CN102558172B - 5,8-bis-replaces-1,6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof, Preparation Method And The Use - Google Patents

5,8-bis-replaces-1,6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof, Preparation Method And The Use Download PDF

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CN102558172B
CN102558172B CN201010615647.7A CN201010615647A CN102558172B CN 102558172 B CN102558172 B CN 102558172B CN 201010615647 A CN201010615647 A CN 201010615647A CN 102558172 B CN102558172 B CN 102558172B
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compound
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naphthyridine
alkyl
hnmr
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CN102558172A (en
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龙亚秋
丁健
王勇
谢华
曾立凡
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Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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Abstract

The present invention discloses 5,8-bis-and replaces-1,6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof and their preparation method, purposes, and comprises the pharmaceutical composition of this compound.More specifically, the invention discloses that structural formula I, II or III represent 5,8-bis-replaces-1,6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof and their preparation method, and provide this compound and the pharmaceutical composition containing this compound as the treatment of Mutiple Targets tyrosine protein kinase inhibitor for tumor disease etc. and the tyrosine protein kinase particularly disease that c-Src is relevant.

Description

5,8-bis-replaces-1,6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof, Preparation Method And The Use
Technical field
The present invention relates to medical art, be specifically related to 5, 8-bis-replaces-1, 6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof and their preparation method, the invention still further relates to 5, 8-bis-replaces-1, 6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof and the pharmaceutical composition containing this compound are used for mammary cancer as Mutiple Targets tyrosine protein kinase inhibitor, ovarian cancer, malignant melanoma, Skin Squamous Cell Carcinoma, colorectal carcinoma, lung cancer, liver cancer, carcinoma of the pancreas, acute myeloid leukaemia, the treatment of prostate cancer etc. and the Tyrosylprotein kinase particularly disease that c-Src is relevant.
Background technology
Malignant tumour is a kind of common disease and frequently-occurring disease of serious threat human health, with cell or mutant abnormality proliferation and tissue transfer towards periphery for feature, the death that the mankind cause because of malignant tumour occupy the second of all mortalities, is only second to cardiovascular and cerebrovascular diseases.The methods for the treatment of of tumour has operative treatment, radiotherapy and pharmacological agent (chemotherapy) etc., but to a great extent still based on chemotherapy, especially for the appearance of the targeting antineoplastic medicine thing of the key enzyme design in tumour mechanism, chemotherapy is made can successfully to heal the sick or extend significantly the life-span of patient.
In recent years, tyrosine protein kinase (Proteintyrosinekinase, PTK), as the target of targeting antineoplastic medicine thing, has caused medicine scholar interest widely.Tyrosine protein kinase is the important factor in signal transduction process, participates in a series of cell function, with Growth of Cells, differentiation, the closely related [MicroscResTech.2003Jan1 of propagation; 60 (1): 70-75], it can the γ phosphate of catalysis ATP be transferred on the tyrosine residues of many key proteins, makes phenolic hydroxyl group phosphorylation.The expression product of many cancer genes also all has PTK activity, and the PTK activity in a lot of malignant conversioning cell is far away higher than normal cell.If PTK therefore can be suppressed active, just likely block the growth of tumour cell.PTK has become noticeable antitumor drug novel targets [CurrDrugTargets.2003, Feb; 4 (2): 113-121].
The antitumour drug of target PTK achieves rapid progress at last decade, Gleevec, Iressa and Erlotinib are successively by U.S. FDA approval listing, sufficient proof receptor tyrosine kinase is an effective antitumour drug target, and Mutiple Targets tyrosine-kinase enzyme level (multipletargetedtyrosinekinaseinhibition) also becomes oncotherapy New Policy [EuropeanJ.Cancer.2006, the Jun of prospect as rich as Croesus; 42,1351-1356].Because most tumour is not that dependence one bars pathway is to maintain its growth and survival, so, Mutiple Targets medicine can suppress the multi-step of multiple signal pathway or a bars pathway, not only has synergy, and not easily inducing tumor cell produces resistance.The new ideas of this molecular targeted tumor pharmacother also obtain successful clinical evidence, the Mutiple Targets medicine of the multiple Tyrosylprotein kinase such as target c-Raf and VEGFR-2, β-PDGFR while of as recently by the treatment renal cell carcinoma of FDA approval listing and the medicine BAY43-9006 (Sorafenib) of gastrointestinal stromal tumor being exactly.Another new tyrosine-kinase enzyme level SU11248 (Sutent) being used for treatment of gastrointestinal stromal by FDA approval is also suppress many Tyrosylprotein kinase paths such as VEGFR, α-PDGFR simultaneously, treatment for other solid tumors provides new Research Thinking [EuropeanJ.Cancer.2006, Jun; 42,1351-1356].
Mostly the histidine kinase inhibitor of bibliographical information is the derivative of pyrimidine or quinazoline structure, of the present invention 1,6-naphthyridine-7-carboxamide derivatives is the multiple kinase inhibitor of a class new texture, show the kinase whose inhibit activities such as c-Src, KDR, EGFR, ErbB2, and effectively suppress a series of tumor cell line as the Growth of Cells of MDA-MB-435, SK-BR-3, A375, A431, HT-29, A-549, BEL-7402, BXPC3, HL-60, PC-3.
Patent documentation related to the present invention is listed as follows:
A series of quinoline vascular endothelial growth factor receptor inhibitors is disclosed in WO98/13350.Wherein also comprise 1,8-naphthyridine analog derivative, such as, embodiment 53:2-acetylaminohydroxyphenylarsonic acid 5-(2-fluoro-5-hydroxy-4-methyl aniline)-1,8-naphthyridine in this patent.
Disclose 4-hydroxyquinoline-2-carboxamide derivatives in WO99/32450 and be used for the treatment of herpesvirus infection.
Disclose Bioquin-7CA's sulfonamide derivatives in WO98/11073 and be used for the treatment of herpesvirus infection.
Disclose 8-hydroxyl-1,6-naphthyridine-7-carbonyl amines compound in WO02/30931 and be used for the treatment of HIV-1 virus infection.
Disclose 5,8-bis-in CN2008102000645.4 to replace-1,6-naphthyridine-7-amidocarbonylation compound and be used for the treatment of mammary cancer, colorectal carcinoma, ovarian cancer, prostate cancer.
Summary of the invention
An object of the present invention is to disclose a class have brand new, potent antitumor activity 5,8-bis-replace-1,6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof.
Another object of the present invention is to provide the preparation method that above-mentioned 5,8-bis-replace-1,6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof.
An also object of the present invention is to provide above-mentioned 5,8-bis-replaces-1,6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof are in the purposes of field of medicaments, they can be used for tumour as Mutiple Targets tyrosine protein kinase inhibitor, comprise the treatment of mammary cancer, ovarian cancer, malignant melanoma, Skin Squamous Cell Carcinoma, colorectal carcinoma, lung cancer, liver cancer, carcinoma of the pancreas, acute myeloid leukaemia, prostate cancer and the Tyrosylprotein kinase particularly disease that c-Src is relevant.
Another object of the present invention is to provide a kind of pharmaceutical composition comprising 5,8-bis-for the treatment of significant quantity and replace-1,6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof.
According to the present invention, described have 5,8-bis-of anti-tumor activity and replace-1,6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof as shown in general structure I, II or III below:
Wherein,
A is: (1) phenyl ring; (2) C 8-C 10the bicyclic carbocyclic ring of a pair of horses going side by side synthesis, one of them is phenyl ring, and another is saturated or undersaturated ring; The rings of (3) 8 ~ 10 atoms a pair of horses going side by side synthesis, and be selected from the heteroatoms in N, O and S containing 0-3, one of them is aromatic ring or hetero-aromatic ring, and another is saturated or undersaturated carbocyclic ring or heterocycle; (4) heteroatomic five yuan or the six-membered Hetero-aromatic in N, O and S is selected from containing 1 ~ 3; Or (5) are selected from heteroatomic ternary to the seven yuan cycloaliphatic ring in N, O and S containing 0 ~ 3;
L is: (1) is key directly; (2) C 1-C 6alkyl; (3) C 2-C 6thiazolinyl; (4) (C 0-C 6alkyl)-(C 3-C 6cycloalkyl)-(C 0-C 6alkyl); Or (5) (C 0-C 6alkyl)-M-(C 0-C 6alkyl), wherein M is N (R a) ,-SO 2-, OC (=O) or C (=O) O; Wherein, the thiazolinyl in (3) can be replaced by 1-3 respective independently substituting group with the alkyl in (2), (4), (5), and described substituting group is selected from following atom or group: C 1-C 6alkyl, C 1-C 6alkoxy C 1-C 6alkyl, C 3-C 8cycloalkyl, halogen, amino, sulfydryl, hydroxyl ,-CF 3,-CN ,-NO 2,-NR ar b,-NR acOR b,-NR acOOR b,-NR asO 2r b,-COOR b,-COR b,-CONR ar b,-SO 2r b,-SO 2nR ar b,-OR awith-OCOR b;
X is N, NH, O or S independently of one another;
Y is (1) C 1-C 6alkyl; (2) C 2-C 6thiazolinyl; (3) (C 0-C 6alkyl)-(C 3-C 6cycloalkyl)-(C 0-C 6alkyl); (4) (C 0-C 6alkyl)-M-(C 0-C 6alkyl), wherein M is N (R a) ,-SO 2-, OC (=O) or C (=O) O; Or (5) (C 0-C 6alkyl)-(C 6-C 10aryl)-(C 0-C 6alkyl); Wherein, the thiazolinyl in (2) can be replaced by 1-3 respective independently substituting group with the alkyl in (1), (3), (4), and described substituting group is selected among following atom or group: C 1-C 6alkyl, C 1-C 6alkoxy C 1-C 6alkyl, C 3-C 8cycloalkyl, halogen, amino, sulfydryl, hydroxyl ,-CF 3,-CN ,-NO 2,-NR ar b,-NR acOR b,-NR acOOR b,-NR asO 2r b,-COOR b,-COR b,-CONR ar b,-SO 2r b,-SO 2nR ar b,-OR awith-OCOR b;
R 1, R 2, R 3, R 4and R 6be hydrogen, halogen, hydroxyl, sulfydryl ,-CF independently of one another 3,-CN ,-NO 2or not replace or independently of one another by following groups that 1-3 substituting group replaces: C 1-C 6alkyl, C 1-C 6alkoxyl group, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 3-C 8cycloalkyl, C 3-C 8cycloalkyloxy, C 6-C 10aryloxy, C 1-C 6alkoxy carbonyl, amino, phenyl, benzyl, naphthyl, C 5-C 10hetero-aromatic ring base or C 3-C 7saturated heterocyclyl; Described substituting group is selected among following atom or group: C 1-C 6alkyl, C 1-C 6alkoxy C 1-C 6alkyl, heterocyclic radical, C 1-C 6heterocyclic radical, Heterocyclylcarbonyl, C that alkyl replaces 1-C 6alkyl heterocyclic, C 6-C 10aryl, C 3-C 8cycloalkyl, halogen, sulfydryl, hydroxyl ,-CF 3,-CN ,-NO 2,-NR ar b,-NR acOR b,-NR acOOR b,-NR asO 2r b,-COOR b,-COR b,-CONR ar b,-SO 2r b,-SO 2nR ar b,-OR awith-OCOR b, and NR ar bjointly can form cyclammonium; Described heterocycle is comprise 1-3 heteroatomic ternary to the seven yuan cycloaliphatic ring be selected from N, O and S;
R 5for hydrogen, hydroxyl or not replace or by 1-3 the independently following groups that replaces of substituting group: C separately 1-C 6alkyl, C 1-C 6alkoxy C 1-C 6alkyl, C 1-C 6alkoxyl group, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 3-C 8cycloalkyl, phenyl, benzyl, naphthyl, C 5-C 10aromatic heterocycle base or C 4-C 7saturated heterocyclyl; Described heterocycle comprises 1-3 the heteroatoms be selected from N, O and S; Described substituting group is selected from following atom or group: C 1-C 6alkyl, C 1-C 6alkoxy C 1-C 6alkyl, halogen, amino, nitro, sulfydryl, hydroxyl ,-CN and-CF 3;
R afor hydrogen, C 1-C 6alkyl, C 3-C 8cycloalkyl or C 6-C 10aryl;
R bfor hydrogen, hydroxyl or not replace or by 1-3 the independently of one another following groups that replaces of substituting group: C 1-C 6alkyl, C 1-C 6alkoxy C 1-C 6alkyl, C 1-C 6alkoxyl group, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 3-C 8cycloalkyl, phenyl, phenylol, benzyl, naphthyl, C 5-C 10aromatic heterocycle base or C 4-C 7saturated heterocyclyl; Described heterocycle comprises 1-3 the heteroatoms be selected from N, O and S; Described substituting group is selected from following atom or group: C 1-C 6alkyl, C 1-C 6alkoxy C 1-C 6alkyl, halogen, amino, nitro, sulfydryl, hydroxyl ,-CN and-CF 3.
In the compound that general structure I, II or III of the present invention represent, preferred compound can represent with general structure IV, V or VI:
Wherein, R 1, R 2, R 6, L, X be identical with general formula I, II or III with the definition of Y, and preferred further:
R 1and R 2be hydrogen, halogen ,-CN ,-CF independently of one another 3,-NO 2, hydroxyl, amino, C 1-C 6alkylamino, C 1-C 6alkyl-carbonyl-amino, C 1-C 6alkyl heterocyclic is amino, C 6-C 10arylamino, C 6-C 10aryl-sulfonyl amino alkyl, C 1-C 6alkoxyl group, C 3-C 8cycloalkyloxy, C 6-C 10aryloxy, C 1-C 6alkyl heterocyclic C 1-C 6alkoxyl group, C 5-C 10hetero-aromatic ring base, heterocyclic radical C 1-C 6alkoxyl group, Heterocyclylcarbonyl C 1-C 6alkoxyl group or C 6-C 10aryl C 1-C 6alkoxyl group; Heterocyclic radical wherein refers to heteroatomic ternary to the seven yuan cycloaliphatic ring be selected from containing 1 ~ 3 in N, O and S;
R 6for hydrogen, halogen ,-CN ,-COOCH 3,
L is C 1-C 6alkyl or-SO 2-;
X is NH;
Y is C 1-C 6alkyl, (C 1-C 6alkyl)-(C 6-C 10aryl)-(C 1-C 6alkyl) or C 3-C 6cycloalkyl.
More preferably, 5,8-described in general formula I bis-replaces-1,6-naphthyridine-7-amidocarbonylation compound, particularly, is following compound:
L is-CH 2-, R 6for Br, R 7for
L is-SO 2-, R 6for Br, R 7for
L is-CH 2-, R 6for-CN, R 7for
L is-CH 2-, R 6for-COOCH 3, R 7for
L is-CH 2-, R 6for
L is-CH 2-, R 6for r 7for
Be compound listed in Table:
More preferably, 5,8-bis-described in general formula I I replaces-1,6-naphthyridine-7-amidocarbonylation dimer compound, particularly, is following compound:
Y is r 6for Br, R 8for
Y is r 6for Br, R 8for
Y is r 6for r 8for
Be compound listed in Table:
More preferably, 5,8-described in general formula III bis-replaces-1,6-naphthyridine-7-amidocarbonylation dimer compound, particularly, is following compound:
R 6for Br, -X-Y-X-be
Be compound listed in Table:
The compound that general structure I, II or III of the present invention represent is by method preparation below:
Wherein, R 6, X with Y definition identical with general formula I, II, III, and be preferably table shown in group.R 7for wherein, A, R 1, R 2, R 3and R 4definition identical with general formula I, II, III.
Reaction reagent and condition: (a) Virahol, backflow, 68%; (b) thionyl chloride, backflow; (c) sodium borohydride, tetrahydrofuran (THF), 0 DEG C, two step productive rates 38%; (d) TsNHCH 2cOOCH 3, DEAD (diethyl azodiformate), triphenylphosphine, tetrahydrofuran (THF), 0 DEG C; (e) sodium methylate, methyl alcohol, 0 DEG C ~ room temperature, two step productive rates 65%; (f) NBS (N-bromo-succinimide), methylene dichloride, room temperature, productive rate 85%; (g) amine, toluene, refluxes 24 hours, productive rate 88%; (h) TsCl, triethylamine, methylene dichloride, productive rate 90%; (i) Isosorbide-5-Nitrae-trans cvclohexvl diamines, tetrahydrofuran (THF), backflow, productive rate 75%-85%; (j) LiOH solution/methyl alcohol, or NaOH solution/THF, backflow, productive rate 90%-100%; (k) EDCI, DMAP, methylene dichloride, sulphonamide, productive rate 60%-85%; (l) trifluoracetic acid/methylene dichloride; (m) CuI, Pd (PPh 3) Cl 2, K 2cO 3, Methyl propiolate, tetrahydrofuran (THF), backflow, productive rate 70%-85%; (n) EDCI, HOAt, DIPEA, amine, methylene dichloride, productive rate 70%-90%.
(1) synthetic method of compound S 1-S21 and S43, S44 is as follows: compound 1 pyridine 2,3-dicarboxylic anhydride selective esterification is obtained compound 2, productive rate 68%.Compound 2 chloro obtains compound 3; Compound 3 obtains compound 4 with the reduction of acyl chlorides formal character, and productive rate is 38%.Compound 4 is obtained by reacting compound 5 by Mitsunobo.Compound 5 obtains 1,6-naphthyridine carbonyl acid methyl esters 6, two step productive rate 65% at sodium methylate ShiShimonoseki ring.Compound 6 with containing R 6compound (as N-N-iodosuccinimide or N-bromo-succinimide) be obtained by reacting 5-R 6-1,6-naphthyridine carbonyl acid methyl esters 7, productive rate 85%.Compound 7 with containing R 7amine amide obtain 1,6-naphthyridine carbonyl amide compound 8, productive rate 88%.8 hydroxyl Ts protections of compound 8 obtain compound 9 with 90% productive rate.The synthetic route of compound 9 sees reference document WO2002030426 and WO2002030930.There is aryl nucleophilic substitution reaction and obtain a series of 5,8-bis-and replace-1,6-naphthyridine-7-amidocarbonylation compound S1-S21 and S43, S44, productive rate 75%-85% in compound 9 and Isosorbide-5-Nitrae-trans cvclohexvl two.
(2) synthetic method of compound S 22-S30 is as follows: compound 7 refluxes with TsCl and triethylamine and obtains compound 10 in 5 hours in methylene dichloride, and trans Isosorbide-5-Nitrae-cyclohexanediamine that compound 10 and single Boc protect is at K 2cO 3within 8 hours, obtain compound 11 with reflux in tetrahydrofuran (THF), compound 11 60 degree of lower 10h in 1NNaOH solution/THF generate compound 12.Compound 12, in EDCI, DMAP and methylene dichloride, obtains compound 13 with corresponding sulfuryl amine reaction 12h under normal temperature.Compound 13 removes Boc generation 5,8-bis-and replaces-1,6-naphthyridine-7-amidocarbonylation compound S22-S30 in the trifluoracetic acid/methylene dichloride of 20%.
(3) synthetic method of compound S 33-S42 is as follows: compound 9 and trans 1,4-cyclohexanediamine reflux in triethylamine, tetrahydrofuran (THF) obtains compound 14 in 8 hours, compound 14 refluxes in Palladous chloride, triphenylphosphine, cuprous iodide, salt of wormwood and THF and Methyl propiolate is obtained by reacting compound 15, compound 15 is sloughed Boc and is obtained 5 in 20% trifluoracetic acid/methylene dichloride, 8-bis-replaces-1,6-naphthyridine-7-amidocarbonylation compound S33-S42.
