CN102516263A - Spirotricyclic compound, its preparation method, and pharmaceutical composition containing it as well as application thereof - Google Patents
Spirotricyclic compound, its preparation method, and pharmaceutical composition containing it as well as application thereof Download PDFInfo
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- CN102516263A CN102516263A CN201110328838XA CN201110328838A CN102516263A CN 102516263 A CN102516263 A CN 102516263A CN 201110328838X A CN201110328838X A CN 201110328838XA CN 201110328838 A CN201110328838 A CN 201110328838A CN 102516263 A CN102516263 A CN 102516263A
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- spiral shell
- indoline
- piperidines
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Abstract
The invention provides a spirotricyclic compound as shown in formula (I), and simultaneously discloses a preparation method of the compound and application thereof, as well as a pharmaceutical composition containing the spirotricyclic compound. Being an inhibitor of protein kinase, the compound in the invention can be used to treat diseases caused by abnormal protein kinase activity, such as tumors and the like.
Description
Technical field
The present invention relates to organic chemistry and pharmaceutical chemistry field, the pharmaceutical composition and the application thereof that are specifically related to a kind of spiral shell tricyclic compounds and preparation method thereof and contain this compounds.
Background technology
Cancer is that two big types of diseases, the especially cancer sickness rate and the mortality ratio in recent years of serious threat human health and life is fast rise trend together with cardiovascular disorder, has surmounted the No.1 killer that cardiovascular disorder becomes human health.
Certain link is closely related unusually in a series of signal transduction path inside and outside the propagation of tumour, apoptosis, transfer etc. and the cell.In these signal transduction pathways, one type of important molecule is exactly a protein kinase.Protein kinase activity not only directly related with tumour unusually also is to cause a series of other human diseasess relevant with inflammation or proliferative response, for example the major cause of rheumatoid arthritis, cardiovascular and nervous system disorders, asthma, psoriatic etc.At present known have more than 400 kind of human diseases directly or indirectly relevant with protein kinase, and this makes protein kinase become another the big type of important drugs target after the G-protein linked receptor.
HGFr (hepatocyte growth factor receptor or HGFR) or title c-Met belong to the tyrosine receptor kinase.Its part is pHGF (hepatocyte growth factor or HGF).Under the normal physiological situation, the combination of c-Met acceptor and HGF and expression are most important to stablizing of environment in mammiferous growth and the tissue, but c-Met acceptor out of control is extremely relevant with the transfer process of tumour with HGF.C-Met acceptor and HGF be unusual high expression level in many tumor tissues, and its expression degree and patient's pernicious prognosis is closely related.The kinase whose point mutation of activation c-Met detects in following tumour: heredity palilate renal cell carcinoma (hereditary papillary renal carcinoma), sporadic palilate renal cell carcinoma (sporadic papillary renal carcinoma), lung cancer, head and neck cancer, children's hepatocellular carcinoma, cancer of the stomach etc.The amplification of c-Met acceptor gene also detects in following tumour in addition: the colorectal carcinoma of cancer of the stomach, transfer, esophageal adenocarcinoma.
Just because of the importance of c-Met in tumour generation, development and transfer, many companies and research institution all are devoted to research and develop the suppressor factor of c-Met.Janssen company report JNJ-33377605 is as micromolecular compound c-Met suppressor factor: H.M.Chen, J.R.Cui, J.E.Hoffman, M.C.Johnson; R.S.Kania, T.Q.Le, M.D.Nambu; M.A.Pairish, H.Shen, M.B.Tran-dube; World Pat.07132308,2007, p.1-110.Pfizer company has reported PF-04217903 as micromolecular compound c-Met suppressor factor: T.B.Lu, R.Alexander, R.W.Connors, M.D.Cummings; R.A.Galemmo, H.R.Hufnagel, D.L.Johnson, E.Khalil; K.A.Leonard, T.P.Markotan, A.C.Maroney, J.L.Sechler; World Pat.07075567,2007, p.1-220.In addition, US2006/0293358A1, WO2005/068473A1, WO2006/086484A1; WO2007/035428A1, WO2007/036630A1, WO2007/041379A1; WO2007/064797A1, WO2007/075567A1, WO2007/111904A2; WO2006/021886A1, WO2004/076412A2, WO2006/021881A2; US2006/0046991A1, patent documents such as US2005/0009840A1 disclose a series of heterogeneous ring compounds as the c-Met SU11752, and diseases such as cancer are had therapeutic action.
As stated; The c-Met tyrosine kinase inhibitor has many pieces of bibliographical informations; Some monoclonal antibodies that are directed against c-Met or HGF and synthesized micromolecule compound are also arranged just at the 1-3 clinical trial phase; But, because the uncertainty of well-known clinical trial, go back none c-Met or the HGF suppressor factor patent medicine that goes through at present.Therefore, the new c-Met suppressor factor of research and development is still very necessary.
Summary of the invention
One of the object of the invention provides a kind of spiral shell tricyclic compounds with protein kinase inhibiting activity and preparation method thereof.
Another object of the present invention provides above-mentioned spiral shell tricyclic compounds and is used to prepare treatment causes the pharmaceutical composition of disease because of the protein kinase abnormal activity application.
A further object of the invention provide a kind of contain above-mentioned spiral shell tricyclic compounds can treat the pharmaceutical composition that causes disease because of the protein kinase abnormal activity.
Technical scheme of the present invention
A kind of spiral shell tricyclic compounds, the molecular structural formula of this compound is suc as formula shown in (I):
In the formula:
R represent hydrogen ,-OH ,-NH
2,-CN ,-CF
3, C
1-6Alkyl, C
3-6Naphthenic base, C
6Aryl, 5-7 unit hetero-aromatic ring base, C
3-6Heterolipid cyclic group, R
1O-, R
1R
2N-, R
1S (=O)
n-, R
1R
2NS (=O)
n-, R
3C (=O)-, R
1R
2NC (=O)-, R
1OC (=O)-, R
1OC (=O) NR
4-, R
1S (=O)
nNR
4-, R
1R
2NC (=NR
5)-, R
1R
2NC (=CHNO
2)-, R
1S (=O) (=NR
5Hydrogen among)-, and the R can be by one or more identical or different G
1Replace;
Wherein, R
1, R
2, R
3, R
4And R
5Expression independently respectively: H, C
1-6Alkyl, C
3-6Naphthenic base, C
6Aryl, 5-7 unit hetero-aromatic ring base, C
3-6The heterolipid cyclic group; Work as R
1And R
2When being connected on the same nitrogen-atoms, can form a C with this nitrogen-atoms
3-6The heterolipid ring, said C
3-6The heterolipid ring comprise one or more O, N, S (=O)
nHeteroatoms; And R
1, R
2, R
3, R
4And R
5In hydrogen can be by one or more identical or different G
2Replace; N=0-2;
Wherein, G
1, G
2Be independently selected from hydrogen ,-OH ,-NH
2,-CN ,-CF
3, halogen, C
1-6Alkyl, C
3-6Naphthenic base, C
2-6Thiazolinyl, C
2-6Alkynyl, C
6Aryl, 5-6 unit heterocyclic aryl, C
3-6Heterolipid cyclic group, C
1-6Alkoxyl group, C
3-6Cycloalkyloxy, C
6Aryloxy, 5-7 unit heteroaryloxy, C
3-6Heterolipid epoxy group(ing), C
1-6Alkylamino, C
3-6Naphthene amino, C
6Virtue is amino, amino, the C of the first heterocycle virtue of 5-7
3-6The heterolipid ring is amino, C
1-6Alkoxy-C O-, C
3-6Cycloalkyloxy-CO-, C
6Aryloxy-CO-, the heterocycle aryloxy-CO-of 5-7 unit, C
3-6Heterolipid epoxy group(ing)-CO-, C
1-6Alkylamino-CO-, C
3-6Naphthene amino-CO-, C
6Virtue amino-CO-, the heterocycle virtue amino-CO-of 5-7 unit, C
3-6Heterolipid ring amino-CO-;
Two keys of
expression or singly-bound;
X
1, X
2, X
3, X
4, X
5, X
6, X
7Independently represent CH, CH respectively
2, any group among the NH, N, O, S.
