CN112010864A - Vascular endothelial growth factor receptor inhibitor and preparation method and application thereof - Google Patents
Vascular endothelial growth factor receptor inhibitor and preparation method and application thereof Download PDFInfo
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- CN112010864A CN112010864A CN202010404785.4A CN202010404785A CN112010864A CN 112010864 A CN112010864 A CN 112010864A CN 202010404785 A CN202010404785 A CN 202010404785A CN 112010864 A CN112010864 A CN 112010864A
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- alkyl
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- azetidinyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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Abstract
The invention provides a vascular endothelial growth factor receptor inhibitor, a preparation method and application thereof, and relates to quinoline or quinazoline derivatives with a structure shown in a formula (I), a pharmaceutical composition containing a compound shown in the formula (I), and application of the compound in preparation of drugs for preventing or treating angiogenesis-related diseases, in particular to application in prevention or treatment of tumors related to protein tyrosine kinase. Wherein each substituent in the formula (I) is defined as the specification.
Description
Technical Field
The application belongs to the technical field of medicines, and particularly relates to a quinoline or quinazoline derivative and application thereof in preparing a medicine for treating malignant tumor diseases.
Background
Receptor tyrosine kinases are a class of enzymes that span the cell membrane and have an extracellular binding domain that binds growth factors, a transmembrane domain, and an intracellular portion that functions as a kinase to phosphorylate specific tyrosine residues in proteins and to influence cell proliferation.
Vascular Endothelial Growth Factor (VEGF), also known as Vascular Permeability Factor (VPF), is a highly specific vascular endothelial cell growth factor, specifically binds to vascular endothelial growth factor receptors (including VEGFR-1, VEGFR-2, VEGFR-3) and activates receptor tyrosine kinases to exert a vascular regulating effect, promoting vascular permeability increase, extracellular matrix degeneration, vascular endothelial cell migration, proliferation and vascularization.
Normal angiogenesis plays an important role in a variety of processes, including embryonic development, wound healing, and the like; undesirable or pathological angiogenesis is associated with disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma. Tumor angiogenesis, the formation of new blood vessels and their permeability are mainly regulated by Vascular Endothelial Growth Factor (VEGF) (of tumor origin), which acts through at least two different receptors: VEGFR-1 and VEGFR-2, receptors are highly specific for vascular endothelial cells (Endocr. Rev.1992,13, 18; FASEB J.1999,13, 9). VEGFR-1 and VEGFR-2 are mainly distributed on the surface of tumor vascular endothelium and regulate the generation of tumor blood vessels; VEGFR-3 is distributed mainly on the surface of lymphatic endothelium and regulates the generation of tumor lymphatic vessels. The high level expression of VEGF and its receptors by most human tumors has led to the hypothesis that VEGF released by tumor cells stimulates capillary growth and tumor endothelial proliferation in a paracrine manner and promotes tumor growth by increasing blood supply.
The effect of VEGF as a tumor angiogenesis factor in vivo is shown in that the inhibition of VEGF expression or VEGF activity by VEGF antibodies, VEGFR-2 negative mutants, VEGF antisense RNA can slow down the growth of glioma cell lines or other tumor cell lines in vivo. Several major mechanisms play important roles in the anti-tumor angiogenesis inhibitory activity: inhibition of blood vessel growth, particularly capillaries, a balance is achieved between cell death and proliferation such that there is no net growth of the tumor; inhibition of tumor cell metastasis due to lack of blood influx and efflux from the tumor; inhibiting the proliferation of endothelial cells and avoiding the paracrine growth-stimulation effect of the endothelial cells of the arranged blood vessels on the surrounding tissues.
A series of VEGFR inhibitors and patent applications for their use in vascular related diseases have been published, including WO 2016091165, WO 2017177962, CN103382206, etc., but there is still a need to develop new VEGFR inhibitors with better potency.
Disclosure of Invention
The invention aims to provide quinoline or quinazoline VEGFR inhibitors with excellent activity.
The invention also aims to provide application of the quinoline or quinazoline VEGFR inhibitor in preparing medicines for preventing or treating angiogenesis-related diseases, in particular tumor diseases related to protein tyrosine kinases.
In order to realize the purpose of the invention, the technical scheme of the invention is as follows:
the invention relates to a compound shown as the following formula (I), a stereoisomer, a pharmaceutically acceptable salt or ester thereof or a solvate thereof:
R1is selected from C1-C8Alkyl, optionally further substituted by one or more groups selected from-COR7Or a 4-10 membered heterocyclic group, said 4-10 membered heterocyclic group being further substituted by amino, hydroxy, - (CH)2)nCN, carboxyl, C1-C4Alkyl or C1-C4Alkoxy groups.
n is selected from 0, 1,2 or 3;
R2selected from H, deuterium or halogen;
x is selected from N or CH; y is selected from O or CR3R4；
R3And R4Each independently selected from H, deuterium, halogen, C1-C8Alkyl radical, C3-C8Cycloalkyl or C1-C8An alkoxy group;
R5selected from H, C1-C8Alkyl or C3-C8A cycloalkyl group; r6Selected from H, C1-C8Alkyl or C3-C8A cycloalkyl group;
R7selected from H, C1-C8Alkyl radical, C3-C8Cycloalkyl or C3-C6Heterocyclic group, said C3-C6The heterocyclic group may further be substituted by hydroxy, carboxy or C1-C4Alkyl groups are substituted.