(4) synthetic method of compound S 46-S51 is as follows: compound 12, in EDCI, HOAt, DIPEA and methylene dichloride, reacts 12h with corresponding amine under normal temperature and obtains compound 16.Compound 16 removes Boc generation 5,8-bis-and replaces-1,6-naphthyridine-7-amidocarbonylation dimer compound S46-S51 in the trifluoracetic acid/methylene dichloride of 20%.
By screening various tumor cell strains, applicant finds: the compound that said structure general formula I, II or III represent has efficient inhibit activities to following cell in 10 μMs: MDA-MB-435, SkBr-3, A375, A431, HT29, A-549, BEL-7402, BXPC3, HL-60, PC-3.
Therefore, the compound that general structure I, II or III represents effectively can treat the disease that MDA-MB-435, SkBr-3, A375, A431, HT29, A-549, BEL-7402, BXPC3, HL-60, PC-3 tumour cell malignant proliferation causes.
The pharmaceutical composition containing the compound that general structure I, II or III represent that technology of pharmaceutics allows can play the disease of effectively treating MDA-MB-435, SkBr-3, A375, A431, HT29, A-549, BEL-7402, BXPC3, HL-60, PC-3 tumour cell malignant proliferation and causing equally.
Compound of the present invention, on the basis of CN2008102000645.4, adds substituent R in general formula I 6, L and R 7structure type, too increase dimeric structure type, these compounds further enhancing the inhibit activities to Tyrosylprotein kinases such as c-Src, KDR, EGFR, ErbB2, Flt-1, and can effectively suppress wider panel of tumor cell lines as the Growth of Cells of MDA-MB-435, SK-BR-3, A375, A431, HT-29, A-549, BEL-7402, BXPC3, HL-60, PC-3.
Embodiment
Preparation embodiment:
Below in conjunction with preparation embodiment, the invention will be further described, but do not limit the present invention.
Compound 1h-NMR spectroscopic data is measured and is used VarianMercury-300MHz or VarianMercury-400MHz nucleus magnetic resonance, and ultimate analysis uses VarioEL determinator, and fusing point Buchi-510 capillary tube technique measures, and temperature is not calibrated.Infrared spectra is by Bio-RadFTS-185 determination of infrared spectroscopy; Mass spectrum EI-MS FinniganMAT95 mass spectrograph, ESI-MS uses FinniganLCQDeca mass spectrograph to measure.Specific rotation is measured by P-1030 (A012360639) automatic polarimeter.Rapid column chromatography carries out on silica gel H (10-40 μM).Reagent purification is with reference to PurificationoflaboratoryChemicals; D.D.Perrin; W.L.F.ArmaregoandD.R.PerrinEds., PergamonPress:Oxiford, 1980.
Pyridine-2,3-dioctyl phthalate-2-isopropyl ester (2)
Compound 1 pyridine 2,3-dicarboxylic anhydride (48.1g, 0.32mol) to be dissolved in the 2-Virahol of 100mL reflux 16 hours, to be then cooled to by solution-20 DEG C to obtain compound as white solid 2 (44.4g, 68%).Fusing point: 140-141 DEG C; 1hNMR (CDCl 3, 300MHz): δ 8.87 (d, J=4.2Hz, 1H), 8.35 (d, J=7.8Hz, 1H), 7.55 (dd, J=5.1,8.1Hz, 1H), 5.36 (septet (septet), J=6.3Hz, 1H), 1.41 (d, J=6.3Hz, 6H).
3-hydroxymethyl-pyridine-2-isopropyl formate (4)
Compound 2 (52.7g, 0.25mol) is dissolved in reflux in the thionyl chloride of 400mL and becomes homogeneous phase to solution, be then spin-dried for solvent.Add the anhydrous THF of 2 × 50mL and revolve steaming, remove residual thionyl chloride.Obtained red liquid is dissolved in the anhydrous THF of 400mL and is cooled to 0 DEG C, add sodium borohydride (28.6g, 0.76mol) in batches, stir 4 hours at 0 DEG C, pour in frozen water by careful for reaction soln, 3 × 200mL dichloromethane extraction, adds anhydrous Na 2sO 4dry.Column chromatography (sherwood oil: ethyl acetate=3: 2) obtain yellow solid compound 4 (18.8g, 38%). 1HNMR(CDCl 3，300MHz)：δ8.69(dd，J＝1.5，4.7Hz，1H)，7.88(dd，J＝1.5，7.7Hz，1H)，7.46(dd，J＝4.7，7.8Hz，1H)，5.35(septet，J＝6.4Hz，1H)，4.81(m，2H)，1.45(d，J＝6.3Hz，6H).EI-MSm/z：195(M) +。
3-{ [methoxycarbonyl-methyl-(toluene-4-alkylsulfonyl)-amino]-methyl }-pyridine-2-carboxylic acids isopropyl ester (5)
By compound 4 (1.734g, 8.89mmol), 2-para toluene sulfonamide acetic acid methyl ester (TsNHCH 2cOOCH 3) (2.163g, 8.89mmol), and triphenylphosphine (3.499g, 13.338mmol) is dissolved in the anhydrous THF of 100mL, is cooled to 0 DEG C, inflated with nitrogen is protected.DEAD (2.165mL, 13.338mmol) is dissolved in the anhydrous THF of 10mL, dropwise adds DEAD.Remove ice bath, stir to be spin-dried for after two hours and obtain red oil compound 5 and be directly used in the next step.
8-hydroxyl-1,6-naphthyridine-7-carboxylate methyl ester (6)
The compound 5 (8.89mmol) upper step be obtained by reacting is dissolved in 50mL anhydrous methanol, is cooled to 0 DEG C.Slowly add sodium methylate (1.681g, 31.123mmol).Remove ice bath, stir 3 hours.Spin off solvent, add 20mL water, 20mL ethyl acetate, organic phase saturated sodium carbonate back extraction.Merge aqueous phase, adjust pH to 7, maintain aqueous phase pH to 7, with dichloromethane extraction 5 times.Organic phase anhydrous sodium sulfate drying, column chromatography (sherwood oil: ethyl acetate=2: 1) obtain pale solid compound 6 (0.62g, two step productive rates 65%).Fusing point: 179-180 DEG C; 1hNMR (CDCl 3, 300MHz): δ 11.79 (s, 1H), 9.20 (s, 1H), 8.85 (s, 1H), 8.32 (d, J=8.2Hz, 1H), 7.71 (dd, J=4.1,8.2Hz, 1H), 4.12 (s, 3H).
5-bromo-8-hydroxyl-1,6-naphthyridine-7-carboxylate methyl ester (7-1)
Under normal temperature, NBS (30mg, 0.167mmol) is joined the 1mLCH of compound 6 (34mg, 0.167mmol) 2cl 2in solution, stir 1 hour.Filter, drying obtains compound as white solid 7-1 (30mg, productive rate 85%); 1hNMR (d 6-DMSO, 300MHz): δ 9.26 (dd, J=1.5,4.2Hz, 1H), 8.59 (dd, J=1.6,8.4Hz, 1H), 8.00 (dd, J=4.2,8.4Hz, 1H), 3.94 (s, 3H).
N-(the chloro-benzyl of 2-)-5-bromo-8-hydroxyl-1,6-naphthyridine-7-amine carboxylic acid (8-1)
By compound 7-1 and 2-chlorobenzylamine reflux 20 hours under nitrogen protection in toluene, be cooled to room temperature.Filter, solids with methanol is washed, and obtains yellow solid compound 8-1, productive rate: 75-85%; 1hNMR (300MHz, CDCl 3): δ 9.21 (d, J=4.2Hz, 1H), 8.54 (d, J=8.4Hz, 1H), 8.28 (m, 1H), 7.74 (dd, J=4.2,8.4Hz, 1H), 7.46 (m, 2H), 7.19 (m, 1H), 4.80 (d, J=6Hz, 2H).
The bromo-7-of toluene-4-sulfonic acid 5-(the chloro-benzylcarbamyl of 2-)-1,6-naphthyridine-8-carboxylicesters (9-1)
The 50 DEG C of stirrings in chloroform of Tosyl chloride, compound 8-1, triethylamine are used saturated ammonium chloride after 5 hours successively, and saturated common salt is washed, dry.Column chromatography obtains compound as white solid 9-1, productive rate: 85-95%; 1hNMR (CDCl 3): δ 9.04 (d, 1H, J=4.2Hz), 8.57 (d, 1H, J=8.7Hz), 8.08 (m, 1H), 7.91 (d, 2H, J=8.1Hz), 7.68 (dd, 1H, J=4.2,8.4Hz), 7.47 (m, 1H), 7.39 (m, 1H), 7.33 (d, 2H, J=8.4Hz), 7.27 (m, 1H), 7.24 (m, 1H), 4.61 (d, J=6.0Hz, 2H), 2.46 (s, 3H).
8-((1r, 4r)-4-aminocyclohexyl is amino) bromo-1, the 6-naphthyridine-7-amine carboxylic acid (S1) of-N-(the chloro-benzyl of 2-)-5-
By compound 9-1, triethylamine and Isosorbide-5-Nitrae-trans cvclohexvl diamines reflux 8 hours in tetrahydrofuran (THF), is spin-dried for THF, adds methylene dichloride, use saturated Na successively 2cO 3the aqueous solution, saturated aqueous ammonium chloride, saturated common salt are washed, anhydrous Na 2sO 4dry.Column chromatography obtains yellow solid compound S1, productive rate: 75-85%. 1HNMR(CDCl 3，300MHz)：δ9.59(d，1H，J＝7.8Hz)，8.94(d，1H，J＝4.2Hz)，8.40(m，2H)，7.59(dd，1H，J＝4.2，7.8Hz)，7.45-7.38(m，2H)，7.25-7.22(m，2H)，4.82(m，1H)，4.73(d，2H，J＝6.6Hz)，2.71(m，1H)，2.17(m，2H)，1.90(m，2H)，1.43-1.25(m，4H)；EI-MSm/z：487(M) +，489(M+2) +。
N-(the chloro-benzyl of 3-)-5-bromo-8-hydroxyl-1,6-naphthyridine-7-amine carboxylic acid (S2-1)
The preparation method of compound S 2-1 and the preparation method of compound 8-1 similar, except replacing 2-chlorobenzylamine with to 3-chlorobenzylamine.Yellow solid, productive rate: 75-85%. 1HNMR(300MHz，CDCl 3)：δ9.20(d，J＝4.2Hz，1H)，8.55(d，J＝8.4Hz，1H)，8.20(m，1H)，7.73(dd，J＝4.2，8.4Hz，1H)，7.38(s，1H)，7.30(m，1H)，7.22(m，3H)，4.68(d，J＝6.3Hz，2H)。
The bromo-7-of toluene-4-sulfonic acid 5-(the chloro-benzylcarbamyl of 3-)-1,6-naphthyridine-8-carboxylicesters (S2-2)
The preparation method of compound S 2-2 and the preparation method of compound 9-1 similar, except replacing compound 8-1 with compound S 2-1.White solid, productive rate: 85-95%. 1HNMR(CDCl 3)：δ9.04(d，1H，J＝4.2Hz)，8.57(d，1H，J＝8.4Hz)，8.01(m，1H)，7.92(d，2H，J＝8.4Hz)，7.69(dd，1H，J＝4.2，8.4Hz)，7.36-7.28(m，6H)，4.61(d，2H，J＝6.6Hz)，2.46(s，3H)。
8-((1r, 4r)-4-aminocyclohexyl is amino) bromo-1, the 6-naphthyridine-7-amine carboxylic acid (S2) of-N-(the chloro-benzyl of 3-)-5-
The preparation method of compound S 2 and the preparation method of compound S 1 similar, except replacing compound 9-1 with compound S 2-2.Greenish yellow solid, productive rate: 75-85%. 1HNMR(300MHz，CDCl 3)：δ9.59(d，1H，J＝8.1Hz)，8.93(d，1H，J＝3.9Hz)，8.43-8.33(m，2H)，7.58(dd，1H，J＝3.9，8.1Hz)，7.35(s，1H)，7.25-7.21(m，3Hz)，4.96(m，1H)，4.60(d，2H，J＝6.3Hz)，2.75(m，1H)，2.17(m，2H)，1.90(m，2H)，1.47-1.24(m，4H)；EI-MSm/z：487(M) +，489(M+2) +。
N-(4-(2-(4-methylpiperazine-1-yl)) ethoxy-benzyl)-5-bromo-8-hydroxyl-1,6-naphthyridine-7-amine carboxylic acid (S3-1)
The preparation method of compound S 3-1 and the preparation method of compound 8-1 similar, except replacing 2-chlorobenzylamine with to 4-(2-(4-methylpiperazine-1-yl)) oxyethyl group benzylamine.Yellow solid, productive rate: 75-85%. 1HNMR(300MHz，CDCl 3)：9.17(d，J＝8.7Hz，1H)，8.51(d，J＝10.2Hz，1H)，8.13(t，J＝6Hz，1H)，7.71(dd，J＝8.7，10.2Hz，1H)，7.3(d，J＝8.4Hz，2H)，6.87(d，J＝8.4Hz，2H)，4.61(d，J＝6Hz，2H)，4.09(t，J＝5.1Hz，2H)，2.99(m，10H)，2.56(s，3H)。
The bromo-7-of toluene-4-sulfonic acid 5-(4-(2-(4-methylpiperazine-1-yl)) ethoxy-benzylcarbamyl)-1,6-naphthyridine-8-carboxylicesters (S3-2)
The preparation method of compound S 3-2 and the preparation method of compound 9-1 similar, except replacing compound 8-1 with compound S 3-1.White solid, productive rate: 85-95%. 1HNMR(300MHz，CDCl 3)：8.97(d，J＝4.2Hz，1H)，8.53(d，J＝10.2Hz，1H)，7.9(d，J＝8.1Hz，2H)，7.66(dd，J＝4.2，10.2Hz，1H)，7.3(m，4H)，6.86(d，J＝9.7Hz，2H)，4.54(d，J＝6Hz，2H)，4.1(t，J＝5.1Hz，2H)，2.95(m，8H)，2.89(t，J＝5.1Hz，2H)，2.64(s，3H)，2.46(s，3H)；MS-ESIm/z：656(M+H) +。
8-((1r, 4r)-4-aminocyclohexyl is amino)-N-(4-(2-(4-methylpiperazine-1-yl)) ethoxy-benzyl) bromo-1, the 6-naphthyridine-7-amine carboxylic acid (S3) of-5-
The preparation method of compound S 3 and the preparation method of compound S 1 similar, except replacing compound 9-1 with compound S 3-2.Greenish yellow solid, productive rate: 75-85%. 1HNMR(300MHz，CDCl 3)：δ9.65(d，J＝8.1Hz，1H)，8.94(d，J＝2.4Hz，1H)，8.4(d，J＝8.4Hz，1H)，8.25(t，1H)，7.58(dd，J＝2.4，8.4Hz，1H)，7.29(d，J＝8.7Hz2H)，6.89(d，J＝9Hz，2H)，4.96(m，1H)，4.56(d，J＝9Hz，2H)，4.10(t，J＝6.3Hz，2H)，2.79(m，3H)，2.62(brs，4H)，2.48(brs，4H)，2.29(s，3H)，2.17(d，J＝12.6Hz，2H)，1.92(d，J＝12.6Hz，2H)，1.29-1.44(m，4H)；MS-EIm/z：595(M) +，597(M+2) +。
N-(4-(5-morpholine) penta oxygen-benzyl)-5-bromo-8-hydroxyl-1,6-naphthyridine-7-amine carboxylic acid (S4-1)
The preparation method of compound S 4-1 and the preparation method of compound 8-1 similar, except replacing 2-chlorobenzylamine with to 4-(5-morpholine) pentyloxy benzylamine.Yellow solid, productive rate: 75-85%. 1HNMR(300MHz，CDCl 3)：9.19(d，J＝2.7Hz，1H)，8.53(d，J＝8.4Hz，1H)，8.11(t，J＝6Hz，1H)，7.72(dd，J＝2.7，8.4Hz，1H)，731(d，J＝8.7Hz，2H)，6.89(d，J＝9Hz，2H)，4.62(d，J＝6Hz，2H)，3.96(t，J＝6.3Hz，2H)，3.72(t，J＝6.3Hz，4H)，2.45(t，J＝6.6Hz，4H)，2.37(t，J＝6.6Hz，2H)，1.80(m，2H)，1.51-1.62(m，4H)。
The bromo-7-of toluene-4-sulfonic acid 5-(4-(5-morpholine) penta oxygen-benzylcarbamyl)-1,6-naphthyridine-8-carboxylicesters (S4-2)
The preparation method of compound S 4-2 and the preparation method of compound 9-1 similar, except replacing compound 8-1 with compound S 4-1.White solid, productive rate: 81.5%. 1HNMR(300MHz，CDCl 3)：9.01(d，J＝2.7Hz，1H)，8.55(d，J＝6.9Hz，1H)，7.92(d，J＝8.7Hz，2H)，7.85(t，J＝6Hz，1H)，7.66(dd，J＝2.7，6.9Hz，1H)，7.27-7.34(m，4H)，6.87(d，J＝8.7Hz，2H)，4.54(d，J＝6Hz，2H)，3.95(t，J＝6.6Hz，2H)，3.77(t，J＝4.8Hz，4H)，2.53(m，4H)，2.41-2.47(m，5H)，1.76-1.85(m，2H)，1.53-1.65(m，4H)。
8-((1r, 4r)-4-aminocyclohexyl is amino) bromo-1, the 6-naphthyridine-7-amine carboxylic acid (S4) of-N-(4-(5-morpholine) penta oxygen-benzyl)-5-
The preparation method of compound S 4 and the preparation method of compound S 1 similar, except replacing compound 9-1 with compound S 4-2.Greenish yellow solid, productive rate: 75-85%. 1hNMR (300MHz, CDCl 3): δ 9.67 (d, J=8.4Hz, 1H), 8.94 (d, J=5.4Hz, 1H), 8.41 (d, J=8.4Hz, 1H), 8.25 (t, J=6Hz, 1H), 7.58 (dd, J=5.4, 8.4Hz, 1H), 7.29 (d, J=8.4Hz, 2H), 6.87 (d, J=8.7Hz, 2H), 4.99 (m, 1H), 4.56 (d, J=6Hz, 2H), 3.96 (t, J=6.3Hz, 2H), 3.72 (t, J=4.5Hz, 4H), 2.91 (m, 1H), 2.44 (m, 4H), 2.36 (t, 2H), 2.22 (m, 2H), 2.02 (m, 2H), 1.76-1.85 (m, 2H), 1.41-1.59 (m, 4H), MS-EIm/z:624 (M) +, 626 (M+2) +, 13cNMR (100MHz, CDCl 3): δ 167.6158.4150.6144.9144.7136.3130.4128.9126.5124.3123.91 14.667.866.958.953.753.450.142.533.733.029.126.223.9, HR-EIMS calculated value: C 32h 41brN 6o 3(M) +: 624.2424, measured value: 624.2428.
The preparation method of following compound S 5-1 ~ S21-1 and the preparation method of compound 8-1 similar, crude product directly throws the next step.
