CN101857594A - Tetrahydropyridoindole compounds, and preparation method and application thereof - Google Patents

Tetrahydropyridoindole compounds, and preparation method and application thereof Download PDF

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CN101857594A
CN101857594A CN 201010205202 CN201010205202A CN101857594A CN 101857594 A CN101857594 A CN 101857594A CN 201010205202 CN201010205202 CN 201010205202 CN 201010205202 A CN201010205202 A CN 201010205202A CN 101857594 A CN101857594 A CN 101857594A
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fluorophenyls
chloro
tetrahydropyridine
pyridyl
indoles
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CN101857594B (en
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吴曙光
张嘉杰
吴少瑜
徐伟
王洪涛
刘中秋
万山河
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Southern Medical University
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Abstract

The invention discloses tetrahydropyridoindole compounds shown as formula (I) (comprising racemates, enantiomers and other stereoisomers) or pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, and also discloses a preparation method and application of the compounds, namely the compounds are inhibitors of protein kinases such as c-Met tyrosine kinase and the like, and can be used for treating diseases caused by abnormal activity of the tyrosine kinases such as tumor and the like, or can be used for preparing medicaments for treating the diseases.

Description

A kind of Tetrahydropyridoindocompounds compounds and its production and application
Technical field
The present invention relates to organic chemistry and pharmaceutical chemistry field, be specifically related to Tetrahydropyridoindocompounds compounds and, the especially preparation method of c-Met inhibitor and application as kinases.
Background technology
Cancer is that two big class disease, the especially cancers 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, the important molecule of a class is exactly a protein kinase.Protein kinase activity unusually not only directly related with tumour 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 class important drugs target after G one protein linked receptor.
Hepatocyte growth factor receptor (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).
C-Met by people such as Cooper find (Cooper, C.S.et al Nature 1984,311,29-33).1984 they when research human osteosarcoma Hos clone, cloned a fragment with activity of conversion, name and be c-Met.C-Met is positioned at human No. 7 karyomit(e)s long-armed (7q31).The about 110kb of c-Met gene size comprises 21 exons.C-Met albumen is by c-Met proto-oncogene encoded protein product.The part of c-Met is a pHGF, also claims the discrete factor (scatter factor).Up to the present, c-Met is the unique high-affinity receptor of pHGF (HGF).HGF combines phosphorylation (Bottaro, D.P.et al Science 1991,251, the 802-804 that causes the poly between the c-Met acceptor and be positioned at a plurality of tyrosine residuess of tenuigenin part self with c-Met cell surface ligand binding site; Naldini, L.et al Oncogene 1991,6 (4), 501-504).The phosphorylation of tyrosine is regulated cell endocytic, enzymatic activity and the substrate combination of c-Met.The activation of c-Met causes the tyrosine phosphorylation of multiple substrate protein, for example Gab1, Grb2, Shc, c-Cbl, thereby further activation signals transferrin PI3K, Akt, PLC-γ, STAT, ERK1 and ERK2 (Birchmeier, C.et al Nature Rev Mol.Cell Biol.2003,4,915-925).C-Met acceptor and HGF all have expression in many tissues, its normal expression mainly is to concentrate on the cell that derives from an epithelium (epithelial) and a matter (mesenchymal).In mammiferous growth and process of tissue reparation, c-Met acceptor and HGF also be proved to be epithelial cell-mesenchymal cell is interacted extremely important, and the performance regulating and controlling effects such as formation of the migration of pair cell, invasion, propagation, survival, angiogenesis, form differentiation, three-dimensional micro structure.
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 corpora mammillaria renal cell carcinoma (hereditarypapillary renal carcinoma), sporadic corpora mammillaria 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 inhibitor of c-Met, are some examples below:
People such as Christensen report PHA-665752 as micromolecular compound c-Met inhibitor: Christensen, J.G.et al Cancer Res.2003,63,7345-7355.
People such as Zou report PF-2341066 as micromolecular compound c-Met inhibitor: Zou, H.Y.et al CancerRes.2007,69,4408-4417.
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 kinase inhibitor, and diseases such as cancer are had therapeutic action.
As mentioned above, the c-Met tyrosine kinase inhibitor has many pieces of bibliographical informations, also have some at the monoclonal antibody of c-Met or HGF and synthesized micromolecule compound 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 inhibitor patent medicine that goes through at present.Therefore, the new c-Met inhibitor of research and development is still very necessary.
Summary of the invention
First purpose of the present invention just is to provide a class to have the Tetrahydropyridoindocompounds compounds of protein kinase inhibiting activity.
Second purpose of the present invention is to provide the preparation method of described Tetrahydropyridoindocompounds compounds.
The 3rd purpose of the present invention is to provide a kind of pharmaceutical composition that comprises described Tetrahydropyridoindocompounds compounds.
A further object of the invention is to provide described Tetrahydropyridoindocompounds compounds to be used to prepare the application of the medicine of the disease that treatment protein kinase abnormal activity causes.
According to the present invention, described compound with protein kinase inhibiting activity is for to have with the Tetrahydropyridoindocompounds compounds shown in the following formula (I),
Figure BSA00000161506100031
Wherein:
X be CH, O, S (=O) nOr N;
Figure BSA00000161506100032
Two keys of expression or singly-bound;
When X be O or S (=O) nThe time, R does not exist;
When X is CH, R be selected from H ,-OH ,-NH 2,-CN ,-CF 3, oxo, halogen, C 1-6Alkyl, C 3-6Cycloalkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, C 6Aryl, C 5-6Heteroaryl, C 3-6Heterolipid cyclic group, R 1O-, R 1R 2N-, R 1S (=O) m-, R 1R 2NS (=O) m-, R 3C (=O)-, R 1R 2NC (=O)-, R 1OC (=O)-, R 3C (=O) O-, R 1R 2NC (=O) O-, R 3C (=O) NR 1-, R 1R 2NC (=O) NR 4-, R 1OC (=O) NR 4-, R 1S (=O) mNR 4-, R 1R 2NS (=O) mNR 4-, R 1R 2NC (=NR 5) NR 4-, R 1R 2NC (=CHNO 2) NR 4-, R 1R 2NC (=NR 5)-, R 1S (=O) (=NR 5) NR 4-or R 1R 2NS (=O) (=NR 5Each hydrogen among)-, and the R can be independently by one or more identical or different G 1Replace;
When X is N, R be selected from H ,-OH ,-NH 2,-CN ,-CF 3, C 1-6Alkyl, C 3-6Cycloalkyl, C 6Aryl, C 5-6Heteroaryl, C 3-6Heterolipid cyclic group, R 1O-, R 1R 2N-, R 1S (=O) m-, R 1R 2NS (=O) m-, R 3C (=O)-, R 1R 2NC (=O)-, R 1OC (=O)-, R 1OC (=O) NR 4-, R 1S (=O) mNR 4-, R 1R 2NC (=NR 5)-, R 1R 2NC (=CHNO 2)-or R 1S (=O) (=NR 5Each hydrogen among)-, and the R can be independently by one or more identical or different G 2Replace;
R 1, R 2, R 3, R 4And R 5Be independently selected from: H, C 1-6Alkyl, C 3-6Cycloalkyl, C 6Aryl, C 5-6Heteroaryl, 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, this C 3-6The heterolipid ring can comprise in addition one or more O, N, S (=O) mDeng heteroatoms; And R 1, R 2, R 3, R 4And R 5In each hydrogen can be independently by one or more identical or different G 3Replace;
G 1, G 2And G 3Be independently selected from H ,-OH ,-NH 2,-CN ,-CF 3, halogen, C 1-6Alkyl, C 3-6Cycloalkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, C 6Aryl, C 5-6Heteroaryl, C 3-6Heterolipid cyclic group, C 1-6Alkoxyl group, C 3-6Cycloalkyloxy, C 6Aryloxy, C 5-6Heteroaryloxy, C 3-6Heterolipid epoxy group(ing), C 1-6Alkylamino, C 3-6Naphthene amino, C 6Virtue is amino, C 5-6Amino, the C of assorted virtue 3-6Heterolipid ring amino, C 1-6Alkoxy-C O-, C 3-6Cycloalkyloxy-CO-, C 6Aryloxy-CO-, C 5-6Heteroaryloxy-CO-, C 3-6Heterolipid epoxy group(ing)-CO-, C 1-6Alkylamino-CO-, C 3-6Naphthene amino-CO-, C 6Virtue amino-CO-, C 5-6Assorted fragrant amino-CO-or C 3-6Heterolipid ring amino-CO-;
n＝0-2；
m＝0-2。
According to a preferred embodiment of the present invention, the molecular structure of described compound is suc as formula shown in (Ia):
Figure BSA00000161506100041
Wherein, R is selected from H, C 1-6Alkyl, C 3-6Cycloalkyl,
C 6Aryl, C 5-6Heteroaryl, C 3-6Heterolipid cyclic group, R 1S (=O) m-, R 1R 2NS (=O) m-, R 3C (=O)-, R 1R 2NC (=O)-, R 1OC (=O)-, R 1R 2NC (=NR 5)-, R 1R 2NC (=CHNO 2)-or R 1S (=O) (=NR 5Each hydrogen among)-, and the R can be independently by one or more identical or different G 2Replace.R is further preferably from H, methyl, ethyl, sec.-propyl, the tertiary butyl, cyclopropyl, formyl radical, ethanoyl, propionyl, different propionyl, 2-amino-2-methyl propionyl, formamyl, methyl-carbamoyl, dimethylamino formyl radical, ethylamino formyl radical, diethylin formyl radical, methylsulfonyl, ethylsulfonyl, third alkylsulfonyl, ring third alkylsulfonyl or benzenesulfonyl.
According to a further advantageous embodiment of the invention, the molecular structure of described compound is suc as formula shown in (Ib):
Figure BSA00000161506100042
Wherein, R is selected from H, C 1-6Alkyl, C 3-6Cycloalkyl, C 6Aryl, C 5-6Heteroaryl, C 3-6Heterolipid cyclic group, R 1S (=O) m-, R 1R 2NS (=O) m-, R 3C (=O)-, R 1R 2NC (=O)-, R 1OC (=O)-, R 1R 2NC (=NR 5)-, R 1R 2NC (=CHNO 2)-or R 1S (=O) (=NR 5Each hydrogen among)-, and the R can be independently by one or more identical or different G 2Replace.R is further preferably from H, methyl, ethyl, sec.-propyl, the tertiary butyl, cyclopropyl, formyl radical, ethanoyl, propionyl, different propionyl, 2-amino-2-methyl propionyl, formamyl, methyl-carbamoyl, dimethylamino formyl radical, ethylamino formyl radical, diethylin formyl radical, methylsulfonyl, ethylsulfonyl, third alkylsulfonyl, ring third alkylsulfonyl or benzenesulfonyl.
