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
halo
aryl
cyano
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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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    • C07D213/04—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
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    • 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
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    • 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
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    • 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
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    • 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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    • 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
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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 inhibitors and methods of making the same
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a VEGFR-2 inhibitor, a preparation method and application thereof.
Background
Persistent angiogenesis can be a cause of, or can lead to, a variety of diseases, such as hemangioma, angiofibroma, malignant renal necrosis, embolic microvascular syndrome, liver cancer, gastrointestinal stromal tumors, and the like.
Persistent angiogenesis is induced by the Vascular Endothelial Growth Factor (VEGF) through its receptors, to allow VEGF to exert this effect, it must bind to the receptor and induce tyrosine phosphorylation.
Direct or indirect inhibition of VEGF receptors may be implicated in the treatment of these diseases as well as other pathological angiogenesis and vascular permeability disorders induced by VEGF such as tumor angiogenesis. For example, it is known that tumor growth can be inhibited with soluble receptors as well as antibodies against VEGF.
VEGFR-2, a major receptor for VEGF, is expressed primarily in vascular endothelial cells and binds to VEGF-A and VEGF-C, stimulating endothelial cell proliferation, increasing vascular permeability and neovascularization. Many of the physiological or pathological changes in endothelial cells caused by VEGF are mainly mediated by VEGFR-2, and small molecule tumor angiogenesis inhibitors targeting VEGFR-2, such as changes in proliferation, migration, survival and permeability, act on the ATP binding site in the VEGFR-2 intracellular kinase active region to competitively inhibit ATP binding to receptors and inhibit VEGFR-2 autophosphorylation, thereby blocking the VEGF/VEGFR signaling pathway.
From a pharmaceutical point of view, it would be very valuable to develop small molecule protein kinase inhibitors against VEGFR-2 for the treatment of diseases associated with vascular growth, and various inhibitors such as quinazoline derivatives, benzothiazole, etc. kinase inhibition have now been disclosed in the art, however there is still a need in the art to develop new protease inhibitors.
Disclosure of Invention
It is an object of the present invention to provide a novel compound, a pharmaceutical composition comprising said compound and the use of said compound or composition for the treatment of diseases mediated by aberrant VEGFR 2.
The present invention relates to a compound of the general formula I:
wherein A representsOrn represents 1 or 2;
x represents halogen or hydrogen;
R1represents optionally one or more positions on the ring, identical or different, substituted by halogen, cyano, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy radicals, OR by radicals-OR3、-SR4、-SOR4、-SO2R4Substituted aryl or heteroaryl, or by a radical-COOR5、-CONR6R7、-NHR15、-SR4、-SOR4、-SO2R4、-SCN、-PO(OR8)(OR9)、-CH＝CH-COR10or-C.ident.C-R10A substituted or unsubstituted nitrogen-containing aromatic heterocycle;
R2represents at one or more optional positions on the benzene ring, same or different, and is selected from hydrogen, halogen, cyano, hydroxy, C1-6Alkoxy, halo C1-6Alkoxy radical, C2-6Alkenyl, cyano-C3-6Cycloalkyl, cyano-C1-6Alkyl, aryl-C1-6Alkoxy, aryloxy, C1-6Alkyl, halo-C1-6Alkyl or a group-SO2R4、OR3、-R3OR-PO (OR)8)(OR9) (ii) a Or, R2Together with any adjacent two carbon atoms of the benzene ring to form C4-6A ring optionally containing a nitrogen, oxygen or sulfur atom, and optionally in one or more positions, the same or different, substituted by halogen, cyano, C1-6Alkyl, halo-C1-6Alkyl, aryl, OR substituted radicals-OR3、-SR4、-SOR4or-SO2R4Substitution;
R3represents hydrogen, C1-12Alkyl, halo-C1-6Alkyl radical, C3-6Cycloalkyl or halo-C3-6Cycloalkyl radicals, or represent insertions thereinC with one or more oxygen atoms1-12Alkyl, or represents the group- (CH)2)mNR6R7、-CH2CN or-CH2CF3；
m represents 1,2 or 3;
R4represents hydroxy, C1-6Alkyl, aryl, heteroaryl or represents the group-NR6R7；
R5Represents hydrogen or represents C optionally substituted by one or more halogens1-6Alkyl radical, C1-6Alkoxy, benzyl, aryl or heteroaryl;
R6and R7Independently of one another, represents hydrogen or represents halogen, cyano, C, optionally in one or more positions, the same or different1-6Alkyl, phenyl, hydroxy-C1-6Alkyl, halo-C1-6Alkyl or by a group-NR11R12、-OR3、C1-6alkyl-OR3、-SR4、-SOR4or-SO2R4Substituted or unsubstituted C1-6Alkyl radical, C3-6Cycloalkyl radical, C3-6Cycloalkenyl, aryl or heteroaryl, or
R6And R7Together with nitrogen atoms to form C3-8Rings which optionally contain further nitrogen, sulfur or oxygen atoms or which may contain groupsAnd optionally in one or more positions, the same or different, by halogen, cyano, C16Alkyl, halo-C1-6Alkyl, aryl, OR substituted radicals-OR3、-SR4、-SOR4or-SO2R4Substitution;
R8and R9Independently of one another, represent hydrogen or C1-6An alkyl group;
R10representsHydrogen, C1-6Alkyl, tri-C1-6Alkylsilyl, aryl, heteroaryl or represents the group-COR14；
R11And R12Independently of one another, represent hydrogen or C1-6Alkyl, or
R11And R12Together forming a 5-7 membered ring which may contain an oxygen or sulphur atom or group-NR13；
R13Represents hydrogen, C1-6An alkyl or aryl group;
R14represents hydrogen, C1-6Alkyl or represents a group-NR6R7；
R15Represents hydrogen, alkylcarbonyl, C3-6Cycloalkyl carbonyl group, C1-6Alkylsulfonyl radical, C3-6Cycloalkylsulfonyl, 4-C1-6Alkylaminosulfonylphenyl, 4-C3-6Cycloalkylaminosulfonylphenyl.
In a preferred embodiment of the invention, R1Represents optionally one or more positions on the ring, identical or different, substituted by halogen, cyano, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy radicals, OR by radicals-OR3、-SO2R4Substituted aryl or heteroaryl, or by a radical-COOR5、-CONR6R7、-NHR15、-SO2R4Substituted or unsubstituted nitrogen-containing aromatic heterocyclic ring.
In another preferred embodiment of the invention, R1Represented by the following structure:
wherein W, D, E independently of one another represent a nitrogen or carbon atom, at least one of whichA nitrogen atom having at most two nitrogen atoms; y represents O or NH; g represents hydrogen or is selected from halogen, cyano, C, the same or different, optionally in one or more positions of the phenyl ring1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy radicals, OR by radicals-OR3、-SO2R4Substituted aryl or heteroaryl groups, or the group-COOR5、-CONR6R7、-NHR15、-SO2R4；R15Represents hydrogen, C1-3Alkylcarbonyl group, C3-4Cycloalkyl carbonyl group, C1-3Alkylsulfonyl, cyclopropylsulfonyl, 4-C1-3Alkylaminosulfonylphenyl, 4-cyclopropylaminosulfonylphenyl.
In another preferred embodiment of the invention, R1Represented by the following structure:
w, D, E independently represent nitrogen or carbon atoms, wherein at least one nitrogen atom and at most two nitrogen atoms are present; y represents O or NH; g represents hydrogen or is selected from halogen, cyano, C, the same or different, optionally in one or more positions of the phenyl ring1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy radicals, OR by radicals-OR3、-SO2R4Substituted aryl or heteroaryl groups, or the group-COOR5、-CONR6R7、-NHR15、-SO2R4；R15Represents hydrogen, C1-3Alkylcarbonyl group, C3-4Cycloalkyl carbonyl group, C1-3Alkylsulfonyl, cyclopropylsulfonyl, 4-C1-3Alkylaminosulfonylphenyl, 4-cyclopropylaminosulfonylphenyl.