A kind of spiral shell tricyclic compounds, the molecular structural formula of this compound is suc as formula shown in (Ia):
A kind of spiral shell tricyclic compounds, the molecular structural formula of this compound is suc as formula shown in (Ib):
A kind of spiral shell tricyclic compounds, the molecular structural formula of this compound is suc as formula shown in (Ic):
A kind of spiral shell tricyclic compounds, the molecular structural formula of this compound is suc as formula shown in (Id):
A kind of spiral shell tricyclic compounds, the molecular structural formula of this compound is suc as formula shown in (Ie):
A kind of spiral shell tricyclic compounds, the molecular structural formula of this compound is suc as formula shown in (If):
A kind of spiral shell tricyclic compounds, the molecular structural formula of this compound is suc as formula shown in (Ig):
A kind of spiral shell tricyclic compounds, the molecular structural formula of this compound is suc as formula shown in (Ih):
A kind of spiral shell tricyclic compounds is following any one compound:
5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
6-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-6-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-6-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-6-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-6-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-6-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
2-oxygen base-5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-6-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
2-oxygen base-6-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-6-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
1 '-ethanoyl-5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethanoyl-6-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-6-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-6-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
5-[3-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
6-[3-(6-quinolyl methyl)-1H-[1,2,4] triazole [3,4-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-5-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-6-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-5-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-6-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-5-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-6-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-5-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-6-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-5-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-6-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
2-oxygen base-5-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-6-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-5-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
2-oxygen base-6-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-5-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-6-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
1 '-ethanoyl-5-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethanoyl-6-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-5-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-6-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-5-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-6-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
5-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
6-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-5-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-6-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-5-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-6-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-5-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-6-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-5-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-6-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-5-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-6-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
2-oxygen base-5-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-6-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-5-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
2-oxygen base-6-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-5-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-6-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
1 '-ethanoyl-5-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethanoyl-6-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-5-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-6-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-5-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-6-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
5-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
6-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-5-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-6-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-5-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-6-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-5-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-6-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-5-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-6-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-5-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-6-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
2-oxygen base-5-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-6-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-5-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
2-oxygen base-6-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-5-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-6-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
1 '-ethanoyl-5-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethanoyl-6-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-5-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-6-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-5-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-6-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
6-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-6-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-6-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-6-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-6-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-6-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
2-oxygen base-5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-6-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
2-oxygen base-6-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-6-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
1 '-ethanoyl-5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethanoyl-6-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-6-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-6-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
5-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
6-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-5-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-6-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-5-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-6-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-5-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-6-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-5-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-6-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-5-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-6-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
2-oxygen base-5-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-6-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-5-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
2-oxygen base-6-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-5-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-6-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
1 '-ethanoyl-5-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethanoyl-6-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-5-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-6-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-5-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-6-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
5-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
6-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-5-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-6-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-5-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-6-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-5-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-6-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-5-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-6-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-5-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-6-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
2-oxygen base-5-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-6-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-5-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
2-oxygen base-6-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-5-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-6-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
1 '-ethanoyl-5-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethanoyl-6-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-5-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-6-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-5-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-6-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
5-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
5-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
6-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-5-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-6-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-5-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-6-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-5-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-6-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-5-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-6-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-5-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-6-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
2-oxygen base-5-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-6-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-5-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
2-oxygen base-6-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-5-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-6-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
1 '-ethanoyl-5-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethanoyl-6-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-5-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-6-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-5-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-6-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
A kind of spiral shell tricyclic compounds also comprises the raceme or the corresponding isomer of above-mentioned any one spiral shell tricyclic compounds.
Another technical scheme of the present invention is a kind of preparation method of spiral shell tricyclic compounds: the compound shown in the compound shown in the formula (II) and formula (III) or the formula (IV) carried out the Suzuki linked reaction processes the compound shown in the described formula (I),
The present invention also has the application of a technical scheme for the pharmaceutical composition be made up of a kind of spiral shell tricyclic compounds, it is characterized in that being used to treat the disease that causes because of the protein kinase abnormal activity.
The disease of treating in the application of the pharmaceutical composition that a kind of spiral shell tricyclic compounds is formed is a cancer.
The disease of treating in the application of the pharmaceutical composition that a kind of spiral shell tricyclic compounds is formed is a lung cancer; Osteocarcinoma; Carcinoma of the pancreas; Skin carcinoma; Head and neck cancer; Skin or intraocular melanoma; Uterus carcinoma; Ovarian cancer; The rectum cancer; The anal region cancer; Cancer of the stomach; Colorectal carcinoma; Mammary cancer; Carcinoma of fallopian tube; Carcinoma of endometrium; Cervical cancer; Carcinoma of vagina; The vaginal orifice cancer; Hodgkin; Esophagus cancer; Carcinoma of small intestine; The endocrine system cancer; Thyroid carcinoma; Parathyroid carcinoma; Soft tissue sarcoma; Urethral carcinoma; Penile cancer; Prostate cancer; Chronic or acute leukemia; Bladder cancer; Kidney or carcinoma of ureter; Nervus centralis cental system vegetation; The spinal column axis tumour; Pituitary adenoma; The stomach and intestine mesenchymal neoplasm; Colorectal carcinoma; Nonsmall-cell lung cancer; Small cell lung cancer; Mastocytosis; Glioma; Sarcoma; A kind of or any several kinds combination in the lymphoma.
The disease of treating in the application of the pharmaceutical composition that a kind of spiral shell tricyclic compounds is formed is psoriatic, liver cirrhosis, mellitus, the disease that relates to angiogenesis, disease of eye, rheumatic arthritis, disease of immune system, cardiovascular disorder, kidney disease.
The pharmaceutical composition of the disease that to be a kind of treatment cause because of the kinases abnormal activity that the present invention also has a technical scheme; Said pharmaceutical composition comprises above-mentioned any one or any several kinds of compounds or its at pharmacy acceptable salt, solvate, prodrug, or the raceme of above-mentioned any one or a few compound, enantiomer or it is at pharmacy acceptable salt, solvate or prodrug.
Pharmaceutical composition of the present invention also comprises one or more pharmaceutically acceptable carriers.
Pharmaceutical composition of the present invention also contains one or more in antibacterial agent, anti-mycotic agent, VITAMINs and the antitumor drug.
The dosage form of pharmaceutical composition of the present invention is following: (1) oral preparation; (2) injection; (3) anus suppository; (4) nostril inhalation; (5) eye drops; (6) skin patch.
Through a series of evidence; A kind of spiral shell tricyclic compounds of the present invention has following beneficial effect: (1) is through suppressing Tyrosylprotein kinase c-Met activity test; Can find out obviously no matter The compounds of this invention is can the kinase whose activity of very effective inhibition c-Met or equal in the MKN45 stomach cancer cell at biochemical condition.Deducibility thus, The compounds of this invention is inhibited for the disease that causes owing to the protein kinase abnormal activity.(2), can obviously find out the effectively increment of anticancer of The compounds of this invention through the effect test of growth of tumour cell.Infer that thus the medicine that contains The compounds of this invention can be applied to treatment for cancer.(3) thus compound of the present invention can play collaborative (synergistic) or adduction (additive) effect with common use of other antitumor drugs.(4) The compounds of this invention also can with other tumor therapy, for example radiotherapy, interventional therapy etc. are together used.This shows that a kind of spiral shell tricyclic compounds of the present invention is a kind of effectively material of arrestin kinase activity; Therefore the pharmaceutical composition of being made up of compound according to the invention also can be used as a kind of medicine of effective arrestin kinases disease that abnormal activity causes; The said medicine of being made up of spiral shell tricyclic compounds of the present invention can be used for treatment because of the unusual caused disease of protein kinase activity simultaneously.