According to the present invention, described Tetrahydropyridoindocompounds compounds preferentially is selected from following listed compound (table 1):
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(the 2-methyl isophthalic acid, 3,4, the 5-tetrahydropyridine is [4,3-b] indoles-8-yl also) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-ethyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-8-yl also) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-n-propyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-8-yl also) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-sec.-propyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-8-yl also) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-cyclopropyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-8-yl also) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-cyclobutyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-8-yl also) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-cyclopentyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-8-yl also) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-cyclohexyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-8-yl also) pyridyl-2-amine;
8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-formaldehyde also;
1-[8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-yl also] ethyl ketone;
1-[8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-yl also] third-1-ketone;
8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indole-2-carboxylic acid tert-butyl ester also;
8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indole-2-ethyl formate also;
8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indole-2-ethyl formate also;
8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indole-2-carboxylic acid isopropyl ester also;
N-[2-[8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-yl also]-1,1-dimethyl-2-oxygen base ethyl] t-butyl carbamate;
2-amino-1-[8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-yl also]-2-methyl-prop-1-ketone;
2-hydroxyl-1-[8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-yl also }-2-methyl-prop-1-ketone;
8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-methane amide also;
8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-the N-methyl isophthalic acid, 3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-methane amide also;
8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-N, N-dimethyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-2-methane amide also;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-methyl sulphonyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-8-yl also) pyridine-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-ethylsulfonyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-8-yl also) pyridine-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-7-yl) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(the 2-methyl isophthalic acid, 3,4, the 5-tetrahydropyridine is [4,3-b] indoles-7-yl also) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-ethyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-7-yl also) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-n-propyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-8-yl also) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-sec.-propyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-7-yl also) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-cyclopropyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-7-yl also) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-cyclobutyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-7-yl also) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-cyclopentyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-7-yl also) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group 1-5-(2-cyclohexyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-7-yl also) pyridyl-2-amine;
7-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-formaldehyde also;
1-[7-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-yl also] ethyl ketone;
1-[7-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-yl also] third-1-ketone;
7-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indole-2-carboxylic acid tert-butyl ester also;
7-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indole-2-ethyl formate also;
7-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indole-2-ethyl formate also;
7-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indole-2-carboxylic acid isopropyl ester also;
N-[2-[7-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-yl also]-1,1-dimethyl-2-oxygen base ethyl] t-butyl carbamate;
2-amino-1-[7-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-yl also }-2-methyl-prop-1-ketone;
2-hydroxyl-1-[7-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-yl also }-2-methyl-prop-1-ketone;
7-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-methane amide also;
7-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-the N-methyl isophthalic acid, 3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-methane amide also;
7-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-N, N-dimethyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-2-methane amide also;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-methyl sulphonyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-7-yl also) pyridine-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-ethylsulfonyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-7-yl also) pyridine-2-amine.
Compound of the present invention can be raceme, enantiomer and other steric isomer or wherein pharmacy acceptable salt, hydrate, solvate or prodrug.
Below the general formula of Shi Yonging is represented symbol, and for example, halo etc. except as otherwise noted, only are applicable to this part.
Tetrahydropyridoindocompounds compounds of the present invention can obtain by chemosynthesis, and wherein a kind of synthetic method is the compound shown in compound shown in the formula (II) and the formula (III) to be carried out the Suzuki linked reaction make the volution target compound,
Figure BSA00000161506100081
Wherein, the Suzuki linked reaction is the organic chemical reactions be familiar with of personnel in the art.
Compound (II) can by with document (WO2004/076412A2﹠amp; WO2006/021881A2) similarly method preparation.
Compound (III) is synthetic by following method:
Figure BSA00000161506100082
Wherein, the definition of X and R is the same with the definition in the claim 1.
According to a preferred embodiment of the present invention, compound of the present invention has protein kinase inhibiting activity.Therefore; another aspect of the present invention; provide a kind of compound of the present invention (to comprise raceme and enantiomer; or it is at pharmacy acceptable salt, solvate or prodrug) be used for the treatment of because of protein kinase; especially the disease that causes of c-Met abnormal activity, method for cancer for example, or be used for the preparation treatment because of protein kinase; especially the disease that causes of c-Met abnormal activity, for example application of the medicine of cancer.Preferably, described compound is that formula (I), formula (Ia) and compound (Ib) (comprise raceme and enantiomer, or it are at pharmacy acceptable salt, solvate or prodrugs; Preferred, described compound is a compound listed in the table 1, comprises raceme and enantiomer, or it is at pharmacy acceptable salt, solvate or prodrug.
According to the present invention, described treatment is by with compound of the present invention (comprise raceme and enantiomer, or it being at pharmacy acceptable salt, solvate or prodrug) and protein kinase, for example c-Met contact, thus suppress its kinase catalytic activity.
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 inhibitor of Tyrosylprotein kinase c-Met.Described c-Met inhibitor is an activeconstituents with above-mentioned formula (I) compound, can make various concrete formulations medically commonly used, and the effective content of its Chinese style (I) compound can be tested definite as required.
C-Met of the present invention is meant hepatocyte growth factor receptor (hepatocyte growth factor receptor orHGFR), belongs to the tyrosine receptor kinase, and its part is pHGF (hepatocyte growth factor orHGF).
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.
Cancer of the present invention includes but not limited to: lung cancer, osteocarcinoma, carcinoma of the pancreas, skin carcinoma, head or 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, adrenal carcinoma, soft tissue sarcoma, urethral carcinoma, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or carcinoma of ureter, renal cell carcinoma, carcinoma of renal pelvis, nervus centralis cental system (CNS) vegetation, primary CNS lymphoma, the spinal column axis tumour, the brain stem neurospongioma, pituitary adenoma, the stomach and intestine mesenchymal neoplasm, renal cell carcinoma, colorectal carcinoma, nonsmall-cell lung cancer, neuroendocrine glue tumour, small cell lung cancer, mastocytosis, neurospongioma, sarcoma, acute myeloid leukemia, prostate cancer, any combination of lymphoma and these cancers.
Inventing described other disease includes but not limited to: psoriatic (or claim psoriasis), liver cirrhosis, diabetes, the disease that relates to angiogenesis, the disease that relates to restenosis, disease of eye be AMD, rheumatic arthritis and other inflammation, disease of immune system for example atherosclerosis, kidney disease etc. of auto-immune disease (for example, AIDS etc.), cardiovascular disorder for example for example.
Thereby compound of the present invention can play the method for collaborative (synergistic) or adduction (additive) effect with the common use of other antitumor drugs.These antitumour drugs include but not limited to: mitotic inhibitor, alkylating agent (Fluracil (fluorouracil or 5-FU) for example, Leukovorin, UFT, capecitabine, gemcitabine, cytarabine, busulfan, improsulfan, piposulfan, benzodepa, carboquone, meturedepa, uredepa, altretamine, triethylenemelamine, chlorambucil, cyclophosphamide, dacarbazine etc.), antimetabolitas (for example, methotrexale, pteropterin, mercaptopurine, thioguanine etc.), cell cycle inhibitor, topoisomerase enzyme inhibitor, biological respinse is regulated base, antibody, the cell mycin, microtubule-acting agent (for example, taxol (Taxol), Docetaxel (Taxotere), Ai PomeisuA ﹠amp; B (Epothilone A﹠amp; B etc.)), platinum complex (for example, carboplatin, cis-platinum etc.), Tri-Biocin (for example, bleomycin, gengshengmeisu etc.), amcinonide (for example, corticosteroids etc. on sex hormones, the kidney), plant medicine (for example, vincristine(VCR), colchicine, camptothecine etc.), kinases inhibitor (
Figure BSA00000161506100101
Figure BSA00000161506100102
Deng), hdac inhibitor (for example,
Figure BSA00000161506100103
(SAHA) etc.), anti-inflammatory drug (for example, NSAID (non-steroidal anti-inflammatory drug) (NSAlDs), selectivity or non-selective cyclooxygenase 2 (COX2) inhibitor etc.), for example, traditional NSAIDs is (for example, Ibuprofen BP/EP, naproxen, acetylsalicylic acid etc.) and COX2 inhibitor (for example, celecoxib optionally
Figure BSA00000161506100104
Cut down ground former times cloth
Figure BSA00000161506100105
Parecoxib
Figure BSA00000161506100106
Chinese mugwort holder former times cloth
Figure BSA00000161506100107
Deng) and any combination of these medicines.
The invention provides compound among a kind of the present invention and other tumor therapy, for example the method together used such as radiotherapy, interventional therapy.
A kind of pharmaceutical composition of the present invention, this pharmaceutical composition include any compound of the invention described above or its at pharmacy acceptable salt, solvate or prodrug, and preferred, described compound is suc as formula the compound shown in (Ia) and the formula (Ib); Preferred, described compound is a compound (comprising raceme and enantiomer) listed in the claim 8, or it is at pharmacy acceptable salt, solvate or prodrug.Described pharmaceutical composition can also include one or more pharmaceutically acceptable carriers.
According to a preferred embodiment of the present invention, described compound (comprising raceme and enantiomer) or its have the c-Met of inhibition kinase activity, its IC at pharmacy acceptable salt, solvate or prodrug 50Value less than 5 μ M, preferably less than 2 μ M, more preferably less than 1 μ M, further preferably less than 500nM, further preferably less than 300nM, more further preferably less than 200nM, more further preferably less than 100nM, most preferably less than 50nM.Professional in this area is easy to measure the IC of these compounds under certain test condition 50Value.
According to a preferred embodiment of the present invention, the dosage form of described pharmaceutical composition can be following any: tablet, capsule, injection, aerosol, gelifying agent, suppository, pill, syrup, collyrium, drops, paste, patch, emulsion etc.
The definition of term
Unless stated otherwise, the meaning of the term that uses in the application's claim and other part is with being as the criterion of defining below.The variable group that in this section, uses, for example R a, R b, m etc. only is applicable to this section.In addition, the many groups that define in this section can be substituted in addition.Typical substituting group listed in this section 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 by 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: the Phenylsulfonic acid of hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, perchloric acid, acetic acid, citric acid, oxalic acid, lactic acid, oxysuccinic acid, Whitfield's ointment, tartrate, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, replacement (for example, p-methyl benzenesulfonic acid), Yi Yansuan, oleic acid, tannic acid, pantothenic acid, xitix, Succinic Acid, toxilic acid, gentisinic acid, fumaric acid, gluconic acid, 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, potassium hydroxide, lithium hydroxide, ironic hydroxide, calcium hydroxide, hydrated barta, aluminium hydroxide, magnesium hydroxide, 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 bicarbonate, 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, ethylene glycol, propylene glycol, polyoxyethylene glycol, acetone etc.
" hydrate " refers to solvate, and solvent wherein is a water.
" prodrug (prodrug) " refers to by 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, is converted to the compound of being represented by formula I among the present invention in its body." 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 as 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 may 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 the effect of the arrestin kinase activity identical with compound among the present invention, 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 the effect of the arrestin kinase activity identical with compound among the present invention, 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, cyclodextrin, Magnesium Stearate, Mierocrystalline cellulose, magnesiumcarbonate, acrylate copolymer or methacrylate polymer, gel (gelatin), water, polyoxyethylene glycol, propylene glycol, ethylene glycol, Viscotrol C or hydrogenated castor oil or many oxyethyl groups hydrogenated castor oil, sesame oil, 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, VITAMIN, mineral substance, trace element, sweeting agent, pigment, essence or their combination etc.
" alkyl " refers to have the saturated hydrocarbon group of the straight or branched that specifies number carbon atom, for example C 1-12Alkyl refers to contain minimum 1, the straight or branched group of maximum 12 carbon atoms.C 0Covalent single bond of alkyl represent.Alkyl among the present invention includes but not limited to: methyl, ethyl, propyl group, butyl, sec.-propyl, neo-pentyl, 2-methyl isophthalic acid-hexyl etc.In the alkyl one or all hydrogen atom can be replaced by following groups: cycloalkyl, aryl, heteroaryl, heterolipid ring, halogen, amino, hydroxyl, cyano group, nitro, carboxyl, sulfydryl, oxygen base (oxo), alkoxyl group, aryloxy, alkyl thiol, aryl sulfydryl, carbonyl, thiocarbonyl group, C-amide group, N-amide group, O-ammonia carbonyl oxygen base, N-ammonia carbonyl oxygen base, O-sulfo-ammonia carbonyl oxygen base, N-sulfo-ammonia carbonyl oxygen base, C-ester group, O-ester group and-NR aR b, wherein, R aAnd R bBe selected from respectively: hydrogen, alkyl, cycloalkyl, aryl, ethanoyl, carbonyl, alkylsulfonyl, trifyl etc., and R aAnd R bCan form 5-or 6-unit heterolipid ring together with nitrogen-atoms.