The bromo-7-of toluene-4-sulfonic acid 5-(4-(thiophene-2-base) benzylcarbamyl)-1,6-naphthyridine-8-carboxylicesters (S5-2)
The preparation method of compound S 5-2 and the preparation method of compound 9-1 similar, except replacing compound 8-1 with compound S 5-1.White solid, productive rate: 85-95%. 1HNMR(300MHz，CDCl 3)：9.04(d，J＝3.9Hz，1H)，8.57(d，J＝8.4Hz，1H)，7.92-8(m，2H)，7.68(dd，J＝3.9，8.4Hz，1H)，7.61(d，J＝8.4Hz，2H)，7.4(d，J＝8.4Hz，2H)，7.26-7.34(m，4H)，7.08(m，1H)，4.64(d，J＝6.3Hz，2H)，2.46(s，3H)。
8-((1r, 4r)-4-aminocyclohexyl is amino) bromo-1, the 6-naphthyridine-7-amine carboxylic acid (S5) of-N-(4-(thiophene-2-base) benzyl)-5-
The preparation method of compound S 5 and the preparation method of compound S 1 similar, except replacing compound 9-1 with compound S 5-2.Greenish yellow solid, productive rate: 75-85%. 1hNMR (300MHz, CDCl 3): δ 9.65 (d, J=8.4Hz, 1H), 8.95 (d, J=3.9Hz, 1H), 8.42 (d, J=8.1Hz, 1H), 8.34 (t, J=6.3Hz, 1H), 7.61 (m, 3H), 7.4 (d, J=7.8Hz, 2H), 7.26-7.31 (m, 2H), 7.08 (m, 1H), 4.99 (m, 1H), 4.65 (d, J=6.3Hz, 2H), 2.76 (m, 1H), 2.19 (d, J=12.3Hz, 2H), 1.91 (d, J=11.7Hz, 2H), 1.26-1.45 (m, 4H); MS-EIm/z:535 (M) +, 537 (M+2) +; Anal. calculated value: C 26h 26brN 5o scH 3cOOH:C56.38, H5.07, N11.74, measured value: C56.67, H5.00, N11.70.
The bromo-7-of toluene-4-sulfonic acid 5-((pyridine-2-base) methylcarbamoyl)-1,6-naphthyridine-8-carboxylicesters (S6-2)
The preparation method of compound s 6-2 and the preparation method of compound 9-1 similar, except replacing compound 8-1 with compound s 6-1.White solid, productive rate: 85-95%. 1HNMR(300MHz，CDCl 3)：9.05(d，J＝4.2Hz，1H)，8.57-8.60(m，2H)，8.51(t，J＝5.7Hz，1H)，7.9(d，J＝8.1Hz，2H)，7.68(dd，1H)，7.36(d，1H)，7.29(m，2H)，7.21(m，1H)，4.69(d，J＝5.7Hz，2H)，2.43(s，3H)。
8-((1r, 4r)-4-aminocyclohexyl is amino) bromo-1, the 6-naphthyridine-7-amine carboxylic acid (S6) of-N-((pyridine-2-base) methyl)-5-
The preparation method of compound s 6 and the preparation method of compound S 1 similar, except replacing compound 9-1 with compound s 6-2.Greenish yellow solid, productive rate: 75-85%. 1hNMR (300MHz, CDCl 3): δ 9.6 (d, J=8.4Hz, 1H), 8.94 (d, J=3.9Hz, 1H), 8.73 (m, 1H), 8.61 (d, J=4.8Hz, 1H), 8.43 (d, J=10.2Hz, 1H), 7.68 (t, 1H), 7.58 (dd, J=3.9, 10.2Hz, 1H), 7.36 (d, J=7.8Hz, 1H), 7.2 (t, 2H), 4.95 (m, 1H), 4.77 (d, J=6Hz, 2H), 2.74 (m, 1H), 2.16 (d, J=13.5Hz, 2H), 1.9 (d, J=12.6Hz, 2H), 1.23-1.43 (m, 4H), MS-EIm/z:454 (M) +, 456 (M+2) +, Anal. calculated value: C 21h 23brN 6o1/2CF 3cOOHCH 3oH:C50.74, H5.09, N15.44, measured value: C50.81, H4.95, N15.29.
The bromo-7-of toluene-4-sulfonic acid 5-(the chloro-benzylcarbamyl of 3-trifluoromethyl-4-)-1,6-naphthyridine-8-carboxylicesters (S7-2)
The preparation method of compound S 7-2 and the preparation method of compound 9-1 similar, except replacing compound 8-1 with compound S 7-1.White solid, productive rate: 85-95%. 1HNMR(300MHz，CDCl 3)：9.01(d，J＝4.2Hz，1H)，8.57(d，J＝8.1Hz，1H)，8.09(t，J＝6.3Hz，1H)，7.91(d，J＝8.4Hz，2H)，7.67-7.7(m，2H)，7.47-7.56(m，2H)，7.31(d，2H)，4.68(d，J＝6.3Hz，2H)，2.46(s，3H)。
8-((1r, 4r)-4-aminocyclohexyl is amino) bromo-1, the 6-naphthyridine-7-amine carboxylic acid (S7) of-N-(the chloro-benzyl of 3-trifluoromethyl-4-)-5-
The preparation method of compound S 7 and the preparation method of compound S 1 similar, except replacing compound 9-1 with compound S 7-2.Greenish yellow solid, productive rate: 75-85%. 1hNMR (300MHz, CDCl 3): δ 9.54 (d, J=8.1Hz, 1H), 8.95 (d, J=3.9Hz, 1H), 8.41 (m, 2H), 7.68 (s, 1H), 7.6 (dd, J=8.1,3.9Hz, 1H), 7.48 (m, 2H), 4.97 (m, 1H), 4.64 (d, J=6.9Hz, 2H), 2.74 (m, 1H), 2.17 (d, J=14.4Hz, 2H), 1.9 (d, J=12Hz, 2H), 1.26-1.43 (m, 4H); MS-EIm/z:555 (M) +, 557 (M+2) +; Anal. calculated value: C 23h 22brClF 3n 5o1/4CH 3oH:C49.44, H4.10, N12.40, measured value: C49.74, H4.32, N12.06.
The bromo-7-of toluene-4-sulfonic acid 5-(2-chloro-5-trifluoromethyl-benzylamino formyl)-1,6-naphthyridine-8-carboxylicesters (S8-2)
The preparation method of compound S 8-2 and the preparation method of compound 9-1 similar, except replacing compound 8-1 with compound S 8-1.White solid, productive rate: 85-95%. 1HNMR(300MHz，CDCl 3)：9.02(d，J＝4.2Hz，1H)，8.56(d，J＝8.4Hz，1H)，8.15(t，J＝6.3Hz，1H)，7.9(d，J＝8.4Hz，2H)，7.75(s，1H)，7.67(dd，J＝8.4，8.4Hz，1H)，7.5(t，2H)，7.31(d，J＝8.1Hz，2H)，4.75(d，J＝6.3Hz，2H)，2.45(s，3H)。
8-((1r, 4r)-4-aminocyclohexyl is amino) bromo-1, the 6-naphthyridine-7-amine carboxylic acid (S8) of-N-(2-chloro-5-romethyl-benzy)-5-
The preparation method of compound S 8 and the preparation method of compound S 1 similar, except replacing compound 9-1 with compound S 8-2.Greenish yellow solid, productive rate: 75-85%. 1hNMR (300MHz, CDCl 3): δ 9.52 (d, J=8.4Hz, 1H), 8.96 (d, J=3.9Hz, 1H), 8.42-8.46 (m, 2H), 7.67 (s, 1H), 7.61 (dd, J=8.4,3.9Hz, 1H), 7.51 (m, 2H), 4.97 (m, 1H), 4.64 (d, J=6.3Hz, 2H), 2.76 (m, 1H), 2.18 (d, J=12.3Hz, 2H), 1.91 (d, J=10.5Hz, 2H), 1.26-1.46 (m, 4H); 13cNMR (100MHz, CDCl 3): δ 168.0150.7145.0144.9137.1136.4130.0129.5129.2126.8125.81 25.4125.0124.5124.4123.2122.377.377.277.076.753.850.040. 735.233.231.6; MS-EIm/z:555 (M) +, 557 (M+2) +; Anal. calculated value: C 23h 22brClF 3n 5o1/5CF 3cOOH3/5C 6h 14: C51.37, H4.89, N11.09, measured value: C51.30, H4.97, N11.07.
The bromo-7-of toluene-4-sulfonic acid 5-(3,4,5-trimethoxy-benzyl carbamyl)-1,6-naphthyridine-8-carboxylicesters (S9-2)
The preparation method of compound S 9-2 and the preparation method of compound 9-1 similar, except replacing compound 8-1 with compound S 9-1.White solid, productive rate: 85-95%. 1HNMR(300MHz，CDCl 3)：8.98(d，J＝4.5Hz，1H)，8.57(d，J＝8.4Hz，1H)，7.93(m，3H)，7.67(dd，J＝4.5，8.4Hz，1H)，7.32(d，J＝8.1Hz，2H)，6.66(s，2H)，4.62(d，J＝6Hz，2H)，3.87(s，6H)，3.84(s，3H)，2.47(s，3H)。
8-((1r, 4r)-4-aminocyclohexyl is amino) bromo-1, the 6-naphthyridine-7-amine carboxylic acid (S9) of-N-(3,4,5-trimethoxy-benzyl)-5-
The preparation method of compound S 9 and the preparation method of compound S 1 similar, except replacing compound 9-1 with compound S 9-2.Greenish yellow solid, productive rate: 75-85%. 1hNMR (300MHz, CDCl 3): 9.61 (d, J=7.8Hz, 1H), 8.95 (d, J=6Hz, 1H), 8.42 (d, J=8.7Hz, 1H), 8.30 (t, J=6.3Hz, 1H), 7.6 (dd, J=6,8.7Hz, 1H), 6.61 (s, 2H), 4.97 (m, 1H), 4.57 (d, J=6.3Hz, 2H), 3.87 (s, 6H), 3.84 (s, 3H), 2.77 (m, 1H), 2.18 (d, J=12.9Hz, 2H), 1.92 (d, J=12.9Hz, 2H), 1.25-1.48 (m, 4H); MS-EIm/z:543 (M) +, 545 (M+2) +; Anal. calculated value: C 25h 30brN 5o 41/4CF 3cOOH:C53.46, H5.32, N12.22, measured value: C53.52, H5.45, N11.93.
The bromo-7-of toluene-4-sulfonic acid 5-(3,4-difluoro-benzylamino formyl)-1,6-naphthyridine-8-carboxylicesters (S10-2)
The preparation method of compound S 10-2 and the preparation method of compound 9-1 similar, except replacing compound 8-1 with compound S 10-1.White solid, productive rate: 85-95%. 1HNMR(300MHz，CDCl 3)：9.02(d，J＝4.2Hz，1H)，8.57(d，J＝10.2Hz，1H)，8.02(t，J＝6.3Hz，1H)，7.92(d，J＝5.4Hz，2H)，7.69(dd，J＝4.2，10.2Hz，1H)，7.33(d，J＝7.8Hz，2H)，7.11-7.25(m，3H)，4.6(d，J＝6.3Hz，2H)，2.47(s，3H)。
8-((1r, 4r)-4-aminocyclohexyl is amino) bromo-1, the 6-naphthyridine-7-amine carboxylic acid (S10) of-N-(3,4-diiluoro-benzyl)-5-
The preparation method of compound S 10 and the preparation method of compound S 1 similar, except replacing compound 9-1 with compound S 10-2.Greenish yellow solid, productive rate: 75-85%. 1hNMR (300MHz, CDCl 3): δ 9.59 (d, J=8.7Hz, 1H), 8.95 (d, J=5.7Hz, 1H), 8.43 (d, J=6.6Hz, 2H), 8.36 (t, J=6Hz, 1H), 7.61 (dd, J=5.7,6.6Hz, 1H), 7.09-7.22 (m, 3H), 4.99 (m, 1H), 4.58 (d, J=6Hz, 2H), 2.86 (m, 1H), 2.19 (m, 2H), 1.98 (m, 2H), 1.40 (m, 4H); MS-EIm/z:489 (M) +, 491 (M+2) +; Anal. calculated value: C 22h 22brF 2n 5o:C53.89, H4.52, N14.28, measured value: C53.81, H4.61, N14.06.
The bromo-7-of toluene-4-sulfonic acid 5-(3,5-bis-trifluoromethyl-benzylamino formyl)-1,6-naphthyridine-8-carboxylicesters (S11-2)
The preparation method of compound S 11-2 and the preparation method of compound 9-1 similar, except replacing compound 8-1 with compound S 11-1.White solid, productive rate: 85-95%. 1HNMR(300MHz，CDCl 3)：9.02(d，J＝4.5Hz，1H)，8.58(d，J＝8.7Hz，1H)，8.19(t，J＝6.3Hz，1H)，7.91(d，J＝8.4Hz，2H)，7.87(s，2H)，7.81(s，1H)，7.69(dd，J＝4.5，8.7Hz，1H)，7.31(d，J＝7.8Hz，2H)，4.79(d，J＝6.3Hz，2H)，2.46(s，3H)。
8-((1r, 4r)-4-aminocyclohexyl is amino) bromo-1, the 6-naphthyridine-7-amine carboxylic acid (S11) of-N-(3,5-bis-romethyl-benzy)-5-
The preparation method of compound S 11 and the preparation method of compound S 1 similar, except replacing compound 9-1 with compound S 11-2.Greenish yellow solid, productive rate: 75-85%. 1hNMR (300MHz, CDCl 3): δ: 9.52 (d, J=8.4Hz, 1H), 8.96 (d, J=2.4Hz, 1H), 8.42-8.49 (m, 2H), 7.79-7.82 (m, 3H), 7.62 (dd, J=8.4,2.4Hz, 1H), 4.98 (m, 1H), 4.74 (d, J=6.3Hz, 2H), 2.78 (m, 1H), (2.19 d, J=13.2Hz, 2H), (1.92 d, J=11.4Hz, 2H), 1.25-1.43 (m, 4H); MS-EIm/z:589 (M) +, 591 (M+2) +; Anal. calculated value: C 24h 22brF 6n 5o1/6C 6h 14: C49.33, H3.94, N11.69, measured value: C49.33, H3.91, N11.71.
The bromo-7-of toluene-4-sulfonic acid 5-(4-(4-methyl benzenesulfonamide) Methyl-benzvl) carbamyl)-1,6-naphthyridine-8-carboxylicesters (S12-2)
The preparation method of compound S 12-2 and the preparation method of compound 9-1 similar, except replacing compound 8-1 with compound S 12-1.White solid, productive rate: 85-95%. 1HNMR(300MHz，CDCl 3)：9.00(d，J＝3.9Hz，1H)，8.56(d，J＝8.4Hz，1H)，7.91-7.93(m，3H)，7.76(d，J＝7.8Hz，2H)，7.68(dd，J＝3.9，8.4Hz，1H)，7.30-7.33(m，6H)，7.19(d，J＝7.8Hz，2H)，4.59-4.61(m，3H)，4.12(d，J＝6.3Hz，2H)，2.47(s，3H)，2.43(s，3H)。
8-((1r, 4r)-4-aminocyclohexyl is amino) bromo-1, the 6-naphthyridine-7-amine carboxylic acid (S12) of-N-(4-(4-methyl benzenesulfonamide) Methyl-benzvl)-5-
The preparation method of compound S 12 and the preparation method of compound S 1 similar, except replacing compound 9-1 with compound S 12-2.Greenish yellow solid, productive rate: 75-85%. 1hNMR (300MHz, CDCl 3): 9.51 (d, J=5.7Hz, 1H), 8.95 (d, J=4.2Hz, 1H), 8.41 (d, J=10.2Hz, 1H), 8.27 (t, J=6Hz, 1H), 7.76 (d, J=8.1Hz, 2H), 7.59 (dd, J=4.2, 10.2Hz, 1H), 7.29-7.33 (m, 4H), 7.18 (d, J=7.8Hz, 2H), 4.92 (m, 1H), 4.12 (d, J=6Hz, 2H), 3.52 (br, 1H), 2.74 (m, 1H), 2.43 (s, 3H), 2.16 (d, J=12.3Hz, 2H), 1.89 (d, J=12.3Hz, 2H), 1.25-1.41 (m, 4H), MS-EIm/z:636 (M) +, 638 (M+2) +, HR-EIMS calculated value: C 30h 33brN 6o 3s (M) +: 636.1518, measured value: 636.1526.
The bromo-7-of toluene-4-sulfonic acid 5-((thiophene-2-base) methylcarbamoyl)-1,6-naphthyridine-8-carboxylicesters (S13-2)
The preparation method of compound S 13-2 and the preparation method of compound 9-1 similar, except replacing compound 8-1 with compound S 13-1.White solid, productive rate: 85-95%. 1HNMR(300MHz，CDCl 3)：9.05(d，J＝2.4Hz，1H)，8.57(d，J＝8.7Hz，1H)，7.94(d，J＝8.1Hz，2H)，7.68(dd，J＝2.4，8.7Hz，1H)，7.34(d，J＝8.1Hz，2H)，7.25-7.27(m，1H)，7.07(m，1H)，6.99(m，1H)，4.77(d，J＝4.5Hz，2H)，2.48(s，3H)。
8-((1r, 4r)-4-aminocyclohexyl is amino) bromo-1, the 6-naphthyridine-7-amine carboxylic acid (S13) of-N-((thiophene-2-base) methyl)-5-
The preparation method of compound S 13 and the preparation method of compound S 1 similar, except replacing compound 9-1 with compound S 13-2.Greenish yellow solid, productive rate: 75-85%. 1hNMR (300MHz, CDCl 3): δ 9.6 (d, J=7.8Hz, 1H), 8.95 (d, J=4.5Hz, 1H), 8.42 (d, J=8.4Hz, 1H), 8.32 (t, J=6Hz, 1H), 7.59 (dd, J=4.5Hz, 8.4Hz, 1H), 7.23-7.25 (m, 1H), 7.07 (m, 1H), 6.98 (m, 1H), 4.98 (m, 1H), 4.80 (d, J=6Hz, 2H), 2.81 (m, 1H), 2.19 (d, J=11.4Hz, 2H), 1.94 (d, J=12.3Hz, 2H), 1.31-1.49 (m, 4H); MS-EIm/z:459 (M) +, 461 (M+2) +; Anal. calculated value: C 20h 22brN 5o1/2H 2o:C51.68, H5.08, N14.70, measured value: C51.71, H4.85, N14.46.
