CN104163794A - 2-amino aromatic ring vascular endothelial growth factor receptor (VEGFR) inhibitor, preparation method and use thereof - Google Patents
2-amino aromatic ring vascular endothelial growth factor receptor (VEGFR) inhibitor, preparation method and use thereof Download PDFInfo
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- CN104163794A CN104163794A CN201310484602.4A CN201310484602A CN104163794A CN 104163794 A CN104163794 A CN 104163794A CN 201310484602 A CN201310484602 A CN 201310484602A CN 104163794 A CN104163794 A CN 104163794A
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- 0 CCC(C(C**C(C)C)C1)C1C1C(*2)C2C(C)C1 Chemical compound CCC(C(C**C(C)C)C1)C1C1C(*2)C2C(C)C1 0.000 description 2
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- C07—ORGANIC CHEMISTRY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D231/38—Nitrogen atoms
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Abstract
The present invention relates to a novel-structure 2-amino pyridine compound represented by a formula (I), and a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof, and further relates to a preparation method of the compound, a drug composition containing the therapeutically effective dose of the compound, and a use of the compound as a protein tyrosine kinase inhibitor, especially as a Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) Kinase Domain Receptor (KDR) inhibitor in preparation of drugs for prevention and/or treatment of diseases associated with VEGFR-2 abnormality. The formula (I) is shown as follows.
Description
Technical field:
The present invention relates to the compound new as vascular endothelial growth factor receptor (VEGFR) kinase inhibitor, they preparation and as prevention or treatment by the purposes of medicine that continues blood vessel and occur the disease causing.
Background technology:
Known numerous disease is relevant to lasting blood vessel generation, and for example, disease is as tumor growth or transforming growth; Psoriatic; Sacroiliitis is as rheumatoid arthritis, vascular tumor, endometriosis, hemangiofibroma; Illness in eye is as diabetic retinopathy, neovascular glaucoma; Ephrosis is as glomerulonephritis, diabetic nephritis, malignant nephrosclerosis, thrombotic microangiopathy syndrome, transplant rejection and glomerulopathy; Fibrotic disease is as liver cirrhosis, mesangial cell proliferative disease and arteriosclerosis.
(lymphangiogenesis) occurs lymphatic vessel is the process of following growth and metastasis of tumours.Its lymphedema, lymphangiectasis, lymphangioma and lymphangiosarcoma and therein in the asthma of lymphatic vessel long-term overexpression in lung obviously.
Continuing blood vessel occurs by the VEGF factor via its receptor-inducible.For making VEGF bring into play this effect, need to make VEGF and described receptors bind, and induce tyrosine phosphorylation.
Directly or indirectly suppressing described vegf receptor can occur and vascular permeability symptom for the pathologic vessels of preventing or treat these diseases and other VEGF-induction, as tumor vessel.For example, known cancer growth can be suppressed by soluble receptors and VEGF antibody, and the latter's example is Avastin, and its therapeutic domain has been introduced in human cancer treatment.
In WO00/27820, report effective in the following areas anthranilic acid acid amides; Treatment psoriatic; Sacroiliitis is as rheumatoid arthritis, vascular tumor, hemangiofibroma; Illness in eye is as diabetic retinopathy, neovascular glaucoma; Ephrosis is as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic capillary blood vessel syndrome, transplant rejection and glomerulopathy; Fibrotic disease is as liver cirrhosis, mesangial cell proliferative disease, arteriosclerosis, neural tissue injury, and after foley's tube treatment, in blood vessel prosthesis or after keeping blood vessel not block as support with mechanism for suppressing vascular reocclusion.
In WO04/13102, also report effective in the following areas anthranilic acid acid amides; Treatment tumour or transforming growth, psoriatic, Kaposi sarcoma, restenosis are as the restenosis of stent-induced, endometriosis, crohn, Hodgkin's disease, leukemia; Sacroiliitis is as rheumatoid arthritis, vascular tumor, hemangiofibroma; Illness in eye is as diabetic retinopathy, neovascular glaucoma; Ephrosis is as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, transplant rejection and glomerulopathy; Fibrotic disease is as liver cirrhosis, mesangial cell proliferative disease, arteriosclerosis, neural tissue injury, with after foley's tube treatment, in blood vessel prosthesis or after keeping blood vessel not block as support with mechanism for suppressing vascular reocclusion, as immunosuppressor, as the support without in scar healing, senile keratosis and contact dermatitis.
But, need preparation to indication compounds effective as much as possible.To continue blood vessel generation and lymphatic vessel generation in order reducing, to continue blocking VEGF-mediated signal transduction and expect.Suitable combination thing for long-term treatment should seldom or not have drug-drug interactions potential.Cytochrome P450 isozyme plays a crucial role in drug degradation.The fact that patient may express the described isozyme of different relative quantities also makes this problem complicated.The inhibition of these isozymes may cause less desirable drug interaction, particularly in the case of many patients (suffering from the patient of various disease conditions).The inhibition of the Cytochrome P450 isozyme of for example metabolism parent drug can cause systemic toxic concentration.Also there is a problem in the combined therapy together with other medicines treatment, the inhibition of the Cytochrome P450 isozyme of metabolism merging medicine can cause the systemic toxic concentration of described merging medicine.In the time of cancer therapy, combine that to give the situation of various kinds of cell Depressant especially true.
Summary of the invention:
The present invention finds, the compound of general formula as described below (I) has more favourable physical chemistry and/or pharmacokinetic property, stop for example Tyrosylprotein kinase phosphorylation or stop and continue blood vessel generation, and therefore stop tumor growth and spread, they especially effectively suppress vegf receptor kinase and reduce drug-drug interactions potential thus.
Therefore, the compound of formula (I) is suitable for for example treating or preventing the inhibition disease useful to it of blood vessel generation and/or vegf receptor kinase.Compound and isomer, diastereo-isomerism, enantiomer, tautomer and the salt of formula (I) are provided in one aspect of the invention:
Wherein:
A ring is five yuan of fragrant heterocycles, hexa-atomic fragrant heterocycle, preferably pyrazole ring, phenyl ring, pyridine ring;
L is-CONH-,-CONHCO-,-NHCONH-,-NHCO-,-NHCOCH
2-,-CONHCH
2-,-NH--SO-,-SO
2-,-SO
2nH-,-CO-,-CO
2-,-NHCH
2-; Preferably L is-CONH-,-NHCOCH
2-,-CONHCH
2-;
Q is-CONH-,-CONHCO-,-NHCONH-,-NHCO-,-NHCOCH
2-,-CONHCH
2-,-SO-,-SO
2-,-SO
2nH-,-CO-,-CO
2-,-NHCH
2-; Preferably Q is-NHCO-,-NHCOCH
2-,-NHCH
2-;
R
1, R
2be aryl or heteroaryl its can be optionally in one or more positions in identical or different mode by halogen, hydroxyl, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl, aralkoxy, C
1-C
12-alkoxyl group, halo-C
1-C
6-alkyl, cyano group-C
1-C
6-alkyl ,-SO
2r
3,-OR
4,-SOR
5,-COR
3,-CO
2r
3,-NR
6r
7or NCOR
3replace wherein C
1-C
12-alkyl can be by-OR
4,-NR
6r
7or NCOR
3replace; Be preferably phenyl, its can be optionally in one or more positions in identical or different mode by halogen, hydroxyl, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl, aralkoxy, C
1-C
12-alkoxyl group, halo-C
1-C
6-alkyl, cyano group-C
1-C
6-alkyl ,-SO
2r
3,-OR
4,-SOR
5,-COR
3,-CO
2r
3,-NR
6r
7or NCOR
3replace, wherein C1-C12-alkyl can be by-OR
4,-NR
6r
7or NCOR
3replace; More preferably phenyl its can be optionally in one or more positions in identical or different mode by halogen, halo-C
1-C
6-alkyl, cyano group-C
1-C
6-alkyl ,-NR
6r
7or NCOR
3replace,
R
3hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl
R
4hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, halo-C
1-C
6-alkyl;
R
5hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, halo-C
1-C
6-alkyl;
R
6and R
7independent of each other is hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl, aralkoxy, C
1-C
12-alkoxyl group, halo-C
1-C
6-alkyl, cyano group-C
1-C
6-alkyl ,-SO
2r
3,-OR
4,-SOR
5,-COR
3,-CO
2r
3or-NR
6r
7.