" cycloalkyl " or " cycloalkanes " refers to have and specifies number the single, double of carbon atom or polycyclic hydrocarbon group, dicyclo or when encircling more, can be to condense (two ring or shared two the adjacent carbon atoms of a plurality of ring) or to screw togather the form combination of (two ring or the shared carbon atom of a plurality of ring), C for example 1-12Cycloalkyl refers to contain minimum 1, maximum 12 single, double or polycyclic hydrocarbon groups.C 0Cycloalkyl is represented a covalent single bond.Can contain undersaturated pair of key or triple bond in the cycloalkyl, but not have the πDian Zi system of total conjugated.Cycloalkyl among the present invention includes but not limited to: cyclopropyl, cyclobutyl, cyclohexyl, cyclopentenyl, cycloheptatriene base, diamantane etc.:
In cycloalkyl or the cycloalkanes one or all hydrogen atom can be replaced by following groups: alkyl, aryl, heteroaryl, heterolipid ring, halogen, amino, hydroxyl, cyano group, nitro, carboxyl, sulfydryl, oxygen base (oxo), alkoxyl group, aryloxy, alkyl thiol, aryl sulfydryl, carbonyl, thiocarbonyl group, C-amide group, N-amide group, O-ammonia carbonyl oxygen base, N-ammonia carbonyl oxygen base, O-sulfo-ammonia carbonyl oxygen base, N-sulfo-ammonia carbonyl oxygen base, C-ester group, O-ester group and-NR aR b, wherein, R aAnd R bBe selected from respectively: hydrogen, alkyl, cycloalkyl, aryl, ethanoyl, carbonyl, alkylsulfonyl, trifyl etc., and R aAnd R bCan form 5-or 6-unit heterolipid ring together with nitrogen-atoms.
" thiazolinyl " refers to contain the alkyl of at least two carbon atoms and two keys.Thiazolinyl among the present invention includes but not limited to: vinyl, 2-propenyl, 1-pentenyl etc.
" alkynyl " refers to contain at least two carbon atoms and a triple-linked alkyl.Alkynyl among the present invention includes but not limited to: vinyl, 2-propenyl, 1-pentenyl etc.
" halogen " refers to fluorine, chlorine, bromine or iodine.
" alkoxyl group " refers to have the alkyl that specifies number carbon atom and links to each other with other groups by Sauerstoffatom, i.e. alkyl-O-.Alkoxyl group among the present invention includes but not limited to: methoxyl group, oxyethyl group, propoxy-, butoxy, cyclopentyloxy, cyclohexyloxy, isopropoxy, neopentyl oxygen, 2-methyl isophthalic acid-hexyloxy etc.
" cycloalkyloxy " refers to have the cycloalkyl that specifies number carbon atom and links to each other with other groups by Sauerstoffatom, i.e. cycloalkyl-O-.Cycloalkyloxy among the present invention includes but not limited to: cyclopropane oxygen base, tetramethylene oxygen base, hexamethylene alkoxyl group etc.
" aryl " refers to monocycle, dicyclo or the many cyclic groups be made up of 6-12 carbon atom, wherein has at least a ring to have the πDian Zi system of total conjugated and meets the N+2 rule, promptly has aromaticity, but the whole conjugation of whole group.Aryl also can occur with the form of arylidene, promptly with other groups two or more tie points is arranged in the aryl structure.Aryl among the present invention includes but not limited to: phenyl, naphthyl, indenyl, indanyl, tetraline etc.In the aryl one or all hydrogen atom can be replaced by following groups: alkyl, cycloalkyl, heteroaryl, heterolipid ring, halogen, amino, hydroxyl, cyano group, nitro, carboxyl, sulfydryl, oxygen base (oxo), alkoxyl group, aryloxy, alkyl thiol, aryl sulfydryl, carbonyl, thiocarbonyl group, C-amide group, N-amide group, O-ammonia carbonyl oxygen base, N-ammonia carbonyl oxygen base, O-sulfo-ammonia carbonyl oxygen base, N-sulfo-ammonia carbonyl oxygen base, C-ester group, O-ester group and-NR aR b, wherein, R aAnd R bBe selected from respectively: hydrogen, alkyl, cycloalkyl, aryl, ethanoyl, carbonyl, alkylsulfonyl, trifyl etc., and R aAnd R bCan form 5-or 6-unit heterolipid ring together with nitrogen-atoms.
" heteroaryl " refers to monocycle, dicyclo or the many cyclic groups be made up of the atom of 5-12 except hydrogen atom, wherein at least one atom be O, N, S (=O) m(wherein m=0-2), P or Si, and, wherein have at least a ring to have the πDian Zi system of total conjugated and meet the N+2 rule, promptly have aromaticity, but the whole conjugation of whole group.Heteroaryl also can occur with the form of inferior heteroaryl, promptly with other groups two or more tie points is arranged in the heteroaryl structure.Heteroaryl among the present invention includes but not limited to: arsenic pyridine, arsenic heavy stone used as an anchor ketone, tetrahydrochysene arsenic heavy stone used as an anchor ketone, miaow pyridine, pyrazine, pyridazine, imidazoles, thiazole, thiophene, furans, indoles, azaindole, benzoglyoxaline, indoline, indolone, quinoline are given repeated exhortations etc.:
Figure BSA00000161506100141
In the heteroaryl one or all hydrogen atom can be replaced by following groups: alkyl, cycloalkyl, aryl, heterolipid ring, halogen, amino, hydroxyl, cyano group, nitro, carboxyl, sulfydryl, oxygen base (oxo), alkoxyl group, aryloxy, alkyl thiol, aryl sulfydryl, carbonyl, thiocarbonyl group, C-amide group, N-amide group, O-ammonia carbonyl oxygen base, N-ammonia carbonyl oxygen base, O-sulfo-ammonia carbonyl oxygen base, N-sulfo-ammonia carbonyl oxygen base, C-ester group, O-ester group and-NR aR b, wherein, R aAnd R bBe selected from hydrogen, alkyl, cycloalkyl, aryl, ethanoyl, carbonyl, alkylsulfonyl, trifyl etc. respectively, and R aAnd R bCan form 5-or 6-unit heterolipid ring together with nitrogen-atoms.
" heterolipid cyclic group or heterolipid ring " refers to monocycle, dicyclo or multi-ring alkyl or the alkane be made up of 3 to 12 atoms except hydrogen atom, wherein at least one atom be O, N, S (=O) m(wherein m=0-2), P or Si.Except that singly-bound, also can contain two keys or three key, but these pairs key or three key do not constitute whole conjugated aromatic structures in this ring.These monocycles, dicyclo or multi-ring alkyl or alkane can exist with the form of condensed ring, bridged ring or volution.Heterolipid cyclic group or heterolipid ring among the present invention include but not limited to: piperidines, morpholine, piperazine, tetramethyleneimine, indoline, tetrahydropyridine, tetrahydrofuran (THF), tropanol etc.:
Figure BSA00000161506100151
In heterolipid cyclic group or the heterolipid ring one or all hydrogen atom can be replaced by following groups: alkyl, cycloalkyl, aryl, heteroaryl, heterolipid ring, halogen, amino, hydroxyl, cyano group, nitro, carboxyl, sulfydryl, oxygen base (oxo), alkoxyl group, aryloxy, alkyl thiol, aryl sulfydryl, carbonyl, thiocarbonyl group, C-amide group, N-amide group, O-ammonia carbonyl oxygen base, N-ammonia carbonyl oxygen base, O-sulfo-ammonia carbonyl oxygen base, N-sulfo-ammonia carbonyl oxygen base, C-ester group, O-ester group and-NR aR b, wherein, R aAnd R bBe selected from respectively: hydrogen, alkyl, cycloalkyl, aryl, ethanoyl, carbonyl, alkylsulfonyl, trifyl etc., and R aAnd R bCan form 5-or 6-unit heterolipid ring together with nitrogen-atoms.
" aryloxy " refers to that aryl links to each other with other groups by Sauerstoffatom, i.e. aryl-O-.Aryloxy among the present invention includes but not limited to: phenoxy group, naphthyloxy etc.
" heteroaryloxy " refers to that heteroaryl links to each other with other groups by Sauerstoffatom, i.e. heteroaryl-O-.Heteroaryloxy among the present invention includes but not limited to: 4-arsenic pyridine oxygen base, 2-thiophene oxy etc.
" alkylamino " refers to have the alkyl that specifies number carbon atom and links to each other with other groups by nitrogen-atoms, i.e. alkyl-NH-or (alkyl) 2N-.Alkylamino among the present invention includes but not limited to: methylamino-, ethylamino, third amino, dimethylamino etc.
" naphthene amino " refers to have the cycloalkyl that specifies number carbon atom and links to each other with other groups by nitrogen-atoms, i.e. cycloalkyl-NH-or (cycloalkyl) 2N-.Naphthene amino among the present invention includes but not limited to: cyclopropane amino, tetramethylene amino etc.
" virtue is amino " refers to that aryl links to each other with other groups by nitrogen-atoms, i.e. aryl-NH-or (aryl) 2N-.Fragrant amino among the present invention includes but not limited to: phenylamino, naphthylamino, diphenylamino etc.
" assorted virtue is amino " refers to that heteroaryl links to each other with other groups by nitrogen-atoms, i.e. heteroaryl-NH-or (heteroaryl) 2N-.Assorted fragrant amino among the present invention includes but not limited to: 4-arsenic pyridine amino, 3-thiophene amino etc.
" amino " refers to H 2N-or hydrogen atom substituted H wherein 2N-, i.e. R aHN-and R aR bN-.
" oxo " or " oxygen base " refers to=O that promptly Sauerstoffatom is connected with heteroatomss such as carbon or N, S, P by two keys.The example that is replaced by the oxygen base includes but not limited to:
Figure BSA00000161506100161
" hydroxyl " refers to-OH.
" nitro " refers to-NO 2
" carboxyl " refers to-CO 2H.
" sulfydryl " refers to-SH.
" alkyl thiol " refers to alkyl-S-.
" aryl sulfydryl " refers to aryl-S-.
" carbonyl " refer to-C (=O)-.
" thiocarbonyl group " refer to-C (=S)-.
" C-amide group " refers to-C (=O) NR aR b
" N-amide group " refers to C (=O) NR a-.
" O-ammonia carbonyl oxygen base " refers to-O-C (=O) NR aR b
" N-ammonia carbonyl oxygen base " refers to O-C (=O) NR a-.
" O-sulfo-ammonia carbonyl oxygen base " refers to-O-C (=S) NR aR b
" N-sulfo-ammonia carbonyl oxygen base " refers to O-C (=S) NR a-.
" C-ester group " refers to-C (=O) OR a
" N-ester group " refers to C (=O) O-.
" ethanoyl " refers to CH 3C (=O)-.
" alkylsulfonyl " refers to-SO 2R a
" trifyl " refers to CF 3SO 2-.
