-6Alkyl, C1-6Alkoxyl, benzyl, aryl Or heteroaryl；
R6And R7Separate representative hydrogen or represent optionally at one or more position, identical or different By halogen, cyano group, C1-6Alkyl, phenyl, hydroxyl-C1-6Alkyl, halo-C1-6Alkyl or by group-NR11R12、-OR3、C1-6Alkane Base-OR3、-SR4、-SOR4Or-SO2R4The C for replacing or not being substituted1-6Alkyl, C3-6Cycloalkyl, C3-6Cycloalkenyl group, aryl or miscellaneous Aryl, or
R6And R7C is formed together with nitrogen-atoms3-8Ring, the ring are optional comprising other nitrogen, sulfur or oxygen atom, Huo Zheke Comprising groupAnd can optionally in one or more positions, identical or different by halogen, cyano group, C16Alkyl, Halo-C1-6Alkyl, aryl or by group-OR3、-SR4、-SOR4Or-SO2R4Replace；
R8And R9Separate representative hydrogen or C1-6Alkyl；
R10Represent hydrogen, C1-6Alkyl, three C1-6AIkylsilyl groups, aryl, heteroaryl represent group-COR14；
R11And R12Separate representative hydrogen or C1-6Alkyl, or
R11And R125-7 yuan of rings are formed together, and the ring can include oxygen or sulphur atom or group-NR13；
R13Represent hydrogen, C1-6Alkyl or aryl；
R14Represent hydrogen, C1-6Alkyl represents group-NR6R7；
R15Represent hydrogen, alkyl-carbonyl, C3-6Naphthene base carbonyl, C1-6Alkyl sulphonyl, C3-6Naphthene sulfamide base, 4-C1-6Alkane Base aminosulfonvlphenyl, 4-C3-6Cycloalkyl amino sulfonvlphenyl.
In a preferred embodiment of the invention, R1Represent at one or more position on ring optional, identical Or different by halogen, cyano group, C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkyl, halo C1-6Alkoxyl, or by group- OR3、-SO2R4Substituted aryl or heteroaryl, or by group-COOR5、-CONR6R7、-NHR15、-SO2R4Replace or not by The nitrogenous aromatic heterocycle for replacing.
In another preferred embodiment of the present invention, R1By following representations：
Wherein, the separate representative nitrogen of W, D, E or carbon atom, wherein at least one nitrogen-atoms, at most have two nitrogen Atom；Y represents O or NH；G represent hydrogen or optionally at one or more position of phenyl ring, same or different It is selected from halogen, cyano group, C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkyl, halo C1-6Alkoxyl, or by group-OR3、- SO2R4Substituted aryl or heteroaryl, or group-COOR5、-CONR6R7、-NHR15、-SO2R4；R15Represent hydrogen, C1-3Alkyl oxycarbonyl Base, C3-4Naphthene base carbonyl, C1-3Alkyl sulphonyl, Cyclopropylsulfonyl, 4-C1-3Alkyl amino sulfonyl phenyl, 4- cyclopropyl Aminosulfonvlphenyl.
In another preferred embodiment of the present invention, R1By following representations：
Wherein, the separate representative nitrogen of W, D, E or carbon atom, wherein at least one nitrogen-atoms, at most have two nitrogen Atom；Y represents O or NH；G represent hydrogen or optionally at one or more position of phenyl ring, same or different It is selected from halogen, cyano group, C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkyl, halo C1-6Alkoxyl, or by group-OR3、- SO2R4Substituted aryl or heteroaryl, or group-COOR5、-CONR6R7、-NHR15、-SO2R4；R15Represent hydrogen, C1-3Alkyl oxycarbonyl Base, C3-4Naphthene base carbonyl, C1-3Alkyl sulphonyl, Cyclopropylsulfonyl, 4-C1-3Alkyl amino sulfonyl phenyl, 4- cyclopropyl Aminosulfonvlphenyl.
In another preferred embodiment of the present invention, R2Represent one or more position on phenyl ring optional Place, identical or different selected from hydrogen, halogen, cyano group, C1-6Alkoxyl, halo C1-6Alkoxyl, cyano group-C3-6Cycloalkyl, cyanogen Base-C1-6Alkyl, aryl-C1-6Alkoxyl, aryloxy, C1-6Alkyl, halo-C1-6Alkyl or group-R3, or
R2C is formed together with two carbon atoms of arbitrary neighborhood on phenyl ring4-6Ring, the ring are optional comprising nitrogen-atoms, oxygen Atom or sulphur atom, and optional at one or more position, identical or different by halogen, cyano group, C1-6Alkane Base, halo-C1-6Alkyl, aryl or by group-OR3、-SO2R4Replace.
In another preferred embodiment of the present invention, R2Represent one or two positions on phenyl ring optional Place, identical or different selected from hydrogen, halogen, cyano group, C1-6Alkoxyl, halo C1-6Alkoxyl, cyano group-C3-6Cycloalkyl, cyanogen Base-C1-6Alkyl, aryl-C1-6Alkoxyl, aryloxy, C1-6Alkyl, halo-C1-6Alkyl or group-R3, or
R2C is formed together with two carbon atoms of arbitrary neighborhood on phenyl ring4-6Ring, the ring can include nitrogen-atoms, and can appoint Choosing at one or more position, identical or different by halogen, cyano group, C1-6Alkyl, halo-C1-6Alkyl, aryl Replace.
In another preferred embodiment of the present invention, R1By following representations：
Wherein, p represents 1,2 or 3；
SimultaneouslyBy following representations：
The compound of the present invention is preferably selected from following compounds：
3- ((4- chloro- 3- (trifluoromethyl) benzyls) amino) -1- (4- pyridylmethyls) pyridine -2 (1H) -one
N- (4- chloro- 3- (trifluoromethyl) phenyl) the fluoro- 5- of -2- ((4- pyridylmethyls) amino) Benzoylamide
N- (4- chloro- 3- (trifluoromethyl) phenyl) -3- ((4- pyridylmethyls) amino) Benzoylamide
3- ((4- chloro- 3- (trifluoromethyl) benzyls) amino) -1- (2- (4- pyridine radicals) ethyl) pyridine -2 (1H) -one
N- (4- (3- ((4- chloro- 3- (trifluoromethyl) benzyls) amino) -1 (2H)-methyl of -2- oxo pyridines base) pyridine -2- Base) acetamide
3- ((4- chloro- 3- (trifluoromethyl) benzyls) amino) -1- ((2- ((4- mesyls) phenyl) amino) pyridine -4- Base) methyl) pyridine -2 (1H) -one
N- (4- chloro- 3- (trifluoromethyl) phenyl) the fluoro- 5- of -2- (((2- ((4- (mesyl) phenyl) amino) pyridine -4- Base) methyl) amino) Benzoylamide
N- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (((2- ((4- (mesyl) phenyl) amino) pyridin-4-yl) first Base) amino) Benzoylamide
4- (3- ((4- chloro- 3- (trifluoromethyl) benzyls) amino) -1 (2H)-methyl of -2- oxo pyridines base)-N- cyclopropyl Picolinamide
4- (((3- ((4- chloro- 3- (trifluoromethyl) phenyl) carbamoyl) -4- fluorophenyls) amino) methyl)-N- rings third Yl pyridines amide
4- (((3- ((4- chloro- 3- (trifluoromethyl) phenyl) carbamoyl) phenyl) amino) methyl)-N- cyclopropyl pyrroles Pyridine amide
3- ((4- chloro- 3- (trifluoromethyl) benzyls) amino) -1- ((6,7- dimethoxy-quinoline -4- bases) methyl) pyridine -2 (1H) -one
N- (4- chloro- 3- (trifluoromethyl) phenyl) -5- (((6,7- dimethoxy-quinoline -4- bases) methyl) amino) -2- is fluoro- Benzoylamide
N- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (((6,7- dimethoxy-quinoline -4- bases) methyl) amino) benzoyl Amine
3- ((4- chloro- 3- (trifluoromethyl) benzyls) amino) -1- ((6,7- dimethoxyquinazoline -4- bases) methyl) pyrrole Pyridine -2 (1H) -one
N- (4- chloro- 3- (trifluoromethyl) phenyl) -5- (((6,7- dimethoxyquinazoline -4- bases) methyl) amino) -2- Fluoro- Benzoylamide
N- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (((6,7- dimethoxyquinazoline -4- bases) methyl) amino) benzene first Amide
2- methyl -2- (4- (((2- oxo -1- (4- pyridylmethyls) -1,2- dihydropyridine -3- bases) amino) methyl) benzene Base) propionitrile
2- methyl -2- (4- (((2- oxo -1- (2- (4- pyridine radicals) ethyl) -1,2- dihydropyridine -3- bases) amino) first Base) phenyl) propionitrile
N- (4- (2- dicyanopropane -2- bases) phenyl) -3- ((4- pyridylmethyls) amino) Benzoylamide
N- (4- (2- dicyanopropane -2- bases) phenyl) the fluoro- 5- of -2- ((4- pyridylmethyls) amino) Benzoylamide
4- ((2- oxo -3- ((4- trifluoromethoxies) phenyl) amino) -1 (2H)-yl of pyridine) methyl) pyridine carboxylic acid methyl ester
1- ((4- aminothiophenes [2.3-d] pyrimidine -5- bases) methyl) -3- ((4- phenoxy benzyls) amino) pyridine -2 (1H) -one
5 (((4- aminothiophenes [2.3-d] pyrimidine -5- bases) methyl) amino) -2- fluoro-N- (4- ((4- methyl piperazines - 1- yls) methyl) -3- (trifluoromethyl) phenyl) Benzoylamide
4- (((3- ((3,3- dimethyl indole quinoline -6- bases) carbamoyl) -4- difluorophenyls) amino) methyl) pyridine Methyl formate
The compound of the present invention can be prepared by any conventional meanses, provide the conjunction for synthesizing these compounds in embodiment Suitable method.Generally, compound of formula I can be prepared according to synthesis path described below.
