CN101638383B - Quinoline as well as pharmaceutical composition and use thereof - Google Patents

Quinoline as well as pharmaceutical composition and use thereof Download PDF

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CN101638383B
CN101638383B CN 200910152097 CN200910152097A CN101638383B CN 101638383 B CN101638383 B CN 101638383B CN 200910152097 CN200910152097 CN 200910152097 CN 200910152097 A CN200910152097 A CN 200910152097A CN 101638383 B CN101638383 B CN 101638383B
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expression
alkyl
formula
compound
hydrogen atom
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CN101638383A (en
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易崇勤
赵鸿莲
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New Founder Holdings Development Co ltd
Peking University Medical Management Co ltd
Peking University Founder Group Co Ltd
PKU Healthcare Industry Group
PKUCare Pharmaceutical R&D Center
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Peking University Founder Group Co Ltd
PKU International Healthcare Group Co Ltd
PKUCare Pharmaceutical R&D Center
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Abstract

The invention relates to a quinoline shown in the general formula (I) or a salt accepted in pharmacy, hydrate or solvate, an optical active body or racemate or diastereoisomer mixture thereof, having excellent proteinkinase suppressive activity of tyrosine specificity. The quinoline and the pharmaceutical composition are effective for treating/preventing various cancers, diseases based on arteriosclerosis or chronic eczema.

Description

Quinoline and pharmaceutical composition thereof and purposes
Technical field
The present invention relates to a kind of novel quinoline.More particularly, (hereinafter referred to as Tyrosylprotein kinase) suppresses active quinoline to the present invention relates to have TSPK.In addition, the present invention relates to contain the pharmaceutical composition of this quinoline and pharmaceutically acceptable carrier, the tyrosine kinase inhibitor that contains this quinoline and carcinostatic agent, to based on the hyperfunction treatment of diseases that causes of tyrosine kinase activity and/or prophylactic agents such as arteriosclerotic disease and chronic eczema.
Background technology
In the chemotherapy of cancer, the inhibition DNA that use synthesize or directly suppress fissional medicine more.But, these medicines all are to play a role as cytotoxicity at present, though the cancer cells to division rapidly is effective, but as a rule, because its cytotoxicity is not limited to cancer cells, therefore normal cell is also shown strong toxicity, there is the problem that has side effects in its result in utilizing the chemotherapy of this medicine.As the other approach with the mechanism effect beyond described, known have raising to the process for selective of the propagation inhibition of cancer cells.
Tyrosylprotein kinase is the enzyme with the tyrosine residues phosphorylation in the protein, is knownly bringing into play the effect at important and center at cytodifferentiation, propagation or cell internal information conducting system.Consider simultaneously, if the control of tyrosine kinase activity has been subjected to destruction, then can cause the unusual of cytodifferentiation, propagation or cell internal information transmission mechanism, directly relate to the morbidity of a lot of diseases.For example except arteriosclerosis [Am.J.Physiol., 1991,260 (4-part 1), C721-C730; Biochem.Biophys.Commun., 1993,192 (3), 1319-1326. etc.], outside the chronic eczema [J.Invest.Deruatol., 1990,75,75-95], also find to compare with normal cell the unusual [Cell of tyrosine kinase activity in tumour cell; 1987,50,823].Now the multiplicaiton factor receptor tyrosine kinase (hereinafter referred to as receptor tyrosine kinase) of clear and definite wherein HER2 (being also referred to as ErbB2 or Neu), EGF acceptor etc. and cancer be formed with much relations, also found hyperfunction [the Cancer Res. of receptor tyrosine kinase activity in people's cancer, 1991,51,4430-4435; Cancer Res., 1992,52,3636-3641; Cancer Chemother.Pharmacol., 1993,32,1-19. etc.].In addition, report is found these receptor tyrosine kinases superfluous [Med.Bull., 1991,47,87 in a lot of tumour such as brain, lung, stomach, intestines, pancreas Tibetan, incidence, esophagus, wing moon bright, kidney, prostate gland, ovary, breast, uterus, Tiroidina; Expert.Opin.Invest.Drugs, 1994,3 (6), 577-595; Te Kaiping 5-208911].
In addition, also show and EGF receptor related [J.Biol.Chem., 1995,912,895-898 even have in the blood vessel hyperplasia of much relations in the transfer with cancer; Cancer Res., 1995,55,3772-3776].Therefore think the medicine that suppresses Tyrosylprotein kinase, not only as prevention or the curative of described disease, and have new mechanism of action, as being applicable to that the little carcinostatic agent of multiple cancer and side effect also is effective.At present, the research of various tyrosine kinase inhibitors is in progress, though open nearest paper [Drugs of theFuture 199924 (5), the 515-537 that flat 6-73025 communique, spy are opened flat 5-208911 communique, No. 2994165 communique of Japan's special permission, the special flat 12-508657 communique of table or Diane H.Boschelli the spy; ] open, but still do not reach practical degree.EGF acceptor, HER2, four kinds of acceptors of ErbB3 and ErbB4 all belong to ErbB family, find to form between these acceptors xenogenesis complex body and interact in the cell internal information transmits [J.Clin.Oncol.200119 (18s), 32s-40s].For example, the common appearance of known because EGF acceptor and HER2 only makes the cancerization based on the EGF acceptor further accelerate [Cell 198758,287-292].In addition, be reported in mammary cancer, oral carcinoma, the lung cancer etc., in case occur EGF acceptor and HER2 jointly, then cause more back bad [Clin.Cancer Res.19995,4164-4174].In addition, also be reported in the mammary cancer the common appearance of EGF acceptor and HER2 relevant with the endocrinotherapy antagonism [J.Steroid Biochem.198934,123-131].
Summary of the invention
The object of the invention is to provide the medicine that suppresses the EGF receptor tyrosine kinase and the medicine that suppresses EGF receptor tyrosine kinase and HER2 Tyrosylprotein kinase both sides.The double inhibitors of EGF acceptor and HER2 is compared with only acting on independent kinase whose medicine, not only has indication advantage widely, but also has the advantage by the stronger result for the treatment of of synergy performance of two inhibition.
Compound of the present invention has lasting enzyme inhibition, compares with the reversible inhibitor of reporting in the past, can obtain good result for the treatment of.
The inventor etc. have carried out research with keen determination in order to solve described problem, found that the quinoline of ad hoc structure has strong tyrosine-kinase enzyme inhibition activity and the inhibited proliferation of cancer cells, thereby have finished the present invention.
One aspect of the present invention provides quinoline shown in general formula (I) or its pharmacy acceptable salt, their solvate, their optically active body or raceme or their non-enantiomer mixture,
Figure G2009101520977D00021
In the formula (I)
[A]：
N represents 1 or 2 integer,
R 1Expression halogen atom, cyano group, C 1-C 5Alkyl, C 1-C 5Alkoxyl group or-NR 14R 15, wherein: R 14And R 15Independently represent C separately 1-C 5Alkyl;
R 2Expression R 27SO 2NH-, wherein: R 27Expression morpholino base replaces or unsubstituted C 1-C 5Alkyl, C 1-C 5Alkoxyl group, CHC 3OCH 2CONH-, CH 3SCH 2CH 2CONH-, NCCH 2CONH-,
In the formula: X represents-C (O)-or-SO 2-, R 4, R 5And R 6Separately independent expression hydrogen atom,
Figure G2009101520977D00032
In the formula: R 7Expression morpholino base replaces or unsubstituted C 1-C 5Alkyl;
R 3Expression
In the formula: R 8, R 9Independently represent a) hydrogen atom, b separately) C 1-C 5Alkoxyl group replaces or unsubstituted C 1-C 5Alkyl or c) R 8And R 9Form together ring and expression by exist or do not exist-O-or-NR 10-C 3-C 8Ring alkylidene group, wherein R 10Expression hydrogen atom or C 1-C 5Alkyl, m are represented 0 or 1 integer, R 11, R 12Independently represent hydrogen atom separately, Y represents C 1-C 5Alkoxyl group, N-methyl-(N-methyl piperidine-4-yl) be amino ,-N (R 16)-(CO) u-(CR 17R 18) v-(CO) j-R 19, R wherein 16Expression C 1-C 5Alkoxyl group replaces or unsubstituted C 1-C 5Alkyl, R 17, R 18Independent expression hydrogen atom separately, u and j represent 0 or 1, v represent 1 or 2 integer, R 19Expression hydrogen atom, cyano group, C 1-C 5Alkoxyl group, morpholino, 4-C 1-C 5Alkylpiperazine-1-base or two (C 1-C 5Alkyl) amino, wherein, 1) u and j represent simultaneously at 0 o'clock, and v represents 2,2) R 19During expression cyano group, j represents 0,
Figure G2009101520977D00034
In the formula: p and q independently represent 2 or 3 integer separately, Z represents-O-, carbonyl or-NR 20-, wherein: R 20Expression is hydrogen atom, b a)) C 1-C 5Alkyl sulphonyl, c) C 1-C 5Alkyloyl, d) C 1-C 5Alkoxy carbonyl or e) by cyano group, hydroxyl or C 1-C 5Alkoxyl group replaces or unsubstituted C 1-C 5Alkyl, or
In the formula: r and t independently represent 1 or 2 integer separately, and k represents that 0, W represents hydrogen atom, hydroxyl, C 1-C 5Alkoxyl group, carboxyl, two (C 1-C 5Alkyl) amino;
Perhaps
[B]
N represents 1 or 2 integer,
R 1Expression halogen atom, C 1-C 5Alkoxyl group, C 1-C 5Alkyloyl or C 2-C 5Alkynyl,
R 2Expression
Figure G2009101520977D00042
In the formula: R 8, R 9Independently represent hydrogen atom, C separately 1-C 5Alkoxyl group replaces or unsubstituted C 1-C 5Alkyl, or R 8And R 9Form ring expression C together 3-C 8The ring alkylidene group, m represents 0 or 1 integer, R 11R 12Independent expression hydrogen atom separately, Y represent N-methyl-(N-methyl piperidine-4-yl) amino ,-N (R 16)-(CO) u-(CR 17R 18) v-(CO) j-R 19, R wherein 16Expression hydrogen atom or C 1-C 5Alkoxyl group replaces or unsubstituted C 1-C 5Alkyl, R 17, R 18Independent expression hydrogen atom separately, u and j represent 0 or 1, v represent 2, R 19Expression hydrogen atom, C 1-C 5Alkoxyl group, morpholino, 4-C 1-C 5Alkylpiperazine-1-base or two (C 1-C 5Alkyl) amino,
Figure G2009101520977D00043
In the formula: p and q independently represent 2 or 3 integer separately, Z represents-O-or-NR 20-, wherein: R 20Expression C 1-C 5Alkyl sulphonyl, C 1-C 5Alkyloyl or by cyano group or C 1-C 5Alkoxyl group replaces or unsubstituted C 1-C 5Alkyl, or
Figure G2009101520977D00044
In the formula: r and t represent independently that separately 2, k represents that 0, W represents hydrogen atom, hydroxyl or C 1-C 5Alkoxyl group,
R 3Expression
Figure G2009101520977D00051
In the formula: X represents-C (O)-, R 4, R 5And R 6Independent expression hydrogen atom, or C separately 1-C 5Alkoxyl group.
Alternative, quinoline of the present invention or its pharmacy acceptable salt, their solvate, their optically active body or raceme or their non-enantiomer mixture, shown in general formula (I),
Figure G2009101520977D00052
In the formula (I):
N represents 1 or 2 integer,
R 1, expression halogen atom, cyano group, C 1-C 5Alkyl, C 1-C 5Alkoxyl group or-NR 14R 15, wherein: R 14And R 15Independently represent C separately 1-C 5Alkyl,
R 2Expression R 27SO 2NH-, wherein: R 27The expression morpholino replaces or unsubstituted C 1-C 5Alkyl, C 1-C 5Alkoxyl group, CH 3COCH 2CONH-, CH 3SCH 2CH 2CONH-, NCCH 2CONH-,
Figure G2009101520977D00053
In the formula: X represents-C (O)-or-SO 2-, R 4, R 5And R 6Separately independent expression hydrogen atom or
Figure G2009101520977D00054
In the formula: R 7Expression C 1-C 5Alkyl,
R 3Expression
Figure G2009101520977D00055
In the formula: R 8, R 9Independently represent a) hydrogen atom, b separately) C 1-C 5Alkoxyl group replaces or unsubstituted C 1-C 5Alkyl, m are represented 1 integer, R 11, R 12Independently represent hydrogen atom separately, Y represents C 1-C 5Alkoxyl group, N-methyl-(N-methyl piperidine-4-yl) be amino ,-N (R 16)-(CO) u-(CR 17R 18) v-(CO) j-R 19, R wherein 16Expression C 1-C 5Alkoxyl group replaces or unsubstituted C 1-C 5Alkyl, R 17, R 18Independent expression hydrogen atom separately, u and j represent 0 or 1, v represent 1 or 2 integer, R 19Expression hydrogen atom, cyano group, C 1-C 5Alkoxyl group, morpholino, 4-C 1-C 5Alkylpiperazine-1-base or two (C 1-C 5Alkyl) amino, wherein, 1) u and j represent simultaneously at 0 o'clock, and v represents 2,2) R 19During expression cyano group, j represents 0,
Figure G2009101520977D00061
In the formula: p and q independently represent 2 or 3 integer separately, Z represents-O-, carbonyl or-NR 20-, wherein: R 20Expression hydrogen atom, C 1-C 5Alkyl sulphonyl, C 1-C 5Alkyloyl, C 1-C 5Alkoxy carbonyl or by cyano group or C 1-C 5Alkoxyl group replaces or unsubstituted C 1-C 5Alkyl or
Figure G2009101520977D00062
In the formula: r and t independently represent 1 or 2 integer separately, and k represents that 0, W represents hydrogen atom, hydroxyl, C 1-C 5Alkoxyl group, carboxyl, two (C 1-C 5Alkyl) amino.
Alternative, quinoline of the present invention or its pharmacy acceptable salt, their solvate, their optically active body or raceme or their non-enantiomer mixture, shown in general formula (I),
In the formula (I):
N represents 1 or 2 integer,
R 1Expression halogen atom, cyano group, C 1-C 5Alkyl, C 1-C 5Alkoxyl group ,-NR 14R 15, wherein: R 14And R 15Independently represent C separately 1-C 5Alkyl,
R 2Expression
Figure G2009101520977D00064
In the formula: X represents-C (O)-or-SO 2-, R 4, R 5And R 6Independently represent hydrogen atom separately, or
Figure G2009101520977D00071
In the formula: R 7The expression morpholino replaces or unsubstituted C 1-C 5Alkyl,
R 3Expression
Figure G2009101520977D00072
In the formula: R 8, R 9Independently represent hydrogen atom, C separately 1-C 5Alkoxyl group replaces or unsubstituted C 1-C 5Alkyl, perhaps R 8And R 9Form together ring and expression by exist or do not exist-O-,-NR 10-C 3-C 8Ring alkylidene group, wherein R 10Expression hydrogen atom or C 1-C 5Alkyl, m are represented 0 or 1 integer, R 11, R 12Independently represent hydrogen atom separately, Y represents C 1-C 5Alkoxyl group, N-methyl-(N-methyl piperidine-4-yl) be amino ,-N (R 16)-(CO) u-(CR 17R 18) v-(CO) j-R 19, R wherein 16Expression C 1-C 5Alkoxyl group replaces or unsubstituted C 1-C 5Alkyl, R 17, R 18Independent expression hydrogen atom separately, u and j represent 0 or 1, v represent 1 or 2 integer, R 19Expression hydrogen atom, cyano group, C 1-C 5Alkoxyl group, morpholino, 4-C 1-C 5Alkylpiperazine-1-base or two (C 1-C 5Alkyl) amino, wherein, 1) u and j represent simultaneously at 0 o'clock, and v represents 2,2) R 19During expression cyano group, j represents 0,
Figure G2009101520977D00073
In the formula: p and q independently represent 2 or 3 integer separately, Z represents-O-, carbonyl or-NR 20-, wherein: R 20Expression hydrogen atom or do not replace or by cyano group or C 1-C 5The C that alkoxyl group replaces 1-C 5Alkyl, or
Figure G2009101520977D00074
In the formula: r and t independently represent 1 or 2 integer separately, and k represents that 0, W represents hydrogen atom, hydroxyl, C 1-C 5Alkoxyl group, carboxyl, two (C 1-C 5Alkyl) amino.