Pharmaceutical composition and application thereof
Compound among the present invention (comprising raceme, enantiomer and other steric isomer) or its by preparation (formulation) process, reach pharmaceutical composition that pharmaceutically commonly used assistant agent be prepared into easy administration with the pharmaceutically acceptable carrier that is fit at pharmacy acceptable salt, hydrate, solvate or prodrug.This pharmaceutical composition is used for the treatment of Mammals, human patient for example, the disease that causes because of the abnormal movement of protein kinase, for example cancer.
Route of administration
The route of administration of the pharmaceutical composition among the present invention includes but not limited to: oral (for example tablet or capsule), injection (for example, intravenous injection, subcutaneous injection, intramuscular injection, eyeball injection, abdominal injection etc.), anus plug (suppository), 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.
Formulation method
The preparation process of the compound among the present invention adopts medicine industry method commonly used, for example, and mixing, dissolving, granulation, grinding, emulsification, capsule, sugar-coat, lyophilize, cryospray etc.
The dosage form of drug regimen can be following any: tablet, capsule, injection, aerosol, gelifying agent, suppository, pill, syrup, collyrium, drops, paste, patch, emulsion etc.Preparation and medicine-feeding technology are seen " Remington ' sPharmacological Sciences, " Mack Publishing Co., Easton, PA latest edition.
The dosage form of oral administration can be, but be not limited to tablet, capsule, syrup, gel, pill, suspension etc.Carrier, assistant agent and vehicle that preparation uses are, but be not limited to, lime carbonate, calcium phosphate, various sugar (for example, lactose, N.F,USP MANNITOL etc.), starch, cyclodextrin, Magnesium Stearate, Mierocrystalline cellulose, magnesiumcarbonate, acrylate copolymer or methacrylate polymer, polyvidone (PVP), gel (gelatin), water, polyoxyethylene glycol, propylene glycol, ethylene glycol, Viscotrol C or hydrogenated castor oil or many oxyethyl groups hydrogenated castor oil, sesame oil, Semen Maydis oil, peanut wet goods.
The dosage form of drug administration by injection is, but is not limited to sterile solution, suspension, emulsion etc.
The dosage form that anus thrusts medicine is, but is not limited to suppository, gelifying agent etc.
The dosage form of nostril inhalation is, but is not limited to sprays, aerosol etc.
Compound among the present invention can be present in the form of pharmacy acceptable salt in the preparation, inorganic or the organic acid that is used to form salt includes but not limited to: hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, perchloric acid, acetic acid, citric acid, oxalic acid, lactic acid, oxysuccinic acid, Whitfield's ointment, tartrate, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, the Phenylsulfonic acid (for example, p-methyl benzenesulfonic acid) that replaces, Yi Yansuan, oleic acid, tannic acid, pantothenic acid, xitix, Succinic Acid, toxilic acid, gentisinic acid, fumaric acid, gluconic acid, uronic acid, glucaric acid or sucrose acid, formic acid, phenylformic acid, L-glutamic acid, pamoic acid, Sorbic Acid etc.Inorganic or the organic bases that is used to form salt includes but not limited to: sodium hydroxide, potassium hydroxide, lithium hydroxide, ironic hydroxide, calcium hydroxide, hydrated barta, aluminium hydroxide, magnesium hydroxide, zinc hydroxide, ammoniacal liquor, the hydroxide organic quaternary ammonium salt, yellow soda ash, salt of wormwood, Quilonum Retard, lime carbonate, barium carbonate, magnesiumcarbonate, the carbonating organic quaternary ammonium salt, sodium bicarbonate, saleratus, lithium bicarbonate, Calcium hydrogen carbonate, barium bicarbonate, Magnesium hydrogen carbonate, carbonic acid hydrogenation organic quaternary ammonium salt etc.
Dosage
(for example, cancer) therapeutic action, the administration of compound or its pharmaceutical composition must reach effective dose to disease in order to bring into play compound among the present invention.The estimation of effective dose reaches to be determined all should be able to accomplish for one of skill in the art.For the chemical compound lot among the present invention, effective dose can be tested from biochemistry and cell and be begun estimation, for example, measures the compound needed concentration of the kinase whose activity to 50% of arrestin, i.e. IC under biochemical condition or cell condition among the present invention 50Value, again according in the animal model (for example, mouse, rat etc.), under the condition of certain dosage, compound concentrations in the test blood, the IC in the contrast cell 50Value and estimation in animal, to cause with cell in equal or better protein kinase is active suppresses needed administration effective dose, estimate effective dose in human body at last by animal data.This wherein also need consider the toxicity that compound may cause the animal that comprises the people under finite concentration.
The content range of compound among the present invention in aforementioned pharmaceutical composition is 0.001-100%.It is per kg body weight per day 0.1-500 milligram 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 the 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 to some extent according to the disease of employed compound or its pharmaceutical composition and application, 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.
Drug packages
The packaging group of the pharmaceutical composition among the present invention below is some examples, but is not limited to these like the packaged form of general Western medicine:
The pharmaceutical composition of solid form is made generally in tablet, pill or capsule, these medicines glass of can directly packing into, plastics, in papery or the metal bottle, bottle is outer to be sticked about the medicine name, composition, content of effective, produce or expiration date, the disease that is suitable for, usage and consumption, possible side effect, contact details during emergency situation, keeping and storage information, the information of manufacturer, the label of other precaution etc., enclose brochure in the bottle, on this book except have the bottle label all information outside, the more detailed information that also comprises the pharmaceutical composition among the present invention, for example compound structure, molecular weight, physicochemical property, the mechanism of action, IC 50Information such as value, pharmacokinetics, drug fever mechanics, toxicology data, metabolism situation, clinical experiment data also comprise the approval documents information of national drug and food control office etc.Sometimes, also need put into siccative etc. in the bottle to keep the quality of medicine.
The pharmaceutical composition of liquid form is generally packed in glass, plastics or metal bottle or the flexible pipe, and outer packaging and built-in brochure and solid pharmaceutical are similar.These glass, plastics or metal bottle or flexible pipe are loaded in the other plastics or carton, also need put into the buffering and the protection weighting material that prevent leak of liquid in these plastics or the carton.If the liquid medicine of aerosol form, in generally pack into the withstand voltage metal or plastic containers, this container is with devices such as reducing valve.
Embodiment
Below in conjunction with specific embodiment the present invention is described in further detail, so that the public further understands beneficial effect of the present invention.
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: dimethyl sulfoxide (DMSO)
TMS: tetramethylsilane
DCM: methylene dichloride
CDCl 3: deuterochloroform
CD 3OD: deuterated methanol
DME:1, the 2-glycol dimethyl ether
THF: tetrahydrofuran (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 obtain (deuterium is a solvent for DMSO, deuterochloroform, deuterated methanol etc., and TMS is interior mark) on Varian INOVA 500NB instruments.Mass spectrum obtains (adopting ESI or APCI ion source ZQ4000, U.S. Waters company) by liquid chromatograph-mass spectrometer.UV spectrum is recorded by the UV-3010 ultraviolet spectrophotometer of HIT.Infrared spectra uses NICOLET6700 infrared spectrometric analyzer (KBr compressing tablet).High performance liquid chromatography uses Waters 2695ZORBAX high performance liquid chromatograph (Bx-C 85 μ, 150 * 4.6mm chromatographic column).Measurement of melting point is used the digital fusing point instrument 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 PIChemicals; 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 drying not generally, 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 1:3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl) pyridyl-2-amine,
Figure BSA00000161506100201
This compound is by 5-bromo-3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-2-aminopyridine and 8-(4,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles carries out the Suzuki linked reaction and obtains, and concrete synthesis step is as follows:
1, preparation 5-bromo-3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 2-aminopyridine:
1-1, preparation 1-(2,6-two chloro-3-fluorophenyls) ethanol
Figure BSA00000161506100202
Under 0 ℃ of degree and nitrogen protection, (30g 145mmol) is dissolved in 80 ml methanol ethyl ketone, slowly adds NaBH in this solution in batches with 1-(2,6-two chloro-3-fluorophenyls) 4(12.07g, 319mmol), after adding, this mixture at room temperature stirred 6 hours, was chilled to 0 ℃, and carefully adding 4N hydrochloric acid cancellation reaction is about 2 up to pH.This mixture concentrates with Rotary Evaporators, adds ether (300mL) and water (300mL).Separatory, (2 * 300mL) extract water, and organic phase merges, dry (Na with ether 2SO 4), concentrate and to obtain buttery target product 28.5g (yield: 94%). 1H-NMR(CDCl 3，500MHz)：δ(ppm)1.65(d，J＝7.2Hz，3H)，5.56(q，J＝7.2Hz，1H)，7.01-7.04(m，1H)，7.24-7.31(m，1H)。
1-2, preparation 1-(2,6-two chloro-3-fluorophenyls) ethyl acetic ester
Figure BSA00000161506100211
Under 0 ℃ of degree, the 1-(2 that step 1-1 is obtained, 6-two chloro-3-fluorophenyls) ethanol (25g, 120mmol) be dissolved in the methylene dichloride (180mL), add then Et3N (58.6mL, 420mmol) and 4-dimethylaminopyridine (2.92g, 23.9mmol), stir down, slowly drip acetic anhydride (13.6ml, 143.5mmol).After adding, this mixture stirred 2 hours down at 0 ℃, added entry (40mL) then.After the stirring at room 5 hours, add ether (300mL).Separatory, (2 * 300mL) extract water, and organic phase merges also uses 4N hydrochloric acid (80mL), saturated NaHCO successively with ether 3The aqueous solution (80mL) and saturated aqueous common salt (100mL) washing.Dry (Na 2SO 4), concentrate and to obtain oily target product 27.3g (yield: 91%). 1H-NMR(CDCl 3，500MHz)：δ(ppm)1.65(d，J＝7.2Hz，3H)，2.01(s，3H)，6.40(q，J＝7.2Hz，1H)，7.01-7.04(m，1H)，7.23-7.29(m，1H)。
1-3, preparation (1S)-1-(2,6-two chloro-3-fluorophenyls) ethanol
Figure BSA00000161506100212
Following three pieces of documents disclose the catalytic ester hydrolysis of use Pig Liver Esterase chiral separation 1-(2,6-two chloro-3-fluorophenyls) ethyl acetic ester and have prepared the method for this compound: (a) Ohno, M.; Otsuka, M.Org.React.1989,37,1; (b) Zhu, L.-M.; Tedford, M.C.Tetrahedron 1990,46, and 6587; (c) Tamm, C.PureAppl.Chem.1992,64,1187.
According to the disclosed technical intelligence of above-mentioned document, the concrete synthesis step that is adopted among the present invention is as described below: be equipped with in the three-necked bottle of pH meter in one and add entry (200mL), 1M K 2HPO 4The aqueous solution (1.5mL), 1M KH 2PO 4The aqueous solution (0.6mL) and Pig Liver Esterase (120mg ,～15600units from Sigma-Aldrich, Catalog#46058, Enzyme Commission 3.1.1.1, CAS#9016-18-6).1-(2 with step 1-2 acquisition, 6-two chloro-3-fluorophenyls) ethyl acetic ester (24g, 95.6mmol) slowly be added dropwise in the above-mentioned solution, between the reaction period, pH with 1M NaOH aqueous solution conditioned reaction mixture remains between the 6.5-8.5, follows the tracks of the ester that reacts up to about 50% with high performance liquid chromatography and TLC and changes into alcohol (approximately needing 25 hours).During the transformation efficiency of reaction to 50%, add ether (300mL), with diatomite filtration gained mixture, and with ether (3 * 100mL) wash filter residues.Separatory, (2 * 300mL) extract water, and organic phase merges, dry (Na with ether 2SO 4), concentrate and to obtain the oily crude product.Gained oily crude product through silica gel column chromatography (petrol ether/ethyl acetate: 9/1) purifying just obtain target product (1S)-1-(2,6-two chloro-3-fluorophenyls) ethanol (9.793g, yield: 49%), [α] D 25:-11.7 ° (c=5.6, methylene dichloride) and recovery (1R)-1-(2,6-two chloro-3-fluorophenyls) ethyl acetic ester (11.882g, yield: 49.5%).These two products are very easy separating under above-mentioned column chromatography condition, obtains pure products respectively.