In the molecular structural formula (I) of a kind of spiral shell tricyclic compounds of the present invention, X
1, X
2, X
3, X
4, X
5, X
6And X
7Expression independently respectively: CH, CH
2, among the NH, N, O, several kinds of groups of S any one, concrete molecular structural formula such as table 1:
Table 1
Preferred version wherein is a table 2:
Table 2
Among the preparation method of a kind of spiral shell tricyclic compounds according to the invention, synthetic The compounds of this invention formula (I) compound used therefor formula (II) is with formula (III) or radicals R, X (IV)
1, X
2, X
3, X
4, X
5, X
6, X
7Represent that with above-mentioned group in the formula (I) implication is identical.Wherein compound (II) can be through preparing with the similar method of document (WO2007/075567A1 & US2008/0030457A1, patent documentations such as WO2007/132308).Compound (III) or (IV) synthetic by following method:
The compounds of this invention is used for treating the application because of the caused disease of protein kinase abnormal activity; Described protein kinase is that c-Met is meant HGFr (hepatocyte growth factor receptor or HGFR); Belong to the tyrosine receptor kinase, its part is pHGF (hepatocyte growth factor or HGF).
Compound of the present invention (for example in biochemical condition or cell) under external artificial environment contacts with Tyrosylprotein kinase c-Met; Suppress its kinase catalytic activity; Activity to Tyrosylprotein kinase c-Met has restraining effect, can be used for preparing the suppressor factor of Tyrosylprotein kinase c-Met.Described c-Met suppressor factor is an activeconstituents with above-mentioned formula (I) compound, can process various concrete formulations medically commonly used, and the effective content of its Chinese style (I) compound can be tested definite as required.Use the compound of the present invention of effective dose can treat Mammals, for example human, the disease that causes because of the protein kinase abnormal activity, for example cancer.
Compound according to the invention is being treated because of protein kinase activity in the unusual caused disease, and described kidney is adrenal carcinoma, renal cell carcinoma, carcinoma of renal pelvis; Glioma is brain stem neurospongioma, neuroendocrine glia tumour, neurospongioma.
Compound according to the invention treatment because of the caused disease of protein kinase abnormal activity in, except that tumour, can also be psoriatic (or title psoriasis), liver cirrhosis, mellitus, the disease that relates to angiogenesis, the disease that relates to restenosis, disease of eye (for example AMD), rheumatic arthritis and other inflammation, disease of immune system (for example AIDS etc.), cardiovascular disorder (for example atherosclerosis), kidney disease etc.
The route of administration of the pharmaceutical composition among the present invention includes but not limited to: oral (for example tablet or capsule, syrup, gel, pill, suspension-s etc.), injection (for example, intravenous injection, subcutaneous injection, intramuscular injection, eyeball injection, abdominal injection etc.), anus plug (suppository, gelifying agent etc.), eye drip, nostril suction or spraying etc.Also can use drug delivery system, for example, liposome (liposome), slow release method etc., the method for wherein preferentially selecting for use are oral and injection, and the method for more preferably selecting for use is oral.
Wherein carrier, assistant agent and the vehicle of the use of the preparation of oral administration are but are not limited to: lime carbonate, calcium phosphate, various sugar (for example lactose, N.F,USP MANNITOL etc.), starch, Schardinger dextrins, Magnesium Stearate, Mierocrystalline cellulose, magnesiumcarbonate, XPA or methacrylate polymer, polyvidone (PVP), gel (gelatin), water, polyoxyethylene glycol, Ucar 35, terepthaloyl moietie, Viscotrol C, THIXCIN, many oxyethyl groups THIXCIN, til, Semen Maydis oil, peanut wet goods.
Aforementioned pharmaceutical compositions preparation process adopts medicine industry method commonly used, for example, and mixing, dissolving, granulation, grinding, emulsification, capsule, sugar-coat, lyophilize, cryospray etc.
The content range of compound among the present invention in aforementioned pharmaceutical composition is 0.001～100%.It is 0.1～500 milligram of per kg body weight per day that this pharmaceutical composition is applied to the mammiferous effective dose that comprises the people, and the dosage of optimization is that per kg body weight per day is used 1～100 milligram.In this effective dosage ranges, the compound among the present invention is brought into play its arrestin kinase activity and is treated the pharmacological action of the disease (for example cancer) that causes because of the paraprotein kinase activity.The frequency of utilization of medicine changes according to the disease of employed compound or its pharmaceutical composition and application to some extent, normally administration every day 1-6 time of the pharmaceutical composition among the present invention, and the administration frequency of optimization is administration every day 1-3 time.
Terminological interpretation
The meaning being as the criterion of the term that uses in the application's claim and other part unless stated otherwise, with following definition.The variable group that in this joint, uses, for example R
a, R
b, m etc. only is applicable to this joint.In addition, many groups of definition can be substituted in addition in this joint.Typical substituting group listed in this joint has been the effect of example, is not to be used for limiting the application's the claim and the content of other part.
" pharmacy acceptable salt " refers to compound and inorganic or organic acid, or the salt inorganic or that organic bases forms through chemical reaction among the present invention, and this salt keeps the biological activity and the validity of the compound among the present invention.Described inorganic or organic acid example is: hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, perchloric acid, acetic acid, Hydrocerol A, oxalic acid, lactic acid, oxysuccinic acid, Whitfield's ointment, tartrate, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, substituted Phenylsulfonic acid (for example, p-methyl benzenesulfonic acid), Yi Yansuan, oleic acid, tannic acid, pantothenic acid, xitix, Succinic Acid, toxilic acid, gentisinic acid, fumaric acid, glucono-, uronic acid, glucaric acid or sucrose acid, formic acid, phenylformic acid, L-glutamic acid, pamoic acid, Sorbic Acid etc.Described example inorganic or organic bases is sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate, ironic hydroxide, calcium hydroxide, hydrated barta, white lake, Marinco H, zinc hydroxide, ammoniacal liquor, hydroxide organic quaternary ammonium salt, yellow soda ash, salt of wormwood, Quilonum Retard, lime carbonate, barium carbonate, magnesiumcarbonate, carbonating organic quaternary ammonium salt, sodium hydrogencarbonate, saleratus, lithium bicarbonate, Calcium hydrogen carbonate, barium bicarbonate, Magnesium hydrogen carbonate, carbonic acid hydrogenation organic quaternary ammonium salt etc.
" solvate " refers to that compound and the solvent chemically commonly used among the present invention waits the stable material of formation with covalent linkage, hydrogen bond, ionic linkage, Van der Waals (Van der Waals) power, complexing, inclusion (inclusion), solvent wherein for example: methyl alcohol, ethanol, propyl alcohol, butanols, terepthaloyl moietie, Ucar 35, polyoxyethylene glycol, acetone etc.
" hydrate " refers to solvate, and solvent wherein is a water.
" prodrug (prodrug) " refers to through the method for chemosynthesis or physics the compound among the present invention is converted into another kind of compound, after this compound is given Mammals, in its body, is converted to the compound of being represented by formula I among the present invention." prodrug " method of utilization is normally in order to overcome the bad or not good enough physicochemical property of medical compounds itself or to become the property of medicine (drug-likeness).
" raceme, enantiomer and other steric isomer " refers to that compound has identical molecular formula and molecular weight; Yet owing to the different bonding modes between the atom and arrangement space order forms different compounds, such compound is isomer or title steric isomer.When these steric isomers mirror each other, promptly look the same, but can not overlap fully, and just like the left hand and the right hand, these compounds are enantiomer.The absolute configuration of enantiomer use usually (R)-and (S)-or R-and S-indicate.The rule of the absolute configuration of concrete definite enantiomer is seen Chapter 4 of " Advanced Organic Chemistry, " 4
ThEdition (by J.March, John Wiley and Sons, New York, 1992).(R)-and (S)-enantiomer has opposite turning effort to polarized light, promptly left-handed and dextrorotation.When (R)-and (S)-enantiomer by 1: 1 mixed or when existing, this mixture does not have turning effort to polarized light, at this moment this mixture is called raceme.
Compound among the present invention also possibly exist tautomer (tautomers), rotational isomer (rotamers), cis-trans-isomer etc., and these notions all can be at " the Advanced Organic Chemistry, " 4 of J.March
ThFind and obtain understanding among the edition.As long as these isomer have with the present invention in the effect of the identical arrestin kinase activity of compound, these isomer also are covered by among the present invention.
After compound among the present invention is given people's for example Mammals; General knowledge according to this area; Probably become various meta-bolitess by different enzymes metabolisms in animal body; As long as these meta-bolitess have with the present invention in the effect of the identical arrestin kinase activity of compound, these meta-bolitess also are covered by among the present invention.