Above-mentioned quinoline or its pharmacy acceptable salt, their solvate, their optically active body or raceme or their non-enantiomer mixture, in examples more of the present invention, in general formula (I), n represents 2, R 1The expression halogen atom; In other examples of the present invention, in general formula (I), n represents 1, R 1Expression C 1-C 5Alkoxyl group, C 2-C 5Alkynyl or C 1-C 5Alkyloyl.
Suitable, quinoline of the present invention or its pharmacy acceptable salt, their solvate, their optically active body or raceme or their non-enantiomer mixture, in general formula (I), R 2Expression R 27SO 2NH-, wherein: R 27Expression C 1-C 5Alkyl, C 1-C 5Alkoxyl group or
In the formula: X represents-C (O)-, R 4, R 5And R 6Independently represent hydrogen atom separately.
Further, above-mentioned quinoline or its pharmacy acceptable salt, their solvate, their optically active body or raceme or their non-enantiomer mixture, in general formula (I), R 3Expression
Figure G2009101520977D00082
In the formula: R 8, R 9Independently represent a) hydrogen atom, b separately) C 1-C 5Alkoxyl group replaces or unsubstituted C 1-C 5Alkyl, perhaps c) R 8And R 9Form ring together, expression C 3-C 8The ring alkylidene group or existence-O-,-NR 10-C 3-C 8The ring alkylidene group, R wherein 10The expression hydrogen atom, m represents 0 or 1, R 11, R 12Represent hydrogen atom respectively, Y represents C 1-C 5Alkoxyl group, N-methyl-(N-methyl piperidine-4-yl) be amino ,-N (R 16)-(CO) u-(CR 17R 18) v-(CO) j-R 19, R wherein 16Expression C 1-C 5Alkoxyl group replaces or unsubstituted C 1-C 5Alkyl, R 17, R 18Independent expression hydrogen atom separately, u and j represent 0 or 1, v represent 0 or 1, R 19Expression hydrogen atom, cyano group, C 1-C 5Alkoxyl group, morpholino, 4-C 1-C 5Alkylpiperazine-1-base or (C 1-C 5Alkyl) amino, wherein, 1) u and j represent simultaneously at 0 o'clock, and v represents 2,2) work as R 19During for cyano group, j represents 0,
In the formula: p and q independently represent 2 or 3 integer separately, Z represents-O-,-NR 20-, wherein: R 20Expression is hydrogen atom, b a)) C 1-C 5Alkyl sulphonyl, c) C 1-C 5Alkyloyl, d) C 1-C 5Alkoxy carbonyl or e) by cyano group or C 1-C 5Alkoxyl group replaces or unsubstituted C 1-C 5Alkyl, or
Figure G2009101520977D00084
In the formula: r and t independently represent separately 1 or 2, k represent that 0, W represents hydrogen atom, hydroxyl, C 1-C 5Alkoxyl group, carboxyl.
Especially, in general formula (I), R 3Expression
Figure G2009101520977D00091
In the formula: R 8, R 9Independent a) expression hydrogen atom, b separately) expression C 1-C 5Alkoxyl group replaces or unsubstituted C 1-C 5Alkyl, perhaps c) R 8And R 9Form ring together, expression by exist or do not exist-O-,-NR 10-C 3-C 8The ring alkylidene group, R wherein 10The expression hydrogen atom, m represents 0 or 1, R 11, R 12The expression hydrogen atom, Y represents C 1-C 5Alkoxyl group, N-methyl-(N-methyl piperidine-4-yl) be amino ,-N (R 16)-(CO) u-(CR 17R 18) v-(CO) j-R 19, R wherein 16Expression C 1-C 5Alkoxyl group replaces or unsubstituted C 1-C 5Alkyl, R 17, R 18Independent expression hydrogen atom separately, u and j represent 0 or 1, v represent 2, R 19Expression hydrogen atom, cyano group, C 1-C 5Alkoxyl group, morpholino, 4-C 1-C 5Alkylpiperazine-1-base or two (C 1-C 5Alkyl) amino, wherein, 1) u and j represent simultaneously at 0 o'clock, and v represents 2,2) work as R 19During for cyano group, j represents 0,
Figure G2009101520977D00092
In the formula: p and q independently represent 2 or 3 integer separately, and Z represents-O-,-NR 20-, wherein: R 20Expression is hydrogen atom, b a)) C 1-C 5Alkyl sulphonyl, c) C 1-C 5Alkyloyl, d) C 1-C 5Alkoxy carbonyl or e) do not replace or by cyano group or C 1-C 5The C that alkoxyl group replaces 1-C 5Alkyl, or
Figure G2009101520977D00093
In the formula: r and t independently represent separately 1 or 2, k represent that 0, W represents hydrogen atom, hydroxyl, C 1-C 5Alkoxyl group, carboxyl.
Perhaps, in general formula (I), R 3Expression
Figure G2009101520977D00094
In the formula: R 8, R 9Independent a) expression hydrogen atom, b separately) expression C 1-C 5Alkoxyl group replaces or unsubstituted C 1-C 5Alkyl, m represent 0 or 1, R 11, R 12Represent hydrogen atom respectively, Y represents
Figure G2009101520977D00101
In the formula: p and q represent that 2, Z represents-NR 20-, wherein: R 20Expression is by cyano group or C 1-C 5Alkoxyl group replaces or unsubstituted C 1-C 5Alkyl.
Quinoline of the present invention or its pharmacy acceptable salt, their solvate, their optically active body or raceme or their non-enantiomer mixture, preferred, in general formula (I), n represents 2, R 1The expression halogen atom, R 2Expression
Figure G2009101520977D00102
In the formula: X represents-C (O)-, R 4, R 5And R 6The expression hydrogen atom,
R 3Expression
Figure G2009101520977D00103
In the formula: R 8, R 9Expression C 1-C 5Alkoxyl group replaces or unsubstituted C 1-C 5Alkyl, m represent 0 or 1, Y represent N-methyl-(N-methyl piperidine 4-yl) amino ,-N (R 16)-(CO) u-(CR 17R 18) v-(CO) j-R 19, R wherein 16Expression C 1-C 5Alkyl, R 17, R 18Independently represent hydrogen atom separately, u and j represent that 0, v represents 2, R 19Expression two (C 1-C 5Alkyl) amino, or
Figure G2009101520977D00104
In the formula: p and q represent 2, Z represent-CO-,-NR 20-, wherein: R 20Expression hydrogen atom, C 1-C 5Alkyl.
Especially the quinoline shown in following formula 1a or the 1f, or its pharmacy acceptable salt, their solvate, their optically active body or raceme or their non-enantiomer mixture,
Figure G2009101520977D00111
The present invention provides a kind of pharmaceutical composition on the other hand, it contains above-mentioned any one or multiple quinoline or its pharmacy acceptable salt, their solvate, their optically active body or raceme or their non-enantiomer mixture and pharmaceutically acceptable carrier.
Further aspect of the present invention provides above-mentioned quinoline or its pharmacy acceptable salt, their solvate, their optically active body or raceme or the purposes of their non-enantiomer mixture in the medicine of preparation TSPK inhibitor.Wherein said TSPK is selected from but is not limited to: epidermal growth factor recipient tyrosine specificity protein kinase and human epidermal growth factor receptor 2's TSPK.
In addition, the present invention also provide above-mentioned quinoline or its pharmacy acceptable salt, they solvate, they optically active body or raceme or their non-enantiomer mixture for the preparation of the purposes in the medicine of the active hyperfunction disease that causes that treats and/or prevents TSPK, and they are for the preparation of the purposes in the medicine of the disease that treats and/or prevents cancer, arteriosclerosis disease and chronic eczema.
In addition, in following the present invention, these simply are called " tyrosine kinase inhibitor ".
Below the present invention is described in detail.
Compound of the present invention is the quinoline shown in the above-mentioned general formula (I).
As the halogen atom that in each substituting group of described general formula (I), defines, can enumerate fluorine atom, chlorine atom, bromine atoms, iodine atom, as C 1-C 5Alkyl can be enumerated methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, neo-pentyl etc., as C 1-C 5Alkoxyl group can be enumerated methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, n-pentyloxy, neopentyl oxygen etc., as C 2-C 5Alkenyl can be enumerated vinyl, 1-propenyl, 2-propenyl, 1-butylene base, 2-methacrylic-1-base alkynyl, crotyl, 1-pentenyl, pentenyl etc., as C 2-C 5Alkynyl can be enumerated ethynyl, 1-proyl, ethyl acetylene base, 1-pentynyl etc., as C 1-C 5Alkyloyl can be enumerated formyl radical, ethanoyl, propionyl, butyryl radicals, isovaleryl, pentanoyl etc.
Quinoline of the present invention changes salt by known method into according to corresponding acid or alkali.For example can enumerate the inorganic acid salt of hydrochloride, vitriol, carbonate, phosphoric acid salt etc. as salt; Or the organic acid salt of formate, acetate, propionic salt, lactic acid salt, oxalate, fumarate, maleate, Citrate trianion, tartrate, benzoate, phthalate, mesylate, tosilate, isethionate, glucuronate, gluconate etc.In addition, can also enumerate an alkali metal salt of sodium salt, sylvite etc.; The salt of the alkaline-earth metal of magnesium salts, calcium salt etc.; Or the salt of acceptable organic amine salt (tetramethyl-amine, triethylamine, benzylamine, phenylethylamine, monoethanolamine, diethanolamine, three (ethylol amine), Methionin, arginine etc.) on the ammonium salt, pharmacology.
Quinoline of the present invention can be got various three-dimensional arrangements.When for example chiral carbon being considered as the center, its absolute configuration can be (S) body, also can be (R) body, or raceme.Any mixture of the optical isomer of pure form or diastereomer, these isomer or raceme etc. include within the scope of the present invention.
In addition, the quinoline shown in the formula (I) for example can be that the form of the such solvation of hydrate or non-solventization exists, and the present invention includes all this solvation forms with antitumour activity.
Below, the preferred object lesson of The compounds of this invention has been shown in following table 1-6.Me represents methyl in the table, and Et represents ethyl, and Pr represents propyl group.
Table 1
Figure G2009101520977D00131
Figure G2009101520977D00151
Table 2
Figure G2009101520977D00161
Figure G2009101520977D00171
Figure G2009101520977D00181
Table 3
Figure G2009101520977D00211
Table 4
Figure G2009101520977D00221
Figure G2009101520977D00231
Table 5
Figure G2009101520977D00241
Table 6
Figure G2009101520977D00261
Figure G2009101520977D00271
In the compound shown in the described general formula (I), R 2, R 3In one of them contains the compound of amido linkage, for example can be by following path of preparing (circuit 1).
Figure G2009101520977D00281
Circuit 1
[in the formula: R 31Expression
(each symbol and described same meaning in the formula.), in addition, R 31Be combined among 6 or 7 of quinoline ring either party ,-NH 2With-NO 2Be combined in a remaining side, remaining symbol and described same meaning.]
For example can be by compound (I ') by at ether solvents such as tetrahydrofuran (THF) (THF), ether; Varsol such as toluene, heptane; In the non-proton property polar solvents such as dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) (DMSO), acetonitrile; In the protic polar solvent or their mixed solvent of methyl alcohol, the trimethyl carbinol, water etc., at the triethylamine of 0-10 equivalent or ethamine, pyridine, 4-(N, N dimethylamine) under the existence of the mineral alkali of pyridine nitrogenous bases such as (DMAP) or yellow soda ash, sodium bicarbonate etc., or under non-existent situation, make corresponding SULPHURYL CHLORIDE, sulphonic acid anhydride, acyl chlorides or 5 minutes-48 hours method of anhydride reaction with-20 ℃～200 ℃ temperature, perhaps by making corresponding sulfonic acid or carboxylic acid and for example or the Carbodiimides of cyclohexyl carbodiimide etc.; The condensation reaction of the activator coexistence of carbonyl dimidazoles, diphenylphosphine acid azide etc. prepares compound (I).In addition; can be by 2-haloethyl sulfuryl halide and compound (I ') by in the presence of the alkali of the triethylamine of surplus etc. or with alkaline purification, preparing ethene sulphonamide body, also can prepare ethanoyl ethanamide body by reaction in toluene, acetonitrile equal solvent by compound (I ') and ethanoyl ketene in addition.
Compound (I ') can be by the nitro-compound of correspondence (I ") at ether solvents such as THF, ether; In the non-proton property polar solvent of the varsol of toluene, heptane etc., DMF, acetonitrile etc.; In the protic polar solvent or their mixed solvent of methyl alcohol, ethanol, water etc., at the mineral acid of the hydrochloric acid of 0.1-10 equivalent, sulfuric acid etc.; The organic acid of acetic acid etc. exists down or under the non-existent situation, prepares with+20 ℃～+ 200 ℃ thermotonus 5 minutes-48 hours with reduced iron, zinc end or the tin chloride etc. of 1-50 equivalent, also can be at the FeCl of 0.1-10 equivalent 3Deng molysite exist down by making 5 minutes-48 hours method of hydrazine reaction, perhaps by based on LiAlH 4, NaBH 4, NaAlH 2(OCH 2CH 2OMe) 2Deng metal complex, NaH etc. metal hydride method of reducing and prepare.
In addition, the compound of described general formula (I '), (I "), (I) can prepare by the following method.
(circuit 2)
Figure G2009101520977D00291
[in the formula: the amide group of P ' expression amino, nitro, alkoxyl group or sulphonamide, acrylamide etc., Q represents the elimination base of halogen atom, trifyl (OTf) etc., P ' and Q are combined on 6 or 7 of quinoline ring; M represents hydrogen atom, Li, MgBr, SnR 3, B (OR) 2M ' expression Li, MgBr, SnR 3, AlR 2, B (OR) 2, ZrCp 2The atoms metal of Cl (in the formula: R represents hydrogen atom or low alkyl group, Cp representative ring pentadienyl) etc. or the halogen atom of atom (group) or Br, I etc.; Other as aforementioned definitions].
For example can be by compound (II ') and compound (III) or compound (III ') by at ether solvents such as THF, ether; Varsols such as toluene; In the non-proton property polar solvents such as DMF, dimethyl sulfoxide (DMSO), acetonitrile; In the protic polar solvent or their mixed solvent of methyl alcohol, the trimethyl carbinol, water etc., at the mineral alkali of the triethylamine of 0-10 equivalent or nitrogenous base such as ethamine, pyridine or yellow soda ash, sodium bicarbonate, cesium fluoride etc., the Pd (PPh of 0.001-0.5 equivalent 3) 4, Pd (OAc) 2, PdCl 2, (PPh 3) 2Deng the existence of copper compound of coordination compound, the CuI of 0.001-0.5 equivalent etc. of caesium under, make reaction preparation in 5 minutes～48 hours compound (I '), (II ') or (I) with+20 ℃～+ 200 ℃ temperature.At this moment, compound (III) (M=H) can use in the varsol of ether solvent at THF, ether etc., benzene, toluene etc., the acetylide (III) [M=Li, MgX (X represents halogen atom)] that for example can make the Grignard reagent effect of lithium alkylide, ethyl-magnesium-bromides etc. such as butyllithium and allocate, in addition, also can use therein for example can make with chlorination trialkyl tin compound, zinc chloride or the effect of tri-alkoxy boron compound and allocate (III) [M=SnR 3, ZnCl, B (OR ') 2] (in the formula: R represents low alkyl group, R ' expression hydrogen atom or low alkyl group).In addition, under the situation of (III ') (M '=Br, I), can make this compound (III ') (M '=Br, I) and (II ') for example at ether solvents such as THF, ether; Varsols such as toluene; In the non-proton property polar solvents such as DMF, DMSO, acetonitrile; In the protic polar solvent or their mixed solvent of methyl alcohol, the trimethyl carbinol, water etc., at the mineral alkali of the triethylamine of 0-10 equivalent or nitrogenous base such as ethamine, pyridine or yellow soda ash, sodium bicarbonate, cesium fluoride etc., the Pd (PPh of 0.001-0.5 equivalent 3) 4, Pd (OAc) 2, PdCl 2, (PPh 3) 2Or under the existence of the coordination compound of the palladium of Pd/C etc., the hexa methyl ditin by making 0.5-5 equivalent or the described general formula of two (pinacol salt) two boranes coexistence preparation (I '), (I ") or (I) shown in compound.Can make in addition, (III ') (M '=Br, I) for example at ether solvents such as THF, ether; Varsols such as toluene utilize n-Butyl Lithium, tert-butyl lithium etc. to carry out lithiumation, form (III ') (M '=Li) after, with the Pd (PPh of 0.001-0.5 equivalent 3) 4, Pd (OAc) 2, PdCl 2, (PPh 3) 2Deng palladium coordination compound together, make with (II ') reaction to prepare.