1-4, preparation 3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 2-nitropyridine
Figure BSA00000161506100221
(2.09g is among the dried THF that 10mmol) is dissolved in (80 milliliters) for ethanol with (1S)-1-(2,6-two chloro-3-fluorophenyls) that step 1-3 obtains.Then, under room temperature and nitrogen protection, add 3-hydroxyl-2-nitropyridine (1.54g; 11mmol) and triphenyl phosphorus (3.409g, 13mmol), wait fully dissolving after; be chilled to 0 ℃, add diisopropyl azodiformate (DIAD, 2.63g; 13mmol); after adding, this mixture stirred 16 hours down at 0 ℃, and rotary evaporation removes and desolvates; (petrol ether/ethyl acetate: 4/1) purifying gets white solid target product (3.046g, yield: 92%) to the oily residue with silica gel column chromatography. 1H-NMR(CDCl 3，500MHz)：δ(ppm)1.86(d，J＝6.4Hz，3H)，6.10(q，J＝6.4Hz，1H)，7.09(dd，J＝7.6，8.8Hz，1H)，7.21(dd，J＝8.4，1.2Hz，1H)，7.31(dd，J＝4.8，8.8Hz，1H)，7.37(dd，J＝4.8，8.0Hz，1H)，8.04(dd，J＝1.6，4.4Hz，1H)。Mass spectrum m/z:330.94[M+H, 35Cl, 35Cl], 332.92[M+H, 35Cl, 37Cl].
1-5, preparation 3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 2-aminopyridine
Figure BSA00000161506100222
Get the 3-[(1R that step 1-4 obtains)-1-(2; 6-two chloro-3-fluorophenyls) oxyethyl group]-2-nitropyridine (2.649g; 8mmol) be dissolved in the ethanol (15mL); add iron powder (3.575g; 64mmol) mix, under nitrogen protection in 90 ℃ of oil baths vigorous stirring, add 0.8mL 1M HCl (aq) with syringe; after spending 10 minutes, add 0.8mL 1M HCl (aq) again.Continue to stir 30 minutes, TLC shows that reaction finishes.Be chilled to room temperature, use diatomite filtration, (3 * 10mL) wash filter residue with ethanol.Merge organic phase, rotary evaporation remove desolvate light brown solid target product (2.41g, yield: 100%). 1H-NMR(CDCl 3，500MHz)：δ(ppm)1.81(d，J＝6.8Hz，3H)，5.03(s，br，2H)，6.01(q，J＝6.8Hz，1H)，6.47(dd，J＝4.8，7.6Hz，1H)，6.70(d，J＝8.0Hz，1H)，7.05(t，J＝8.8Hz，1H)，7.28(dd，J＝4.0，8.0Hz，1H)，7.57(d，J＝5.2Hz，1H)。Mass spectrum m/z:301.00[M+H, 35Cl, 35Cl], 302.77[M+H, 35Cl, 37Cl].
1-6, preparation 5-bromo-3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 2-aminopyridine
Figure BSA00000161506100231
3-[(1R with step 1-5 acquisition)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-(1.506g 5mmol) is dissolved in the acetonitrile (20mL) the 2-aminopyridine.Then, at 0 ℃ of degree and under stirring, (0.908g 5.1mmol), after adding, continues to stir 30 minutes in add the N-bromo-succinimide in batches.Rotary evaporation removes and desolvates, and crude product obtains white solid target product (1.045g, yield: 55%) with silica gel chromatography. 1H-NMR(CDCl 3，500MHz)：δ(ppm)1.81(d，J＝6.8Hz，3H)，4.85(s，br，2H)，6.98(q，J＝6.8Hz，1H)，6.82(d，J＝2.0Hz，1H)，7.08(t，J＝8.4Hz，1H)，7.31(dd，J＝4.8，8.8Hz，1H)，7.65(d，J＝2.0Hz，1H)。Mass spectrum m/z:378.84[M+H, 35Cl, 35Cl, 79Br], 380.82[M+H, 35Cl, 35Cl, 81Br or 35Cl, 37Cl, 79Br], 382.80[M+H, 35Cl, 37Cl, 81Br or 37Cl, 37Cl, 79Br].
2, preparation 8-(4,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Its step is as follows:
2-1, preparation 8-bromo-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Figure BSA00000161506100241
The described synthetic method of this step is with reference to Fischer indole synthesis (J.-P.H é nichart et al J.Heterocycl.Chem.2006,43,571-578) improve formation slightly, detailed process is as follows: 4-bromophenyl-hydrazine hydrochloride (224mg, 1mmol) with N-tertbutyloxycarbonyl-4-piperidone (199mg, 1mmol) be dissolved in 10 milliliters of HCl saturated ethanolic soln (by logical dry HCl gas in dehydrated alcohol and make), this solution under agitation refluxed 3 hours, LC-MS shows that reaction finishes.After being chilled to room temperature, rotary evaporation removes and desolvates the saturated NaHCO of crude product 3The aqueous solution (10mL) is handled and is extracted (3 * 20mL) with DCM.Organic phase merges, dry (Na 2SO 4), concentrate the crude product obtain with silica gel column chromatography (7M NH 3Methanol solution/DCM:5/95) purifying obtains target product (195mg, yield: 78%). 1H-NMR(CD 3OD，500MHz)：δ(ppm)2.82(t，J＝5.6Hz，2H)，3.15(t，J＝5.6Hz，2H)，3.95(s，2H)，7.11(dd，J＝1.6，8.8Hz，1H)，7.18(d，J＝8.4Hz，1H)，7.46(d，J＝1.6Hz，1H)。Mass spectrum m/z:251.01[M+H, 79Br], 252.99[M+H, 81Br].
2-2, preparation 8-(4,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles
Under nitrogen, with the 8-bromo-2,3 of step 2-1 acquisition, 4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles (125mg, 0.5mmol), connection sheet pure boric acid ester (140mg, 0.55mmol) and Potassium ethanoate (add PdCl among the 147mg, DMSO solution (0.2ml) 1.5mmol) 2(dppf) .CH 2Cl 2(20.4mg 0.025mmol), blasted nitrogen 2 minutes in gained solution, stirred 16 hours down in 80 ℃ of degree then.LC-MS shows that reaction finishes, be chilled to room temperature after, add entry (2mL), extract (3 * 5mL) with DCM.Organic phase merges, dry (Na 2SO 4), concentrate target product (150mg, the yield: 100%) obtain.Mass spectrum m/z:298.20[M+H], 299.16[M+H, 100%], 300.18[M+H].
3, preparation 3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl) pyridyl-2-amine
The 5-bromo-3-[(1R that step 1-6 is obtained)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 2-aminopyridine (75.8mg, 0.2mmol), the 8-(4 that obtains of step 2-2,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl)-2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles (72mg, 0.24mmol) and salt of wormwood (82.9mg, 0.6mmol) be dissolved in the DME/ water mixed solution (4/1,2.0ml).Then, under nitrogen, add Pd (PPh 3) 4(11.6mg 0.01mmol), blasted nitrogen 2 minutes in the gained mixture, stirred 18 hours down in 80 ℃ of degree then.LC-MS shows that reaction finishes, be chilled to room temperature after, add entry (5mL), extract (3 * 10mL) with DCM.Organic phase merges, dry (Na 2SO 4), concentrate the crude product obtain with silica gel column chromatography (7M NH 3Methanol solution/DCM:5/95) purifying obtains target product (77.6mg, yield: 82%).Its analytical data is as follows: 1H-NMR (CD 3OD, 500MHz): δ (ppm) 1.90 (d, J=6.8Hz, 3H), 2.85 (t, J=5.2Hz, 2H), 3.22 (t, J=5.6Hz, 2H), 4.05 (d, J=5.2Hz, 2H), 6.20 (q, J=6.8Hz, 1H), 7.03 (d, J=2.0Hz, 1H), 7.08 (dd, J=1.6,8.4Hz, 1H), 7.22-7.23 (m, 2H), 7.26 (d, J=8.4Hz, 1H), 7.46 (m, 1H), 7.72 (d, J=1.6Hz, 1H).Mass spectrum m/z:471.05[M+H, 35Cl, 35Cl], 473.02[M+H, 35Cl, 37Cl].
Embodiment 2:3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(the 2-methyl isophthalic acid, 3,4, the 5-tetrahydropyridine is [4,3-b] indoles-8-yl also) pyridyl-2-amine
Figure BSA00000161506100251
1, preparation 2-methyl-8-(4,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl)-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles also, and its step is as follows:
1-1, preparation 8-bromo-2-methyl isophthalic acid, 3,4, the 5-tetrahydropyridine is [4,3-b] indoles also
Figure BSA00000161506100252
(224mg, 1mmol) (113mg 1mmol) is raw material, according to the identical method preparation of the step 2-1 in the foregoing description 1 with N-methyl-4-piperidone to use 4-bromophenyl-hydrazine hydrochloride. 1H-NMR(CD 3OD，500MHz)：δ(ppm)2.53(s，3H)，2.83-2.90(m，4H)，3.62(s，2H)，7.11(dd，J＝1.6，8.4Hz，1H)，7.18(d，J＝8.4Hz，1H)，7.47(d，J＝1.6Hz，1H)。Mass spectrum m/z:264.99[M+H, 79Br], 266.97[M+H, 81Br].
1-2, preparation 2-methyl-8-(4,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl)-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles also
Figure BSA00000161506100261
The 8-bromo-2-methyl isophthalic acid that is obtained with step 1-1,3,4, the 5-tetrahydropyridine also [4,3-b] indoles (132mg, 0.5mmol) and the commercially available pure boric acid ester of connection sheet (140mg 0.55mmol) be raw material, prepares according to the method for the step 2-2 among the embodiment 1.Mass spectrum m/z:312.18[M+H], 313.14[M+H, 100%], 314.23[M+H].
2, preparation 3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(the 2-methyl isophthalic acid, 3,4, the 5-tetrahydropyridine is [4,3-b] indoles-8-yl also) pyridyl-2-amine
The 5-bromo-3-[(1R that step 1-6 among the embodiment 1 is obtained)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 2-aminopyridine (75.8mg, 0.2mmol), step 1-2 obtains in the present embodiment 2-methyl-8-(4,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl)-1,3,4, the 5-tetrahydropyridine also [4,3-b] indoles (75mg, 0.24mmol) and salt of wormwood (82.9mg, 0.6mmol) be dissolved in the DME/ water mixed solution (4/1,2.0ml).Then, under nitrogen, add Pd (PPh 3) 4(11.6mg 0.01mmol), blasted nitrogen 2 minutes in the gained mixture, stirred 18 hours down in 80 ℃ of degree then.LC-MS shows that reaction finishes, be chilled to room temperature after, add entry (5mL), extract (3 * 10mL) with DCM.Organic phase merges, dry (Na 2SO 4), concentrate the crude product obtain with silica gel column chromatography (7MNH 3Methanol solution/DCM:5/95) purifying obtains target product (yield is 78%). 1H-NMR(CD 3OD，500MHz)：δ(ppm)1.89(d，J＝6.4Hz，3H)，2.59(m，2H)，2.92(s，3H)，3.23(m，2H)，3.72(d，J＝6.8Hz，2H)，6.20(q，J＝6.4Hz，1H)，7.03(d，J＝2.0Hz，1H)，7.07(dd，J＝2.0，8.4Hz，1H)，7.22(m，1H)，7.24-7.28(m，2H)，7.46(m，1H)，7.72(d，J＝1.6Hz，1H)。Mass spectrum m/z:485.05[M+H, 35Cl, 35Cl], 487.05[M+H, 35Cl, 37Cl].
