CN102558172A - 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds, dimer compounds of 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds, and preparation method and use of 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds and dimer compounds of 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds - Google Patents
5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds, dimer compounds of 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds, and preparation method and use of 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds and dimer compounds of 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds Download PDFInfo
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- 0 CC[C@](CC[C@](C=C)Nc1c2ncccc2c(*)nc1C(***C(c1nc(*)c(cccn2)c2c1NC(CC1)CCC1N)=O)=O)N Chemical compound CC[C@](CC[C@](C=C)Nc1c2ncccc2c(*)nc1C(***C(c1nc(*)c(cccn2)c2c1NC(CC1)CCC1N)=O)=O)N 0.000 description 5
- SYSZENVIJHPFNL-UHFFFAOYSA-N COc(cc1)ccc1I Chemical compound COc(cc1)ccc1I SYSZENVIJHPFNL-UHFFFAOYSA-N 0.000 description 2
- VLVCDUSVTXIWGW-UHFFFAOYSA-N Nc(cc1)ccc1I Chemical compound Nc(cc1)ccc1I VLVCDUSVTXIWGW-UHFFFAOYSA-N 0.000 description 2
- PCEMCFNBRWRRHC-UHFFFAOYSA-N CC(C)(C)OC(NC(CC1)CCC1Nc1c2ncccc2c(C#CC(OC)=O)nc1C(NCc(cc1)ccc1Cl)=O)=O Chemical compound CC(C)(C)OC(NC(CC1)CCC1Nc1c2ncccc2c(C#CC(OC)=O)nc1C(NCc(cc1)ccc1Cl)=O)=O PCEMCFNBRWRRHC-UHFFFAOYSA-N 0.000 description 1
- RXYPXQSKLGGKOL-UHFFFAOYSA-N CN1CCN(C)CC1 Chemical compound CN1CCN(C)CC1 RXYPXQSKLGGKOL-UHFFFAOYSA-N 0.000 description 1
- OBLKGLNRMMXCFW-UHFFFAOYSA-O CNC(CC1)CCC1[NH3+] Chemical compound CNC(CC1)CCC1[NH3+] OBLKGLNRMMXCFW-UHFFFAOYSA-O 0.000 description 1
- RMIVMBYMDISYFZ-UHFFFAOYSA-N CNCCCCN Chemical compound CNCCCCN RMIVMBYMDISYFZ-UHFFFAOYSA-N 0.000 description 1
- HIBVKSYTHWWICX-UHFFFAOYSA-N COC(CC(c(nc1C(NCc(cc2C(F)(F)F)ccc2Cl)=O)c(cccn2)c2c1NC(CC1)CCC1N)=O)=O Chemical compound COC(CC(c(nc1C(NCc(cc2C(F)(F)F)ccc2Cl)=O)c(cccn2)c2c1NC(CC1)CCC1N)=O)=O HIBVKSYTHWWICX-UHFFFAOYSA-N 0.000 description 1
- PNQVAYAGIUJQLU-UHFFFAOYSA-N COC(CC(c(nc1C(NCc(ccc(Cl)c2)c2Cl)=O)c(cccn2)c2c1NC(CC1)CCC1N)=O)=O Chemical compound COC(CC(c(nc1C(NCc(ccc(Cl)c2)c2Cl)=O)c(cccn2)c2c1NC(CC1)CCC1N)=O)=O PNQVAYAGIUJQLU-UHFFFAOYSA-N 0.000 description 1
- WDCSXBRXJCGXNG-UHFFFAOYSA-N COC(c1ncc(cccn2)c2c1O)=O Chemical compound COC(c1ncc(cccn2)c2c1O)=O WDCSXBRXJCGXNG-UHFFFAOYSA-N 0.000 description 1
- MKARNSWMMBGSHX-UHFFFAOYSA-N Cc1cc(N)cc(C)c1 Chemical compound Cc1cc(N)cc(C)c1 MKARNSWMMBGSHX-UHFFFAOYSA-N 0.000 description 1
- LVNDUJYMLJDECN-UHFFFAOYSA-N Cc1cc(N)cc(N)c1 Chemical compound Cc1cc(N)cc(N)c1 LVNDUJYMLJDECN-UHFFFAOYSA-N 0.000 description 1
- JJYPMNFTHPTTDI-UHFFFAOYSA-N Cc1cccc(N)c1 Chemical compound Cc1cccc(N)c1 JJYPMNFTHPTTDI-UHFFFAOYSA-N 0.000 description 1
- MFSDBLORDPHTSJ-UHFFFAOYSA-N NC(CC1)CCC1Nc(c(C(NS(c(cc([s]1)Cl)c1Cl)(=O)=O)=O)n1)c2ncccc2c1Br Chemical compound NC(CC1)CCC1Nc(c(C(NS(c(cc([s]1)Cl)c1Cl)(=O)=O)=O)n1)c2ncccc2c1Br MFSDBLORDPHTSJ-UHFFFAOYSA-N 0.000 description 1
- VZXIWXPLEIVOLO-UHFFFAOYSA-N NC(CC1)CCC1Nc(c1c2cccn1)c(C(NCc1ncccc1)=O)nc2Br Chemical compound NC(CC1)CCC1Nc(c1c2cccn1)c(C(NCc1ncccc1)=O)nc2Br VZXIWXPLEIVOLO-UHFFFAOYSA-N 0.000 description 1
- NAQMVNRVTILPCV-UHFFFAOYSA-O NCCCCCC[NH3+] Chemical compound NCCCCCC[NH3+] NAQMVNRVTILPCV-UHFFFAOYSA-O 0.000 description 1
- FZGQKXXRWSUULW-HOTGVXAUSA-N N[C@@H](CCC1)CC[C@H]1Nc(c(C(NCc(cccc1)c1Cl)=O)n1)c2ncccc2c1Br Chemical compound N[C@@H](CCC1)CC[C@H]1Nc(c(C(NCc(cccc1)c1Cl)=O)n1)c2ncccc2c1Br FZGQKXXRWSUULW-HOTGVXAUSA-N 0.000 description 1
- FOQYZFIIDYJAAH-IKVFXUPASA-N N[C@H](CC1)CC[C@@H]1Nc(c1c2cccn1)c(C(NCCCCNC(c(nc(c1c3nccc1)Br)c3NC(CC1)CCC1N)=O)=O)nc2Br Chemical compound N[C@H](CC1)CC[C@@H]1Nc(c1c2cccn1)c(C(NCCCCNC(c(nc(c1c3nccc1)Br)c3NC(CC1)CCC1N)=O)=O)nc2Br FOQYZFIIDYJAAH-IKVFXUPASA-N 0.000 description 1
Abstract
The invention discloses 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds, dimer compounds of the 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds, a preparation method and use of the 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds and the dimer compounds of the 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds, and pharmaceutical compositions containing the 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds. More specifically, the invention discloses the 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds expressed by structural formulae I and II or III, the dimer compounds of the 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds and the preparation method of the 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds and the dimer compounds of the 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds, and provides the use of the 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds and the pharmaceutical compositions containing the 5,8-disubstituted-1,6-naphthyridine-7-carbonyl amide compounds in the treatment of diseases related to protein tyrosine kinase, in particular to c-Src, such as tumor diseases, by serving as a multi-target spot protein tyrosine kinase inhibitor.
Description
Technical field
The present invention relates to medical technical field; Be specifically related to 5; 8-two replaces-1; 6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof and their preparation method; The invention still further relates to 5,8-two replaces-1, and 6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof and the pharmaceutical composition that contains this compound are used for mammary cancer, ovarian cancer, malignant melanoma, skin squama cancer, colorectal carcinoma, lung cancer, liver cancer, carcinoma of the pancreas, acute myeloid leukaemia, prostate cancer etc. and the particularly treatment of c-Src diseases associated of Tyrosylprotein kinase as many target spots tyrosine protein kinase inhibitor.
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 towards periphery tissue to shift be characteristics; The death that the mankind cause because of malignant tumour occupy second of all disease death rates, is only second to cardiovascular and cerebrovascular diseases.The tumor treatment method has operative treatment, radiotherapy and pharmacological agent (chemotherapy) etc.; But be main still to a great extent with chemotherapy; Especially to the appearance of the targeting antineoplastic medicine thing of the design of the key enzyme in the tumour mechanism, make chemotherapy successfully to heal the sick or prolong patient's life-span significantly.
In recent years, (Protein tyrosine kinase PTK) as the target of targeting antineoplastic medicine thing, has caused medicine scholar extensive interest to LCK.LCK is the important factor in the signal transduction process, participates in a series of cell functions, with cell growth, differentiation, closely related [the Microsc Res Tech.2003Jan 1 of propagation; 60 (1): 70-75], the γ phosphate that it can catalysis ATP is transferred on the tyrosine residues of many key proteins, makes the phenolic hydroxyl group phosphorylation.Many cancer expression of gene products also all have the PTK activity, and the PTK activity in a lot of malignant conversioning cells is higher than normal cell far away.Therefore if can suppress the PTK activity, just might block the growth of tumour cell.PTK has become noticeable antitumor drug novel targets [Curr Drug Targets.2003, Feb; 4 (2): 113-121].
The antitumour drug of target PTK has been obtained rapid progress at last decade; Gleevec, Iressa and Erlotinib are successively gone on the market by drugs approved by FDA; Proved that fully receptor tyrosine kinase is an effective antitumour drug target; And many target spots Tyrosylprotein kinase suppresses oncotherapy New Policy [European J.Cancer.2006, Jun that (multiple targeted tyrosine kinase inhibition) also becomes prospect as rich as Croesus; 42,1351-1356].Because most tumours are not to rely on a bars pathway to keep its growth and survival; So; It is rapid that many target drugs can suppress the multistep of a multiple signal pathway or a bars pathway, not only has synergy, and be difficult for inducing tumor cell and produce resistance.The new ideas of this molecular targeted tumor pharmacother have also obtained successful clinical evidence, as being exactly many target drugs of while target c-Raf and multiple Tyrosylprotein kinase such as VEGFR-2, β-PDGFR recently by the medicine BAY43-9006 (Sorafenib) of the treatment kidney cell tumour of FDA approval listing and gastrointestinal stromal tumor.Another is suppressed many Tyrosylprotein kinase paths such as VEGFR, α-PDGFR simultaneously by the new Tyrosylprotein kinase inhibition SU11248 (Sutent) that the FDA approval is used for the gastrointestinal stromal tumor treatment; For the treatment of other solid tumors provides new research thinking [European J.Cancer.2006, Jun; 42,1351-1356].
Mostly the propylhomoserin SU11752 of bibliographical information is the verivate of pyrimidine or quinazoline structure; Of the present invention 1; 6-naphthyridine-7-carboxamide derivatives is the multiple SU11752 of one type of new texture; Show kinase whose inhibition such as c-Src, KDR, EGFR, ErbB2 actively, and effectively suppress the cell growth of a series of tumor cell lines such as MDA-MB-435, SK-BR-3, A375, A431, HT-29, A-549, BEL-7402, BXPC3, HL-60, PC-3.
The patent documentation relevant with the present invention listed as follows:
A series of quinoline vascular endothelial growth factor receptor inhibitors have been disclosed among the WO98/13350.Wherein also comprise 1,8-naphthyridine analog derivative, the embodiment 53:2-acetylaminohydroxyphenylarsonic acid 5-in this patent (2-fluoro-5-hydroxy-4-methyl aniline)-1 for example, 8-naphthyridine.
Disclose 4-hydroxyquinoline-2-carboxamide derivatives among the WO99/32450 and be used to treat herpesvirus infection.
Disclose Bioquin-7CA's sulfonamide derivatives among the WO98/11073 and be used to treat herpesvirus infection.
Disclosed 8-hydroxyl-1 among the WO02/30931,6-naphthyridine-7-carbonyl amines compound is used to treat the HIV-1 virus infection.
Disclosed 5 among the CN2008102000645.4,8-two replaces-1, and 6-naphthyridine-7-amidocarbonylation compound is used to treat mammary cancer, colorectal carcinoma, ovarian cancer, prostate cancer.
Summary of the invention
An object of the present invention is to disclose one type and have brand new, imitate 5 of anti-tumor activity by force, 8-two replaces-1,6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof.
It is above-mentioned 5 that another object of the present invention provides, and 8-two replaces-1, the preparation method of 6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof.