The implementation scheme of the invention is characterized in that:
R1is selected from C1-C8Alkyl, optionally further substituted by one or more groups selected from-COR7Azetidinyl or
Said azetidinyl group being further substituted by hydroxy, - (CH)2)nCN or carboxyl.
n is selected from 0 or 1;
R2is halogen;
x is selected from N or CH;
y is selected from O or CR3R4；
R3And R4Each independently selected from H, deuterium, halogen, C1-C8Alkyl radical, C3-C8Cycloalkyl or C1-C8An alkoxy group;
R5selected from H, C1-C8Alkyl or C3-C8A cycloalkyl group;
R6selected from H, C1-C8Alkyl or C3-C8A cycloalkyl group;
R7is an azetidinyl group, which may be further substituted with a hydroxy group.
An embodiment of the present invention is a compound described by general formula (II), a stereoisomer, a pharmaceutically acceptable salt or ester thereof, or a solvate thereof:
R1is selected from C1-C8Alkyl, optionally further substituted by one or more groups selected from-COR7Azetidinyl or
Said azetidinyl group being further substituted by hydroxy, - (CH)2)nCN or carboxyl.
n is selected from 0 or 1;
R7is composed of
The implementation scheme of the invention is characterized in that:
R1is C1-C4Alkyl, optionally further substituted by one or more groups selected from-COR7An azetidinyl group,
By a substituent ofSaid azetidinyl group may be further substituted with hydroxy, - (CH)2)nCN or carboxyl.
n is selected from 0 or 1; r7Is composed of
The compounds of the present invention are selected from the following structures:
in another aspect, the present invention provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or ester or solvate thereof, comprising the steps of:
wherein R is1、R2、R3、R4、R5、R6X, Y are as defined for the compounds of formula (I).
The compound of formula (I) or the pharmaceutically acceptable salt, ester or solvate thereof is a novel VEGFR inhibitor, so that the compound can be used for preparing a medicament for preventing or treating angiogenesis related diseases, in particular for preventing or treating malignant tumor diseases related to protein tyrosine kinases.
As a further preferred embodiment, the tumor is selected from the group consisting of: ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, leukemia, lymphoma, non-hodgkin's lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumors, thyroid cancer, cholangiocarcinoma, endometrial cancer, kidney cancer, anaplastic large cell lymphoma, acute myeloid leukemia, multiple myeloma, melanoma or mesothelioma, soft tissue sarcoma.
In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or ester or solvate thereof, as an active ingredient and a pharmaceutically acceptable carrier.
The invention also provides application of the pharmaceutical composition in preparing a medicament for preventing or treating malignant tumors.
Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.
"C" in the invention1-C8Alkyl "refers to straight chain alkyl groups and branched chain-containing alkyl groups comprising from 1 to 8 carbon atoms, alkyl refers to saturated aliphatic hydrocarbon groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branched isomers thereof, and the like.
As used herein, "cycloalkyl" refers to a saturated monocyclic hydrocarbon substituent, "C3-C8Cycloalkyl "refers to monocyclic cycloalkyl groups comprising 3 to 8 carbon atoms, for example: non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
"Heterocyclyl" as used herein refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents wherein one or more ring atoms are selected from nitrogen, oxygen, or heteroatoms of S (O) r (where r is an integer 0, 1, 2), but does not include the ring portion of-O-O-, -O-S-, or-S-S-, and the remaining ring atoms are carbon. "4-10 membered heterocyclyl" refers to a cyclic group containing from 4 to 10 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
"alkoxy" in the context of the present invention means-O- (alkyl) wherein alkyl is as defined above. "C1-C8Alkoxy "means an alkyloxy group having 1 to 8 carbons, and non-limiting examples include methoxy, ethoxy, propoxy, butoxy, and the like.
"halogen" means fluorine, chlorine, bromine or iodine.
"pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, in admixture with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
In the preparation steps of the present invention, abbreviations for reagents used respectively represent:
DCM dichloromethane
DIEA N, N-diisopropylethylamine
MTBE methyl tert-butyl ether
EA Ethyl acetate
PE Petroleum Ether
THF tetrahydrofuran
TFAA trifluoroacetic anhydride
EtOH ethanol
BnBr benzyl bromide
DMAP 4-dimethylaminopyridine
TFA trifluoroacetic acid
MsCl-p-methylbenzenesulfonyl chloride
DMAC Dimethylacetamide
TBDPSCl tert-butyldiphenylchlorosilane
TBAB tetrabutylammonium bromide
Drawings
FIG. 1 NMR spectra of the compound of example 1;
Detailed Description
The invention is illustrated below with reference to specific examples. It will be understood by those skilled in the art that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention in any way.
The experimental procedures in the following examples are conventional unless otherwise specified. The raw materials and reagents used in the following examples are all commercially available products unless otherwise specified.
Example 1
2- (9- (4-fluoro-2-methyl-1H-indol-5-yl) oxy) -1, 2-dihydrofuran [3,2-f ] quinolin-4-yl) oxy) -1- (3-hydroxyazetidin-1-yl) ethan-1-one
Step 1 Synthesis of 2, 3-dihydrobenzofuran-7-carbonyl chloride
In a single-neck flask, 2, 3-dihydrobenzofuran-7-carboxylic acid (13.65g, 83.15mmol) and SOCl were added in this order under ice-cooling2(70ml), the reaction was terminated at 60 ℃ for 1 h. Cooling to room temperature, and concentrating under reduced pressure to obtain white solid. Without further purification, the reaction mixture was directly used in the next reaction.