In another preferred embodiment of the invention, R2Represents an optional radical on the benzene ringIs selected from hydrogen, halogen, cyano, C, at one or more positions, the same or different1-6Alkoxy, halo C1-6Alkoxy, cyano-C3-6Cycloalkyl, cyano-C1-6Alkyl, aryl-C1-6Alkoxy, aryloxy, C1-6Alkyl, halo-C1-6Alkyl or a radical-R3Or is or
R2Together with any adjacent two carbon atoms of the benzene ring to form C4-6A ring optionally containing a nitrogen, oxygen or sulfur atom, and optionally in one or more positions, the same or different, substituted by halogen, cyano, C1-6Alkyl, halo-C1-6Alkyl, aryl, OR substituted radicals-OR3、-SO2R4And (4) substitution.
In another preferred embodiment of the invention, R2Represents at one or two optional positions on the benzene ring, same or different, selected from hydrogen, halogen, cyano, C1-6Alkoxy, halo C1-6Alkoxy, cyano-C3-6Cycloalkyl, cyano-C1-6Alkyl, aryl-C1-6Alkoxy, aryloxy, C1-6Alkyl, halo-C1-6Alkyl or a radical-R3Or is or
R2Together with any adjacent two carbon atoms of the benzene ring to form C4-6A ring which may contain a nitrogen atom and which may be optionally substituted in one or more positions, identically or differently, by halogen, cyano, C1-6Alkyl, halo-C1-6Alkyl and aryl substitution.
In another preferred embodiment of the invention, R1Represented by the following structure:
wherein p represents 1,2 or 3;
at the same timeRepresented by the following structure:
the compounds of the invention are preferably selected from the following compounds:
3- ((4-chloro-3- (trifluoromethyl) benzyl) amino) -1- (4-pyridylmethyl) pyridin-2 (1H) -one
N- (4-chloro-3- (trifluoromethyl) phenyl) -2-fluoro-5- ((4-pyridylmethyl) amino) benzamide
N- (4-chloro-3- (trifluoromethyl) phenyl) -3- ((4-pyridylmethyl) amino) benzamide
3- ((4-chloro-3- (trifluoromethyl) benzyl) amino) -1- (2- (4-pyridinyl) ethyl) pyridin-2 (1H) -one
N- (4- (3- ((4-chloro-3- (trifluoromethyl) benzyl) amino) -2-oxopyridin-1 (2H) -methyl) pyridin-2-yl) acetamide
3- ((4-chloro-3- (trifluoromethyl) benzyl) amino) -1- ((2- ((4-methanesulfonyl) phenyl) amino) pyridin-4-yl) methyl) pyridin-2 (1H) -one
N- (4-chloro-3- (trifluoromethyl) phenyl) -2-fluoro-5- (((2- ((4- (methylsulfonyl) phenyl) amino) pyridin-4-yl) methyl) amino) benzamide
N- (4-chloro-3- (trifluoromethyl) phenyl) -3- (((2- ((4- (methylsulfonyl) phenyl) amino) pyridin-4-yl) methyl) amino) benzamide
4- (3- ((4-chloro-3- (trifluoromethyl) benzyl) amino) -2-oxopyridinyl-1 (2H) -methyl) -N-cyclopropylpicolinamide
4- (((3- ((4-chloro-3- (trifluoromethyl) phenyl) carbamoyl) -4-fluorophenyl) amino) methyl) -N-cyclopropylpicolinamide
4- (((3- ((4-chloro-3- (trifluoromethyl) phenyl) carbamoyl) phenyl) amino) methyl) -N-cyclopropylpicolinamide
3- ((4-chloro-3- (trifluoromethyl) benzyl) amino) -1- ((6, 7-dimethoxyquinolin-4-yl) methyl) pyridin-2 (1H) -one
N- (4-chloro-3- (trifluoromethyl) phenyl) -5- (((6, 7-dimethoxyquinolin-4-yl) methyl) amino) -2-fluoro-benzamide
N- (4-chloro-3- (trifluoromethyl) phenyl) -3- (((6, 7-dimethoxyquinolin-4-yl) methyl) amino) benzamide
3- ((4-chloro-3- (trifluoromethyl) benzyl) amino) -1- ((6, 7-dimethoxyquinazolin-4-yl) methyl) pyridin-2 (1H) -one
N- (4-chloro-3- (trifluoromethyl) phenyl) -5- (((6, 7-dimethoxyquinazolin-4-yl) methyl) amino) -2-fluoro-benzamide
N- (4-chloro-3- (trifluoromethyl) phenyl) -3- (((6, 7-dimethoxyquinazolin-4-yl) methyl) amino) benzamide
2-methyl-2- (4- (((2-oxo-1- (4-pyridylmethyl) -1, 2-dihydropyridin-3-yl) amino) methyl) phenyl) propionitrile
2-methyl-2- (4- (((2-oxo-1- (2- (4-pyridyl) ethyl) -1, 2-dihydropyridin-3-yl) amino) methyl) phenyl) propionitrile
N- (4- (2-cyanopropan-2-yl) phenyl) -3- ((4-pyridylmethyl) amino) benzamide
N- (4- (2-cyanopropan-2-yl) phenyl) -2-fluoro-5- ((4-pyridylmethyl) amino) benzamide
4- ((2-oxo-3- ((4-trifluoromethoxy) phenyl) amino) pyridin-1 (2H) -yl) methyl) picolinic acid methyl ester
1- ((4-aminothiophene [2.3-d ] pyrimidine-5-yl) methyl) -3- ((4-phenoxybenzyl) amino) pyridin-2 (1H) -one
5 (((4-aminothiophen [2.3-d ] pyrimidin-5-yl) methyl) amino) -2-fluoro-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide
4- (((3- ((3, 3-Dimethylindolinyl-6-Yl) carbamoyl) -4-fluorophenyl) amino) methyl) picolinic acid methyl ester
The compounds of the invention may be prepared by any conventional means, and suitable methods for synthesizing these compounds are provided in the examples. In general, the compounds of formula I may be prepared according to the synthetic routes described below.
1) When A representsWhen the compound of the general formula I is represented by the structural formulaThe synthesis method can be performed according to scheme (one) or scheme (two):
scheme I
Wherein R is1、R2N is as defined in formula I.
When n in the compound of formula I' represents 2, the synthesis can also be carried out with reference to scheme (ii):
scheme (II):
wherein R is1、R2As defined in formula I.
2) When A representsWhen the compound of the general formula I is represented by the structural formulaThe synthesis method can be performed according to scheme (three) or scheme (four):
scheme (III):
wherein R is1、R2X is as defined in formula I.
Scheme (IV):
wherein R is1、R2X is as defined in formula I.
The invention also provides a pharmaceutical composition comprising at least one compound of the invention and pharmaceutically acceptable salts, crystals or mixtures thereof and at least one pharmaceutically acceptable excipient, or adjuvant, or carrier.
The invention also provides a method for testing the influence of the compound of the general formula I on the VEGFR-2 inhibitory activity, which specifically comprises the following steps: an ATP solution diluted with a reaction buffer and VEGFR-2 protein were added to an enzyme plate containing 0.01M sodium phosphate buffer (pH 7.2-7.4), 0.15M sodium chloride solution and an enzymatic reaction substrate. And then setting an experimental group and a blank group, namely adding reaction liquid containing a compound to be detected and reaction liquid not containing the compound to be detected into the system respectively, sequentially adding primary anti-PY 99, carrying out shaking table reaction at 37 ℃ for 0.5 hour, and carrying out shaking table reaction at 37 ℃ for 0.5 hour on a secondary anti-horseradish peroxidase labeled goat anti-mouse IgG. And finally adding OPD color developing solution to react for 10 minutes, adding sulfuric acid to stop the reaction, and measuring the OD value of absorbance.
The inhibition of the compound was determined by the following formula:
the compounds of the invention have an inhibition rate of more than or equal to 10 percent through detection by using the method; the preferred compound of the invention has an inhibition rate of more than or equal to 30 percent; further preferred compounds of the invention have an inhibition rate of greater than or equal to 50%; thus, the effect of the compounds of the present invention was determined to be a potent VEGFR-2 inhibitor.