An also purpose of the present invention provides above-mentioned 5; 8-two replaces-1; 6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof are in the purposes of field of medicaments; They can be used as many target spots tyrosine protein kinase inhibitor and are used for tumour, comprise mammary cancer, ovarian cancer, malignant melanoma, skin squama cancer, colorectal carcinoma, lung cancer, liver cancer, carcinoma of the pancreas, acute myeloid leukaemia, prostate cancer and the particularly treatment of c-Src diseases associated of Tyrosylprotein kinase.
A purpose more of the present invention provides a kind of 5 of treatment significant quantity that comprises, and 8-two replaces-1, the pharmaceutical composition of 6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof.
According to the present invention, described have 5 of an anti-tumor activity, and 8-two replaces-1, and 6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof are shown in following general structure I, II or III:
Wherein,
A is: (1) phenyl ring; (2) C
8-C
10A pair of horses going side by side synthetic bicyclic carbocyclic ring, one of them is a phenyl ring, another is saturated or undersaturated ring; (3) 8～10 atoms a pair of horses going side by side synthetic rings, and contain 0-3 and be selected from the heteroatoms among N, O and the S, one of them is aromatic ring or hetero-aromatic ring, another be saturated perhaps undersaturated carbocyclic ring or heterocycle; (4) contain 1～3 heteroatomic five yuan or six-membered Hetero-aromatic that is selected among N, O and the S; Or 0～3 heteroatomic ternary to seven yuan cycloaliphatic ring that is selected among N, O and the S is contained in (5);
L is: (1) is key directly; (2) C
1-C
6Alkyl; (3) C
2-C
6Thiazolinyl; (4) (C
0-C
6Alkyl)-(C
3-C
6Naphthenic base)-(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 by 1-3 independent substituent replacement separately with the alkyl in (2), (4), (5), and said substituting group is selected from following atom or group: C
1-C
6Alkyl, C
1-C
6Alkoxy C
1-C
6Alkyl, C
3-C
8Naphthenic base, 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
6Naphthenic base)-(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 by 1-3 independent substituent replacement separately with the alkyl in (1), (3), (4), and said substituting group is selected among following atom or the group: C
1-C
6Alkyl, C
1-C
6Alkoxy C
1-C
6Alkyl, C
3-C
8Naphthenic base, 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 independently of one another hydrogen, halogen, hydroxyl, sulfydryl ,-CF
3,-CN ,-NO
2Perhaps do not replace or independently of one another by 1-3 the substituted following groups of substituting group: C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Naphthenic base, 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; Said substituting group is selected among following atom or the group: C
1-C
6Alkyl, C
1-C
6Alkoxy C
1-C
6Alkyl, heterocyclic radical, C
1-C
6The substituted heterocyclic radical of alkyl, heterocyclic radical carbonyl, C
1-C
6Alkyl heterocyclic, C
6-C
10Aryl, C
3-C
8Naphthenic base, 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
bCan form cyclammonium jointly; Said heterocycle is to comprise that 1-3 is selected from heteroatomic ternary to the seven yuan cycloaliphatic ring among N, O and the S;
R
5For hydrogen, hydroxyl or do not replace or by 1-3 the substituted following groups of independent substituent: 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
8Naphthenic base, phenyl, benzyl, naphthyl, C
5-C
10Aromaticity heterocyclic radical or C
4-C
7Saturated heterocyclyl; Said heterocycle comprises that 1-3 is selected from the heteroatoms among N, O and the S; Said 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
aBe hydrogen, C
1-C
6Alkyl, C
3-C
8Naphthenic base or C
6-C
10Aryl;
R
bFor hydrogen, hydroxyl or do not replace or by 1-3 the substituted following groups of substituting group: C independently of one another
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
8Naphthenic base, phenyl, phenylol, benzyl, naphthyl, C
5-C
10Aromaticity heterocyclic radical or C
4-C
7Saturated heterocyclyl; Said heterocycle comprises that 1-3 is selected from the heteroatoms among N, O and the S; Said 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
Preferred compound can be represented with general structure IV, V or VI in the compound that general structure I of the present invention, II or III represent:
Wherein, R
1, R
2, R
6, L, X and Y definition and general formula I, II or III in identical, and further preferred:
R
1And R
2Be independently of one another hydrogen, halogen ,-CN ,-CF
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, heterocyclic radical carbonyl C
1-C
6Alkoxyl group or C
6-C
10Aryl C
1-C
6Alkoxyl group; Heterocyclic radical wherein is meant and contains 1～3 heteroatomic ternary to seven yuan cycloaliphatic ring that is selected among N, O and the 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
6Naphthenic base.
More preferably, general formula I is described 5, and 8-two replaces-1, and 6-naphthyridine-7-amidocarbonylation compound particularly, is following compound:
L is-CH
2-, R
6Be Br, R
7For
L is-SO
2-, R
6Be 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 the listed compound of following table:
More preferably, general formula I I is described 5, and 8-two replaces-1, and 6-naphthyridine-7-amidocarbonylation dimer compound particularly, is following compound:
Y does
R
6Be Br, R
8For
Y does
R
6Be Br, R
8For
Y does
R
6For
R
8For
Be the listed compound of following table:
More preferably, general formula III is described 5, and 8-two replaces-1, and 6-naphthyridine-7-amidocarbonylation dimer compound particularly, is following compound:
R
6For Br,
-X-Y-X-does
Be the listed compound of following table:
The compound that general structure I of the present invention, II or III represent prepares through following method:
Wherein, R
6, X and Y definition and general formula I, II, III in identical, and be preferably the group shown in the table.R
7For
Wherein, A, R
1, R
2, R
3And R
4Definition and general formula I, II, III in identical.
Reaction reagent and condition: (a) Virahol, reflux 68%; (b) thionyl chloride refluxes; (c) Peng Qinghuana, THF, 0 ℃, two step productive rates 38%; (d) TsNHCH
2COOCH
3, DEAD (diethyl azodiformate), triphenylphosphine, THF, 0 ℃; (e) sodium methylate, methyl alcohol, 0 ℃～room temperature, two step productive rates 65%; (f) NBS (N-bromo-succinimide), methylene dichloride, room temperature, productive rate 85%; (g) amine, toluene refluxed productive rate 88% 24 hours; (h) TsCl, triethylamine, methylene dichloride, productive rate 90%; (i) 1, the trans cyclohexanediamine of 4-, THF refluxes productive rate 75%-85%; (j) LiOH solution/methyl alcohol, or NaOH solution/THF refluxes 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, the propynoic acid methyl esters, THF refluxes productive rate 70%-85%; (n) EDCI, HOAt, DIPEA, amine, methylene dichloride, productive rate 70%-90%.
(1) compound method of compound S 1-S21 and S43, S44 is following: with compound 1 pyridine 2,3-dicarboxylic anhydride selective esterification obtains compound 2, productive rate 68%.Compound 2 chloros obtain compound 3; Compound 3 obtains compound 4 with the selective reduction of acyl chlorides form, and productive rate is 38%.Compound 4 obtains compound 5 through the Mitsunobo reaction.Ring obtains 1 to compound 5 in sodium methylate ShiShimonoseki, 6-naphthyridine carbonyl acid methyl esters 6, two step productive rate 65%.Compound 6 with contain R
6Compound (like N-iodo succimide or N-bromo-succinimide) reaction obtain 5-R
6-1,6-naphthyridine carbonyl acid methyl esters 7, productive rate 85%.Compound 7 with contain R
7Amine amideization obtain 1,6-naphthyridine carbonyl amide compound 8, productive rate 88%.8 hydroxyls of compound 8 obtain compound 9 with the Ts protection with 90% productive rate.The synthetic route of compound 9 see reference document WO 2002030426 and WO2002030930.The aryl nucleophilic substitution reactions take place and obtain a series ofly 5 in compound 9 and 1, the trans hexamethylene of 4-two, and 8-two replaces-1,6-naphthyridine-7-amidocarbonylation compound S1-S21 and S43, S44, productive rate 75%-85%.
(2) compound method of compound S 22-S30 is following: compound 7 refluxes in methylene dichloride with triethylamine with TsCl and obtained compound 10 in 5 hours, and it is trans 1 that compound 10 and single Boc protect, and the 4-cyclohexanediamine is at K
2CO
3Obtained compound 11 in 8 hours with reflux in the THF, compound 11 is the following 10h generation compound 12 of 60 degree in 1N NaOH solution/THF.Compound 12 is in EDCI, DMAP and methylene dichloride, and normal temperature obtains compound 13 with corresponding sulfuryl amine reaction 12h down.Compound 13 removes Boc and generates 5 in trifluoracetic acid/methylene dichloride of 20%, 8-two replaces-1,6-naphthyridine-7-amidocarbonylation compound S22-S30.
(3) compound method of compound S 33-S42 is following: compound 9 and trans 1; 4-cyclohexanediamine reflux in triethylamine, THF obtained compound 14 in 8 hours; Compound 14 refluxes in Palladous chloride, triphenylphosphine, cuprous iodide, salt of wormwood and THF and the reaction of propynoic acid methyl esters obtains compound 15; Compound 15 is sloughed Boc and is obtained 5 in 20% trifluoracetic acid/methylene dichloride, 8-two replaces-1,6-naphthyridine-7-amidocarbonylation compound S33-S42.
(4) compound method of compound S 46-S51 is following: compound 12 is in EDCI, HOAt, DIPEA and methylene dichloride, and normal temperature obtains compound 16 with corresponding amine reaction 12h down.Compound 16 removes Boc and generates 5 in trifluoracetic acid/methylene dichloride of 20%, 8-two replaces-1,6-naphthyridine-7-amidocarbonylation dimer compound S46-S51.
Through various tumor cell strains is screened, the applicant finds: the compound that said structure general formula I, II or III represent has inhibition efficiently active to following cell in 10 μ M: MDA-MB-435, SkBr-3, A375, A431, HT 29, A-549, BEL-7402, BXPC3, HL-60, PC-3.
Therefore, the compound represented of general structure I, II or III can efficacious therapy MDA-MB-435, the disease that causes of SkBr-3, A375, A431, HT 29, A-549, BEL-7402, BXPC3, HL-60, PC-3 tumour cell malignant proliferation.
The pharmaceutical composition that contains the compound that general structure I, II or III represent that allows on the technology of pharmaceutics can play the disease that efficacious therapy MDA-MB-435, SkBr-3, A375, A431, HT 29, A-549, BEL-7402, BXPC3, HL-60, PC-3 tumour cell malignant proliferation cause equally.
Compound of the present invention has increased substituent R in the general formula I on the basis of CN2008102000645.4
6, L and R
7Structure type; Also increased dimeric structure type; These compounds have further strengthened the inhibition of Tyrosylprotein kinases such as c-Src, KDR, EGFR, ErbB2, Flt-1 active, and can effectively suppress the cell growth of wider serial tumor cell line such as MDA-MB-435, SK-BR-3, A375, A431, HT-29, A-549, BEL-7402, BXPC3, HL-60, PC-3.
Embodiment
Preparation embodiment:
Embodiment further describes the present invention below in conjunction with preparation, but does not limit the present invention.
Compound
1The H-NMR spectroscopic data is measured and is used Varian Mercury-300MHz or VarianMercury-400MHz nucleus magnetic resonance, ultimate analysis to use Vario EL determinator, and fusing point is measured with the Buchi-510 capillary tube technique, and temperature is not calibrated.Ir spectra is by Bio-Rad FTS-185 determination of infrared spectroscopy; Mass spectrum EI-MS is with Finnigan MAT 95 mass spectrographs, and ESI-MS uses Finnigan LCQ Deca mass spectrograph to measure.Specific rotation is measured by the automatic polarimeter of P-1030 (A012360639).Rapid column chromatography carries out on silica gel H (10-40 μ M).The reagent purifying is with reference to Purification of laboratory Chemicals; D.D.Perrin; W.L.F.Armarego and D.R.Perrin Eds., Pergamon Press:Oxiford, 1980.
Pyridine-2,3-dioctyl phthalate-2-isopropyl ester (2)
With compound 1 pyridine 2, (48.1g 0.32mol) was dissolved in the 2-Virahol of 100mL reflux 16 hours to the 3-dicarboxylic anhydride, then solution was cooled to-20 ℃ and obtained white solid compound 2 (44.4g, 68%).Fusing point: 140-141 ℃;
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)
(52.7g 0.25mol) is dissolved in that reflux to solution becomes homogeneous phase in the thionyl chloride of 400mL, revolves dried solvent then with compound 2.Add the anhydrous THF of 2 * 50mL and revolve steaming, remove residual thionyl chloride.Resulting red liquid be dissolved among the anhydrous THF of 400mL be cooled to 0 ℃, add in batches Peng Qinghuana (28.6g, 0.76mol), 0 ℃ was stirred 4 hours down, with careful the pouring in the frozen water of reaction soln, 3 * 200mL dichloromethane extraction adds anhydrous Na
2SO
4Dry.Column chromatography (sherwood oil: ETHYLE ACETATE=3: 2) obtain yellow solid compound 4 (18.8g, 38%).