Aryl and heteroaryl are selected from: pyrroles, pyrazoles, imidazoles, indoles, quinoline, purine, benzo five-membered heterocycle, five-membered ring hexa-member heterocycle.
The particular compound of formula (I) can be:
N-(4-acrylamido phenyl)-2-((4-picolyl) amino) niacinamide (XF-1)
N-(3-acrylamido phenyl)-2-((4-picolyl) amino) niacinamide (XF-2)
N-(4-acrylamido benzyl)-2-((4-picolyl) amino) niacinamide (XF-3)
N-(3-acrylamido benzyl)-2-((4-picolyl) amino) niacinamide (XF-4)
N-(4-chloro-phenyl-)-2-(3-acrylamide benzylamine) niacinamide (XF-5)
1-(the chloro-3-trifluoromethyl of 4-)-3-(2-((4-picolyl) amino)-3-pyridyl) urea (XF-6)
1-(4-chloro-phenyl-)-3-(2-((4-picolyl) amino)-3-pyridyl) urea (XF-7)
1-(3-trifluoromethyl)-3-(2-((4-picolyl) amino)-3-pyridyl) urea (XF-8)
1-(4-nitrophenyl)-3-(2-((4-picolyl) amino)-3-pyridyl) urea (XF-9)
1-(3-nitrophenyl)-3-(2-((4-picolyl) amino)-3-pyridyl) urea (XF-10)
1-(4-aminophenyl)-3-(2-((4-picolyl) amino)-3-pyridyl) urea (XF-11)
1-(3-aminophenyl)-3-(2-((4-picolyl) amino)-3-pyridyl) urea (XF-12)
1-(4-acrylamido benzyl)-3-(2-((4-picolyl) amino)-3-pyridyl) urea (XF-13)
4-((4-nitrobenzyl amino)-N-(4-(morpholine methyl) phenyl)-1H-3-pyrazole amide (XF-20)
And isomer, diastereomer, enantiomer, tautomer and salt.
In second aspect present invention, the compound that comprises at least one formula (I) or the medicine of its isomer, diastereomer, enantiomer, tautomer or salt are provided.
In a third aspect of the present invention, the compound that comprises at least one formula (I) or the medicine of its isomer, diastereomer, enantiomer, tautomer or salt and at least one pharmaceutically acceptable carrier, thinner or vehicle are provided.
In a fourth aspect of the present invention, the change platform thing that comprises at least one formula (I) or the medicine of its isomer, diastereomer, enantiomer, tautomer or salt are provided, and there is relevant disease and/or with excessive lymphatic vessel, relevant disease occur in it for preventing or treating to lasting blood vessel.
In a fifth aspect of the present invention, the change platform thing that comprises the formula of at least planting (1) or the medicine of its irregular part, diastereomer, enantiomer, tautomer or salt are provided, it is for prevention or treatment tumor growth or transforming growth; Psoriatic; Kaposi sarcoma: the restenosis including the restenosis of stent-induced; Crohn; Hodgkin's disease; Leukemia; Sacroiliitis including Lou rheumatic arthritis, vascular tumor, hemangiofibroma residence endometrium ectopia; Illness in eye including diabetic retinopathy, neovascular glaucoma; Corneal transplantation: the ephrosis including glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, transplant rejection and glomerulopathy; Fibrotic disease including liver cirrhosis: mesangial cell hyperplasia thromboembolism; In blood vessel prosthesis or after keeping blood vessel not block with mechanism, the immunosuppressor as supporting without scar healing: senile keratosis: contact dermatitis; And asthma.
In a sixth aspect of the present invention, the change platform thing that comprises at least one formula (I) or the medicine of its isomer, diastereomer, enantiomer, tautomer or salt are provided, vegf receptor kinase-3 inhibitor that it occurs as lymphatic vessel.
In a seventh aspect of the present invention, the compound that comprises at least one formula (I) or the medicine of its isomer, diastereomer, enantiomer, tautomer or salt are provided, it is used for the treatment of in the method for human body or animal body.
In a eighth aspect of the present invention, the compound that comprises the formula of at least planting (I) or the medicine of its isomer, diastereomer, enantiomer, tautomer or salt are provided, it is for the preparation of the medicine for the treatment of disease, for described disease, it is useful suppressing blood vessel generation and/or lymphatic vessel generation and/or vegf receptor kinase.
In a ninth aspect of the present invention, the compound that comprises the formula of at least planting (I) or the medicine of its isomer, diastereomer, enantiomerism part, tautomer or salt are provided, it is as the inhibitor of Tyrosylprotein kinase VEGFR-1 and VEGFR-2.
Part of compounds preparation method of the present invention is as follows:
Route one:
Route two:
Route three:
Route four:
The compounds of this invention can prepare by above-mentioned preparation method, selects corresponding raw material according to the difference of substituent difference and substituting group position.
Pharmacology test result shows, the compound of general formula I and pharmacy acceptable salt thereof have good inhibition activity to VEGFR-2, and therefore, compound of Formula I and pharmacy acceptable salt thereof can be used for the treatment of the clinical disease relevant with VEGFR-2.The described disease relevant with VEGFR-2 can be melanoma, liver cancer, kidney, acute leukemia, nonsmall-cell lung cancer, prostate cancer, thyroid carcinoma, skin carcinoma, colorectal carcinoma, carcinoma of the pancreas, ovarian cancer, mammary cancer, myelodysplastic syndrome, the esophageal carcinoma, gastrointestinal cancer or mesothelioma.
Part pharmacology test and result below:
One, VEGFR-2 kinase inhibiting activity experiment
Experimental technique:
(1) in reaction vessel, every hole adds KDR kinase solution 2 μ l, substrate solution 2 μ l, damping fluid or compound to be sieved 4 μ l, ATP2 μ l.React 1 hour.
(2) every hole adds TK-Ab5 μ l, SA-XL665 5 μ l, incubated at room 1 hour.
(3) utilize Beckman Coulter detection platform HTRF module to detect.
Calculate:
Primary dcreening operation result
Sieve again result
Two, the proliferation inhibition test of target compound to human umbilical vein endothelial cell
1, experimental procedure
Before detecting, cell is processed 24-72 hour with testing compound,
add in cell culture medium according to ten times of Dilution ratios, 37 DEG C, lucifuge is hatched 1-4 hour.Use 50 μ l 3%SDS to add 100 μ l to contain
cell system in termination reaction.Adopt the long microwell plate plate reading of all-wave (Safire2, Switzerland) to detect fluorescent value, instrument arranges Em:540nm, Em:585nm.
Adopt Prism5.0 (Graphpad Software, USA) statistical analysis software calculated activity Compound I C50.
FRET (fluorescence resonance energy transfer) for compound (FRET) method of synthesized is measured the inhibition activity to CDK2/A, and with positive control drug comparison, filter out active compound preferably.CDK2/A by purifying or directly buy test kit obtain.