According to the invention, the compounds of the general formula I can be used as medicaments on the basis of their inhibitory activity with respect to the phosphorylation of VEGF receptors. Depending on their mode of action, the compounds provided by the present invention are suitable for the treatment of diseases caused by persistent angiogenesis.
Since the compounds of formula I have been identified as VEGFR-2 inhibitors, they are particularly suitable for the treatment of diseases which are caused or promoted by persistent angiogenesis or increased vascular permeability by the VEGF receptor.
The invention also relates to the use of the compounds according to the invention for the preparation of a medicament for the treatment of diseases caused by persistent angiogenesis.
Interpretation of terms
As used herein, the term "alkyl" refers to a branched or straight chain hydrocarbon group in which all carbon-carbon bonds are single bonds, while the term "cycloalkyl" refers to a monocyclic ring containing 3 to 6 carbon atoms.
The term "halo C" as used herein1-6Alkyl "refers to an alkyl group containing 1 to 6 carbon atoms substituted with one or more halogen atoms which may be the same or different, the term" haloC3-6CycloalkanesBy "radical" is meant a cycloalkyl radical containing from 3 to 6 carbon atoms, substituted by one or more identical or different halogen atoms, the term "cyano radical C1-6Alkyl "refers to an alkyl group containing 1 to 6 carbon atoms substituted with one or more cyano groups, and the term" cyano C3-6Cycloalkyl "refers to cycloalkyl groups containing 3 to 6 carbon atoms substituted with one or more cyano groups.
As used herein, the term "alkenyl" refers to a branched or straight chain hydrocarbon group in which one or more carbon-carbon bonds are double bonds, while the term "cycloalkenyl" refers to a monocyclic ring of 3 to 6 carbon atoms in which one or more carbon-carbon bonds are double bonds.
The term "alkoxy" as used herein refers to the group-OR, wherein R refers to alkyl, as defined above.
The term "halo C" as used herein1-6Alkoxy "means an alkoxy group containing 1 to 6 carbon atoms substituted with one or more of the same or different halogen atoms.
As used herein, the term "aryl" refers to a monocyclic or polycyclic hydrocarbon group of 6 to 14 carbon atoms which is an aromatic ring having at least one point providing a point of attachment for the group. Polycyclic aryl groups can have isolated rings (e.g., diphenyl) or fused rings (e.g., naphthyl) in which at least one ring is aromatic.
As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic hydrocarbon group of 6 to 14 carbon atoms containing one or more nitrogen, oxygen or sulfur atoms in the ring, which is an aromatic ring having at least one point providing a point of attachment for the group.
As used herein, a "nitrogen-containing heterocyclic aromatic ring" refers to a monocyclic or polycyclic hydrocarbon group of 5 to 14 carbon atoms, said ring containing at least one nitrogen atom, said hydrocarbon group being an aromatic ring having at least one point providing a point of attachment for the group.
The following table lists the english abbreviations that appear in the present invention and all the english and chinese designations that they represent, and indicates that english abbreviations not included in the following table have the generally accepted meaning.
Detailed Description
The present invention will be further described with reference to the following examples, but the present invention is not limited to these examples.
The methods used in the following examples are conventional methods unless otherwise specified. The starting materials and reagents described in the present invention can be obtained commercially or by simple synthesis.
Example 1: 3- ((4-chloro-3- (trifluoromethyl) benzyl) amino) -1- (4-pyridylmethyl) pyridin-2 (1H) -one (Compound 1)
Step A:
synthesis of Compound 1-a: 4-chloromethylpyridine hydrochloride (39.3mmol), 3-nitro-2-pyridone (35.7mmol), potassium carbonate (89.2mmol) and DMF (250mL) were added to a reaction flask, and after stirring at 50 ℃ for 4 hours, water (250mL) was added for dilution, EA (3X 250mL) was extracted, saturated sodium chloride (100mL) was washed, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and column chromatography (EA first, DCM: MeOH: 20:1) was performed to obtain a total of 8g of a yellow solid (compound 1-a).
And B:
synthesis of Compound 1-b: 1-a (26mmol), Pd/C (0.6g) and methanol (30mL) were added to the reaction flask, the system was hydrogenated under pressure (0.4bar), and after stirring for 4 hours, Pd/C was removed by filtration, and the solvent was evaporated under reduced pressure to obtain a brown solid (compound 1-b) in an amount of 4.2g in total.
And C:
synthesis of Compound 1: adding 1-b (9.4mmol), 4-chloro-3-trifluoromethylbenzaldehyde (10.4mmol), DCM (50mL) and 5 drops of AcOH into a reaction bottle, stirring the system at room temperature for 1 hour to generate a very small amount of product, evaporating the solvent under reduced pressure, adding ethanol (40mL), heating and refluxing the oil bath for 4 hours to find that only a small amount of raw material remains, cooling the system, adding NaBH (OAc)3(14mmol), stirred at room temperature for 3 hours, reacted completely, and saturated NaHCO was added3Quench (20mL), EA (3X 100mL), extract, wash with saturated NaCl (100mL), anhydrous Na2SO4Drying, filtering, evaporating the solvent under reduced pressure, separating by column chromatography to obtain 1.2g of crude product, dissolving the crude product in a mixed solvent of DCM (10mL) and MeOH (20: 1), dropwise adding EA under stirring at room temperature until just solid is separated out, stirring for 0.5 h, filtering, and washing with EA (2mL) to obtain 500mg of off-white solid (compound 1).
1H NMR(400MHz,DMSO)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).
Example 2: n- (4-chloro-3- (trifluoromethyl) phenyl) -2-fluoro-5- ((4-pyridylmethyl) amino) benzamide (Compound 2)
Step A:
synthesis of Compound 2-a: 2-fluoro-5-nitrobenzoic acid (27mmol), DCM (100mL), 10 drops of DMF were added to the reaction flask, oxalyl chloride (81mmol) was added dropwise with stirring at 0 deg.C, after dropping, the flask was moved to room temperature and stirred for 2 hours, the solvent and excess oxalyl chloride were evaporated under reduced pressure, DCM (100mL), TEA (40.5mmol), and 2-chloro-5-aminotrifluoromethylbenzene (27mmol) were added, stirred for 1 hour at room temperature, the solvent was evaporated under reduced pressure, acetone (8mL) was added to dissolve, EA was added dropwise with stirring at room temperature until just solid precipitated, giving a white solid (Compound 2-a) of 9.2g in total.
And B:
synthesis of Compound 2-b: 2-a (16.6mmol), scrap iron (165.5mmol), ethanol (100ml) and 60 drops of ACOH are added into a reaction bottle, heated under reflux and stirred for 6 hours, cooled to room temperature, filtered, the filtrate is evaporated to dryness under reduced pressure, and separated by column chromatography (eluent is PE/EA) to obtain 6g of yellow solid (compound 2-b).
And C:
synthesis of Compound 2: 2-b (12mmol), 4-chloromethylpyridine hydrochloride (36mmol), NaH (24mmol), NaI (12mmol) and DMF (150mL) were added to the reaction flask, and after stirring the system at 60 ℃ for 20 hours, water (150mL) was added for dilution, EA (3X 150mL) was extracted, washed with saturated NaCl (150mL), and Na anhydrous2SO4Drying, filtering, adding activated carbon (15g), refluxing and stirring for 1 hour to removeColor, filter, evaporate solvent under reduced pressure, column chromatography (DCM/MeOH system) to give crude EA (15mL) slurried, filter, then add methanol (10mL) slurried, filter to give an off-white solid (compound 2).
1H NMR(400MHz,DMSO)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).
Example 3: n- (4-chloro-3- (trifluoromethyl) phenyl) -3- ((4-pyridylmethyl) amino) benzamide (compound 3)
Step A:
synthesis of Compound 3-a: 3-aminobenzoic acid (145.8mmol) and methanol (250mL) are added into a reaction bottle, and SOCl is added dropwise under stirring at the temperature of 0 ℃ of the system2(218.7mmol), stirring at room temperature for 20 hours after dropping, evaporating the solvent to dryness under reduced pressure, pulping with EA (80mL), and filtering to obtain a white solid (Compound 3-a) of 26g in total.