1) when A is representedWhen, compound of Formula I is by structural formula Represent, its synthetic method can refer to scheme () or scheme (two) and carry out：
Scheme (one)
Wherein, R1、R2, n is as defined in formula I.
When the n in formula I ' compounds represents 2, its synthetic method may further reference scheme (two) and carry out：
Scheme (two)：
Wherein, R1、R2As defined in formula I.
2) when A is representedWhen, compound of Formula I is by structural formulaTable Show, its synthetic method can refer to scheme (three) or scheme (four) and carry out：
Scheme (three)：
Wherein, R1、R2, X is as defined in formula I.
Scheme (four)：
Wherein, R1、R2, X is as defined in formula I.
Present invention also offers a kind of pharmaceutical composition, it is comprising at least one compound of the present invention and its pharmaceutically Acceptable salt, crystallization or mixture and at least one pharmaceutically acceptable excipient or adjuvant or carrier.
Present invention also offers the method for testing that a kind of compound of Formula I is affected on VEGFR-2 inhibitory activity, specific bag Include：By the sodium phosphate buffer containing 0.01M (pH 7.2-7.4), the sodium chloride solution of 0.15M and enzymatic reaction substrate The ATP solution for adding reaction buffer to dilute in enzyme mark version and VEGFR-2 albumen.Subsequently experimental group and blank group are set, Add reactant liquor containing testing compound respectively in above-mentioned system and without testing compound reactant liquor, sequentially add one and resist PY99,37 DEG C of shaking tables react 0.5 hour, the IgG of two anti-horseradish peroxidase-labeled sheep anti mouses, and 37 DEG C of shaking table reactions 0.5 are little When.It is eventually adding after OPD nitrite ions react 10 minutes and adds sulphuric acid terminating reaction, mensuration absorbance OD value.
The suppression ratio of compound is tried to achieve by following equation：
Found using said method detection, suppression ratio >=10% that chemical compound lot of the invention has；Of the invention preferred Suppression ratio >=30% that has of compound；Suppression ratio >=50% that the further preferred compound of the present invention has；Thus true Fixed, the effect of the compounds of this invention is a kind of effective VEGFR-2 inhibitor.
According to the present invention, compound of Formula I can based on they relative to the phosphorylation of vegf receptor inhibitory activity It is used as medicine.According to their binding mode, the compound that the present invention is provided is suitable for treatment is led by persistence angiogenesis The disease of cause.
As compound of Formula I has been determined as VEGFR-2 inhibitor, so they are particularly suitable for treating those and are received by VEGF Continue the disease that angiogenesis or vascular permeability increase and cause or promote caused by body.
The invention further relates to compound of the present invention is being prepared for disease caused by treating by by persistence angiogenesis Application in the medicine of disease.
Term is explained
Term used herein " alkyl " refers to that wherein all carbon-carbon bonds are all the side chains or straight-chain alkyl of singly-bound, And term " cycloalkyl " is referred to containing the monocyclic of 3-6 carbon atom.
Term used herein " halo C1-6Alkyl " refers to halogen atoms identical or different by one or more The alkyl containing 1-6 carbon atom for replacing, term " halo C3-6Cycloalkyl " refers to identical or different by one or more Halogen atom replace the cycloalkyl containing 3-6 carbon atom, term " cyano group C1-6Alkyl " is referred to by one or more cyanogen The alkyl containing 1-6 carbon atom that base replaces, and term " cyano group C3-6Cycloalkyl " is referred to and is replaced by one or more cyano group The cycloalkyl containing 3-6 carbon atom.
Term used herein " thiazolinyl " refers to that one or more carbon-carbon bond is the side chain or straight chain of double bond Alkyl, and term " cycloalkenyl group " refer to monocyclic containing 3-6 carbon atom, one or more carbon-carbon bond be double bond.
Term used herein " alkoxyl " refers to-OR groups, and wherein R refers to alkyl, as defined above.
Term used herein " halo C1-6Alkoxyl " refers to that halogens identical or different by one or more are former The alkoxyl containing 1-6 carbon atom that son replaces.
Term used herein " aryl " refers to that the monocyclic or multi-ring alkyl of 6-14 carbon atom, the alkyl are There is at least one aromatic ring for providing radical attachment point.Polyaromatic can have isolated ring of the wherein at least one ring for aromatic ring (such as diphenyl) or condensed ring (such as naphthyl).
Term used herein " heteroaryl " refers to the monocyclic or multi-ring alkyl of 6-14 carbon atom, in the ring Contain one or more nitrogen-atoms, oxygen atom or sulphur atom, the alkyl is radical attachment point to be provided with least one Aromatic ring.
" nitrogenous aromatic heterocycle " used by the present invention refers to the monocyclic or multi-ring alkyl of 5-14 carbon atom, the ring In contain at least one nitrogen-atoms, the alkyl be with least one provide radical attachment point aromatic ring.
The listed in Table english abbreviation occurred from the present invention and its representative Chinese and English full name, if any not being contained in In the present invention, then representing which and obtaining generally accepted implication occur in english abbreviation in following table.
Specific embodiment
With reference to embodiment, the invention will be further described, but the protection content of the present invention is not limited only to these realities Apply example.
In the following example, method therefor if no special instructions, is conventional method.Raw material of the present invention and reagent Commercially available purchase can be passed through or obtained by simple synthesis.
Embodiment 1：3- ((4- chloro- 3- (trifluoromethyl) benzyls) amino) -1- (4- pyridylmethyls) pyridine -2 (1H) -one (compound 1)
Step A：
The synthesis of compound 1-a：4- chloromethyl pyridine hydrochlorides (39.3mmol), 3- nitro -2- pyrroles is added in reaction bulb Pyridine ketone (35.7mmol), potassium carbonate (89.2mmol) and DMF (250mL), after the stirring 4 hours of 50 DEG C of system, add water (250mL) Dilution, EA (3*250mL) are extracted, and saturated sodium-chloride (100mL) is washed, anhydrous sodium sulfate drying, are filtered, evaporated under reduced pressure solvent, Column chromatography for separation (is first used EA, then uses DCM:MeOH=20:1) yellow solid (compound 1-a) common 8g is obtained.