Concrete grammar: CDK2/A uses after being diluted to suitable concn with kinase dilution liquid.In kinase reaction mixture, contain CDK2/A, peptide substrate, HEPES (pH7.5), BRIJ-35, MgCl
2and EDTA.CDK2phospho-peptide substrate, as 100% phosphorylation contrast, does not add ATP as 0% phosphorylation contrast.Under room temperature, react after 1h, in reaction system, add the appropriate Development Reagent A diluting.Under room temperature, continue reaction 1h, add Stop Reagent stopped reaction.Excitation wavelength 400nm, detect wavelength is the fluorescence intensity of 445nm (coumarin) and 520nm (fluorescein) simultaneously.Press formula and calculate test-compound inhibiting rate.
2, primary dcreening operation result (n=2)
2, sieve again result
Brief description of the drawings:
Fig. 1 is XF-2VEGFR-2IC
50graphic representation
Fig. 2 is XF-4VEGFR-2IC
50graphic representation
Fig. 3 is XF-5VEGFR-2IC
50graphic representation
Fig. 4 is XF-7VEGFR-2IC
50graphic representation
Fig. 5 is XF-8VEGFR-2IC
50graphic representation
Fig. 6 is XF-1HUVEC IC
50graphic representation
Fig. 7 is XF-9HUVEC IC
50graphic representation
Compound preparation of the present invention
Following examples are explained compound preparation of the present invention, and the scope of the compound of request protection is not limited to these embodiment.
Embodiment:
Fusing point is measured with b shape melting point tube, and medium is methyl-silicone oil, and thermometer is not proofreaied and correct; Nicolet Impact410 type determination of infrared spectroscopy for IR spectrum, KBr compressing tablet; For 1HNMR, JEOL FX90Q type fourier transform NMR instrument, BRUKER ACF-300 type nuclear magnetic resonance analyser and BRUKER AM-500 type nuclear magnetic resonance analyser complete (mark in TMS); MS measures with Nicolet2000 type Fourier transform mass spectrometer and MAT-212 type mass spectrograph; CEM Discover single mold microwave instrument for microwave reaction.
Embodiment 1
The preparation of 2-chloronicotinoyl chloride (A)
2-chlorine apellagrin (4.13g, 26.21mmol), toluene 15ml, anhydrous DMF 125 μ l are dropped in 50ml eggplant-shape bottle successively, stir, constant pressure funnel drips sulfur oxychloride 2.5ml, after dropwising, is heated to 80 DEG C of reactions 5 hours.In question response liquid, white solid disappears, and is yellow transparent aqueous.Use water distilling apparatus instead, except desolventizing.Be heated to 150 DEG C, reaction solution boiling reflux, while rising to 160 DEG C, there is liquid in returnable bottle.Steaming solvent is transparent light yellow liquid, and reaction solution is brown color, separates out solid.Decompress filter precipitate, toluene wash filter cake, drying under reduced pressure obtains buff powder.
Embodiment 2
The preparation of N-(3-nitrobenzyl)-2-chloro-nicotinamide (B)
By above-mentionedly preparing gained A (0.5g, 2.84mmol), 3-nitro benzyl amine hydrochlorate (0.55g, 2.91mmol) drops into 100ml eggplant-shape bottle successively, after adding 50ml THF to dissolve, drip triethylamine to reaction solution and be alkalescence, normal-temperature reaction.TLC detection reaction is complete, adds water 50ml, ethyl acetate 40ml, and organic phase is extracted with ethyl acetate.Merge organic phase, anhydrous magnesium sulfate drying, filtering siccative, underpressure distillation, except desolventizing, obtains white solid 0.55g, yield 66.5%.
Embodiment 3
The preparation of N-(3-nitrobenzyl)-2-(pyridine-4-methylamino) niacinamide (C)
By above-mentionedly preparing gained compd B (0.2g, 0.68mmol), 4-pyridyl-methanamine (0.16g, 1.48mmol) drops into microwave tube successively, after adding 4ml propyl carbinol to dissolve, then adds DIPEA (0.48ml, 2.72mmol).Microwave reaction condition is 120 DEG C, 200Pa, 250W, reacts 14 hours.Add methylene chloride/methanol (10: 1) 20ml, water extraction, reclaims organic phase, anhydrous magnesium sulfate drying, and underpressure distillation is except desolventizing.Silica gel column chromatography separates (petrol ether/ethyl acetate=1: 1.5), obtain product 0.14g, yield 56.2%.
Embodiment 4
N-(3-aminobenzyl)-2-pyridine-4-methylamino) preparation of niacinamide (D4)
By the above-mentioned gained Compound C (0.12g for preparing, 0.33mmol), reduced iron powder (56mg, 0.99mmol), ammonium chloride (35.4mg, 0.66mmol) add successively 50ml eggplant-shape bottle, add 70% Virahol 20ml to dissolve rear reaction solution clarification, visible iron powder, 78 DEG C of heating reflux reactions 4 hours, TLC monitors reaction process, treats that raw material point disappears, stopped reaction.Sand core funnel paving diatomite filtration is removed most of iron powder, methanol wash, and filtrate is light/dark balance.Underpressure distillation, except desolventizing, adds water 30ml, ethyl acetate 30ml, ethyl acetate extraction.Merge organic phase, anhydrous magnesium sulfate drying.Filtering siccative, underpressure distillation, except desolventizing, obtains 0.11g.
Embodiment 5
The preparation of N-(4-acrylamide phenyl)-2-(pyridine-4-methylamino) niacinamide (XF-1)
The above-mentioned gained Compound D 1 (90mg, 0.28mmol) of preparing is dropped into 50ml eggplant-shape bottle, after adding 10ml tetrahydrofuran (THF) to dissolve, splash into triethylamine (118 μ l, 0.894mmol).Acrylate chloride (23 μ l, 0.28mmol) is dissolved in 5ml tetrahydrofuran (THF), and 0 DEG C slowly splashes into reaction solution, room temperature reaction.TLC monitors reaction process, treats that raw material point disappears, stopped reaction.Add water 20ml, ethyl acetate 30ml, ethyl acetate extraction, merges organic phase, anhydrous magnesium sulfate drying.Filtering siccative, underpressure distillation is except desolventizing.Silica gel column chromatography separate dichloromethane/methyl alcohol (60: 1), obtains 90mg, yield 85.5%.
1H-NMR[300MHz，DMSO-d
6]δ10.27(s，1H)，10.18(s，1H)，8.49(m，3H)，8.15(m，2H)，7.67(s，4H)，7.30(d，J＝5.34Hz，2H)，6.71(t，J＝4.89Hz，1H)，6.49(m，1H)，6.28(m，1H)，5.76(m，1H)，4.70(d，J＝5.85Hz，2H)。
Embodiment 6
The preparation of N-(3-acrylamide phenyl)-2-(pyridine-4-methylamino) niacinamide (XF-2)
The above-mentioned gained Compound D 2 (90mg, 0.28mmol) of preparing is dropped into 50ml eggplant-shape bottle, after adding 10ml tetrahydrofuran (THF) to dissolve, splash into triethylamine (118 μ l, 0.894mmol).Acrylate chloride (23 μ l, 0.28mmol) is dissolved in 5ml tetrahydrofuran (THF), and 0 DEG C slowly splashes into reaction solution, room temperature reaction.TLC monitors reaction process, treats that raw material point disappears, stopped reaction.Add water 20ml, ethyl acetate 30ml, ethyl acetate extraction, merges organic phase, anhydrous magnesium sulfate drying.Filtering siccative, underpressure distillation is except desolventizing.Silica gel column chromatography separate dichloromethane/methyl alcohol (60: 1), obtains 90mg, yield 85.5%.