The bromo-7-of toluene-4-sulfonic acid 5-((indoles-5-base-1-H) methylcarbamoyl)-1,6-naphthyridine-8-carboxylicesters (S14-2)
The preparation method of compound S 14-2 and the preparation method of compound 9-1 similar, except replacing compound 8-1 with compound S 14-1.White solid, productive rate: 85-95%. 1HNMR(300MHz，CDCl 3)：9.05(d，J＝4.5Hz，1H)，8.55(d，J＝8.4Hz，1H)，8.21(m，1H)，7.95(d，J＝8.4Hz，2H)，7.87(t，J＝5.7Hz，1H)，7.65-7.69(m，2H)，7.21-7.42(m，4H)，6.56(m，1H)，4.68(d，J＝5.7Hz，2H)，2.46(s，3H)。
8-((1r, 4r)-4-aminocyclohexyl is amino)-N-((indoles-5-base-1-H) methyl) bromo-1, the 6-naphthyridine-7-amine carboxylic acid (S14) of-5-
The preparation method of compound S 14 and the preparation method of compound S 1 similar, except replacing compound 9-1 with compound S 14-2.Greenish yellow solid, productive rate: 75-85%. 1hNMR (300MHz, CDCl 3) δ 9.7 (d, J=9Hz, 1H), 8.94 (d, J=3.9Hz, 1H), 8.41 (d, J=7.8Hz, 1H), 8.29 (t, J=5.1Hz, 1H), 8.19 (m, 1H), 7.66 (s, 1H), 7.57 (dd, J=3.9, 7.8Hz, 1H), 7.4 (d, J=7.8Hz, 1H), 7.23-7.26 (m, 1H), 6.55 (m, 1H), 4.97 (m, 1H), 4.73 (d, J=5.1Hz, 2H), 2.8 (m, 1H), 2.2 (d, J=14.7Hz, 2H), 1.95 (d, J=12.9Hz, 2H), 1.36-1.46 (m, 4H), MS-EIm/z:492 (M) +, 494 (M+2) +, Anal. calculated value: C 21h 23brN 6o2/5CF 3cOOH3/4CH 3oH:C54.50, H5.08, N14.93, measured value: C54.56, H4.84, N14.66.
The bromo-7-of toluene-4-sulfonic acid 5-((naphthalene-1-base) methylcarbamoyl)-1,6-naphthyridine-8-carboxylicesters (S15-2)
The preparation method of compound S 15-2 and the preparation method of compound 9-1 similar, except replacing compound 8-1 with compound S 15-1.White solid, productive rate: 85-95%. 1HNMR(300MHz，CDCl 3)：9.01(d，J＝4.2Hz，1H)，8.53(d，J＝8.7Hz，1H)，8.13(d，J＝8.1Hz，1H)，7.96(d，J＝8.1Hz，2H)，7.84-7.93(m，1H)，7.66(dd，J＝4.2Hz，8.7Hz，2H)，7.45-7.6(m，4H)，7.33(d，J＝8.1Hz，2H)，5.09(d，J＝5.4Hz，2H)，2.45(s，3H)；MS-ESIm/z：562(M+H) +，564(M+2+H) +。
8-((1r, 4r)-4-aminocyclohexyl is amino) bromo-1, the 6-naphthyridine-7-amine carboxylic acid (S15) of-N-((naphthalene-1-base) methyl)-5-
The preparation method of compound S 15 and the preparation method of compound S 1 similar, except replacing compound 9-1 with compound S 15-2.Greenish yellow solid, productive rate: 75-85%. 1hNMR (300MHz, CDCl 3): δ 9.69 (d, J=8.1Hz, 1H), 8.95 (d, J=4.2Hz, 1H), 8.4 (d, J=8.7Hz, 1H), 8.29 (t, J=6Hz, 1H), 8.12 (d, J=7.5Hz, 1H), 7.82-7.91 (m, 2H), 7.44-7.6 (m, 5H), 5.10 (d, J=6Hz, 2H), 4.98 (m, 1H), 2.82 (m, 1H), 2.21 (d, J=12Hz, 2H), 1.96 (d, J=11.4Hz, 2H), 1.29-1.52 (m, 4H); MS-EIm/z:503 (M) +, 505 (M+2) +; Anal. calculated value: C 26h 26brN 5o1/5CF 3cOOH2/5C 6h 14: C61.58, H5.71, N12.47, measured value: C61.61, H5.62, N12.53.
The bromo-7-of toluene-4-sulfonic acid 5-(3-trifluoromethyl-4-Methoxy-benzylamino formyl)-1,6-naphthyridine-8-carboxylicesters (S16-2)
The preparation method of compound S 16-2 and the preparation method of compound 9-1 similar, except replacing compound 8-1 with compound S 16-1.White solid, productive rate: 85-95%. 1HNMR(300MHz，CDCl 3)：9.01(d，J＝5.7Hz，1H)，8.57(d，J＝6.9Hz，1H)，7.91-7.97(m，3H)，7.68(dd，J＝5.7，6.9Hz，1H)，7.57(m，2H)，7.33(d，J＝5.7Hz，2H)，7.00(d，J＝9.3Hz，1H)，4.6(d，J＝6Hz，2H)，3.9(s，3H)，2.47(s，3H)。
8-((1r, 4r)-4-aminocyclohexyl is amino) bromo-1, the 6-naphthyridine-7-amine carboxylic acid (S16) of-N-(3-trifluoromethyl-4-methyoxy-benzyl)-5-
The preparation method of compound S 16 and the preparation method of compound S 1 similar, except replacing compound 9-1 with compound S 16-2.Greenish yellow solid, productive rate: 75-85%. 1hNMR (300MHz, CDCl 3): δ 9.6 (d, J=8.4Hz, 1H), 8.95 (d, J=4.2Hz, 1H), 8.42 (d, J=8.4Hz, 1H), 8.31 (t, J=6.3Hz, 1H), 7.51-7.61 (m, 3H), 6.99 (d, J=8.7Hz, 1H), 4.97 (m, 1H), (4.59 d, J=6.3Hz, 2H), 3.9 (s, 3H), 2.78 (m, 1H), 2.18 (d, J=12.3Hz, 2H), 1.92 (d, J=13.2Hz, 2H), 1.25-1.48 (m, 4H); 13cNMR (100MHz, CDCl 3): δ 167.8156.7150.6145.0136.3132.6130.4126.6126.6126.5124.91 24.4124.3123.6122.2118.9118.6112.256.053.750.042.035.033 .2; MS-EIm/z:551 (M) +, 553 (M+2) +; Anal. calculated value: C 24h 25brF 3n 5o 21/5C 6h 14: C53.14, H4.92, N12.29, measured value: C53.04, H4.83, N12.31.
The bromo-7-of toluene-4-sulfonic acid 5-(the chloro-benzylcarbamyl of 2-methoxyl group-5-)-1,6-naphthyridine-8-carboxylicesters (S17-2)
The preparation method of compound S 17-2 and the preparation method of compound 9-1 similar, except replacing compound 8-1 with compound S 17-1.White solid, productive rate: 85-95%. 1HNMR(300MHz，CDCl 3)：9.07(d，J＝4.5Hz，1H)，8.56(d，J＝8.7Hz，1H)，8.1(t，J＝6.6Hz，1H)，7.90(d，J＝8.1Hz，2H)，7.68(dd，J＝4.5，8.7Hz，1H)，7.30-7.34(m，3H)，7.21-7.26(m，1H)，6.82(d，J＝9Hz，1H)，4.54(d，J＝6.6Hz，2H)，3.91(s，3H)，2.46(s，3H)。
8-((1r, 4r)-4-aminocyclohexyl is amino) bromo-1, the 6-naphthyridine-7-amine carboxylic acid (S17) of-N-(the chloro-benzyl of 2-methoxyl group-5-)-5-
The preparation method of compound S 17 and the preparation method of compound S 1 similar, except replacing compound 9-1 with compound S 17-2.Greenish yellow solid, productive rate: 75-85%. 1hNMR (300MHz, CDCl 3): δ 9.59 (d, J=8.1Hz, 1H), 8.94 (d, J=3Hz, 1H), 8.4-8.49 (m, 2H), 7.58 (dd, J=3Hz, 1H), 7.2-7.29 (m, 2H), 6.81 (d, J=8.7Hz, 1H), 4.95 (m, 1H), 4.59 (d, J=6.3Hz, 2H), 3.9 (s, 3H), 2.77 (m, 1H), 2.17 (d, J=11.7Hz, 2H), 1.91 (d, J=14.1Hz, 2H), 1.25-1.47 (m, 4H); MS-EIm/z:517 (M) +, 519 (M+2) +; Anal. calculated value: C 23h 25brClN 5o 23/20C 6h 14: C53.98, H5.14, N13.17, measured value: C53.87, H5.12, N12.97.
The bromo-7-of toluene-4-sulfonic acid 5-(4-phenoxy-benzyl carbamyl)-1,6-naphthyridine-8-carboxylicesters (S18-2)
The preparation method of compound S 18-2 and the preparation method of compound 9-1 similar, except replacing compound 8-1 with compound S 18-1.White solid, productive rate: 85-95%. 1HNMR(300MHz，CDCl 3)：δ9.03(d，J＝4.2Hz，1H)，8.65(d，J＝8.4Hz，1H)，7.93(m，3H)，7.68(dd，J＝4.2，8.4Hz，1H)，7.31-7.37(m，6H)，7.10(t，J＝6Hz，1H)，6.98-7.03(m，4H)，4.60(d，J＝6Hz，2H)，2.47(s，3H)。
8-((1r, 4r)-4-aminocyclohexyl is amino) bromo-1, the 6-naphthyridine-7-amine carboxylic acid (S18) of-N-(4-phenoxy-benzyl)-5-
The preparation method of compound S 18 and the preparation method of compound S 1 similar, except replacing compound 9-1 with compound S 18-2.Greenish yellow solid, productive rate: 75-85%. 1hNMR (300MHz, CDCl 3): δ 9.65 (d, J=7.8Hz, 1H), 8.94 (d, J=3.9Hz, 1H), 8.42 (d, J=8.7Hz, 1H), 8.31 (t, J=6Hz, 1H), 7.59 (dd, J=3.9, 8.7Hz, 1H), 7.26-7.36 (m, 5H), 7.10 (t, J=6.9Hz, 1H), 6.98-7.03 (m, 3H), 4.99 (m, 1H), 4.61 (d, J=6Hz, 2H), 2.77 (m, 1H), 2.18 (d, J=12.9Hz, 2H), 1.91 (d, J=12.3Hz, 2H), 1.25-1.49 (m, 4H), MS-EIm/z:545 (M) +, 547 (M+2) +, HR-EIMS calculated value: C 28h 28brN 5o 2(M) +: 545.1426, measured value: 545.1427, Anal. calculated value: C 28h 28brN 5o 2: C61.58, H5.13, N12.71, measured value: C61.54, H5.16, N12.82.
The bromo-7-of toluene-4-sulfonic acid 5-(the chloro-4-hexamethylene alkoxyl group-benzylcarbamyl of 3-)-1,6-naphthyridine-8-carboxylicesters (S19-2)
The preparation method of compound S 19-2 and the preparation method of compound 9-1 similar, except replacing compound 8-1 with compound S 19-1.White solid, productive rate: 85-95%. 1HNMR(300MHz，CDCl 3)：δ9.04(d，J＝4.2Hz，1H)，8.57(d，J＝8.7Hz，1H)，7.91-7.94(m，3H)，7.68(dd，J＝4.2，8.7Hz，1H)，7.37(s，1H)，7.33(d，J＝8.1Hz，2H)，7.19-7.22(m，1H)，6.93(d，1H)，4.52(d，J＝6Hz，2H)，4.29(m，1H)，2.47(s，3H)，1.92-1.96(m，2H)，1.79-1.83(m，2H)，1.62-1.65(m，2H)，1.34-1.39(m，4H)。
8-((1r, 4r)-4-aminocyclohexyl is amino) bromo-1, the 6-naphthyridine-7-amine carboxylic acid (S19) of-N-(3-chloro-4-hexamethylene alkoxyl group-benzyl)-5-
The preparation method of compound S 19 and the preparation method of compound S 1 similar, except replacing compound 9-1 with compound S 19-2.Greenish yellow solid, productive rate: 75-85%. 1hNMR (300MHz, CDCl 3): δ 9.63 (d, J=8.4Hz, 1H), 8.95 (d, J=2.7Hz, 1H), 8.42 (d, J=10.2Hz, 1H), 8.28 (t, J=7.8Hz, 1H), 7.59 (dd, J=2.7, 10.2Hz, 1H), 7.37 (s, 1H), 7.19 (d, J=8.1Hz, 2H), 6.93 (d, J=8.4Hz, 2H), 4.98 (m, 1H), 4.3 (d, J=7.8Hz, 2H), 4.26 (m, 1H), 2.87 (m, 1H), 2.19 (m, 2H), 1.5-1.69 (m, 6H), 1.25-1.41 (m, 10H), MS-ESIm/z:588 (M+H) +, 586 (M-2+H) +, HR-ESIMS calculated value: C 28h 33brClN 5o 2(M+Na) +: 608.1404, measured value: 608.1401, Anal. calculated value: C 28h 33brClN 5o 21/4C 6h 14: C58.23, H6.05, N11.51, measured value: C58.27, H6.33, N11.70.
The bromo-7-of toluene-4-sulfonic acid 5-(3-trifluoromethyl-4-hexamethylene alkoxyl group-benzylcarbamyl)-1,6-naphthyridine-8-carboxylicesters (S20-2)
The preparation method of compound S 20-2 and the preparation method of compound 9-1 similar, except replacing compound 8-1 with compound S 20-1.White solid, productive rate: 85-95%. 1HNMR(300MHz，CDCl 3)：δ9.02(d，J＝4.5Hz，1H)，8.57(d，J＝8.4Hz，1H)，7.93(m，3H)，7.68(dd，J＝4.5，8.4Hz，1H)，7.49-7.55(m，2H)，7.33(d，J＝8.4Hz，2H)，6.98(d，1H)，4.58(d，J＝6.3Hz，2H)，4.41(m，1H)，2.47(s，3H)，1.87-1.9(m，2H)，1.77-1.81(m，2H)，1.63-1.69(m，2H)，1.38-1.43(m，4H)。
8-((1r, 4r)-4-aminocyclohexyl is amino) bromo-1, the 6-naphthyridine-7-amine carboxylic acid (S20) of-N-(3-trifluoromethyl-4-hexamethylene alkoxyl group-benzyl)-5-
The preparation method of compound S 20 and the preparation method of compound S 1 similar, except replacing compound 9-1 with compound S 20-2.Greenish yellow solid, productive rate: 75-85%. 1hNMR (300MHz, CDCl 3): δ 9.61 (d, J=8.4Hz, 1H), 8.95 (d, J=2.7Hz, 1H), 8.42 (d, J=8.7Hz, 1H), 8.29 (t, J=6.3Hz, 1H), 7.59 (dd, J=2.7, 8.7Hz, 1H), 7.55 (s, 1H), 7.46 (d, J=6.3Hz, 1H), 6.97 (d, J=8.4Hz, 1H), 4.98 (m, 1H), 4.57 (d, J=6.3Hz, 2H), 4.39 (m, 1H), 2.83 (m, 1H), 2.19 (m, 2H), 1.86-1.97 (m, 5H), 1.51-1.54 (m, 3H), 1.25-1, 45 (m, 10H), 13cNMR (100MHz, CDCl 3) δ 167.7155.2150.6145.0144.9136.3132.3129.7126.7126.6124.41 24.3123.6114.375.753.750.042.134.833.231.225.523.0, MS-ESIm/z:620 (M+H) +, 622 (M+2+H) +, Anal. calculated value: C 29h 33brF 3n 5o 2: C56.13, H5.36, N11.29, measured value: C55.84, H5.37, N11.20.
The bromo-7-of toluene-4-sulfonic acid 5-(4-cyclopropane Methoxy-benzylamino formyl)-1,6-naphthyridine-8-carboxylicesters (S21-2)
The preparation method of compound S 21-2 and the preparation method of compound 9-1 similar, except replacing compound 8-1 with compound S 21-1.White solid, productive rate: 85-95%. 1HNMR(300MHz，CDCl 3)：δ9.03(d，J＝4.2Hz，1H)，8.56(d，J＝10.2Hz，1H)，7.93(d，J＝8.4Hz，2H)，7.85(t，J＝5.7Hz，1H)，7.67(dd，J＝4.2，10.2Hz，1H)，7.26-7.36(m，4H)，6.9(d，J＝8.4Hz，2H)，4.54(d，J＝5.7Hz，2H)，3.8(d，2H)，2.47(s，3H)，1.25(m，1H)，0.64(m，2H)，0.35(m，2H)。
8-((1r, 4r)-4-aminocyclohexyl is amino) bromo-1, the 6-naphthyridine-7-amine carboxylic acid (S21) of-N-(4-cyclopropane methyoxy-benzyl)-5-
The preparation method of compound S 21 and the preparation method of compound S 1 similar, except replacing compound 9-1 with compound S 21-2.Greenish yellow solid, productive rate: 75-85%. 1hNMR (300MHz, CDCl 3): δ 9.64 (d, J=8.1Hz, 1H), 8.94 (d, J=4.2Hz, 1H), 8.4 (d, J=8.4Hz, 1H), 8.24 (t, J=5.7Hz, 1H), 7.57 (dd, J=4.2, 8.4Hz, 1H), 7.29 (d, J=8.7Hz, 2H), 6.89 (d, J=8.4Hz, 2H), 4.96 (m, 1H), 4.56 (d, J=5.7Hz, 2H), 3.79 (d, 2H), 2.76 (m, 1H), 2.17 (d, J=11.7Hz, 2H), 1.91 (d, J=11.7Hz, 2H), 1.23-1.48 (m, 5H), 0.63 (m, 2H), 0.34 (m, 2H), 13cNMR (100MHz, CDCl 3) δ 167.6158.3150.5145.0144.9136.3130.5129.0126.5124.3124.21 23.9114.772.853.750.042.535.133.210.23.1, MS-ESIm/z:526 (M+H) +, 524 (M-2+H) +, Anal. calculated value: C 26h 30brN 5o 2: C59.54, H5.77, N13.35, measured value: C59.56, H5.85, N13.05.
Toluene-4-sulfonic acid 5-bromo-7-methoxycarbonyl-1,6-naphthyridine-8-carboxylicesters (10)
The preparation method of compound 10 and the preparation method of compound 9-1 similar, except replacing compound 8-1 with compound 7-1.White solid, productive rate: 85-95%. 1HNMR(300MHz，CDCl 3)：δ9.06(dd，1H，J＝1.5，4.2Hz)，8.60(dd，1H，J＝1.5，8.7Hz)，7.86(d，2H，J＝8.4Hz)，7.72(dd，1H，J＝4.2，8.4Hz)，7.34(d，2H，J＝8.4Hz)，3.83(s，3H)，2.47(s，3H)；EI-MSm/z：436(M) +。
The tertiary butyl (1r, 4r)-4-(bromo-1, the 6-naphthyridine-8-of 7-(methoxy carbonic acyl radical)-5-is amino) cyclohexyl carbamate (11)
The preparation method of compound 11 and the preparation method of compound S 1 similar, except replacing compound 9-1 with compound 10.Greenish yellow solid, productive rate: 75-85%. 1HNMR(300MHz，CDCl 3)：δ8.95(dd，1H，J＝1.5，4.2Hz)，8.88(d，1H，J＝7.5Hz)，8.47(dd，1H，J＝1.5，8.4Hz)，7.64(dd，1H，J＝4.2，8.4Hz)，4.92(m，1H)，4.42(m，1H)，3.97(s，3H)，3.47(m，1H)，2.20(m，2H)，2.05(m，2H)，1.44(s，9H)，1.43-1.23(m，4H)；EI-MSm/z：478(M) +，480(M+2) +。
The bromo-8-of 5-((1r, 4r)-4-t-butoxycarbonyl amino Cyclohexylamino)-1,6-naphthyridine-7-carboxylic acid (12)
Compound 12 is by compound 11 in 1NNaOH solution/THF, and under 60 degree, 10h hydrolysis is obtained.Greenish yellow solid, productive rate: 75-85%.Fusing point: 122-126 DEG C; 1hNMR (300MHz, CDCl 3): δ 8.96 (dd, 1H, J=1.5,4.2Hz), 8.88 (d, 1H, J=7.5Hz), 8.45 (dd, 1H, J=1.5,8.4Hz), 7.64 (dd, 1H, J=4.2,8.4Hz), 4.96 (m, 1H), 4.41 (m, 1H), 3.47 (m, 1H), 2.21 (m, 2H), 2.08 (m, 2H), 1.44 (s, 9H), 1.43-1.23 (m, 4H); EI-MSm/z:464 (M) +, 466 (M+2) +.