And B:
synthesis of Compound 3-b: the reaction flask was charged with 3-a (53.3mmol), 4-chloromethylpyridine hydrochloride (79.9mmol), K2CO3(239.8mmol), NaI (7.99mmol) and DMF (250mL) were stirred at 40 ℃ for 20 hours, diluted with water (250mL), extracted with EA (3X 250mL), washed with saturated NaCl (250mL), and dried over Na2SO4Drying, filtering, evaporating the solvent under reduced pressure, and separating by column chromatography (DCM/MeOH system) to obtain crude productTotal 6g of the solid (Compound 3-b) was obtained. And C:
synthesis of Compound 3: tBuOK (16.5mmol) and THF (50mL) were added to the flask, stirred at room temperature for 5min, 3-b (8.3mmol) and 2-chloro-5-aminotrifluorotoluene (8.3mmol) were added rapidly, the system was stirred at room temperature for 2h, the solvent was evaporated under reduced pressure, diluted with water (50mL), EA (3X 50mL) was extracted, washed with saturated NaCl (50mL), anhydrous Na2SO4Drying, filtering, evaporating the solvent under reduced pressure, column chromatography (DCM/MeOH system) to give the crude product, slurrying the crude EA (10mL), filtering, then adding methanol (5mL), slurrying, filtering to give an off-white solid (Compound 3).
1H NMR(400MHz,DMSO)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).
Example 4: 3- ((4-chloro-3- (trifluoromethyl) benzyl) amino) -1- (2- (4-pyridinyl) ethyl) pyridin-2 (1H) -one (compound 4) step a:
synthesis of Compound 4-a: the reaction flask was charged with 4-vinylpyridine (71.4mmol), 3-nitro-2-pyridone (35.7mmol) and ethanol (200mL), the system was heated from room temperature to 80 ℃, stirred for 10 hours, cooled to room temperature, the solvent was evaporated under reduced pressure, and column chromatography was performed (EA first, and then DCM: MeOH: 20:1) to give a total of 8g of a yellow solid (compound 4-a).
And B:
synthesis of Compound 4-b: 4-a (24.5mmol), Pd/C (0.6g) and methanol (30mL) were added to the reaction flask, the system was hydrogenated under pressure (0.4bar), and after stirring for 4 hours, Pd/C was removed by filtration, and the solvent was evaporated under reduced pressure to give a brown solid (compound 4-b) in an amount of 5g in total.
And C:
synthesis of Compound 4: the flask was charged with 4-b (9.3mmol), 4-chloro-3-trifluoromethylbenzaldehyde (25.7mmol), DCM (50mL), NaBH (OAc)3(6.4g), and 5 drops of AcOH, the system was stirred at room temperature for 20 hours, then saturated NaHCO was added3Quench (20mL), EA (3X 150mL), extract, wash with saturated NaCl (150mL), anhydrous Na2SO4Drying, filtering, evaporating the solvent under reduced pressure, separating by column chromatography to obtain 1.7g of a blue crude product, dissolving the crude product in a mixed solvent of DCM and MeOH-20: 1, dropwise adding EA under stirring at room temperature until solid is separated out, stirring for 0.5 hour, filtering, and washing with EA (10mL) to obtain an off-white solid (compound 4).
1H NMR(400MHz,DMSO)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).
Example 5: compounds 5 to 11
Compounds 5-13 were synthesized by conducting the three-step reaction of step A, B, C in a similar manner to example 1 or example 4, as shown in the following Table:
example 6: compounds 14 to 25
Compounds 14-25 were synthesized in a manner analogous to example 2 or example 3, by carrying out the three-step reaction of step A, B, C in sequence, as shown in the following Table:
part of the starting materials involved in the synthesis of the above compounds were synthesized as shown in the following examples:
example 7: n- (4- (chloromethyl) pyridin-2-yl) acetamide hydrochloride (Compound 26)
The reaction flask was charged with acetic acid (27mmol), DCM (100mL), 10 drops of DMF, oxalyl chloride (81mmol) was added dropwise with stirring at 0 ℃, after completion of addition, the flask was allowed to stir at room temperature for 2 hours, the solvent and excess oxalyl chloride were evaporated under reduced pressure, DCM (100mL), TEA (40.5mmol) and 2-amino-4-chloromethylpyridine hydrochloride (27mmol) were added, the flask was stirred at room temperature for 1 hour, the solvent was evaporated under reduced pressure, acetone (8mL) was added to dissolve, EA was added dropwise with stirring at room temperature until just a solid precipitated, giving a white solid (compound 26) of total 4.6 g.
Example 8: n- (4- (chloromethyl) pyridin-2-yl) cyclopropylcarboxamide (Compound 27)
The title compound was synthesized in a similar manner to example 7.
Example 9: n- (4- (chloromethyl) pyridin-2-yl) methanesulfonamide (compound 28)
The title compound was synthesized in a similar manner to example 7.
Example 10: 4-chloromethyl-N- (4- (methylsulfonyl) phenyl) pyridin-2-amine (Compound 29)
The reaction flask was charged with 2-amino-4-chloromethylpyridine hydrochloride (53.3mmol), 4-chlorophenylmethylsulfone (79.9mmol), K2CO3(239.8mmol), NaI (7.99mmol) and DMF (250mL) were stirred at 40 ℃ for 20 hours, diluted with water (250mL), extracted with EA (3X 250mL), washed with saturated NaCl (250mL), and dried over Na2SO4Drying, filtering, evaporating the solvent under reduced pressure, and separating by column chromatography to obtain 7.9g of crude product (compound 29).
Example 11: 4- ((4- (chloromethyl) pyridin-2-yl) amino) -N-methylbenzenesulfonamide (compound 30)
The title compound was synthesized in a similar manner to example 10.
Example 12: 4- ((4- (chloromethyl) pyridin-2-yl) amino) -N-methylbenzamide (Compound 31)
The title compound was synthesized in a similar manner to example 10.
Example 13: 2-methoxycarbonyl-4- (chloromethyl) pyridine (compound 32)
4- (hydroxymethyl) pyridine-2-carboxylic acid (145.8mmol), methanol (150mL) and DCM (150mL) are added into a reaction flask, SOCl is dropwise added at 0 ℃ under the protection of nitrogen in the system and stirring2(1.46mol), after stirring at room temperature for 3 hours after dropping, the solvent was evaporated under reduced pressure, EA (80mL) was slurried, and filtered to give a total of 22g of a white solid (compound 32).
Example 14: (4- (chloromethyl) pyridin-2-yl) -N-cyclopropylcarboxamide (Compound 33)
4- (hydroxymethyl) pyridine-2-carboxylic acid (145.8mmol), DCM (200mL) and 10 drops of DMF were added to a reaction flask, and SOCl was added dropwise with stirring at 0 deg.C2(1.75mol), after moving to room temperature after stirring for 2 hours, the solvent was evaporated under reduced pressure, then DCM (100mL), TEA (40.5mmol), and cyclopropylamine (175mmol) were added, stirred at room temperature for 1 hour, the solvent was evaporated under reduced pressure, and EA was added dropwise under stirring at room temperature until just a solid precipitated, giving a total of 26g of white solid (compound 33). Example 15: 4-chloromethyl-6, 7-dimethoxyquinoline (Compound 34)
4-carbinol-6, 7-dimethoxyquinoline (145.8mmol) and DCM (150mL) are added into a reaction bottle, SOCl is dropwise added under the protection of nitrogen in the system and stirring at 0 DEG C2(1.46mol), stirring at room temperature for 3 hours after dripping, decompressing and evaporating the solvent, pulping by EA (90mL), and filtering to obtain pink solidThe total amount of the compound (compound 34) was 27 g.
Example 16: 4-bromomethyl-6, 7-dimethoxyquinazoline (Compound 35)
Adding 6, 7-dimethoxy-4-methyl quinazoline (147mmol), NBS (147mmol), benzoyl peroxide (25mmol) and carbon tetrachloride (300mL) into a reaction bottle, heating and refluxing the system for 5 hours, cooling, adding water (250mL), DCM (3X 250mL) into the system in sequence for extraction, washing with saturated NaCl (250mL), and adding anhydrous Na into the system2SO4Drying, filtering, evaporating the solvent under reduced pressure, and separating by column chromatography to obtain 14.2g total of pink solid (compound 35).