1H-NMR[300MHz，DMSO-d
6]δ10.33(s，1H)，10.20(s，1H)，8.48(m，2H)，8.18(m，3H)，7.45(m，3H)，7.31(m，3H)，6.71(m，1H)，6.51(m，1H)，6.29(d，J＝16.83Hz，1H)，5.77(d，J＝9.18Hz，1H)，4.70(s，2H)。
Embodiment 7
The preparation of N-(4-acrylamide benzyl)-2-(pyridine-4-methylamino) niacinamide (XF-3)
The above-mentioned gained compound d3 (0.12g, 0.36mmol) of preparing is dropped into 50ml eggplant-shape bottle, after adding 20ml tetrahydrofuran (THF) to dissolve, splash into triethylamine (150 μ l, 1.08mmol).Acrylate chloride (30 μ l, 0.36mmol) is dissolved in 5ml tetrahydrofuran (THF), and 0 DEG C slowly splashes into reaction solution, room temperature reaction.TLC monitors reaction process, treats that raw material point disappears, stopped reaction.Add water 20ml, ethyl acetate 30ml, ethyl acetate extraction, merges organic phase, anhydrous magnesium sulfate drying.Filtering siccative, underpressure distillation is except desolventizing.Silica gel column chromatography separates (methylene chloride/methanol=60: 1), obtain 88mg, yield 63.3%.
1H-NMR[300MHz，DMSO-d
6]δ10.15(s，1H)，9.11(s，1H)，8.85(s，1H)，8.49(s，2H)，8.10(m，2H)，7.64(d，J＝7.32Hz，2H)，7.30(m，3H)，6.62(m，1H)，6.48(m，1H)，6.27(d，J＝16.23Hz，1H)，5.76(s，2H)，4.69(m，2H)，4.42(m，2H)。
Embodiment 8
The preparation of N-(3-acrylamide benzyl)-2-(pyridine-4-methylamino) niacinamide (XF-4)
The above-mentioned gained Compound D 4 (0.12g, 0.36mmol) of preparing is dropped into 50ml eggplant-shape bottle, after adding 20ml tetrahydrofuran (THF) to dissolve, splash into triethylamine (150 μ l, 1.08mmol).Acrylate chloride (30 μ l, 0.36mmol) is dissolved in 5ml tetrahydrofuran (THF), and 0 DEG C slowly splashes into reaction solution, room temperature reaction.TLC monitors reaction process, treats that raw material point disappears, stopped reaction.Add water 20ml, ethyl acetate 30ml, ethyl acetate extraction, merges organic phase, anhydrous magnesium sulfate drying.Filtering siccative, underpressure distillation is except desolventizing.Silica gel column chromatography separates (methylene chloride/methanol=60: 1), obtain 82mg, yield 58.8%.
1H-NMR[300MHz，DMSO-d
6]δ10.15(s，1H)，9.17(s，1H)，8.85(s，1H)，8.46(t，J＝1.35Hz，2H)，8.13(m，1H)，8.06(d，J＝1.56Hz，1H)，7.61(d，J＝7.53Hz，2H)，7.28(m，3H)，7.05(d，J＝7.2Hz，1H)，6.64(d，J＝2.88Hz，1H)，6.42(m，1H)，6.27(d，J＝2.0Hz，1H)，5.77(d，J＝12.45Hz，1H)，4.68(d，J＝5.76Hz，2H)，4.46(d，J＝5.55Hz，2H)。
Embodiment 9
The preparation of N-(4-chloro-phenyl-)-2-(3-acrylamide benzylamine) niacinamide (XF-5)
To prepare gained compound H (50mg, 0.14mmol) and drop into 50ml eggplant-shape bottle, after adding 10ml tetrahydrofuran (THF) to dissolve, splash into triethylamine (59 μ l, 0.43mmol).Acrylate chloride (12 μ l, 0.14mmol) is dissolved in 5ml tetrahydrofuran (THF), and 0 DEG C slowly splashes into reaction solution, room temperature reaction.TLC monitors reaction process, treats that raw material point disappears, stopped reaction.Add water 20ml, ethyl acetate 30ml, ethyl acetate extraction, merges organic phase, anhydrous magnesium sulfate drying.Filtering siccative, underpressure distillation is except desolventizing.Silica gel column chromatography separate dichloromethane/methyl alcohol (60: 1), obtains 49mg, yield 85.96%.
1H-NMR[300MHz，DMSO-d
6]δ10.37(s，1H)，10.14(s，1H)，8.41(s，1H)，8.22(s，1H)，8.12(d，J＝7.38Hz，1H)，7.76(m，2H)，7.63(m，2H)，7.42(d，J＝8.52Hz，2H)，7.29(m，1H)，7.06(d，J＝6.42Hz，1H)，6.71(m，1H)，6.48(m，1H).，6.26(m，1H).，5.75(m，1H)，4.65(s，2H)。
Embodiment 10
The preparation of 3-nitro-N-(pyridine-4-methyl) pyridine-2-amine (I)
By chloro-2-3-nitropyridine (2.5g, 16mmol), Dipea (2.6g, 20mmol) join in 100ml round-bottomed flask and add 50mlTHF, 4-aminomethyl pyridine (2.15g, 20mmol), stirring at room temperature 8h, underpressure distillation goes out desolventizing, adds 10ml ethyl acetate washing solid, obtains sterling 3.3g. yield 89.6%.
Embodiment 11
N-2-(pyridine-4-methyl) pyridine-2, the preparation of 3-diamines (J)
By the above-mentioned gained Compound I (76mg for preparing, 0.33mmol), reduced iron powder (56mg, 0.99mmol), ammonium chloride (35.4mg, 0.66mmol) add successively 50ml eggplant-shape bottle, add 70% Virahol 20ml to dissolve rear reaction solution clarification, visible iron powder, 78 DEG C of heating reflux reactions 4 hours, TLC monitors reaction process, treats that raw material point disappears, stopped reaction.Sand core funnel paving diatomite filtration is removed most of iron powder, methanol wash, and filtrate is light/dark balance.Underpressure distillation, except desolventizing, adds water 30ml, ethyl acetate 30ml, ethyl acetate extraction.Merge organic phase, anhydrous magnesium sulfate drying.Filtering siccative, underpressure distillation, except desolventizing, obtains 61mg, yield 92.4%.
Embodiment 12
The preparation of 1-(the chloro-3-trifluoromethyl of 4-)-3-(2-((4-picolyl) amino)-3-pyridyl) urea (XF-6)
By the compound J (0.1g, 0.5mmol) of above-mentioned preparation, 4-chloro-3-trifluoromethylbenzene based isocyanate (0.12g, 0.55mmol), adds in 50ml single port bottle, adds 12ml anhydrous methylene chloride, room temperature reaction 5 hours.Separate out solid, filter to obtain sterling 0.12g, yield 57.14%.
1H-NMR[300MHz，DMSO-d
6]δ9.35(s，1H)，8.46(d，J＝5.85Hz，2H)，8.14(d，J＝2.25Hz，1H)，8.05(s，1H)，7.82(m，1H)，7.69(m，2H)，7.49(d，J＝1.44Hz，1H)，7.34(d，J＝5.64Hz，2H)，6.78(t，J＝5.73Hz，1H)，6.61(m，1H)，4.6(d，J＝5.73Hz，2H)。
Embodiment 13
The preparation of 1-(4-chloro-phenyl-)-3-(2-((4-picolyl) amino)-3-pyridyl) urea (XF-7)
By the compound J (0.1g, 0.5mmol) of above-mentioned preparation, 4-chloro-phenyl-isocyanic ester (85mg, 0.55mmol), adds in 50ml single port bottle, adds 12ml anhydrous methylene chloride, room temperature reaction 5 hours.Separate out solid, filter to obtain sterling 0.10g, yield 56.50%.