Step 2 Synthesis of N-methoxy-N-methyl-2, 3-dihydrobenzofuran-7-carboxamide
At room temperature, in2, 3-dihydrobenzofuran-7-carbonyl chloride (15.18g, 83.13mmol) was added to a single-neck flask, dissolved in DCM (150ml), DIEA (30ml) was added dropwise in ice bath and N, O-dimethylhydroxylamine hydrochloride (9.73g, 99.75mmol) was added, and the reaction was terminated at room temperature for 1 h. Extraction with EA, twice washing with saturated brine, drying the organic phase over anhydrous sodium sulfate, filtration, concentration, and purification by column chromatography (EA/PE system) gave 16.37g of yellow solid with a yield of 95% over the two steps.1H NMR(400MHz,DMSO-d6)7.30(dd,J＝7.3,0.9Hz,1H),7.09(d,J＝7.5Hz,1H),6.86(t,J＝7.5Hz,1H),4.56(t,J＝8.7Hz,2H),3.55(s,3H),3.20(t,J＝8.8Hz,2H),3.18(s,3H)。
Step 3 Synthesis of 1- (2, 3-dihydrobenzofuran-7-yl) ethanone
To a three-necked flask were added N-methoxy-N-methyl-2, 3-dihydrobenzofuran-7-carboxamide (16.37g, 78.99mmol), THF (450ml), N at room temperature in that order2The reaction mixture was replaced three times, and a THF solution of methylmagnesium bromide (170.00ml, 170.00mmol) was added dropwise to the mixture under ice-cooling, followed by completion of the reaction at room temperature for 1 hour. And (3) moving the reaction system to an ice bath, and adjusting the pH to 3-4 by using 1N hydrochloric acid. Then, the mixture was extracted with EA, washed twice with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (EA/PE system) to obtain 11.11g of an off-white solid with a yield of 85%.1H NMR(400MHz,DMSO-d6)7.53(d,J＝7.9Hz,1H),7.46(dd,J＝7.2,1.1Hz,1H),6.91(t,J＝7.5Hz,1H),4.68(t,J＝8.8Hz,2H),3.23(t,J＝8.8Hz,2H),2.52(s,3H)。
Step 4 Synthesis of 1- (5-nitro-2, 3-dihydrobenzofuran-7-yl) ethanone
Adding H into a three-neck bottle under ice bath2SO4(50ml), 1- (2, 3-dihydrobenzofuran-7-yl) ethanone (11.10g, 68.44mmol) and KNO were added portionwise with stirring3(11.76g，116.32mmol)，The reaction was terminated at 0 ℃ for 1.5 h. Slowly pouring the reaction solution into ice water, stirring for 10min, extracting and separating liquid by using EA, washing an organic phase by using a saturated sodium bicarbonate solution and a saturated saline solution once respectively, drying the organic phase by using anhydrous sodium sulfate, filtering, concentrating, and purifying by column chromatography (EA/PE system) to obtain 12.20g of a yellow solid with the yield of 86%.1H NMR(400MHz,DMSO-d6)8.39(d,J＝2.2Hz,1H),8.33-8.29(m,1H),4.90(t,J＝8.8Hz,2H),3.35(t,J＝8.9Hz,2H),2.58(s,3H)。
Step 5 Synthesis of (5-nitro-2, 3-dihydrobenzofuran-7-yl) acetate
Adding TFAA (200ml) into a single-mouth bottle, and dropwise adding H at-10 DEG C2O2(50ml) after dropping, a solution of 1- (5-nitro-2, 3-dihydrobenzofuran-7-yl) ethanone (19.00g, 91.70mmol) in DCM (45ml) was added dropwise after stirring at that temperature for 20min, and the reaction was terminated at room temperature for 3h after dropping. Extract with EA, wash twice with saturated brine, dry the organic phase over anhydrous sodium sulfate, filter, concentrate to give a yellow solid, which is not further purified and directly put into the next reaction.
Step 6 Synthesis of 5-Nitro-2, 3-dihydrobenzofuran-7-ol
(5-nitro-2, 3-dihydrobenzofuran-7-yl) acetate (20.47g, 91.71mmol) and EtOH (250ml) were added sequentially to a single-necked flask at room temperature, and a 40% NaOH solution (25ml) was added dropwise thereto under ice-cooling, followed by reaction at room temperature for 0.5 h. Adjusting the pH value to 3-4 with 2N hydrochloric acid in ice bath, extracting with EA, washing twice with saturated saline solution, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating, and purifying by column chromatography (EA/PE system) to obtain 15.00g of yellow solid with yield of 90% in two steps.1H NMR(400MHz,DMSO-d6)7.70–7.64(m,1H),7.54(d,J＝2.3Hz,1H),4.70(t,J＝8.9Hz,2H),3.26(t,J＝8.8Hz,2H)。MS(ESI)m/z:180.0[M-H]-。
Step 7 Synthesis of 7-benzyloxy-5-nitro-2, 3-dihydrobenzofuran
At room temperature, 5-nitro-7-hydroxy-2, 3-dihydrobenzofuran (15.0g, 82.80mmol), DMF (300ml), K were added to a single-neck flask in this order2CO3(171.66g, 1242.02mmol) and BnBr (17.00g, 99.40mmol), and the reaction was terminated at 80 ℃ for 0.5 h. Extract with EA, wash twice with saturated brine, dry the organic phase over anhydrous sodium sulfate, filter, concentrate, slurry with PE (250ml) at room temperature for 30min, filter to obtain a yellow solid 19.42g with 87% yield.1H NMR(400MHz,DMSO-d6)7.87–7.83(m,1H),7.80(d,J＝2.0Hz,1H),7.47–7.33(m,5H),5.24(s,2H),4.74(t,J＝8.9Hz,2H),3.30(t,J＝8.9Hz,2H)。
To a single-neck flask were added 7-benzyloxy-5-nitro-2, 3-dihydrobenzofuran (19.00g, 70.04mmol), EtOH (450ml), H in that order at room temperature2O(112ml)、NH4Cl (15.69g, 293.33mmol), warmed to 80 deg.C, Fe powder (30.00g, 537.20mmol) was added and the reaction was stopped at this temperature for 1.5 h. Filtering, adding H into the filtrate2And O, extracting with EA for three times, combining organic phases, drying by anhydrous sodium sulfate, filtering, concentrating, and purifying by column chromatography (EA/PE system) to obtain a black solid 14.71g with the yield of 87%.1H NMR(400MHz,DMSO-d6)7.42–7.29(m,5H),6.14(s,1H),6.11(s,1H),5.00(s,2H),4.37(t,J＝8.6Hz,2H),3.01(t,J＝8.5Hz,2H)。MS(ESI)m/z:242.2[M+H]+。
To a single-neck flask were added successively isopropylidene cyclo-malonate (8.36g, 58.00mmol) and triethyl orthoformate (29.37ml, 176.58mmol) at room temperature, and the reaction was terminated at 80 ℃ for 1 hour. The product was used in the next reaction without further treatment.