Step B：
The synthesis of compound 1-b：1-a (26mmol), Pd/C (0.6g) and methanol (30mL), system is added in reaction bulb Pressurization (0.4bar) hydrogenation, after stirring 4 hours, is filtered to remove Pd/C, and evaporated under reduced pressure solvent obtains brown solid (compound 1- B) common 4.2g.
Step C：
The synthesis of compound 1：1-b (9.4mmol), the chloro- 3- trifluoromethylated benzaldehydes of 4- is added in reaction bulb (10.4mmol), the drops of DCM (50mL) and 5 AcOH, after system is stirred at room temperature 1 hour, only very small amount product is generated, and decompression is steamed Dry solvent, adds ethanol (40mL), oil bath heating to flow back 4 hours and find that raw material is only remaining a small amount of, adds NaBH after system cooling (OAc)3(14mmol), it is stirred at room temperature 3 hours, reaction completely, adds saturation NaHCO3(20mL) it is quenched, EA (3*100mL) extracts Take, saturation NaCl (100mL) is washed, anhydrous Na2SO4Dry, filter, evaporated under reduced pressure solvent, column chromatography for separation obtain crude product Above-mentioned crude product is dissolved in (10mL) DCM by 1.2g:MeOH=20:In 1 mixed solvent, be stirred at room temperature down and EA be added dropwise over to proper There is well solid to separate out, after stirring 0.5 hour, filter, EA (2mL) washings obtain off-white powder (compound 1) common 500mg.
1H NMR (400MHz, DMSO) δ 8.54 (d, J=6.4Hz, 2H), 7.83 (s, 1H), 7.68 (d, J=8.3Hz, 1H), 7.62 (d, J=8.3Hz, 1H), 7.44 (d, J=6.4Hz, 2H), 7.04 (dd, J=5.4,3.0Hz, 1H), 6.42 (t, J =6.5Hz, 1H), 6.16 (s, 1H), 6.15 (d, J=2.5Hz, 1H), 5.29 (s, 2H), 4.39 (d, J=6.5Hz, 2H).
Embodiment 2：N- (4- chloro- 3- (trifluoromethyl) phenyl) the fluoro- 5- of -2- ((4- pyridylmethyls) amino) Benzoylamide (compound 2)
Step A：
The synthesis of compound 2-a：2- fluorine-5-nitro benzoic acids (27mmol), DCM (100mL), 10 drops are added in reaction bulb DMF, is added dropwise over oxalyl chloride (81mmol) under 0 DEG C of stirring, and drop is moved to after finishing after being stirred at room temperature 2 hours, evaporated under reduced pressure solvent with And unnecessary oxalyl chloride, it is subsequently added the chloro- 5- amino trifluoromethylbenzene of DCM (100mL), TEA (40.5mmol), and 2- (27mmol), it is stirred at room temperature 1 hour, evaporated under reduced pressure solvent, adds acetone (8mL) dissolving, be stirred at room temperature down and be added dropwise over EA extremely Just there is solid to separate out, obtain white solid (compound 2-a) common 9.2g.
Step B：
The synthesis of compound 2-b：2-a (16.6mmol), iron filings (165.5mmol), ethanol (100ml) is added in reaction bulb And 60 drop ACOH, it is heated to reflux stirring 6 hours, is cooled to room temperature, filters, filtrate decompression is evaporated, column chromatography for separation (eluant For PE/EA), obtain yellow solid (compound 2-b) common 6g.
Step C：
The synthesis of compound 2：2-b (12mmol), 4- chloromethyl pyridine hydrochlorides (36mmol), NaH is added in reaction bulb (24mmol), NaI (12mmol) and DMF (150mL), after the stirring 20 hours of 60 DEG C of system, add water (150mL) dilution, EA (3* 150mL) extract, saturation NaCl (150mL) is washed, anhydrous Na2SO4Dry, filter, add activated carbon (15g) return stirring 1 little When decolourize, filter, evaporated under reduced pressure solvent, column chromatography for separation (DCM/MeOH systems) obtain crude product, by above-mentioned crude product EA (15mL) Beating, filters, and subsequently adds methanol (10mL) beating, filters, obtain off-white powder (compound 2).
1H NMR (400MHz, DMSO) δ 10.69 (s, 1H), 8.51 (d, J=5.9Hz, 2H), 8.30 (d, J=2.0Hz, 1H), 7.98 (dd, J=8.9,2.0Hz, 1H), 7.71 (d, J=8.8Hz, 1H), 7.35 (d, J=5.7Hz, 2H), 7.08 (t, J =9.4Hz, 1H), 6.81 (dd, J=5.6,3.0Hz, 1H), 6.71 (dt, J=8.6,3.6Hz, 1H), 6.59 (t, J= 6.3Hz, 1H), 4.36 (d, J=6.2Hz, 2H).
Embodiment 3：N- (4- chloro- 3- (trifluoromethyl) phenyl) -3- ((4- pyridylmethyls) amino) Benzoylamide (chemical combination Thing is 3)
Step A：
The synthesis of compound 3-a：3- amino benzoic Acid (145.8mmol) and methanol (250mL), body is added in reaction bulb It is lower Deca SOCl of 0 DEG C of stirring2(218.7mmol), drip and be stirred at room temperature 20 hours after finishing, evaporated under reduced pressure solvent, EA (80mL) are beaten Slurry, filters, obtains white solid (compound 3-a) common 26g.
Step B：
The synthesis of compound 3-b：3-a (53.3mmol), 4- chloromethyl pyridine hydrochlorides is added in reaction bulb (79.9mmol), K2CO3(239.8mmol), NaI (7.99mmol) and DMF (250mL), after the stirring 20 hours of 40 DEG C of system, Add water (250mL) dilution, and EA (3*250mL) is extracted, and saturation NaCl (250mL) is washed, anhydrous Na2SO4Dry, filter, decompression is steamed Dry solvent, column chromatography for separation (DCM/MeOH systems) obtain crude solid (compound 3-b) common 6g.Step C：
The synthesis of compound 3：TBuOK (16.5mmol) and THF (50mL) is added in reaction bulb, 5min is stirred at room temperature, It is rapidly added 3-b (8.3mmol) and 2- chloro- 5- 5 amido benzotrifluorides (8.3mmol), system is stirred at room temperature 2 hours, decompression is steamed Dry solvent, add water (50mL) dilution, and EA (3*50mL) is extracted, and saturation NaCl (50mL) is washed, anhydrous Na2SO4Dry, filter, subtract Pressure solvent evaporated, column chromatography for separation (DCM/MeOH systems) obtain crude product, and above-mentioned crude product EA (10mL) is beaten, and filter, subsequently Methanol (5mL) beating is added, is filtered, is obtained off-white powder (compound 3).
1H NMR (400MHz, DMSO) δ 10.48 (s, 1H), 8.51 (dd, J=4.5,1.5Hz, 2H), 8.35 (d, J= 2.5Hz, 1H), 8.08 (dd, J=8.8,2.5Hz, 1H), 7.69 (d, J=8.8Hz, 1H), 7.36 (d, J=5.9Hz, 2H), 7.23 (t, J=7.8Hz, 1H), 7.14 (dd, J=10.9,4.9Hz, 2H), 6.77 (dd, J=8.0,1.7Hz, 1H), 6.70 (t, J=6.2Hz, 1H), 4.40 (d, J=6.2Hz, 2H).
Embodiment 4：3- ((4- chloro- 3- (trifluoromethyl) benzyls) amino) -1- (2- (4- pyridine radicals) ethyl) pyridine -2 (1H) -one (compound 4) step A：
The synthesis of compound 4-a：4-vinylpridine (71.4mmol), 3- nitro -2- pyridones is added in reaction bulb (35.7mmol) and ethanol (200mL), system is heated to 80 DEG C by room temperature, after stirring 10 hours, is cooled to room temperature, and decompression is steamed Dry solvent, column chromatography for separation (are first used EA, then use DCM:MeOH=20:1), yellow solid (compound 4-a) common 8g is obtained.