1H?NMR(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-MS?m/z：195(M)
+。
3-{ [methoxycarbonyl methyl-(toluene-4-alkylsulfonyl)-amino]-methyl }-pyridine-2-carboxylic acids isopropyl ester (5)
With compound 4 (1.734g, 8.89mmol), 2-tolysulfonyl glycine methyl esters (TsNHCH
2COOCH
3) (2.163g, 8.89mmol), and triphenylphosphine (3.499g 13.338mmol) is dissolved among the anhydrous THF of 100mL, is cooled to 0 ℃, inflated with nitrogen protection.(2.165mL 13.338mmol) is dissolved among the anhydrous THF of 10mL DEAD, dropwise adds DEAD.Remove ice bath, stir to revolve after two hours and driedly obtain red oily fluid cpds 5 and directly be used for down step reaction.
8-hydroxyl-1,6-naphthyridine-7-carboxylate methyl ester (6)
The compound 5 (8.89mmol) that the reaction of last step is obtained is dissolved in the 50mL anhydrous methanol, is cooled to 0 ℃.Slow adding sodium methylate (1.681g, 31.123mmol).Remove ice bath, stirred 3 hours.Spin off solvent, add 20mL water, 20mL ETHYLE ACETATE, organic phase is used the saturated sodium carbonate back extraction.Merge water, transfer pH to 7, keep water pH to 7, with dichloromethane extraction 5 times.Organic phase is used anhydrous sodium sulfate drying, column chromatography (sherwood oil: ETHYLE ACETATE=2: 1) obtain pale solid compound 6 (0.62g, two step productive rates 65%).Fusing point: 179-180 ℃;
1H NMR (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)
(30mg 0.167mmol) joins compound 6 (34mg, 1mLCH 0.167mmol) with NBS under the normal temperature
2Cl
2In the solution, stirred 1 hour.Filter, drying obtains white solid compound 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-(2-chloro-benzyl)-5-bromo-8-hydroxyl-1,6-naphthyridine-7-carboxylic acid amine (8-1)
With compound 7-1 and 2-chlorobenzylamine reflux 20 hours under the nitrogen protection in toluene, be cooled to room temperature.Filter, solid is washed with methyl alcohol, obtains yellow solid compound 8-1, productive rate: 75-85%;
1H NMR (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).
Toluene-4-sulfonic acid 5-bromo-7-(2-chloro-benzylamino formyl)-1,6-naphthyridine-8-carboxylicesters (9-1)
The 50 ℃ of stirrings in chloroform of Tosyl chloride, compound 8-1, triethylamine are used saturated ammonium chloride after 5 hours, saturated common salt washing, drying successively.Column chromatography obtains white solid compound 9-1, productive rate: 85-95%;
1H NMR (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)-the amino hexamethylene of 4-is amino)-N-(2-chloro-benzyl)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S1)
With compound 9-1, triethylamine and 1, the trans cyclohexanediamine of 4-reflux 8 hours in THF is revolved and is done THF, adds methylene dichloride, uses saturated Na successively
2CO
3The aqueous solution, saturated aqueous ammonium chloride, saturated common salt washing, anhydrous Na
2SO
4Dry.Column chromatography obtains yellow solid compound S 1, productive rate: 75-85%.
1H?NMR(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-MS?m/z：487(M)
+，489(M+2)
+。
N-(3-chloro-benzyl)-5-bromo-8-hydroxyl-1,6-naphthyridine-7-carboxylic acid amine (S2-1)
The preparation method of the preparation method of compound S 2-1 and compound 8-1 is similar, except using the 3-chlorobenzylamine is replaced the 2-chlorobenzylamine.Yellow solid, productive rate: 75-85%.
1H?NMR(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)。
Toluene-4-sulfonic acid 5-bromo-7-(3-chloro-benzylamino formyl)-1,6-naphthyridine-8-carboxylicesters (S2-2)
The preparation method of the preparation method of compound S 2-2 and compound 9-1 is similar, except replacing compound 8-1 with compound S 2-1.White solid, productive rate: 85-95%.
1H?NMR(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)-the amino hexamethylene of 4-is amino)-N-(3-chloro-benzyl)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S2)
The preparation method of the preparation method of compound S 2 and compound S 1 is similar, except replacing compound 9-1 with compound S 2-2.The yellow-green colour solid, productive rate: 75-85%.
1H?NMR(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-MS?m/z：487(M)
+，489(M+2)
+。
N-(4-(2-(4-N-METHYL PIPERAZINE-1-yl)) ethoxy-benzyl)-5-bromo-8-hydroxyl-1,6-naphthyridine-7-carboxylic acid amine (S3-1)
The preparation method of the preparation method of compound S 3-1 and compound 8-1 is similar, except using 4-(2-(4-N-METHYL PIPERAZINE-1-yl)) oxyethyl group benzylamine is replaced the 2-chlorobenzylamine.Yellow solid, productive rate: 75-85%.
1H?NMR(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)。
Toluene-4-sulfonic acid 5-bromo-7-(4-(2-(4-N-METHYL PIPERAZINE-1-yl)) ethoxy-benzylamino formyl)-1,6-naphthyridine-8-carboxylicesters (S3-2)
The preparation method of the preparation method of compound S 3-2 and compound 9-1 is similar, except replacing compound 8-1 with compound S 3-1.White solid, productive rate: 85-95%.
1H?NMR(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-ESI?m/z：656(M+H)
+。
8-((1r, 4r)-the amino hexamethylene of 4-is amino)-N-(4-(2-(4-N-METHYL PIPERAZINE-1-yl)) ethoxy-benzyl)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S3)
The preparation method of the preparation method of compound S 3 and compound S 1 is similar, except replacing compound 9-1 with compound S 3-2.The yellow-green colour solid, productive rate: 75-85%.
1H?NMR(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(br?s，4H)，2.48(br?s，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-EI?m/z：595(M)
+，597(M+2)
+。
N-(4-(5-morpholine) penta oxygen-benzyl)-5-bromo-8-hydroxyl-1,6-naphthyridine-7-carboxylic acid amine (S4-1)
The preparation method of the preparation method of compound S 4-1 and compound 8-1 is similar, except using 4-(5-morpholine) pentyloxy benzylamine is replaced the 2-chlorobenzylamine.Yellow solid, productive rate: 75-85%.
1H?NMR(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)。
Toluene-4-sulfonic acid 5-bromo-7-(4-(5-morpholine) penta oxygen-benzylamino formyl)-1,6-naphthyridine-8-carboxylicesters (S4-2)
The preparation method of the preparation method of compound S 4-2 and compound 9-1 is similar, except replacing compound 8-1 with compound S 4-1.White solid, productive rate: 81.5%.
1H?NMR(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)-the amino hexamethylene of 4-is amino)-N-(4-(5-morpholine) penta oxygen-benzyl)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S4)
The preparation method of the preparation method of compound S 4 and compound S 1 is similar, except replacing compound 9-1 with compound S 4-2.The yellow-green colour solid, productive rate: 75-85%.
1H NMR (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-EI m/z:624 (M)
+, 626 (M+2)
+ 13C NMR (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 the preparation method of following compound S 5-1～S21-1 and compound 8-1 is similar, and crude product is directly cast the step reaction.
Toluene-4-sulfonic acid 5-bromo-7-(4-(thiophene-2-yl) benzylamino formyl)-1,6-naphthyridine-8-carboxylicesters (S5-2)
The preparation method of the preparation method of compound S 5-2 and compound 9-1 is similar, except replacing compound 8-1 with compound S 5-1.White solid, productive rate: 85-95%.
1H?NMR(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)-the amino hexamethylene of 4-is amino)-N-(4-(thiophene-2-yl) benzyl)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S5)
The preparation method of the preparation method of compound S 5 and compound S 1 is similar, except replacing compound 9-1 with compound S 5-2.The yellow-green colour solid, productive rate: 75-85%.
1H NMR (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-EI m/z:535 (M)
+, 537 (M+2)
+Anal. calculated value: C
26H
26BrN
5O
SCH
3COOH:C 56.38, and H 5.07, and N 11.74, measured value: C 56.67, and H 5.00, and N 11.70.
Toluene-4-sulfonic acid 5-bromo-7-((pyridine-2-yl) methylamino formyl)-1,6-naphthyridine-8-carboxylicesters (S6-2)
The preparation method of the preparation method of compound s 6-2 and compound 9-1 is similar, except replacing compound 8-1 with compound s 6-1.White solid, productive rate: 85-95%.
1H?NMR(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)-the amino hexamethylene of 4-is amino)-N-((pyridine-2-yl) methyl)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S6)
The preparation method of the preparation method of compound s 6 and compound S 1 is similar, except replacing compound 9-1 with compound s 6-2.The yellow-green colour solid, productive rate: 75-85%.
1H NMR (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-EI m/z:454 (M)
+, 456 (M+2)
+Anal. calculated value: C
21H
23BrN
6O1/2CF
3COOHCH
3OH:C 50.74, and H 5.09, N15.44, and measured value: C 50.81, H 4.95, and N 15.29.
Toluene-4-sulfonic acid 5-bromo-7-(3-trifluoromethyl-4-chloro-benzylamino formyl)-1,6-naphthyridine-8-carboxylicesters (S7-2)
The preparation method of the preparation method of compound S 7-2 and compound 9-1 is similar, except replacing compound 8-1 with compound S 7-1.White solid, productive rate: 85-95%.
1H?NMR(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)-the amino hexamethylene of 4-is amino)-N-(3-trifluoromethyl-4-chloro-benzyl)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S7)
The preparation method of the preparation method of compound S 7 and compound S 1 is similar, except replacing compound 9-1 with compound S 7-2.The yellow-green colour solid, productive rate: 75-85%.
1H NMR (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-EI m/z:555 (M)
+, 557 (M+2)
+Anal. calculated value: C
23H
22BrClF
3N
5O1/4CH
3OH:C 49.44, and H 4.10, and N 12.40, measured value: C 49.74, and H 4.32, and N 12.06.
Toluene-4-sulfonic acid 5-bromo-7-(2-chloro-5-trifluoromethyl-benzylamino formyl)-1,6-naphthyridine-8-carboxylicesters (S8-2)
The preparation method of the preparation method of compound S 8-2 and compound 9-1 is similar, except replacing compound 8-1 with compound S 8-1.White solid, productive rate: 85-95%.
1H?NMR(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)-the amino hexamethylene of 4-is amino)-N-(2-chloro-5-trifluoromethyl-benzyl)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S8)
The preparation method of the preparation method of compound S 8 and compound S 1 is similar, except replacing compound 9-1 with compound S 8-2.The yellow-green colour solid, productive rate: 75-85%.
1H NMR (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);
13C NMR (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-EI m/z:555 (M)
+, 557 (M+2)
+Anal. calculated value: C
23H
22BrClF
3N
5O1/5CF
3COOH3/5C
6H
14: C 51.37, and H 4.89, and N 11.09, measured value: C 51.30, and H 4.97, and N 11.07.
Toluene-4-sulfonic acid 5-bromo-7-(3,4,5-trimethoxy-benzylamino formyl)-1,6-naphthyridine-8-carboxylicesters (S9-2)
The preparation method of the preparation method of compound S 9-2 and compound 9-1 is similar, except replacing compound 8-1 with compound S 9-1.White solid, productive rate: 85-95%.
1H?NMR(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)-the amino hexamethylene of 4-is amino)-N-(3,4,5-trimethoxy-benzyl)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S9)
The preparation method of the preparation method of compound S 9 and compound S 1 is similar, except replacing compound 9-1 with compound S 9-2.The yellow-green colour solid, productive rate: 75-85%.
1H NMR (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-EI m/z:543 (M)
+, 545 (M+2)
+Anal. calculated value: C
25H
30BrN
5O
41/4CF
3COOH:C 53.46, and H 5.32, and N 12.22, measured value: C 53.52, and H 5.45, N11.93.