1H-NMR[300MHz，DMSO-d
6]δ8.94(s，1H)，8.46(d，J＝5.8Hz，2H)，7.86(s，1H)，7.78(d，J＝4.9Hz，1H)，7.55-7.44(m，3H)，7.37-7.25(m，4H)，6.69(t，J＝5.5Hz，1H)，6.59(m，1H)，4.59(d，J＝5.6Hz，2H)。
Embodiment 14
The preparation of 1-(3-trifluoromethyl)-3-(2-((4-picolyl) amino)-3-pyridyl) urea (XF-8)
By the compound J (0.1g, 0.5mmol) of above-mentioned preparation, m-trifluoromethylphenyl isocyanic ester (0.103g, 0.55mmol), adds in 50ml single port bottle, adds 12ml anhydrous methylene chloride, room temperature reaction 5 hours.Separate out solid, filter to obtain sterling 81mg, yield 41.97%.
1H-NMR[300MHz，DMSO-d
6]δ9.16(s，1H)，8.45(d，J＝5.3Hz，2H)，8.02(s，1H)，7.95(s，1H)，7.79(d，J＝4.3Hz，1H)，7.60(d，J＝7.6Hz，1H)，7.51(m，2H)，7.31(m，3H)，6.72(t，J＝5.7Hz，1H)，6.59(m，1H)，4.59(d，J＝5.7Hz，2H)。
Embodiment 15
The preparation of 1-(4-nitrophenyl)-3-(2-((4-picolyl) amino)-3-pyridyl) urea (XF-9)
By the compound J of above-mentioned preparation (0.29g, 1.45mmol, p-nitrophenyl based isocyanate (0.26g, 1.6mmol), add in 50ml single port bottle, add 15ml anhydrous methylene chloride, room temperature reaction 5h. separates out solid, filters to obtain sterling 0.49g, yield 92.8%.
1H-NMR[300MHz，DMSO-d
6：δ9.6(1H，s)，8.4(2H，s)，8.2(2H，d，J＝8.8Hz)，8.0(1H，s)，7.8(1H，s)，7.7(2H，d，J＝6.9Hz)，7.5(1H，d，J＝6.6Hz)，7.3(2H，s)，6.8(1H，s)，6.6(1H，d，J＝4.9Hz)，4.6(2H，s)。
Embodiment 16
The preparation of 1-(3-nitrophenyl)-3-(2-((4-picolyl) amino)-3-pyridyl) urea (XF-10)
By the compound J (0.29g, 1.45mmol) of above-mentioned preparation, m-nitro based isocyanate (0.26g, 1.6mmol), adds in 50ml single port bottle, adds 15ml anhydrous methylene chloride, room temperature reaction 5h..Separate out solid, filter to obtain sterling 0.51g, yield 94.9%.
1H-NMR[300MHz，DMSO-d
6]δ9.38(s，1H)，8.56(s，1H)，8.45(d，J＝5.8Hz，2H)，8.00(s，1H)，7.93-7.69(m，3H)，7.55(dd，J＝16.0，7.9Hz，2H)，7.33(d，J＝5.2Hz，2H)，6.75(t，J＝5.8Hz，1H)，6.59(dd，J＝7.5，5.0Hz，1H)，4.59(d，J＝5.8Hz，2H)。
Embodiment 17
The preparation of 1-(4-aminophenyl)-3-(2-((4-picolyl) amino)-3-pyridyl) urea (XF-11).
By XF-9 (30mg, 0.08mmol), reduced iron powder (13.4mg, 0.24mmol), ammonium chloride (8.6mg, 0.16mmol) add successively 10ml eggplant-shape bottle, add 70% Virahol 5ml to dissolve rear reaction solution clarification, visible iron powder, 78 DEG C of heating reflux reactions 4 hours, TLC monitors reaction process, treats that raw material point disappears, stopped reaction.Sand core funnel paving diatomite filtration is removed most of iron powder, methanol wash, and filtrate is light/dark balance.Underpressure distillation, except desolventizing, obtains 23mg.Yield 86.1%.
1H-NMR[300MHz，DMSO-d
6]δ8.45(d，J＝5.7Hz，2H)，8.31(s，1H)，7.75(m，2H)，7.56(d，J＝6.8Hz，1H)，7.32(d，J＝5.4Hz，2H)，7.09(d，J＝8.4Hz，2H)，6.65-6.46(m，4H)，4.71(s，2H)，4.58(d，J＝5.6Hz，2H)。
Embodiment 18
The preparation of 1-(3-aminophenyl)-3-(2-((4-picolyl) amino)-3-pyridyl) urea (XF-12)
By XF-10 (30mg, 0.08mmol), reduced iron powder (13.4mg, 0.24mmol), ammonium chloride (8.6mg, 0.16mmol) add successively 10ml eggplant-shape bottle, add 70% Virahol 5ml to dissolve rear reaction solution clarification, visible iron powder, 78 DEG C of heating reflux reactions 4 hours, TLC monitors reaction process, treats that raw material point disappears, stopped reaction.Sand core funnel paving diatomite filtration is removed most of iron powder, methanol wash, and filtrate is light/dark balance.Underpressure distillation, except desolventizing, obtains 25mg product, yield 93.6%.
1H-NMR[300MHz，DMSO-d
6]δ8.55-8.36(m，3H)，7.81(s，1H)，7.74(d，J＝4.9Hz，1H)，7.57(d，J＝?7.5Hz，1H)，7.32(d，J＝5.3Hz，2H)，6.87(d，J＝8.0Hz，1H)，6.76(s，1H)，6.68-6.52(m，3H)，6.17(d，J＝8.1Hz，1H)，5.00(s，2H)，4.58(d，J＝5.9Hz，2H)。
Embodiment 19
The preparation of 1-(4-acrylamido benzyl)-3-(2-((4-picolyl) amino)-3-pyridyl) urea (XF-13)
XF-11 (60mg, 0.18mmol) is dropped into 25ml eggplant-shape bottle, after adding 10ml tetrahydrofuran (THF) to dissolve, splash into triethylamine (75.2 μ l, 0.54mmol).Acrylate chloride (17.6 μ l, 0.216mmol) is dissolved in 5ml tetrahydrofuran (THF), and 0 DEG C slowly splashes into reaction solution, room temperature reaction.TLC monitors reaction process, treats that raw material point disappears, stopped reaction.Add water 20ml, ethyl acetate 30ml, ethyl acetate extraction, merges organic phase, anhydrous magnesium sulfate drying.Filtering siccative, underpressure distillation is except desolventizing.Silica gel column chromatography separate dichloromethane/methyl alcohol (60: 1), obtains 15mg, yield 21.4%.
1H-NMR[300MHz，DMSO-d
6]δ10.03(s，1H)，8.45(d，J＝5.8Hz，2H)，7.84(d，J＝7.5Hz，1H)，7.65(d，J＝4.8Hz，2H)，7.47-7.55(m，5H)，7.37(d，J＝4.8Hz，3H)，6.52(m，1H)，6.43(m，1H)，6.22(dd，J＝16.9，2.0Hz，1H)，5.70(dd，J＝10.0Hz，2.0Hz，1H)，4.58(d，J＝5.4Hz，2H)。
Embodiment 20
The preparation of 4-(4-nitrobenzyl) morpholine (K)
Will be to nitro bromobenzyl (2g, 9.26mmol), triethylamine (0.94g, 9.26mmol) join in 100ml round-bottomed flask, add 50ml methylene dichloride, morpholine (0.89g, 10.18mmol), stirring at room temperature 2h, add water washing repeatedly, retain organic layer, decompression steams solvent, obtain crude product 1.02g, directly cast single step reaction.
1H-NMR[300MHz，DMSO-d6]δ7.6(d，J＝8.7Hz，2H)，6.9(d，J＝8.7Hz，2H)，3.3-3.5(m，6H)，2.3(m，4H)。
Embodiment 21
The preparation of 4-((4-morpholinyl) methyl) aniline (L)
By the above-mentioned gained compound K (1.02g for preparing, 4.50mol) join in 250ml reaction flask, after 100ml dissolve with methanol, add two hydrated stannous chloride (5g, 22.5mmol) back flow reaction 5h, reaction stops, after being spin-dried for, add 70ml water sodium carbonate to adjust PH to retain organic layer with EA extraction after neutrality, after being spin-dried for, obtain 0.85g, yield 45.45%.