Embodiment 3:8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-formaldehyde also
Concrete synthesis step is as follows:
1, preparation (8-(4,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl)-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-formaldehyde also, and its step is as follows:
1-1, preparation 8-bromo-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-formaldehyde also
With formic acid (68mg, 1.48mmol) and EDC.HCl (284mg 1.48mmol) is suspended among the DCM (100mL), under agitation, drip diisopropyl ethyl amine (380mg, 2.96mmol).Add the back stirring at room half an hour, add the 8-bromo-2,3,4 that the step 2-1 among the embodiment 1 obtains, (185mg 0.74mmol), continues to stir 2 hours 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles.Rotary evaporation removes and desolvates, the crude product that obtains silica gel column chromatography (7M NH 3Methanol solution/DCM:5/95) purifying obtains target product (167mg, yield: 81%). 1H-NMR(CD 3OD，500MHz)：δ(ppm)2.71(t，J＝5.6Hz，2H)，3.42(t，J＝5.6Hz，2H)，4.01(s，2H)，7.06(dd，J＝1.6，8.8Hz，1H)，7.28(d，J＝8.4Hz，1H)，7.61(d，J＝1.6Hz，1H)，7.94(s，1H)
(8-(4,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl)-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-formaldehyde also for 1-2, preparation
Figure BSA00000161506100272
Under nitrogen, with the 8-bromo-1,3 that obtains among the step 1-1,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-formaldehyde (139.5mg also, 0.5mmol), connection sheet pure boric acid ester (140mg, 0.55mmol) and Potassium ethanoate (add PdCl among the 147mg, DMSO solution (0.2ml) 1.5mmol) 2(dppf) .CH 2Cl 2(20.4mg 0.025mmol), blasted nitrogen 2 minutes in gained solution, stirred 16 hours down in 80 ℃ of degree then.LC-MS shows that reaction finishes, be chilled to room temperature after, add entry (2mL), extract (3 * 5mL) with DCM.Organic phase merges, dry (Na 2SO 4), concentrate target product (158mg, the yield: 97%) obtain.Mass spectrum m/z:326.18[M+H], 328.18[M+H, 100%], 327.18[M+H].
2, preparation 8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-formaldehyde also
The 5-bromo-3-[(1R that step 1-6 among the embodiment 1 is obtained)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 2-aminopyridine (75.8mg, 0.2mmol), the step 1-2 in the present embodiment obtain (8-(4,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl)-1,3,4, the 5-tetrahydropyridine also [4,3-b] indoles-2-formaldehyde (78mg, 0.24mmol) and salt of wormwood (82.9mg, 0.6mmol) be dissolved in the DME/ water mixed solution (4/1,2.0ml).Then, under nitrogen, add Pd (PPh 3) 4(11.6mg 0.01mmol), blasted nitrogen 2 minutes in the gained mixture, stirred 18 hours down in 80 ℃ of degree then.LC-MS shows that reaction finishes, be chilled to room temperature after, add entry (5mL), extract (3 * 10mL) with DCM.Organic phase merges, dry (Na 2SO 4), concentrate the crude product obtain with silica gel column chromatography (7M NH 3Methanol solution/DCM:5/95) purifying obtains target product (78.8mg, yield: 79%). 1H-NMR(CD 3OD，500MHz)：δ(ppm)1.90(d，J＝6.8Hz，3H)，2.85(t，J＝5.2Hz，2H)，3.22(t，J＝5.6Hz，2H)，4.05(d，J＝5.2Hz，2H)，6.20(q，J＝6.8Hz，1H)，7.03(d，J＝2.0Hz，1H)，7.08(dd，J＝1.6，8.4Hz，1H)，7.22-7.23(m，2H)，7.26(d，J＝8.4Hz，1H)，7.46(m，1H)，7.72(d，J＝1.6Hz，1H)。Mass spectrum m/z:471.05[M+H, 35Cl, 35Cl], 473.02[M+H, 35Cl, 37Cl].
Embodiment 4:8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is the another kind of method of [4,3-b] indoles-2-formaldehyde also, by the 3-[(1R of preparation among the embodiment 1)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl) pyridine-2-base amine and formic acid reacts and obtains, and concrete synthesis step is as follows:
Figure BSA00000161506100281
With formic acid (6.8mg, 0.148mmol) and EDC.HCl (28.4mg 0.148mmol) is suspended among the DCM (20mL), under agitation, drip diisopropyl ethyl amine (38mg, 0.296mmol).Add the back stirring at room half an hour, add the 3-[(1R that embodiment 1 obtains)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl) (35mg 0.074mmol), continues to stir 2 hours pyridyl-2-amine.Rotary evaporation removes and desolvates, the crude product that obtains silica gel column chromatography (7M NH 3Methanol solution/DCM:5/95) purifying obtains target product (32mg, yield: 88%). 1H-NMR(CD 3OD，500MHz)：δ(ppm)1.90(d，J＝6.8Hz，3H)，2.94(t，J＝6.0Hz，2H)，3.86(t，J＝6.0Hz，2H)，4.71(d，J＝6.4Hz，2H)，6.21(q，J＝6.8Hz，1H)，7.04(d，J＝1.6Hz，1H)，7.10(dt，J＝2.0，8.4Hz，1H)，7.24-7.31(m，3H)，7.49(m，1H)，7.73(d，J＝2.0Hz，1H)，8.26(s，1H)。Mass spectrum m/z:499.02[M+H, 35Cl, 35Cl], 500.99[M+H, 35Cl, 37Cl].
Embodiment 5:8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indole-2-carboxylic acid tert-butyl ester also
Figure BSA00000161506100291
Synthesis step is as follows:
1, preparation 8-(4,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl)-1,3,4, the 5-tetrahydropyridine is [4,3-b] indole-2-carboxylic acid tert-butyl ester also:
1-1, preparation 8-bromo-1,3,4, the 5-tetrahydropyridine is [4,3-b] indole-2-carboxylic acid tert-butyl ester also
Figure BSA00000161506100292
The 8-bromo-2,3,4 that the 2-1 step obtains among the embodiment 1,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles (251mg, 1mmol) with (Boc) 2O (262mg 1.2mmol) is dissolved among the DCM (8mL), under agitation, the dropping diisopropyl ethyl amine (258mg, 2mmol).Add the back in stirring at room one hour, TLC shows that reaction finishes.Rotary evaporation removes and desolvates, the crude product that obtains silica gel column chromatography (7M NH 3Methanol solution/DCM:5/95) purifying obtains target product (274mg, yield: 78%). 1H-NMR(CDCl 3，500MHz)：δ(ppm)1.50(s，9H)，2.83(t，J＝5.2Hz，2H)，3.81(t，J＝5.2Hz，2H)，4.58(s，2H)，7.17(d，J＝8.4Hz，1H)，7.24(d，J＝8.4Hz，1H)，7.57(s，1H)，7.92(s，br，1H)。Mass spectrum m/z:350.99[M+H, 79Br], 352.97[M+H, 81Br].
1-2, preparation 8-(4,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl)-1,3,4, the 5-tetrahydropyridine is [4,3-b] indole-2-carboxylic acid tert-butyl ester also
Figure BSA00000161506100293
The 8-bromo-1,3,4 for preparing from step 1-1,5-tetrahydropyridine also [4,3-b] indole-2-carboxylic acid tert-butyl ester set out, and with reference to the method for the step 1-2 among the embodiment 3, prepare target compound (yield: 85%).Its analytical data is as follows: 1H-NMR (CDCl 3, 500MHz): δ (ppm) 1.50 (s, 9H), 2.82 (t, J=5.2Hz, 2H), 3.82 (t, J=5.2Hz, 2H), 4.60 (s, 2H), 7.17 (d, J=8.4Hz, 1H), 7.23 (dd, J=2.0,8.0Hz, 1H), 7.62 (s, 1H), 7.96 (s, br, 1H).Mass spectrum m/z:399.14[M+H].
2, preparation 8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indole-2-carboxylic acid tert-butyl ester also
The 5-bromo-3-[(1R that step 1-6 among the embodiment 1 is obtained)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 2-aminopyridine (75.8mg, 0.2mmol), the 8-(4 that obtains of the step 1-2 in the present embodiment, 4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl)-1,3,4, the 5-tetrahydropyridine also [4,3-b] indole-2-carboxylic acid tert-butyl ester (96mg, 0.24mmol) and salt of wormwood (82.9mg, 0.6mmol) be dissolved in the DME/ water mixed solution (4/1,2.0ml).Then, under nitrogen, add Pd (PPh 3) 4(11.6mg 0.01mmol), blasted nitrogen 2 minutes in the gained mixture, stirred 18 hours down in 80 ℃ of degree then.LC-MS shows that reaction finishes, be chilled to room temperature after, add entry (5mL), extract (3 * 10mL) with DCM.Organic phase merges, dry (Na 2SO 4), concentrate the crude product obtain with silica gel column chromatography (7M NH 3Methanol solution/DCM:5/95) purifying obtains target product (77mg, yield: 68%). 1H-NMR(CDCl 3，500MHz)：δ(ppm)1.53(s，9H)，1.87(d，J＝6.8Hz，3H)，2.82(t，J＝5.2Hz，2H)，3.86(t，J＝5.2Hz，2H)，4.67(s，2H)，4.85(s，br，2H)，6.14(q，J＝6.8Hz，1H)，6.99-7.06(m，2H)，7.20(d，J＝8.0Hz，1H)，7.27-7.34(m，2H)，7.46(t，J＝7.6Hz，1H)，7.55(m，1H)，7.67(m，1H)，7.90(s，1H)。Mass spectrum m/z:570.99[M+H, 35Cl, 35Cl], 572.90[M+H, 35Cl, 37Cl].
Embodiment 6:3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl) pyridine-2-base amine hydrochlorate
The 8-[6-amino that embodiment 5 is obtained-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4,5-tetrahydropyridine also [4,3-b] (57.1mg 0.1mmol) is dissolved in DCM (5mL) to the indole-2-carboxylic acid tert-butyl ester, drips 4M HCl De dioxane solution (2mL) then, stirring at room 1 hour, draining solvent obtains 55mg (yield: product 100%) without purifying, is directly used in following reaction.Its analytical data is as follows: mass spectrum m/z:471.05[M+H, 35Cl, 35Cl], 473.02[M+H, 35Cl, 37Cl].
Embodiment 7:8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-methane amide also
Figure BSA00000161506100311
3-[(1R with embodiment 6 acquisitions)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl) pyridine-(27mg 0.05mmol) is dissolved among the DCM (2mL) 2-base amine hydrochlorate, adds Me then 3Si-NCO (28.8mg, 0.25mmol) and diisopropyl ethyl amine (64.2mg, 0.5mmol), 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 target product (42mg, yield: 82%). 1H-NMR(CD 3OD，500MHz)：δ(ppm)1.89(d，J＝6.8Hz，3H)，2.85(t，J＝5.6Hz，2H)，3.81(t，J＝5.6Hz，2H)，4.62(s，2H)，6.20(q，J＝6.8Hz，1H)，7.04(d，J＝1.6Hz，1H)，7.06(dd，J＝1.6，8.4Hz，1H)，7.23-7.28(m，2H)，7.31(d，J＝1.6Hz，1H)，7.49(dd，J＝4.8，8.8Hz，1H)，7.72(d，J＝2.0Hz，1H)。Mass spectrum m/z:514.02[M+H, 35Cl, 35Cl], 515.93[M+H, 35Cl, 37Cl].