Example 17: 4-bromomethyl-7-methyl-7H-pyrrolo [2,3-d ] pyrimidine (Compound 36)
The title compound was synthesized in a similar manner to example 16.
Example 18: 5- (bromomethyl) thieno [2,3-d ] pyrimidin-4-amine (compound 37)
The title compound was synthesized in a similar manner to example 16.
Example 19: compound 38
Step A:
synthesis of Compound 38-a: adding p-methyl benzyl cyanide (500mmol) and DMF (1000mL) into a reaction flask, adding sodium hydrogen (1mol) into the reaction flask under stirring at 0 ℃, keeping the temperature and stirring for 0.5 h, moving to room temperature, adding methyl iodide (1mol), stirring at room temperature overnight, adding methanol (100mL) to quench, then sequentially adding water (250mL), DCM (3X 250mL) for extraction, washing with saturated NaCl (250mL), and adding anhydrous Na2SO4The mixture was dried, filtered, and the solvent was evaporated under reduced pressure to give 65g in total of a yellow oil (compound 38-a).
And B:
synthesis of Compound 38-b: 38-a (100mmol), pyridine (100mL), water (200mL) and potassium permanganate (500mmol) are added into a reaction bottle, the system is heated and refluxed for 2 hours, the pyridine is evaporated under reduced pressure, the filtrate is filtered thermally, 6M HCl of the filtrate is acidified to pH 5-6, and the precipitated solid is filtered and dried to obtain 15.2g of the compound 38-b.
And C: 2- (4-formylphenyl) -2-methylpropanenitrile (Compound 38)
Synthesis of compound 38: adding 38-b (74mmol) and THF (200mL) into a reaction bottle, cooling the system to-20 ℃, and dropwise adding LiAlH while stirring4(285mmol), stirring at room temperature for 4 hours, then stirring at room temperature for 1 hour, quenching with saturated ammonium chloride (300mL), then adding sodium hydroxide (200mL), stirring for 1 hour, then adding water (150mL), filtering, washing the filtrate with diethyl ether (150mL), and concentrating the organic phase to give an intermediateThe crude product was placed in a reaction flask, followed by addition of DCM (300mL), stirring the system in an ice bath, addition of PCC (230mmol), continued stirring for 1 hour, followed by addition of saturated sodium bicarbonate (50mL), quenching, followed by addition of water (250mL), DCM (3X 250mL) extraction, washing with saturated NaCl (250mL), anhydrous Na2SO4Drying, filtration and evaporation of the solvent under reduced pressure gave a total of 4.6g of a yellow oil (compound 38).
Example 20: 1- (4-formylphenyl) -1-cyano-cyclopentane (compound 39)
The title compound was synthesized in a similar manner to example 19.
Example 21: 1- (4-formylphenyl) -1-cyano-cyclopropane (compound 40)
The title compound was synthesized in a similar manner to example 19.
Example 22:
inhibition of VEGFR-2 kinase Activity in the Presence of certain Compounds of the invention
An ATP solution diluted with a reaction buffer and VEGFR-2 protein were added to an enzyme plate containing 0.01M sodium phosphate buffer (pH 7.2-7.4), 0.15M sodium chloride solution and an enzymatic reaction substrate. Then, an experimental group and a blank group are set, namely, 10 mu M of reaction solution of the compound 1 and reaction solution without the compound 1 are respectively added into the system, primary anti-PY 99 is sequentially added, shaking table reaction is carried out at 37 ℃ for 0.5 hour, and secondary anti-horseradish peroxidase labeled goat anti-mouse IgG is carried out at 37 ℃ for 0.5 hour in shaking table reaction. And finally adding OPD color developing solution for reaction for 10 minutes, adding sulfuric acid to terminate the reaction, measuring the OD value of absorbance, and calculating the inhibition rate by the following formula:
the results are shown in the following table:
concentration (μ M) Inhibition ratio (%)
Compound 2 10 54.73
Compound 3 10 90.25
Compound 4 10 18.00
Compound 24 10 99.89
In addition, the invention also carries out mouse VEGFR-2 biochemical detection according to the patent ZL200480021091.1 (see the patent ZL200480021091.1, page 31, example 8), and the compounds also show remarkable inhibition on VEGFR-2 kinase, wherein the inhibition effect of certain compounds on VEGFR-2 kinase activity shows an IC50 value of 1 mu M or even lower.

Claims (10)

1. A compound according to formula I:
wherein,
a representsn represents 1 or 2; x represents halogen or hydrogen;
R1represents optionally one or more positions on the ring, identical or different, substituted by halogen, cyano, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy radicals, OR by radicals-OR3、-SR4、-SOR4、-SO2R4Substituted aryl or heteroaryl, or by a radical-COOR5、-CONR6R7、-NHR15、-SR4、-SOR4、-SO2R4、-SCN、-PO(OR8)(OR9)、-CH＝CH-COR10or-C.ident.C-R10A substituted or unsubstituted nitrogen-containing aromatic heterocycle;
R2represents at one or more optional positions on the benzene ring, same or different, and is selected from hydrogen, halogen, cyano, hydroxy, C1-6Alkoxy, halo C1-6Alkoxy radical, C2-6Alkenyl, cyano-C3-6Cycloalkyl, cyano-C1-6Alkyl, aryl-C1-6Alkoxy, aryloxy, C1-6Alkyl, halo-C1-6Alkyl or a group-SO2R4、OR3、-R3OR-PO (OR)8)(OR9) (ii) a Or, R2Together with any adjacent two carbon atoms of the benzene ring to form C4-6A ring optionally containing a nitrogen, oxygen or sulfur atom, and optionally in one or more positions, the same or different, substituted by halogen, cyano, C1-6Alkyl, halo-C1-6Alkyl, aryl, OR substituted radicals-OR3、-SR4、-SOR4or-SO2R4Substitution;
R3represents hydrogen, C1-12Alkyl, halo-C1-6Alkyl radical, C3-6Cycloalkyl or halo-C3-6Cycloalkyl or represents C wherein one or more oxygen is inserted1-12Alkyl, or represents the group- (CH)2)mNR6R7、-CH2CN or-CH2CF3；
m represents 1,2 or 3;
R4represents hydroxy, C1-6Alkyl, aryl, heteroaryl or represents the group-NR6R7；
R5Represents hydrogen or represents C optionally substituted by one or more halogens1-6Alkyl radical, C1-6Alkoxy, benzyl, aryl or heteroaryl;
R6and R7Independently of one another, represents hydrogen or represents halogen, cyano, C, optionally in one or more positions, the same or different1-6Alkyl, phenyl, hydroxy-C1-6Alkyl, halo-C1-6Alkyl or by a group-NR11R12、-OR3、C1-6alkyl-OR3、-SR4、-SOR4or-SO2R4Substituted or unsubstituted C1-6Alkyl radical, C3-6Cycloalkyl radical, C3-6Cycloalkenyl, aryl or heteroaryl, or
R6And R7Together with nitrogen atoms to form C3-8Rings which optionally contain further nitrogen, sulfur or oxygen atoms or which may contain groupsAnd optionally in one or more positions, the same or different, by halogen, cyano, C1-6Alkyl, halo-C1-6Alkyl, aryl, OR substituted radicals-OR3、-SR4、-SOR4or-SO2R4Substitution;
R8and R9Independently of one another, represent hydrogen or C1-6An alkyl group;
R10represents hydrogen, C1-6Alkyl, tri-C1-6Alkylsilyl, aryl, heteroaryl or represents the group-COR14；
R11And R12Independently of one another, represent hydrogen or C1-6Alkyl, or
R11And R12Together forming a 5-7 membered ring which may contain an oxygen or sulphur atom or group-NR13；
R13Represents hydrogen, C1-6An alkyl or aryl group;
R14represents hydrogen, C1-6Alkyl or represents a group-NR6R7；
R15Represents hydrogen, alkylcarbonyl, C3-6Cycloalkyl carbonyl group, C1-6Alkylsulfonyl radical, C3-6Cycloalkylsulfonyl, 4-C1-6Alkylaminosulfonylphenyl, 4-C3-6Cycloalkylaminosulfonylphenyl.