The tertiary butyl (1r, 4r)-4-(bromo-1, the 6-naphthyridine-8-of 7-(4-methoxybenzenesulphoismide base formyl)-5-is amino) cyclohexyl carbamate (S22-1)
Compound 12 in EDCI, DMAP and methylene dichloride, under normal temperature with 12h reacted to methoxybenzenesulphoismide obtain compound S 22-1.Greenish yellow solid, productive rate: 75-85%. 1HNMR(300MHz，CDCl 3)：δ10.27(s，1H)，9.22(m，1H)，8.93(d，J＝6Hz，1H)，8.44(d，J＝6.9Hz，1H)，8.12(d，J＝9Hz，2H)，7.64(dd，J＝6，6.9Hz，1H)，7.02(d，J＝9Hz，2H)，4.99(brs，1H)，4.39(brs，1H)，3.89(s，3H)，3.46(brs，1H)，2.14(d，J＝12.3Hz，2H)，2.05(d，J＝11.4Hz，2H)，1.45(s，9H)，1.26-1.39(m，4H)。
8-((1r, 4r)-4-aminocyclohexyl is amino) bromo-1, the 6-naphthyridine-7-amine carboxylic acid (S22) of-N-(4-MethOxybenzenesulfonyl)-5-
Compound S 22-1 removes Boc and generates compound S 22 in the trifluoracetic acid/methylene dichloride of 20%.Greenish yellow solid, productive rate: 75-85%. 1hNMR (300MHz, d 6-DMSO): δ 9.1 (d, J=6.9Hz, 1H), 9.0 (d, J=5.4Hz, 1H), 8.39 (d, J=8.4Hz, 1H), 7.83 (d, J=8.7Hz, 2H), 7.77 (dd, J=5.4,8.4Hz, 1H), 6.99 (d, J=9Hz, 2H), 4.59 (brs, 1H), 3.81 (s, 3H), 3.05 (m, 1H), 2.06 (d, J=12Hz, 2H), 1.95 (d, J=13.8Hz, 2H), 1.39-1.51 (m, 2H), 1.21-1.33 (m, 2H); MS-EIm/z:171ArSO 2 +, 362 (M-HSO 2) +; MS-ESIm/z:556 (M+Na-2) +, 558 (M+Na) +; Anal. calculated value: C 22h 24brN 5o 4s5/4H 2o:C47.44, H4.80, N12.57, measured value: C47.19, H4.88, N12.93.
The tertiary butyl (1r, 4r)-4-(bromo-1, the 6-naphthyridine-8-of 7-(4-chlorobenzenesulfonyl amido formyl)-5-is amino) cyclohexyl carbamate (S23-1)
The preparation method of compound S 23-1 and the preparation method of compound S 22-1 similar, except with p-chloro benzenesulfonamide replace to methoxybenzenesulphoismide.Greenish yellow solid, productive rate: 75-85%. 1HNMR(300MHz，CDCl 3)：δ10.31(s，1H)，9.18(m，1H)，8.94(d，J＝3.9Hz，1H)，8.45(d，J＝8.4Hz，1H)，8.12(d，J＝8.4Hz，2H)，7.65(dd，J＝3.9，8.4Hz，1H)，7.54(d，J＝8.7Hz，2H)，4.99(brs，1H)，4.39(brs，1H)，3.46(brs，1H)，2.14(d，J＝12Hz，2H)，2.06(d，J＝10.5Hz，2H)，1.45(s，9H)，1.26-1.39(m，4H)；MS-ESIm/z：640(M+H) +，638(M-2+H) +。
8-((1r, 4r)-4-aminocyclohexyl is amino) bromo-1, the 6-naphthyridine-7-amine carboxylic acid (S23) of-N-(4-chlorobenzenesulfonyl)-5-
The preparation method of compound S 23 and the preparation method of compound S 22 similar, except replacing compound S 22-1 with compound S 23-1.Greenish yellow solid, productive rate: 75-85%. 1hNMR (300MHz, d 6-DMSO): δ 9.17 (d, J=8.1Hz, 1H), 8.99 (d, J=2.7Hz, 1H), 8.37 (d, J=9.9Hz, 1H), 7.88 (d, J=8.7Hz, 2H), 7.75 (dd, J=2.7,9.9Hz, 1H), 7.52 (d, J=8.4Hz, 2H), 4.58 (brs, 1H), 3.05 (t, 1H), 2.05 (d, J=11.1Hz, 2H), 1.96 (d, J=10.5Hz, 2H), 1.45 (m, 2H), 1.24 (m, 2H); 13cNMR (100MHz, d 6-DMSO): δ 170.0151.5144.4142.0135.8134.9132.7129.0127.8125.1124.71 24.552.548.831.728.9; MS-ESIm/z:540 (M+H) +, 538 (M-2+H) +; Anal. calculated value: C 21h 21brClN 5o 3s5/4H 2o:C44.93, H4.22, N12.48, measured value: C44.79, H4.25, N12.70.
The tertiary butyl (1r, 4r)-4-(bromo-1, the 6-naphthyridine-8-of 7-(3-chlorobenzenesulfonyl amido formyl)-5-is amino) cyclohexyl carbamate (S24-1)
The preparation method of compound S 24-1 and the preparation method of compound S 22-1 similar, except replacing methoxybenzenesulphoismide with chlorobenzene sulfonamide.Greenish yellow solid, productive rate: 75-85%. 1HNMR(300MHz，CDCl 3)：δ10.32(s，1H)，9.19(d，1H)，8.94(d，J＝5.4Hz，1H)，8.45(d，J＝6.6Hz，1H)，8.16(s，1H)，8.08(d，J＝7.5Hz，1H)，7.59-7.67(m，2H)，7.51(t，2H)，5.0(brs，1H)，4.38(brs，1H)，3.45(brs，1H)，2.15(d，J＝12Hz，2H)，2.06(d，J＝8.7Hz，2H)，1.45(s，9H)，1.29-1.4(m，4H)。
8-((1r, 4r)-4-aminocyclohexyl is amino) bromo-1, the 6-naphthyridine-7-amine carboxylic acid (S24) of-N-(3-chlorobenzenesulfonyl)-5-
The preparation method of compound S 24 and the preparation method of compound S 22 similar, except replacing compound S 22-1 with compound S 24-1.Greenish yellow solid, productive rate: 75-85%. 1hNMR (300MHz, d 6-DMSO): δ 9.08 (brs, 1H), 9.02 (d, J=4.2Hz, 1H), 8.4 (d, J=8.7Hz, 1H), 7.9 (s, 1H), 7.76-7.85 (m, 2H), 7.49-7.59 (m, 2H), 4.59 (brs, 1H), 3.04 (t, 1H), (2.06 d, J=10.8Hz, 2H), (1.96 d, J=11.4Hz, 2H), 1.44 (m, 2H), 1.25 (m, 2H); 13cNMR (100MHz, d 6-DMSO): δ 151.6144.3135.9132.6130.6130.1126.9125.7125.2125.052.648 .731.628.9; MS-ESIm/z:540 (M+H) +, 538 (M-2+H) +; Anal. calculated value: C 21h 21brClN 5o 3s5/3H 2o:C44.34, H4.31, N12.31, measured value: C44.56, H4.34, N12.03.
The tertiary butyl (1r, 4r)-4-(bromo-1, the 6-naphthyridine-8-of 7-(3,5-difluorobenzenesulfonamide base formyl)-5-is amino) cyclohexyl carbamate (S25-1)
The preparation method of compound S 25-1 and the preparation method of compound S 22-1 similar, except with 3,5-difluorobenzenesulfonamide replace to methoxybenzenesulphoismide.Greenish yellow solid, productive rate: 75-85%. 1HNMR(300MHz，CDCl 3)δ10.33(s，1H)，9.18(d，1H)，8.96(d，J＝5.4Hz，1H)，8.46(d，J＝8.7Hz，1H)，7.73(m，2H)，7.67(dd，J＝5.4，8.7Hz，1H)，7.09(t，1H)，5.03(brs，1H)，4.38(brs，1H)，3.46(brs，1H)，2.16(d，J＝12Hz，2H)，2.07(d，J＝11.4Hz，2H)，1.45(s，9H)，1.31-1.38(m，4H)。
8-((1r, 4r)-4-aminocyclohexyl is amino) bromo-1, the 6-naphthyridine-7-amine carboxylic acid (S25) of-N-(3,5-difluorobenzenesulfonamide base)-5-
The preparation method of compound S 25 and the preparation method of compound S 22 similar, except replacing compound S 22-1 with compound S 25-1.Greenish yellow solid, productive rate: 75-85%. 1hNMR (300MHz, d 6-DMSO): δ 9.00 (m, 2H), 8.38 (d, J=6.3Hz, 1H), 7.45-7.81 (m, 4H), 7.5 (m, 2H), 7.39 (m, 1H), 4.56 (brs, 1H), (3.06 t, 1H), 2.08 (d, J=10.5Hz, 2H), 1.94 (d, J=10.5Hz, 2H), 1.44 (m, 2H), 1.25 (m, 2H); 13cNMR (100MHz, d 6-DMSO) δ 170.4162.8162.7160.3160.2151.4149.6144.3141.7135.8132.81 25.2124.7124.4110.5110.3105.752.548.831.628.9; MS-EIm/z:177ArSO 2 +, 362 (M-HSO 2) +; Anal. calculated value: C 21h 20brF 2n 5o 3s1/10C 6h 14: C47.26, H3.93, N12.76, measured value: C47.14, H3.93, N12.64.
The tertiary butyl (1r, 4r)-4-(bromo-1, the 6-naphthyridine-8-of 7-(2,5-dichloro-thiophene-3-base sulfoamido formyl)-5-is amino) cyclohexyl carbamate (S26-1)
The preparation method of compound S 26-1 and the preparation method of compound S 22-1 similar, except with 2,5-dichloro-thiophene-3-base sulphonamide replace to methoxybenzenesulphoismide.Greenish yellow solid, productive rate: 75-85%. 1HNMR(300MHz，CDCl 3)δ10.45(s，1H)，9.16(d，1H)，8.96(d，J＝6Hz，1H)，8.47(d，J＝9.9Hz，1H)，7.67(dd，J＝6，9.9Hz，1H)，7.4(s，1H)，5.03(brs，1H)，4.38(brs，1H)，3.47(brs，1H)，2.17(d，J＝12.6Hz，2H)，2.07(d，J＝15Hz，2H)，1.45(s，9H)，1.31-1.41(m，4H)。
8-((1r, 4r)-4-aminocyclohexyl is amino) bromo-1, the 6-naphthyridine-7-amine carboxylic acid (S26) of-N-(2,5-dichloro-thiophene-3-base alkylsulfonyl)-5-
The preparation method of compound S 26 and the preparation method of compound S 22 similar, except replacing compound S 22-1 with compound S 26-1.Greenish yellow solid, productive rate: 75-85%. 1hNMR (300MHz, d 6-DMSO): δ 9.12 (d, J=8.1Hz, 1H), 9.01 (d, J=4.2Hz, 1H), 8.39 (d, J=6.9Hz, 1H), 7.76-7.8 (m, 3H), 7.24 (s, 1H), 4.59 (brs, 1H), 3.05 (t, 1H), 2.08 (d, J=11.1Hz, 2H), 1.96 (d, J=10.5Hz, 2H), 1.39-1.51 (m, 2H), 1.24-1.34 (m, 2H); MS-ESIm/z:578 (M+H) +; Anal. calculated value: C 19h 18brCl 2n 5o 3s 21/10CF 3cOOH1/20C 6h 14: C39.36, H3.18, N11.77, measured value: C39.40, H3.47, N11.65.
The tertiary butyl (1r, 4r)-4-(bromo-1, the 6-naphthyridine-8-of 7-(4-trifluoromethyl benzene sulfonamide base formyl)-5-is amino) cyclohexyl carbamate (S27-1)
The preparation method of compound S 27-1 and the preparation method of compound S 22-1 similar, except with 4-trifluoromethyl benzene sulfonamide replace to methoxybenzenesulphoismide.Greenish yellow solid, productive rate: 75-85%. 1HNMR(300MHz，CDCl 3)：δ10.35(s，1H)，9.17(d，1H)，8.94(d，J＝4.2Hz，1H)，8.45(d，J＝8.7Hz，1H)，8.32(d，J＝8.4Hz，2H)，7.84(d，J＝8.1Hz，2H)，7.65(dd，J＝4.2，8.7Hz，1H)，5.01(brs，1H)，4.39(brs，1H)，3.46(brs，1H)，2.14(d，J＝11.7Hz，2H)，2.06(d，J＝10.8Hz，2H)，1.45(s，9H)，1.29-1.39(m，4H)。
8-((1r, 4r)-4-aminocyclohexyl is amino) bromo-1, the 6-naphthyridine-7-amine carboxylic acid (S27) of-N-(4-tnBuoromethyl-benzenesulfonyl)-5-
The preparation method of compound S 27 and the preparation method of compound S 22 similar, except replacing compound S 22-1 with compound S 27-1.Greenish yellow solid, productive rate: 75-85%. 1hNMR (300MHz, d 6-DMSO): δ 9.01-9.05 (m, 2H), 8.39 (d, J=9.9Hz, 1H), 8.07 (d, J=8.4Hz, 2H), 7.85 (d, J=8.1Hz, 2H), 7.78 (dd, J=9.9Hz, 1H), 4.58 (brs, 1H), 3.06 (brs, 1H), 2.06 (d, J=12Hz, 2H), 1.95 (d, J=13.8Hz, 2H), 1.39-1.5 (m, 2H), 1.24-1.32 (m, 2H); MS-ESIm/z:574 (M+H) +, 572 (M-2+H) +; Anal. calculated value: C 22h 21brF 3n 5o 3s5/4CH 3oH1/2CF 3cOOH:C43.51, H3.99, N10.46, measured value: C43.71, H4.20, N10.33.
The tertiary butyl (1r, 4r)-4-(bromo-1, the 6-naphthyridine-8-of 7-(4-P-acetamido benzene sulfonyl carbamoyl)-5-is amino) cyclohexyl carbamate (S28-1)
The preparation method of compound S 28-1 and the preparation method of compound S 22-1 similar, except with 4-P-acetamido benzene sulfonyl amine replace to methoxybenzenesulphoismide.Greenish yellow solid, productive rate: 75-85%. 1HNMR(300MHz，CDCl 3)：δ10.27(s，1H)，9.16(d，1H)，8.93(d，J＝3.9Hz，1H)，8.44(d，J＝8.7Hz，1H)，8.12(d，J＝9Hz，2H)，7.71(d，J＝8.7Hz，2H)，7.64(dd，J＝3.9，8.7Hz，1H)，7.52(brs，1H)，4.97(brs，1H)，4.41(brs，1H)，3.44(brs，1H)，2.22(s，3H)，2.11(d，J＝11.4Hz，2H)，2.02(d，J＝12Hz，2H)，1.45(s，9H)，1.28-1.41(m，4H)。
8-((1r, 4r)-4-aminocyclohexyl is amino) bromo-1, the 6-naphthyridine-7-amine carboxylic acid (S28) of-N-(4-P-acetamido benzene sulfonyl base)-5-
The preparation method of compound S 28 and the preparation method of compound S 22 similar, except replacing compound S 22-1 with compound S 28-1.Greenish yellow solid, productive rate: 75-85%. 1HNMR(300MHz，d 6-DMSO)：δ10.5(s，1H)，9.15(brs，1H)，9.01(d，J＝3.9Hz，1H)，8.38(d，J＝8.4Hz，1H)，7.86(d，J＝8.7Hz，2H)，7.79(dd，J＝3.9，8.4Hz，1H)，7.73(d，J＝8.7Hz，2H)，4.61(brs，1H)，3.01(t，1H)，2.08(s，3H)，1.94-2.05(m，4H)，1.38-1.5(m，2H)，1.2-1.28(m，2H)； 13CNMR(100MHz，d 6-DMSO)：δ169.1151.7144.3136.0128.3125.4125.1118.152.748.831.628.924.2；MS-ESIm/z：561(M+H) +，563(M+H+2) +。
The tertiary butyl (1r, 4r)-4-(bromo-1, the 6-naphthyridine-8-of 7-(2-chlorobenzenesulfonyl amido formyl)-5-is amino) cyclohexyl carbamate (S29-1)
The preparation method of compound S 29-1 and the preparation method of compound S 22-1 similar, except with 2-chlorobenzene sulfonamide replace to methoxybenzenesulphoismide.Greenish yellow solid, productive rate: 75-85%. 1HNMR(300MHz，CDCl 3)：δ10.62(s，1H)，9.07(d，1H)，8.93(d，J＝4.2Hz，1H)，8.47(d，J＝6.9Hz，1H)，8.37(m，1H)，7.65(dd，J＝4.2，6.9Hz，1H)，7.48-7.59(m，3H)，4.98(brs，1H)，4.36(brs，1H)，3.42(brs，1H)，2.11(d，J＝12.3Hz，2H)，2.03(d，J＝10.8Hz，2H)，1.44(s，9H)，1.25-1.38(m，4H)；MS-ESIm/z：640(M+H) +，638(M-2+H) +。
8-((1r, 4r)-4-aminocyclohexyl is amino) bromo-1, the 6-naphthyridine-7-amine carboxylic acid (S29) of-N-(2-chlorobenzenesulfonyl)-5-
The preparation method of compound S 29 and the preparation method of compound S 22 similar, except replacing compound S 22-1 with compound S 29-1.Greenish yellow solid, productive rate: 75-85%. 1hNMR (300MHz, d 6-DMSO): δ 9.06 (brs, 1H), 8.46 (d, J=8.1Hz, 1H), 8.16 (d, J=4.2Hz, 1H), 7.89 (brs, 2H), 7.63 (m, 2H), 7.37 (brs, 1H), 7.21 (brs, 1H), 7.04 (brs, 1H), 4.64 (brs, 1H), 3.55 (brs, 1H), 3.04 (brs, 1H), 2.06 (d, J=13.2Hz, 2H), 1.94 (d, J=13.8Hz, 2H), 1.27-1.47 (m, 4H); MS-EIm/z:175ArSO 2 +, 362 (M-HSO 2) +; Anal. calculated value: C 21h 21brClN 5o 3s1/5CF 3cOOH3/4H 2o:C44.69, H3.98, N12.18, measured value: C44.95, H4.22, N11.90.