Toluene-4-sulfonic acid 5-bromo-7-(3,4-two fluoro-benzylamino formyls)-1,6-naphthyridine-8-carboxylicesters (S10-2)
The preparation method of the preparation method of compound S 10-2 and compound 9-1 is similar, except replacing compound 8-1 with compound S 10-1.White solid, productive rate: 85-95%.
1H?NMR(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)-the amino hexamethylene of 4-is amino)-N-(3,4-two fluoro-benzyls)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S10)
The preparation method of the preparation method of compound S 10 and compound S 1 is similar, except replacing compound 9-1 with compound S 10-2.The yellow-green colour solid, productive rate: 75-85%.
1H NMR (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-EI m/z:489 (M)
+, 491 (M+2)
+Anal. calculated value: C
22H
22BrF
2N
5O:C 53.89, and H 4.52, and N 14.28, measured value: C 53.81, and H 4.61, and N 14.06.
Toluene-4-sulfonic acid 5-bromo-7-(3,5-two trifluoromethyls-benzylamino formyl)-1,6-naphthyridine-8-carboxylicesters (S11-2)
The preparation method of the preparation method of compound S 11-2 and compound 9-1 is similar, except replacing compound 8-1 with compound S 11-1.White solid, productive rate: 85-95%.
1H?NMR(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)-the amino hexamethylene of 4-is amino)-N-(3,5-two trifluoromethyls-benzyl)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S11)
The preparation method of the preparation method of compound S 11 and compound S 1 is similar, except replacing compound 9-1 with compound S 11-2.The yellow-green colour solid, productive rate: 75-85%.
1H NMR (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-EI m/z:589 (M)
+, 591 (M+2)
+Anal. calculated value: C
24H
22BrF
6N
5O1/6C
6H
14: C 49.33, and H 3.94, and N 11.69, measured value: C 49.33, and H 3.91, and N 11.71.
Toluene-4-sulfonic acid 5-bromo-7-(4-(4-methyl benzenesulfonamide) methyl-benzyl) carbamyl)-1,6-naphthyridine-8-carboxylicesters (S12-2)
The preparation method of the preparation method of compound S 12-2 and compound 9-1 is similar, except replacing compound 8-1 with compound S 12-1.White solid, productive rate: 85-95%.
1H?NMR(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)-the amino hexamethylene of 4-is amino)-N-(4-(4-methyl benzenesulfonamide) methyl-benzyl)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S12)
The preparation method of the preparation method of compound S 12 and compound S 1 is similar, except replacing compound 9-1 with compound S 12-2.The yellow-green colour solid, productive rate: 75-85%.
1H NMR (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-EI m/z:636 (M)
+, 638 (M+2)
+HR-EIMS calculated value: C
30H
33BrN
6O
3S (M)
+: 636.1518, measured value: 636.1526.
Toluene-4-sulfonic acid 5-bromo-7-((thiophene-2-yl) methylamino formyl)-1,6-naphthyridine-8-carboxylicesters (S13-2)
The preparation method of the preparation method of compound S 13-2 and compound 9-1 is similar, except replacing compound 8-1 with compound S 13-1.White solid, productive rate: 85-95%.
1H?NMR(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)-the amino hexamethylene of 4-is amino)-N-((thiophene-2-yl) methyl)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S13)
The preparation method of the preparation method of compound S 13 and compound S 1 is similar, except replacing compound 9-1 with compound S 13-2.The yellow-green colour solid, productive rate: 75-85%.
1H NMR (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-EI m/z:459 (M)
+, 461 (M+2)
+Anal. calculated value: C
20H
22BrN
5O1/2H
2O:C 51.68, and H 5.08, and N 14.70, measured value: C 51.71, and H 4.85, and N 14.46.
Toluene-4-sulfonic acid 5-bromo-7-((indoles-5-base-1-H) methylamino formyl)-1,6-naphthyridine-8-carboxylicesters (S14-2)
The preparation method of the preparation method of compound S 14-2 and compound 9-1 is similar, except replacing compound 8-1 with compound S 14-1.White solid, productive rate: 85-95%.
1H?NMR(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)-the amino hexamethylene of 4-is amino)-N-((indoles-5-base-1-H) methyl)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S14)
The preparation method of the preparation method of compound S 14 and compound S 1 is similar, except replacing compound 9-1 with compound S 14-2.The yellow-green colour solid, productive rate: 75-85%.
1H NMR (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-EI m/z:492 (M)
+, 494 (M+2)
+Anal. calculated value: C
21H
23BrN
6O2/5CF
3COOH3/4CH
3OH:C54.50, H 5.08, and N 14.93, measured value: C 54.56, and H 4.84, and N 14.66.
Toluene-4-sulfonic acid 5-bromo-7-((naphthalene-1-yl) methylamino formyl)-1,6-naphthyridine-8-carboxylicesters (S15-2)
The preparation method of the preparation method of compound S 15-2 and compound 9-1 is similar, except replacing compound 8-1 with compound S 15-1.White solid, productive rate: 85-95%.
1H?NMR(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-ESI?m/z：562(M+H)
+，564(M+2+H)
+。
8-((1r, 4r)-the amino hexamethylene of 4-is amino)-N-((naphthalene-1-yl) methyl)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S15)
The preparation method of the preparation method of compound S 15 and compound S 1 is similar, except replacing compound 9-1 with compound S 15-2.The yellow-green colour solid, productive rate: 75-85%.
1H NMR (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-EI m/z:503 (M)
+, 505 (M+2)
+Anal. calculated value: C
26H
26BrN
5O1/5CF
3COOH2/5C
6H
14: C 61.58, and H 5.71, and N 12.47, measured value: C 61.61, and H 5.62, N12.53.
Toluene-4-sulfonic acid 5-bromo-7-(3-trifluoromethyl-4-methoxyl group-benzylamino formyl)-1,6-naphthyridine-8-carboxylicesters (S16-2)
The preparation method of the preparation method of compound S 16-2 and compound 9-1 is similar, except replacing compound 8-1 with compound S 16-1.White solid, productive rate: 85-95%.
1H?NMR(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)-the amino hexamethylene of 4-is amino)-N-(3-trifluoromethyl-4-methoxyl group-benzyl)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S16)
The preparation method of the preparation method of compound S 16 and compound S 1 is similar, except replacing compound 9-1 with compound S 16-2.The yellow-green colour solid, productive rate: 75-85%.
1H NMR (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);
13C NMR (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-EI m/z:551 (M)
+, 553 (M+2)
+Anal. calculated value: C
24H
25BrF
3N
5O
21/5C
6H
14: C 53.14, and H 4.92, and N 12.29, measured value: C 53.04, and H 4.83, and N 12.31.
Toluene-4-sulfonic acid 5-bromo-7-(2-methoxyl group-5-chloro-benzylamino formyl)-1,6-naphthyridine-8-carboxylicesters (S17-2)
The preparation method of the preparation method of compound S 17-2 and compound 9-1 is similar, except replacing compound 8-1 with compound S 17-1.White solid, productive rate: 85-95%.
1H?NMR(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)-the amino hexamethylene of 4-is amino)-N-(2-methoxyl group-5-chloro-benzyl)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S17)
The preparation method of the preparation method of compound S 17 and compound S 1 is similar, except replacing compound 9-1 with compound S 17-2.The yellow-green colour 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-EI m/z:517 (M)
+, 519 (M+2)
+Anal. calculated value: C
23H
25BrClN
5O
23/20C
6H
14: C 53.98, and H 5.14, and N 13.17, measured value: C 53.87, and H 5.12, and N 12.97.
Toluene-4-sulfonic acid 5-bromo-7-(4-phenoxy-benzylamino formyl)-1,6-naphthyridine-8-carboxylicesters (S18-2)
The preparation method of the preparation method of compound S 18-2 and compound 9-1 is similar, except replacing compound 8-1 with compound S 18-1.White solid, productive rate: 85-95%.
1H?NMR(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)-the amino hexamethylene of 4-is amino)-N-(4-phenoxy-benzyl)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S18)
The preparation method of the preparation method of compound S 18 and compound S 1 is similar, except replacing compound 9-1 with compound S 18-2.The yellow-green colour solid, productive rate: 75-85%.
1H NMR (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-EI m/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: C 61.58, and H 5.13, and N 12.71, measured value: C 61.54, and H 5.16, and N 12.82.
Toluene-4-sulfonic acid 5-bromo-7-(3-chloro-4-hexamethylene alkoxyl group-benzylamino formyl)-1,6-naphthyridine-8-carboxylicesters (S19-2)
The preparation method of the preparation method of compound S 19-2 and compound 9-1 is similar, except replacing compound 8-1 with compound S 19-1.White solid, productive rate: 85-95%.
1H?NMR(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)-the amino hexamethylene of 4-is amino)-N-(3-chloro-4-hexamethylene alkoxyl group-benzyl)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S19)
The preparation method of the preparation method of compound S 19 and compound S 1 is similar, except replacing compound 9-1 with compound S 19-2.The yellow-green colour solid, productive rate: 75-85%.
1H NMR (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-ESI m/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: C 58.23, and H 6.05, and N 11.51, measured value: C 58.27, and H 6.33, and N 11.70.
Toluene-4-sulfonic acid 5-bromo-7-(3-trifluoromethyl-4-hexamethylene alkoxyl group-benzylamino formyl)-1,6-naphthyridine-8-carboxylicesters (S20-2)
The preparation method of the preparation method of compound S 20-2 and compound 9-1 is similar, except replacing compound 8-1 with compound S 20-1.White solid, productive rate: 85-95%.
1H?NMR(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)-the amino hexamethylene of 4-is amino)-N-(3-trifluoromethyl-4-hexamethylene alkoxyl group-benzyl)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S20)
The preparation method of the preparation method of compound S 20 and compound S 1 is similar, except replacing compound 9-1 with compound S 20-2.The yellow-green colour solid, productive rate: 75-85%.
1H NMR (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);
13C NMR (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-ESI m/z:620 (M+H)
+, 622 (M+2+H)
+Anal. calculated value: C
29H
33BrF
3N
5O
2: C 56.13, and H 5.36, and N 11.29, measured value: C 55.84, and H 5.37, and N 11.20.
Toluene-4-sulfonic acid 5-bromo-7-(4-Trimetylene methoxyl group-benzylamino formyl)-1,6-naphthyridine-8-carboxylicesters (S21-2)
The preparation method of the preparation method of compound S 21-2 and compound 9-1 is similar, except replacing compound 8-1 with compound S 21-1.White solid, productive rate: 85-95%.
1H?NMR(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)-the amino hexamethylene of 4-is amino)-N-(4-Trimetylene methoxyl group-benzyl)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S21)
The preparation method of the preparation method of compound S 21 and compound S 1 is similar, except replacing compound 9-1 with compound S 21-2.The yellow-green colour solid, productive rate: 75-85%.
1H NMR (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);
13C NMR (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-ESI m/z:526 (M+H)
+, 524 (M-2+H)
+Anal. calculated value: C
26H
30BrN
5O
2: C 59.54, and H 5.77, and N 13.35, measured value: C 59.56, H5.85, and N 13.05.
Toluene-4-sulfonic acid 5-bromo-7-methoxycarbonyl-1,6-naphthyridine-8-carboxylicesters (10)
The preparation method of the preparation method of compound 10 and compound 9-1 is similar, except replacing compound 8-1 with compound 7-1.White solid, productive rate: 85-95%.
1H?NMR(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-MS?m/z：436(M)
+。
The tertiary butyl (1r, 4r)-4-(7-(methoxy carbonic acyl radical)-5-bromo-1,6-naphthyridine-8-is amino) cyclohexyl carbamate (11)
The preparation method of the preparation method of compound 11 and compound S 1 is similar, except replacing compound 9-1 with compound 10.The yellow-green colour solid, productive rate: 75-85%.
1H?NMR(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-MS?m/z：478(M)
+，480(M+2)
+。
5-bromo-8-((1r, 4r)-4-t-butoxycarbonyl amino hexamethylene is amino)-1,6-naphthyridine-7-carboxylic acid (12)
In 1NNaOH solution/THF, under 60 degree, the 10h hydrolysis makes compound 12 by compound 11.The yellow-green colour solid, productive rate: 75-85%.Fusing point: 122-126 ℃;
1H NMR (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-(7-(4-methoxybenzenesulphoismide base formyl)-5-bromo-1,6-naphthyridine-8-is amino) cyclohexyl carbamate (S22-1)
Compound 12 is in EDCI, DMAP and methylene dichloride, and normal temperature obtains compound S 22-1 down with to methoxybenzenesulphoismide reaction 12h.The yellow-green colour solid, productive rate: 75-85%.