To a single-necked flask were added 7-benzyloxy-2, 3-dihydrobenzofuran-5-amine (13.99g, 57.98mmol), 5- (ethoxymethylene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione (11.61g, 57.99mmol), and isopropanol (350ml) in this order at room temperature, followed by reaction at 80 ℃ for 0.5 h. The temperature is reduced to room temperature, and the deep yellow solid 19.05g is obtained by suction filtration, and the yield of the two steps is 83 percent.1H NMR(400MHz,DMSO-d6)8.50(d,J＝16.0Hz,1H),7.46–7.32(m,5H),7.26(d,J＝1.1Hz,1H),7.08(s,1H),5.15(s,2H),4.56(t,J＝8.8Hz,2H),3.19(t,J＝8.7Hz,2H),1.66(s,6H)。MS(ESI)m/z:394.2[M-H]-。
At room temperature, 5- ((7-benzyloxy-2, 3-dihydrobenzofuran-5-ylamino) methylene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione (1.5g, 3.79mmol) and diphenyl ether (18ml) were sequentially added to a microwave reaction flask, stirred in a 70 ℃ water bath for 15min, and then transferred to a microwave to react at 220 ℃ for 0.5h to terminate. Cooling to room temperature, adding PE, pulping for 1h, and performing suction filtration to obtain 1.02g of yellow solid with the yield of 92%. Without further purification, the reaction mixture was directly used in the next reaction.1H NMR(400MHz,DMSO-d6)7.67(t,J＝4.0Hz,1H),7.49–7.33(m,5H),6.92(s,1H),5.83(d,J＝7.2Hz,1H),5.19(s,2H),4.58(t,J＝9.1Hz,2H),3.66(t,J＝9.0Hz,2H)。MS(ESI)m/z:294.2[M+H]+。
Sequentially adding 4-benzyloxy-1, 2-dihydrofuro [3,2-f ] into a three-neck flask at room temperature]Quinolin-9-ol (6.17g, 21.04mmol), phosphorus oxychloride (60ml), N2The displacement was carried out three times, and the reaction was terminated at 107 ℃ for 0.5 h. Concentration gave a black crude product which was purified by column chromatography (MeOH/DCM system) to give 3.62g of a yellow solid in 55% yield.1H NMR(400MHz,DMSO-d6)8.51(d,J＝4.8Hz,1H),7.51–7.45(m,4H),7.44–7.33(m,3H),5.32(s,2H),4.76(t,J＝9.2Hz,2H),3.88(t,J＝9.2Hz,2H)。MS(ESI)m/z:312.2[M+H]+。
Sequentially adding 4-benzyloxy-9-chloro-1, 2-dihydrofuro [3,2-f ] into a microwave reaction bottle at room temperature]Quinoline (3.62g, 11.61mmol), 2-methyl-4-fluoro-5-hydroxy-1-hydroindole (3.84g, 23.25mmol), DMAP (2.41g, 19.73mmol), 2, 6-lutidine (72ml), N2The displacement is carried out three times, and the reaction is terminated by 2.5h under the microwave at 200 ℃. After concentration, extraction with EA was carried out, washing was carried out twice with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (THF/DCM system) to obtain 1.29g of a yellow solid with a yield of 25%.1H NMR(400MHz,DMSO-d6)8.35(d,J＝5.2Hz,1H),7.52(d,J＝7.2Hz,2H),7.45–7.34(m,4H),7.20(d,J＝8.6Hz,1H),6.98(t,J＝8.1Hz,1H),6.31(d,J＝5.1Hz,1H),6.27(s,1H),5.31(s,2H),4.75(t,J＝9.1Hz,2H),3.81(t,J＝9.1Hz,2H),2.41(s,3H)。MS(ESI)m/z:441.2[M+H]+。
Adding 4-benzyloxy-9- (4-fluoro-2 methyl-1-hydroindol-5-yloxy) -1, 2-dihydrofuro [3,2-f ] to a three-necked flask at room temperature]Quinoline (0.62g, 1.41mmol), N2After three times of substitution, TFA (12ml) and H were added2O (3ml), and the reaction was terminated at 85 ℃ for 3 h. Extracting with mixed solution of EA and THF, washing twice with saturated saline, back-extracting the water phase with EA once, mixing the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating, and purifying by column chromatography (EA/MeOH system) to obtain yellow solid 0.31g with 50% yield.1H NMR(400MHz,DMSO-d6)8.28(d,J＝5.2Hz,1H),7.19(d,J＝8.6Hz,1H),7.17(s,1H),6.97(t,J＝8.1Hz,1H),6.26(s,1H),6.22(d,J＝5.1Hz,1H),4.73(t,J＝9.1Hz,2H),3.79(t,J＝9.1Hz,2H),2.41(s,3H)。MS(ESI)m/z:351.2[M+H]+。
Step 15: synthesis of 2-chloro-1- (3-hydroxyazetidin-1-yl) ethan-1-one