The tertiary butyl (1r, 4r)-4-(bromo-1, the 6-naphthyridine-8-of 7-(2-methoxyl group-4-methyl-5-chloro-benzene sulfonamido formyl)-5-is amino) cyclohexyl carbamate (S30-1)
The preparation method of compound S 30-1 and the preparation method of compound S 22-1 similar, except replacing methoxybenzenesulphoismide with 2-methoxyl group-4-methyl-5-chloro-benzsulfamide.Greenish yellow solid, productive rate: 75-85%. 1HNMR(300MHz，CDCl 3)δ10.56(s，1H)，9.17(brs，1H)，8.94(d，J＝4.2Hz，1H)，8.46(d，J＝8.4Hz，1H)，8.1(s，1H)，7.65(dd，J＝4.2，8.4Hz，1H)，6.85(s，1H)，4.98(brs，1H)，4.36(brs，1H)，3.95(s，3H)，3.43(brs，1H)，2.42(s，3H)，2.01-2.14(m，4H)，1.45(s，9H)，1.27-1.37(m，4H)。
8-((1r, 4r)-4-aminocyclohexyl is amino) bromo-1, the 6-naphthyridine-7-amine carboxylic acid (S30) of-N-(2-methoxyl group-4-methyl-5-chloro-benzenesulfonyl)-5-
The preparation method of compound S 30 and the preparation method of compound S 22 similar, except replacing compound S 22-1 with compound S 30-1.Greenish yellow solid, productive rate: 75-85%. 1HNMR(300MHz，d 6-DMSO)：δ9.05(brs，1H)，8.4(d，J＝7.2Hz，1H)，7.79-7.84(m，2H)，7.18-7.23(m，3H)，4.54(brs，1H)，3.82(s，3H)，3.01(brs，1H)，2.38(s，3H)，2.06(d，J＝9.9Hz，2H)，1.97(d，J＝12.3Hz，2H)，1.39-1.47(m，2H)，1.24-1.36(m，2H)；MS-ESIm/z：584(M+H) +。
8-((1r, 4r)-4-aminocyclohexyl is amino)-N-(the fluoro-benzyl of 4-)-5-cyano group-1,6-naphthyridine-7-amine carboxylic acid (S31)
The preparation method of compound S 31 and the preparation method of compound S 1 similar, greenish yellow solid, productive rate: 75-85%. 1HNMR(300MHz，CDCl 3)：δ9.60(d，1H，J＝8.1Hz)，9.30(dd，1H，J＝1.5，4.2Hz)，8.40(dd，1H，J＝1.2，8.7Hz)，8.33(m，1H)，7.58(dd，1H，J＝4.2，8.4Hz)，7.30(s，4H)，4.96(m，1H)，4.59(d，2H，J＝6.0Hz)，2.77(m，1H)，2.17(m，2H)，1.94(m，2H)，1.43-1.24(m，4H)；EI-MSm/z：418(M) +。
8-((1r, 4r)-4-aminocyclohexyl is amino)-7-(the fluoro-benzylcarbamyl of 4-)-1,6-naphthyridine-5-methyl-formiate (S32)
The preparation method of compound S 32 and the preparation method of compound S 1 similar, greenish yellow solid, productive rate: 75-85%. 1HNMR(300MHz，CDCl 3)：δ9.58(d，1H，J＝8.1Hz)，9.29(dd，1H，J＝1.2，4.5Hz)，8.40(dd，1H，J＝1.2，8.7Hz)，8.33(m，1H)，7.58(dd，1H，J＝4.2，8.4Hz)，7.30(s，4H)，4.96(m，1H)，4.59(d，2H，J＝6.0Hz)，3.89(s，3H)，2.77(m，1H)，2.17(m，2H)，1.94(m，2H)，1.43-1.24(m，4H)；EI-MSm/z：451(M) +。
The iodo-7-of toluene-4-sulfonic acid 5-(3-trifluoromethyl-benzylamino formyl)-1,6-naphthyridine-8-carboxylicesters (S33-2)
The preparation method of compound S 33-2 and the preparation method of compound 9-1 similar, except replacing compound 8-1 with compound S 33-1.White solid, productive rate: 85-95%. 1HNMR(300MHz，CDCl 3)：8.97(d，J＝3.3Hz，1H)，8.41(d，J＝8.4Hz，1H)，8.1(t，J＝6Hz，1H)，7.91(d，J＝8.1Hz，2H)，7.45-7.68(m，5H)，7.4(d，J＝8.4Hz，2H)，7.26-7.34(m，4H)，7.31(d，J＝8.4Hz，2H)，4.71(d，J＝6Hz，2H)，2.45(s，3H)。
8-((1r, 4r)-4-aminocyclohexyl is amino) iodo-1, the 6-naphthyridine-7-amine carboxylic acid (S33-3) of-N-(3-romethyl-benzy)-5-
The preparation method of compound S 33-3 and the preparation method of compound S 1 similar, except replacing compound 9-1 with compound S 33-2.Greenish yellow solid, productive rate: 75-85%. 1HNMR(300MHz，CDCl 3)：9.63(d，J＝7.8Hz，1H)，8.88(d，J＝5.7Hz，1H)，8.41(t，J＝6.6Hz，1H)，8.25(d，J＝8.4Hz，1H)，7.45-7.62(m，5H)，4.95(m，1H)，4.7(d，J＝6.6Hz，2H)，4.39(brs，1H)，3.47(m，1H)，2.19(d，J＝14.4Hz，2H)，2.06(d，J＝12Hz，2H)，1.45(s，9H)，1.23-1.45(m，4H)。
3-{5-[8-((1r, 4r)-4-(tertbutyloxycarbonyl ammonia) Cyclohexylamino)-7-(3-trifluoromethyl benzyl carbamyl)-1,6-phthalazinyl] } Methyl propiolate (S33-4)
By compound S 33-3 (84mg, 1.25mmol), Methyl propiolate (100ul; 6mmol); Palladous chloride (1mg, 0.05mmol), triphenylphosphine (2.6mg; 0.01mmol); cuprous iodide (2.0mg, 0.01mmol) and salt of wormwood (34mg, 0.25mmol) are dissolved in 5mLTHF; nitrogen protection, reflux 14 hours.Reaction system cools, and is spin-dried for THF, adds 20mL methylene dichloride, saturated common salt washing twice, organic phase anhydrous sodium sulfate drying.Silica gel column chromatography (sherwood oil: ethyl acetate=4: 1) obtain greenish yellow solid compound S 33-475mg, productive rate: 97%. 1HNMR(300MHz，CDCl 3)：δ10.41(d，J＝10.8Hz，1H)，8.92(d，J＝4.2Hz，1H)，8.66(m，1H)，8.52(d，J＝8.4Hz，1H)，7.46-7.62(m，5H)，5.11(m，1H)，4.69(d，2H)，4.4(brs，1H)，3.88(s，3H)，3.5(m，1H)，2.24(d，J＝12.6Hz，2H)，2.1(d，J＝11.7Hz，2H)，1.45(s，9H)，1.24-1.45(m，4H)。
3-{5-[8-((1r, 4r)-4-aminocyclohexyl is amino)-7-(3-trifluoromethyl benzyl carbamyl)-1,6-phthalazinyl] } Methyl propiolate (S33)
Compound S 33 by compound S 33-4 20% trifluoracetic acid/de-Boc of methylene dichloride room temperature reaction 2 hours obtain.Greenish yellow solid, productive rate: 70-85%. 1hNMR (300MHz, CDCl 3): δ 10.38 (d, J=8.1Hz, 1H), 8.93 (d, J=6Hz, 1H), 8.67 (t, J=6.3Hz, 1H), 8.51 (d, J=8.1Hz, 1H), 7.45-7.61 (m, 5H), 5.14 (m, 1H), 4.68 (d, 2H), 3.88 (s, 3H), 2.77 (m, 1H), 2.23 (d, J=11.4Hz, 2H), 1.93 (d, J=12.3Hz, 2H), 1.3-1.47 (m, 4H); MS-EIm/z:525 (M) +, 526 (M+1) +; Anal. calculated value: C 27h 26f 3n 5o 31/4CF 3cOOH:C59.62, H4.78, N12.64, measured value: C59.50, H4.90, N12.63.
The iodo-7-of toluene-4-sulfonic acid 5-(3,4-dichloro-benzyl carbamyl)-1,6-naphthyridine-8-carboxylicesters (S34-2)
The preparation method of compound S 34-2 and the preparation method of compound 9-1 similar, except replacing compound 8-1 with compound S 34-1.White solid, productive rate: 85-95%. 1HNMR(300MHz，CDCl 3)：8.97(d，J＝3.9Hz，1H)，8.39(d，J＝8.7Hz，1H)，8.08(t，J＝6.3Hz，1H)，7.91(d，J＝8.4Hz，2H)，7.66(dd，J＝3.9，8.7Hz)，7.41-7.48(m，2H)，7.32(d，J＝8.4Hz，2H)，7.23-7.25(m，1H)，4.61(d，J＝6.3Hz，2H)，2.46(s，3H)。
8-((1r, 4r)-4-aminocyclohexyl is amino) iodo-1, the 6-naphthyridine-7-amine carboxylic acid (S34-3) of-N-(3,4-dichloro-benzyl)-5-
The preparation method of compound S 34-3 and the preparation method of compound S 1 similar, except replacing compound 9-1 with compound S 34-2.Greenish yellow solid, productive rate: 75-85%. 1HNMR(300MHz，CDCl 3)：9.60(d，J＝8.1Hz，1H)，8.88(d，J＝5.7Hz，1H)，8.37(t，J＝5.7Hz，1H)，8.25(d，J＝8.4Hz，1H)，7.57(dd，J＝5.7，8.4Hz，1H)，7.4-7.46(m，2H)，7.2-7.23(m，1H)，4.95(m，1H)，4.59(d，J＝5.7Hz，2H)，4.39(br，1H)，3.47(m，1H)，2.18(d，J＝13.5Hz，2H)，2.06(d，J＝12.6Hz，2H)，1.45(s，9H)，1.27-1.29(m，4H)；MS-ESIm/z：670(M+H) +，672(M+2+H) +。
3-{5-[8-((1r, 4r)-4-(tertbutyloxycarbonyl ammonia) Cyclohexylamino)-7-(3,4-dichloro-benzyl carbamyl)-1,6-phthalazinyl] } Methyl propiolate (S34-4)
The preparation method of compound S 34-4 and the preparation method of compound S 33-4 similar, except replacing compound S 33-3 with compound S 34-3.Greenish yellow solid, productive rate: 75-95%. 1HNMR(300MHz，CDCl 3)：10.37(d，J＝8.1Hz，1H)，8.92(d，J＝2.1Hz，1H)，8.63(t，J＝6.6Hz，1H)，8.51(d，J＝8.1Hz，1H)，7.59(dd，J＝2.1，8.1Hz，1H)，7.4-7.46(m，2H)，7.2-7.23(m，1H)，5.1(m，1H)，4.57(d，J＝6.6Hz，2H)，4.42(br，1H)，3.88(s，3H)，3.48(m，1H)，2.24(d，J＝12Hz，2H)，2.09(d，J＝10.8Hz，2H)，1.45(s，9H)，1.25-1.38(m，4H)。
3-{5-[8-((1r, 4r)-4-aminocyclohexyl is amino)-7-(3,4-dichloro-benzyl carbamyl)-1,6-phthalazinyl] } Methyl propiolate (S34)
The preparation method of compound S 34 and the preparation method of compound S 33 similar, except replacing compound S 33-4 with compound S 34-4.Greenish yellow solid, productive rate: 70-85%. 1hNMR (300MHz, CDCl 3): δ 10.36 (d, J=8.1Hz, 1H), 8.93 (d, J=6Hz, 1H), 8.64 (t, J=6.3Hz, 1H), 8.51 (d, J=6.9Hz, 1H), 7.59 (dd, J=6,6.9Hz, 1H), 7.4-7.46 (m, 2H), 7.2-7.22 (m, 1H), 5.1 (m, 1H), 4.57 (d, J=6.3Hz, 2H), 3.88 (s, 3H), 2.79 (m, 1H), 2.23 (d, J=12.3Hz, 2H), 1.95 (d, J=12.3Hz, 2H), 1.25-1.52 (m, 4H); MS-EIm/z:525 (M) +, 527 (M+2) +; Anal. calculated value: C 26h 25cl 2n 5o 31/5CF 3cOOH3/10C 6h 14: C58.90, H5.15, N12.18, measured value: C59.04, H5.12, N12.30.
The iodo-7-of toluene-4-sulfonic acid 5-(2,4-dichloro-benzyl carbamyl)-1,6-naphthyridine-8-carboxylicesters (S35-2)
The preparation method of compound S 35-2 and the preparation method of compound 9-1 similar, except replacing compound 8-1 with compound S 35-1.White solid, productive rate: 85-95%. 1HNMR(300MHz，CDCl 3)8.97(d，J＝4.5Hz，1H)，8.40(d，J＝8.4Hz，1H)，8.12(t，J＝6.3Hz，1H)，7.90(d，J＝8.1Hz，2H)，7.66(dd，J＝4.5，8.4Hz，1H)，7.43(d，J＝8.4Hz，2H)，7.32(d，J＝8.4Hz，2H)，7.22-7.25(m，1H)，4.68(d，J＝6.3Hz，2H)，2.47(s，3H)。
8-((1r, 4r)-4-aminocyclohexyl is amino) iodo-1, the 6-naphthyridine-7-amine carboxylic acid (S35-3) of-N-(2,4-dichloro-benzyl)-5-
The preparation method of compound S 35-3 and the preparation method of compound S 1 similar, except replacing compound 9-1 with compound S 35-2.Greenish yellow solid, productive rate: 75-85%. 1HNMR(300MHz，CDCl 3)：9.58(d，J＝8.4Hz，1H)，8.87(d，J＝3.9Hz，1H)，8.42(t，J＝6.9Hz，1H)，8.25(d，J＝8.4Hz，1H)，7.57(dd，J＝3.9，8.4Hz，1H)，7.36-7.41(m，2H)，7.22-7.26(m，1H)，4.94(m，1H)，4.68(d，J＝6.9Hz，2H)，4.37(br，1H)，3.46(m，1H)，2.17(d，J＝12Hz，2H)，2.05(d，J＝13.5Hz，2H)，1.44(s，9H)，1.25-1.38(m，4H)。
3-{5-[8-((1r, 4r)-4-(tertbutyloxycarbonyl ammonia) Cyclohexylamino)-7-(2,4-dichloro-benzyl carbamyl)-1,6-phthalazinyl] } Methyl propiolate (S35-4)
The preparation method of compound S 35-4 and the preparation method of compound S 33-4 similar, except replacing compound S 33-3 with compound S 35-3.Greenish yellow solid, productive rate: 75-95%. 1HNMR(300MHz，CDCl 3)δ10.37(d，J＝8.1Hz，1H)，8.92(d，J＝3.9Hz，1H)，8.61(t，J＝6.3Hz，1H)，7.35-7.41(m，2H)，7.21-7.26(m，1H)，5.10(m，1H)，4.68(d，J＝6.3Hz，2H)，4.39(br，1H)，3.88(s，3H)，3.48(m，1H)，2.23(d，J＝12.3Hz，2H)，2.08(d，J＝12.9Hz，2H)，1.45(s，9H)，1.25-1.38(m，4H)；MS-EIm/z：625(M) +，627(M+2) +。
3-{5-[8-((1r, 4r)-4-aminocyclohexyl is amino)-7-(2,4-dichloro-benzyl carbamyl)-1,6-phthalazinyl] } Methyl propiolate (S35)
The preparation method of compound S 35 and the preparation method of compound S 33 similar, except replacing compound S 33-4 with compound S 35-4.Greenish yellow solid, productive rate: 70-85%.IR (film) v max=3427,2920,2202,1709,1643,1606,1576,1500,1358,1230,1138,822cm -1; 1hNMR (300MHz, CDCl 3) δ 10.35 (d, J=6.9Hz, 1H), 8.93 (s, 1H), 8.62 (t, J=5.7Hz, 1H), 8.52 (d, J=6.9Hz, 1H), 7.58 (dd, J=6.9Hz, 1H), 7.34-7.41 (m, 2H), 7.21-7.24 (m, 1H), 5.14 (m, 1H), 4.67 (d, J=5.7Hz, 2H), 3.88 (s, 3H), 2.88 (m, 1H), 2.25 (s, 2H), 2.01 (s, 2H), 1.42-1.52 (m, 4H); MS-EIm/z:525 (M) +, 527 (M+2) +; Anal. calculated value: C 26h 25cl 2n 5o 31/5CF 3cOOHCH 3oH:C56.62, H5.06, N12.05, measured value: C56.73, H4.87, N11.81.
The iodo-7-of toluene-4-sulfonic acid 5-(the chloro-benzylcarbamyl of 3-)-1,6-naphthyridine-8-carboxylicesters (S36-2)
The preparation method of compound S 36-2 and the preparation method of compound 9-1 similar, except replacing compound 8-1 with compound S 36-1.White solid, productive rate: 85-95%. 1HNMR(300MHz，CDCl 3)：9.00(d，J＝3.9Hz，1H)，8.40(d，J＝8.4Hz，1H)，8.04(t，J＝6.3Hz，1H)，7.92(d，J＝8.4Hz，2H)，7.66(dd，J＝3.9，8.4Hz，1H)，7.37(s，1H)，7.29-7.34(m，5H)，4.62(d，J＝6.3Hz，2H)，2.46(s，3H)。
8-((1r, 4r)-4-aminocyclohexyl is amino) iodo-1, the 6-naphthyridine-7-amine carboxylic acid (S36-3) of-N-(the chloro-benzyl of 3-)-5-
The preparation method of compound S 36-3 and the preparation method of compound S 1 similar, except replacing compound 9-1 with compound S 36-2.Greenish yellow solid, productive rate: 75-85%. 1HNMR(300MHz，CDCl 3)：9.64(d，J＝6.6Hz，1H)，8.87(d，J＝3.6Hz，1H)，8.36(t，J＝6.3Hz，1H)，8.25(d，J＝8.4Hz，1H)，7.57(dd，J＝3.6，8.4Hz，1H)，7.36(s，1H)，7.25-7.28(m，3H)，4.96(m，1H)，4.62(d，J＝6.3Hz，2H)，4.38(br，1H)，3.47(m，1H)，2.19(d，J＝12Hz，2H)，2.07(d，J＝12.3Hz，2H)，1.45(s，9H)，1.26-1.4(m，4H)；MS-ESIm/z：636(M+H) +。
3-{5-[8-((1r, 4r)-4-(tertbutyloxycarbonyl ammonia) Cyclohexylamino)-7-(the chloro-benzylcarbamyl of 3-)-1,6-phthalazinyl] } Methyl propiolate (S36-4)
The preparation method of compound S 36-4 and the preparation method of compound S 33-4 similar, except replacing compound S 33-3 with compound S 36-3.Greenish yellow solid, productive rate: 75-95%. 1HNMR(300MHz，CDCl 3)：δ10.42(d，J＝6.6Hz，1H)，8.92(d，J＝5.7Hz，1H)，8.61(t，J＝6.3Hz，1H)，8.52(d，J＝8.4Hz，1H)，7.58(dd，J＝5.7，8.4Hz，1H)，7.36(s，1H)，7.23-7.28(m，3H)，5.09(m，1H)，4.61(d，J＝6.3Hz，2H)，4.39(br，1H)，3.87(s，3H)，3.50(m，1H)，2.24(d，J＝13.5Hz，2H)，2.09(d，J＝14.4Hz，2H)，1.45(s，9H)，1.25-1.38(m，4H)。
3-{5-[8-((1r, 4r)-4-aminocyclohexyl is amino)-7-(the chloro-benzylcarbamyl of 3-)-1,6-phthalazinyl] } Methyl propiolate (S36)
The preparation method of compound S 36 and the preparation method of compound S 33 similar, except replacing compound S 33-4 with compound S 36-4.Greenish yellow solid, productive rate: 70-85%. 1hNMR (300MHz, CDCl 3): δ 10.40 (d, J=7.5Hz, 1H), 8.93 (d, J=3.9Hz, 1H), 8.63 (t, J=6.6Hz, 1H), 8.51 (d, J=8.1Hz, 1H), 7.59 (dd, J=3.9,8.1Hz, 1H), 7.36 (s, 1H), 7.26-7.28 (m, 3H), 5.13 (m, 1H), 4.61 (d, J=6.6Hz, 2H), 3.88 (s, 3H), 2.77 (m, 1H), 2.23 (d, J=12Hz, 2H), 1.93 (d, J=12.6Hz, 2H), 1.25-1.44 (m, 4H); 13cNMR (100MHz, CDCl 3): δ 167.9154.3150.1145.9141.8140.5134.4133.9129.9128.4127.61 27.4125.7124.7124.4121.483.582.153.852.949.942.334.933.0; MS-EIm/z:491 (M) +, 493 (M+2) +; Anal. calculated value: C 26h 26clN 5o 31/10C 6h 14: C63.81, H5.52, N13.99, measured value: C63.98, H5.49, N13.99.