1H?NMR(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(br?s，1H)，4.39(br?s，1H)，3.89(s，3H)，3.46(br?s，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)-the amino hexamethylene of 4-is amino)-N-(4-anisole alkylsulfonyl)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S22)
Compound S 22-1 removes Boc and generates compound S 22 in trifluoracetic acid/methylene dichloride of 20%.The yellow-green colour solid, productive rate: 75-85%.
1H NMR (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 (br s, 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-EI m/z:171ArSO
2 +, 362 (M-HSO
2)
+MS-ESI m/z:556 (M+Na-2)
+, 558 (M+Na)
+Anal. calculated value: C
22H
24BrN
5O
4S5/4H
2O:C 47.44, and H 4.80, and N 12.57, measured value: C 47.19, and H 4.88, and N 12.93.
The tertiary butyl (1r, 4r)-4-(7-(4-chlorobenzene sulfonamide base formyl)-5-bromo-1,6-naphthyridine-8-is amino) cyclohexyl carbamate (S23-1)
The preparation method of the preparation method of compound S 23-1 and compound S 22-1 is similar, except replacing methoxybenzenesulphoismide with p-chloro benzenesulfonamide.The yellow-green colour 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(br?s，1H)，4.39(br?s，1H)，3.46(br?s，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-ESI?m/z：640(M+H)
+，638(M-2+H)
+。
8-((1r, 4r)-the amino hexamethylene of 4-is amino)-N-(4-chlorobenzene alkylsulfonyl)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S23)
The preparation method of the preparation method of compound S 23 and compound S 22 is similar, except replacing compound S 22-1 with compound S 23-1.The yellow-green colour solid, productive rate: 75-85%.
1H NMR (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 (br s, 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);
13C NMR (100MHz, d
6-DMSO): δ 170.0151.5144.4142.0135.8134.9132.7129.0127.8125.1124.71 24.552.548.831.728.9; MS-ESI m/z:540 (M+H)
+, 538 (M-2+H)
+Anal. calculated value: C
21H
21BrClN
5O
3S5/4H
2O:C 44.93, and H 4.22, and N 12.48, measured value: C 44.79, and H 4.25, and N 12.70.
The tertiary butyl (1r, 4r)-4-(7-(3-chlorobenzene sulfonamide base formyl)-5-bromo-1,6-naphthyridine-8-is amino) cyclohexyl carbamate (S24-1)
The preparation method of the preparation method of compound S 24-1 and compound S 22-1 is similar, except chlorobenzene sulfonamide between usefulness replaces methoxybenzenesulphoismide.The yellow-green colour solid, productive rate: 75-85%.
1H?NMR(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(br?s，1H)，4.38(br?s，1H)，3.45(br?s，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)-the amino hexamethylene of 4-is amino)-N-(3-chlorobenzene alkylsulfonyl)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S24)
The preparation method of the preparation method of compound S 24 and compound S 22 is similar, except replacing compound S 22-1 with compound S 24-1.The yellow-green colour solid, productive rate: 75-85%.
1H NMR (300MHz, d
6-DMSO): δ 9.08 (br s, 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 (br s, 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);
13C NMR (100MHz, d
6-DMSO): δ 151.6144.3135.9132.6130.6130.1126.9125.7125.2125.052.648 .731.628.9; MS-ESI m/z:540 (M+H)
+, 538 (M-2+H)
+Anal. calculated value: C
21H
21BrClN
5O
3S5/3H
2O:C 44.34, and H 4.31, and N 12.31, measured value: C 44.56, and H 4.34, and N 12.03.
The tertiary butyl (1r, 4r)-4-(7-(3,5-difluoro benzene sulfonamido formyl)-5-bromo-1,6-naphthyridine-8-is amino) cyclohexyl carbamate (S25-1)
The preparation method of the preparation method of compound S 25-1 and compound S 22-1 is similar, and except with 3,5-difluoro benzsulfamide replaces methoxybenzenesulphoismide.The yellow-green colour solid, productive rate: 75-85%.
1H?NMR(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(br?s，1H)，4.38(br?s，1H)，3.46(br?s，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)-the amino hexamethylene of 4-is amino)-N-(3,5-difluoro benzene sulfonamido)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S25)
The preparation method of the preparation method of compound S 25 and compound S 22 is similar, except replacing compound S 22-1 with compound S 25-1.The yellow-green colour solid, productive rate: 75-85%.
1H NMR (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 (br s, 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);
13C NMR (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-EI m/z:177ArSO
2 +, 362 (M-HSO
2)
+Anal. calculated value: C
21H
20BrF
2N
5O
3S1/10C
6H
14: C 47.26, and H 3.93, and N 12.76, measured value: C 47.14, and H 3.93, N12.64.
The tertiary butyl (1r, 4r)-4-(7-(2,5-dichloro-thiophene-3-base sulfoamido formyl)-5-bromo-1,6-naphthyridine-8-is amino) cyclohexyl carbamate (S26-1)
The preparation method of the preparation method of compound S 26-1 and compound S 22-1 is similar, and except with 2,5-dichloro-thiophene-3-base sulphonamide replaces methoxybenzenesulphoismide.The yellow-green colour 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(br?s，1H)，4.38(br?s，1H)，3.47(br?s，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)-the amino hexamethylene of 4-is amino)-N-(2,5-dichloro-thiophene-3-base alkylsulfonyl)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S26)
The preparation method of the preparation method of compound S 26 and compound S 22 is similar, except replacing compound S 22-1 with compound S 26-1.The yellow-green colour solid, productive rate: 75-85%.
1H NMR (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 (br s; 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-ESI m/z:578 (M+H)
+Anal. calculated value: C
19H
18BrCl
2N
5O
3S
21/10CF
3COOH1/20C
6H
14: C39.36, H 3.18, and N 11.77, measured value: C 39.40, and H 3.47, and N 11.65.
The tertiary butyl (1r, 4r)-4-(7-(4-trifluoromethyl benzene sulfonamido formyl)-5-bromo-1,6-naphthyridine-8-is amino) cyclohexyl carbamate (S27-1)
The preparation method of the preparation method of compound S 27-1 and compound S 22-1 is similar, except replacing methoxybenzenesulphoismide with 4-trifluoromethyl benzsulfamide.The yellow-green colour solid, productive rate: 75-85%.
1H?NMR(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(br?s，1H)，4.39(br?s，1H)，3.46(br?s，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)-the amino hexamethylene of 4-is amino)-N-(4-trifluoromethyl benzenesulfonyl)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S27)
The preparation method of the preparation method of compound S 27 and compound S 22 is similar, except replacing compound S 22-1 with compound S 27-1.The yellow-green colour solid, productive rate: 75-85%.
1H NMR (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 (br s, 1H), 3.06 (br s, 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-ESI m/z:574 (M+H)
+, 572 (M-2+H)
+Anal. calculated value: C
22H
21BrF
3N
5O
3S5/4CH
3OH1/2CF
3COOH:C 43.51, and H 3.99, and N 10.46, measured value: C 43.71, H4.20, and N 10.33.
The tertiary butyl (1r, 4r)-4-(7-(4-P-acetamido benzene sulfonyl amido formyl)-5-bromo-1,6-naphthyridine-8-is amino) cyclohexyl carbamate (S28-1)
The preparation method of the preparation method of compound S 28-1 and compound S 22-1 is similar, except replacing methoxybenzenesulphoismide with 4-P-acetamido benzene sulfonyl amine.The yellow-green colour solid, productive rate: 75-85%.
1H?NMR(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(br?s，1H)，4.97(br?s，1H)，4.41(br?s，1H)，3.44(br?s，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)-the amino hexamethylene of 4-is amino)-N-(4-P-acetamido benzene sulfonyl base)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S28)
The preparation method of the preparation method of compound S 28 and compound S 22 is similar, except replacing compound S 22-1 with compound S 28-1.The yellow-green colour solid, productive rate: 75-85%.
1H?NMR(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(br?s，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)；
13C?NMR(100MHz，d
6-DMSO)：δ169.1151.7144.3136.0128.3125.4125.1118.152.748.831.628.924.2；MS-ESI?m/z：561(M+H)
+，563(M+H+2)
+。
The tertiary butyl (1r, 4r)-4-(7-(2-chlorobenzene sulfonamide base formyl)-5-bromo-1,6-naphthyridine-8-is amino) cyclohexyl carbamate (S29-1)
The preparation method of the preparation method of compound S 29-1 and compound S 22-1 is similar, except replacing methoxybenzenesulphoismide with the 2-chlorobenzene sulfonamide.The yellow-green colour solid, productive rate: 75-85%.
1H?NMR(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(br?s，1H)，4.36(br?s，1H)，3.42(br?s，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-ESI?m/z：640(M+H)
+，638(M-2+H)
+。
8-((1r, 4r)-the amino hexamethylene of 4-is amino)-N-(2-chlorobenzene alkylsulfonyl)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S29)
The preparation method of the preparation method of compound S 29 and compound S 22 is similar, except replacing compound S 22-1 with compound S 29-1.The yellow-green colour solid, productive rate: 75-85%.
1H NMR (300MHz, d
6-DMSO): δ 9.06 (br s, 1H), 8.46 (d, J=8.1Hz, 1H), 8.16 (d, J=4.2Hz, 1H); 7.89 (br s, 2H), 7.63 (m, 2H), 7.37 (br s, 1H), 7.21 (br s, 1H); 7.04 (br s, 1H), 4.64 (br s, 1H), 3.55 (br s, 1H), 3.04 (br s, 1H); 2.06 (d, J=13.2Hz, 2H), 1.94 (d, J=13.8Hz, 2H), 1.27-1.47 (m, 4H); MS-EI m/z:175ArSO
2 +, 362 (M-HSO
2)
+Anal. calculated value: C
21H
21BrClN
5O
3S1/5CF
3COOH3/4H
2O:C 44.69, and H 3.98, and N 12.18, measured value: C 44.95, and H 4.22, and N 11.90.
The tertiary butyl (1r, 4r)-4-(7-(2-methoxyl group-4-methyl-5-chloro-benzene sulfonamido formyl)-5-bromo-1,6-naphthyridine-8-is amino) cyclohexyl carbamate (S30-1)
The preparation method of the preparation method of compound S 30-1 and compound S 22-1 is similar, except replacing methoxybenzenesulphoismide with 2-methoxyl group-4-methyl-5-chloro-benzsulfamide.The yellow-green colour solid, productive rate: 75-85%.
1H?NMR(300MHz，CDCl
3)δ10.56(s，1H)，9.17(br?s，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(br?s，1H)，4.36(br?s，1H)，3.95(s，3H)，3.43(br?s，1H)，2.42(s，3H)，2.01-2.14(m，4H)，1.45(s，9H)，1.27-1.37(m，4H)。
8-((1r, 4r)-the amino hexamethylene of 4-is amino)-N-(2-methoxyl group-4-methyl-5-chloro-benzenesulfonyl)-5-bromo-1,6-naphthyridine-7-carboxylic acid amine (S30)
The preparation method of the preparation method of compound S 30 and compound S 22 is similar, except replacing compound S 22-1 with compound S 30-1.The yellow-green colour solid, productive rate: 75-85%.
1H?NMR(300MHz，d
6-DMSO)：δ9.05(br?s，1H)，8.4(d，J＝7.2Hz，1H)，7.79-7.84(m，2H)，7.18-7.23(m，3H)，4.54(br?s，1H)，3.82(s，3H)，3.01(br?s，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-ESI?m/z：584(M+H)
+。
8-((1r, 4r)-the amino hexamethylene of 4-is amino)-N-(4-fluoro-benzyl)-5-cyanic acid-1,6-naphthyridine-7-carboxylic acid amine (S31)
The preparation method of the preparation method of compound S 31 and compound S 1 is similar, yellow-green colour solid, productive rate: 75-85%.
1H?NMR(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)-the amino hexamethylene of 4-is amino)-7-(4-fluoro-benzylamino formyl)-1,6-naphthyridine-5-methyl-formiate (S32)
The preparation method of the preparation method of compound S 32 and compound S 1 is similar, yellow-green colour solid, productive rate: 75-85%.
1H?NMR(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-MS?m/z：451(M)
+。
Toluene-4-sulfonic acid 5-iodo-7-(3-trifluoromethyl-benzylamino formyl)-1,6-naphthyridine-8-carboxylicesters (S33-2)
The preparation method of the preparation method of compound S 33-2 and compound 9-1 is similar, except replacing compound 8-1 with compound S 33-1.White solid, productive rate: 85-95%.