By compound (II ') (P '=NO 2) be converted to compound (II ') (P '=NH 2) method, can use the method that is reduced to (I ') by above-claimed cpd (I "), by compound (II ') (P '=NH 2) be converted to (the II ') amide group of expression sulphonamide, acrylamide etc. (P ') and can use by the condensation reaction of above-claimed cpd (I ') condensation for (I).
In addition, in the compound shown in the described general formula (I), R 2, R 3In one of them compound of representing with alkoxyl group also can by (II ') (P ' expression C 1-C 5Alkoxyl group) and the prepared in reaction (route 2) between compound (III) or the compound (III ').
In addition, in the compound shown in described general formula (I ') or (I "), R 3With
Figure G2009101520977D00301
(in the formula: Y, R 8, R 9, R 11, R 12And m is identical with described definition) compound of expression, can be by R in the compound shown in described general formula (I ') or (I ") 3With
Figure G2009101520977D00302
(in the formula: Y, R 8, R 9, R 11, R 12And m is identical with described definition) expression compound, for example at ether solvents such as THF, ether; Varsols such as toluene; In the non-proton property polar solvents such as halohydrocarbon such as methylene dichloride, DMF, acetonitrile; In the protic polar solvent or their mixed solvent of methyl alcohol, the trimethyl carbinol, water etc., by based on the Pd/BaSO with 0.0001-0.5 equivalent 4, PtO 2, Pd/C etc. is as the method for the catalytic hydrogenating reduction of catalyzer or for example utilize the LiAlH of 0.1-5 equivalent 4, (i-Bu) 2The reaction of the hydrometallation of AlH, two boranes, the method that then is hydrolyzed and preparing.
Below narrate the preparation method of compound (III) and (III ').
Compound (III) for example can be by the alkyne series compound (III) of correspondence (M=H) at ether solvents such as THF, ether; Varsols such as toluene; In non-proton property such as DMF, the acetonitrile polar solvent or in their mixed solvent or under solvent-free condition, with-30 ℃～+ 150 ℃ temperature, by for example utilizing LiAlH 4, (i-Bu) 2AlH, R 3SnH, Cp 2Zr (H) Cl, Cp 2TiCl 2The hydrometallation reaction of-RMgX (Cp representative ring pentadienyl, R represents low alkyl group, X represents halogen atom) and preparing.In addition, halogenating agent that also can be by for example utilizing iodine, N-iodate succinimide, N-bromination succinimide etc. replenishes them and is converted to compound (III ') (M '=Br, I).
(circuit 3)
[in the formula: R 23Expression
Figure G2009101520977D00312
(in the formula: each symbol and above-mentioned same meaning.), X 1, X 2While or side expression bromine atoms or chlorine atom].
The method of compound (III) shown in (M=H) for example can pass course 3 is prepared.Namely, can be with the pure oxidation of correspondence and in the aldehyde for preparing, by in appropriate solvent such as methylene dichloride, tetracol phenixin, the for example carbon tetrabromide of 0.1-10 equivalent and triphenylphosphine separately, in the method that makes reaction reaction in 5 minutes-48 hours under-20 ℃～+ 50 ℃ the temperature or in THF, ether equal solvent or their mixed solvent, for example make (EtO)-10 ℃～+ 100 ℃ temperature 2P (O) CCl 3With 5 minutes～48 hours method of organolithium compound such as n-Butyl Lithium reaction and prepare the halo alkene, and then for example in THF, ether equal solvent or their mixed solvent, after under-100 ℃～+ 100 ℃ the temperature it being handled 5 minutes～48 hours, the method by hydrolysis prepares compound (III) with the organolithium compound of n-Butyl Lithium etc.Also can protect the functional group in the compound as required and carry out this conversion.
(route 4)
Figure G2009101520977D00313
[in the formula: R 24Expression hydrogen atom or trialkylsilkl, M 1Expression Li, MgBr or CeCl 3Deng atoms metal (group), R 27Expression hydrogen atom, C 1-C 5Alkyl or C 1-C 5Alkyloyl, R 25, R 26Or represent R separately 16-(CR 17R 18) v-(CO) j-R 19(each symbol and described same meaning in the formula), or and form ring together,
Figure G2009101520977D00314
(each symbol and described same meaning in the formula) or
(each symbol and described same meaning in the formula.)。]
In addition, especially at preparation compound (III) (m=0, M=H, Y as defined above, but remove the situation of Y=H) time (route 4), can in the ketone or aldehyde of correspondence, by in appropriate solvent such as THF, ether, toluene, make ethynyl magnesium halogenide, trimethyl silyl ethinylation lithium maybe can make they and for example CeCl 3The ethinylation agent of the ethynyl lithium compound etc. of reaction and allotment-100 ℃～+ 100 ℃ thermotonus 5 minutes～48 hours and preparation alcoholization body (III) (m=0, M=H, Y=OH).Can be by the alcoholization body in the appropriate solvent of methylene dichloride, toluene, acetonitrile etc.; in the presence of the alkali of pyridine or triethylamine etc. or these alkali double as solvents use; the acylating agent of the acyl chlorides of the acid anhydrides of use acetic anhydride etc., Acetyl Chloride 98Min. etc. etc. or the alkylating agent of alkyl halide, alkyl mesylate etc.; prepared acidylate body or etherificate body (III) (m=0 in 5 minutes～48 hours by reaction under 0 ℃～150 ℃ temperature; M=H, Y=C1-C5 alkoxyl group or C 1-C 5Alkyloyl).Here, also can use in ketone, make ethinylation agent reaction after, do not separate the alcoholization body separately, but utilize the method for the alcoholate that produces in the acylating agent of acid anhydrides, acyl chlorides etc. or the direct capture system of alkylating agent.In addition, can be by the alcoholization body by in the appropriate solvent of acetonitrile, toluene, THF etc., with suitable Lewis acid, for example Sc (OTf) of-30 ℃～120 ℃ temperature in 0.0001-0.5 equivalent 3, BF 3.OEt 2Existence under, make the method for acid anhydrides, acyl chloride reaction and prepare the acidylate body.When using trimethylammonium acetylene lithium, can be as required before acidylate operation or etherificate operation or carry out afterwards taking off the trimethyl silyl processing based on well-established law.
Can be by the acidylate style as in the appropriate solvent of THF, methylene dichloride, toluene, acetonitrile etc.; in the presence of copper compounds such as CuCl, the CuI of 0.001 equivalent～0.5 equivalent or copper powder; by being reacted, corresponding amine prepared (III) [m=0 in 5 minutes～48 hours under 0 ℃～+ 100 ℃ temperature; M=H, Y=NR 25R 26(R in the formula 25, R 26With described definition)].With respect to (III) [m=0, M=H, the Y=NHR that can prepare by this method 16(R in the formula 16With described definition)], can be by the ether solvent at THF, ether etc.; The varsol of toluene, heptane etc.; In the non-proton property polar solvent of DMF, dimethyl sulfoxide (DMSO), acetonitrile etc.; Methyl alcohol; the number butanols; in the protic polar solvent or their admixture solvent of water etc.; triethylamine in 0～10 equivalent; or ethamine; pyridine; the nitrogenous base of DMAP etc. or yellow soda ash; under the existence of the mineral alkali of sodium bicarbonate etc.; perhaps under the non-existent situation; make corresponding carboxylic acid chloride or acid anhydrides in 5 minutes～48 hours method of-20 ℃～+ 200 ℃ reactions; perhaps by carbonization or imines class based on the carboxylic acid that makes correspondence and for example dicyclohexyl carbodiimide etc.; carbonyl dimidazoles; the condensation reaction of coexistence such as the condensing agent of diphenylphosphine acid azide etc. and prepare (III) [m=0; M=H, Y=N (R 16(the CR of)-(CO) 17R 18) v-(CO) j-R 19(R in the formula 16～R 19, j and v and definition as described].
At preparation compound (III) (M=1-3, M=H, Y=NR 25R 26, R 25, R 26With described definition, but remove the situation of Y=H) time, can represent the halogen atom of chlorine, bromine etc. or with the compound of the elimination basis representation of tosylate, metilsulfate etc. by Y in the compound (III) of correspondence, for example in the appropriate solvent of acetonitrile, THF, DMF etc., in the presence of the alkali of yellow soda ash, diisopropylethylamine, sodium hydride etc. or under the non-existent situation, under-20 ℃～+ 150 ℃ temperature, make the amine reaction 5 minutes～72 hours of 0.5～100 corresponding equivalent and prepare (III) [m=1～3, M=H, Y=NR 25R 26(in the formula: NR 25, R 26With described definition)].In addition, with respect to (III) [m=1～3, M=H, the Y=NHR by this method preparation 16(R in the formula 16With described definition)], can by with above-mentioned (III) [m=0, M=H, Y=NHR 16(R in the formula 16With described definition)] situation under used identical condensation reaction and prepare compound (III) [m=1～3, M=H, Y=N (R 16(the CR of)-(CO) 17R 18) v-(CO) j-R 19(R in the formula 16-R 19, j and v and definition as described].
Quinoline of the present invention, can be used as with respect to the hyperfunction treatment of diseases that causes of tyrosine kinase activity and/or prophylactic agent, that is, carcinostatic agent, with respect to the medicine that treats and/or prevents based on the disease (for example ischemic heart disease or acute coronary syndrome etc.) of arteriosclerosis effect or chronic eczema.
When the compound of the present invention shown in the described general formula (I) is used as described purpose, normally with whole body or local oral or non-oral form administration.Dosage is according to age, body weight, symptom, result for the treatment of, medication, treatment time etc. and different.Usually the scope of everyone a 1mg～5g of grownup, once-a-day～for several times oral, the perhaps scope of everyone a 1mg～5g of grownup, non-oral administration once-a-day～for several times, perhaps intravenously administrable continuously in 1～24 hour on the one.Certainly, as described above, because dosage changes because of various conditions, therefore the amount of also lacking than above-mentioned dosage is arranged with regard to enough situations, the situation that must surpass above-mentioned scope is also arranged.
When taking compound of the present invention, can be used as uses such as solids composition, liquid composition and other composition for oral administration, the injection that is used for non-oral administration, external application agent, patch, suppository.Compound can be taken separately, and a part that also can be used as the pharmaceutically acceptable composition that contains pharmaceutically acceptable vehicle is taken.Also can be simultaneously or take in the compound shown in the described general formula (I) more than one successively.
Being used for oral solids composition, comprise tablet, pill, capsule, powder, granule etc.In capsule, comprise hard capsule and soft capsule.In this solids composition, one or more active substance mixes with a kind of inert diluent, for example lactose, N.F,USP MANNITOL, glucose, hydroxypropylcellulose, avicel cellulose, starch, polyvinylpyrrolidone, silicic acid magnesium aluminate at least.Composition can contain inert diluent additive in addition according to well-established law, for example the lubricant of talcum powder, Magnesium Stearate, solid shape polyoxyethylene glycol, Sodium Lauryl Sulphate BP/USP class; The disintegrating agent of Mierocrystalline cellulose R-Glyceric acid calcium class; The stablizer of lactose class; The dissolving auxiliary of L-glutamic acid or aspartic acid class.Tablet or pill can carry out dressing with the film with gastric solubility or enteric solubility matters of white sugar, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate etc. as required, also can carry out two-layer above dressing in addition.In addition, also can comprise as the gelatin class can absorbing material capsule.
Be used for oral liquid composition, contain pharmaceutically acceptable solution, opacifying agent, suspension agent, syrup, elixir etc., can also contain used inert diluent, for example water or other solvent usually; Solvating agent and emulsifying agent, ethylene glycol for example, the fatty acid ester of Virahol, ethyl-carbonate, vinyl acetic monomer, benzylalcohol, st-yrax acid benzyl ester, propylene glycol, 1,3 butylene glycol, dimethyl formamide, Oleum Gossypii semen, Apios americanaoil, Fructus Maydis oil, sweet oil, Viscotrol C and sesame oil, glycerine, tetrahydrofurfuryl alcohol, polyoxyethylene glycol and sorbitanic or the mixture of these materials etc.Except this inert diluent, its composition can also contain the auxiliary of wetting agent, clouding agent class; Sweeting agent; Flavour agent; Perfume compound; Sanitas.
Suspension liquid; except the active ingredient beyond the region of objective existence; can also contain clouding agent for example oxyethyl group isostearoyl base alcohol, polyoxyethylene sorbitol and sorbitanic, micro-crystalline Mierocrystalline cellulose, methyl hydroxylation aluminium, bentonite, agar and tragacanth or their mixture etc.
As being used for other oral composition, contain one or more kinds of active substances, comprise the sprays that forms prescription according to known method.Said composition except containing inert diluent, can also contain infiltrative buffer reagents such as the stablizer of sodium bisulfite class and maintenance, for example sodium-chlor, Trisodium Citrate or citric acid.Spray preparing process for example has been disclosed in No. the 2868691st, United States Patent (USP) and with in No. 3095355 each number communique.
As the composition for injection for non-oral administration of the present invention, contain on the physiology acceptable sterilization back water-based or nonaqueous solution, clouding agent, opacifying agent.Solution, clouding agent as water-based for example contain distilled water for injection and physiological saline.As nonaqueous solution, clouding agent, propylene glycol, polyoxyethylene glycol, sweet oil, ethanol, polysorbate80 etc. are for example arranged.This composition can also further contain the auxiliary of sanitas, wetting agent, emulsifying agent, dispersion agent, stablizer (for example lactose), dissolving auxiliary (for example L-glutamic acid, aspartic acid) class.They can be for example by bacterium keep strainer filtration, sterilize by cooperation or the irradiation of sterilant.In addition, they also can be behind the aseptic solids composition of preparation, for example before the use of lyophilize product, be dissolved in sterilized water or aseptic injection with solvent in and use.
As being used for non-other oral composition, contain one or more kinds of active substances, comprise liquid for external use, ointment, Liniment, suppository and the hysterophore etc. that form prescription by well-established law.
Embodiment
The present invention is described in detail below to enumerate embodiment and synthesis example, but so long as do not break away from aim of the present invention, all be included within the scope of the invention.The invention is not restricted to following examples.In these, short of special record, each operation is all carried out in such a way.
1) operation carries out under rare gas element, for example nitrogen atmosphere envrionment temperature, namely 18～25 ℃.
2) concentrate and to rotate thin film evaporation by reducing pressure down and carry out, drying is for example carried out in anhydrous sodium sulphate, by removing by filter siccative.
3) for example adopt in refining recrystallization, under outstanding turbid state, stir outstandingly wash, distil or column chromatography (based on the flash chromatography method).In column chromatography, utilize for example enforcement such as chloroform-methanol of suitable developping agent.
4) structure of the purpose compound of described general formula (I) by hydrogen ( 1H or 1H) nucleus magnetic resonance (NMR) method (300MHz or 270MHz be not if having special record then for 300MHz) and/or mass spectroscopy confirm. 1HNMR is not if there is special appointment, then at deuterated dimethyl sulfoxide (DMSO-d 6, DMSO-d 5) or deuterochloroform (CDCl 3, CDCl 3) middle mensuration, chemical displacement value is to represent for the δ value of benchmark (δ .ppm) in order to tetramethylsilane (TMS), the peak splits branch to be represented with the following methods: and s, unimodal, d, bimodal, t, triplet, q, quartet, m, multiplet, br, broad peak.