Step B：
The synthesis of compound 4-b：4-a (24.5mmol), Pd/C (0.6g) and methanol (30mL), body is added in reaction bulb System's pressurization (0.4bar) hydrogenation, after stirring 4 hours, is filtered to remove Pd/C, and evaporated under reduced pressure solvent obtains brown solid (compound 4-b) common 5g.
Step C：
The synthesis of compound 4：4-b (9.3mmol), the chloro- 3- trifluoromethylated benzaldehydes of 4- is added in reaction bulb (25.7mmol), DCM (50mL), NaBH (OAc)3(6.4g), and 5 drop AcOH, after system is stirred at room temperature 20 hours, add full And NaHCO3(20mL) it is quenched, EA (3*150mL) is extracted, saturation NaCl (150mL) is washed, anhydrous Na2SO4Dry, filter, subtract Pressure solvent evaporated, column chromatography for separation obtain blue crude product 1.7g, above-mentioned crude product are dissolved in DCM just:MeOH=20:1 mixing In solvent, being stirred at room temperature down and EA being added dropwise over to there is just solid to separate out, after stirring 0.5 hour, filter, EA (10mL) is washed Arrive off-white powder (compound 4).
1H NMR (400MHz, DMSO) δ 8.45 (d, J=6.2Hz, 2H), 7.81 (s, 1H), 7.68 (d, J=8.2Hz, 1H), 7.58 (d, J=8.3Hz, 1H), 7.52 (d, J=6.3Hz, 2H), 6.81 (dd, J=6.6,1.4Hz, 1H), 6.36 (t, J =6.6Hz, 1H), 6.04 (d, J=5.9Hz, 1H), 5.99 (t, J=7.0Hz, 1H), 4.37 (d, J=6.4Hz, 2H), 4.23 (t, J=7.1Hz, 2H), 3.15 (t, J=7.1Hz, 2H).
Embodiment 5：Compound 5-11
Step A, B, C three-step reaction synthesis compound 5- are carried out successively in the method similar with embodiment 1 or embodiment 4 13, as shown in the table：
Embodiment 6：Compound 14-25
Step A, B, C three-step reaction synthesis compound are carried out successively in the method similar with embodiment 2 or embodiment 3 14-25, as shown in the table：
The part material being related in the building-up process of above-claimed cpd synthesizes as shown in following examples：
Embodiment 7：N- (4- (chloromethyl) pyridine -2- bases) acetamide hydrochloride (compound 26)
Acetic acid (27mmol) is added in reaction bulb, and DCM (100mL), 10 drop DMF are added dropwise over oxalyl chloride under 0 DEG C of stirring (81mmol), drip after moving to and be stirred at room temperature 2 hours after finishing, evaporated under reduced pressure solvent and unnecessary oxalyl chloride are subsequently added DCM (100mL), TEA (40.5mmol), and 2- amino -4- chloromethyl pyridine hydrochlorides (27mmol), is stirred at room temperature 1 hour, subtracts Pressure solvent evaporated, adds acetone (8mL) dissolving, is stirred at room temperature down and is added dropwise over EA to there is just solid to separate out, obtains white solid Body (compound 26) common 4.6g.
Embodiment 8：N- (4- (chloromethyl) pyridine -2- bases) cyclopropyl carboxamide (compound 27)
With method synthesising title compound similar to Example 7.
Embodiment 9：N- (4- (chloromethyl) pyridine -2- bases) Methanesulfomide (compound 28)
With method synthesising title compound similar to Example 7.
Embodiment 10：4- chloromethyl-N- (4- (mesyl) phenyl) pyridine -2- amine (compound 29)
2- amino -4- chloromethyl pyridine hydrochlorides (53.3mmol), 4- Chlorophenylmethyl sulfones is added in reaction bulb (79.9mmol), K2CO3(239.8mmol), NaI (7.99mmol) and DMF (250mL), after the stirring 20 hours of 40 DEG C of system, Add water (250mL) dilution, and EA (3*250mL) is extracted, and saturation NaCl (250mL) is washed, anhydrous Na2SO4Dry, filter, decompression is steamed Dry solvent, column chromatography for separation obtain crude product (compound 29) common 7.9g.
Embodiment 11：4- ((4- (chloromethyl) pyridine -2- bases) amino)-N- methyl benzenesulfonamides (compound 30)
With method synthesising title compound similar to Example 10.
Embodiment 12：4- ((4- (chloromethyl) pyridine -2- bases) amino)-N-methyl-benzamide (compound 31)
With method synthesising title compound similar to Example 10.
Embodiment 13：2- methoxycarbonyl -4- (chloromethyl) pyridines (compound 32)
4- (methylol) pyridine-2-carboxylic acids (145.8mmol), methanol (150mL) and DCM is added in reaction bulb (150mL), under the protection of system nitrogen, dropwise Deca SOCl under 0 DEG C of stirring2(1.46mol), drip finish be stirred at room temperature 3 hours after, subtract Pressure solvent evaporated, EA (80mL) are beaten, and filter, obtain white solid (compound 32) common 22g.
Embodiment 14：(4- (chloromethyl) pyridine -2- bases)-N- cyclopropyl carboxamides (compound 33)
Addition 4- (methylol) pyridine-2-carboxylic acids (145.8mmol) in reaction bulb, the drop DMF of DCM (200mL) and 10,0 DEG C stirring under be added dropwise over SOCl2(1.75mol), after, drop Bi Yizhi is stirred at room temperature 2 hours, evaporated under reduced pressure solvent is subsequently added DCM (100mL), TEA (40.5mmol), and cyclopropylamine (175mmol), are stirred at room temperature 1 hour, evaporated under reduced pressure solvent, room temperature EA is added dropwise under stirring to there is just solid to separate out, and obtains white solid (compound 33) common 26g.Embodiment 15：4- chloromethanes Base -6,7- dimethoxy-quinolines (compound 34)
4- methanol-based -6,7- dimethoxy-quinolines (145.8mmol), DCM (150mL), system nitrogen is added in reaction bulb Under protection, dropwise Deca SOCl under 0 DEG C of stirring2(1.46mol), drip finish be stirred at room temperature 3 hours after, evaporated under reduced pressure solvent, EA (90mL) it is beaten, filters, obtain pink solid (compound 34) common 27g.
Embodiment 16：4- bromomethyl -6,7- dimethoxyquinazolines (compound 35)
6,7- dimethoxy-4 's-methylquinazolin (147mmol), NBS (147mmol), benzoyl peroxide is added in reaction bulb Formyl (25mmol), and carbon tetrachloride (300mL), system are heated to reflux 5 hours, and after cooling, system sequentially adds water (250mL), DCM (3*250mL) extractions, saturation NaCl (250mL) are washed, anhydrous Na2SO4Dry, filter, evaporated under reduced pressure solvent, Column chromatography for separation, obtains pink solid (compound 35) common 14.2g.
Embodiment 17：4- bromomethyls -7- methyl -7H- pyrrolo-es [2,3-d] pyrimidine (compound 36)
With method synthesising title compound similar to Example 16.
Embodiment 18：5- (bromomethyl) thieno [2,3-d] pyrimidine -4- amine (compound 37)
With method synthesising title compound similar to Example 16.
Embodiment 19：Compound 38
Step A：
The synthesis of compound 38-a：Add to methylbenzeneacetonitrile (500mmol), DMF (1000mL) in reaction bulb, 0 DEG C is stirred Lower addition sodium hydrogen (1mol) is mixed, and insulated and stirred 0.5 hour to be moved to and iodomethane (1mol) is added under room temperature, is stirred overnight at room temperature, plus Enter methanol (100mL) to be quenched, subsequently add water (250mL) successively, DCM (3*250mL) is extracted, saturation NaCl (250mL) is washed, nothing Water Na2SO4Dry, filter, evaporated under reduced pressure solvent obtains yellow oil (compound 38-a) common 65g.