1H?NMR(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)-the amino hexamethylene of 4-is amino)-N-(3-trifluoromethyl-benzyl)-5-iodo-1,6-naphthyridine-7-carboxylic acid amine (S33-3)
The preparation method of the preparation method of compound S 33-3 and compound S 1 is similar, except replacing compound 9-1 with compound S 33-2.The yellow-green colour solid, productive rate: 75-85%.
1H?NMR(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(br?s，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) hexamethylene is amino)-7-(3-trifluoromethyl benzyl carbamyl)-1, the 6-phthalazinyl] propynoic acid methyl esters (S33-4)
With compound S 33-3 (84mg, 1.25mmol), the propynoic acid methyl esters (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) be dissolved among the 5mL THF nitrogen protection, reflux 14 hours.The reaction system cooling is revolved and is done THF, adds the 20mL methylene dichloride, saturated common salt washing twice, and organic phase is used anhydrous sodium sulfate drying.Silica gel column chromatography (sherwood oil: ETHYLE ACETATE=4: 1) obtain yellow-green colour solid chemical compound S33-475mg, productive rate: 97%.
1H?NMR(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(br?s，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)-the amino hexamethylene of 4-is amino)-7-(3-trifluoromethyl benzyl carbamyl)-1, the 6-phthalazinyl] propynoic acid methyl esters (S33)
Compound S 33 took off Boc in 2 hours by compound S 33-4 at trifluoracetic acid/methylene dichloride room temperature reaction of 20% and obtains.The yellow-green colour solid, productive rate: 70-85%.
1H NMR (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-EI m/z:525 (M)
+, 526 (M+1)
+Anal. calculated value: C
27H
26F
3N
5O
31/4CF
3COOH:C 59.62, and H 4.78, and N 12.64, measured value: C 59.50, and H 4.90, and N 12.63.
Toluene-4-sulfonic acid 5-iodo-7-(3,4-two chloro-benzylamino formyls)-1,6-naphthyridine-8-carboxylicesters (S34-2)
The preparation method of the preparation method of compound S 34-2 and compound 9-1 is similar, except replacing compound 8-1 with compound S 34-1.White solid, productive rate: 85-95%.
1H?NMR(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)-the amino hexamethylene of 4-is amino)-N-(3,4-two chloro-benzyls)-5-iodo-1,6-naphthyridine-7-carboxylic acid amine (S34-3)
The preparation method of the preparation method of compound S 34-3 and compound S 1 is similar, except replacing compound 9-1 with compound S 34-2.The yellow-green colour solid, productive rate: 75-85%.
1H?NMR(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) hexamethylene is amino)-7-(3,4-two chloro-benzylamino formyls)-1, the 6-phthalazinyl] propynoic acid methyl esters (S34-4)
The preparation method of the preparation method of compound S 34-4 and compound S 33-4 is similar, except replacing compound S 33-3 with compound S 34-3.The yellow-green colour solid, productive rate: 75-95%.
1H?NMR(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)-the amino hexamethylene of 4-is amino)-7-(3,4-two chloro-benzylamino formyls)-1, the 6-phthalazinyl] propynoic acid methyl esters (S34)
The preparation method of the preparation method of compound S 34 and compound S 33 is similar, except replacing compound S 33-4 with compound S 34-4.The yellow-green colour solid, productive rate: 70-85%.
1H NMR (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-EI m/z:525 (M)
+, 527 (M+2)
+Anal. calculated value: C
26H
25Cl
2N
5O
31/5CF
3COOH3/10C
6H
14: C 58.90, and H 5.15, and N 12.18, measured value: C 59.04, and H 5.12, and N 12.30.
Toluene-4-sulfonic acid 5-iodo-7-(2,4-two chloro-benzylamino formyls)-1,6-naphthyridine-8-carboxylicesters (S35-2)
The preparation method of the preparation method of compound S 35-2 and compound 9-1 is similar, except replacing compound 8-1 with compound S 35-1.White solid, productive rate: 85-95%.
1H?NMR(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)-the amino hexamethylene of 4-is amino)-N-(2,4-two chloro-benzyls)-5-iodo-1,6-naphthyridine-7-carboxylic acid amine (S35-3)
The preparation method of the preparation method of compound S 35-3 and compound S 1 is similar, except replacing compound 9-1 with compound S 35-2.The yellow-green colour solid, productive rate: 75-85%.
1H?NMR(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) hexamethylene is amino)-7-(2,4-two chloro-benzylamino formyls)-1, the 6-phthalazinyl] propynoic acid methyl esters (S35-4)
The preparation method of the preparation method of compound S 35-4 and compound S 33-4 is similar, except replacing compound S 33-3 with compound S 35-3.The yellow-green colour solid, productive rate: 75-95%.
1H?NMR(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-EI?m/z：625(M)
+，627(M+2)
+。
3-{5-[8-((1r, 4r)-the amino hexamethylene of 4-is amino)-7-(2,4-two chloro-benzylamino formyls)-1, the 6-phthalazinyl] propynoic acid methyl esters (S35)
The preparation method of the preparation method of compound S 35 and compound S 33 is similar, except replacing compound S 33-4 with compound S 35-4.The yellow-green colour solid, productive rate: 70-85%.IR (film) v
Max=3427,2920,2202,1709,1643,1606,1576,1500,1358,1230,1138,822cm
-1 1H NMR (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-EI m/z:525 (M)
+, 527 (M+2)
+Anal. calculated value: C
26H
25Cl
2N
5O
31/5CF
3COOHCH
3OH:C 56.62, and H 5.06, and N 12.05, measured value: C 56.73, and H 4.87, N11.81.
Toluene-4-sulfonic acid 5-iodo-7-(3-chloro-benzylamino formyl)-1,6-naphthyridine-8-carboxylicesters (S36-2)
The preparation method of the preparation method of compound S 36-2 and compound 9-1 is similar, except replacing compound 8-1 with compound S 36-1.White solid, productive rate: 85-95%.
1H?NMR(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)-the amino hexamethylene of 4-is amino)-N-(3-chloro-benzyl)-5-iodo-1,6-naphthyridine-7-carboxylic acid amine (S36-3)
The preparation method of the preparation method of compound S 36-3 and compound S 1 is similar, except replacing compound 9-1 with compound S 36-2.The yellow-green colour solid, productive rate: 75-85%.
1H?NMR(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-ESI?m/z：636(M+H)
+。
3-{5-[8-((1r, 4r)-4-(tertbutyloxycarbonyl ammonia) hexamethylene is amino)-7-(3-chloro-benzylamino formyl)-1, the 6-phthalazinyl] propynoic acid methyl esters (S36-4)
The preparation method of the preparation method of compound S 36-4 and compound S 33-4 is similar, except replacing compound S 33-3 with compound S 36-3.The yellow-green colour solid, productive rate: 75-95%.
1H?NMR(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)-the amino hexamethylene of 4-is amino)-7-(3-chloro-benzylamino formyl)-1, the 6-phthalazinyl] propynoic acid methyl esters (S36)
The preparation method of the preparation method of compound S 36 and compound S 33 is similar, except replacing compound S 33-4 with compound S 36-4.The yellow-green colour solid, productive rate: 70-85%.
1H NMR (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);
13C NMR (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-EI m/z:491 (M)
+, 493 (M+2)
+Anal. calculated value: C
26H
26ClN
5O
31/10C
6H
14: C 63.81, and H 5.52, and N 13.99, measured value: C 63.98, and H 5.49, N13.99.
Toluene-4-sulfonic acid 5-iodo-7-(4-chloro-benzylamino formyl)-1,6-naphthyridine-8-carboxylicesters (S37-2)
The preparation method of the preparation method of compound S 37-2 and compound 9-1 is similar, except replacing compound 8-1 with compound S 37-1.White solid, productive rate: 85-95%.
1H?NMR(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)-the amino hexamethylene of 4-is amino)-N-(4-chloro-benzyl)-5-iodo-1,6-naphthyridine-7-carboxylic acid amine (S37-3)
The preparation method of the preparation method of compound S 37-3 and compound S 1 is similar, except replacing compound 9-1 with compound S 37-2.The yellow-green colour solid, productive rate: 75-85%.
1H?NMR(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-ESI?m/z：636(M+H)
+。
3-{5-[8-((1r, 4r)-4-(tertbutyloxycarbonyl ammonia) hexamethylene is amino)-7-(4-chloro-benzylamino formyl)-1, the 6-phthalazinyl] propynoic acid methyl esters (S37-4)
The preparation method of the preparation method of compound S 37-4 and compound S 33-4 is similar, except replacing compound S 33-3 with compound S 37-3.The yellow-green colour solid, productive rate: 75-95%.
1H?NMR(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)-the amino hexamethylene of 4-is amino)-7-(4-chloro-benzylamino formyl)-1, the 6-phthalazinyl] propynoic acid methyl esters (S37)
The preparation method of the preparation method of compound S 37 and compound S 33 is similar, except replacing compound S 33-4 with compound S 37-4.The yellow-green colour solid, productive rate: 70-85%.
1H NMR (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-EI m/z:491 (M)
+, 493 (M+2)
+Anal. calculated value: C
26H
26ClN
5O
3: C 63.48, and H 5.33, and N 14.24, measured value: C 63.11, and H 5.33, and N 13.87.
3-{5-[8-((1r, 4r)-the amino hexamethylene of 4-is amino)-7-(3,4-two chloro-benzylamino formyls)-1, the 6-phthalazinyl]-3-propanedioic acid methyl esters (S38)
Compound S 38 was obtained by compound S 34-4 40 degree reactions in trifluoracetic acid/methylene dichloride of 20% in 2 hours.The yellow-green colour solid, productive rate: 70-85%.
1H?NMR(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-EI?m/z：543(M)
+，545(M+2)
+。
3-{5-[8-((1r, 4r)-the amino hexamethylene of 4-is amino)-7-(2,4-two chloro-benzylamino formyls)-1, the 6-phthalazinyl]-3-propanedioic acid methyl esters (S39)
The preparation method of the preparation method of compound S 39 and compound S 38 is similar, except replacing compound S 34-4 with compound S 35-4.The yellow-green colour solid, productive rate: 70-85%.IR(film)v
max＝3423，2926，1678，1647，1508，1207，1138，800cm
-1；
1H?NMR(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)；
13C?NMR(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-EI?m/z：543(M)
+，545(M+2)
+。
Toluene-4-sulfonic acid 5-iodo-7-(3-trifluoromethyl-4-chloro-benzylamino formyl)-1,6-naphthyridine-8-carboxylicesters (S40-2)
The preparation method of the preparation method of compound S 40-2 and compound 9-1 is similar, except replacing compound 8-1 with compound S 40-1.White solid, productive rate: 85-95%.
1H?NMR(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-ESI?m/z：662(M+H)
+。
8-((1r, 4r)-the amino hexamethylene of 4-is amino)-N-(3-trifluoromethyl-4-chloro-benzyl)-5-iodo-1,6-naphthyridine-7-carboxylic acid amine (S40-3)
The preparation method of the preparation method of compound S 40-3 and compound S 1 is similar, except replacing compound 9-1 with compound S 40-2.The yellow-green colour solid, productive rate: 75-85%.
1H?NMR(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) hexamethylene is amino)-7-(3-trifluoromethyl-4-chloro-benzylamino formyl)-1, the 6-phthalazinyl] propynoic acid methyl esters (S40-4)
The preparation method of the preparation method of compound S 40-4 and compound S 33-4 is similar, except replacing compound S 33-3 with compound S 40-3.The yellow-green colour solid, productive rate: 75-95%.
1H?NMR(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)-the amino hexamethylene of 4-is amino)-7-(3-trifluoromethyl-4-chloro-benzylamino formyl)-1, the 6-phthalazinyl] propynoic acid methyl esters (S40)
The preparation method of the preparation method of compound S 40 and compound S 33 is similar, except replacing compound S 33-4 with compound S 40-4.The yellow-green colour solid, productive rate: 70-85%.
1H NMR (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-EI m/z:559 (M)
+, 561 (M+2)
+Anal. calculated value: C
27H
25ClF
3N
5O
31/3H
2O:C 57.30, and H 4.57, and N 12.37, measured value: C57.55, and H 4.78, and N 12.07.
3-{5-[8-((1r, 4r)-the amino hexamethylene of 4-is amino)-7-(3-trifluoromethyl-4-chloro-benzylamino formyl)-1, the 6-phthalazinyl]-3-propanedioic acid methyl esters (S41)
The preparation method of the preparation method of compound S 41 and compound S 38 is similar, except replacing compound S 34-4 with compound S 40-4.The yellow-green colour solid, productive rate: 70-85%.