5) use following abbreviation: normal hexane (Hex or hexane); The Ac ethanoyl; The Ms methylsulfonyl; The Tf trifyl; EDC 1-[3-(dimethylamino) propyl group]-the 3-ethyl-carbodiimide hydrochloride.
＜synthesis example 1:1-(1,1-dimethyl-2-propyl group)-4-methylpiperazine (4a) 〉
Make acetic acid 1,1-dimethyl-2-propyl diester (2-methyl-3-crotonylene-Ji acetate) (51.5g, 408.2mmol), cupric chloride (I) (2.02g, 20.4mmol), triethylamine (56.6mL, 408.2mmol) and (54.3mL, THF 489.9mmol) (480mL) the solution reaction 2 hours under refluxing of 1-methylpiperazine.Concentration of reaction solution adds t-butyl methyl ether (200mL) in residue, resultant extracts with dilute hydrochloric acid.Add the 6N aqueous sodium hydroxide solution until water layer demonstration alkalescence, with dichloromethane extraction (500mL * 1,150mL * 3) on the ice-cold following extraction liquid limit of stirring.Use 14% ammoniacal liquor, then clean extraction liquid with saturated aqueous common salt, then dry concentrating.The dark brown solid that generates by sublimation purifying (60 ℃/5～6Torr), obtain the colourless crystallization (49.07g, 72%) of title compound.
Figure G2009101520977D00361
4a： 1H NMR(CDCl 3)δppm：1.40(s，6H)，2.28(s，1H)，2.28(s，3H)，2.49(t，4H)，2.69(t，4H)。
＜synthesis example 2:4-(3-chloro-4-fluoroanilino)-7-[3-methyl-3-(4-methyl isophthalic acid-piperazinyl)-ethyl acetylene base]-6-amino-3-itrile group quinoline (2a) 〉
1) with 4 of 96.5mmol, the 3-chloro-4-fluoroaniline of 7-two chloro-6-nitro-3-itrile group quinoline and 14.05g (96.5mmol) is dissolved in the 900ml 2-propyl alcohol, and 3.5h refluxes under the nitrogen protection.(ethyl acetate: normal hexane=1: 1) no raw material point occurs TLC.At room temperature stir and spend the night, filter, with the washing of 2-propyl alcohol, obtain 4-(3-chloro-4-fluoroanilino)-7-chloro-6-nitro-3-itrile group quinoline 36.5g.
2) at 4-(3-chloro-4-fluoroanilino)-7-chloro-6-nitro-3-itrile group quinoline (40.1mmol), 1-(1,1-dimethyl-2-propyl group)-4-methylpiperazine (4a) (10.0g, 60.1mmol), cupric iodide (I) is (380mg) and in the DMF solution (70mL) of tetrakis triphenylphosphine palladium (1.39g), feed nitrogen down after 15 minutes at 50 ℃, add triethylamine (13.9mL, 100.0mmol), stirred 50 minutes down for 140 ℃ at oil bath temperature.Put cold back concentration of reaction solution, add sodium bicarbonate aqueous solution (300mL).Resultant extracts with ethyl acetate (200mL * 2), and drying concentrates.Residue is by silica gel chromatography column chromatography (chloroform-methanol; Ethyl acetate-methyl alcohol), obtain 4-(3-chloro-4-fluoroanilino)-7-[3-methyl-3-(4-methyl isophthalic acid-piperazinyl)-ethyl acetylene base of purpose nitro-body]-the 6-nitro-3-itrile group quinoline (3a) is (7.25g).
Figure G2009101520977D00362
3a： 1H NMR(CDCl 3)δppm：1.54(s，6H)，2.28(s，3H)，2.53(t，4H)，2.82(t，4H)，7.23(t，J＝8.5Hz，1H)，7.57(m，1H)，7.96(m，1H)，8.06(s，1H)，8.93(s，1H)，9.12(s，1H)，10.02(s，1H)。
3) (1.71g, ethanol 30.6mmol) (100mL)-water (50mL) suspension liquid refluxed 20 minutes to make nitro-body 3a (7.64mmol), acetic acid (5mL) and iron powder.In ice-cold downhill reaction liquid, add 10% aqueous sodium carbonate (90mL), stir under the room temperature after 1 hour, filter with C salt.Residue cleans with ethanol (150mL * 30), adds water (100mL) after filtrate is concentrated, the leaching precipitate, and the resultant water cleans.Drying under reduced pressure obtains the amino body 4-(3-chloro-4-fluoroanilino) of purpose-7-[3-methyl-3-(4-methyl isophthalic acid-piperazinyl)-ethyl acetylene base]-6-amino-3-itrile group quinoline (2a) is (3.02g).
Figure G2009101520977D00371
2a： 1H NMR(CDCl 3)δppm：1.55(s，6H)，2.30.(s，3H)，2.53(t，4H)，2.80(t，4H)，4.53(m，2H)，6.97(s，1H)，7.13(s，1H)，7.18(t，J＝8.7Hz，1H)，7.53(m，1H)，7.88(s，1H)，7.95(s，1H)，8.61(s，1H)。
＜synthesis example 3:4-(3-chloro-4-fluoroanilino)-7-bromo-6-nitro-3-itrile group quinoline 〉
1) 2-cyano group-3-ethoxy ethyl acrylate is in three mouthfuls of reaction flasks that fractional column is housed of 2000ml, the ethyl cyanoacetate, 833ml (5.0mol) triethyl orthoformate, the 27.8ml aceticanhydride that add 280ml (2.5mol) react 3h down at 120 ℃, the distillate distillation is reclaimed, cooling adds the 187ml dehydrated alcohol, crystallisation by cooling, filter crude product, dry back dehydrated alcohol recrystallization, get the 312.2g light yellow crystal, yield is 88.0%.
2) 4-hydroxyl-6 nitros-7-bromo-3-itrile group quinoline
3-bromo-4-N-methyl-p-nitroaniline (Mieczyslaw Makosza and Maciej Bialecki with 0.324mol, JOrg Chem, 1998,63,4878-4888) and 77.2g (0.456mol) 2-cyano group-3-ethoxy ethyl acrylate be dissolved in 210ml reflux in toluene 16h.The ice bath cooling is filtered, and the ether washing obtains the 94.2g solid.The solid of obtaining (37.5g, 0.123mol), the 2.5L dowtherm joins in the 5L three-necked bottle, and nitrogen protection at 256 ℃ of stirring 1.25h that reflux, is cooled to room temperature.The solid that obtains filters with the dilution of 2L ether, obtains 24.2g 4-hydroxyl-6 nitros-7-bromo-3-itrile group quinoline.
3) 4-chloro-6 nitros-7-bromo-3-itrile group quinoline adds 77mmol 4-hydroxyl-6 nitros-7-bromo-3-itrile group quinoline and 120ml phosphorus oxychloride in the round-bottomed flask of 1L, and 2.5h refluxes under the nitrogen protection.TLC (ethyl acetate: normal hexane=1: 1) do not have raw material point residue.The remaining phosphorus oxychloride of Rotary Evaporators evaporate to dryness.The solid that ice bath cooling is remaining is poured in the 250ml frozen water, uses the 200ml dichloromethane extraction respectively 3 times, merges organic phase, anhydrous magnesium sulfate drying, and solvent evaporated obtains 16.3g 4-chloro-6 nitros-7-bromo-3-itrile group quinoline.
By with synthesis example 2-1) same method is converted to 4-(3-chloro-4-fluoroanilino)-6-nitro-7-bromo-3-itrile group quinoline (1.38g) with this mixture (1.26g).
Figure G2009101520977D00381
4-(3-chloro-4-fluoroanilino)-6-nitro-7-bromo-3-itrile group quinoline.
1H NMR(DMSO-d 6)δppm：7.45(t，J＝9.1Hz，1H)，7.76(m，1H)，8.13(m，1H)，8.28(s，1H)，8.76(s，1H)，9.39(s，1H)，10.11(s，1H)。
＜embodiment 1 〉
At room temperature with the amino body 2a (13.4mmol) of synthesis example 2 gained, vinylformic acid (1.38mL, 20.1mmol), triethylamine (2.8mL, 20.1mmol) and EDC (3.86g, one night of DMF 20.1mmol) (100mL) solution stirring.In reaction solution, add vinylformic acid (0.46mL, 6.71mmol), triethylamine (0.93mL, 6.71mmol) and EDC (1.29g 6.71mmol), further stirs a night.Reaction solution is poured in the sodium bicarbonate aqueous solution (300mL) into filtering mixt.Residue cleans with water-ethanol, drying.After heated and stirred is slightly made with extra care thing in water-ethanol, cold going to room temperature.The leaching throw out, drying obtains purpose compound 1a (3.41g, 50%).
Figure G2009101520977D00382
1a： 1H NMR(DMSO-d 6)δppm：1.44(s，6H)，2.15(s，3H)，2.35(t，4H)，2.64(t，4H)，5.89(d，J＝10.3Hz，1H)，6.35(d，J＝16.7Hz，1H)，6.58(dd，J＝10.3，16.7Hz，1H)，7.45(t，J＝9.1Hz，1H)，7.86(m，2H)，8.20(s，1H)，8.69(s，1H)，8.73(s，1H)，9.91(s，1H)，10.12(s，1H)。
＜embodiment 2 〉
4-(3-chloro-4-the fluoroanilino)-6-nitro-7-bromo-3-itrile group quinoline and 1-(1, the 1-dimethyl-2-propyl group) morpholine (4b) that utilize synthesis example 3 to obtain, by with synthesis example 2-2) 3) identical method obtains the amino body of compound.Obtain compound 1b by the method identical with embodiment 1 by compound 2b.
Wherein used 4b utilizes morpholine to replace morpholine to prepare by the method identical with synthesis example 3 in the reaction.
Figure G2009101520977D00391
1b (productive rate 87%): 1H NMR (DMSO-d 6) δ ppm:1.45 (s, 6H), 2.63 (m, 4H), 4.19 (m, 4H), 5.86 (d, J=10.5Hz, 1H), 6.36 (d, J=16.4Hz, 1H), 6.58 (dd, J=10.5,16.4Hz, 1H), 7.45 (t, J=8.9Hz, 1H), 7.85 (m, 2H), 8.20 (s, 1H), 8.69 (s, 1H), 8.73 (s, 1H), 9.93 (s, 1H), 10.10 (s, 1H).
Figure G2009101520977D00392
2b (productive rate 79%): 1H NMR (DMSO-d 6) δ ppm:1.45 (s, 6H), 2.67 (m, 4H), 3.63 (m, 4H), 5.49 (m, 2H), 6.93 (s, 1H), 7.15 (s, 1H), 7.18 (t, J=8.7Hz, 1H), 7.55 (s, 1H), 7.84 (s, 1H), 7.97 (s, 1H), 8.63 (s, 1H).
Figure G2009101520977D00393
4b (productive rate 73%): 1H NMR (DMSO-d 6) δ ppm:1.39 (s, 6H), 2.33 (s, 1H), 2.64 (t, J=4.7Hz, 4H), 3.72 (t, J=4.7Hz, 4H).
＜synthesis example 5:4-(3-chloro-4-fluoroanilino)-6-amino-7-bromo-3-itrile group quinoline (5) 〉
Adding reduced iron in ethanol (2.5L) (84.28,1.51mol) with 1.5mol/L hydrochloric acid (605mL), be heated to 90 ℃ while stirring.Added 4-(3-chloro-4-fluoroanilino)-6-nitro-7-bromo-3-itrile group quinoline 30g every 30 minutes in this mixed solution of clockwise, add altogether 4 times.Make reflux after 5 hours, interior temperature is transferred to 50 ℃, transferring to pH value with 2 Equivalent Hydrogen aqueous solution of sodium oxide (450mL) and 1 Equivalent Hydrogen aqueous solution of sodium oxide is 7～8, stirs for some time.Add ethyl acetate (1L) and C salt (300g), continue to stir for some time, remove by filter C salt.Residue THF-ethyl acetate (1: 1,1L) clean concentrating under reduced pressure filtrate.Add water (1L) in concentrated solution, the leaching resultant reduces pressure following 60 ℃ of one nights of drying, obtains title compound (108.76g)
Figure G2009101520977D00401
5： 1H NMR(DMSO-d 6)δppm：5.64(s，2H)，7.41(t，J＝9.3Hz，1H)，7.56(m，1H)，7.76(m，1H)，7.91(s，1H)，8.17(s，1H)，8.35(s，1H)，9.71(s，1H)。
＜synthesis example 6〉[4-(1,1-dimethyl-2-propyl group)-1-piperazinyl] acetonitrile (4c) synthetic
1-(1,1-dimethyl-2-propyl group) piperazine (350mg, 2.3mmol), (480mg, (0.176mL 2.53mmol) stirred 30 minutes under the room temperature salt of wormwood to add the bromo acetonitrile in methyl ethyl ketone 3.45mmol) (MEK) suspension liquid (10mL).Reaction solution dilutes with MEK, filters.Concentrated filtrate obtains the white solid (0.439g, quantitative) of title compound.
Figure G2009101520977D00402
4c： 1H NMR(300MHz，CDCl 3)δppm：1.43(s，6H)，2.35(s，1H)，2.69(m，8H)，3.54(s，2H).
＜embodiment 3 〉
1) at compound 5 (2.72mmol), [4-(1,1-dimethyl-2-propyl group)-1-piperazinyl] second eyeball (4c) (624mg, 3.26mmol) middle triethylamine (15mL) and the DMF (3.5mL) of adding.For the degassing of reducing pressure of this mixed solution, carry out nitrogen replacement 3 times, add triphenylphosphine (35mg, 0.16mmol) and palladium (II) (18mg 0.08mmol), stirred 4 hours at 80 ℃.After reaction solution is cooled to room temperature, the underpressure distillation desolventizing.In residue, add sodium bicarbonate aqueous solution, use ethyl acetate extraction.Organic layer is used anhydrous sodium sulfate drying, the underpressure distillation desolventizing after water, saturated aqueous common salt clean successively.Residue obtains purpose coupling compound 2c (1.07g) with silica gel column chromatography chromatography (ethyl acetate-methyl alcohol).
Figure G2009101520977D00411
2c： 1H NMR(270MHz，DMSO-d 6)δppm：1.41(s，6H)，2.34(s，1H)，2.65(m，8H)，3.54(s，2H)，5.51(s，2H)，6.93(s，1H)，7.15(s，1H)，7.23(t，J＝8.7Hz，1H)，7.57(s，1H)，7.94(s，1H)，8.12(s，1H)，8.73(s，1H)。
2) at room temperature with compound 2c (1.04mmol), vinylformic acid (0.36mL, 5.2mmol), triethylamine (0.22mL, 1.56mmol) and EDC (297mg, one night of DMF 1.56mmol) (7mL) solution stirring.Reaction solution is removed in underpressure distillation, reaction solution is poured in the sodium bicarbonate aqueous solution (70mL) into filtering mixt.Residue cleans with water-ethanol.Thick refining thing with the solid substance water-ethyl alcohol recrystallization that obtains, obtains purpose compound 1c (38mg, 61%) by the silica gel column chromatography chromatography.
Figure G2009101520977D00412
1c： 1H NMR(DMSO-d 6)δppm：1.41(s，6H)，2.34(s，1H)，2.65(m，8H)，3.54(s，2H)，5.86(d，J＝10.1Hz，1H)，6.32(d，J＝16.9Hz，1H)，6.56(dd，J＝16.9，10.1Hz，1H)，7.47(t，J＝8.6Hz，1H)，7.89(m，2H)，8.20(s，1H)，8.42(s，1H)，8.69(s，1H)，9.81(s，1H)，10.04(s，1H)。
＜embodiment 4～25 〉
With reference to following reaction process 5, will with 4-(3-chloro-4-fluoroanilino)-6-amino-7-bromo-3-itrile group quinoline (5) and corresponding alkyne series compound 4 as initial substance, method by identical with embodiment 3 is prepared as follows the amino body 2 shown in the table 10, compound 1.The spectroscopic data of each compound is asked for an interview table 10
Figure G2009101520977D00413
Reaction process 5
Table 10
Figure G2009101520977D00431
Figure G2009101520977D00441
Figure G2009101520977D00451
＜synthesis example 7～12〉alkyne series 4 synthetic
The alkyne series compound 4 that uses as initial substance in described embodiment 3～25 is removed outside the situation shown in the following synthesis example, and is synthetic according to the method for synthesis example 1.In addition, according to circumstances use is transformed to corresponding hydrochloride (4N hydrochloric acid-ethyl acetate).Yield and 1HNMR spectroscopic data note is in table.