The iodo-7-of toluene-4-sulfonic acid 5-(the chloro-benzylcarbamyl of 4-)-1,6-naphthyridine-8-carboxylicesters (S37-2)
The preparation method of compound S 37-2 and the preparation method of compound 9-1 similar, except replacing compound 8-1 with compound S 37-1.White solid, productive rate: 85-95%. 1HNMR(300MHz，CDCl 3)：8.97(d，J＝4.2Hz，1H)，8.39(d，J＝9Hz，1H)，8.00(t，J＝6.3Hz，1H)，7.91(d，J＝8.1Hz，2H)，7.65(dd，J＝4.2，9Hz)，7.3-7.33(m，6H)，4.61(d，J＝6.3Hz，2H)，2.46(s，3H)。
8-((1r, 4r)-4-aminocyclohexyl is amino) iodo-1, the 6-naphthyridine-7-amine carboxylic acid (S37-3) of-N-(the chloro-benzyl of 4-)-5-
The preparation method of compound S 37-3 and the preparation method of compound S 1 similar, except replacing compound 9-1 with compound S 37-2.Greenish yellow solid, productive rate: 75-85%. 1HNMR(300MHz，CDCl 3)：9.64(d，J＝8.1Hz，1H)，8.87(d，J＝3.9Hz，1H)，8.33(t，J＝6Hz，1H)，8.24(d，J＝9Hz，1H)，7.56(dd，J＝3.9，9Hz，1H)，7.31(s，4H)，4.95(m，1H)，4.60(d，J＝6Hz，2H)，4.37(br，1H)，3.49(m，1H)，2.18(d，J＝12.9Hz，2H)，2.06(d，J＝13.8Hz，2H)，1.44(s，9H)，1.26-1.39(m，4H)；MS-ESIm/z：636(M+H) +。
3-{5-[8-((1r, 4r)-4-(tertbutyloxycarbonyl ammonia) Cyclohexylamino)-7-(the chloro-benzylcarbamyl of 4-)-1,6-phthalazinyl] } Methyl propiolate (S37-4)
The preparation method of compound S 37-4 and the preparation method of compound S 33-4 similar, except replacing compound S 33-3 with compound S 37-3.Greenish yellow solid, productive rate: 75-95%. 1HNMR(300MHz，CDCl 3)10.43(d，J＝8.4Hz，1H)，8.92(d，J＝5.7Hz，1H)，8.59(t，J＝6.3Hz，1H)，8.51(d，J＝8.4Hz，1H)，7.59(dd，J＝5.7，8.4Hz，1H)，7.32(s，4H)，5.11(m，1H)，4.59(d，J＝6.3Hz，2H)，4.40(br，1H)，3.88(s，3H)，3.50(m，1H)，2.24(d，J＝12.3Hz，2H)，2.09(d，J＝12.3Hz，2H)，1.45(s，9H)，1.26-1.38(m，4H)。
3-{5-[8-((1r, 4r)-4-aminocyclohexyl is amino)-7-(the chloro-benzylcarbamyl of 4-)-1,6-phthalazinyl] } Methyl propiolate (S37)
The preparation method of compound S 37 and the preparation method of compound S 33 similar, except replacing compound S 33-4 with compound S 37-4.Greenish yellow solid, productive rate: 70-85%. 1hNMR (300MHz, CDCl 3): δ 10.41 (d, J=8.7Hz, 1H), 8.93 (d, J=4.2Hz, 1H), 8.60 (t, J=6.3Hz, 1H), 8.51 (d, J=8.4Hz, 1H), 7.59 (dd, J=4.2,8.4Hz, 1H), 7.32 (s, 4H), 5.13 (m, 1H), 4.59 (d, J=6.3Hz, 2H), 3.88 (s, 3H), 3.53 (br, 1H), 2.80 (m, 1H), 2.23 (d, J=12Hz, 2H), 1.96 (d, J=14.1Hz, 2H), 1.33-1.48 (m, 4H); MS-EIm/z:491 (M) +, 493 (M+2) +; Anal. calculated value: C 26h 26clN 5o 3: C63.48, H5.33, N14.24, measured value: C63.11, H5.33, N13.87.
3-{5-[8-((1r, 4r)-4-aminocyclohexyl is amino)-7-(3,4-dichloro-benzyl carbamyl)-1,6-phthalazinyl] }-3-methylmalonate (S38)
Compound S 38 is obtained by compound S 34-4 40 degree of reactions in the trifluoracetic acid/methylene dichloride of 20% for 2 hours.Greenish yellow solid, productive rate: 70-85%. 1HNMR(300MHz，CDCl 3)：δ10.74(d，J＝9Hz，1H)，9.69(d，J＝8.7Hz，1H)，8.89(d，J＝4.2Hz，1H)，8.76(t，J＝6.3Hz，1H)，7.56-7.62(m，1H)，7.40-7.43(m，2H)，7.26-7.30(m，1H)，5.21(m，1H)，4.61(d，J＝6.3Hz，2H)，3.93(s，2H)，3.57(s，3H)，2.78(m，1H)，2.23(d，J＝13.5Hz，2H)，1.94(d，J＝12.3Hz，2H)，1.25-1.49(m，4H)；MS-EIm/z：543(M) +，545(M+2) +。
3-{5-[8-((1r, 4r)-4-aminocyclohexyl is amino)-7-(2,4-dichloro-benzyl carbamyl)-1,6-phthalazinyl] }-3-methylmalonate (S39)
The preparation method of compound S 39 and the preparation method of compound S 38 similar, except replacing compound S 34-4 with compound S 35-4.Greenish yellow solid, productive rate: 70-85%.IR(film)v max＝3423，2926，1678，1647，1508，1207，1138，800cm -1； 1HNMR(300MHz，CDCl 3)：δ10.72(br，1H)，9.69(d，J＝9.3Hz，1H)，8.89(s，1H)，8.70(t，J＝6Hz，1H)，7.59(m，1H)，7.39-7.42(m，2H)，7.22-7.26(m，1H)，5.19(m，1H)，4.71(d，J＝6Hz，2H)，3.97(s，2H)，3.59(s，3H)，2.76(m，1H)，2.22(d，J＝11.4Hz，2H)，1.93(d，J＝13.5Hz，2H)，1.25-1.48(m，4H)； 13CNMR(100MHz，CDCl 3)：δ192.0169.9168.4149.5147.6141.9134.6134.1133.7131.8130.1129.3127.2126.3125.3121.854.152.449.948.640.635.033.029.6；MS-EIm/z：543(M) +，545(M+2) +。
The iodo-7-of toluene-4-sulfonic acid 5-(the chloro-benzylcarbamyl of 3-trifluoromethyl-4-)-1,6-naphthyridine-8-carboxylicesters (S40-2)
The preparation method of compound S 40-2 and the preparation method of compound 9-1 similar, except replacing compound 8-1 with compound S 40-1.White solid, productive rate: 85-95%. 1HNMR(300MHz，CDCl 3)：8.95(d，J＝4.2Hz，1H)，8.39(d，J＝8.7Hz，1H)，8.11(t，J＝6.6Hz，1H)，7.90(d，J＝7.8Hz，2H)，7.71(s，1H)，7.66(dd，J＝4.2，8.7Hz)，7.47-7.56(m，2H)，7.31(d，J＝8.4Hz，2H)，4.68(d，J＝6.6Hz，2H)，2.46(s，3H)；MS-ESIm/z：662(M+H) +。
8-((1r, 4r)-4-aminocyclohexyl is amino) iodo-1, the 6-naphthyridine-7-amine carboxylic acid (S40-3) of-N-(the chloro-benzyl of 3-trifluoromethyl-4-)-5-
The preparation method of compound S 40-3 and the preparation method of compound S 1 similar, except replacing compound 9-1 with compound S 40-2.Greenish yellow solid, productive rate: 75-85%. 1HNMR(300MHz，CDCl 3)：9.58(d，J＝8.1Hz，1H)，8.88(d，J＝4.8Hz，1H)，8.41(t，J＝6.6Hz，1H)，8.25(d，J＝9.9Hz，1H)，7.68(s，1H)，7.58(dd，J＝4.8，9.9Hz，1H)，7.46-7.52(m，2H)，4.96(m，1H)，4.65(d，J＝6.6Hz，2H)，4.39(br，1H)，3.48(m，1H)，2.18(d，J＝12.6Hz，2H)，2.06(d，J＝13.8Hz，2H)，1.44(s，9H)，1.23-1.38(m，4H)。
3-{5-[8-((1r, 4r)-4-(tertbutyloxycarbonyl ammonia) Cyclohexylamino)-7-(the chloro-benzylcarbamyl of 3-trifluoromethyl-4-)-1,6-phthalazinyl] } Methyl propiolate (S40-4)
The preparation method of compound S 40-4 and the preparation method of compound S 33-4 similar, except replacing compound S 33-3 with compound S 40-3.Greenish yellow solid, productive rate: 75-95%. 1HNMR(300MHz，CDCl 3)：10.35(d，J＝8.4Hz，1H)，8.93(d，J＝4.2Hz，1H)，8.67(t，J＝6.6Hz，1H)，8.51(d，J＝8.1Hz，1H)，7.68(s，1H)，7.60(dd，J＝4.2，8.1Hz，1H)，7.46-7.52(m，2H)，5.11(m，1H)，4.63(d，J＝6.6Hz，2H)，4.42(br，1H)，3.88(s，3H)，3.49(m，1H)，2.24(d，J＝10.2Hz，2H)，2.09(d，J＝13.8Hz，2H)，1.45(s，9H)，1.25-1.38(m，4H)。
3-{5-[8-((1r, 4r)-4-aminocyclohexyl is amino)-7-(the chloro-benzylcarbamyl of 3-trifluoromethyl-4-)-1,6-phthalazinyl] } Methyl propiolate (S40)
The preparation method of compound S 40 and the preparation method of compound S 33 similar, except replacing compound S 33-4 with compound S 40-4.Greenish yellow solid, productive rate: 70-85%. 1hNMR (300MHz, CDCl 3): δ 10.32 (d, J=8.4Hz, 1H), 8.94 (d, J=6Hz, 1H), 8.68 (t, J=6Hz, 1H), 8.52 (d, J=6.3Hz, 1H), 7.69 (s, 1H), 7.60 (dd, J=6,6.3Hz, 1H), 7.46-7.53 (m, 2H), 5.14 (m, 1H), 4.63 (d, J=6Hz, 2H), 3.88 (s, 3H), 2.81 (m, 1H), 2.24 (d, J=12.3Hz, 2H), 1.96 (d, J=13.5Hz, 2H), 1.33-1.51 (m, 4H); MS-EIm/z:559 (M) +, 561 (M+2) +; Anal. calculated value: C 27h 25clF 3n 5o 31/3H 2o:C57.30, H4.57, N12.37, measured value: C57.55, H4.78, N12.07.
3-{5-[8-((1r, 4r)-4-aminocyclohexyl is amino)-7-(the chloro-benzylcarbamyl of 3-trifluoromethyl-4-)-1,6-phthalazinyl] }-3-methylmalonate (S41)
The preparation method of compound S 41 and the preparation method of compound S 38 similar, except replacing compound S 34-4 with compound S 40-4.Greenish yellow solid, productive rate: 70-85%. 1hNMR (300MHz, CDCl 3): δ 10.72 (d, J=8.4Hz, 1H), 9.68 (d, J=8.7Hz, 1H), 8.91 (d, J=3.9Hz, 1H), 8.83 (t, J=6.9Hz, 1H), 7.80 (s, 1H), 7.56-7.63 (m, 2H), 7.48 (d, J=8.4Hz, 2H), 5.20 (m, 1H), 4.66 (d, J=6.9Hz, 2H), 3.92 (s, 2H), 3.54 (s, 3H), 2.83 (m, 1H), 2.25 (d, J=11.1Hz, 2H), 1.98 (d, J=11.4Hz, 2H), 1.38-1.49 (m, 4H), MS-EIm/z:577 (M) +, 579 (M+2) +, Anal. calculated value: C 27h 27clF 3n 5o 41/3C 6h 14: C57.41, H5.26, N11.54, measured value: C57.34, H5.11, N11.24.
The iodo-7-of toluene-4-sulfonic acid 5-(4-hexamethylene alkoxyl group-benzylcarbamyl)-1,6-naphthyridine-8-carboxylicesters (S42-2)
The preparation method of compound S 42-2 and the preparation method of compound 9-1 similar, except replacing compound 8-1 with compound S 42-1.White solid, productive rate: 85-95%. 1HNMR(300MHz，CDCl 3)：8.98(d，J＝4.2Hz，1H)，8.38(d，J＝8.4Hz，1H)，7.92(d，J＝8.1Hz，2H)，7.87(t，J＝6.3Hz，1H)，7.65(dd，J＝4.2，8.4Hz)，7.3-7.34(m，4H)，6.89(d，J＝8.4Hz，2H)，4.54(d，J＝63Hz，2H)，4.25(m，1H)，2.47(s，3H)，1.96-2.01(m，2H)，1.79-1.83(m，2H)，1.31-1.53(m，6H)。
8-((1r, 4r)-4-aminocyclohexyl is amino) iodo-1, the 6-naphthyridine-7-amine carboxylic acid (S42-3) of-N-(4-hexamethylene alkoxyl group-benzyl)-5-
The preparation method of compound S 42-3 and the preparation method of compound S 1 similar, except replacing compound 9-1 with compound S 42-2.Greenish yellow solid, productive rate: 75-85%. 1HNMR(300MHz，CDCl 3)：9.43(d，J＝8.1Hz，1H)，8.87(d，J＝4.2Hz，1H)，8.22-8.27(m，2H)，7.55(dd，J＝4.2Hz，1H)，7.26-7.3(m，2H)，6.89(d，J＝9Hz，2H)，4.94(m，1H)，4.56(d，J＝6.6Hz，2H)，4.39(br，1H)，4.23(m，1H)，3.49(m，1H)，2.16-2.20(m，2H)，1.97-2.09(m，4H)，1.78(m，2H)，1.45(s，9H)，1.26-1.49(m，10H)。
3-{5-[8-((1r, 4r)-4-(tertbutyloxycarbonyl ammonia) Cyclohexylamino)-7-(4-hexamethylene alkoxyl group-benzylcarbamyl)-1,6-phthalazinyl] } Methyl propiolate (S42-4)
The preparation method of compound S 42-4 and the preparation method of compound S 33-4 similar, except replacing compound S 33-3 with compound S 42-3.Greenish yellow solid, productive rate: 75-95%. 1HNMR(300MHz，CDCl 3)：10.54(d，J＝8.1Hz，1H)，8.91(d，J＝4.2Hz，1H)，8.47-8.52(m，2H)，7.57(dd，J＝4.2Hz，1H)，7.26-7.29(m，2H)，6.89(d，J＝8.7Hz，2H)，5.11(m，1H)，4.55(d，J＝6Hz，2H)，4.40(br，1H)，4.23(m，1H)，3.87(s，3H)，3.51(m，1H)，1.79-2.26(m，8H)，1.46(s，9H)，1.25-1.38(m，10H)。
3-{5-[8-((1r, 4r)-4-aminocyclohexyl is amino)-7-(4-hexamethylene alkoxyl group-benzylcarbamyl)-1,6-phthalazinyl] } Methyl propiolate (S42)
The preparation method of compound S 42 and the preparation method of compound S 33 similar, except replacing compound S 33-4 with compound S 42-4.Greenish yellow solid, productive rate: 70-85%. 1hNMR (300MHz, CDCl 3): δ 10.50 (d, J=8.1Hz, 1H), 8.93 (d, J=6Hz, 1H), 8.48-8.51 (m, 2H), 7.57 (dd, J=6Hz, 1H), 7.26-7.29 (m, 2H), 6.89 (d, J=8.7Hz, 2H), 5.13 (m, 1H), 4.54 (d, J=6Hz, 2H), 4.24 (m, 1H), 3.87 (s, 3H), 2.95 (m, 1H), 1.78-2.29 (m, 8H), 1.25-1.49 (m, 10H); MS-ESIm/z:556 (M+1) +; Anal. calculated value: C 32h 37n 5o 43/10CF 3cOOH:C66.38, H6.37, N11.87, measured value: C66.72, H5.99, N11.55.
Compound S 43
The preparation method of compound S 43 and the preparation method of compound S 1 similar.Greenish yellow solid, productive rate: 75-85%. 1HNMR(300MHz，CDCl 3)：δ9.72(brs，2H)，8.82(d，J＝4.2Hz，2H)，8.35(d，J＝8.4Hz，2H)，8.22(m，2H)，7.50(dd，J＝4.2，8.4Hz，2H)，7.35(m，4H)，7.03(t，J＝8.5Hz，4H)，4.57(d，J＝6Hz，4H)，4.35(t，J＝6.6Hz，4H)，2.15(t，J＝6.6Hz，2H)；MS-EIm/z：788(M) +，790(M+2) +。
Compound S 44
The preparation method of compound S 44 and the preparation method of compound S 1 similar.Greenish yellow solid, productive rate: 75-85%. 1HNMR(300MHz，CDCl 3)：δ9.63(d，J＝8.7Hz，2H)，8.96(d，J＝4.2Hz，2H)，8.42(m，4H)，7.70(s，2H)，7.62(dd，J＝3.9Hz，2H)，7.50(m，4H)，5.12(m，2H)，4.66(d，J＝6Hz，4H)，2.23-2.25(m，4H)，1.25(m，4H)；MS-ESIm/z：999(M+H) +，1001(M+2+H) +。
Compound S 45
The preparation method of compound S45 and the preparation method of compound S 33 similar.Greenish yellow solid, productive rate: 75-85%. 1HNMR(300MHz，CDCl 3)：8.95(s，2H)，8.72(t，J＝6.3Hz，2H)，8.53(d，J＝6.9Hz，2H)，7.71(s，2H)，7.62(dd，J＝6.9Hz，2H)，7.50(m，4H)，5.29(m，2H)，4.65(d，J＝6.3Hz，4H)，3.89(s，6H)，3.50(m，2H)，2.30-2.32(m，4H)，1.25(m，4H)；MS-ESIm/z：1003(M+H) +，1005(M+2+H) +。
Compound S 46-1
Compound 12 and HOAt, EDCI, DIPEA, in methylene dichloride, react 12h with Isosorbide-5-Nitrae-dibenzylamine under normal temperature and obtain compound S 46-1.Greenish yellow solid, productive rate: 75-85%. 1HNMR(300MHz，CDCl 3)：9.67(d，J＝8.4Hz，2H)，8.93(d，J＝5.7Hz，2H)，8.41(d，J＝6.9Hz，2H)，8.31(t，J＝6.3Hz，2H)，7.58(dd，J＝5.7，6.9Hz，2H)，7.38(s，4H)，4.94(m，2H)，4.63(d，J＝63Hz，4H)，3.48(m，2H)，2.19(d，J＝12.3Hz，4H)，2.06(d，J＝12.6Hz，4H)，1.45(s，18H)，1.25-1.40(m，8H)；MS-ESIm/z：1299(M-H) +。
Compound S 46
The preparation method of compound S 46 and the preparation method of compound S 22 similar, except replacing compound S 22-1 with compound S 46-1.Greenish yellow solid, productive rate: 75-85%. 1hNMR (300MHz, CD 3oD): 8.94 (s, 2H), 8.42 (d, J=8.4Hz, 2H), 7.68 (m, 2H), 7.35 (s, 4H), 4.53 (s, 4H), 3.14 (m, 4H), 2.24-2.28 (m, 4H), 2.05-2.1 (m, 4H), 1.35-1.58 (m, 8H); MS-ESIm/z:831 (M+H) +, 833 (M+2+H) +; HR-ESIMS calculated value: C 38h 42br 2n 10o 2(M+Na) +: 851.1757, measured value: 851.1740.