1H NMR (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-EI m/z:577 (M)
+, 579 (M+2)
+Anal. calculated value: C
27H
27ClF
3N
5O
41/3C
6H
14: C 57.41, and H 5.26, and N 11.54, measured value: C 57.34, and H 5.11, and N 11.24.
Toluene-4-sulfonic acid 5-iodo-7-(4-hexamethylene alkoxyl group-benzylamino formyl)-1,6-naphthyridine-8-carboxylicesters (S42-2)
The preparation method of the preparation method of compound S 42-2 and compound 9-1 is similar, except replacing compound 8-1 with compound S 42-1.White solid, productive rate: 85-95%.
1H?NMR(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)-the amino hexamethylene of 4-is amino)-N-(4-hexamethylene alkoxyl group-benzyl)-5-iodo-1,6-naphthyridine-7-carboxylic acid amine (S42-3)
The preparation method of the preparation method of compound S 42-3 and compound S 1 is similar, except replacing compound 9-1 with compound S 42-2.The yellow-green colour solid, productive rate: 75-85%.
1H?NMR(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) hexamethylene is amino)-7-(4-hexamethylene alkoxyl group-benzylamino formyl)-1, the 6-phthalazinyl] propynoic acid methyl esters (S42-4)
The preparation method of the preparation method of compound S 42-4 and compound S 33-4 is similar, except replacing compound S 33-3 with compound S 42-3.The yellow-green colour solid, productive rate: 75-95%.
1H?NMR(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)-the amino hexamethylene of 4-is amino)-7-(4-hexamethylene alkoxyl group-benzylamino formyl)-1, the 6-phthalazinyl] propynoic acid methyl esters (S42)
The preparation method of the preparation method of compound S 42 and compound S 33 is similar, except replacing compound S 33-4 with compound S 42-4.The yellow-green colour solid, productive rate: 70-85%.
1H NMR (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-ESI m/z:556 (M+1)
+Anal. calculated value: C
32H
37N
5O
43/10CF
3COOH:C 66.38, and H 6.37, and N 11.87, measured value: C 66.72, and H 5.99, and N 11.55.
Compound S 43
The preparation method of the preparation method of compound S 43 and compound S 1 is similar.The yellow-green colour solid, productive rate: 75-85%.
1HNMR(300MHz，CDCl
3)：δ9.72(br?s，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-EI?m/z：788(M)
+，790(M+2)
+。
Compound S 44
The preparation method of the preparation method of compound S 44 and compound S 1 is similar.The yellow-green colour 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-ESI?m/z：999(M+H)
+，1001(M+2+H)
+。
Compound S 45
The preparation method of the preparation method of compound S45 and compound S 33 is similar.The yellow-green colour 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-ESI?m/z：1003(M+H)
+，1005(M+2+H)
+。
Compound S 46-1
Compound 12 and HOAt, EDCI, DIPEA are in methylene dichloride, and normal temperature is down with 1, and 4-dibenzyl amine reaction 12h obtains compound S 46-1.The yellow-green colour solid, productive rate: 75-85%.
1H?NMR(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 the preparation method of compound S 46 and compound S 22 is similar, except replacing compound S 22-1 with compound S 46-1.The yellow-green colour solid, productive rate: 75-85%.
1H NMR (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-ESI m/z:831 (M+H)
+, 833 (M+2+H)
+HR-ESI MS calculated value: C
38H
42Br
2N
10O
2(M+Na)
+: 851.1757, measured value: 851.1740.
Compound S 47-1
The preparation method of the preparation method of compound S 47-1 and compound S 46-1 is similar, and except with 1, the 6-hexanediamine replaces 1, the 4-dibenzyl amine.The yellow-green colour solid, productive rate: 70-85%.
1H?NMR(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-ESI?m/z：1011(M+H)
+。
Compound S 47
The preparation method of the preparation method of compound S 47 and compound S 22 is similar, except replacing compound S 22-1 with compound S 47-1.The yellow-green colour solid, productive rate: 70-85%.
1H?NMR(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-ESI?m/z：811(M+H)
+。
Compound S 48-1
The preparation method of the preparation method of compound S 48-1 and compound S 46-1 is similar, and except with 1, the 3-tn replaces 1, the 4-dibenzyl amine.The yellow-green colour solid, productive rate: 70-85%.
1H?NMR(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-ESI?m/z：969(M+H)
+。
Compound S 48
The preparation method of the preparation method of compound S 48 and compound S 22 is similar, except replacing compound S 22-1 with compound S 48-1.The yellow-green colour solid, productive rate: 70-85%.
1H?NMR(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)；
13C?NMR(100MHz，CD
3OD)：δ170.0153.0146.4145.8138.0128.2126.7126.6125.954.651.338.733.930.9；MS-ESI?m/z：769(M+H)
+。
Compound S 49-1
The preparation method of the preparation method of compound S 49-1 and compound S 46-1 is similar, and except with 1, the 4-tetramethylenediamine replaces 1, the 4-dibenzyl amine.The yellow-green colour solid, productive rate: 70-85%.
1H?NMR(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(br?s，4H)，1.44(s，18H)，1.23-1.39(m，8H)；MS-ESI?m/z：983(M+H)
+。
Compound S 49
The preparation method of the preparation method of compound S 49 and compound S 22 is similar, except replacing compound S 22-1 with compound S 49-1.The yellow-green colour solid, productive rate: 70-85%.
1H?NMR(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(br?s，4H)，1.36-1.62(m，8H)；MS-ESI?m/z：783(M+H)
+。
Compound S 50-1
The preparation method of the preparation method of compound S 50-1 and compound S 46-1 is similar, and except with trans 1, the 4-cyclohexanediamine replaces 1, the 4-dibenzyl amine.The yellow-green colour solid, productive rate: 70-85%.
1H?NMR(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-ESI?m/z：1009(M+H)
+。
Compound S 50
The preparation method of the preparation method of compound S 50 and compound S 22 is similar, except replacing compound S 22-1 with compound S 50-1.The yellow-green colour solid, productive rate: 70-85%.
1H?NMR(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)；
13C?NMR(100MHz，CD
3OD)：δ169.2153.2146.5145.8138.2128.3127.0126.8126.054.751.349.749.533.032.330.1；MS-ESI?m/z：809(M+H)
+。
Compound S 51-1
The preparation method of the preparation method of compound S 51-1 and compound S 46-1 is similar, except replacing 1 with piperazine, the 4-dibenzyl amine.The yellow-green colour solid, productive rate: 70-85%.
1H?NMR(300MHz，CDCl
3)：8.94(d，J＝12.3Hz，2H)，8.44(dd，J＝8.1Hz，2H)，7.65(m，2H)，6.43(br?s，2H)，4.47(m，2H)，4.00(s，2H)，3.91(br?s，2H)，3.58-3.64(m，4H)，3.48(br?s，2H)，2.10(t，J＝12.9Hz，10H)，1.44(s，18H)，1.25-1.38(m，6H)；MS-ESI?m/z：981(M+H)
+。
Compound S 51
The preparation method of the preparation method of compound S 51 and compound S 22 is similar, except replacing compound S 22-1 with compound S 51-1.The yellow-green colour solid, productive rate: 70-85%.
1H?NMR(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(br?s，2H)，3.69(br?s，2H)，3.60(s，2H)，3.52(br?s，2H)，3.17(m，2H)，2.16(d，J＝12.9Hz，8H)，1.43-1.57(m，8H)；
13C?NMR(100MHz，CD
3OD)：δ170.1169.9154.8145.3139.4138.5129.6129.3126.9126.154.051.048.643.232.831.3；MS-ESI?m/z：781(M+H)
+。
EXPERIMENTAL EXAMPLE 1:5,8-two replaces-1, and 6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof are to the in-vitro multiplication restraining effect of human cancer cell strain
Cell strain: human breast cancer cell strain 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 carcinoma cell line A-549, human hepatoma cell strain BEL-7402, human pancreas cancer cell strain BXPC3; People's acute myeloid leukaemia cell strain HL-60, Human Prostate Cancer Cells strain PC-3 is available from the biological article of USS collecting center.
Method: the bright B of sulphonyl Luo Dan (sulforhodamine B; SRB) method; Specific as follows: the different types of tumour cell that some amount is in logarithmic phase is inoculated in 96 well culture plates respectively, behind the cultivation 24h cell attachment, adds the test-compound of the present invention of different concns; Each concentration is established three multiple holes, and sets the contrast of DMSO solution and the acellular zeroing hole of respective concentration.Behind the treated with medicaments cell 72h, the nutrient solution that inclines adds 10% trichoroacetic acid(TCA) solution of 100 μ L ice precooling, in 4 ℃ of fixed cell 1h, and with distilled water wash 5 times, seasoning in the air.Add then 100 μ L SRB (4mg/mL) (Sigma, St Louis, MO, USA) solution, the 15min that dyes in the room temperature removes staining fluid, with 1% Glacial acetic acid min. 99.5 washing 5 times, dry air.The Tris solution (pH 10.5) that adds 150 μ L10mM at last, wavelengthtunable decline and measure the OD value under the orifice plate ELIASA 515nm wavelength.Calculate the inhibiting rate of medicine cell growth with formula: inhibiting rate (%)=(OD contrast-OD dosing)/OD contrast * 100%.
The result: a plurality of compounds of the present invention show good antineoplastic activity to various tumor cell strains.Part of compounds has reached 90% to tumour cell in-vitro multiplication 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 μ M concentration.Concrete data are seen 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
A plurality of compound of the present invention shows good antineoplastic activity to various tumor cell strains; Under 10 μ M concentration to MDA-MB-435, SK-BR-3, A375; A431, the inhibiting rate of tumor cell lines such as HT-29, A-549, BEL-7402, BXPC3, HL-60, PC-3 has reached 90%.
The compound of representing based on general structure I, II or III has good inhibition active to kinds of tumor cells, and the applicant is further to 5, and 8-two replaces-1, and the antitumor mechanism of 6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof is studied.The applicant adopts enzyme-linked immunosorbent assay (ELISA) to find 5, and 8-two replaces-1,6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof under 10 μ M to multiple Tyrosylprotein kinase (EGFR; ErbB2; C-Src, KDR Flt-1) has good restraining active.
Embodiment 2:5,8-two replaces-1, and 6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof are to the restraining effect of 5 kinds of protein tyrosine kinases
Protein tyrosine kinase: c-Src, EGFR express for this laboratory utilizes insect baculovirus expression system; Activated intracellular kinase district tyrosine-kinase zymoprotein with the acquisition of Ni-NTA post affinity purification; And the warp detection meets requirement of experiment ,-70 ℃ of packing, preservation.KDR, Flt-1 available from Upstate company (Waltham, MA, USA); ErbB2 available from Calbiochem company (Darmstadt, Germany).
Experimental technique: enzyme-linked immunosorbent assay (ELISA) method is adopted in tyrosine kinase activity test, and is specific as follows: at first (Glu, Tyr) 4:1 (20 μ g/mL, 37 ℃ are spent the night) coated elisa plate are washed dry for standby behind the plate with enzyme reaction substrate Poly.When reacting; Every hole adds the ATP solution 80 μ L (final concentration of ATP is 5 μ M) with the reaction buffer dilution earlier; The test-compound or the DMSO solvent control 10 μ L that add gradient concentration then; The Tyrosylprotein kinase 10 μ L that add respectively at last with the reaction buffer dilution react to start, and put 37 ℃ of shaking tables reaction 1h.After reaction finished, T-PBS washed plate three times.Every then hole adds 100 μ L PY99 antibody (antibody is with the T-PBS dilution that contains BSA 5mg/ml), 37 ℃ of shaking table reaction 0.5h.T-PBS washes plate three times.The IgG 100 μ L/ holes (antibody is with the T-PBS dilution that contains BSA 5mg/mL) that add the horseradish peroxidase-labeled sheep anti mouse, 37 ℃ of shaking table reaction 0.5h.T-PBS washes plate three times.The OPD colour developing liquid 100 μ L/ holes that add 2mg/mL then, 25 ℃ of lucifuge reaction 1-10min.Add 2M H
2SO
450 μ L/ hole stopped reactions, with the wavelengthtunable orifice plate ELIASA reading that declines, wavelength is 492nm.The inhibiting rate of sample is tried to achieve through formula:
The experiment repetition suppresses the IC of PTK more than 3 times with Logit method computerized compound
50Value and SD value.