Step B：
The synthesis of compound 38-b：Addition 38-a (100mmol) in reaction bulb, pyridine (100mL), water (200mL), and Potassium permanganate (500mmol), system are heated to reflux 2 hours, remove pyridine under reduced pressure, and heat filter, filtrate 6M HCl are acidified to pH for 5- 6, the solid filtration drying of precipitation obtains the common 15.2g of compound 38-b.
Step C：2- (4- Fonnylphenyls) -2- methyl propionitrile (compound 38)
The synthesis of compound 38：38-b (74mmol), THF (200mL) are added in reaction bulb, system is cooled to -20 DEG C, stirs Mix down and be added dropwise over LiAlH4(285mmol), insulated and stirred 4 hours, are subsequently stirred at room temperature 1 hour, add saturated ammonium chloride (300mL) it is quenched, is subsequently added sodium hydroxide (200mL), stirring adds water (150mL) after 1 hour, filters, filtrate ether (150mL) wash, organic faciess are concentrated, and are obtained crude intermediate, are placed in reaction bulb, are subsequently added DCM (300mL), and system is put Stir in ice bath, add PCC (230mmol), continue stirring 1 hour, be subsequently added saturated sodium bicarbonate (50mL) and be quenched, subsequently Add water (250mL) successively, and DCM (3*250mL) is extracted, and saturation NaCl (250mL) is washed, anhydrous Na2SO4Dry, filter, decompression Solvent evaporated, obtains yellow oil (compound 38) common 4.6g.
Embodiment 20：1- (4- Fonnylphenyls) -1- cyano group-Pentamethylene. (compound 39)
With method synthesising title compound similar to Example 19.
Embodiment 21：1- (4- Fonnylphenyls) -1- cyano group-cyclopropane (compound 40)
With method synthesising title compound similar to Example 19.
Embodiment 22:
Inhibitory action in the presence of some compounds of the present invention to VEGFR-2 kinase activities
By the sodium phosphate buffer containing 0.01M (pH 7.2-7.4), the sodium chloride solution of 0.15M and enzymatic reaction bottom The ATP solution for adding reaction buffer to dilute in the enzyme mark version of thing and VEGFR-2 albumen.Experimental group and blank are subsequently set Group, i.e., add the reactant liquor and the reactant liquor without compound 1 of 10 μM of compounds 1 respectively in above-mentioned system, sequentially add one Anti- PY99,37 DEG C of shaking tables react 0.5 hour, the IgG of two anti-horseradish peroxidase-labeled sheep anti mouses, 37 DEG C of shaking table reactions 0.5 Hour.It is eventually adding after OPD nitrite ions react 10 minutes and adds sulphuric acid terminating reaction, mensuration absorbance OD value, and by following Formula calculates suppression ratio：
As a result as shown in the table：
Concentration (μM) Suppression ratio (%)
Compound 2 10 54.73
Compound 3 10 90.25
Compound 4 10 18.00
Compound 24 10 99.89
Additionally, the present invention has carried out mice VEGFR-2 biochemistry detection (referring to special always according to patent ZL200480021091.1 Sharp ZL200480021091.1, page 31,8), compound of the present invention also shows to show VEGFR-2 kinases embodiment Write and suppress, some of which compound shows 1 μM of even lower IC50 value to the inhibitory action of VEGFR-2 kinase activities.

Claims (10)

1. one kind compound as described in formula I：
Wherein,
A is representedN represents 1 or 2；X represents halogen or hydrogen；
R1Represent at one or more position on ring optional, same or different by halogen, cyano group, C1-6Alkyl, C1-6Alkane Epoxide, halo C1-6Alkyl, halo C1-6Alkoxyl, or by group-OR3、-SR4、-SOR4、-SO2R4Substituted aryl or heteroaryl Base, or by group-COOR5、-CONR6R7、-NHR15、-SR4、-SOR4、-SO2R4、-SCN、-PO(OR8)(OR9) ,-CH=CH- COR10Or-C ≡ C-R10The nitrogenous aromatic heterocycle for replacing or not being substituted；
R2Represent at one or more position optional on phenyl ring, identical or different selected from hydrogen, halogen, cyano group, hydroxyl Base, C1-6Alkoxyl, halo C1-6Alkoxyl, C2-6Thiazolinyl, cyano group-C3-6Cycloalkyl, cyano group-C1-6Alkyl, aryl-C1-6Alcoxyl Base, aryloxy, C1-6Alkyl, halo-C1-6Alkyl or group-SO2R4、OR3、-R3Or-PO (OR8)(OR9)；Or, R2With On phenyl ring, two carbon atoms of arbitrary neighborhood form C together4-6Ring, the ring are optional former comprising nitrogen-atoms, oxygen atom or sulfur Son, and optional at one or more position, identical or different by halogen, cyano group, C1-6Alkyl, halo- C1-6Alkyl, aryl or by group-OR3、-SR4、-SOR4Or-SO2R4Replace；
R3Represent hydrogen, C1-12Alkyl, halo-C1-6Alkyl, C3-6Cycloalkyl or halo-C3-6Cycloalkyl, or represent wherein insert Enter the C of one or more oxygen1-12Alkyl, or represent group-(CH2)mNR6R7、-CH2CN or-CH2CF3；
M represents 1,2 or 3；
R4Representation hydroxy, C1-6Alkyl, aryl, heteroaryl represent group-NR6R7；
R5Represent hydrogen or represent optionally by the C of one or more halogen substiuteds1-6Alkyl, C1-6Alkoxyl, benzyl, aryl or miscellaneous Aryl；
R6And R7Separate representative hydrogen or represent optionally at one or more position, identical or different by halogen Element, cyano group, C1-6Alkyl, phenyl, hydroxyl-C1-6Alkyl, halo-C1-6Alkyl or by group-NR11R12、-OR3、C1-6Alkyl- OR3、-SR4、-SOR4Or-SO2R4The C for replacing or not being substituted1-6Alkyl, C3-6Cycloalkyl, C3-6Cycloalkenyl group, aryl or heteroaryl Base, or
R6And R7C is formed together with nitrogen-atoms3-8Ring, the ring are optional comprising other nitrogen, sulfur or oxygen atom, or can include GroupAnd can optionally in one or more positions, identical or different by halogen, cyano group, C1-6Alkyl, halogen Generation-C1-6Alkyl, aryl or by group-OR3、-SR4、-SOR4Or-SO2R4Replace；
R8And R9Separate representative hydrogen or C1-6Alkyl；
R10Represent hydrogen, C1-6Alkyl, three C1-6AIkylsilyl groups, aryl, heteroaryl represent group-COR14；
R11And R12Separate representative hydrogen or C1-6Alkyl, or
R11And R125-7 yuan of rings are formed together, and the ring can include oxygen or sulphur atom or group-NR13；
R13Represent hydrogen, C1-6Alkyl or aryl；
R14Represent hydrogen, C1-6Alkyl represents group-NR6R7；
R15Represent hydrogen, alkyl-carbonyl, C3-6Naphthene base carbonyl, C1-6Alkyl sulphonyl, C3-6Naphthene sulfamide base, 4-C1-6Alkyl ammonia Base sulfonvlphenyl, 4-C3-6Cycloalkyl amino sulfonvlphenyl.