Embodiment 8:N-[2-[8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-yl also]-1,1-dimethyl-2-oxygen base ethyl] t-butyl carbamate
Figure BSA00000161506100312
3-[(1R with embodiment 6 acquisitions)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl) pyridine-2-base amine hydrochlorate (27mg, 0.05mmol) be dissolved among the DCM (2mL), add then 2-(t-butoxycarbonyl amino)-2 Methylpropionic acid (15.2mg, 0.075mmol), EDC.HCl (14.4mg, 0.075mmol) and the dropping diisopropyl ethyl amine (38.5mg, 0.3mmol), gained mixture stirring at room 16 hours, the decompressing and extracting solvent, crude product silica gel column chromatography (7M NH 3Methanol solution/DCM:5/95) purifying obtains target product (22.3mg, yield: 68%). 1H-NMR(CDCl 3，500MHz)：δ(ppm)1.25(s，9H)，1.58(s，6H)，1.89(d，J＝6.4Hz，3H)，2.88(t，J＝5.6Hz，2H)，4.10(t，J＝5.6Hz，2H)，4.89(s，2H)，6.15(q，J＝6.8Hz，1H)，7.07(d，J＝2.0Hz，1H)，7.0-8-7.12(m，1H)，7.21-7.24(m，2H)，7.34(m，1H)，7.85(s，1H)，7.90(d，J＝1.6Hz，1H)。Mass spectrum m/z:656.07[M+H, 35Cl, 35Cl], 657.98[M+H, 35Cl, 37Cl].
Embodiment 9:2-amino-1-[8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-yl also }-2-methyl-prop-1-keto hydrochloride
Figure BSA00000161506100321
The N-[2-[8-[6-amino that embodiment 8 is obtained-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4,5-tetrahydropyridine also [4,3-b] indoles-2-yl]-1,1-dimethyl-2-oxygen base ethyl] (20mg 0.03mmol) is dissolved in DCM (5mL) to t-butyl carbamate, drips 4M HCl De dioxane solution (2mL) then, stirring at room 1 hour is drained solvent and is obtained 18.9mg (yield: product dihydrochloride 100%).Its analytical data is as follows: mass spectrum m/z:555.98[M+H, 35Cl, 35Cl], 557.96[M+H, 35Cl, 37Cl].
Embodiment 10:3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-methyl sulphonyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-8-yl also) pyridine-2-amine
Figure BSA00000161506100322
3-[(1R with embodiment 6 acquisitions)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl) pyridine-(10mg 0.018mmol) is dissolved in DCM (2mL) to 2-base amine hydrochlorate, add Methanesulfonyl chloride (2.5mg, 0.022mmol) and diisopropyl ethyl amine (23.1mg, 0.18mmol), the gained mixture was in stirring at room 6 hours, the decompressing and extracting solvent, crude product silica gel column chromatography (7M NH 3Methanol solution/DCM:5/95) purifying obtains target product (8.3mg, yield: 82%).Mass spectrum m/z:549.32[M+H, 35Cl, 35Cl], 551.31[M+H, 35Cl, 37Cl].
Embodiment 11:5-[(2aS, 9bR)-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl]-3-[(1R)-and 1-(2,6-two chloro-3-fluorophenyls) oxyethyl group] pyridine-2-base amine
Figure BSA00000161506100331
Concrete synthesis step is as follows:
1, preparation (4aS, 9bR)-8-(4,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl)-2,3,4,4a, 5,9b-six hydrogen-1H-pyridine
1-1, preparation (4aS, 9bR)-8-bromo-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles
Figure BSA00000161506100332
According to synthetic (the B.E.Maryanoff et al J.Org.Chem.1981 of literature method, 46,355-360) and slightly change: at 0 ℃ of degree and under stirring, the 8-bromo-2,3 that in embodiment 1, obtains among the step 2-1,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles (250mg, (5mL) adds trifluoracetic acid (1.8mL in dried THF solution 1.0mmol), 24mmol), BH then 3.THF (8mmoL), the gained reaction mixture stirred 30 minutes down in 0 ℃ of degree for 8mL, 1M solution, and LC-MS demonstration reaction is finished.Rotary evaporation removes and desolvates the saturated NaHCO of crude product 3The aqueous solution (5mL) is handled and is extracted (3 * 15mL) with DCM.Organic phase merges, dry (Na 2SO 4), concentrate the crude product obtain with silica gel column chromatography (7M NH 3Methanol solution/DCM:5/95) purifying obtains target product (182mg, yield: 72%). 1H-NMR(CD 3OD，500MHz)：δ(ppm)2.20-2.12(m，2H)，3.24(t，J＝4.4Hz，2H)，3.34-3.38(m，2H)，3.61(t，J＝6.4Hz，1H)，3.93(m，1H)，6.64(d，J＝8.4Hz，1H)，7.19(dd，J＝2.4，8.4Hz，1H)，7.30(d，J＝2.0Hz，1H)。Mass spectrum m/z:252.99[M+H, 79Br], 254.83[M+H, 81Br].
1-2, preparation (4aS, 9bR)-8-(4,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl)-2,3,4,4a, 5,9b-six hydrogen-1H-pyridine
With obtain among the step 1-1 (4aS, 9bR)-8-bromo-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles (126mg, 0.5mmol) according to the method preparation of step 2-2 among the embodiment 1, yield: 95%.Mass spectrum m/z:300.18[M+H], 301.13[M+H, 100%], 302.16[M+H].
2, preparation 5-[(2aS, 9bR)-2,3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl]-3-[(1R)-and 1-(2,6-two chloro-3-fluorophenyls) oxyethyl group] pyridine-2-base amine
The 5-bromo-3-[(1R that obtains with embodiment 1 step 1-6)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 2-aminopyridine (75.8mg, 0.2mmol) and (4aS that obtains among the above-mentioned steps 1-2,9bR)-8-(4,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl)-2,3,4,4a, 5, (72mg, 0.24mmol) method according to step 3 among the embodiment 1 prepares yield: 86% to 9b-six hydrogen-1H-pyridine. 1H-NMR(CD 3OD，500MHz)：δ(ppm)1.88(d，J＝6.8Hz，3H)，1.76-1.96(m，2H)，2.76-2.91(m，2H)，2.96-3.01(m，1H)，3.08-3.14(m，1H)，3.86(m，1H)，6.19(q，J＝6.8Hz，1H)，6.70(d，J＝2.0Hz，1H)，6.93(d，J＝1.6，1H)，7.00-7.05(m，2H)，7.24(m，1H)，7.45(m，1H)，7.63(d，J＝1.6Hz，1H)。Mass spectrum m/z:473.02[M+H, 35Cl, 35Cl], 475.00[M+H, 35Cl, 37Cl].
Embodiment 12:5-[(4aS, 9bR)-the 2-methyl isophthalic acid, 3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl]-3-[(1R)-and 1-(2,6-two chloro-3-fluorophenyls) oxyethyl group] pyridine-2-base amine
Figure BSA00000161506100341
Concrete synthesis step is as follows:
1, preparation (4aS, 9bR)-2-methyl-8-(4,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl)-1,3,4,4a, 5, the 9b-hexahydropyridine is [4,3-b] indoles also, and its step is as follows:
1-1, preparation (4aS, 9bR)-8-bromo-2-methyl isophthalic acid, 3,4,4a, 5, the 9b-hexahydropyridine is [4,3-b] indoles also
Figure BSA00000161506100342
With the 8-bromo-2-methyl-2,3,4 that step 1-1 among the embodiment 2 obtains, (264mg, 1.0mmol) method according to step 1-1 among the embodiment 11 prepares yield: 69% to 5-tetrahydrochysene-1H-pyrido [4,3-b] indoles. 1H-NMR(CD 3OD，500MHz)：δ(ppm)2.20-2.22(m，2H)，2.84(s，3H)，2.86-2.90(m，2H)，3.33-3.44(m，3H)，3.90(m，1H)，6.64(d，J＝8.4Hz，1H)，7.18(dd，J＝2.0，8.4Hz，1H)，7.26(d，J＝2.0Hz，1H)。Mass spectrum m/z:267.04[M+H, 79Br], 268.88[M+H, 81Br].
1-2, preparation (4aS, 9bR)-2-methyl-8-(4,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl)-1,3,4,4a, 5, the 9b-hexahydropyridine is [4,3-b] indoles also
Figure BSA00000161506100351
With obtain among the above-mentioned steps 1-1 (4aS, 9bR)-8-bromo-2-methyl isophthalic acid, 3,4,4a, 5, the 9b-hexahydropyridine also [4,3-b] indoles (134mg, 0.5mmol) according to the method preparation of step 1-2 among the embodiment 11, yield: 98%.Mass spectrum m/z:314.16[M+H], 315.11[M+H, 100%], 316.14[M+H].
2, preparation compound 5-[(4aS, 9bR)-the 2-methyl isophthalic acid, 3,4,4a, 5,9b-six hydrogen-1H-pyrido [4,3-b] indoles-8-yl]-3-[(1R)-and 1-(2,6-two chloro-3-fluorophenyls) oxyethyl group] pyridine-2-base amine
The 5-bromo-3-[(1b that obtains with embodiment 1 step 1-6]-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group b] and the 2-aminopyridine (75.8mg, 0.2mmol) and (4aS that obtains among the above-mentioned steps 1-2,9bR)-2-methyl-8-(4,4,5,5-tetramethyl--1,3,2-two oxa-s pentaborane-2-yl)-1,3,4,4a, 5, the 9b-hexahydropyridine is [4,3-b] indoles (75mg also, 0.24mmol) prepare yield: 89% according to the method for step 3 among the embodiment 1.Mass spectrum m/z:487.03[M+H, 35Cl, 35Cl], 489.05[M+H, 35Cl, 37Cl].
Embodiment 13
This example is that the prepared compound of the foregoing description suppresses the active effect experiment of Tyrosylprotein kinase c-Met, and concrete experimental technique is as described below.
1, the biochemical 503nhibiting concentration (IC of c-Met 50) experiment
Biochemical 503nhibiting concentration (the IC of c-Met 50) use contain 200ng/ μ L biotinylated poly-(Glu, Tyr), the 384-orifice plate of the Triphosaden (ATP) of 0.334mM vanadate, 2 μ M (Km).Damping fluid: 50mM HEPES (pH=7.4), 5mM MgCl 2, 5mM MnCl 2And 1% glycerine.Compound adds with DMSO solution form, and final DMSO concentration is 1%.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 allow and react on room temperature and carried out 1 hour.The PT66 of suitable amount adds in the hand-hole for acceptor bead, reads plate with AlphaQuest after 1 hour.503nhibiting concentration is the mean value 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 with PBST washing 4 times, add the anti-c-Met tyrosine phosphorylation of rabbit (pYpYpY1230/1234/1235) antibody, 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 (tetramethyl benzidine), reacts after 30 minutes, adds reaction terminating liquid.The absorption value of test wavelength 450 nanometers obtains IC with data by the processing of Excel Fit software analysis 50Curve and numerical value.503nhibiting concentration is the mean value of at least twice test.