" pharmaceutical composition " refers to one or more or its pharmacy acceptable salt, solvate, hydrate or prodrug and other chemical ingredients in the compound among the present invention, and for example pharmaceutically acceptable carrier mixes.The purpose of pharmaceutical composition is to promote administration to give the process of animal.
" pharmaceutically acceptable carrier " refers to the non-active ingredient in the pharmaceutical composition, such as but not limited to: lime carbonate, calcium phosphate, various sugar (for example lactose, N.F,USP MANNITOL etc.), starch, Schardinger dextrins, Magnesium Stearate, Mierocrystalline cellulose, magnesiumcarbonate, XPA or methacrylate polymer, gel (gelatin), water, polyoxyethylene glycol, Ucar 35, terepthaloyl moietie, Viscotrol C or THIXCIN or many oxyethyl groups THIXCIN, til, Semen Maydis oil, peanut wet goods.
In the aforesaid pharmaceutical composition; Except comprising pharmaceutically acceptable carrier; Can also be included in assistant agent commonly used in medicine (agent), for example: antibacterial agent, anti-mycotic agent, biocide, preservative, toning agent, solubilizing agent, thickening material, tensio-active agent, complexing agent, protein, amino acid, fat, carbohydrate, VITAMINs, mineral substance, trace element, sweeting agent, pigment, essence or their combination etc.
" C
1-6Alkyl " be C
1-6Saturated or undersaturated alkyl, for example methyl, ethyl, vinyl, ethynyl, propyl group, sec.-propyl, propenyl, normal-butyl, isobutyl-, the tertiary butyl, crotonyl etc.
" C
3-6Naphthenic base " be C
3-6Saturated or undersaturated naphthenic base, for example cyclopropyl, cyclopropenyl radical, cyclobutyl, cyclobutene base, cyclopentyl, cyclohexyl, cyclohexenyl, cyclic group dialkylene etc.
" 5-7 unit hetero-aromatic ring base " for by carbon atom with contain one or more O, N, S (=O)
nThe ring-type heteroaryl that contains 5-7 atomic building that heteroatoms constitutes, for example furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, pyranyl, pyridyl, thiapyran base, pyridazinyl, pyrimidyl etc.
" alkoxyl group " refers to have the alkyl that specifies number carbon atom and links to each other with other groups through Sauerstoffatom, for example methoxyl group, oxyethyl group, propoxy-, butoxy, cyclopentyloxy etc.
" cycloalkyloxy " refers to have the naphthenic base that specifies number carbon atom and links to each other with other groups through Sauerstoffatom.For example Trimetylene oxygen base, tetramethylene oxygen base etc.
" heterolipid ring or heterolipid cyclic group " can be tetrahydrofuran base, tetrahydropyridine, piperidyl, morpholinyl etc.
Embodiment
Below in conjunction with specific embodiment the present invention is done further explain, so that the public further understands beneficial effect of the present invention, but specific embodiments of the invention does not have restriction.
Be english abbreviation and the corresponding Chinese implication that occurs in an embodiment below.If occur not listing in this abbreviation among the embodiment, then represent generally accepted implication.
DMSO: DMSO 99.8MIN.; TMS: TMS; DCM: methylene dichloride;
CDCl
3: deuterochloroform; CD
3OD: deuterated methanol; DME:1, the 2-glycol dimethyl ether;
THF: THF; Aq.: the aqueous solution; TLC: thin-layer chromatography;
LC-MS: liquid chromatograph mass spectrography; G: gram; Mg: milligram;
Mmol: mmole; μ M: micromole; μ L: microlitre;
NM: nmole; M: volumetric molar concentration; N: equivalent concentration;
M/z: mass-to-charge ratio; δ: chemical shift
EDC.HCl:1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride.
Common experimental conditions:
Proton nmr spectra and carbon are composed and on Varian INOVA 500NB instrument, are obtained (deuterium is a solvent for DMSO, deuterochloroform, deuterated methanol etc., and TMS is interior mark).Mass spectrum obtains (adopting ESI or APCI ion source ZQ4000, U.S. Waters company) by liquid chromatographmass spectrometer.UV spectrum is recorded by the UV-3010 ultraviolet spectrophotometer of HIT.Ir spectra uses NICOLET6700 infrared spectrometric analyzer (KBr compressing tablet).Performance liquid chromatography uses Waters 2695 ZORBAX high performance liquid chromatograph (Bx-C
85 μ, 150 * 4.6mm chromatographic column).Measurement of melting point is used the digital fusing point appearance of Electrothermal IA9100, and does not proofread and correct.
Starting raw material, reagent and solvent are generally bought from following supplier: Beta-Pharma, Shanghai; Shanghai PI Chemicals; AndaChem, Taiyuan; Shanghai FWD Chemicals; Sigma-Aldrich, Milwaukee, WI, USA; Acros, Morris Plains, NJ, USA; Frontier Scientific, Logan, Utah, USA; Alfa Aesar, Ward Hill, MA, USA etc. or utilize the method for bibliographical information synthetic.Unless otherwise indicated, solvent is generally without drying, and directly uses supplier's product or through molecular sieve drying.Anhydrous solvent directly uses supplier's (for example Sigma-Aldrich) product or steams through CaH or sodium Metal 99.5.
Embodiment 1
Synthesizing of 5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone
Step 1:{2-oxygen base spiral shell [indoline-3,4 '-piperidines]-5-yl } boric acid sheet alcohol ester synthetic
Under nitrogen, in the DMSO solution (0.2ml) of 5-bromine spiral shell [indoline-3,4 '-piperidines]-2-ketone (140.6mg or 0.5mmol), the couplet pure boric acid ester of sheet (140mg or 0.55mmol) and Potassium ethanoate (147mg or 1.5mmol), add PdCl
2(dppf) .CH
2Cl
2(20.4mg or 0.025mmol) blasted nitrogen 2 minutes in gained solution, stirred 16 hours down in 80 ℃ then.LC-MS shows that reaction finishes, be chilled to room temperature after, add 2mL water, extract (extracting each use 5mL 3 times) with DCM.Organic phase merges, uses Na
2SO
4Dry, the concentrated title product 162mg that obtains, (productive rate: 98.7%).Mass spectrum m/z:328.07 [M+H
+], 329.08 [M+H
+, 100%], 330.11 [M+H
+].
Synthesizing of step 2:5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone
Under nitrogen; Toward 6-[(6-bromine triazole [4; 5-b] pyrazine-1-yl) methyl] (method shown in the WO2007/132308 of pressing prepares quinoline; 68.2mg or 0.2mmol), the DME/ water mixed solution of { 2-oxygen base spiral shell [indoline-3,4 '-piperidines]-5-yl } boric acid sheet alcohol ester (78.8mg or 0.24mmol) and salt of wormwood (82.9mg or 0.6mmol) (4/1, add Pd (PPh in 2.0ml)
3)
4(11.6mg or 0.01mmol) blasted nitrogen 2 minutes in the gained mixture, stirred 18 hours down in 80 ℃ then.LC-MS shows that reaction finishes, be chilled to room temperature after, add 5mL water, extract (extracting each use 10mL 3 times) with DCM.Organic phase merges, uses Na
2SO
4Dry, the concentrated crude product that obtains is with silica gel column chromatography (7MNH
3Methanol solution/DCM:5/95) purifying obtains title product 61.9mg, (productive rate: 67%).Mass spectrum m/z:463.21 [M+H
+].
Embodiment 2
Synthesizing of 6-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone
Step 1:{2-oxygen base spiral shell [indoline-3,4 '-piperidines]-6-yl } boric acid sheet alcohol ester synthetic
With reference to instance 1 method, from 6-bromine spiral shell [indoline-3,4 '-piperidines]-2-ketone preparation, yield: 96.9%.Mass spectrum m/z:328.07 [M+H
+], 329.08 [M+H
+, 100%], 330.11 [M+H
+].
Synthesizing of step 2:6-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone
Method preparation with reference to embodiment 1.Productive rate: 73%.Mass spectrum m/z:463.23 [M+H
+].