2. compound of Formula I according to claim 1, it is characterised in that：
A is representedN represents 1 or 2；X represents halogen or hydrogen；
R1Represent at one or more position on ring optional, same or different by halogen, cyano group, C1-6Alkyl, C1-6Alkane Epoxide, halo C1-6Alkyl, halo C1-6Alkoxyl, or by group-OR3、-SO2R4Substituted aryl or heteroaryl, or quilt Group-COOR5、-CONR6R7、-NHR15、-SO2R4The nitrogenous aromatic heterocycle for replacing or not being substituted；
R2Represent at one or more position optional on phenyl ring, identical or different selected from hydrogen, halogen, cyano group, hydroxyl Base, C1-6Alkoxyl, halo C1-6Alkoxyl, C2-6Thiazolinyl, cyano group-C3-6Cycloalkyl, cyano group-C1-6Alkyl, aryl-C1-6Alcoxyl Base, aryloxy, C1-6Alkyl, halo-C1-6Alkyl or group-SO2R4、OR3、-R3Or-PO (OR8)(OR9)；Or, R2With On phenyl ring, two carbon atoms of arbitrary neighborhood form C together4-6Ring, the ring are optional former comprising nitrogen-atoms, oxygen atom or sulfur Son, and optional at one or more position, identical or different by halogen, cyano group, C1-6Alkyl, halo- C1-6Alkyl, aryl or by group-OR3、-SR4、-SOR4Or-SO2R4Replace；
R3Represent hydrogen, C1-12Alkyl, halo-C1-6Alkyl, C3-6Cycloalkyl or halo-C3-6Cycloalkyl, or represent wherein insert Enter the C of one or more oxygen1-12Alkyl, or represent group-(CH2)mNR6R7、-CH2CN or-CH2CF3；
M represents 1,2 or 3；
R4Representation hydroxy, C1-6Alkyl, aryl, heteroaryl represent group-NR6R7；
R5Represent hydrogen or represent optionally by the C of one or more halogen substiuteds1-6Alkyl, C1-6Alkoxyl, benzyl, aryl or miscellaneous Aryl；
R6And R7Separate representative hydrogen or represent optionally at one or more position, identical or different by halogen Element, cyano group, C1-6Alkyl, phenyl, hydroxyl-C1-6Alkyl, halo-C1-6Alkyl or by group-NR11R12、-OR3、C1-6Alkyl- OR3、-SR4、-SOR4Or-SO2R4The C for replacing or not being substituted1-6Alkyl, C3-6Cycloalkyl, C3-6Cycloalkenyl group, aryl or heteroaryl Base, or
R6And R7C is formed together with nitrogen-atoms3-8Ring, the ring are optional comprising other nitrogen, sulfur or oxygen atom, or can include GroupAnd can optionally in one or more positions, identical or different by halogen, cyano group, C1-6Alkyl, halogen Generation-C1-6Alkyl, aryl or by group-OR3、-SR4、-SOR4Or-SO2R4Replace；
R8And R9Separate representative hydrogen or C1-6Alkyl；
R10Represent hydrogen, C1-6Alkyl, three C1-6AIkylsilyl groups, aryl, heteroaryl represent group-COR14；
R11And R12Separate representative hydrogen or C1-6Alkyl, or
R11And R125-7 yuan of rings are formed together, and the ring can include oxygen or sulphur atom or group-NR13；
R13Represent hydrogen, C1-6Alkyl or aryl；
R14Represent hydrogen, C1-6Alkyl represents group-NR6R7；
R15Represent hydrogen, alkyl-carbonyl, C3-6Naphthene base carbonyl, C1-6Alkyl sulphonyl, C3-6Naphthene sulfamide base, 4-C1-6Alkyl ammonia Base sulfonvlphenyl, 4-C3-6Cycloalkyl amino sulfonvlphenyl.
3. compound of Formula I according to claim 2, it is characterised in that：
A is representedN represents 1 or 2；X represents halogen or hydrogen；
R1By following representations：
Wherein, the separate representative nitrogen of W, D, E or carbon atom, wherein at least one nitrogen-atoms, at most have two nitrogen-atoms；
Y represents O or NH；
G represent hydrogen or optionally at one or more position of phenyl ring, same or different selected from halogen, cyano group, C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkyl, halo C1-6Alkoxyl, or by group-OR3、-SO2R4Substituted aryl or Heteroaryl, or group-COOR5、-CONR6R7、-NHR15、-SO2R4；
R2Represent at one or more position optional on phenyl ring, identical or different selected from hydrogen, halogen, cyano group, hydroxyl Base, C1-6Alkoxyl, halo C1-6Alkoxyl, C2-6Thiazolinyl, cyano group-C3-6Cycloalkyl, cyano group-C1-6Alkyl, aryl-C1-6Alcoxyl Base, aryloxy, C1-6Alkyl, halo-C1-6Alkyl or group-SO2R4、OR3、-R3Or-PO (OR8)(OR9), or
R2C is formed together with two carbon atoms of arbitrary neighborhood on phenyl ring4-6Ring, the ring are optional comprising nitrogen-atoms, oxygen atom Or sulphur atom, and optional at one or more position, identical or different by halogen, cyano group, C1-6Alkyl, Halo-C1-6Alkyl, aryl or by group-OR3、-SR4、-SOR4Or-SO2R4Replace；
R3Represent hydrogen, C1-12Alkyl, halo-C1-6Alkyl, C3-6Cycloalkyl or halo-C3-6Cycloalkyl, or represent wherein insert Enter the C of one or more oxygen1-12Alkyl, or represent group-(CH2)mNR6R7、-CH2CN or-CH2CF3；
M represents 1,2 or 3；
R4Representation hydroxy, C1-6Alkyl, aryl, heteroaryl represent group-NR6R7；
R5Represent hydrogen or represent optionally by the C of one or more halogen substiuteds1-6Alkyl, C1-6Alkoxyl, benzyl, aryl or miscellaneous Aryl；
R6And R7Separate representative hydrogen or represent optionally at one or more position, identical or different by halogen Element, cyano group, C1-6Alkyl, phenyl, hydroxyl-C1-6Alkyl, halo-C1-6Alkyl or by group-NR11R12、-OR3、C1-6Alkyl- OR3、-SR4、-SOR4Or-SO2R4The C for replacing or not being substituted1-6Alkyl, C3-6Cycloalkyl, C3-6Cycloalkenyl group, aryl or heteroaryl Base, or
R6And R7C is formed together with nitrogen-atoms3-8Ring, the ring are optional comprising other nitrogen, sulfur or oxygen atom, or can include GroupAnd can optionally in one or more positions, identical or different by halogen, cyano group, C1-6Alkyl, halogen Generation-C1-6Alkyl, aryl or by group-OR3、-SR4、-SOR4Or-SO2R4Replace；
R8And R9Separate representative hydrogen or C1-6Alkyl；
R10Represent hydrogen, C1-6Alkyl, three C1-6AIkylsilyl groups, aryl, heteroaryl represent group-COR14；
R11And R12Separate representative hydrogen or C1-6Alkyl, or
R11And R125-7 yuan of rings are formed together, and the ring can include oxygen or sulphur atom or group-NR13；
R13Represent hydrogen, C1-6Alkyl or aryl；
R14Represent hydrogen, C1-6Alkyl represents group-NR6R7；
R15Represent hydrogen, C1-3Alkyl-carbonyl, C3-4Naphthene base carbonyl, C1-3Alkyl sulphonyl, Cyclopropylsulfonyl, 4-C1-3Alkyl ammonia Base sulfonvlphenyl, 4- cyclopropylamino sulfonvlphenyls.