2. Compounds of general formula I according to claim 1, characterized in that:
a representsn represents 1 or 2; x represents halogen or hydrogen;
R1represents optionally one or more positions on the ring, identical or different, substituted by halogen, cyano, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy radicals, OR by radicals-OR3、-SO2R4Substituted aryl or heteroaryl, or by a radical-COOR5、-CONR6R7、-NHR15、-SO2R4A substituted or unsubstituted nitrogen-containing aromatic heterocycle;
R2represents at one or more optional positions on the benzene ring, same or different, and is selected from hydrogen, halogen, cyano, hydroxy, C1-6Alkoxy, halo C1-6Alkoxy radical, C2-6Alkenyl, cyano-C3-6Cycloalkyl, cyano-C1-6Alkyl, aryl-C1-6Alkoxy, aryloxy, C1-6Alkyl, halo-C1-6Alkyl or a group-SO2R4、OR3、-R3OR-PO (OR)8)(OR9) (ii) a Or, R2Together with any adjacent two carbon atoms of the benzene ring to form C4-6A ring which optionally contains a nitrogen atom, an oxygen atom or a sulfur atom, and may containOptionally in one or more positions, the same or different, by halogen, cyano, C1-6Alkyl, halo-C1-6Alkyl, aryl, OR substituted radicals-OR3、-SR4、-SOR4or-SO2R4Substitution;
R3represents hydrogen, C1-12Alkyl, halo-C1-6Alkyl radical, C3-6Cycloalkyl or halo-C3-6Cycloalkyl or represents C wherein one or more oxygen is inserted1-12Alkyl, or represents the group- (CH)2)mNR6R7、-CH2CN or-CH2CF3；
m represents 1,2 or 3;
R4represents hydroxy, C1-6Alkyl, aryl, heteroaryl or represents the group-NR6R7；
R5Represents hydrogen or represents C optionally substituted by one or more halogens1-6Alkyl radical, C1-6Alkoxy, benzyl, aryl or heteroaryl;
R6and R7Independently of one another, represents hydrogen or represents halogen, cyano, C, optionally in one or more positions, the same or different1-6Alkyl, phenyl, hydroxy-C1-6Alkyl, halo-C1-6Alkyl or by a group-NR11R12、-OR3、C1-6alkyl-OR3、-SR4、-SOR4or-SO2R4Substituted or unsubstituted C1-6Alkyl radical, C3-6Cycloalkyl radical, C3-6Cycloalkenyl, aryl or heteroaryl, or
R6And R7Together with nitrogen atoms to form C3-8Rings which optionally contain further nitrogen, sulfur or oxygen atoms or which may contain groupsAnd optionally in one or more positions, the same or different, by halogen, cyano, C1-6Alkyl, halo-C1-6Alkyl, aryl, OR substituted radicals-OR3、-SR4、-SOR4or-SO2R4Substitution;
R8and R9Independently of one another, represent hydrogen or C1-6An alkyl group;
R10represents hydrogen, C1-6Alkyl, tri-C1-6Alkylsilyl, aryl, heteroaryl or represents the group-COR14；
R11And R12Independently of one another, represent hydrogen or C1-6Alkyl, or
R11And R12Together forming a 5-7 membered ring which may contain an oxygen or sulphur atom or group-NR13；
R13Represents hydrogen, C1-6An alkyl or aryl group;
R14represents hydrogen, C1-6Alkyl or represents a group-NR6R7；
R15Represents hydrogen, alkylcarbonyl, C3-6Cycloalkyl carbonyl group, C1-6Alkylsulfonyl radical, C3-6Cycloalkylsulfonyl, 4-C1-6Alkylaminosulfonylphenyl, 4-C3-6Cycloalkylaminosulfonylphenyl.
3. Compounds of general formula I according to claim 2, characterized in that:
a representsn represents 1 or 2; x represents halogen or hydrogen;
R1represented by the following structure:
w, D, E independently represent nitrogen or carbon atoms, wherein at least one nitrogen atom and at most two nitrogen atoms are present;
y represents O or NH;
g generationEpihydrogen or optionally in one or more positions of the phenyl ring, identical or different, from halogen, cyano, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy radicals, OR by radicals-OR3、-SO2R4Substituted aryl or heteroaryl groups, or the group-COOR5、-CONR6R7、-NHR15、-SO2R4；
R2Represents at one or more optional positions on the benzene ring, same or different, and is selected from hydrogen, halogen, cyano, hydroxy, C1-6Alkoxy, halo C1-6Alkoxy radical, C2-6Alkenyl, cyano-C3-6Cycloalkyl, cyano-C1-6Alkyl, aryl-C1-6Alkoxy, aryloxy, C1-6Alkyl, halo-C1-6Alkyl or a group-SO2R4、OR3、-R3OR-PO (OR)8)(OR9) Or is or
R2Together with any adjacent two carbon atoms of the benzene ring to form C4-6A ring optionally containing a nitrogen, oxygen or sulfur atom, and optionally in one or more positions, the same or different, substituted by halogen, cyano, C1-6Alkyl, halo-C1-6Alkyl, aryl, OR substituted radicals-OR3、-SR4、-SOR4or-SO2R4Substitution;
R3represents hydrogen, C1-12Alkyl, halo-C1-6Alkyl radical, C3-6Cycloalkyl or halo-C3-6Cycloalkyl or represents C wherein one or more oxygen is inserted1-12Alkyl, or represents the group- (CH)2)mNR6R7、-CH2CN or-CH2CF3；
m represents 1,2 or 3;
R4represents hydroxy, C1-6Alkyl, aryl, heteroaryl or represents the group-NR6R7；
R5Represents hydrogen or representsC optionally substituted by one or more halogens1-6Alkyl radical, C1-6Alkoxy, benzyl, aryl or heteroaryl;
R6and R7Independently of one another, represents hydrogen or represents halogen, cyano, C, optionally in one or more positions, the same or different1-6Alkyl, phenyl, hydroxy-C1-6Alkyl, halo-C1-6Alkyl or by a group-NR11R12、-OR3、C1-6alkyl-OR3、-SR4、-SOR4or-SO2R4Substituted or unsubstituted C1-6Alkyl radical, C3-6Cycloalkyl radical, C3-6Cycloalkenyl, aryl or heteroaryl, or
R6And R7Together with nitrogen atoms to form C3-8Rings which optionally contain further nitrogen, sulfur or oxygen atoms or which may contain groupsAnd optionally in one or more positions, the same or different, by halogen, cyano, C1-6Alkyl, halo-C1-6Alkyl, aryl, OR substituted radicals-OR3、-SR4、-SOR4or-SO2R4Substitution;
R8and R9Independently of one another, represent hydrogen or C1-6An alkyl group;
R10represents hydrogen, C1-6Alkyl, tri-C1-6Alkylsilyl, aryl, heteroaryl or represents the group-COR14；
R11And R12Independently of one another, represent hydrogen or C1-6Alkyl, or
R11And R12Together forming a 5-7 membered ring which may contain an oxygen or sulphur atom or group-NR13；
R13Represents hydrogen, C1-6An alkyl or aryl group;
R14represents hydrogen, C1-6Alkyl or represents a group-NR6R7；
R15Represents hydrogen, C1-3Alkylcarbonyl group, C3-4Cycloalkyl carbonyl group, C1-3Alkylsulfonyl, cyclopropylsulfonyl, 4-C1-3Alkylaminosulfonylphenyl, 4-cyclopropylaminosulfonylphenyl.