＜synthesis example 7 〉
4g: ice-cold stir down the halid 0.5M THF of ethynyl magnesium solution (360mL 180mmol), drips 1,3-diethoxy acetone (21.93g, 150mmol).After 30 minutes, (18.4mg 195mmol), stirred 1 hour under the room temperature acetic anhydride that drips in ice-cold stirring down.After reaction finishes, add ammonia chloride water solution, use ethyl acetate extraction.Organic layer cleans with saturated sodium bicarbonate aqueous solution, saturated aqueous common salt, uses anhydrous magnesium sulfate drying, obtains the two ethoxyl methyls of 1,1--2-propyl diester (31.36g, 97%) by concentrating.
Make acetic acid 1, and two (the ethoxyl methyl)-2-propyl diesters of 1-(15.00g, 70mmol) and 1-methylpiperazine (8.41g, 84mmol), cupric chloride (I) (350mg), (9.7mL 70mmol) is dissolved in THF (150mL) solution reflux 2 hours to triethylamine.Reaction adds in reaction solution after finishing tBuOMe uses the 3N hcl as extraction agent.With the 6N aqueous sodium hydroxide solution with in the extraction liquid and after, use ethyl acetate extraction, organic layer use anhydrous magnesium sulfate drying after cleaning with 7% ammonia chloride water solution and water, by the concentrated title compound 4g (15.30g, 86%) that obtains.
＜synthesis example 8 〉
4o: with 1-(1,1-dimethyl-2-propyl group) piperazine-4-alcohol 4k[uses 4-hydroxyl piperazine as initial substance, method according to synthesis example 1 is synthetic, yield is 54%] (6.Og, 36.0mmol) be dissolved among the THF (100mL), add NaH (1.73g) and methyl iodide (7.7g), stirred one day under the room temperature.Concentration of reaction solution adds water, and uses dichloromethane extraction, the organic layer dried over mgso.After concentrating organic layer, residue is dissolved in the ethyl acetate, drips 4N hydrochloric acid-ethyl acetate (9mL) down ice-cold, the throw out that leaching generates, drying obtains 4oHCl (4.0g, 51%).
＜synthesis example 9 〉
4m: at the ice-cold 4-(1 that stirs down, 1-dimethyl-2-propyl group) piperazine [uses superfluous piperazine (2.5 equivalent) as initial substance, method according to synthesis example 1 is synthetic, yield is 42%] (6.0g, 40.0mmol), the dichloromethane solution (60mL) of pyridine (3.50mL), add methylsulfonyl chloride (5.6g).After slowly being warming up to room temperature, adding water and use dichloromethane extraction.Extraction liquid cleans with copper sulfate solution, water and saturated aqueous common salt successively, uses dried over mgso.Concentrated organic layer obtains the faint yellow solid (7.80g, 85%) of compound 4m.
＜synthesis example 10 〉
4r: with 1-(1,1-dimethyl-2-propyl group) piperazine (5.0g, 33mmol), 2-chloroethyl methyl ether (4.7g, 50mmol), sodium iodide (35.0g, 233mmol), salt of wormwood (9.2g, 66mmol) outstanding turbid in methyl ethyl ketone (150mL), with reaction solution reflux 3 days.The underpressure distillation desolventizing adds ethyl acetate in residue, use the 3N hcl as extraction agent.Extraction liquid with in the 6N aqueous sodium hydroxide solution and after, use dichloromethane extraction, after the cleaning of organic layer water, use anhydrous magnesium sulfate drying.After the underpressure distillation desolventizing, residue is dissolved in the ethyl acetate, adds 4N hydrochloric acid-ethyl acetate (17.0mL).The crystallization that filtration is separated out, drying under reduced pressure obtain the faint yellow crystallization (7.44g, 79%) of compound 4r.
＜synthesis example 11 〉
4s: with 1-(1,1-dimethyl-2-propyl group) piperazine (5.0g, 33mmol), (2.6g 49mmol) is dissolved in the methyl alcohol (50mL) vinyl cyanide, stirs under the room temperature 3 hours, and 55 ℃ were stirred 4 hours down.Concentration of reaction solution, drying under reduced pressure obtain the yellow-white crystallization (6.51g, 96%) of compound 4s.
＜synthesis example 12 〉
4v: make toluene-4-sulfonic acid 3-butynyl ester (4.0g, 17.8mmol), morpholine (2.94mL, 26.7mmol), (2.96g, 21.4mmol) acetonitrile suspension liquid (40mL) refluxed 2.5 hours salt of wormwood.Put cold after, filtering mixt, residue is used tBuOMe (20mL) cleans.Concentrated filtrate adds tBuOMe (40mL), resultant extracts with 3N hydrochloric acid (30mL * 1,10mL * 1).In extraction liquid, add the 6N aqueous sodium hydroxide solution until showing alkalescence, with methylene dichloride (40mL * 1,20mL * 1) extraction.Organic layer is dry to be concentrated, and obtains the oily mater (2.44g, 98%) of compound 4v.With this oily matter 4v (3.94g 28.2mmol) is dissolved in the ether (20mL), the 4N hydrochloric acid-ethyl acetate of on ice bath, dripping while stirring (7.8mL, 31.2mmol).After at room temperature stirring 30 minutes, after leaching precipitate, residue clean with ether, obtain the white solid (3.78g, 76%) of compound 4vHCl by drying under reduced pressure.
＜embodiment 26 〉
1) (5.5mL in ethanolic soln 40mmol) (30mL), adds diethylamine hydrochloride (3.26g under room temperature at triethylamine, 40mmol), titanium tetraisopropylate (11.8mL, 40mmol) and 1-(1,1-dimethyl-2-propyl group) piperazine-4-ketone (41) (3.3g, 20mmol).Stir after 7 hours, add NaBH 4(1.13g 30mmol), at room temperature stirs a night.Reaction solution is poured in 5% ammoniacal liquor (80mL), added methylene dichloride (100mL).C salt filtering mixt, the leaching thing cleans with methylene dichloride (30mL * 3).With dry behind the organic layer separatory, filter by silicagel column.Concentrated filtrate makes gained solid (about 100 ℃ of oil bath temperature/0.1mmHg), the obtain colourless crystallization of [1-(1,1-dimethyl-2-propyl group)-4-piperazinyl] dimethyl amine (4aa) that under reduced pressure distils.
2) for 4-(3-chloro-4-fluoroanilino)-6-amino-7-bromo-3-itrile group quinoline (1.52mmol), compound 4aa (383mg, 1.97mmol), DMF (2.4ml) solution of triethylamine (12mL), under reduced pressure after the degassing, carry out nitrogen replacement operation 3 times, add triphenylphosphine (24mg, 0.09mmol), palladium (II) (10mg, 0.05mmol) stirred 3 hours down at 80 ℃.After reaction solution is cooled to room temperature, the underpressure distillation desolventizing.In residue, add sodium bicarbonate aqueous solution, use ethyl acetate extraction.Organic layer water (* 3), saturated aqueous common salt successively cleans, and behind anhydrous sodium sulfate drying, the underpressure distillation desolventizing obtains amino body 2aa.
3) at room temperature with amino body 2aa (690mg, 1.43mmol), vinylformic acid (0.49mL, 7.2mmol), triethylamine (0.30mL, 2.15mmol) and EDC (410mg, one night of DMF 2.15mmol) (8mL) solution stirring.Reaction solution is removed in underpressure distillation, adds saturated sodium bicarbonate aqueous solution in residue, uses ethyl acetate extraction.Organic layer water (* 3), saturated aqueous common salt successively cleans, behind anhydrous sodium sulfate drying, and the underpressure distillation desolventizing.Thick refining thing is refining by silica gel column chromatography chromatography (chloroform-methanol-triethylamine), and the thick refining thing water-ethyl alcohol recrystallization with gained obtains purpose compound 1aa (127mg).
Figure G2009101520977D00491
1aa： 1H NMR(270MHz，DMSO-d 6)δppm：1.49(s，6H)，2.17(s，6H)，2.65(m，8H)，5.84(d，J＝10.1Hz，1H)，6.33(d，J＝16.7Hz，1H)，6.56(dd，J＝16.7，10.1Hz，1H)，7.45(t，J＝8.9Hz，1H)，7.83(m，2H)，8.19(s，1H)，8.69(s，1H)，8.76(s，1H)，9.87(s，1H)，10.06(s，1H)。
＜embodiment 27 〉
1) 4-(3-chloro-4-fluoroanilino)-6-nitro-7-bromo-3-itrile group quinoline (7.55mmol) and the alkyne series 4ab (1.76g synthetic according to the method for synthesis example 1,9.06mmol) and the DMF solution (9mL) of triethylamine (60mL), under reduced pressure after the degassing, carry out nitrogen replacement operation 3 times, add triphenylphosphine (118mg, 0.46mmol), (51mg 0.23mmol), stirred 3 hours down at 80 ℃ palladium (II).After reaction solution is cooled to room temperature, the underpressure distillation desolventizing.In residue, add sodium bicarbonate aqueous solution, use ethyl acetate extraction.Organic layer water (* 3), saturated aqueous common salt successively cleans, and behind anhydrous magnesium sulfate drying, the underpressure distillation desolventizing obtains nitro-body 3ab.
3ab： 1H NMR(270MHz，DMSO-d 6)δppm：1.45(s，6H)，1.64(m，4H)，2.16(s，3H)，2.33(s，3H)，2.56(m，4H)，2.87(m，1H)，7.45(t，J＝9.1Hz，1H)，7.76(m，1H)，8.13(m，1H)，8.28(s，1H)，8.76(s，1H)，9.39(s，1H)，10.32(s，1H)。
Figure G2009101520977D00501
4ab[is synthetic according to the method for synthesis example 1, yield 69%]: 1H NMR (300MHz, DMSO-d 6) δ ppm:1.31 (s, 6H), 1.58 (m, 4H), 2.11 (s, 3H), 2.21 (s, 3H), 2.56 (m, 4H), 2.87 (m, 1H), 3.11 (s, 1H).
2) make nitro-body 3ab, 1N hydrochloric acid (22.5mL, 22.5mmol) and iron powder (2.09g, ethanol 37.5mmol) (70mL) mixing solutions refluxed 1.5 hours.After with 50 ℃ of reaction solution modulation, add the 1N aqueous sodium hydroxide solution (22.5mL 22.5mmol), stirred 30 minutes down at 50 ℃, reaction solution is transferred to room temperature after, filter with C salt.Residue cleans with ethyl acetate, after filtrate is concentrated, adds sodium bicarbonate aqueous solution in residue, uses ethyl acetate extraction.Organic layer water (* 3), saturated aqueous common salt successively cleans, and behind anhydrous sodium sulfate drying, the underpressure distillation desolventizing makes residue outstanding turbid in acetonitrile, stirs under reflux.After transferring to room temperature, leaching obtains the amino body 2ab (2.78g) of purpose.
Figure G2009101520977D00502
2ab： 1H NMR(270MHz，DMSO-d 6)δppm：1.43(s，6H)，1.68(m，4H)，2.16(s，3H)，2.31(s，3H)，2.56(m，4H)，2.85(m，1H)，5.53(s，2H)，7.42(t，J＝9.2Hz，1H)，7.50(s，1H)，7.57(s，1H)，7.80(s，1H)，8.21(s，1H)，8.39(s，1H)，9.63(s，1H)。
3) by with embodiment 26-3) identical method is converted to purpose compound 1ab with amino body 2ab.
Figure G2009101520977D00503
1ab： 1H NMR(270MHz，DMSO-d 6)δppm：1.45(s，6H)，1.64(m，4H)，2.18(s，3H)，2.35(s，3H)，2.56(m，4H)，2.87(m，1H)，5.85(d，J＝10.3Hz，1H)，6.33(d，J＝17.0Hz，1H)，6.56(dd，J＝17.0，10.3Hz，1H)，7.46(t，J＝9.2Hz，1H)，7.78(s，1H)，7.81(m，1H)，8.18(s，1H)，8.62(s，1H)，8.86(s，1H)，9.98(s，1H)，10.21(s，1H)。
＜embodiment 28 〉
Use by the method identical with synthesis example 12 by 1-methylpiperazine and synthetic 4ac (yield 80%) and 4-(3-chloro-4-the fluoroanilino)-6-nitro-7-bromo-3-itrile group quinoline of toluene-4-sulfonic acid 3-butynyl ester as initial substance, be converted to 3ac, 2ac and 1ac by the method identical with above-described embodiment 27.
Figure G2009101520977D00511
4ac： 1H NMR(300MHz，CDCl 3)δppm：1.95(t，J＝2.9Hz，1H)，2.28(s，3H)，2.38(dt，J＝2.9，7.7Hz，2H)，2.46(m，4H)，2.53(m，4H)，2.61(t，J＝7.7Hz，2H)。
3ac： 1H NMR(270MHz，DMSO-d 6)δppm：2.13(s，3H)，2.33(m，4H)，2.47(m，4H)，2.57-2.75(m，4H)，7.48(t，J＝9.2Hz，1H)，7.73(m，1H)，7.90(s，1H)，8.14(s，1H)，8.72(s，1H)，9.38(s，1H)，10.32(s，1H)。
Figure G2009101520977D00513
2ac： 1H NMR(270MHz，DMSO-d 6)δppm：2.17(s，3H)，2.35(m，4H)，2.47(m，4H)，2.57-2.78(m，4H)，5.86(s，2H)，6.93(s，1H)，7.15(s，1H)，7.23(t，J＝8.7Hz，1H)，7.57(s，1H)，7.94(s，1H)，8.12(s，1H)，8.73(s，1H)。
Figure G2009101520977D00514
1ac： 1H NMR(270MHz，DMSO-d 6)δppm：2.18(s，3H)，2.33(m，4H)，2.47(m，4H)，2.57-2.75(m，4H)，5.86(d，J＝10.0Hz，1H)，6.35(d，J＝17.0Hz，1H)，6.65(dd，J＝17.0，10.0Hz，1H)，7.45(t，J＝8.9Hz，1H)，7.85(m，2H)，8.19(s，1H)，8.59(s，1H)，8.76(s，1H)，9.87(s，1H)，10.08(s，1H)。
＜embodiment 29 〉
Under nitrogen atmosphere, in room temperature with compound 2a (2.40g, 5.3mmol), the THF (15mL) of 10% palladium carbon (170mg)-ethanol (15mL) mixed solution stirred 12 hours.Reaction solution is carried out C salt filter, concentrated filtrate, residue obtains amino body [m/z=455 (M+1)] (1.69g, 70%) by silica gel column chromatography chromatography (chloroform-methanol).At room temperature should the amino body (330mg, 0.73mmol), EDC (278mg, 1.45mmol), the DMF solution (2mL) of vinylformic acid (99 μ L), triethylamine (200 μ L) stirs a night.In reaction solution, add sodium bicarbonate aqueous solution (40mL), with ethyl acetate (40mL * 1,20mL * 1) extraction.Dry also concentrated extract, the thick refining thing that obtains are washed with acetonitrile is outstanding by silica gel column chromatography chromatography (chloroform-methanol-triethylamine), obtain purpose compound 1ad (200mg, 54%).