1H-NMR[300MHz，DMSO-d6]δ6.9(d，J＝8.4Hz，2H)，6.5(d，J＝8.4Hz，2H)，4.9(s，2H)，3.5(s，2H)，3.2(m，4H)，2.3(m，4H)。
Embodiment 22
N-(4-((4-morpholine) methyl) phenyl)-4-nitro-1H-3-pyrazolecarboxamide (M)
In 100ml there-necked flask, add 4-nitropyrazole-3-formic acid (0.7g, 4.5mmol), methylene dichloride 70ml, oxalyl chloride (0.64ml, 6.75mmol), splash into two DMF, room temperature reaction 4h reaction stops as solution A, by intermediate L (0.85g, 4.5mmol), add in 70ml methylene dichloride, add triethylamine (1.9ml, 13.5mmol) be solution B, solution A is slowly splashed in solution B at 0 DEG C, room temperature reaction 5h, underpressure distillation removes desolventizing and adds water 100ml, ethyl acetate extracts repeatedly, retain organic layer and be spin-dried for to obtain crude product 1.49g, not purified direct input next step.
1H-NMR[300MHz，DMSO-d
6]δ14.2(s，1H)，10.7(s，1H)，8.9(s，1H)，7.6(d，J＝8.4Hz，2H)，7.3(d，J＝8.4Hz，2H)，3.6(t，J＝4.1Hz，4H)，3.4(s，2H)，2.4(t，J＝4.1Hz，4H)。
Embodiment 23
N-(4-((4-morpholine) methyl) phenyl)-4-amino-1H-3-pyrazolecarboxamide (N)
In 250ml there-necked flask, add M (1.49g, 4.5mmol), two hydrated stannous chloride (4g, 18mmol), 100ml methanol eddy 4h, reaction stopped reaction stops, after being spin-dried for, add 70ml water sodium carbonate to adjust PH to retain organic layer with EA extraction after neutrality, be spin-dried for and obtain 1.03g sterling, yield 75.9% by ethyl acetate and methanol mixed solvent recrystallization afterwards.
1H-NMR[300MHz，DMSO-d
6]δ12.7(s，1H)，9.7(s，1H)，7.7(d，J＝8.4Hz，2H)，7.2(m，3H)，4.7(s，2H)，3.6(m，4H)，3.3(s，2H)，2.5(m，4H)。
Embodiment 24
4-(the preparation of (4-nitrobenzyl amino)-N-(4-(morpholine methyl) phenyl)-1H-3-pyrazole amide (XF-20)
In 50ml there-necked flask, add N (0.3g, 1mmol), to nitro bromobenzyl (0.21g, 1mmol), triethylamine (0.21ml, 1.5mmol), DMF15ml room temperature reaction 5h reaction stops, add water 50ml, ethyl acetate extraction, retains organic layer and washes with water, and decompression steams ethyl acetate, column chromatography for separation obtains sterling 0.27g, yield 62.07%.
1H-NMR[300MHz，DMSO-d6]δ12.8(s，1H)，9.78(s，1H)，8.21(d，J＝7.62Hz，2H)，7.76(d，J＝7.83Hz，2H)，7.64(d，J＝7.77Hz，2H)，7.24(d，J＝8.28Hz，2H)，7.14(s，1H)，5.93(t，J＝5.6Hz，1H)，4.39(d，J＝5.85Hz，2H)，3.66(m，4H)，3.41(s，2H)，2.34(m，4H)。
Claims (19)
1. the present invention relates to a kind of novel structure suc as formula the amino aromatic ring compounds of 2-shown in (I), its pharmaceutical salts, its prodrug, its hydrate or solvate, also relate to the preparation method of described compound, the pharmaceutical composition that comprises the described compound for the treatment of effective dose, using and as protein tyrosine kinase inhibitor, especially as VEGF-2 (Vascular Endothelial Growth Factor Receptor2, VEGFR-2, Kinase Domain Receptor, KDR) inhibitor, prevent and/or treat the purposes in the medicine of the abnormal relative disease of VEGFR-2 in preparation.
2. the compound of formula (I) and isomer, diastereo-isomerism, enantiomer, tautomer and salt:
Wherein:
A ring is five yuan of fragrant heterocycles, hexa-atomic fragrant heterocycle, preferably pyrazole ring, phenyl ring, pyridine ring;
L is-CONH-,-CONHCO-,-NHCONH-,-NHCO-,-NHCOCH
2-,-CONHCH
2-,-SO-,-SO
2-,-SO
2nH-,-CO-,-CO
2-,-NHCH
2-;
Q is-CONH-,-CONHCO-,-NHCONH-,-NHCO-,-NHCOCH
2-,-CONHCH
2-,-SO-,-SO
2-,-SO
2nH-,-CO-,-CO
2-,-NHCH
2-;
R
1, R
2be aryl or heteroaryl its can be optionally in one or more positions in identical or different mode by halogen, hydroxyl, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl, aralkoxy, C
1-C
12-alkoxyl group, halo-C
1-C
6-alkyl, cyano group-C
1-C
6-alkyl ,-SO
2r
3,-OR
4,-SOR
5,-COR
3,-CO
2r
3,-NR
6r
7or NCOR
3replace wherein C
1-C
12-alkyl can be by-OR
4,-NR
6r
7or NCOR
3;
R
3hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl
R
4hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, halo-C
1-C
6-alkyl;
R
5hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, halo-C
1-C
6-alkyl;
R
6and R
7independent of each other is hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl, aralkoxy, C
1-C
12-alkoxyl group, halo-C
1-C
6-alkyl, cyano group-C
1-C
6-alkyl ,-SO
2r
3,-OR
4,-SOR
5,-COR
3,-CO
2r
3or-NR
6r
7.
Aryl and heteroaryl are selected from: pyrroles, pyrazoles, imidazoles, indoles, quinoline, purine, benzo five-membered heterocycle, five-membered ring hexa-member heterocycle.
3. the compound of formula (II) and isomer, diastereo-isomerism, enantiomer, tautomer and salt:
Wherein:
X is N or CH;
L is-CONH-,-CONHCO-,-NHCONH-,-NHCO-,-NHCOCH
2-,-CONHCH
2-,-SO-,-SO
2-,-SO
2nH-,-CO-,-CO
2-,-NHCH
2-;
Q is-CONH-,-CONHCO-,-NHCONH-,-NHCO-,-NHCOCH
2-,-CONHCH
2-,-SO-,-SO
2-,-SO
2nH-,-CO-,-CO
2-,-NHCH
2-;
R
1, R
2be aryl or heteroaryl its can be optionally in one or more positions in identical or different mode by halogen, hydroxyl, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl, aralkoxy, C
1-C
12-alkoxyl group, halo-C
1-C
6-alkyl, cyano group-C
1-C
6-alkyl ,-SO
2r
3,-OR
4,-SOR
5,-COR
3,-CO
2r
3,-NR
6r
7or NCOR
3replace wherein C
1-C
12-alkyl can be by-OR
4,-NR
6r
7or NCOR
3;
R
3hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl
R
4hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, halo-C
1-C
6-alkyl;
R
5hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, halo-C
1-C
6-alkyl;
R
6and R
7independent of each other is hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl, aralkoxy, C
1-C
12-alkoxyl group, halo-C
1-C
6-alkyl, cyano group-C
1-C
6-alkyl ,-SO
2r
3,-OR
4,-SOR
5,-COR
3,-CO
2r
3or-NR
6r
7.