Embodiment 3
Synthesizing of 1 '-methyl-5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone
Synthesizing of step 1:5-bromo-1 '-methylspiro [indoline-3,4 '-piperidines]-2-ketone
5-bromine spiral shell [indoline-3,4 '-piperidines]-2-ketone (1.686g or 6mmol) is suspended among the 15mL THF, and is chilled to-78 ℃, stirs to drip 1MNaN (SiMe down
3)
2THF solution (30mL or 30mmol).Add the back in-78 ℃ of stirrings 30 minutes, add 2-chloro-N-(2-chloroethyl)-N-methyl ethyl-amine hydrochloride solid (1155g or 6mmol) then.Add continued and stirred 30 minutes, rose to stirring at room then two days.TLC shows that reaction finishes, and in this pink suspension-s, carefully adds 4M aqueous hydrochloric acid 10mL, is adjusted to pH ≈ 9 with strong aqua then, and extracts (extracting each 80mL of use 3 times) with DCM.Organic phase merges, uses Na
2SO
4Dry, the concentrated crude product that obtains is with silica gel column chromatography (7M NH
3Methanol solution/DCM:5/95) purifying obtains title product 1.38g, (productive rate: 78%).Mass spectrum m/z:294.99 [M+H
+,
79Br], 296.82 [M+H
+,
81Br].
Step 2:{1 '-methyl-2-oxygen base spiral shell [indoline-3,4 '-piperidines]-5-yl } boric acid sheet alcohol ester synthetic
With reference to instance 1 method, from 5-bromo-1 '-methylspiro [indoline-3,4 '-piperidines]-2-ketone preparation, yield: 95.1%.Mass spectrum m/z:342.07 [M+H
+], 343.08 [M+H
+, 100%], 344.11 [M+H
+].
Synthesizing of step 3:1 '-methyl-5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone
With reference to the method preparation of embodiment 1, productive rate: 63%.Mass spectrum m/z:477.20 [M+H
+].
Embodiment 4
Synthesizing of 1 '-methyl-6-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone
Synthesizing of step 1:6-bromo-1 '-methylspiro [indoline-3,4 '-piperidines]-2-ketone
With reference to embodiment 3 methods, from 6-bromine spiral shell [indoline-3,4 '-piperidines]-2-ketone preparation, productive rate: 82.1%.
Mass spectrum m/z:295.00 [M+H
+,
79Br], 296.83 [M+H
+,
81Br].
Step 2:{1 '-methyl-2-oxygen base spiral shell [indoline-3,4 '-piperidines]-6-yl } boric acid sheet alcohol ester synthetic
With reference to embodiment 1 method, from 6-bromo-1 '-methylspiro [indoline-3,4 '-piperidines]-2-ketone preparation, productive rate: 95.9%.Mass spectrum m/z:342.05 [M+H
+], 343.09 [M+H
+, 100%], 344.10 [M+H
+].
Step 3.1 '-methyl-6-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone synthetic
With reference to the method preparation of embodiment 1, productive rate: 69%.Mass spectrum m/z:477.13 [M+H
+].
Embodiment 5
Synthesizing of 2-oxygen base-5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde
Formic acid (6.9mg or 0.15mmol) and EDC.HCl (28.8mg or 0.15mmol) are suspended among the 20mL DCM, under agitation, drip diisopropyl ethyl amine (12.9mg or 0.1mmol).Add the back stirring at room half a hour, add 5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4, the 5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone (46.2mg or 0.1mmol) that embodiment 1 obtains, continue stirring 2 hours.Rotary evaporation removes and desolvates, and the concentrated crude product that obtains is with silica gel column chromatography (7M NH
3Methanol solution/DCM:5/95) purifying obtains title product 38.8mg, (productive rate: 79%).Mass spectrum m/z:49119 [M+H
+].
Embodiment 6
Synthesizing of 2-oxygen base-6-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde
With reference to the method for embodiment 5, from 6-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone preparation that embodiment 2 obtains, productive rate: 75%.Mass spectrum m/z:491.23 [M+H
+].
Embodiment 7
Synthesizing of 2-oxygen base-5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide
5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone (46.3mg or 0.1mmol) that embodiment 1 is obtained is dissolved among the 2mL DCM, adds Me then
3Si-NCO (28.8mg or 0.25mmol) and diisopropyl ethyl amine (32.1mg or 0.25mmol), gained mixture stirring at room 16 hours, the decompressing and extracting solvent, crude product is with silica gel column chromatography (7M NH
3Methanol solution/DCM:5/95) purifying obtains title product 36.9mg, (productive rate: 73%).Mass spectrum m/z:506.19 [M+H
+].
Embodiment 8
Synthesizing of 1 '-methyl sulphonyl-5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone
5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4 with embodiment 1 acquisition; 5-b] pyrazine-6-yl] spiral shell [indoline-3; 4 '-piperidines]-2-ketone (46.3mg or 0.1mmol) is dissolved in 2mL DCM, adds Methanesulfonyl chloride (12.5mg or 0.11mmol) and diisopropyl ethyl amine (12.8mg or 0.1mmol), and the gained mixture was in stirring at room 6 hours; The decompressing and extracting solvent, crude product is with silica gel column chromatography (7M NH
3Methanol solution/DCM:5/95) purifying obtains title product 35.6mg, (productive rate: 66%).Mass spectrum m/z:541.20 [M+H
+].
Embodiment 9
Synthesizing of 5-[3-(6-quinolyl methyl)-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone
Under nitrogen; Toward 6-[(6-bromine [1,2,4] triazole [4; 3-b] pyridazine-3-yl) methyl] quinoline (prepares according to method shown in the WO2007/075567; 68.0mg or 0.2mmol), the DME/ water mixed solution of { 2-oxygen base spiral shell [indoline-3,4 '-piperidines]-5-yl } boric acid sheet alcohol ester (78.8mg or 0.24mmol) and salt of wormwood (82.9mg or 0.6mmol) (4/1, add Pd (PPh in 2.0ml)
3)
4(11.6mg or 0.01mmol) blasted nitrogen 2 minutes in the gained mixture, stirred 18 hours down in 80 ℃ then.LC-MS shows that reaction finishes, be chilled to room temperature after, add 5mL water, extract (extracting each use 10mL 3 times) with DCM.Organic phase merges, uses Na
2SO
4Dry, the concentrated crude product that obtains is with silica gel column chromatography (7M NH
3Methanol solution/DCM:5/95) purifying obtains title product 32.3mg, (productive rate: 70%).Mass spectrum m/z:462.22 [M+H
+].
Embodiment 10
Synthesizing of 6-[3-(6-quinolyl methyl)-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone
With reference to embodiment 9, by { 2-oxygen base spiral shell [indoline-3,4 '-piperidines]-6-yl } boric acid sheet alcohol ester, the preparation of 6-[(6-bromine [1,2,4] triazole [4,3-b] pyridazine-3-yl) methyl] quinoline, productive rate 63%.Mass spectrum m/z:462.19 [M+H
+].
Embodiment 11
Synthesizing of 1 '-methyl-5-[3-(6-quinolyl methyl)-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone
Method with reference to embodiment 3 prepares { 1 '-methyl-2-oxygen base spiral shell [indoline-3,4 '-piperidines]-5-yl } boric acid sheet alcohol ester, then with reference to embodiment 9 preparations, productive rate 66%.Mass spectrum m/z:476.23 [M+H
+].
Embodiment 12
Synthesizing of 2-oxygen base-5-[3-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde
With reference to the method for embodiment 5, compound 5-[3-(6-quinolyl methyl)-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone that obtains from embodiment 9 carries out formylation preparation, productive rate: 80%.Mass spectrum m/z:490.16 [M+H
+].
Embodiment 13
Synthesizing of 1 '-methyl sulphonyl-5-[3-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone
With reference to the method for embodiment 8, compound 5-[3-(6-quinolyl methyl)-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone that obtains from embodiment 9 carries out the methylsulfonyl preparation, productive rate: 61%.Mass spectrum m/z:540.19 [M+H
+].
Embodiment 14
Synthesizing of 5-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone
With reference to the method for embodiment 1, prepare productive rate 60% through the Suzuki linked reaction by { 2-oxygen base spiral shell [indoline-3,4 '-piperidines]-5-yl } boric acid sheet alcohol ester, 6-[(6-bromo-1H-indazole-1-yl) methyl] quinoline.Mass spectrum m/z:460.29 [M+H
+].