4. A compound of formula I according to claim 3, characterized in that:
a representsn represents 1 or 2; x represents halogen or hydrogen;
R1represented by the following structure:
w, D, E independently represent nitrogen or carbon atoms, wherein at least one nitrogen atom and at most two nitrogen atoms are present;
y represents O or NH;
g represents hydrogen or is selected from halogen, cyano, C, the same or different, optionally in one or more positions of the phenyl ring1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy radicals, OR by radicals-OR3、-SO2R4Substituted aryl or heteroaryl groups, or the group-COOR5、-CONR6R7、-NHR15、-SO2R4；
R2Represents at one or more optional positions on the benzene ring, same or different, and is selected from hydrogen, halogen, cyano, hydroxy, C1-6Alkoxy, halo C1-6Alkoxy radical, C2-6Alkenyl, cyano-C3-6Cycloalkyl, cyano-C1-6Alkyl, aryl-C1-6Alkoxy, aryloxy, C1-6Alkyl, halo-C1-6Alkyl or a group-SO2R4、OR3、-R3OR-PO (OR)8)(OR9) Or is or
R2Together with any adjacent two carbon atoms of the benzene ring to form C4-6A ring optionally containing a nitrogen, oxygen or sulfur atom, and optionally in one or more positions, the same or different, substituted by halogen, cyano, C1-6Alkyl, halo-C1-6Alkyl, aryl, OR substituted radicals-OR3、-SR4、-SOR4or-SO2R4Substitution;
R3represents hydrogen, C1-12Alkyl, halo-C1-6Alkyl radical, C3-6Cycloalkyl or halo-C3-6Cycloalkyl or represents C wherein one or more oxygen is inserted1-12Alkyl, or represents the group- (CH)2)mNR6R7、-CH2CN or-CH2CF3；
m represents 1,2 or 3;
R4represents hydroxy, C1-6Alkyl, aryl, heteroaryl or represents the group-NR6R7；
R5Represents hydrogen or represents C optionally substituted by one or more halogens1-6Alkyl radical, C1-6Alkoxy, benzyl, aryl or heteroaryl;
R6and R7Independently of one another, represents hydrogen or represents halogen, cyano, C, optionally in one or more positions, the same or different1-6Alkyl, phenyl, hydroxy-C1-6Alkyl, halo-C1-6Alkyl or by a group-NR11R12、-OR3、C1-6alkyl-OR3、-SR4、-SOR4or-SO2R4Substituted or unsubstituted C1-6Alkyl radical, C3-6Cycloalkyl radical, C3-6Cycloalkenyl, aryl or heteroaryl, or
R6And R7Together with nitrogen atoms to form C3-8Rings which optionally contain further nitrogen, sulfur or oxygen atoms or which may contain groupsAnd optionally in one or more positions, the same or different, by halogen, cyano, C1-6Alkyl, halo-C1-6Alkyl, aryl, OR substituted radicals-OR3、-SR4、-SOR4or-SO2R4Substitution;
R8and R9Independently of one another, represent hydrogen or C1-6An alkyl group;
R10represents hydrogen, C1-6Alkyl, tri-C1-6Alkylsilyl, aryl, heteroaryl or represents the group-COR14；
R11And R12Independently of one another, represent hydrogen or C1-6Alkyl, or
R11And R12Together forming a 5-7 membered ring which may contain an oxygen or sulphur atom or group-NR13；
R13Represents hydrogen, C1-6An alkyl or aryl group;
R14represents hydrogen, C1-6Alkyl or represents a group-NR6R7；
R15Represents hydrogen, C1-3Alkylcarbonyl group, C3-4Cycloalkyl carbonyl group, C1-3Alkylsulfonyl, cyclopropylsulfonyl, 4-C1-3Alkylaminosulfonylphenyl, 4-cyclopropylaminosulfonylphenyl.
5. The compound of formula I according to claim 4, characterized in that:
a representsn represents 1 or 2;
x represents halogen or hydrogen;
R1represented by the following structure:
w, D, E independently represent nitrogen or carbon atoms, wherein at least one nitrogen atom and at most two nitrogen atoms are present; y represents O or NH;
g represents hydrogen or is selected from halogen, cyano, C, the same or different, optionally in one or more positions of the phenyl ring1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy radicals, OR by radicals-OR3、-SO2R4Substituted aryl or heteroaryl groups, or the group-COOR5、-CONR6R7、-NHR15、-SO2R4；
R2Represents at one or more optional positions on the benzene ring, the same or different, selected from hydrogen, halogen, cyano, C1-6Alkoxy, halo C1-6Alkoxy, cyano-C3-6Cycloalkyl, cyano-C1-6Alkyl, aryl-C1-6Alkoxy, aryloxy, C1-6Alkyl, halo-C1-6Alkyl or a radical-R3Or is or
R2Together with any adjacent two carbon atoms of the benzene ring to form C4-6A ring optionally containing a nitrogen, oxygen or sulfur atom, and optionally in one or more positions, the same or different, substituted by halogen, cyano, C1-6Alkyl, halo-C1-6Alkyl, aryl, OR substituted radicals-OR3、-SO2R4Substitution;
R3represents hydrogen, C1-12Alkyl, halo-C1-6Alkyl radical, C3-6Cycloalkyl or halo-C3-6Cycloalkyl or represents C wherein one or more oxygen is inserted1-12Alkyl, or represents the group- (CH)2)mNR6R7、-CH2CN or-CH2CF3；
m represents 1,2 or 3;
R4represents hydroxy, C1-6Alkyl, aryl, heteroaryl or represents the group-NR6R7；
R5Represents hydrogen or represents C optionally substituted by one or more halogens1-6Alkyl radical, C1-6Alkoxy, benzyl, aryl or heteroaryl;
R6and R7Independently of one another, represents hydrogen or represents halogen, cyano, C, optionally in one or more positions, the same or different1-6Alkyl, phenyl, hydroxy-C1-6Alkyl, halo-C1-6Alkyl or by a group-NR11R12、-OR3、C1-6alkyl-OR3、-SR4、-SOR4or-SO2R4Substituted or unsubstituted C1-6Alkyl radical, C3-6Cycloalkyl radical, C3-6Cycloalkenyl, aryl or heteroaryl, or
R6And R7Together with nitrogen atoms to form C3-8Rings which optionally contain further nitrogen, sulfur or oxygen atoms or which may contain groupsAnd optionally in one or more positions, the same or different, by halogen, cyano, C1-6Alkyl, halo-C1-6Alkyl, aryl, OR substituted radicals-OR3、-SR4、-SOR4or-SO2R4Substitution;
R8and R9Independently of one another, represent hydrogen or C1-6An alkyl group;
R10represents hydrogen, C1-6Alkyl, tri-C1-6Alkylsilyl, aryl, heteroaryl or represents the group-COR14；
R11And R12Independently of one another, represent hydrogen or C1-6Alkyl, or
R11And R12Together forming a 5-7 membered ring which may contain an oxygen or sulphur atom or group-NR13；
R13Represents hydrogen, C1-6An alkyl or aryl group;
R14representsHydrogen, C1-6Alkyl or represents a group-NR6R7；
R15Represents hydrogen, C1-3Alkylcarbonyl group, C3-4Cycloalkyl carbonyl group, C1-3Alkylsulfonyl, cyclopropylsulfonyl, 4-C1-3Alkylaminosulfonylphenyl, 4-cyclopropylaminosulfonylphenyl.