3-Hydroxyazetidine hydrochloride (1.00g, 9.13mmol), TEA (1.85g, 18.26mmol) and DCM (10mL) were added to a three-necked flask at room temperature under nitrogen, chloroacetyl chloride (1.25g, 10.95mmol) was added dropwise under ice bath, and the reaction was terminated at 25 ℃ for 2h after dropwise addition. Adding DCM for extraction, washing twice with saturated saline water, drying the organic phase by anhydrous sodium sulfate, filtering, concentrating, adding isopropyl ether for pulping, and performing suction filtration to obtain a light yellow solid 0.43g with the yield of 31%.1H NMR(400MHz,DMSO-d6)4.50–4.43(m,1H),4.34(t,J＝7.4Hz,1H),4.11–4.06(m,3H),3.92(dd,J＝8.9,4.3Hz,1H),3.62(dd,J＝10.2,4.4Hz,1H)。
Step 16: synthesis of 2- (9- (4-fluoro-2-methyl-1H-indol-5-yl) oxy) -1, 2-dihydrofuran [3,2-f ] quinolin-4-yl) oxy) -1- (3-hydroxyazetidin-1-yl) ethan-1-one
Adding 9- (4-fluoro-2-methyl-1-hydroindol-5-yloxy) -1, 2-dihydrofuro [3,2-f ] in a three-necked flask at room temperature]Quinolin-4-ol (0.20g, 0.57mmol), 2-chloro-1- (3-hydroxyazetidin-1-yl) ethan-1-one (0.10g, 0.69mmol), Cs2CO3(0.37g, 1.14mmol) was quenched with DMAC (3mL), nitrogen blanketed, and reacted at 60 ℃ for 1.5 h. EA extraction, saturated brine two times, organic phase through anhydrous sodium sulfate drying, filtering, concentration, column chromatography purification (MeOH/DCM system) yellow solid product 0.08g, yield 32%.1H NMR(300MHz,DMSO-d6)8.36(d,J＝4.9Hz,1H),7.23(s,1H),7.21(d,J＝11.0Hz,1H),6.98(t,J＝8.1Hz,1H),6.32(d,J＝5.0Hz,1H),6.27(s,1H),4.81(s,2H),4.77(t,J＝9.0Hz,2H),4.53–4.44(m,2H),4.13(t,J＝9.0Hz,1H),4.02(d,J＝6.4Hz,1H),3.82(t,J＝9.0Hz,2H),3.67(d,J＝6.4Hz,1H),2.41(s,3H)。MS(ESI)m/z:464.2[M+H]+。
Example 2
1- (2- ((9- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -1, 2-dihydrofuran [3,2-f ] quinolin-4-yl) oxy) ethyl) azetidine-3-cyano
Step 1: synthesis of 4- (2-bromoethoxy) -9- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -1, 2-dihydrofuran [3,2-f ] quinoline
Adding 9- (4-fluoro-2-methyl-1-hydroindol-5-yloxy) -1, 2-dihydrofuro [3,2-f ] to a three-necked flask at room temperature]Quinolin-4-ol (1.00g, 2.85mmol), K2CO3(1.18g, 8.56mmol), 1, 2-dibromoethane(1.61g, 8.56mmol) was quenched with DMAC (5mL), nitrogen blanketed, and reacted at 90 ℃ for 6 h. EA was added thereto and extracted, and the resulting extract was washed twice with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (MeOH/DCM system) to obtain 0.98g of a yellow solid in 70% yield.1H NMR(400MHz,DMSO-d6)8.41(d,J＝5.3Hz,1H),7.35(s,1H),7.21(d,J＝8.6Hz,1H),7.00(t,J＝8.1Hz,1H),6.38(d,J＝5.2Hz,1H),6.27(s,1H),4.78(t,J＝9.2Hz,2H),4.54(t,J＝5.3Hz,2H),3.89(t,J＝5.3Hz,2H),3.83(t,J＝9.1Hz,2H),2.41(s,3H).MS(ESI)m/z:456.8,458.8[M+H]+。
Step 2: synthesis of 1- (2- ((9- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -1, 2-dihydrofuran [3,2-f ] quinolin-4-yl) oxy) ethyl) azetidine-3-cyano
Adding 4- (2-bromoethoxy) -9- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -1, 2-dihydrofuran [3,2-f ] to a four-necked flask at room temperature]Quinoline (0.60g, 1.31mmol), 3-cyanoazetidine (0.16g, 1.97mmol), Cs2CO3(1.28g, 3.94mmol) was reacted with DMF (24mL) under nitrogen at 80 ℃ for 2 h. EA was added for extraction, and the mixture was washed twice with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reverse phase column (0.05% phosphoric acid aqueous solution/acetonitrile system) to obtain a white-like solid product (0.40 g) in a yield of 66%.1H NMR(400MHz,DMSO-d6)8.36(d,J＝5.3Hz,1H),7.29(s,1H),7.21(d,J＝8.5Hz,1H),6.99(t,J＝8.0Hz,1H),6.31(d,J＝5.3Hz,1H),6.27(s,1H),4.75(t,J＝9.1Hz,2H),4.14(t,J＝5.3Hz,2H),3.81(t,J＝9.2Hz,2H),3.56(q,J＝7.0Hz,2H),3.53–3.48(m,J＝6.6Hz,1H),3.39(t,J＝6.0Hz,2H),2.85(t,J＝5.2Hz,2H),2.42(s,3H)。MS(ESI)m/z:459.1[M+H]+。
Example 3
2- (1- (2- ((9- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) 1, 2-dihydrofuran [3,2-f ] quinolin-4-yl) oxy) ethyl) azetidin-3-yl) acetonitrile