Aryl and heteroaryl are selected from: pyrroles, pyrazoles, imidazoles, indoles, quinoline, purine, benzo five-membered heterocycle, five-membered ring hexa-member heterocycle.
4. the compound of formula (III) and isomer, diastereo-isomerism, enantiomer, tautomer and salt:
Wherein:
L is-CONH-,-CONHCO-,-NHCONH-,-NHCO-,-NHCOCH
2-,-CONHCH
2-,-SO-,-SO
2-,-SO
2nH-,-CO-,-CO
2-,-NHCH
2-;
Q is-CONH-,-CONHCO-,-NHCONH-,-NHCO-,-NHCOCH
2-,-CONHCH
2-,-SO-,-SO
2-,-SO
2nH-,-CO-,-CO
2-,-NHCH
2-;
R
1, R
2be aryl or heteroaryl its can be optionally in one or more positions in identical or different mode by halogen, hydroxyl, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl, aralkoxy, C
1-C
12-alkoxyl group, halo-C
1-C
6-alkyl, cyano group-C
1-C
6-alkyl ,-SO
2r
3,-OR
4,-SOR
5,-COR
3,-CO
2r
3,-NR
6r
7or NCOR
3replace wherein C
1-C
12-alkyl can be by-OR
4,-NR
6r
7or NCOR
3;
R
3hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl
R
4hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, halo-C
1-C
6-alkyl;
R
5hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, halo-C
1-C
6-alkyl;
R
6and R
7independent of each other is hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl, aralkoxy, C
1-C
12-alkoxyl group, halo-C
1-C
6-alkyl, cyano group-C
1-C
6-alkyl ,-SO
2r
3,-OR
4,-SOR
5,-COR
3,-CO
2r
3or-NR
6r
7.
Aryl and heteroaryl are selected from: pyrroles, pyrazoles, imidazoles, indoles, quinoline, purine, benzo five-membered heterocycle, five-membered ring hexa-member heterocycle.
5. the compound of formula (IV) and isomer, diastereo-isomerism, enantiomer, tautomer and salt:
Wherein:
X is N or CH;
L is-CONH-,-CONHCO-,-NHCONH-,-NHCO-,-NHCOCH
2-,-CONHCH
2-,-SO-,-SO
2-,-SO
2nH-,-CO-,-CO
2-,-NHCH
2-;
R
1, R
2be aryl or heteroaryl its can be optionally in one or more positions in identical or different mode by halogen, hydroxyl, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl, aralkoxy, C
1-C
12-alkoxyl group, halo-C
1-C
6-alkyl, cyano group-C
1-C
6-alkyl ,-SO
2r
3,-OR
4,-SOR
5,-COR
3,-CO
2r
3,-NR
6r
7or NCOR
3replace wherein C
1-C
12-alkyl can be by-OR
4,-NR
6r
7or NCOR
3;
R
3hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl
R
4hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, halo-C
1-C
6-alkyl;
R
5hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, halo-C
1-C
6-alkyl;
R
6and R
7independent of each other is hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl, aralkoxy, C
1-C
12-alkoxyl group, halo-C
1-C
6-alkyl, cyano group-C
1-C
6-alkyl ,-SO
2r
3,-OR
4,-SOR
5,-COR
3,-CO
2r
3or-NR
6r
7.
Aryl and heteroaryl are selected from: pyrroles, pyrazoles, imidazoles, indoles, quinoline, purine, benzo five-membered heterocycle, five-membered ring hexa-member heterocycle.
6. the compound of formula (V) and isomer, diastereo-isomerism, enantiomer, tautomer and salt:
Wherein:
L is-CONH-,-CONHCO-,-NHCONH-,-NHCO-,-NHCOCH
2-,-CONHCH
2-,-SO-,-SO
2-,-SO
2nH-,-CO-,-CO
2-,-NHCH
2-;
R
1, R
2be aryl or heteroaryl its can be optionally in one or more positions in identical or different mode by halogen, hydroxyl, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl, aralkoxy, C
1-C
12-alkoxyl group, halo-C
1-C
6-alkyl, cyano group-C
1-C
6-alkyl ,-SO
2r
3,-OR
4,-SOR
5,-COR
3,-CO
2r
3,-NR
6r
7or NCOR
3replace wherein C
1-C
12-alkyl can be by-OR
4,-NR
6r
7or NCOR
3replace;
R
3hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl
R
4hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, halo-C
1-C
6-alkyl;
R
5hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, halo-C
1-C
6-alkyl;
R
6and R
7independent of each other is hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl, aralkoxy, C
1-C
12-alkoxyl group, halo-C
1-C
6-alkyl, cyano group-C
1-C
6-alkyl ,-SO
2r
3,-OR
4,-SOR
5,-COR
3,-CO
2r
3or-NR
6r
7.
Aryl and heteroaryl are selected from: pyrroles, pyrazoles, imidazoles, indoles, quinoline, purine, benzo five-membered heterocycle, five-membered ring hexa-member heterocycle.
7. the compound of formula (VI) and isomer, diastereo-isomerism, enantiomer, tautomer and salt:
Wherein:
X is N or CH;
R
1, R
2be aryl or heteroaryl its can be optionally in one or more positions in identical or different mode by halogen, hydroxyl, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl, aralkoxy, C
1-C
12-alkoxyl group, halo-C
1-C
6-alkyl, cyano group-C
1-C
6-alkyl ,-SO
2r
3,-OR
4,-SOR
5,-COR
3,-CO
2r
3,-NR
6r
7or NCOR
3replace wherein C
1-C
12-alkyl can be by-OR
4,-NR
6r
7or NCOR
3replace;
R
3hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl
R
4hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, halo-C
1-C
6-alkyl;
R
5hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, halo-C
1-C
6-alkyl;
R
6and R
7independent of each other is hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl, aralkoxy, C
1-C
12-alkoxyl group, halo-C
1-C
6-alkyl, cyano group-C
1-C
6-alkyl ,-SO
2r
3,-OR
4,-SOR
5,-COR
3,-CO
2r
3or-NR
6r
7
Aryl and heteroaryl are selected from: pyrroles, pyrazoles, imidazoles, indoles, quinoline, purine, benzo five-membered heterocycle, five-membered ring hexa-member heterocycle.
8. the compound of formula (VII) and isomer, diastereo-isomerism, enantiomer, tautomer and salt:
Wherein:
X is N or CH;
R
1, R
2be aryl or heteroaryl its can be optionally in one or more positions in identical or different mode by halogen, hydroxyl, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl, aralkoxy, C
1-C
12-alkoxyl group, halo-C
1-C
6-alkyl, cyano group-C
1-C
6-alkyl ,-SO
2r
3,-OR
4,-SOR
5,-COR
3,-CO
2r
3,-NR
6r
7or NCOR
3replace, wherein C1-C12-alkyl can be by-OR
4,-NR
6r
7or NCOR
3replace;
R
3hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl
R
4hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, halo-C
1-C
6-alkyl;
R
5hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, halo-C
1-C
6-alkyl;
R
6and R
7independent of each other is hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl, aralkoxy, C
1-C
12-alkoxyl group, halo-C
1-C
6-alkyl, cyano group-C
1-C
6-alkyl ,-SO
2r
3,-OR
4,-SOR
5,-COR
3,-CO
2r
3or-NR
6r
7;
Aryl and heteroaryl are selected from: pyrroles, pyrazoles, imidazoles, indoles, quinoline, purine, benzo five-membered heterocycle, five-membered ring hexa-member heterocycle.