Embodiment 15
Synthesizing of 6-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone
With reference to the method for embodiment 1, prepare productive rate 64% through the Suzuki linked reaction by { 2-oxygen base spiral shell [indoline-3,4 '-piperidines]-6-yl } boric acid sheet alcohol ester, 6-[(6-bromo-1H-indazole-1-yl) methyl] quinoline.Mass spectrum m/z:460.26 [M+H
+].
Embodiment 16
Synthesizing of 5-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone
With reference to the method for embodiment 1, prepare productive rate 60% through the Suzuki linked reaction by { 2-oxygen base spiral shell [indoline-3,4 '-piperidines]-5-yl } boric acid sheet alcohol ester, 6-[(5-bromo-3H-[1,2,3] triazole [4,5-d] pyrimidin-3-yl) methyl] quinoline.Mass spectrum m/z:463.20 [M+H
+].
Embodiment 17
Synthesizing of 6-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone
With reference to the method for embodiment 1, prepare productive rate 62% through the Suzuki linked reaction by { 2-oxygen base spiral shell [indoline-3,4 '-piperidines]-6-yl } boric acid sheet alcohol ester, 6-[(5-bromo-3H-[1,2,3] triazole [4,5-d] pyrimidin-3-yl) methyl] quinoline.Mass spectrum m/z:463.23 [M+H
+].
Embodiment 18
Synthesizing of 1 '-methyl-5-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone
With reference to the method for embodiment 1, prepare productive rate 59% through the Suzuki linked reaction by { 1 '-methyl-2-oxygen base spiral shell [indoline-3,4 '-piperidines]-5-yl } boric acid sheet alcohol ester, 6-[(5-bromo-3H-[1,2,3] triazole [4,5-d] pyrimidin-3-yl) methyl] quinoline.Mass spectrum m/z:477.13 [M+H
+].
Embodiment 19
Synthesizing of 2-oxygen base-5-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde
With reference to the method for embodiment 5, from compound 5-[3-(the 6-quinolyl first of embodiment 16 acquisitions
Base)-and 3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone carries out formylation and prepares productive rate: 76%.Mass spectrum m/z:491.19 [M+H
+].
Embodiment 20
Synthesizing of 1 '-methyl sulphonyl-5-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone
With reference to the method for embodiment 8, compound 5-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone that obtains from embodiment 16 carries out the methylsulfonyl preparation, productive rate: 63%.Mass spectrum m/z:541.19 [M+H
+].
Embodiment 21
Synthesizing of 5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone
With reference to the method for embodiment 1, prepare productive rate 66% through the Suzuki linked reaction by { 2-oxygen base spiral shell [indoline-3,4 '-piperidines]-5-yl } boric acid sheet alcohol ester, 6-[(2-bromo-9H-purine-9-yl) methyl] quinoline.Mass spectrum m/z:462.19 [M+H
+].
Embodiment 22
Synthesizing of 6-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone
With reference to the method for embodiment 1, prepare productive rate 64% through the Suzuki linked reaction by { 2-oxygen base spiral shell [indoline-3,4 '-piperidines]-6-yl } boric acid sheet alcohol ester, 6-[(2-bromo-9H-purine-9-yl) methyl] quinoline.Mass spectrum m/z:462.22 [M+H
+].
Embodiment 23
Synthesizing of 1 '-methyl-5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone
With reference to the method for embodiment 1, prepare productive rate 60% through the Suzuki linked reaction by { 1 '-methyl-2-oxygen base spiral shell [indoline-3,4 '-piperidines]-5-yl } boric acid sheet alcohol ester, 6-[(2-bromo-9H-purine-9-yl) methyl] quinoline.Mass spectrum m/z:474.15 [M+H
+].
Embodiment 24
Synthesizing of 2-oxygen base-5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde
With reference to the method for embodiment 5, compound 5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone that obtains from embodiment 21 carries out formylation preparation, productive rate: 79%.Mass spectrum m/z:490.14 [M+H
+].
Embodiment 25
N, N-dimethyl--2-oxygen base-5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide synthetic
Compound 5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone (46.2mg or 0.1mmol) that embodiment 21 is obtained is dissolved among the 2mL DCM, adds Me then
2NCOCl (12.9mg or 0.12mmol) and diisopropyl ethyl amine (32.1mg or 0.25mmol), gained mixture stirring at room 8 hours, the decompressing and extracting solvent, crude product is with silica gel column chromatography (7M NH
3Methanol solution/DCM:5/95) purifying obtains title product 46.4mg, (productive rate: 87%).Mass spectrum m/z:533.29 [M+H
+].
Embodiment 26
Synthesizing of 1 '-methyl sulphonyl-5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone
With reference to the method for embodiment 8, compound 5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone that obtains from embodiment 21 carries out the methylsulfonyl preparation, productive rate: 58%.Mass spectrum m/z:540.09 [M+H
+].
Embodiment 27
Synthesizing of 5-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone
With reference to the method for embodiment 1, prepare productive rate 66% through the Suzuki linked reaction by { 2-oxygen base spiral shell [indoline-3,4 '-piperidines]-5-yl } boric acid sheet alcohol ester, 6-[(5-bromo-[1,2,3] triazole [1,5-a] pyrimidin-3-yl) methyl] quinoline.Mass spectrum m/z:462.12 [M+H
+].
Embodiment 28
Synthesizing of 6-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone
With reference to the method for embodiment 1, prepare productive rate 63% through the Suzuki linked reaction by { 2-oxygen base spiral shell [indoline-3,4 '-piperidines]-6-yl } boric acid sheet alcohol ester, 6-[(5-bromo-[1,2,3] triazole [1,5-a] pyrimidin-3-yl) methyl] quinoline.Mass spectrum m/z:462.15 [M+H
+].
Embodiment 29
Synthesizing of 1 '-methyl-5-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone
With reference to the method for embodiment 3, prepare productive rate 60% through the Suzuki linked reaction by { 1 '-methyl-2-oxygen base spiral shell [indoline-3,4 '-piperidines]-5-yl } boric acid sheet alcohol ester, 6-[(5-bromo-[1,2,3] triazole [1,5-a] pyrimidin-3-yl) methyl] quinoline.Mass spectrum m/z:476.18 [M+H
+].
Embodiment 30
Synthesizing of 2-oxygen base-5-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde
With reference to the method for embodiment 5, compound 5-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone that obtains from embodiment 27 carries out formylation preparation, productive rate: 75%.Mass spectrum m/z:490.14 [M+H
+].
Embodiment 31
Synthesizing of 1 '-methyl sulphonyl-5-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone
With reference to the method for embodiment 8, compound 5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone that obtains from embodiment 27 carries out the methylsulfonyl preparation, productive rate: 62%.Mass spectrum m/z:540.17 [M+H
+].
Embodiment 32
Synthesizing of 5-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone
With reference to the method for embodiment 1, prepare productive rate 66% through the Suzuki linked reaction by { 2-oxygen base spiral shell [indoline-3,4 '-piperidines]-5-yl } boric acid sheet alcohol ester, 6-[(5-bromo-3H-pyrazoles [4,3-d] pyrimidin-3-yl) methyl] quinoline.Mass spectrum m/z:462.11 [M+H
+].
Embodiment 33
Synthesizing of 6-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone
With reference to the method for embodiment 1, prepare productive rate 66% through the Suzuki linked reaction by { 2-oxygen base spiral shell [indoline-3,4 '-piperidines]-6-yl } boric acid sheet alcohol ester, 6-[(5-bromo-3H-pyrazoles [4,3-d] pyrimidin-3-yl) methyl] quinoline.Mass spectrum m/z:462.14 [M+H
+].
Embodiment 34
Synthesizing of 5-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone
With reference to the method for embodiment 1, prepare productive rate 63% through the Suzuki linked reaction by { 2-oxygen base spiral shell [indoline-3,4 '-piperidines]-5-yl } boric acid sheet alcohol ester, 5-bromo-3-(6-quinolyl methyl) furans [3,2-b] pyridine.Mass spectrum m/z:461.23 [M+H
+].
Embodiment 35
Synthesizing of 6-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone
With reference to the method for embodiment 1, prepare productive rate 60% through the Suzuki linked reaction by { 2-oxygen base spiral shell [indoline-3,4 '-piperidines]-6-yl } boric acid sheet alcohol ester, 5-bromo-3-(6-quinolyl methyl) furans [3,2-b] pyridine.Mass spectrum m/z:461.28 [M+H
+].