4. compound of Formula I according to claim 3, it is characterised in that：
A is representedN represents 1 or 2；X represents halogen or hydrogen；
R1By following representations：
Wherein, the separate representative nitrogen of W, D, E or carbon atom, wherein at least one nitrogen-atoms, at most have two nitrogen-atoms；
Y represents O or NH；
G represent hydrogen or optionally at one or more position of phenyl ring, same or different selected from halogen, cyano group, C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkyl, halo C1-6Alkoxyl, or by group-OR3、-SO2R4Substituted aryl or Heteroaryl, or group-COOR5、-CONR6R7、-NHR15、-SO2R4；
R2Represent at one or more position optional on phenyl ring, identical or different selected from hydrogen, halogen, cyano group, hydroxyl Base, C1-6Alkoxyl, halo C1-6Alkoxyl, C2-6Thiazolinyl, cyano group-C3-6Cycloalkyl, cyano group-C1-6Alkyl, aryl-C1-6Alcoxyl Base, aryloxy, C1-6Alkyl, halo-C1-6Alkyl or group-SO2R4、OR3、-R3Or-PO (OR8)(OR9), or
R2C is formed together with two carbon atoms of arbitrary neighborhood on phenyl ring4-6Ring, the ring are optional comprising nitrogen-atoms, oxygen atom Or sulphur atom, and optional at one or more position, identical or different by halogen, cyano group, C1-6Alkyl, Halo-C1-6Alkyl, aryl or by group-OR3、-SR4、-SOR4Or-SO2R4Replace；
R3Represent hydrogen, C1-12Alkyl, halo-C1-6Alkyl, C3-6Cycloalkyl or halo-C3-6Cycloalkyl, or represent wherein insert Enter the C of one or more oxygen1-12Alkyl, or represent group-(CH2)mNR6R7、-CH2CN or-CH2CF3；
M represents 1,2 or 3；
R4Representation hydroxy, C1-6Alkyl, aryl, heteroaryl represent group-NR6R7；
R5Represent hydrogen or represent optionally by the C of one or more halogen substiuteds1-6Alkyl, C1-6Alkoxyl, benzyl, aryl or miscellaneous Aryl；
R6And R7Separate representative hydrogen or represent optionally at one or more position, identical or different by halogen Element, cyano group, C1-6Alkyl, phenyl, hydroxyl-C1-6Alkyl, halo-C1-6Alkyl or by group-NR11R12、-OR3、C1-6Alkyl- OR3、-SR4、-SOR4Or-SO2R4The C for replacing or not being substituted1-6Alkyl, C3-6Cycloalkyl, C3-6Cycloalkenyl group, aryl or heteroaryl Base, or
R6And R7C is formed together with nitrogen-atoms3-8Ring, the ring are optional comprising other nitrogen, sulfur or oxygen atom, or can include GroupAnd can optionally in one or more positions, identical or different by halogen, cyano group, C1-6Alkyl, halogen Generation-C1-6Alkyl, aryl or by group-OR3、-SR4、-SOR4Or-SO2R4Replace；
R8And R9Separate representative hydrogen or C1-6Alkyl；
R10Represent hydrogen, C1-6Alkyl, three C1-6AIkylsilyl groups, aryl, heteroaryl represent group-COR14；
R11And R12Separate representative hydrogen or C1-6Alkyl, or
R11And R125-7 yuan of rings are formed together, and the ring can include oxygen or sulphur atom or group-NR13；
R13Represent hydrogen, C1-6Alkyl or aryl；
R14Represent hydrogen, C1-6Alkyl represents group-NR6R7；
R15Represent hydrogen, C1-3Alkyl-carbonyl, C3-4Naphthene base carbonyl, C1-3Alkyl sulphonyl, Cyclopropylsulfonyl, 4-C1-3Alkyl ammonia Base sulfonvlphenyl, 4- cyclopropylamino sulfonvlphenyls.
5. compound of Formula I according to claim 4, it is characterised in that：
A is representedN represents 1 or 2；
X represents halogen or hydrogen；
R1By following representations：
Wherein, the separate representative nitrogen of W, D, E or carbon atom, wherein at least one nitrogen-atoms, at most have two nitrogen-atoms； Y represents O or NH；
G represent hydrogen or optionally at one or more position of phenyl ring, same or different selected from halogen, cyano group, C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkyl, halo C1-6Alkoxyl, or by group-OR3、-SO2R4Substituted aryl or Heteroaryl, or group-COOR5、-CONR6R7、-NHR15、-SO2R4；
R2Represent at one or more position optional on phenyl ring, identical or different selected from hydrogen, halogen, cyano group, C1-6 Alkoxyl, halo C1-6Alkoxyl, cyano group-C3-6Cycloalkyl, cyano group-C1-6Alkyl, aryl-C1-6Alkoxyl, aryloxy, C1-6 Alkyl, halo-C1-6Alkyl or group-R3, or
R2C is formed together with two carbon atoms of arbitrary neighborhood on phenyl ring4-6Ring, the ring are optional comprising nitrogen-atoms, oxygen atom Or sulphur atom, and optional at one or more position, identical or different by halogen, cyano group, C1-6Alkyl, Halo-C1-6Alkyl, aryl or by group-OR3、-SO2R4Replace；
R3Represent hydrogen, C1-12Alkyl, halo-C1-6Alkyl, C3-6Cycloalkyl or halo-C3-6Cycloalkyl, or represent wherein insert Enter the C of one or more oxygen1-12Alkyl, or represent group-(CH2)mNR6R7、-CH2CN or-CH2CF3；
M represents 1,2 or 3；
R4Representation hydroxy, C1-6Alkyl, aryl, heteroaryl represent group-NR6R7；
R5Represent hydrogen or represent optionally by the C of one or more halogen substiuteds1-6Alkyl, C1-6Alkoxyl, benzyl, aryl or miscellaneous Aryl；
R6And R7Separate representative hydrogen or represent optionally at one or more position, identical or different by halogen Element, cyano group, C1-6Alkyl, phenyl, hydroxyl-C1-6Alkyl, halo-C1-6Alkyl or by group-NR11R12、-OR3、C1-6Alkyl- OR3、-SR4、-SOR4Or-SO2R4The C for replacing or not being substituted1-6Alkyl, C3-6Cycloalkyl, C3-6Cycloalkenyl group, aryl or heteroaryl Base, or
R6And R7C is formed together with nitrogen-atoms3-8Ring, the ring are optional comprising other nitrogen, sulfur or oxygen atom, or can include GroupAnd can optionally in one or more positions, identical or different by halogen, cyano group, C1-6Alkyl, halogen Generation-C1-6Alkyl, aryl or by group-OR3、-SR4、-SOR4Or-SO2R4Replace；
R8And R9Separate representative hydrogen or C1-6Alkyl；
R10Represent hydrogen, C1-6Alkyl, three C1-6AIkylsilyl groups, aryl, heteroaryl represent group-COR14；
R11And R12Separate representative hydrogen or C1-6Alkyl, or
R11And R125-7 yuan of rings are formed together, and the ring can include oxygen or sulphur atom or group-NR13；
R13Represent hydrogen, C1-6Alkyl or aryl；
R14Represent hydrogen, C1-6Alkyl represents group-NR6R7；
R15Represent hydrogen, C1-3Alkyl-carbonyl, C3-4Naphthene base carbonyl, C1-3Alkyl sulphonyl, Cyclopropylsulfonyl, 4-C1-3Alkyl ammonia Base sulfonvlphenyl, 4- cyclopropylamino sulfonvlphenyls.