1ad： 1H NMR(300MHz，DMSO-d 6)δppm：1.03(s，6H)，1.99(s，3H)，2.00-2.25(m，4H)，2.25-2.60(m，4H)，5.73(d，J＝12.9Hz，1H)，5.81(d，J＝10.4Hz，1H)，6.30(d，J＝16.9Hz，1H)，6.48(d，J＝12.9Hz，1H)，6.59(dd，J＝10.4，16.9Hz，1H)，7.47(t，1H)，7.85(m，2H)，8.19(s，1H)，8.42(s，1H)，8.76(s，1H)，9.87(s，1H)，10.01(s，1H)。
＜embodiment 30 〉
Under 80 ℃ with compound 4ac (333mg, 2.18mmol), (764mg, 2.62mmol) and 2, (4mg, mixture 0.02mmol) stirred 2 hours 2 '-Diisopropyl azodicarboxylate tri-n-butyltin hydride.In this solution, add compound 5 (670mg, 1.80mmol), palladium (II) (10mg), triphenylphosphine (24mg), DMF (1.3mL) and triethylamine (7mL), stirred 4 hours at 80 ℃.In this reaction mixture, add Pd 2(dba) 3(dba=dibenzylidenacetone) (15mg), under refluxing, further stirred 4 hours.Put cold back and add potassium fluoride aqueous solution (50mL), stir for some time under the room temperature.Resultant also concentrates organic layer with ethyl acetate extraction (50mL * 1,20mL * 2), drying.Residue obtains containing the oily mater (1.02g) of object by silica gel column chromatography chromatography (chloroform-methanol-triethylamine).Utilize this oily mater (500mg) and EDC (345mg, 1.8mmol), vinylformic acid (0.123mL, 1.8mmol), (0.25mL 1.8mmol) and DMF (4.0mL), reacts by the method identical with embodiment 1 triethylamine.Thick refining thing adds a spot of acetonitrile by silica gel column chromatography chromatography (chloroform-methanol-triethylamine) in the oily mater (180mg) of gained, make crystallization.And then add acetonitrile (4mL), and stir under refluxing, be cooled to room temperature, the leaching precipitate obtains purpose compound 1ae (95mg, theoretical yield 21%).
Figure G2009101520977D00531
1ae： 1H NMR(300MHz，DMSO-d 6)δppm：1.99(s，3H)，2.10-2.50(m，12H)，5.82(dd，J＝1.5，10.2Hz，1H)，6.26(dd，J＝1.5，17.1Hz，1H)，6.52(dt，J＝6.0，15.8Hz，1H)，6.58(dd，J＝10.2，17.1Hz，1H)，6.77(d，J＝15.8Hz，1H)，7.42(t，J＝9.1Hz，1H)，7.80(m，1H)，7.90(s，1H)，8.15(dd，J＝2.4，6.7Hz，1H)，8.51(s，1H)，8.56(s，1H)，9.87(s，1H)，10.03(s，1H)。
＜embodiment 31〉1a2 tosilate (1a2TsOH)
Ethanol-ethyl acetate solution (1: 7, adding compound 1a (10.00g) 140mL) stirs, filter, [using ethanol-ethyl acetate (1: 7,10mL) clean] in the solution of gained, with tosic acid (TsOH) 1 hydrate (7.37g) be dissolved in ethanol-ethyl acetate solution (1: 7,20mL) in, adding filtration at room temperature [ethanol-ethyl acetate (1: 7,10mL) clean] gained solution.Stir under the room temperature after 3 hours, the solid that leaching generates, the following 70 ℃ of dryings that reduce pressure 5 hours obtain the faint yellow crystallization (15.96g) of title compound.
1a·2TsOH： 1H NMR(DMSO-d 6)δppm：1.52(s，6H)，2.26(s，6H)，2.48(m，2H)，2.76(s，3H)，3.04(m，2H)，3.25(m，2H)，3.47(m，2H)，5.91(d，J＝10.2Hz，1H)，6.38(d，J＝16.9Hz，1H)，6.62(dd，J＝10.2Hz，16.9Hz，1H)，7.10(d，J＝7.9Hz，2H)，7.49(d，J＝7.9Hz，2H)，7.57(t，J＝9.0Hz，1H)，7.72(m，1H)，7.93(s，1H)，8.05(dd，J＝2.5Hz，6.8Hz，1H)，8.88(s，1H)，8.94(s，1H)，9.39(s，1H)，10.13(s，1H)，11.30(s，1H)。
＜embodiment 32〉1a3 hydrochloride (1a3HCl)
In THF (40mL), add compound 1a (1.549g) and stir, and the solution of its filtration [cleaning with THF (6.5mL)] gained is ice-cold, and 4 equivalent hydrochloric acid-ethyl acetate solutions (2.37mL) drip.The ice-cold stirring down after 5 hours filtered, and drying under reduced pressure obtains the yellow solid (1.89g) of title compound.
1a·3HCl： 1H NMR(DMSO-d 6)δppm：1.68(s，6H)，2.83(s，3H)，3.25-3.90(m，8H)，5.96(dd，J＝1.9，10.3Hz，1H)，6.39(dd，J＝1.9，17.0Hz，1H)，6.86(dd，J＝10.3，17.0Hz，1H)，7.58(t，J＝9.2Hz，1H)，7.74(m，1H)，8.04(dd，J＝2.7，6.8Hz，1H)，8.22(s，1H)，8.97(s，1H)，9.05(s，1H)，9.91(s，1H)，10.47(s，1H)。
＜embodiment 33〉1a2 hydrochloride (1a2HCl)
Add 1a (1.27g) dissolving in THF (38mL), 4 equivalent hydrochloric acid-ethyl acetate solutions (1.28mL) while stirring drip.After stirring a night under the room temperature, filter, obtain the white solid (1.17g) of title compound by drying.Make this coarse crystallization (0.16g) be suspended in Virahol (IPA)-THF (1: 1,10mL) in, in 70 ℃ of stirrings of oil bath temperature.Put cold after, the leaching resultant, decompression is down dry, obtains the crystalline powder (78mg) of title compound.
1a 2HCl： 1H NMR(DMSO-d 6)δppm：1.55(s，6H)，2.80(s，3H)，2.90-3.80(m，8H)，5.90(dd，1H)，6.39(dd，1H)，6.70(dd，1H)，7.55(t，1H)，7.75(m，1H)，8.05(dd，1H)，8.08(s，1H)，8.91(s，2H)，9.91(s，1H)，10.30(s，1H).
＜embodiment 34〉1a hydrochloride (1aHCl)
In THF (3mL), add compound 1a (150mg), gained solution is carried out ice-cold, the 4 equivalent hydrochloric acid-ethyl acetate solutions that drip while stirring (81 μ L).After stirring a night under the room temperature, leaching, drying under reduced pressure obtains the white solid (140mg) of title compound.
1a·HCl： 1H NMR(DMSO-d 6)δppm：1.47(s，6H)，2.78(s，3H)，2.61(m，2H)，3.02(m，2H)，3.10-3.75(m，4H)，5.86(dd，1H)，6.39(dd，1H)，6.71(dd，1H)，7.58(t，1H)，6.84(m，1H)，7.92(s，1H)，8.21(s，1H)，8.65(s，1H)，8.70(s，1H)，9.93(s，1H)，10.10(s，1H)。
＜embodiment 35〉1a2 mesylate (1a2MsOH)
In THF (30mL), add compound 1a (1.50g), dissolving, 3 equivalent hydrochloric acid-methylsulfonic acids (MsOH)-THF solution (1.99mL) drips.After stirring a night under the room temperature, add THF (15mL) leaching, decompression is dry down, obtains the white solid (1.98g) of title compound.
1a·2MsOH： 1H NMR(DMSO-d 6)δppm：1.48(s，6H)，2.34(s，6H)，2.81(s，3H)，2.40-2.70(m，2H)，2.90-3.80(m，6H)，5.91(dd，1H)，6.39(dd，1H)，6.57(m，1H)，7.53(t，1H)，7.75(m，1H)，7.95(s，1H)，8.10(s，1H)，8.84(s，1H)，8.87(s，1H)，9.92(s，1H)，10.04(s，1H)。
＜embodiment 36〉1a tosilate (1aTsOH)
In ethyl acetate (70mL), add compound 1a (1.00g), dissolving, 0.25 equivalent tosic acid-ethyl acetate solution (8.27mL) while stirring at room temperature drips.Stir under the room temperature after 2 hours, leaching, decompression is dry down, obtains the white solid (1.23g) of title compound.
1a·TsOH： 1H NMR(DMSO-d 6)δppm：1.49(s，6H)，2.28(s，3H)，2.50(m，2H)，2.80(s，3H)，3.06(m，2H)，3.20-3.70(m，4H)，5.90(d，1H)，6.38(d，1H)，6.60(dd，1H)，7.10(d，J＝7.9Hz，2H)，7.40-7.60(m，3H)，7.81(m，1H)，7.92(s，1H)，8.10(m，1H)，8.70(s，1H)，8.79(s，1H)，9.35(s，1H)，9.98(s，1H)，10.20(s，1H)。
＜embodiment 37〉1a stilbene-4,4'-bis-(1-azo-3, 4-dihydroxy-benzene)-2,2'-disulfonate (1a (CH 2SO 3H) 2)
In acetone (4mL), add compound 1a (100mg), dissolving, 0.5 equivalent that at room temperature drips while stirring is to ethionic acid-acetone soln (0.4mL).After stirring a night under the room temperature, leaching, decompression is dry down, obtains the white solid (89mg) of title compound.
1a· H 2SO 3H) 2： 1H NMR(DMSO-d 6)δppm：1.45(s，6H)，2.60(m，2H)，2.70-2.90(m，7H)，2.90-3.80(m，6H)，5.90(d，1H)，6.38(d，1H)，6.60(dd，1H)，7.51(t，1H)，7.80(m，1H)，7.98(s，1H)，8.12(s，1H)，8.76(s，2H)，9.40(s，1H)，10.03(s，1H)，10.50(s，1H)。
＜embodiment 38〉1a2 ethanedisulphonate (1a2 (CH 2SO 3H) 2)
In acetone (2mL), add compound 1a (100mg), dissolving, 0.5 equivalent that at room temperature drips while stirring is to ethionic acid-acetone soln (0.8mL).After stirring a night under the room temperature, leaching, decompression is dry down, obtains the white solid (122mg) of title compound.
1a·2(
Figure G2009101520977D00552
H 2SO 3H) 2： 1H NMR(DMSO-d 6)δppm：1.60(d，J＝2.6，6H)，2.70-3.00(m，13H)，3.20(m.2H)，3.60(m，4H)，5.40(d，1H)，6.60(dd，1H)，7.60(t，1H)，7.70(m，1H)，8.00(s，1H)，8.10(s，1H)，8.92(s，1H)，9.00(s，1H)，9.80(s，1H)，10.20(s，1H)。
＜embodiment 39〉1a2 benzene sulfonate (1a2PhSO 3H)
In acetone (3mL), add compound 1a (100mg), dissolving, 0.5 equivalent P-TOLUENE SULFO ACID 99-acetone soln (0.8mL) while stirring at room temperature drips.After stirring a night under the room temperature, leaching, decompression is dry down, obtains the white solid (60mg) of title compound.
1a·2PhSO 3H： 1H NMR(DMSO-d 6)δppm：1.49(s，6H)，2.60(m，2H)，2.81(s，3H)，3.10(M，2H)，3.30(d，2H)3.50(d，2H)，5.90(d，1H)，6.39(d，1H)，6.60(dd，1H)7.32(m，6H)，7.60(m，5H)，7.75(m，1H)，7.92(s，1H)，8.07(m，1H)，8.88(s，1H)，8.96(s，1H)，9.23(s，1H)，9.91(s，1H)，10.10(s，1H)。
＜synthesis example 13〉trifluoromethanesulfonic acid 4-(3-acetylbenzene amido)-7-methoxyl group-3-itrile group-6-quinolyl ester (6a) synthetic
1) acetic acid 4-chloro-7-methoxyl group-3-itrile group-6-quinolyl ester is (with 3-methoxyl group-4-acetoxyl group oil of mirbane (Kanta De, Tetrahedron Letters (2004) such as Surya, 45 (14), 2919-2922) be raw material, by synthetic embodiment 2-2) 3) identical method obtains the amino body of compound.Method by synthetic embodiment 3 is synthetic) (14.8mmol) and 3-aminoacetophenone (2.0g, aqueous isopropanol 14.8mmol) (200mL) reflux 5 hours.Put cold after, the leaching throw out obtains acetic acid 4-(3-acetylbenzene amido)-7-methoxyl group-3-itrile group-6-quinolyl ester.In the methanol solution (100mL) of this compound (7.74mmol), add 28% ammoniacal liquor (2mL), stir under the room temperature after 4 hours, reflux.The throw out that leaching generates, decompression is dry down, obtains 4-(3-acetylbenzene amido)-6-hydroxyl 7-methoxyl group-3-itrile group quinoline (2.07g).
2) ice bath stir 4-(3-acetylbenzene amido)-6-hydroxyl 7-methoxyl group-3-itrile group quinoline (2.8mmol), pyridine (.34mL, acetonitrile solution 4.2mmol) (20mL), the trifluoromethanesulfanhydride anhydride that drips (0.57mL, 0.34mmol).Slowly this reaction solution is warming up to room temperature, at room temperature stir 2 hours after, concentrate, in residue, add sodium bicarbonate aqueous solution, stirred 30 minutes under the room temperature.Leaching resultant, drying under reduced pressure obtain title compound 6a (1.20g).
1H NMR(300MHz，CDCl 3)δppm：2.65(s，3H)，4.01(s，3H)，7.40(s，1H)，7.53(t，J＝7.9Hz，1H)，7.76(d，J＝7.8Hz，1H)，7.83(m，1H)，7.91(s，1H)，8.16(s，1H)，8.24(s，1H)，8.75(s，1H)。
＜synthesis example 14〉trifluoromethanesulfonic acid 4-(3-chloro-4-fluoroanilino)-7-methoxyl group-3-itrile group-6-quinolyl ester (6b) synthetic
Utilize 4-(3-chloro-4-fluoroanilino)-6-hydroxyl-7-methoxyl group-3-itrile group-quinolyl, by with synthesis example 13-2) identical method obtains purpose compound 6-triflate body 6b.
Figure G2009101520977D00562
6b： 1H NMR(300MHz，DMSO-d 6)δppm：4.07(s，3H)，7.43(t，J＝9.1Hz，1H)，7.51(s，1H)，7.76(m，1H)，8.09(s，1H)，8.64(s，1H)，8.78(s，1H)，9.94(s，1H)。
＜synthesis example 15〉trifluoromethanesulfonic acid 4-(3-anisole amido)-7-methoxyl group-3-itrile group-6-quinolyl ester (6c) synthetic
Utilize 4-(3-anisole amido)-6-hydroxyl-7-methoxyl group-3-itrile group quinoline and synthesis example 13-2) identical method obtains purpose compound 6-triflate body 6c.
Figure G2009101520977D00571
6c： 1H NMR(300MHz，DMSO-d 6)δppm：3.75(s，3H)，4.06(s，3H)，6.75(m，1H)，7.34(m，2H)，7.44(m，1H)，7.51(s，1H)，8.61(s，1H)，8.74(s，1H)，9.82(s，1H)。
＜synthesis example 16〉trifluoromethanesulfonic acid 4-(3-acetylbenzene amido)-6-methoxyl group-3-itrile group-7-quinolyl ester (6d) synthetic
1) utilize 4-chloro-6-methoxyl group-7-benzyloxy-3-itrile group quinoline and 3-chloro-4-fluoroaniline, the method by synthesis example 13 is converted to 4-(3-chloro-4-fluoroanilino)-6-methoxyl group-7-benzyloxy-3-itrile group quinoline.In this compound (412mL), add trifluoroacetic acid (7mL), made reflux 90 minutes, the reaction solution of putting after cold is injected frozen water.The leaching precipitate makes filter go up thing and is dissolved in the methyl alcohol, adds rare ammoniacal liquor until showing alkalescence.The leaching throw out, after water, ether cleaned, drying under reduced pressure obtained 4-(3-chloro-4-fluoroanilino)-6-methoxyl group-7-hydroxyl-3-itrile group quinoline.To this compound by with synthesis example 13-2) same method, react.After reaction finishes, this reaction solution is injected 1N hydrochloric acid, use ethyl acetate extraction, organic layer use anhydrous magnesium sulfate drying after water, sodium bicarbonate aqueous solution, saturated aqueous common salt clean successively, distills under the decompression and removes solvent.Residue is refining with silica gel chromatography column chromatography (hexane-ethyl acetate), obtains the 7-triflate body 6d (66%) of purpose compound.