Embodiment 36
This example is the effect experiment that the foregoing description 1～35 prepared compound suppresses Tyrosylprotein kinase c-Met activity and growth of tumour cell, and concrete experimental technique and experimental result are following.
1, the biochemical 503nhibiting concentration (IC of c-Met
50) experiment
Biochemical 503nhibiting concentration (the IC of c-Met
50) detection: the 384-orifice plate: every hole adds the Triphosaden (ATP) that contains 200ng/ μ L biotinylation polytyrosine and L-glutamic acid (Glu: Tyr, 4: 1), 0.334mM vannadate, 2 μ M of 10 μ L.Damping fluid: 50mM HEPES (pH=7.4), 5mM MgCl
2, 5mM MnCl
2And 1% glycerine.The compound dissolution that the embodiment of the invention 1～35 is prepared is in the DMSO of 1% concentration solution.The c-Met enzyme is diluted to optimum concn with following damping fluid: 50mM Tris (pH=7.4), 1% glycerine, 0.03%Brij35,0.24mM EGTA, 1mM DTT and 0.003%BSA.Add the enzyme initiation reaction, and let and react on room temperature and carried out 1 hour.Add 15 μ L damping fluids, 5 μ L can with vitamin H bonded donor magnetic bead, 5 μ L can with phosphorylated tyrosine bonded acceptor magnetic bead, hatch 1 hour after,, read plate with AlphaQuest.503nhibiting concentration is the MV of at least twice test.
2, c-Met 503nhibiting concentration (IC in the MKN45 cell
50) experiment
(available from Japanese Riken Cell Bank) is inoculated in the RPMI164096 porocyte culture plate that contains 10%FCS with the MKN45 stomach cancer cell; Cultivate after 48 hours; The DMSO solution of compound joins in the enchylema, and the ultimate density scope of compound is 0.0001-10 μ M.After hatching 4 hours; After twice of washed cell on ice, every hole adds 110 μ L cell pyrolysis liquids, puts cracking on ice after 20 minutes with PBS (4 ℃); 100 μ L cell lysates are transferred in the 96 hole brassboards that are combined with c-Met antibody in advance, placed 4 ℃ to spend the night.Cell lysate in the 96 hole brassboards discarded in second day; At room temperature, add the anti-c-Met tyrosine phosphorylation of rabbit (pYpYpY1230/1234/1235, the antibody of both anti-c-Met1230/1234/1235 position phosphorylated tyrosine) antibody with PBST washing 4 times; In incubated at room after 2 hours; Discard antibody and washed twice, add anti-rabbit igg horseradish hydroperoxy acid enzyme afterwards, put 30 minutes after scouring of room temperature 3 times.Every subsequently hole adds 100 μ L substrate TMB (TMB), reacts after 30 minutes, adds reaction terminating liquid.The absorption value of test wavelength 450 nanometers obtains IC with data through the processing of Excel Fit software analysis
50Curve and numerical value.503nhibiting concentration is the MV of at least twice test.
3, compound is to the influence of the MKN45 stomach cancer cell line propagation of c-Met high expression level
Collect the MKN45 stomach cancer cell of logarithmic phase, the adjustment concentration of cell suspension divides in 96 orifice plates 10000/hole.Put 37 ℃, 5%CO
2Incubator was cultivated 24 hours.Synthetic compound 20 μ l among the embodiment 1～35 of adding different concns continue to cultivate 72 hours.Add the fresh RPMI RPMI-1640 of 80 μ l, add 20ul MTT solution (5mg/ml, i.e. 0.5%MTT) again, continue to cultivate 4h.Centrifugal, carefully sop up supernatant then, every hole adds the 150ul DMSO 99.8MIN., puts low-speed oscillation 10min on the shaking table, and crystallisate is fully dissolved.Measure the light absorption value in each hole at enzyme-linked immunosorbent assay instrument 490nm place.Zeroing hole (substratum, MTT, DMSO 99.8MIN.) is set simultaneously, control wells (the medicine dissolution medium of cell, same concentrations, nutrient solution, MTT, DMSO 99.8MIN.), every settings 3 multiple holes.Calculate inhibiting rate=[(contrast-blank)-(administration-blank)]/(contrast-blank) * 100%.Data are obtained IC through the processing of Excel Fit software analysis
50Curve and numerical value.
4, experimental result see the following form (table 3):
Table 3
Visible by above-mentioned experimental data: 1, the biochemical 503nhibiting concentration (IC of c-Met
50), the compound in the embodiment of the invention 1～35 is very obvious to the restraining effect of c-Met protein kinase, and the biochemical 503nhibiting concentration (IC of c-Met of compound prepared among the embodiment 34,35 is only arranged
50) value is greater than 1 μ M, other all below 1 μ M, compound has reached 0.0147 μ M among the best embodiment 4 of effect; 2, c-Met 503nhibiting concentration IC in the MKN45 cell
50, the compound in the embodiment of the invention 1～35 also has the good restraining effect to the c-Met protein kinase, and c-Met 503nhibiting concentration IC in the MKN45 cell of compound prepared among the embodiment 14,15,21,23,34,35 is only arranged
50Value is greater than 1 μ M, other all below 1 μ M, compound has reached 0.0507 μ M among the best embodiment 8 of effect; 3, MKN45 cell proliferation IC
50Value, the compound in the embodiment of the invention 1～35 is also apparent in view to the influence of the MKN45 stomach cancer cell line propagation of c-Met high expression level, only the IC of compound in embodiment 34,35
50Value is all greater than 100 μ M, other IC
50Be worth all less than 100 μ M the best IC of the effect of compound among the embodiment 4
50Value is merely 0.630 μ M.
This shows; The compounds of this invention can be used for treatment because of the caused disease of protein kinase abnormal activity, for example: cancer, psoriatic, liver cirrhosis, mellitus, the disease that relates to angiogenesis, disease of eye, rheumatic arthritis, disease of immune system, cardiovascular disorder, kidney disease etc.
Claims (20)
1. spiral shell tricyclic compounds, the molecular structural formula of this compound is suc as formula shown in (I):
In the formula:
R represent hydrogen ,-OH ,-NH
2,-CN ,-CF
3, C
1-6Alkyl, C
3-6Naphthenic base, C
6Aryl, 5-7 unit hetero-aromatic ring base, C
3-6Heterolipid cyclic group, R
1O-, R
1R
2N-, R
1S (=O)
n-, R
1R
2NS (=O)
n-, R
3C (=O)-, R
1R
2NC (=O)-, R
1OC (=O)-, R
1OC (=O) NR
4-, R
1S (=O)
nNR
4-, R
1R
2NC (=NR
5)-, R
1R
2NC (=CHNO
2)-, R
1S (=O) (=NR
5Hydrogen among)-, and the R can be by one or more identical or different G
1Replace;
Wherein, R
1, R
2, R
3, R
4And R
5Expression independently respectively: H, C
1-6Alkyl, C
3-6Naphthenic base, C
6Aryl, 5-7 unit hetero-aromatic ring base, C
3-6The heterolipid cyclic group; Work as R
1And R
2When being connected on the same nitrogen-atoms, can form a C with this nitrogen-atoms
3-6The heterolipid ring, said C
3-6The heterolipid ring comprise one or more O, N, S (=O)
nHeteroatoms; And R
1, R
2, R
3, R
4And R
5In hydrogen can be by one or more identical or different G
2Replace; N=0-2;
Wherein, G
1, G
2Be independently selected from hydrogen ,-OH ,-NH
2,-CN ,-CF
3, halogen, C
1-6Alkyl, C
3-6Naphthenic base, C
2-6Thiazolinyl, C
2-6Alkynyl, C
6Aryl, 5-6 unit heterocyclic aryl, C
3-6Heterolipid cyclic group, C
1-6Alkoxyl group, C
3-6Cycloalkyloxy, C
6Aryloxy, 5-7 unit heteroaryloxy, C
3-6Heterolipid epoxy group(ing), C
1-6Alkylamino, C
3-6Naphthene amino, C
6Virtue is amino, amino, the C of the first heterocycle virtue of 5-7
3-6The heterolipid ring is amino, C
1-6Alkoxy-C O-, C
3-6Cycloalkyloxy-CO-, C
6Aryloxy-CO-, the heterocycle aryloxy-CO-of 5-7 unit, C
3-6Heterolipid epoxy group(ing)-CO-, C
1-6Alkylamino-CO-, C
3-6Naphthene amino-CO-, C
6Virtue amino-CO-, the heterocycle virtue amino-CO-of 5-7 unit, C
3-6Heterolipid ring amino-CO-;
Two keys of
expression or singly-bound;
X
1, X
2, X
3, X
4, X
5, X
6, X
7Independently represent CH, CH respectively
2, any group among the NH, N, O, S.