Compound S 47-1
The preparation method of compound S 47-1 and the preparation method of compound S 46-1 similar, except with 1,6-hexanediamine replace Isosorbide-5-Nitrae-dibenzylamine.Greenish yellow solid, productive rate: 70-85%. 1HNMR(300MHz，CDCl 3)：9.68(d，J＝8.1Hz，2H)，8.92(d，J＝3.9Hz，2H)，8.40(d，J＝8.7Hz，2H)，8.01(t，J＝5.7Hz，2H)，7.57(dd，J＝3.9，8.7Hz，2H)，4.91(m，2H)，4.37(m，2H)，3.39-3.49(m，6H)，2.17(d，J＝11.4Hz，4H)，2.05(d，J＝11.4Hz，4H)，1.68(m，6H)，1.44(s，18H)，1.21-1.39(m，10H)；MS-ESIm/z：1011(M+H) +。
Compound S 47
The preparation method of compound S 47 and the preparation method of compound S 22 similar, except replacing compound S 22-1 with compound S 47-1.Greenish yellow solid, productive rate: 70-85%. 1HNMR(300MHz，CD 3OD)：8.99(d，J＝6Hz，2H)，8.50(d，J＝8.4Hz，2H)，7.73(dd，J＝6，8.4Hz，2H)，4.96(m，2H)，3.40(t，J＝6.6Hz，4H)，3.16(m，2H)，2.29(d，J＝12Hz，4H)，2.09(d，J＝11.4Hz，4H)，1.64-1.71(m，4H)，1.37-1.59(m，12H)；MS-ESIm/z：811(M+H) +。
Compound S 48-1
The preparation method of compound S 48-1 and the preparation method of compound S 46-1 similar, except with 1,3-propylene diamine replace Isosorbide-5-Nitrae-dibenzylamine.Greenish yellow solid, productive rate: 70-85%. 1HNMR(300MHz，CDCl 3)：9.69(d，J＝6.9Hz，2H)，8.92(d，J＝4.2Hz，2H)，839(d，J＝8.4Hz，2H)，8.26(t，J＝5.7Hz，2H)，7.57(dd，J＝4.2，8.4Hz，2H)，4.91(m，2H)，4.39(m，2H)，3.45-3.59(m，6H)，2.18(d，J＝11.7Hz，4H)，2.06(d，J＝10.5Hz，4H)，1.44(s，18H)，1.21-1.34(m，10H)；MS-ESIm/z：969(M+H) +。
Compound S 48
The preparation method of compound S 48 and the preparation method of compound S 22 similar, except replacing compound S 22-1 with compound S 48-1.Greenish yellow solid, productive rate: 70-85%. 1HNMR(300MHz，CD 3OD)：8.92(d，J＝3Hz，2H)，8.31(d，J＝8.4Hz，2H)，7.66(dd，J＝3，8.4Hz，2H)，4.83(m，2H)，3.52(t，J＝6Hz，4H)，3.14(m，2H)，2.26(d，J＝12Hz，4H)，2.07(d，J＝11.4Hz，4H)，1.95(m，2H)，1.39-1.61(m，8H)； 13CNMR(100MHz，CD 3OD)：δ170.0153.0146.4145.8138.0128.2126.7126.6125.954.651.338.733.930.9；MS-ESIm/z：769(M+H) +。
Compound S 49-1
The preparation method of compound S 49-1 and the preparation method of compound S 46-1 similar, except replacing Isosorbide-5-Nitrae-dibenzylamine with Putriscine.Greenish yellow solid, productive rate: 70-85%. 1HNMR(300MHz，CDCl 3)：9.68(d，J＝7.8Hz，2H)，8.91(d，J＝3.9Hz，2H)，8.14(d，J＝8.4Hz，2H)，8.04(t，J＝6Hz，2H)，7.57(dd，J＝3.9，8.4Hz，2H)，4.92(m，2H)，4.39(m，2H)，3.48(m，6H)，2.17(d，J＝12.6Hz，4H)，2.05(d，J＝11.4Hz，4H)，1.77(brs，4H)，1.44(s，18H)，1.23-1.39(m，8H)；MS-ESIm/z：983(M+H) +。
Compound S 49
The preparation method of compound S 49 and the preparation method of compound S 22 similar, except replacing compound S 22-1 with compound S 49-1.Greenish yellow solid, productive rate: 70-85%. 1HNMR(300MHz，CD 3OD)：8.97(d，J＝2.7Hz，2H)，8.48(d，J＝9.6Hz，2H)，7.73(dd，J＝2.7，9.6Hz，2H)，4.92(m，2H)，3.45(m，4H)，3.15(m，2H)，2.27(d，J＝11.7Hz，4H)，2.08(d，J＝12.6Hz，4H)，1.75(brs，4H)，1.36-1.62(m，8H)；MS-ESIm/z：783(M+H) +。
Compound S 50-1
The preparation method of compound S 50-1 and the preparation method of compound S 46-1 similar, except replacing Isosorbide-5-Nitrae-dibenzylamine with trans Isosorbide-5-Nitrae-cyclohexanediamine.Greenish yellow solid, productive rate: 70-85%. 1HNMR(300MHz，CDCl 3)：9.70(d，J＝8.4Hz，2H)，8.93(d，J＝5.7Hz，2H)，8.43(d，J＝10.5Hz，2H)，7.85(d，J＝8.1Hz，2H)，7.58(dd，J＝5.7，10.5Hz，2H)，4.93(m，2H)，4.38(m，1H)，3.96(m，1H)，3.48(m，2H)，2.18(d，J＝7.8Hz，8H)，2.06(d，J＝11.1Hz，4H)，1.45(s，18H)，1.25-1.39(m，12H)；MS-ESIm/z：1009(M+H) +。
Compound S 50
The preparation method of compound S 50 and the preparation method of compound S 22 similar, except replacing compound S 22-1 with compound S 50-1.Greenish yellow solid, productive rate: 70-85%. 1HNMR(300MHz，CD 3OD)：9.02(d，J＝4.2Hz，2H)，8.54(d，J＝10.2Hz，2H)，7.76(dd，J＝4.2，10.2Hz，2H)，4.97(m，2H)，3.92(m，4H)，3.18(m，2H)，2.31(d，J＝11.7Hz，4H)，2.12(m，8H)，1.43-1.67(m，12H)； 13CNMR(100MHz，CD 3OD)：δ169.2153.2146.5145.8138.2128.3127.0126.8126.054.751.349.749.533.032.330.1；MS-ESIm/z：809(M+H) +。
Compound S 51-1
The preparation method of compound S 51-1 and the preparation method of compound S 46-1 similar, except replacing Isosorbide-5-Nitrae-dibenzylamine with piperazine.Greenish yellow solid, productive rate: 70-85%. 1HNMR(300MHz，CDCl 3)：8.94(d，J＝12.3Hz，2H)，8.44(dd，J＝8.1Hz，2H)，7.65(m，2H)，6.43(brs，2H)，4.47(m，2H)，4.00(s，2H)，3.91(brs，2H)，3.58-3.64(m，4H)，3.48(brs，2H)，2.10(t，J＝12.9Hz，10H)，1.44(s，18H)，1.25-1.38(m，6H)；MS-ESIm/z：981(M+H) +。
Compound S 51
The preparation method of compound S 51 and the preparation method of compound S 22 similar, except replacing compound S 22-1 with compound S 51-1.Greenish yellow solid, productive rate: 70-85%. 1HNMR(300MHz，CD 3OD)：9.05(d，J＝12Hz，2H)，8.54(dd，J＝8.1Hz，2H)，7.80(m，2H)，4.05(s，2H)，3.93(brs，2H)，3.69(brs，2H)，3.60(s，2H)，3.52(brs，2H)，3.17(m，2H)，2.16(d，J＝12.9Hz，8H)，1.43-1.57(m，8H)； 13CNMR(100MHz，CD 3OD)：δ170.1169.9154.8145.3139.4138.5129.6129.3126.9126.154.051.048.643.232.831.3；MS-ESIm/z：781(M+H) +。
EXPERIMENTAL EXAMPLE 1:5,8-bis-replaces-1,6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof to the in-vitro multiplication restraining effect of man―machine systems
Cell strain: Breast cancer lines MDA-MB-435, human oophoroma cell line SK-BR-3, people's malignant melanoma cell strain A375, human skin squamous cell carcinoma strain A431, human colon cancer cell strain HT-29, human lung cancer cell lines A-549, Human Hepatic Carcinoma Cell Line BEL-7402, human pancreas cancer cell strain BXPC3, human muscle creatine kinase cell line HL-60, human prostate cancer cell line PC-3 purchased from American standard biological product collecting center.
Method: the bright B (sulforhodamineB of sulphonyl Luo Dan, SRB) method, specific as follows: different types of tumour cell some amount being in logarithmic phase is inoculated in 96 well culture plates respectively, after cultivating 24h cell attachment, add the test-compound of the present invention of different concns, each concentration establishes three wells, and sets the DMSO solution control of respective concentration and acellular zeroing hole.After treated with medicaments cell 72h, incline nutrient solution, adds the solution of trichloroacetic acid of 10% of 100 μ L ice precoolings, in 4 DEG C of fixed cell 1h, with distilled water wash 5 times, and seasoning in air.Then add 100 μ LSRB (4mg/mL) (Sigma, StLouis, MO, USA) solution, dye in room temperature 15min, removes staining fluid, washs 5 times, dry air with 1% Glacial acetic acid.Finally add the Tris solution (pH10.5) of 150 μ L10mM, wavelengthtunable declines under orifice plate microplate reader 515nm wavelength and measures OD value.Inhibiting rate with following formulae discovery medicine cell growth: inhibiting rate (%)=(OD contrasts-OD dosing)/OD contrasts × 100%.
Result: multiple compound of the present invention shows good anti-tumor activity to various tumor cell strains.Part of compounds reaches 90% to Proliferation of Tumor Cells In Vitro inhibiting rates such as MDA-MB-435, SK-BR-3, A375, A431, HT-29, A-549, BEL-7402, BXPC3, HL-60, PC-3 under 10 μMs of concentration.Concrete data are in Table 1-10.
The inhibiting rate % of table 1 pair growth of tumour cell
The inhibiting rate % of table 2 pair growth of tumour cell
The inhibiting rate % of table 3 pair growth of tumour cell
The inhibiting rate % of table 4 pair growth of tumour cell
The inhibiting rate % of table 5 pair growth of tumour cell
The inhibiting rate % of table 6 pair growth of tumour cell
The inhibiting rate % of table 7 pair growth of tumour cell
The inhibiting rate % of table 8 pair growth of tumour cell
The inhibiting rate % of table 9 pair growth of tumour cell
The inhibiting rate % of table 10 pair growth of tumour cell
Multiple compound of the present invention shows good anti-tumor activity to various tumor cell strains, to MDA-MB-435, SK-BR-3, A375 under 10 μMs of concentration, the inhibiting rate of the tumor cell line such as A431, HT-29, A-549, BEL-7402, BXPC3, HL-60, PC-3 reaches 90%.
The compound that structure based general formula I, II or III represent has good inhibit activities to kinds of tumor cells, and applicant is studied the antitumor machanism that 5,8-bis-replaces-1,6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof further.Applicant adopts enzyme-linked immunosorbent assay (ELISA) to find 5,8-bis-replaces-1,6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof under 10 μMs to multiple Tyrosylprotein kinase (EGFR, ErbB2, c-Src, KDR, Flt-1) there is good inhibit activities.
Embodiment 2:5,8-bis-replaces-1,6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof to the restraining effect of 5 kinds of protein tyrosine kinases
Protein tyrosine kinase: c-Src, EGFR utilize insect baculovirus expression system to express for this laboratory, with the activated intracellular kinase district protein tyrosine kinase that Ni-NTA post affinity purification obtains, and meet requirement of experiment after testing ,-70 DEG C of packing, preserve.KDR, Flt-1 are purchased from Upstate company (Waltham, MA, USA); ErbB2 is purchased from Calbiochem company (Darmstadt, Germany).
Experimental technique: tyrosine kinase activity test adopts enzyme-linked immunosorbent assay (ELISA) method, specific as follows: first by enzyme reaction substrate Poly (Glu, Tyr) 4:1 (20 μ g/mL, 37 DEG C are spent the night) coated elisa plate, it is for subsequent use to wash plate post-drying.When reacting, every hole first adds the ATP solution 80 μ L (final concentration of ATP is 5 μMs) with reaction buffer dilution, then test-compound or the DMSO solvent control 10 μ L of gradient concentration is added, finally to add with the Tyrosylprotein kinase 10 μ L of reaction buffer dilution to start reaction respectively, put 37 DEG C of shaking tables and react 1h.After reaction terminates, T-PBS washes plate three times.Then every hole adds 100 μ LPY99 antibody (T-PBS of antibody containing BSA5mg/ml dilutes), 37 DEG C of shaking table reaction 0.5h.T-PBS washes plate three times.Add the IgG100 μ L/ hole (T-PBS of antibody containing BSA5mg/mL dilutes) of horseradish peroxidase-labeled sheep anti mouse, 37 DEG C of shaking table reaction 0.5h.T-PBS washes plate three times.Then the OPD nitrite ion 100 μ L/ hole of 2mg/mL is added, 25 DEG C of lucifuge reaction 1-10min.Add 2MH 2sO 450 μ L/ hole stopped reactions, to decline orifice plate microplate reader reading with wavelengthtunable, wavelength is 492nm.The inhibiting rate of sample is tried to achieve by following formula:
Experiment repetition more than 3 times, suppresses the IC of PTK with Logit method computerized compound 50value and SD value.
Result: research finds that multiple compound (comprises EGFR, ErbB2, c-Src to tested Tyrosylprotein kinase, KDR, Flt-1) have inhibit activities in various degree, part of compounds under 10 μMs of concentration to c-Src, KDR kinase inhibition rate up to 90%, be even better than positive control drug.Pointing out compound useful effect of the present invention in above-mentioned Tyrosylprotein kinase, is the multiple receptor tyrosine kinases inhibitor of novel structure.Detailed data is in table 11.In table, space represents and does not carry out dependence test, without related data.
Table 11 compound under 10 μMs to the inhibiting rate of Tyrosylprotein kinase (EGFR, ErbB2, c-Src, KDR, Flt-1)
As can be seen from the experimental result of table 11, compound useful effect of the present invention, in above-mentioned Tyrosylprotein kinase, is the multiple receptor tyrosine kinases inhibitor of novel structure.A lot of compound to Src, KDR kinases at 10 μMs of lower inhibiting rates up to 90%, be even better than positive control drug.

Claims (8)

1. 5,8-bis-shown in general structure II or III replaces the dimer compound of-1,6-naphthyridine-7-amidocarbonylation compound:
Wherein,
A is phenyl ring;
L is C 1-C 6alkyl;
X is NH independently of one another;
Y is (1) C 1-C 6alkyl; (3) (C 0-C 6alkyl)-(C 3-C 6cycloalkyl)-(C 0-C 6alkyl); Or (5) (C 0-C 6alkyl)-(C 6-C 10aryl)-(C 0-C 6alkyl);
R 1, R 2, R 3and R 4be hydrogen, halogen or-CF independently of one another 3;
R 5for hydrogen or C 1-C 6alkyl;
R 6the following groups being halogen independently or not replacing or be substituted with a substituent independently of one another: C 2-C 6alkynyl; Described substituting group is selected from-COR b;
R bfor hydrogen or unsubstituted following groups: C 1-C 6alkyl or C 1-C 6alkoxyl group.
2. 5,8-bis-shown in general structure II or III according to claim 1 replace the dimer compound of-1,6-naphthyridine-7-amidocarbonylation compound, it is characterized in that, represent further with general structure V or VI:
Wherein, R 1, R 2, R 6, L, X be identical with claim 1 with the definition of Y.
3. 5,8-bis-shown in general structure II or III according to claim 2 replace the dimer compound of-1,6-naphthyridine-7-amidocarbonylation compound, it is characterized in that, in general structure V or VI:
R 1and R 2be hydrogen, halogen or-CF independently of one another 3;
R 6for halogen or l is C 1-C 6alkyl;
X is NH;
Y is C 1-C 6alkyl, (C 1-C 6alkyl)-(C 6-C 10aryl)-(C 1-C 6alkyl) or C 3-C 6cycloalkyl.
4. one kind 5,8-bis-replaces the dimer compound of-1,6-naphthyridine-7-amidocarbonylation compound, it is characterized in that, is specially following compound:
Wherein,
Y is r 6for Br, R 8for
Y is r 6for Br, R 8for
Y is r 6for r 8for or,
Wherein,
R 6for Br ,-X-Y-X-are
5. shown in general structure II or III 5 according to any one of claims 1 to 3,8-bis-replaces-1, the dimer compound or according to claim 45 of 6-naphthyridine-7-amidocarbonylation compound, 8-bis-replaces the purposes of dimer compound in the medicine preparing tyrosine protein kinase inhibitor of-1,6-naphthyridine-7-amidocarbonylation compound.
6. shown in general structure II or III 5 according to any one of claims 1 to 3,8-bis-replaces-1, the dimer compound or according to claim 45 of 6-naphthyridine-7-amidocarbonylation compound, 8-bis-replaces the purposes of dimer compound in the medicine preparing Tumor suppression of-1,6-naphthyridine-7-amidocarbonylation compound.
7. purposes according to claim 6, wherein, described tumour comprises mammary cancer, ovarian cancer, malignant melanoma, Skin Squamous Cell Carcinoma, colorectal carcinoma, lung cancer, liver cancer, carcinoma of the pancreas, acute myeloid leukaemia and prostate cancer.
8. a pharmaceutical composition, it comprises shown in general structure II or III 5 according to any one of the claims 1 to 3 for the treatment of significant quantity, 8-bis-replaces-1, the dimer compound or according to claim 45 of 6-naphthyridine-7-amidocarbonylation compound, 8-bis-replaces the dimer compound of-1,6-naphthyridine-7-amidocarbonylation compound.
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