Adding 4- (2-bromoethoxy) -9- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -1, 2-dihydrofuran [3,2-f ] to a four-necked flask at room temperature]Quinoline (0.40g, 0.87mmol), 2- (azetidin-3-yl) acetonitrile hydrochloride (0.18g, 1.31mmol), Cs2CO3(0.86g, 2.6mmol) was reacted with DMF (20mL) under nitrogen at 80 ℃ for 2 h. EA was added for extraction, and the mixture was washed twice with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reverse phase column (0.05% phosphoric acid aqueous solution/acetonitrile system) to obtain a white-like solid product (0.24 g) in a yield of 58%.1H NMR(400MHz,DMSO-d6)8.36(d,J＝5.2Hz,1H),7.29(s,1H),7.21(d,J＝8.6Hz,1H),6.98(t,J＝8.1Hz,1H),6.31(d,J＝5.3Hz,1H),6.26(s,1H),4.75(t,J＝9.1Hz,2H),4.13(t,J＝5.4Hz,2H),3.81(t,J＝9.2Hz,2H),3.45(t,J＝7.2Hz,2H),2.98(t,J＝6.7Hz,2H),2.82(t,J＝5.4Hz,2H),2.78(d,J＝6.8Hz,2H),2.69(q,J＝6.5Hz,1H),2.42(s,3H)。MS(ESI)m/z:473.0[M+H]+。
Example 4
9- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -4- (2- ((4aR,7aS) -hexahydro-6H- [1,4] dioxa [2,3-c ] pyrrol-6 yl) ethoxy) -1, 2-dihydrofuran [3,2-f ] quinoline
Step 1: synthesis of tert-butyl (4aR,7aS) -hexahydro-6H- [1,4] dioxa [2,3-c ] pyrrolidine-6-carboxylate
Tert-butyl (3R,4S) -3, 4-dihydroxypyrrolidine-1-carboxylate (1.00g, 4.92mmol), TBAB (0.32g, 0.98mmol), 40% NaOH solution (15mL) and 1, 2-dichloroethane (15mL) were added to a three-necked flask at room temperature under nitrogen and reacted at 55 ℃ for 16.5h to terminate. Adding EA for extraction, and saturating with saltWashing with water twice, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating, and purifying by column chromatography (PE/EA system) to obtain white solid 0.56g with yield of 50%.1H NMR(400MHz,DMSO-d6)4.11(t,J＝4.1Hz,2H),3.77–3.70(m,2H),3.54–3.45(m,2H),3.39–3.33(m,2H),3.31–3.26(m,2H),1.39(s,9H)。
Step 2: synthesis of (4aR,7aS) -hexahydro-5H- [1,4] dioxa [2,3-c ] -pyrrolidine hydrochloride
Tert-butyl (4aR,7aS) -hexahydro-6H- [1,4] dioxa [2,3-c ] pyrrolidine-6-carboxylate (0.56g, 2.44mmol) and DCM (5mL) were added to a single-neck flask at room temperature, HCl in EA (4N, 1mL) was added dropwise in ice bath, and the reaction was terminated at 20 ℃ for 1H after completion of dropwise addition. Concentration gave 0.40g of a yellow solid in 100% yield.
And step 3: synthesis of 9- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -4- (2- ((4aR,7aS) -hexahydro-6H- [1,4] dioxa [2,3-c ] pyrrol-6 yl) ethoxy) -1, 2-dihydrofuran [3,2-f ] quinoline
Adding 4- (2-bromoethoxy) -9- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -1, 2-dihydrofuran [3,2-f ] to a three-necked flask at room temperature]Quinoline (0.30g, 0.59mmol), (4aR,7aS) -hexahydro-5H- [1,4]]Dioxyheterocyclic [2,3-c ]]Pyrrolidine hydrochloride (0.15g, 0.89mmol), Cs2CO3(0.58g, 1.78mmol) was reacted with DMF (12mL) under nitrogen at 80 ℃ for 2 h. EA was added to extract, the mixture was washed twice with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (0.05% aqueous phosphoric acid/acetonitrile system) to obtain a white-like solid product (0.21 g) in a yield of 64%.1H NMR(400MHz,DMSO-d6)8.36(d,J＝5.2Hz,1H),7.33(s,1H),7.21(d,J＝8.5Hz,1H),6.99(t,J＝8.1Hz,1H),6.31(d,J＝5.2Hz,1H),6.27(s,1H),4.75(t,J＝9.2Hz,2H),4.25(t,J＝5.6Hz,2H),4.03(t,J＝4.3Hz,2H),3.81(t,J＝9.1Hz,2H),3.75–3.67(m,2H),3.52–3.44(m,2H),3.11–2.93(m,4H),2.89(d,J＝8.5Hz,2H),2.42(s,3H)。MS(ESI)m/z:506.1[M+H]+。
Example 5
10- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -4- (2- ((4aR,7aR) -hexahydro-6H- [1,4] dioxa [2,3-c ] pyrrol-6 yl) ethoxy) -1, 2-dihydrofuran [3,2-f ] quinoline
Step 1: synthesis of tert-butyl (4aS,7aS) -hexahydro-6H- [1,4] dioxa [2,3-c ] pyrrolidine-6-carboxylate
Tert-butyl (3S,4S) -3, 4-dihydroxypyrrolidine-1-carboxylate (1.00g, 4.92mmol), TBAB (0.32g, 0.98mmol), 40% NaOH solution (15mL) and 1, 2-dichloroethane (15mL) were added to a three-necked flask at room temperature under nitrogen and reacted at 55 ℃ for 16.5h to terminate. EA was added for extraction, and the mixture was washed twice with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (PE/EA system) to obtain 0.56g of a white solid with a yield of 50%.