3, get the compound for preparing among the embodiment, carry out the biochemical 503nhibiting concentration (IC of c-Met respectively as stated above 50) test and the MKN45 cell in c-Met 503nhibiting concentration (IC 50) test, the results are shown in following table (table 2).
Table 2
Compound The biochemical IC of c-Met 50Value, nM The IC of c-Met in the MKN45 cell 50Value, μ M
Embodiment 1 ??++++ ??0.071
Embodiment 2 ??++++ ??0.02
Embodiment 3/4 ??++++ ??0.002
Embodiment 5 ??++ ??5.6
Embodiment 6 ??++++ ??ND
Embodiment 7 ??+++ ??1.22
Embodiment 8 ??++ ??ND
Embodiment 9 ??+++ ??0.435
Embodiment 10 ??+++ ??ND
Compound The biochemical IC of c-Met 50Value, nM The IC of c-Met in the MKN45 cell 50Value, μ M
Embodiment 11 ??++++ ??ND
Embodiment 12 ??++++ ??ND
Footnote: ++ ++ :≤50nM; +++: 51-100nM; ++: 〉=100nM, but＜100 μ M.
ND: undetermined
Can find out by last table institute column data, the compound overwhelming majority among the present invention no matter at biochemical condition still in cancer cells, all can suppress the kinase whose activity of c-Met very effectively.

Claims (11)

1. a Tetrahydropyridoindocompounds compounds or its are at pharmacy acceptable salt, hydrate, solvate or prodrug, and the molecular structure of this compound is suc as formula shown in (I):
In the formula:
X be CH, O, S (=O) nOr N;
Figure FSA00000161506000012
Two keys of expression or singly-bound;
When X be O or S (=O) nThe time, R does not exist;
When X is CH, R be selected from H ,-OH ,-NH 2,-CN ,-CF 3, oxo, halogen, C 1-6Alkyl, C 3-6Cycloalkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, C 6Aryl, C 5-6Heteroaryl, C 3-6Heterolipid cyclic group, R 1O-, R 1R 2N-, R 1S (=O) m-, R 1R 2NS (=O) m-, R 3C (=O)-, R 1R 2NC (=O)-, R 1OC (=O)-, R 3C (=O) O-, R 1R 2NC (=O) O-, R 3C (=O) NR 1-, R 1R 2NC (=O) NR 4-, R 1OC (=O) NR 4-, R 1S (=O) mNR 4-, R 1R 2NS (=O) mNR 4-, R 1R 2NC (=NR 5) NR 4-, R 1R 2NC (=CHNO 2) NR 4-, R 1R 2NC (=NR 5)-, R 1S (=O) (=NR 5) NR 4-or R 1R 2NS (=O) (=NR 5Each hydrogen among)-, and the R can be independently by one or more identical or different G 1Replace;
When X is N, R be selected from H ,-OH ,-NH 2,-CN ,-CF 3, C 1-6Alkyl, C 3-6Cycloalkyl, C 6Aryl, C 5-6Heteroaryl, C 3-6Heterolipid cyclic group, R 1O-, R 1R 2N-, R 1S (=O) m-, R 1R 2NS (=O) m-, R 3C (=O)-, R 1R 2NC (=O)-, R 1OC (=O)-, R 1OC (=O) NR 4-, R 1S (=O) mNR 4-, R 1R 2NC (=NR 5)-, R 1R 2NC (=CHNO 2)-or R 1S (=O) (=NR 5Each hydrogen among)-, and the R can be independently by one or more identical or different G 2Replace;
R 1, R 2, R 3, R 4And R 5Be independently selected from: H, C 1-6Alkyl, C 3-6Cycloalkyl, C 6Aryl, C 5-6Heteroaryl, 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, this C 3-6The heterolipid ring can comprise in addition one or more O, N, S (=O) mDeng heteroatoms; And R 1, R 2, R 3, R 4And R 5In each hydrogen can be independently by one or more identical or different G 3Replace;
G 1, G 2And G 3Be independently selected from H ,-OH ,-NH 2,-CN ,-CF 3, halogen, C 1-6Alkyl, C 3-6Cycloalkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, C 6Aryl, C 5-6Heteroaryl, C 3-6Heterolipid cyclic group, C 1-6Alkoxyl group, C 3-6Cycloalkyloxy, C 6Aryloxy, C 5-6Heteroaryloxy, C 3-6Heterolipid epoxy group(ing), C 1-6Alkylamino, C 3-6Naphthene amino, C 6Virtue is amino, C 5-6Amino, the C of assorted virtue 3-6Heterolipid ring amino, C 1-6Alkoxy-C O-, C 3-6Cycloalkyloxy-CO-, C 6Aryloxy-CO-, C 5-6Heteroaryloxy-CO-, C 3-6Heterolipid epoxy group(ing)-CO-, C 1-6Alkylamino-CO-, C 3-6Naphthene amino-CO-, C 6Virtue amino-CO-, C 5-6Assorted fragrant amino-CO-or C 3-6Heterolipid ring amino-CO-;
n＝0-2；
m＝0-2。
2. the described Tetrahydropyridoindocompounds compounds of claim 1, the molecular structure of this compound is suc as formula shown in (Ia):
Figure FSA00000161506000021
3. the described Tetrahydropyridoindocompounds compounds of claim 1, the molecular structure of this compound is suc as formula shown in (Ib):
Figure FSA00000161506000022
4. the described Tetrahydropyridoindocompounds compounds of claim 2 is characterized in that R is selected from H, C 1-6Alkyl, C 3-6Cycloalkyl, C 6Aryl, C 5-6Heteroaryl, C 3-6Heterolipid cyclic group, R 1S (=O) m-, R 1R 2NS (=O) m-, R 3C (=O)-, R 1R 2NC (=O)-, R 1OC (=O)-, R 1R 2NC (=NR 5)-, R 1R 2NC (=CHNO 2)-or R 1S (=O) (=NR 5Each hydrogen among)-, and the R can be independently by one or more identical or different G 2Replace.
5. the described Tetrahydropyridoindocompounds compounds of claim 4 is characterized in that R is selected from H, methyl, ethyl, sec.-propyl, the tertiary butyl, cyclopropyl, formyl radical, ethanoyl, propionyl, different propionyl, 2-amino-2-methyl propionyl, formamyl, methyl-carbamoyl, dimethylamino formyl radical, ethylamino formyl radical, diethylin formyl radical, methylsulfonyl, ethylsulfonyl, third alkylsulfonyl, ring third alkylsulfonyl or benzenesulfonyl.
6. the described Tetrahydropyridoindocompounds compounds of claim 3 is characterized in that R is selected from H, C 1-6Alkyl, C 3-6Cycloalkyl, C 6Aryl, C 5-6Heteroaryl, C 3-6Heterolipid cyclic group, R 1S (=O) m-, R 1R 2NS (=O) m-, R 3C (=O)-, R 1R 2NC (=O)-, R 1OC (=O)-, R 1R 2NC (=NR 5)-, R 1R 2NC (=CHNO 2)-or R 1S (=O) (=NR 5Each hydrogen among)-, and the R can be independently by one or more identical or different G 2Replace.
7. the described Tetrahydropyridoindocompounds compounds of claim 6 is characterized in that R is selected from H, methyl, ethyl, sec.-propyl, the tertiary butyl, cyclopropyl, formyl radical, ethanoyl, propionyl, different propionyl, 2-amino-2-methyl propionyl, formamyl, methyl-carbamoyl, dimethylamino formyl radical, ethylamino formyl radical, diethylin formyl radical, methylsulfonyl, ethylsulfonyl, third alkylsulfonyl, ring third alkylsulfonyl or benzenesulfonyl.
8. Tetrahydropyridoindocompounds compounds is selected from following compound (table 1):
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-8-yl) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(the 2-methyl isophthalic acid, 3,4, the 5-tetrahydropyridine is [4,3-b] indoles-8-yl also) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-ethyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-8-yl also) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-n-propyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-8-yl also) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-sec.-propyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-8-yl also) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-cyclopropyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-8-yl also) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-cyclobutyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-8-yl also) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-cyclopentyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-8-yl also) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-cyclohexyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-8-yl also) pyridyl-2-amine;
8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-formaldehyde also;
1-[8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-yl also] ethyl ketone;
1-[8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-yl also] third-1-ketone;
8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indole-2-carboxylic acid tert-butyl ester also;
8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indole-2-ethyl formate also;
8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indole-2-ethyl formate also;
8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indole-2-carboxylic acid isopropyl ester also;
N-[2-[8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-yl also]-1,1-dimethyl-2-oxygen base ethyl] t-butyl carbamate;
2-amino-1-[8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-yl also }-2-methyl-prop-1-ketone;
2-hydroxyl-1-[8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-yl also }-2-methyl-prop-1-ketone;
8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-methane amide also;
8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-the N-methyl isophthalic acid, 3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-methane amide also;
8-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-N, N-dimethyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-2-methane amide also;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-methyl sulphonyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-8-yl also) pyridine-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-ethylsulfonyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-8-yl also) pyridine-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2,3,4,5-tetrahydrochysene-1H-pyrido [4,3-b] indoles-7-yl) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(the 2-methyl isophthalic acid, 3,4, the 5-tetrahydropyridine is [4,3-b] indoles-7-yl also) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-ethyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-7-yl also) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-n-propyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-8-yl also) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-sec.-propyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-7-yl also) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-cyclopropyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-7-yl also) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-cyclobutyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-7-yl also) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-cyclopentyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-7-yl also) pyridyl-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-cyclohexyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-7-yl also) pyridyl-2-amine;
7-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-formaldehyde also;
1-[7-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-yl also] ethyl ketone;
1-[7-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-yl also] third-1-ketone;
7-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indole-2-carboxylic acid tert-butyl ester also;
7-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indole-2-ethyl formate also;
7-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indole-2-ethyl formate also;
7-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indole-2-carboxylic acid isopropyl ester also;
N-[2-[7-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-yl also]-1,1-dimethyl-2-oxygen base ethyl] t-butyl carbamate;
2-amino-1-[7-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-yl also }-2-methyl-prop-1-ketone;
2-hydroxyl-1-[7-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-yl also }-2-methyl-prop-1-ketone;
7-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-1,3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-methane amide also;
7-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-the N-methyl isophthalic acid, 3,4, the 5-tetrahydropyridine is [4,3-b] indoles-2-methane amide also;
7-[6-amino-5-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-the 3-pyridyl]-N, N-dimethyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-2-methane amide also;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-methyl sulphonyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-7-yl also) pyridine-2-amine;
3-[(1R)-1-(2,6-two chloro-3-fluorophenyls) oxyethyl group]-5-(2-ethylsulfonyl-1,3,4,5-tetrahydropyridine be [4,3-b] indoles-7-yl also) pyridine-2-amine.
9. the preparation method of a Tetrahydropyridoindocompounds compounds, this method is made up of following step:
Compound shown in compound shown in the formula (II) and the formula (III) is carried out the Suzuki linked reaction makes the compound shown in the described formula of claim 1 (I),
Figure FSA00000161506000061
X in the formula (III) is identical with the definition of claim 1 with R.
10. the described compound of claim 1-8 is as the application to the inhibited inhibitor of c-Met activity.
11. a c-Met activity inhibitor contains the described compound of the claim 1-8 that suppresses effective dose in this inhibitor.
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CN102503959A (en) * 2011-10-25 2012-06-20 南方医科大学 Tricyclic compounds and preparation method thereof, and medicinal composition containing compounds and application thereof
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