2. a kind of spiral shell tricyclic compounds according to claim 1, the molecular structural formula of this compound is suc as formula shown in (Ia):
3. a kind of spiral shell tricyclic compounds according to claim 1, the molecular structural formula of this compound is suc as formula shown in (Ib):
4. a kind of spiral shell tricyclic compounds according to claim 1, the molecular structural formula of this compound is suc as formula shown in (Ic):
5. a kind of spiral shell tricyclic compounds according to claim 1, the molecular structural formula of this compound is suc as formula shown in (Id):
6. a kind of spiral shell tricyclic compounds according to claim 1, the molecular structural formula of this compound is suc as formula shown in (Ie):
7. a kind of spiral shell tricyclic compounds according to claim 1, the molecular structural formula of this compound is suc as formula shown in (If):
8. a kind of spiral shell tricyclic compounds according to claim 1, the molecular structural formula of this compound is suc as formula shown in (Ig):
9. a kind of spiral shell tricyclic compounds according to claim 1, the molecular structural formula of this compound is suc as formula shown in (Ih):
10. a kind of spiral shell tricyclic compounds according to claim 1 is characterized in that said compound is following any one compound:
5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
6-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-6-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-6-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-6-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-6-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-6-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
2-oxygen base-5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-6-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
2-oxygen base-6-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-6-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
1 '-ethanoyl-5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethanoyl-6-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-6-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-5-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-6-[1-(6-quinolyl methyl)-1H-[1,2,3] triazole [4,5-b] pyrazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
5-[3-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
6-[3-(6-quinolyl methyl)-1H-[1,2,4] triazole [3,4-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-5-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-6-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-5-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-6-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-5-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-6-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-5-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-6-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-5-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-6-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
2-oxygen base-5-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-6-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-5-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
2-oxygen base-6-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-5-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-6-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
1 '-ethanoyl-5-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethanoyl-6-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-5-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-6-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-5-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-6-[1-(6-quinolyl methyl)-1H-[1,2,4] triazole [4,3-b] pyridazine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
5-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
6-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-5-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-6-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-5-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-6-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-5-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-6-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-5-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-6-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-5-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-6-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
2-oxygen base-5-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-6-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-5-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
2-oxygen base-6-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-5-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-6-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
1 '-ethanoyl-5-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethanoyl-6-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-5-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-6-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-5-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-6-[1-(6-quinolyl methyl)-1H-indazole-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
5-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
6-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-5-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-6-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-5-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-6-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-5-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-6-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-5-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-6-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-5-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-6-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
2-oxygen base-5-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-6-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-5-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
2-oxygen base-6-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-5-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-6-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
1 '-ethanoyl-5-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethanoyl-6-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-5-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-6-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-5-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-6-[3-(6-quinolyl methyl)-3H-[1,2,3] triazole [4,5-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
6-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-6-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-6-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-6-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-6-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-6-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
2-oxygen base-5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-6-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
2-oxygen base-6-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-6-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
1 '-ethanoyl-5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethanoyl-6-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-6-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-5-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-6-[9-(6-quinolyl methyl)-9H-purine-2-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
5-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
6-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-5-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-6-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-5-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-6-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-5-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-6-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-5-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-6-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-5-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-6-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
2-oxygen base-5-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-6-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-5-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
2-oxygen base-6-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-5-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-6-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
1 '-ethanoyl-5-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethanoyl-6-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-5-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-6-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-5-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-6-[3-(6-quinolyl methyl)-[1,2,3] triazole [1,5-a] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
5-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
6-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-5-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-6-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-5-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-6-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-5-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-6-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-5-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-6-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-5-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-6-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
2-oxygen base-5-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-6-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-5-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
2-oxygen base-6-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-5-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-6-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
1 '-ethanoyl-5-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethanoyl-6-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-5-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-6-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-5-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-6-[3-(6-quinolyl methyl)-3H-pyrazoles [4,3-d] pyrimidine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
5-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
5-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-5-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
6-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-5-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl-6-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-5-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethyl-6-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-5-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-sec.-propyl-6-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-5-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-hydroxyl-6-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-5-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-amino-6-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
2-oxygen base-5-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-6-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-formaldehyde;
2-oxygen base-5-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
2-oxygen base-6-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-5-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
N, N-dimethyl--2-oxygen base-6-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-1 '-methane amide;
1 '-ethanoyl-5-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-ethanoyl-6-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-5-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-methyl sulphonyl-6-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-5-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
1 '-(2-amino-2-methyl propionyl group)-6-[1-(6-quinolyl methyl) furans [3,2-b] pyridine-6-yl] spiral shell [indoline-3,4 '-piperidines]-2-ketone;
11. raceme or corresponding isomer according to described any one spiral shell tricyclic compounds of claim 1～10.
12. the preparation method of any described any one spiral shell tricyclic compounds of claim of claim 1～10; It is characterized in that: the compound shown in the compound shown in the formula (II) and formula (III) or the formula (IV) is carried out the Suzuki linked reaction process the compound shown in the described formula (I)
13. the application of the pharmaceutical composition of being made up of any one spiral shell tricyclic compounds in the claim 1～10 is characterized in that being used to treat the disease that causes because of the protein kinase abnormal activity.
14. application according to claim 13 is characterized in that described disease is a cancer.
15. application according to claim 14 is characterized in that described disease is a kind of or any several kinds combination in lung cancer, osteocarcinoma, carcinoma of the pancreas, skin carcinoma, head and neck cancer, skin or intraocular melanoma, uterus carcinoma, ovarian cancer, the rectum cancer, anal region cancer, cancer of the stomach, colorectal carcinoma, mammary cancer, carcinoma of fallopian tube, carcinoma of endometrium, cervical cancer, carcinoma of vagina, vaginal orifice cancer, Hodgkin, esophagus cancer, carcinoma of small intestine, endocrine system cancer, thyroid carcinoma, parathyroid carcinoma, soft tissue sarcoma, urethral carcinoma, penile cancer, prostate cancer, chronic or acute leukemia, bladder cancer, kidney or carcinoma of ureter, nervus centralis cental system vegetation, spinal column axis tumour, pituitary adenoma, stomach and intestine mesenchymal neoplasm, colorectal carcinoma, nonsmall-cell lung cancer, small cell lung cancer, mastocytosis, glioma, sarcoma, the lymphoma.
16. application according to claim 13 is characterized in that said disease is psoriatic, liver cirrhosis, mellitus, the disease that relates to angiogenesis, disease of eye, rheumatic arthritis, disease of immune system, cardiovascular disorder, kidney disease.
17. the pharmaceutical composition of the disease that a treatment causes because of the kinases abnormal activity; Said pharmaceutical composition comprises described in the claim 1～10 any one or any several kinds of compounds or its at pharmacy acceptable salt, solvate, prodrug, or the raceme of any one or a few compound described in the claim 1～10, enantiomer or it is at pharmacy acceptable salt, solvate or prodrug.
18. pharmaceutical composition according to claim 17 is characterized in that said pharmaceutical composition also comprises one or more pharmaceutically acceptable carriers.
19. pharmaceutical composition according to claim 17 is characterized in that said pharmaceutical composition also contains one or more in antibacterial agent, anti-mycotic agent, VITAMINs and the antitumor drug.
20., it is characterized in that the dosage form of said pharmaceutical composition is following according to claim 17 or 18 described any one pharmaceutical compositions:
(1) oral preparation; (2) injection; (3) anus suppository; (4) nostril inhalation; (5) eye drops; (6) skin patch.
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