Result: discover that a plurality of compounds (are comprised EGFR, ErbB2, c-Src to trying Tyrosylprotein kinase; KDR; Flt-1) have inhibition in various degree active, part of compounds under 10 μ M concentration to c-Src, KDR kinase inhibition rate up to 90%, even be superior to positive control drug.Pointing out compound useful effect of the present invention in above-mentioned Tyrosylprotein kinase, is many target spots tyrosine kinase inhibitor of novel structure.Detailed data is seen table 11.Dependence test, no related data are represented not carry out in the space in the table.
Table 11 compound under 10 μ M to Tyrosylprotein kinase (EGFR, ErbB2, c-Src, KDR, inhibiting rate Flt-1)
Can find out that from the experimental result of table 11 compound useful effect of the present invention is many target spots tyrosine kinase inhibitor of novel structure in above-mentioned Tyrosylprotein kinase.A lot of compounds even are superior to positive control drug to Src, KDR kinases inhibiting rate under 10 μ M up to 90%.
Claims (9)
1. 5 shown in general structure I, II or the III, 8-two replaces-1,6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof:
Wherein,
A is: (1) phenyl ring; (2) C
8-C
10A pair of horses going side by side synthetic bicyclic carbocyclic ring, one of them is a phenyl ring, another is saturated or undersaturated ring; (3) 8～10 atoms a pair of horses going side by side synthetic rings, and contain 0-3 and be selected from the heteroatoms among N, O and the S, one of them is aromatic ring or hetero-aromatic ring, another be saturated perhaps undersaturated carbocyclic ring or heterocycle; (4) contain 1～3 heteroatomic five yuan or six-membered Hetero-aromatic that is selected among N, O and the S; Or 0～3 heteroatomic ternary to seven yuan cycloaliphatic ring that is selected among N, O and the S is contained in (5);
L is: (1) is key directly; (2) C
1-C
6Alkyl; (3) C
2-C
6Thiazolinyl; (4) (C
0-C
6Alkyl)-(C
3-C
6Naphthenic base)-(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 by 1-3 independent substituent replacement separately with the alkyl in (2), (4), (5), and said substituting group is selected from following atom or group: C
1-C
6Alkyl, C
1-C
6Alkoxy C
1-C
6Alkyl, C
3-C
8Naphthenic base, 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
6Naphthenic base)-(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 by 1-3 independent substituent replacement separately with the alkyl in (1), (3), (4), and said substituting group is selected among following atom or the group: C
1-C
6Alkyl, C
1-C
6Alkoxy C
1-C
6Alkyl, C
3-C
8Naphthenic base, 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 independently of one another hydrogen, halogen, hydroxyl, sulfydryl ,-CF
3,-CN ,-NO
2Perhaps do not replace or independently of one another by 1-3 the substituted following groups of substituting group: C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
2-C
6Thiazolinyl, C
2-C
6Alkynyl, C
3-C
8Naphthenic base, 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; Said substituting group is selected among following atom or the group: C
1-C
6Alkyl, C
1-C
6Alkoxy C
1-C
6Alkyl, heterocyclic radical, C
1-C
6The substituted heterocyclic radical of alkyl, heterocyclic radical carbonyl, C
1-C
6Alkyl heterocyclic, C
6-C
10Aryl, C
3-C
8Naphthenic base, 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
bCan form cyclammonium jointly; Said heterocycle is to comprise that 1-3 is selected from heteroatomic ternary to the seven yuan cycloaliphatic ring among N, O and the S;
R
5For hydrogen, hydroxyl or do not replace or by 1-3 the substituted following groups of independent substituent: 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
8Naphthenic base, phenyl, benzyl, naphthyl, C
5-C
10Aromaticity heterocyclic radical or C
4-C
7Saturated heterocyclyl; Said heterocycle comprises that 1-3 is selected from the heteroatoms among N, O and the S; Said 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
aBe hydrogen, C
1-C
6Alkyl, C
3-C
8Naphthenic base or C
6-C
10Aryl;
R
bFor hydrogen, hydroxyl or do not replace or by 1-3 the substituted following groups of substituting group: C independently of one another
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
8Naphthenic base, phenyl, phenylol, benzyl, naphthyl, C
5-C
10Aromaticity heterocyclic radical or C
4-C
7Saturated heterocyclyl; Said heterocycle comprises that 1-3 is selected from the heteroatoms among N, O and the S; Said 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
2. 5 shown in general structure I according to claim 1, II or the III, 8-two replaces-1, and 6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof is characterized in that, further representes with general structure IV, V or VI:
Wherein, R
1, R
2, R
6, L, X and Y definition and claim 1 in identical.
3. 5 shown in general structure I according to claim 2, II or the III, 8-two replaces-1, and 6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof is characterized in that, among general structure IV, V or the VI:
R
1And R
2Be independently of one another hydrogen, halogen ,-CN ,-CF
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, heterocyclic radical carbonyl C
1-C
6Alkoxyl group or C
6-C
10Aryl C
1-C
6Alkoxyl group; Heterocyclic radical wherein is meant and contains 1～3 heteroatomic ternary to seven yuan cycloaliphatic ring that is selected among N, O and the 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
6Naphthenic base.
4. 5 shown in general structure I according to claim 1, II or the III, 8-two replaces-1, and 6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof is characterized in that, is specially following compound:
Wherein,
L is-CH
2-, R
6Be Br, R
7For
L is-SO
2-, R
6Be 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
R
7For
L is-CH
2-, R
6For
R
7For
Perhaps,
Wherein,
Y does
R
6Be Br, R
8For
Y does
R
6Be Br, R
8For
Y does
R
6For
R
8For
Perhaps,
Wherein,
R
6For Br,
-X-Y-X-does
5. a 8-two replaces-1, the preparation method of 6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof, and this method may further comprise the steps:
Wherein, R
6, X and Y definition and claim 1 in identical; R
7For
Wherein, A, R
1, R
2, R
3And R
4Definition and claim 1 in identical;
Reaction reagent and condition: (a) Virahol, reflux 68%; (b) thionyl chloride refluxes; (c) Peng Qinghuana, THF, 0 ℃, two step productive rates 38%; (d) TsNHCH
2COOCH
3, DEAD (diethyl azodiformate), triphenylphosphine, THF, 0 ℃; (e) sodium methylate, methyl alcohol, 0 ℃～room temperature, two step productive rates 65%; (f) NBS (N-bromo-succinimide), methylene dichloride, room temperature, productive rate 85%; (g) amine, toluene refluxed productive rate 88% 24 hours; (h) TsCl, triethylamine, methylene dichloride, productive rate 90%; (i) 1, the trans cyclohexanediamine of 4-, THF refluxes productive rate 75%-85%; (j) LiOH solution/methyl alcohol, or NaOH solution/THF refluxes 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, the propynoic acid methyl esters, THF refluxes productive rate 70%-85%; (n) EDCI, HOAt, DIPEA, amine, methylene dichloride, productive rate 70%-90%;
(1) compound method of compound S 1-S21 and S43, S44 is following: with compound 1 pyridine 2,3-dicarboxylic anhydride selective esterification obtains compound 2, productive rate 68%; Compound 2 chloros obtain compound 3; Compound 3 obtains compound 4 with the selective reduction of acyl chlorides form, and productive rate is 38%; Compound 4 obtains compound 5 through the Mitsunobo reaction; Ring obtains 1 to compound 5 in sodium methylate ShiShimonoseki, 6-naphthyridine carbonyl acid methyl esters 6, two step productive rate 65%; Compound 6 with contain R
6Compound reaction obtain 5-R
6-1,6-naphthyridine carbonyl acid methyl esters 7, productive rate 85%; Compound 7 with contain R
7Amine amideization obtain 1,6-naphthyridine carbonyl amide compound 8, productive rate 88%; 8 hydroxyls of compound 8 obtain compound 9 with the Ts protection with 90% productive rate; The aryl nucleophilic substitution reactions take place and obtain a series ofly 5 in compound 9 and 1, the trans hexamethylene of 4-two, and 8-two replaces-1,6-naphthyridine-7-amidocarbonylation compound S1-S21 and S43, S44, productive rate 75%-85%;
(2) compound method of compound S 22-S30 is following: compound 7 refluxes in methylene dichloride with TsCl and triethylamine and obtained compound 10 in 5 hours; Compound 10 and single Boc protection trans 1, the 4-cyclohexanediamine is at K
2CO
3Obtained compound 11 in 8 hours with reflux in the THF; Compound 11 is the following 10h generation compound 12 of 60 degree in 1N NaOH solution/THF; Compound 12 is in EDCI, DMAP and methylene dichloride, and normal temperature obtains compound 13 with corresponding sulfuryl amine reaction 12h down; Compound 13 removes Boc and generates 5 in trifluoracetic acid/methylene dichloride of 20%, 8-two replaces-1,6-naphthyridine-7-amidocarbonylation compound S22-S30;
(3) compound method of compound S 33-S42 is following: compound 9 is with trans 1, and 4-cyclohexanediamine reflux in triethylamine, THF obtained compound 14 in 8 hours; Compound 14 refluxes in Palladous chloride, triphenylphosphine, cuprous iodide, salt of wormwood and THF and the reaction of propynoic acid methyl esters obtains compound 15; Compound 15 is sloughed Boc and is obtained 5 in 20% trifluoracetic acid/methylene dichloride, 8-two replaces-1,6-naphthyridine-7-amidocarbonylation compound S33-S42;
(4) compound method of compound S 46-S51 is following: compound 12 is in EDCI, HOAt, DIPEA and methylene dichloride, and normal temperature obtains compound 16 with corresponding amine reaction 12h down; Compound 16 removes Boc and generates 5 in trifluoracetic acid/methylene dichloride of 20%, 8-two replaces-1,6-naphthyridine-7-amidocarbonylation dimer compound S46-S51.
6. 5 shown in the described general structure I of claim 1, II or the III, 8-two replaces-1,6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof the purposes in the medicine of preparation tyrosine protein kinase inhibitor.
7. 5 shown in the described general structure I of claim 1, II or the III, 8-two replaces-1, and 6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof suppress the purposes in the medicine of tumour in preparation.
8. purposes according to claim 7, wherein, said tumour comprises mammary cancer, ovarian cancer, malignant melanoma, skin squama cancer, colorectal carcinoma, lung cancer, liver cancer, carcinoma of the pancreas, acute myeloid leukaemia and prostate cancer.
9. pharmaceutical composition, it comprises 5 shown in the described general structure I of the claim 1 of treating significant quantity, II or the III, and 8-two replaces-1,6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103709162A (en) * | 2012-09-29 | 2014-04-09 | 中国科学院上海药物研究所 | Tri-substituted imidazo diazanaphthalene ketone compounds, preparation method thereof and applications thereof |
| CN112142713A (en) * | 2019-06-27 | 2020-12-29 | 山东润博生物科技有限公司 | Synthesis method of imazethapyr |
| CN112142714A (en) * | 2019-06-27 | 2020-12-29 | 山东润博生物科技有限公司 | Synthetic method of imazapyr |
| CN112142712A (en) * | 2019-06-27 | 2020-12-29 | 山东润博生物科技有限公司 | Synthesis method of imazapic |
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| CN101684119A (en) * | 2008-09-27 | 2010-03-31 | 中国科学院上海药物研究所 | 5,8-disubstituted-1,6-quinazoline-7-amidocarbonylation compound, preparing method, composite and application thereof |
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| CN101684119A (en) * | 2008-09-27 | 2010-03-31 | 中国科学院上海药物研究所 | 5,8-disubstituted-1,6-quinazoline-7-amidocarbonylation compound, preparing method, composite and application thereof |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103709162A (en) * | 2012-09-29 | 2014-04-09 | 中国科学院上海药物研究所 | Tri-substituted imidazo diazanaphthalene ketone compounds, preparation method thereof and applications thereof |
| CN103709162B (en) * | 2012-09-29 | 2016-12-07 | 中国科学院上海药物研究所 | Tri-substituted imidazole benzodiazine ketonic compound and its production and use |
| CN112142713A (en) * | 2019-06-27 | 2020-12-29 | 山东润博生物科技有限公司 | Synthesis method of imazethapyr |
| CN112142714A (en) * | 2019-06-27 | 2020-12-29 | 山东润博生物科技有限公司 | Synthetic method of imazapyr |
| CN112142712A (en) * | 2019-06-27 | 2020-12-29 | 山东润博生物科技有限公司 | Synthesis method of imazapic |
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