Step 2: synthesis of (4aS,7aS) -hexahydro-5H- [1,4] dioxa [2,3-c ] -pyrrolidine hydrochloride
Tert-butyl (4aS,7aS) -hexahydro-6H- [1,4] dioxa [2,3-c ] pyrrolidine-6-carboxylate (0.56g, 2.44mmol) and DCM (5mL) were added to a single-neck flask at room temperature, ethyl acetate hydrochloride (1mL) was added dropwise under ice bath, and the reaction was terminated at 20 ℃ for 1H after completion of dropwise addition. Concentration gave 0.40g of a yellow solid in 100% yield.
And step 3: synthesis of 9- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -4- (2- ((4aR,7aR) -hexahydro-6H- [1,4] dioxa [2,3-c ] pyrrol-6 yl) ethoxy) -1, 2-dihydrofuran [3,2-f ] quinoline
Adding 4- (2-bromoethoxy) -9- ((4-fluoro-2-methyl-1H-indol-5-yl) oxy) -1, 2-dihydrofuran [3,2-f ] to a three-necked flask at room temperature]Quinoline (0.20g, 0.44mmol), (4aS,7aS) -hexahydro-5H- [1,4]]Dioxyheterocyclic [2,3-c ]]Pyrrolidine hydrochloride (0.11g, 0.66mmol), Cs2CO3(0.43g, 1.31mmol) was reacted with DMF (8mL) under nitrogen at 80 ℃ for 2 h. EA was added to extract, the mixture was washed twice with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (0.05% aqueous phosphoric acid/acetonitrile system) to obtain a white-like solid product (0.14 g) in a yield of 64%.1H NMR(400MHz,DMSO-d6)8.35(d,J＝5.2Hz,1H),7.32(s,1H),7.20(d,J＝8.6Hz,1H),6.98(t,J＝8.1Hz,1H),6.30(d,J＝5.3Hz,1H),6.27(s,1H),4.74(t,J＝9.1Hz,2H),4.22(t,J＝5.5Hz,2H),3.83–3.77(m,4H),3.65(d,J＝5.2Hz,2H),3.56(t,J＝6.3Hz,2H),3.08–3.02(m，4H),2.75–2.68(m,2H),2.41(s,3H)。MS(ESI)m/z:506.1[M+H]+。
Example 6
VEGFR kinase Activity assay
The experiment adopts gamma-33p-ATP isotope assay for testing the inhibition of the kinase VEGFR/VEGFR2/VEGFR3 and obtaining the half inhibitory concentration IC of the compound on the inhibitory activity of the enzyme50. The positive control drug, erlotinib, was purchased from Suzhongheng pharmaceutical science, Inc., lot number 2016120201.
1. Basic reaction buffer
20mM Hepes(pH 7.5),10mM MgCl2,1mM EGTA,0.02％Brij35,0.02mg/ml BSA,0.1mM Na3VO4,2mM DTT,1％DMSO。
2. Compound preparation
The compound is dissolved to a specific concentration by using 100% DMSO, and then is diluted into samples to be tested (DMSO solutions) with different concentrations in a gradient manner by using an automatic sample adding device.
3. Reaction step
3.1 diluting the reaction substrate with a basic reaction buffer;
3.2 adding the kinase into the substrate solution, and gently and uniformly mixing;
3.3 adding compounds with different concentrations diluted by 100% DMSO into the kinase solution by adopting an automatic sample adding system, and incubating for 20min at room temperature;
3.4 addition at room temperature33P-ATP (10. mu.M, 10. mu. Ci/. mu.l) initiates the kinase reaction for 2 h.
4. Detection of
The reaction liquid is subjected to ion exchange filtration system to remove unreacted ATP and ADP plasma generated by the reaction, and then the substrate is detected33The amount of P isotope emitted.
5. Data processing
Calculating the kinase activity of the compounds added into inhibitor systems with different concentrations according to the radiation amount to obtain the inhibition effect of the compounds with different concentrations on the kinase activity, and fitting by adopting graphpad prism to obtain the inhibition IC of the compounds50。
The biochemical activity of the compounds of the invention is determined by the above assay, the IC determined50See table 1 for values:
TABLE 1 VEGFR kinase Activity assay results
Note: in the table, "-" indicates no test.
And (4) conclusion: the compounds of the present invention have inhibitory activity against VEGFR kinases.