6. compound of Formula I according to claim 5, it is characterised in that：
A is representedN represents 1 or 2；
X represents halogen or hydrogen；
R1By following representations：
Wherein, the separate representative nitrogen of W, D, E or carbon atom, wherein at least one nitrogen-atoms, at most have two nitrogen-atoms； Y represents O or NH；
G represent hydrogen or optionally at one or more position of phenyl ring, same or different selected from halogen, cyano group, C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkyl, halo C1-6Alkoxyl, or by group-OR3、-SO2R4Substituted aryl or Heteroaryl, or group-COOR5、-CONR6R7、-NHR15、-SO2R4；
R2Represent at one or two positions optional on phenyl ring, identical or different selected from hydrogen, halogen, cyano group, C1-6 Alkoxyl, halo C1-6Alkoxyl, cyano group-C3-6Cycloalkyl, cyano group-C1-6Alkyl, aryl-C1-6Alkoxyl, aryloxy, C1-6 Alkyl, halo-C1-6Alkyl or group-R3, or
R2C is formed together with two carbon atoms of arbitrary neighborhood on phenyl ring4-6Ring, the ring can include nitrogen-atoms, and optional At one or more position, identical or different by halogen, cyano group, C1-6Alkyl, halo-C1-6Alkyl, aryl replace；
R3Represent hydrogen, C1-12Alkyl, halo-C1-6Alkyl, C3-6Cycloalkyl or halo-C3-6Cycloalkyl, or represent wherein insert Enter the C of one or more oxygen1-12Alkyl, or represent group-(CH2)mNR6R7、-CH2CN or-CH2CF3；
M represents 1,2 or 3；
R4Representation hydroxy, C1-6Alkyl, aryl, heteroaryl represent group-NR6R7；
R5Represent hydrogen or represent optionally by the C of one or more halogen substiuteds1-6Alkyl, C1-6Alkoxyl, benzyl, aryl or miscellaneous Aryl；
R6And R7Separate representative hydrogen or represent optionally at one or more position, identical or different by halogen Element, cyano group, C1-6Alkyl, phenyl, hydroxyl-C1-6Alkyl, halo-C1-6Alkyl or by group-NR11R12、-OR3、C1-6Alkyl- OR3、-SR4、-SOR4Or-SO2R4The C for replacing or not being substituted1-6Alkyl, C3-6Cycloalkyl, C3-6Cycloalkenyl group, aryl or heteroaryl Base, or
R6And R7C is formed together with nitrogen-atoms3-8Ring, the ring are optional comprising other nitrogen, sulfur or oxygen atom, or can include GroupAnd can optionally in one or more positions, identical or different by halogen, cyano group, C1-6Alkyl, halogen Generation-C1-6Alkyl, aryl or by group-OR3、-SR4、-SOR4Or-SO2R4Replace；
R8And R9Separate representative hydrogen or C1-6Alkyl；
R10Represent hydrogen, C1-6Alkyl, three C1-6AIkylsilyl groups, aryl, heteroaryl represent group-COR14；
R11And R12Separate representative hydrogen or C1-6Alkyl, or
R11And R125-7 yuan of rings are formed together, and the ring can include oxygen or sulphur atom or group-NR13；
R13Represent hydrogen, C1-6Alkyl or aryl；
R14Represent hydrogen, C1-6Alkyl represents group-NR6R7；
R15Represent hydrogen, C1-3Alkyl-carbonyl, C3-4Naphthene base carbonyl, C1-3Alkyl sulphonyl, Cyclopropylsulfonyl, 4-C1-3Alkyl ammonia Base sulfonvlphenyl, 4- cyclopropylamino sulfonvlphenyls.
Preferably,
A is representedN represents 1 or 2；
X represents halogen or hydrogen；
R1By following representations：
Wherein, p represents 1,2 or 3；
By following representations：
7. the compound of Formula I according to claim 1-6, which is selected from following compounds：
3- ((4- chloro- 3- (trifluoromethyl) benzyls) amino) -1- (4- pyridylmethyls) pyridine -2 (1H) -one；
N- (4- chloro- 3- (trifluoromethyl) phenyl) the fluoro- 5- of -2- ((4- pyridylmethyls) amino) Benzoylamide；
N- (4- chloro- 3- (trifluoromethyl) phenyl) -3- ((4- pyridylmethyls) amino) Benzoylamide；
3- ((4- chloro- 3- (trifluoromethyl) benzyls) amino) -1- (2- (4- pyridine radicals) ethyl) pyridine -2 (1H) -one；
N- (4- (3- ((4- chloro- 3- (trifluoromethyl) benzyls) amino) -1 (2H)-methyl of -2- oxo pyridines base) pyridine -2- bases) Acetamide；
3- ((4- chloro- 3- (trifluoromethyl) benzyls) amino) -1- ((2- ((4- mesyls) phenyl) amino) pyridin-4-yl) first Base) pyridine -2 (1H) -one；
N- (4- chloro- 3- (trifluoromethyl) phenyl) the fluoro- 5- of -2- (((2- ((4- (mesyl) phenyl) amino) pyridin-4-yl) Methyl) amino) Benzoylamide；
N- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (((2- ((4- (mesyl) phenyl) amino) pyridin-4-yl) methyl) Amino) Benzoylamide；
4- (3- ((4- chloro- 3- (trifluoromethyl) benzyls) amino) -1 (2H)-methyl of -2- oxo pyridines base)-N- cyclopropyl pyridines Amide；
4- (((3- ((4- chloro- 3- (trifluoromethyl) phenyl) carbamoyl) -4- fluorophenyls) amino) methyl)-N- cyclopropyl pyrroles Pyridine amide；
4- (((3- ((4- chloro- 3- (trifluoromethyl) phenyl) carbamoyl) phenyl) amino) methyl)-N- cyclopropyl pyridine acyls Amine；
3- ((4- chloro- 3- (trifluoromethyl) benzyls) amino) -1- ((6,7- dimethoxy-quinoline -4- bases) methyl) pyridine -2 (1H) -one；
N- (4- chloro- 3- (trifluoromethyl) phenyl) -5- (((6,7- dimethoxy-quinoline -4- bases) methyl) amino) the fluoro- benzene first of -2- Amide；
N- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (((6,7- dimethoxy-quinoline -4- bases) methyl) amino) Benzoylamide；
3- ((4- chloro- 3- (trifluoromethyl) benzyls) amino) -1- ((6,7- dimethoxyquinazoline -4- bases) methyl) pyridine -2 (1H) -one；
N- (4- chloro- 3- (trifluoromethyl) phenyl) -5- (((6,7- dimethoxyquinazoline -4- bases) methyl) amino) the fluoro- benzene of -2- Methanamide；
N- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (((6,7- dimethoxyquinazoline -4- bases) methyl) amino) benzoyl Amine；
2- methyl -2- (4- (((2- oxo -1- (4- pyridylmethyls) -1,2- dihydropyridine -3- bases) amino) methyl) phenyl) Propionitrile；
2- methyl -2- (4- (((2- oxo -1- (2- (4- pyridine radicals) ethyl) -1,2- dihydropyridine -3- bases) amino) methyl) benzene Base) propionitrile；
N- (4- (2- dicyanopropane -2- bases) phenyl) -3- ((4- pyridylmethyls) amino) Benzoylamide；
N- (4- (2- dicyanopropane -2- bases) phenyl) the fluoro- 5- of -2- ((4- pyridylmethyls) amino) Benzoylamide；
4- ((2- oxo -3- ((4- trifluoromethoxies) phenyl) amino) -1 (2H)-yl of pyridine) methyl) pyridine carboxylic acid methyl ester；
1- ((4- aminothiophenes [2.3-d] pyrimidine -5- bases) methyl) -3- ((4- phenoxy benzyls) amino) pyridine -2 (1H) - Ketone；
5 (((4- aminothiophenes [2.3-d] pyrimidine -5- bases) methyl) amino) -2- fluoro-N- (4- ((4- methyl piperazine -1- Base) methyl) -3- (trifluoromethyl) phenyl) Benzoylamide；
4- (((3- ((3,3- dimethyl indole quinoline -6- bases) carbamoyl) -4- difluorophenyls) amino) methyl) pyridine carboxylic acid Methyl ester.
8. the synthetic method of compound described in claim 1,
1) when A is representedWhen, compound of Formula I is by structural formulaRepresent, Its synthetic method is scheme () or scheme (two)：
Scheme (one)：
Wherein, R1、R2, n is as defined in formula I；
When the n in formula I ' compounds represents 2, its synthetic method may further reference scheme (two) and carry out：
Scheme (two)：
Wherein, R1、R2As defined in formula I；
2) when A is representedWhen, compound of Formula I is by structural formula Represent, its synthetic method is scheme (three) or scheme (four)：
Scheme (three)：
Wherein, R1、R2, X is as defined in formula I；
Scheme (four)：
Wherein, R1、R2, X is as defined in formula I.
9. a kind of pharmaceutical composition, compound wherein comprising any one in claim 1-8 and pharmaceutically acceptable Carrier.
10. in claim 1-7, any one compound is being prepared for disease caused by treating by persistence angiogenesis Application in medicine, the disease are preferably caused by angiogenesis or vascular permeability increase is continued caused by vegf receptor Or the disease for promoting.
CN201610793266.5A 2016-08-31 2016-08-31 VEGFR inhibitor 2 and preparation method thereof Pending CN106496107A (en)

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