Figure G2009101520977D00572
6d： 1H NMR(300MHz，DMSO-d 6)δppm：4.09(s，3H)，7.49(t，J＝9.1Hz，1H)，7.78(m，1H)，7.91(s，1H)，8.10(s，1H)，8.20(s，1H)，8.61(s，1H)，9.92(s，1H)。
＜embodiment 56 〉
At 6-triflate body 6b (12.46mmol) and compound 4a (2.49g, 14.95mmol) DMF solution (20mL) in bubbled 10 minutes with nitrogen after, add triethylamine (4.30mL, 31.15mmol), tetrakis triphenylphosphine palladium (283mg) and copper(I) iodide (I) (95mg), 50 ℃ were stirred 1 hour.Decompression concentrates down, after residue is refining by silicagel column (chloroform-methanol), carries out recrystallization with acetonitrile-water, obtains the white crystals of purpose zygosome 1ba (2.71g).
Figure G2009101520977D00581
1ba： 1H NMR(300MHz，CDCl 3)δppm：1.52(s，6H)，2.32(s，3H)，2.57(m，4H)，2.85(m，4H)，3.98(s，3H)，7.16(t，J＝8.7Hz，1H)，7.18(s，1H)，7.61(m，1H)，7.97(s，1H)，8.06(s，1H)，8.18(s，1H)，9.32(s，1H)。
＜embodiment 57 〉
Utilize 6-triflate body 6b and compound 4c, obtain white～little peachiness crystalline powder of compound 1bb (yield 66%) by the method identical with embodiment 56.
Figure G2009101520977D00582
1bb： 1H NMR(300MHz，CDCl 3)δppm：1.52(s，6H)，2.60-2.80(m，8H)，3.54(s，2H)，3.98(s，3H)，7.16(t，J＝8.7Hz，1H)，7.18(s，1H)，7.61(m，1H)，7.97(s，1H)，8.06(s，1H)，8.18(s，1H)，9.32(s，1H)。
＜embodiment 58 〉
Utilize 6-triflate body 6b and compound 4-(1,1-dimethyl-2-propyl group) piperazine (with reference to synthesis example 9), react by the method identical with embodiment 56.Behind the reaction solution concentrating under reduced pressure, in chloroform-sodium bicarbonate aqueous solution, distribute the concentrating under reduced pressure organic layer.Make the outstanding turbid also stirring in acetonitrile of thick refining thing, with the solid silica gel column chromatography refinement that leaching obtains, obtain the 1bc (yield 73%) of purpose compound.
Figure G2009101520977D00583
1bc： 1H NMR(300MHz，DMSO-d 6)δppm：1.45(s，6H)，2.31(s，1H)，2.83(m，4H)，3.11(m，4H)，3.97(s，3H)，7.22(s，1H)，7.42(t，J＝9.1Hz，1H)，7.81(m，1)，8.16(s，1H)，8.46(s，1H)，8.58(s，1H)，9.83(s，1H)。
4-(1,1-dimethyl-2-propyl group) piperazine (use the piperazine of excess quantity (2.5 equivalent) as initial substance, synthetic by the method identical with synthesis example 1, yield is 42%): 1H NMR (300MHz, DMSO-d 6) δ ppm:1.39 (s, 6H), 2.1 (s, 1H), 2.30 (s, 1H), 2.61 (m, 4H), 2.93 (m, 4H).
＜embodiment 59 〉
With compound 1bc (0.44mmol), N-PROPYLE BROMIDE (40 μ L, 0.44mmol), salt of wormwood (183mg, DMF solution (5mL) heated and stirred to 60 1.32mmol)～70 ℃.Add N-PROPYLE BROMIDE (16 μ L * 2) one by one, heated and stirred was added ethyl acetate and ammonia chloride water solution after 3 hours.Dry organic layer, the underpressure distillation desolventizing, residue is refining with silica gel column chromatography (chloroform-methanol).Concentrate the stream part contain resultant, make be suspended in stir in the acetonitrile-water after, obtain purpose compound 1bd (173mg) by leaching.
Figure G2009101520977D00591
1bd： 1H NMR(300MHz，DMSO-d 6)δppm：0.93(t，J＝7.4Hz，3H)，1.30-1.50(m，2H)，1.42(s，6H)，2.21(t，J＝7.4Hz，2H)，2.41(m，4H)，2.69(m，4H)，4.01(s，3H)，7.22(s，1H)，7.44(t，J＝9.3Hz，1H)，7.83(m，1H)，8.18(s，1H)，8.57(s，1H)，8.68(s，1H)，9.89(s，1H)。
＜embodiment 60 〉
Utilize compound 1bc, iodate Trimethylmethane, be converted to purpose compound 1be (yield 48%) by the method identical with embodiment 59.
Figure G2009101520977D00592
1be： 1H NMR(300MHz，DMSO-d 6)δppm：0.85(d，J＝6.3Hz，6H)，1.43(s，6H)，1.76(m，1H)，2.04(m，2H)，2.39(m，4H)，2.70(m，4H)，4.02(s，3H)，7.22(s，1H)，7.44(t，J＝9.0Hz，1H)，7.84(m，1H)，8.19(m，1H)，8.57(s，1H)，8.69(s，1H)，9.86(s，1H)。
＜embodiment 61 〉
Dichloromethane solution (5mL) at ice-cold down agitate compounds 4a (2.65mmol) adds 4,4,5 therein, 5-tetramethyl--1,3, the 1M THF solution of 2-dioxaborolane (Pin-BH) (2.7mL, 2.7mmol) and RhCl (PPh 3) 3(25mg).Stir under the room temperature after 7 hours, add pin-BH 1M TMF solution (2.7mL, 2.7mmol), further stir a night after, add pin-BH 1MTMF solution (2.7mL, 2.7mmol).Stir after 9 hours, be cooled to-10 ℃, add sodium bicarbonate aqueous solution.Mixture extracts with ether (40mL * 1,10mL * 1), and drying concentrates.In the oily mater (1.08g) of gained, add compound 6d (452mg, 1.0mmol), PdCl 2(dppf) CH 2Cl 2[dppf=1,1-bis (diphenylphosphino) ferrocene] (27mg, 0.03mmol), 2M aqueous sodium carbonate (4.5mL), DMF (6mL).To this mixed solution repeat repeatedly to outgas, after the operation of nitrogen replacement, 80 ℃ were stirred 1 hour down again.After this reaction solution is cooled to room temperature, add water (30mL), resultant is with ethyl acetate extraction (30mL * 3).After organic layer cleans with saturated aqueous common salt (20mL), dry concentrating.In residue, add ether, the elimination insolubles.Concentrated filtrate obtains the oily mater (115mg, 25%) of the 1bf of purpose.It is dissolved in the ether (4mL), in the ice-cold 4N hydrochloric acid/ethyl acetate (61 μ L) that adds down, at room temperature stirs for some time.The leaching throw out obtains the pale yellow powder (as 1 hydrochloride 68mg) of 1bf hydrochloride.
Figure G2009101520977D00601
1bf·HCl： 1H NMR(300MHz，CDCl 3+D 2O)δppm：1.50(s，6H)，2.70(s，3H)，2.80-3.60(m，8H)，3.97(s，3H)，7.12(t，J＝8.8Hz，1H)，7.30(s，1H)，7.71(m，1H)，8.02(s，1H)，8.57(s，1H)，8.72(s，1H)，9.78(s，1H)。
＜embodiment 62 〉
Utilize compound 6a, compound 4a, react by the method identical with embodiment 56, obtain purpose compound 1bg (yield 59%).
Figure G2009101520977D00602
1bg： 1H NMR(300MHz，CDCl 3)δppm：1.53(s，6H)，2.31(s，3H)，2.55(m，4H)，2.65(s，3H)，2.84(m，4H)，3.99(s，3H)，7.20(s，1H)，7.52(t，J＝7.9Hz，1H)，7.74(d，J＝7.7Hz，1H)，7.78(s，1H)，8.05(s，1H)，8.16(s，1H)，9.31(s，1H)。
＜embodiment 63 〉
Utilize compound 6c and compound 4a, react by the method identical with embodiment 56, obtain purpose compound 1bh (yield 68%).
Figure G2009101520977D00611
1bh： 1H NMR(300MHz，DMSO-d 6)δppm：1.43(s，6H)，2.16(s，3H)，2.37(m，4H)，2.69(m，4H)，3.78(s，3H)，3.96(s，3H)，6.70(dd，J＝2.2，8.2Hz，1H)，7.20(s，1H)，7.28(t，J＝8.2Hz，1H)，7.42(m，H)，8.15(s，1H)，8.54(s，1H)，8.60(s，1H)，9.72(s，1H)。
＜embodiment 64,65 〉
Utilize compound 6d, compound 4a and 4c, the method by identical with embodiment 56 is converted to 1bi respectively, 1bj.
＜embodiment 64 〉
Figure G2009101520977D00612
1bi: productive rate 78%; 1H NMR (300MHz, DMSO-d 6) δ ppm:1.45 (s, 6H), 2.18 (s, 3H), 2.40 (m, 4H), 2.68 (m, 4H), 4.00 (s, 3H), 7.47 (t, J=9.2Hz, 1H), 7.75 (s, 1H), 7.81 (m, 1H), 7.88 (s, 1H), 8.13 (s, 1H), 8.54 (s, 1H), 9.77 (s, 1H).
＜embodiment 65 〉
Figure G2009101520977D00621
1bj: productive rate 78%; 1H NMR (300MHz, DMSO-d 6) δ ppm:1.44 (s, 6H), 2.56 (m, 4H), 2.73 (m, 4H), 3.73 (s, 2H), 4.00 (s, 3H), 7.47 (t, J=9.2Hz, 1H), 7.76 (s, 1H), 7.81 (m, 1H), 7.88 (s, 1H), 8.13 (s, 1H), 8.54 (s, 1H), 9.77 (s, 1H).
＜embodiment 66 〉
After pyridine (7mL) solution of the amino body 2c (1.46mmol) that will obtain with the method for embodiment 3 is cooled to 0 ℃-5 ℃, and the methylsulfonyl chloride that slowly drips (125 μ L, 1.61mmol).Reactor is placed intensification naturally in the water-bath, reaction solution is poured in the sodium bicarbonate aqueous solution.The solid that leaching is separated out cleans with cold water.Gained slightly refining thing is washed the compound that obtains by silica gel column chromatography (chloroform-methanol) with acetonitrile is outstanding.Leaching resultant, decompression drying down obtain purpose compound 1ca (552mg).
Figure G2009101520977D00622
1ca: productive rate 68%; 1H NMR (270MHz, DMSO-d 6) δ ppm:1.48 (s, 6H), 2.55 (m, 4H), 2.74 (m, 4H), 3.12 (s, 3H), 3.73 (s, 2H), 7.47 (t, J=9.2Hz, 1H), 7.80 (m, 1H), 7.85 (s, 1H), 8.13 (s, 1H), 8.46 (s, 1H), 8.62 (s, 1H), 9.57 (s, 1H), 10.09 (s, 1H).
＜embodiment 67-77 〉
Synthetic by corresponding amino body 2 by the method identical with embodiment 66.
＜embodiment 67 〉
Figure G2009101520977D00623
1cb: productive rate 24%; 1H NMR (300MHz, DMSO-d 6) δ ppm:2.20 (s, 3H), 2.40 (m, 4H), 2.60 (m, 4H), 3.11 (s, 3H), 3.61 (s, 2H), 7.47 (t, J=9.1Hz, 1H), 7.79 (m, 1H), 7.86 (s, 1H), 8.12 (s, 1H), 8.42 (s, 1H), 8.60 (s, 1H), 9.56 (s, 1H), 10.07 (s, 1H).
＜embodiment 68 〉
Figure G2009101520977D00631
1cc: productive rate 45%; 1H NMR (300MHz, DMSO-d 6) δ ppm:2.59 (m, 4H), 3.13 (s, 3H), 3.63 (m, 6H), 7.47 (t, J=9.1Hz, 1H), 7.79 (m, 1H), 7.89 (s, 1H), 8.13 (s, 1H), 8.45 (s, 1H), 8.62 (s, 1H), 9.57 (s, 1H), 10.10 (s, 1H).
＜embodiment 69 〉
Figure G2009101520977D00632
1cd: productive rate 32%; 1H NMR (300MHz, DMSO-d 6) δ ppm:1.55 (s, 6H), 2.40 (m, 4H), 3.00 (m, 4H), 3.12 (s, 3H), 7.47 (t, J=9.0Hz, 1H), 7.79 (m, 1H), 7.88 (s, 1H), 8.12 (s, 1H), 8.45 (s, 1H), 8.62 (s, 1H), 9.57 (s, 1H), 10.10 (s, 1H).
＜embodiment 70 〉
Figure G2009101520977D00633
1ce: productive rate 49%; 1H NMR (300MHz, DMSO-d 6) δ ppm:2.25-2.80 (m, 8H), 3.11 (s, 3H), 3.58 (m, 4H), 7.44 (t, J=8.9Hz, 1H), 7.79 (m, 2H), 8.11 (s, 2H), 8.43 (s, 1H), 8.58 (s, 1H), 9.57 (s, 1H), 10.06 (s, 1H).
＜embodiment 71 〉
Figure G2009101520977D00641
1cf: productive rate 54%; 1H NMR (300MHz, DMSO-d 6) δ ppm:1.02 (s, 6H), 2.05 (s, 3H), 2.18 (m, 4H), 2.51 (m, 4H), 3.06 (s, 3H), 5.89 (d, J=12.9Hz, 1H), 6.67 (d, J=12.9Hz, 1H), 7.47 (t, J=9.0Hz, 1H), 7.81 (m, 1H), 7.95 (s, 1H), 8.14 (s, 1H), 8.34 (s, 1H), 8.60 (s, 1H), 9.57 (s, 1H), 9.99 (s, 1H).
＜embodiment 72 〉
Figure G2009101520977D00642
1cg: productive rate 62%; 1H NMR (270MHz, DMSO-d 6) δ ppm:1.46 (s, 6H), 2.20 (s, 3H), 2.43 (m, 4H), 2.71 (m, 4H), 3.10 (s, 3H), 7.46 (t, J=9.2Hz, 1H), 7.79 (m, 1H), 7.82 (s, 1H), 8.13 (s, 1H), 8.41 (s, 1H), 8.60 (s, 1H), 9.57 (s, 1H), 10.06 (s, 1H).
＜embodiment 73 〉
Figure G2009101520977D00643
1ch: productive rate 29%; 1H NMR (270MHz, DMSO-d 6) δ ppm:1.01 (t, J=7.3Hz, 3H), 1.46 (s, 6H), 2.35 (q, J=7.3Hz, 2H), 2.50 (m, 4H), 2.72 (m, 4H), 3.09 (s, 3H), 7.46 (t, J=9.2Hz, 1H), 7.81 (m, 2H), 8.12 (s, 1H), 8.38 (s, 1H), 8.59 (s, 1H), 9.56 (s, 1H), 10.04 (s, 1H).
＜embodiment 74 〉
Figure G2009101520977D00651
1ci: productive rate 56%; 1H NMR (270MHz, DMSO-d 6) δ ppm:1.45 (s, 6H), 1.82 (m, 2H), 2.36 (s, 3H), 2.70 (m, 4H), 2.91 (m, 4H), 3.06 (s, 3H), 7.45 (t, J=9.2Hz, 1H), 7.77 (m, 2H), 8.11 (s, 1H), 8.29 (s, 1H), 8.55 (s, 1H), 9.56 (s, 1H), 9.98 (s, 1H).
＜embodiment 75 〉
Figure G2009101520977D00652
1cj: productive rate 46%; 1H NMR (270MHz, DMSO-d 6) δ ppm:1.49 (s, 6H), 1.71 (m, 4H), 2.19 (s, 3H), 2.34 (s, 3H), 2.85 (m, 4H), 3.00 (m, 1H), 3.07 (s, 3H), 7.46 (t, J=9.2Hz, 1H), 7.73 (s, 1H), 7.80 (m, 1H), 8.12 (s, 1H), 8.34 (s, 1H), 8.58 (s, 1H), 9.57 (s, 1H), 10.02 (s, 1H).