Example 7
VEGF-induced HUVEC cell proliferation inhibition assay
The MTT method is adopted in the experiment to test the activity effect of the compound on the HUVEC cell induced by VEGF, and the half inhibition concentration IC of the compound for inhibiting the VEGF-induced HUVEC cell proliferation activity is obtained50。
HUVEC cell lines were grown under conditions of ECM + 5% FBS + 1% ECGS (endothelial cell growth factor additive) + 1% P/S (penicillin streptomycin cocktail)And (5) performing line culture. The day before the experiment was cultured with ECM + 5% FBS. 100 μ L of HUVEC cell suspension in logarithmic growth phase at a density of 5X 10 were seeded in 96-well cell culture plates4Perml, the plates were incubated in an incubator for 24h to allow the cells to adhere (37 ℃ C., 5% CO)2)。
2. Each compound was dissolved in DMSO to prepare a 10mM stock solution, and was diluted to 400-fold the target concentration in a DMSO gradient and 2-fold the target concentration in a serum-free medium, thereby maintaining the DMSO concentration in the drug solution at 0.5%. Different concentrations of the drug solution and 10ng/mL of VEGF165 were added sequentially to the 96-well plate seeded with cells at 100. mu.L/well. Each concentration was plated with 3 replicates, blank control, normal control and VEGF-induced group, continued at 37 deg.C and 5% CO2The culture was continued for 72 h.
3. The incubation was terminated and 20. mu.L of MTT solution (5mg/ml) was added to each well and continued at 37 ℃ with 5% CO2Culturing for 4 hr, removing culture medium, adding DMSO 150 μ L/well, shaking at room temperature for 10min, and measuring OD (OD) at 570nM and 620nM dual wavelengths570-OD620) And calculating IC by Graphpad Prism 6.0 data processing50The value is obtained.
The biochemical activity of the compounds of the invention is determined by the above assay, the IC determined50See table 2 for values:
TABLE 2 VEGF-induced HUVEC cell proliferation inhibition assay
And (4) conclusion: the compounds of the invention have the activity of inhibiting VEGF-induced HUVEC cell proliferation.
Claims (9)
1. A compound of formula (I), a stereoisomer, a pharmaceutically acceptable salt or ester thereof, or a solvate thereof:
R1is selected from C1-C8Alkyl, optionally further substituted by one or more groups selected from-COR7Or a 4-10 membered heterocyclic group, said 4-10 membered heterocyclic group being further substituted by amino, hydroxy, - (CH)2)nCN, carboxyl, C1-C4Alkyl or C1-C4Alkoxy groups.
n is selected from 0, 1,2 or 3;
R2selected from H, deuterium or halogen;
x is selected from N or CH;
y is selected from O or CR3R4；
R3And R4Each independently selected from H, deuterium, halogen, C1-C8Alkyl radical, C3-C8Cycloalkyl or C1-C8An alkoxy group;
R5selected from H, C1-C8Alkyl or C3-C8A cycloalkyl group;
R6selected from H, C1-C8Alkyl or C3-C8A cycloalkyl group;
R7selected from H, C1-C8Alkyl radical, C3-C8Cycloalkyl or C3-C6Heterocyclic group, said C3-C6The heterocyclic group may further be substituted by hydroxy, carboxy or C1-C4Alkyl groups are substituted.
2. The compound of claim 1, wherein:
R1is selected from C1-C8Alkyl, optionally further substituted by one or more groups selected from-COR7Azetidinyl or
Said azetidinyl group being further substituted by hydroxy, - (CH)2)nCN or carboxyl.
n is selected from 0 or 1;
R2is halogen;
x is selected from N or CH;
y is selected from O or CR3R4；
R3And R4Each independently selected from H, deuterium, halogen, C1-C8Alkyl radical, C3-C8Cycloalkyl or C1-C8An alkoxy group;
R5selected from H, C1-C8Alkyl or C3-C8A cycloalkyl group;
R6selected from H, C1-C8Alkyl or C3-C8A cycloalkyl group;
R7is an azetidinyl group, which may be further substituted with a hydroxy group.
3. The compound of claim 1, a stereoisomer, a pharmaceutically acceptable salt, or ester, or a solvate thereof, of formula (I), which is a compound of formula (II), a stereoisomer, a pharmaceutically acceptable salt, or ester, or a solvate thereof:
R1is selected from C1-C8Alkyl, optionally further substituted by one or more groups selected from-COR7Azetidinyl or
Said azetidinyl group being further substituted by hydroxy, - (CH)2)nCN or carboxyl.
n is selected from 0 or 1;
R7is composed of
4. A compound according to claim 3, characterized in that:
R1is C1-C4Alkyl, optionally further substituted by one or more groups selected from-COR7An azetidinyl group,
Said azetidinyl group being further substituted by hydroxy, - (CH)2)nCN or carboxyl.
n is selected from 0 or 1;
R7is composed of
5. A compound, a stereoisomer, a pharmaceutically acceptable salt or ester thereof, or a solvate thereof, characterized in that said compound is selected from the group consisting of:
6. a pharmaceutical composition comprising a compound of any one of claims 1-5, a stereoisomer, pharmaceutically acceptable salt or ester thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.
7. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is a capsule, powder, tablet, granule, pill, injection, syrup, oral liquid, inhalant, ointment, suppository, or patch.
8. Use of a compound according to any one of claims 1 to 5 or a pharmaceutical composition according to any one of claims 6 to 7 in the manufacture of a medicament for the prophylaxis or treatment of a disease mediated by angiogenesis.
9. Use of a compound according to any one of claims 1 to 5 or a pharmaceutical composition according to any one of claims 6 to 7 for the manufacture of a medicament for the prophylaxis or treatment of a malignant tumour.
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