9. the compound of formula (VIII) and isomer, diastereo-isomerism, enantiomer, tautomer and salt:
Wherein:
X is N or CH;
R
1, R
2be aryl or heteroaryl its can be optionally in one or more positions in identical or different mode by halogen, hydroxyl, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl, aralkoxy, C
1-C
12-alkoxyl group, halo-C
1-C
6-alkyl, cyano group-C
1-C
6-alkyl ,-SO
2r
3,-OR
4,-SOR
5,-COR
3,-CO
2r
3,-NR
6r
7or NCOR
3replace wherein C
1-C
12-alkyl can be by-OR
4,-NR
6r
7or NCOR
3replace;
R
3hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl
R
4hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, halo-C
1-C
6-alkyl;
R
5hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, halo-C
1-C
6-alkyl;
R
6and R
7independent of each other is hydrogen, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl, aralkoxy, C
1-C
12-alkoxyl group, halo-C
1-C
6-alkyl, cyano group-C
1-C
6-alkyl ,-SO
2r
3,-OR
4,-SOR
5,-COR
3,-CO
2r
3or-NR
6r
7
Aryl and heteroaryl are selected from: pyrroles, pyrazoles, imidazoles, indoles, quinoline, purine, benzo five-membered heterocycle, five-membered ring hexa-member heterocycle.
10. the compound of any one of claim 1-8, wherein R
2phenyl or pyridyl, its can be optionally in one or more positions in identical or different mode by halogen, hydroxyl, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl, aralkoxy, C
1-C
12-alkoxyl group, halo-C
1-C
6-alkyl, cyano group-C
1-C
6-alkyl ,-SO
2r
3,-OR
4,-SOR
5,-COR
3,-CO
2r
3,-NR
6r
7or NCOR
3replace, wherein C1-C12-alkyl can be by-OR
4,-NR
6r
7or NCOR
3replace;
The compound of any one of 11. claim 1-9, wherein R
1phenyl or pyridyl, its can be optionally in one or more positions in identical or different mode by halogen, hydroxyl, C
1-C
12-alkyl, C
3-C
8-cycloalkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl, aralkoxy, C
1-C
12-alkoxyl group, halo-C
1-C
6-alkyl, cyano group-C
1-C
6-alkyl ,-SO
2r
3,-OR
4,-SOR
5,-COR
3,-CO
2r
3,-NR
6r
7or NCOR
3replace, wherein C1-C12-alkyl can be by-OR
4,-NR
6r
7or NCOR
3replace;
The compound of 12. claim 1-10, it is selected from
N-(4-acrylamido phenyl)-2-((4-picolyl) amino) niacinamide (XF-1)
N-(3-acrylamido phenyl)-2-((4-picolyl) amino) niacinamide (XF-2)
N-(4-acrylamido benzyl)-2-((4-picolyl) amino) niacinamide (XF-3)
N-(3-acrylamido benzyl)-2-((4-picolyl) amino) niacinamide (XF-4)
N-(4-chloro-phenyl-)-2-(3-acrylamide benzylamine) niacinamide (XF-5)
1-(the chloro-3-trifluoromethyl of 4-)-3-(2-((4-picolyl) amino)-3-pyridyl) urea (XF-6)
1-(4-chloro-phenyl-)-3-(2-((4-picolyl) amino)-3-pyridyl) urea (XF-7)
1-(3-trifluoromethyl)-3-(2-((4-picolyl) amino)-3-pyridyl) urea (XF-8)
1-(4-nitrophenyl)-3-(2-((4-picolyl) amino)-3-pyridyl) urea (XF-9)
1-(3-nitrophenyl)-3-(2-((4-picolyl) amino)-3-pyridyl) urea (XF-10)
1-(4-aminophenyl)-3-(2-((4-picolyl) amino)-3-pyridyl) urea (XF-11)
1-(3-aminophenyl)-3-(2-((4-picolyl) amino)-3-pyridyl) urea (XF-12)
1-(4-acrylamido benzyl)-3-(2-((4-picolyl) amino)-3-pyridyl) urea (XF-13)
4-((4-nitrobenzyl amino)-N-(4-(morpholine methyl) phenyl)-1H-3-pyrazole amide (XF-20)
And isomer, diastereomer, enantiomer, tautomer and salt.
The compound of 13. claim 1-11 or its pharmacy acceptable salt, wherein pharmacy acceptable salt comprises the acid salt that general formula (I) compound and following acid form: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid, naphthene sulfonic acid, citric acid, tartrate, lactic acid, pyruvic acid, acetic acid, toxilic acid or succsinic acid, fumaric acid, Whitfield's ointment, phenylacetic acid, tussol.Comprise in addition the acid salt of mineral alkali, as: basic metal positively charged ion, alkaline earth metal cation, ammonium cation salt contained.
14. medicines, any one formula (I) compound that it comprises at least one claim 1-12.
15. medicines, any one formula (I) compound that it comprises at least one claim 1-12 and at least one pharmaceutically acceptable carrier.
The medicine of 16. claims 13 or 14, there is relevant disease and/or with excessive lymphatic vessel, relevant disease occurs in it for preventing or treating to lasting blood vessel.
The medicine of 17. claims 13 or 14, it is for prevention or treatment tumor growth or transforming growth; Psoriatic; Kaposi sarcoma; Crohn; Hodgkin's disease; Leukemia, comprises rheumatoid arthritis, vascular tumor, fibrin knurl; Uterine veil Endometriosis; Illness in eye including diabetic retinopathy, neovascular glaucoma; Corneal transplantation; Ephrosis including glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, transplant rejection and renal glomerulus; Fibrotic disease including liver cirrhosis; Mesangial cell proliferative disease; Arteriosclerosis; Neural tissue injury, and for transplanting the vascular reocclusion after foley's tube treatment, in blood vessel prosthesis or after keeping blood vessel not block with mechanism, as the immunosuppressor of supporting without scar healing; Senile keratosis; Contact dermatitis; Asthma.
The medicine of 18. claims 13 or 14, there is relevant disease and/or with excessive lymphatic vessel, relevant disease occurs in it for preventing or treating to lasting blood vessel.
The medicine of 19. claims 13 or 14, the vegf receptor kinase inhibitor that its effect lymphatic vessel occurs.
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| CN106496107A (en) * | 2016-08-31 | 2017-03-15 | 浙江永宁药业股份有限公司 | VEGFR inhibitor 2 and preparation method thereof |
| US10266488B2 (en) | 2013-10-10 | 2019-04-23 | Eastern Virginia Medical School | 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives as potent and selective inhibitors of 12-lipoxygenase |
| CN111285806A (en) * | 2018-12-06 | 2020-06-16 | 中国医学科学院药物研究所 | Pyrazole compound and preparation method, application and pharmaceutical composition thereof |
| US11873298B2 (en) | 2017-10-24 | 2024-01-16 | Janssen Pharmaceutica Nv | Compounds and uses thereof |
| US11970486B2 (en) | 2017-10-24 | 2024-04-30 | Janssen Pharmaceutica Nv | Compounds and uses thereof |
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| CN1671700A (en) * | 2001-01-12 | 2005-09-21 | 安姆根有限公司 | Substituted alkylamine derivatives and methods of use |
| CN102858765A (en) * | 2010-04-30 | 2013-01-02 | 阿斯特克斯治疗有限公司 | Pyrazolyl quinazoline kinase inhibitors |
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| CN1325384A (en) * | 1998-11-10 | 2001-12-05 | 舍林股份公司 | Anthranilic acid amides and the use thereof as medicaments |
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| CN1518546A (en) * | 2001-05-08 | 2004-08-04 | ���ֹɷݹ�˾ | Selective anthranilamide pyridine amides as inhibitors of VEGRF-2 and VEGFR-3 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US10266488B2 (en) | 2013-10-10 | 2019-04-23 | Eastern Virginia Medical School | 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives as potent and selective inhibitors of 12-lipoxygenase |
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| CN111285806B (en) * | 2018-12-06 | 2022-04-15 | 中国医学科学院药物研究所 | Pyrazole compound and preparation method, application and pharmaceutical composition thereof |
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