6. The compound of formula I according to claim 5, characterized in that:
a representsn represents 1 or 2;
x represents halogen or hydrogen;
R1represented by the following structure:
w, D, E independently represent nitrogen or carbon atoms, wherein at least one nitrogen atom and at most two nitrogen atoms are present; y represents O or NH;
g represents hydrogen or is selected from halogen, cyano, C, the same or different, optionally in one or more positions of the phenyl ring1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy radicals, OR by radicals-OR3、-SO2R4Substituted aryl or heteroaryl groups, or the group-COOR5、-CONR6R7、-NHR15、-SO2R4；
R2Represents at one or two optional positions on the benzene ring, same or different, selected from hydrogen, halogen, cyano, C1-6Alkoxy, halo C1-6Alkoxy, cyano-C3-6Cycloalkyl, cyano-C1-6Alkyl, aryl-C1-6Alkoxy, aryloxy, C1-6Alkyl, halo-C1-6Alkyl or a radical-R3Or is or
R2Together with any adjacent two carbon atoms of the benzene ring to form C4-6A ring which may contain a nitrogen atom and which may be optionally substituted in one or more positions, identically or differently, by halogen, cyano, C1-6Alkyl, halo-C1-6Alkyl and aryl substitution;
R3represents hydrogen, C1-12Alkyl, halo-C1-6Alkyl radical, C3-6Cycloalkyl or halo-C3-6Cycloalkyl or represents C wherein one or more oxygen is inserted1-12Alkyl, or represents the group- (CH)2)mNR6R7、-CH2CN or-CH2CF3；
m represents 1,2 or 3;
R4represents hydroxy, C1-6Alkyl, aryl, heteroaryl or represents the group-NR6R7；
R5Represents hydrogen or represents C optionally substituted by one or more halogens1-6Alkyl radical, C1-6Alkoxy, benzyl, aryl or heteroaryl;
R6and R7Independently of one another, represents hydrogen or represents halogen, cyano, C, optionally in one or more positions, the same or different1-6Alkyl, phenyl, hydroxy-C1-6Alkyl, halo-C1-6Alkyl or by a group-NR11R12、-OR3、C1-6alkyl-OR3、-SR4、-SOR4or-SO2R4Substituted or unsubstituted C1-6Alkyl radical, C3-6Cycloalkyl radical, C3-6Cycloalkenyl, aryl or heteroaryl, or
R6And R7Together with nitrogen atoms to form C3-8Rings which optionally contain further nitrogen, sulfur or oxygen atoms or which may contain groupsAnd may optionally be at one or more locations, the same or notBy halogen, cyano, C1-6Alkyl, halo-C1-6Alkyl, aryl, OR substituted radicals-OR3、-SR4、-SOR4or-SO2R4Substitution;
R8and R9Independently of one another, represent hydrogen or C1-6An alkyl group;
R10represents hydrogen, C1-6Alkyl, tri-C1-6Alkylsilyl, aryl, heteroaryl or represents the group-COR14；
R11And R12Independently of one another, represent hydrogen or C1-6Alkyl, or
R11And R12Together forming a 5-7 membered ring which may contain an oxygen or sulphur atom or group-NR13；
R13Represents hydrogen, C1-6An alkyl or aryl group;
R14represents hydrogen, C1-6Alkyl or represents a group-NR6R7；
R15Represents hydrogen, C1-3Alkylcarbonyl group, C3-4Cycloalkyl carbonyl group, C1-3Alkylsulfonyl, cyclopropylsulfonyl, 4-C1-3Alkylaminosulfonylphenyl, 4-cyclopropylaminosulfonylphenyl.
Preferably, the first and second liquid crystal materials are,
a representsn represents 1 or 2;
x represents halogen or hydrogen;
R1represented by the following structure:
wherein p represents 1,2 or 3;
represented by the following structure:
7. compounds of general formula I according to claims 1-6, selected from the following compounds:
3- ((4-chloro-3- (trifluoromethyl) benzyl) amino) -1- (4-pyridylmethyl) pyridin-2 (1H) -one;
n- (4-chloro-3- (trifluoromethyl) phenyl) -2-fluoro-5- ((4-pyridylmethyl) amino) benzamide;
n- (4-chloro-3- (trifluoromethyl) phenyl) -3- ((4-pyridylmethyl) amino) benzamide;
3- ((4-chloro-3- (trifluoromethyl) benzyl) amino) -1- (2- (4-pyridinyl) ethyl) pyridin-2 (1H) -one;
n- (4- (3- ((4-chloro-3- (trifluoromethyl) benzyl) amino) -2-oxopyridin-1 (2H) -methyl) pyridin-2-yl) acetamide;
3- ((4-chloro-3- (trifluoromethyl) benzyl) amino) -1- ((2- ((4-methanesulfonyl) phenyl) amino) pyridin-4-yl) methyl) pyridin-2 (1H) -one;
n- (4-chloro-3- (trifluoromethyl) phenyl) -2-fluoro-5- (((2- ((4- (methylsulfonyl) phenyl) amino) pyridin-4-yl) methyl) amino) benzamide;
n- (4-chloro-3- (trifluoromethyl) phenyl) -3- (((2- ((4- (methylsulfonyl) phenyl) amino) pyridin-4-yl) methyl) amino) benzamide;
4- (3- ((4-chloro-3- (trifluoromethyl) benzyl) amino) -2-oxopyridinyl-1 (2H) -methyl) -N-cyclopropylpicolinamide;
4- (((3- ((4-chloro-3- (trifluoromethyl) phenyl) carbamoyl) -4-fluorophenyl) amino) methyl) -N-cyclopropylpicolinamide;
4- (((3- ((4-chloro-3- (trifluoromethyl) phenyl) carbamoyl) phenyl) amino) methyl) -N-cyclopropylpicolinamide;
3- ((4-chloro-3- (trifluoromethyl) benzyl) amino) -1- ((6, 7-dimethoxyquinolin-4-yl) methyl) pyridin-2 (1H) -one;
n- (4-chloro-3- (trifluoromethyl) phenyl) -5- (((6, 7-dimethoxyquinolin-4-yl) methyl) amino) -2-fluoro-benzamide;
n- (4-chloro-3- (trifluoromethyl) phenyl) -3- (((6, 7-dimethoxyquinolin-4-yl) methyl) amino) benzamide;
3- ((4-chloro-3- (trifluoromethyl) benzyl) amino) -1- ((6, 7-dimethoxyquinazolin-4-yl) methyl) pyridin-2 (1H) -one;
n- (4-chloro-3- (trifluoromethyl) phenyl) -5- (((6, 7-dimethoxyquinazolin-4-yl) methyl) amino) -2-fluoro-benzamide;
n- (4-chloro-3- (trifluoromethyl) phenyl) -3- (((6, 7-dimethoxyquinazolin-4-yl) methyl) amino) benzamide;
2-methyl-2- (4- (((2-oxo-1- (4-pyridylmethyl) -1, 2-dihydropyridin-3-yl) amino) methyl) phenyl) propionitrile;
2-methyl-2- (4- (((2-oxo-1- (2- (4-pyridyl) ethyl) -1, 2-dihydropyridin-3-yl) amino) methyl) phenyl) propionitrile;
n- (4- (2-cyanopropan-2-yl) phenyl) -3- ((4-pyridylmethyl) amino) benzamide;
n- (4- (2-cyanopropan-2-yl) phenyl) -2-fluoro-5- ((4-pyridylmethyl) amino) benzamide;
methyl 4- ((2-oxo-3- ((4-trifluoromethoxy) phenyl) amino) pyridin-1 (2H) -yl) methyl) picolinate;
1- ((4-aminothiopheno [2.3-d ] pyrimidin-5-yl) methyl) -3- ((4-phenoxybenzyl) amino) pyridin-2 (1H) -one;
5 (((4-aminothiophen [2.3-d ] pyrimidin-5-yl) methyl) amino) -2-fluoro-N- (4- ((4-methylpiperazin-1-yl) methyl) -3- (trifluoromethyl) phenyl) benzamide;
methyl 4- (((3- ((3, 3-dimethylindolin-6-yl) carbamoyl) -4-fluorophenyl) amino) methyl) picolinate.
8. A method of synthesizing the compound of claim 1,
1) when A representsWhen the compound of the general formula I is represented by the structural formulaThe synthesis method is shown as a scheme (I) or a scheme (II):
scheme (I):
wherein R is1、R2N is as defined in formula I;
when n in the compound of formula I' represents 2, the synthesis can also be carried out with reference to scheme (ii):
scheme (II):
wherein R is1、R2As defined in formula I;
2) when A representsWhen the compound of the general formula I is represented by the structural formulaThe synthesis method is shown as a scheme (three) or a scheme (four):
scheme (III):
wherein R is1、R2X is as defined in formula I;
scheme (IV):
wherein R is1、R2X is as defined in formula I.
9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier.
10. The use of a compound according to any one of claims 1 to 7 for the preparation of a medicament for the treatment of diseases which are caused or promoted by persistent angiogenesis or increased vascular permeability which is caused by VEGF receptors.
CN201610793266.5A 2016-08-31 2016-08-31 VEGFR inhibitor 2 and preparation method thereof Pending CN106496107A (en)

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