＜embodiment 76 〉
Figure G2009101520977D00653
1ck: productive rate 24%; 1H NMR (270MHz, DMSO-d 6) δ ppm:2.17 (s, 3H), 2.36 (m, 4H), 2.50 (m, 4H), 2.69 (m, 4H), 3.10 (s, 3H), 7.46 (t, J=9.2Hz, 1H), 7.80 (m, 2H), 8.13 (s, 1H), 8.42 (s, 1H), 8.59 (s, 1H), 9.55 (s, 1H), 10.06 (s, 1H).
＜embodiment 77 〉
1cl: productive rate 31%; 1H NMR (270MHz, DMSO-d 6) δ ppm:1.47 (s, 6H), 2.89 (t, J=6.6Hz, 4H), 3.11 (s, 3H), 3.26 (s, 6H), 3.25-3.51 (m, 4H), 7.49 (t, J=9.2Hz, 1H), 7.80 (m, 1H), 7.89 (s, 1H), 8.13 (s, 1H), 8.45 (s, 1H), 8.62 (s, 1H), 9.53 (s, 1H), 10.09 (s, 1H).
＜embodiment 79 〉
At room temperature will be with amino body 2a (1.00mmol), the 3-methyl sulfo-propionyl chloride (152mg of the method gained of synthesis example 2,1.20mmol), triethylamine (167 μ L, 1.20mmol) DMF (4.5mL) solution stirring 19 hours, and then stirred 6 hours down at 40 ℃.Reaction solution is injected sodium bicarbonate aqueous solution (100mL), with ethyl acetate (100mL * 2) extraction.The gained organic layer cleans with saturated aqueous common salt (100 * 2), behind anhydrous magnesium sulfate drying, and the underpressure distillation desolventizing.Residue passes through silica gel column chromatography (methylene chloride-methanol), and then uses re-crystallizing in ethyl acetate, obtains purpose coupling compound 1af (120mg).
Figure G2009101520977D00662
1af： 1H NMR(300MHz，DMSO-d 6)δppm：1.46(s，6H)，2.12(s，3H)，2.17(s，3H)，2.38(m，4H)，2.67(m，4H)，2.74-2.83(m，4H)，7.46(t，J＝9.0Hz，1H)，7.80-7.85(m，2H)，8.17(s，1H)，8.35(s，1H)，8.62(br s，2H)，9.67(s，1H)，10.03(s，1H)。
＜embodiment 80 〉
At room temperature will be with amino body 2a (1.00mmol), 2-oxo butyrolactone (tetronic the acid) (126mg of the method gained of synthesis example 2,1.50mmol), sodium bicarbonate (423mg, 5.00mmol), HATU (701mg, DMF 1.84mmol) (1.0mL) solution stirring 20 hours.Reaction solution is injected sodium bicarbonate aqueous solution (100mL), with ethyl acetate (50mL * 2) extraction.The gained organic layer cleans with saturated aqueous common salt (50 * 2), behind anhydrous sodium sulfate drying, and the underpressure distillation desolventizing.Residue passes through silica gel column chromatography (methylene chloride-methanol), and then uses re-crystallizing in ethyl acetate, obtains purpose coupling compound 1ag (71mg).
Figure G2009101520977D00671
1ag： 1H NMR(300MHz，DMSO-d 6)δppm：1.45(s，6H)，2.06(s，3H)，2.15(s，3H)，2.37(m，4H)，2.67(m，4H)，7.46(t，J＝9.0Hz，1H)，7.81-7.85(m，2H)，8.19(s，1H)，8.54(s，1H)，8.63(s，1H)，9.98(s，1H)，10.20(s，1H)。
＜embodiment 81 〉
At room temperature make amino body 2a (1.00mmol), diketene (220mg, toluene 2.61mmol) (1.5mL) solution backflow 1.5 hours with the method gained of synthesis example 2.Reaction solution by silica gel column chromatography (methylene chloride-methanol), is obtained purpose coupling compound 1ah (110mg).
Figure G2009101520977D00672
1ah： 1H NMR(300MHz，DMSO-d 6)δppm：1.47(s，6H)，2.21(s，3H)，2.27(s，3H)，2.44(m，4H)，2.67(m，4H)，3.19(s，2H)，7.45(t，J＝9.3Hz，1H)，7.78-7.83(m，2H)，8.14(s，1H)，8.60(s，1H)，8.71(s，1H)，9.95(s，1H)，10.03(s，1H)。
＜embodiment 82 〉
At room temperature will with the amino body 2a (1.00mmol) of the method gained of synthesis example 2, cyanoacetic acid (425mg, 5.00mmol), triethylamine (209 μ L, 1.50mmol), EDC (288mg, DMF 1.5mmol) (5.0mL) solution stirring 14 hours.Reaction solution is injected sodium bicarbonate aqueous solution (100mL), with ethyl acetate (50mL * 2) extraction.The gained organic layer cleans with saturated aqueous common salt (50 * 2), behind anhydrous sodium sulfate drying, and the underpressure distillation desolventizing.Residue passes through silica gel column chromatography (methylene chloride-methanol), and then uses re-crystallizing in ethyl acetate, obtains purpose coupling compound 1ai (189mg).
Figure G2009101520977D00681
1ai： 1H NMR(300MHz，DMSO-d 6)δppm：1.46(s，6H)，2.33(s，3H)，2.64(m，4H)，2.74(m，4H)，4.14(s，2H)，7.45(t，J＝9.0Hz，1H)，7.80-7.86(m，2H)，8.19(s，1H)，8.59(s，1H)，8.64(s，1H)，10.10(s，1H)，10.29(s，1H)。
＜embodiment 83 〉
At room temperature will be with amino body 2a (2.00mmol), 2-chloro-ethane-sulfonyl chloride (840 μ L, pyridine 8.00mmol) (5.0mL) solution stirring 1 hour of the method gained of synthesis example 2.Reaction solution is injected sodium bicarbonate aqueous solution (200mL), with ethyl acetate (200mL * 2) extraction.The gained organic layer cleans with saturated aqueous common salt (300 * 3), behind anhydrous sodium sulfate drying, and the underpressure distillation desolventizing.Residue passes through silica gel column chromatography (methylene chloride-methanol), and then refining with pTLC (methylene chloride-methanol), obtains purpose coupling compound 1aj (9mg).
Figure G2009101520977D00682
1aj： 1H NMR(300MHz，DMSO-d 6)δppm：1.46(s，6H)，2.29(s，3H)，2.55(m，4H)，2.77(m，4H)，5.91(d，J＝9.9Hz，1H)，6.01(d，J＝16.5Hz，1H)，6.85(dd，J＝16.4，9.9Hz)，7.45(t，J＝9.1Hz，1H)，7.74-7.83(m，2H)，8.13(s，1H)，8.35(s，1H)，8.57(s，1H)，9.57(s，1H)，10.00(s，1H)。
＜embodiment 84～87 〉
Use 4-chloro-6-nitro-7-bromo-3-itrile group quinoline and various aniline as initial substance, according to synthesis example 2-1) method, embodiment 3-1) method (also use simultaneously compound 4a), method and the embodiment 3-2 of synthesis example 5) method, synthetic compound 1ak～1an (reaction process 6).
Reaction process 6
Figure G2009101520977D00691
(R in the formula 1Expression m-OMe, m-CN, p-NMe 2, the substituting group of m-Me etc.)
＜embodiment 84 〉
Use the 3-anisidine as aniline, be converted to purpose compound 1ak (yield 40%).
Figure G2009101520977D00692
1ak： 1H NMR(300MHz，DMSO-d 6)δppm：1.45(s，6H)，2.15(s，3H)，2.35(m，4H)，2.63(m，4H)，3.78(s，3H)，5.87(dd，J＝10.3，1.7Hz，1H)，6.32(dd，J＝17.0，1.7Hz，1H)，6.57(dd，J＝17.0，10.1Hz，1H)，6.73(dd，J＝7.8，2.2Hz，1H)，7.29(t，J＝8.2Hz，1H)，7.48-7.55(m，2H)，7.80(s，1H)，8.63(s，1H)，8.78(s，1H)，9.81(s，1H)，9.83(s，1H)。
＜embodiment 85 〉
Use the 3-aminobenzonitrile as aniline, be converted to purpose compound 1al (yield 11%).
Figure G2009101520977D00693
1al： 1H NMR(300MHz，DMSO-d 6)δppm：1.46(s，6H)，2.14(s，3H)，2.34(m，4H)，2.63(m，4H)，5.84(dd，J＝10.3，1.5Hz，1H)，6.33(dd，J＝17.1，1.5Hz，1H)，6.58(dd，J＝17.0，10.3Hz，1H)，7.57-7.64(m，2H)，7.87(s，1H)，8.16(d，J＝7.1Hz，1H)，8.42(s，1H)，8.63(s，1H)，8.71(s，1H)，9.88(s，1H)，10.13(s，1H)。
＜embodiment 86 〉
Use N as aniline, N-dimethyl benzene-1, the 4-diaminobenzene is converted to purpose compound 1am (yield 72%).
Figure G2009101520977D00701
1am： 1H NMR(270MHz，HMSO-d 6)δppm：1.43(s，6H)，2.14(s，3H)，2.35(m，4H)，2.63(m，4H)，2.90(s，6H)，5.82(m，J＝10.0Hz，1H)，6.31(m，J＝17.0Hz，1H)，6.57(dd，J＝17.0，10.0Hz，1H)，6.76(d，J＝9.2Hz，2H)，7.56(d，J＝9.2Hz，2H)，7.75(s，1H)，8.46(s，1H)，8.63(s，1H)，9.70(s，1H)，9.92(s，1H)。
＜embodiment 87 〉
Use meta-aminotoluene as aniline, be converted to purpose compound 1an (yield 63%).
Figure G2009101520977D00702
1an： 1H NMR(270MHz，DMSO-d 6)δppm：1.42(s，6H)，2.16(s，3H)，2.34(m，7H)，2.62(m，4H)，5.83(dd，J＝10.0，1.9Hz，1H)，6.30(dd，J＝17.3，1.9Hz，1H)，6.58(dd，J＝17.3，10.0Hz，1H)，6.93(d，J＝7.0Hz，1H)，7.27(m，1H)，7.63(m，2H)，7.80(s，1H)，8.57(s，1H)，8.70(s，1H)，9.81(s，1H)，9.89(s，1H)。
＜embodiment 118-130 〉
Synthetic by corresponding amino body 2 by the method identical with embodiment 66.
＜embodiment 118 〉
Figure G2009101520977D00711
1cm: productive rate 57%; 1H NMR (270MHz, DMSO-d 6) δ ppm:1.33-1.96 (m, 10H), 2.21 (s, 3H), 2.44 (m, 4H), 2.71 (m, 4H), 3.10 (s, 3H), 7.46 (t, J=9.2Hz, 1H), 7.79 (m, 1H), 7.83 (s, 1H), 8.12 (s, 1H), 8.39 (s, 1H), 8.60 (s, 1H), 9.56 (s, 1H), 10.06 (s, 1H).
＜embodiment 119 〉
1cn: productive rate 62%; 1H NMR (270MHz, DMSO-d 6) δ ppm:1.44 (s, 6H), 2.30 (s, 3H), 2.38 (s, 6H), 2.61 (t, J=6.3Hz, 2H), 2.83 (t, J=6.3Hz, 2H), 2.99 (s, 3H), 7.45 (t, J=9.2Hz, 1H), 7.77 (s, 1H), 7.79 (m, 1H), 8.11 (s, 1H), 8.27 (s, 1H), 8.54 (s, 1H), 9.57 (s, 1H), 9.97 (s, 1H).
＜embodiment 120 〉
Figure G2009101520977D00713
1co: productive rate 41%; 1H NMR (270MHz, DMSO-d 6) δ ppm:1.15 (t, J=7.0Hz, 6H), 2.17 (s, 3H), 2.36 (m, 4H), 2.75 (m, 4H), 3.08 (s, 3H), 3.52 (q, J=7.0Hz, 4H), 3.67 (m, 4H), 7.45 (t, J=9.2Hz, 1H), 7.78 (m, 1H), 7.82 (s, 1H), 8.11 (s, 1H), 8.40 (s, 1H), 8.59 (s, 1H), 9.57 (s, 1H), 10.09 (s, 1H).
＜embodiment 121 〉
Figure G2009101520977D00721
1cp: productive rate 56%; 1H NMR (270MHz, DMSO-d 6) δ ppm:1.45 (s, 6H), 2.34 (s, 3H), 2.71 (t, J=6.3Hz, 2H), 3.12 (s, 3H), 3.26 (s, 3H), 3.43 (t, J=6.3Hz, 2H), 7.47 (t, J=9.0Hz, 1H), 7.81 (m, 1H), 7.84 (s, 1H), 8.13 (s, 1H), 8.45 (s, 1H), 8.62 (s, 1H), 9.56 (s, 1H), 10.08 (s, 1H).
＜embodiment 122 〉
Figure G2009101520977D00722
1cq: productive rate 63%; 1H NMR (270MHz, DMSO-d 6) δ ppm:1.46 (s, 6H), 2.75 (m, 4H), 2.87 (s, 3H), 3.10 (s, 3H), 3.15 (m, 4H), 7.46 (t, J=9.2Hz, 1H), 7.79 (m, 1H), 7.87 (s, 1H), 8.12 (s, 1H), 8.45 (s, 1H), 8.61 (s, 1H), 9.57 (s, 1H), 10.09 (s, 1H).
＜embodiment 123 〉
Figure G2009101520977D00723
1cr: productive rate 55%; 1H NMR (270MHz, DMSO-d 6) δ ppm:0.93 (t, 6H), 1.54 (m, 4H), 2.19 (s, 3H), 2.41 (m, 4H), 2.68 (m, 4H), 3.08 (s, 3H), 7.45 (t, J=9.2Hz, 1H), 7.77 (m, 1H), 7.80 (s, 1H), 8.10 (s, 1H), 8.36 (s, 1H), 8.58 (s, 1H), 9.56 (s, 1H), 10.04 (s, 1H).
＜embodiment 124 〉
Figure G2009101520977D00731
1cs: productive rate 49%; 1H NMR (270MHz, DMSO-d 6) δ ppm:1.32 (m, 2H), 1.46 (s, 6H), 1.69 (m, 2H), 2.37 (m, 2H), 2.96 (m, 2H), 3.10 (s, 3H), 3.21 (s, 3H), 3.40-4.00 (m, 1H), 7.46 (t, J=9.1Hz, 1H), 7.79 (m, 1H), 7.83 (s, 1H), 8.11 (s, 1H), 8.44 (s, 1H), 8.61 (s, 1H), 9.57 (s, 1H), 10.08 (s, 1H).
＜embodiment 125 〉
Figure G2009101520977D00732
1ct: productive rate 34%; 1H NMR (270MHz, DMSO-d 6) δ ppm:1.47 (s, 6H), 1.99 (s, 3H), 2.61 (m, 2H), 2.71 (m, 2H), 3.09 (s, 3H), 3.43 (m, 4H), 7.45 (t, J=9.3Hz, 1H), 7.78 (m, 1H), 7.84 (s, 1H), 8.11 (s, 1H), 8.44 (s, 1H), 8.60 (s, 1H), 9.57 (s, 1H), 10.08 (s, 1H).
＜embodiment 126 〉
1cu: productive rate 69%; 1H NMR (270MHz, DMSO-d 6) δ ppm:1.16 (t, 3H), 1.47 (s, 6H), 2.50 (m, 2H), 2.75 (q, 2H), 2.98 (m, 2H), 3.11 (s, 3H), 3.59 (s, 3H), 7.47 (t, J=9.2Hz, 1H), 7.80 (m, 1H), 7.89 (s, 1H), 8.14 (s, 1H), 8.45 (s, 1H), 8.62 (s, 1H), 9.52 (s, 1H), 10.07 (s, 1H).
＜embodiment 127 〉
Figure G2009101520977D00741
1cv: productive rate 53%; 1H NMR (270MHz, DMSO-d 6) δ ppm:1.46 (s, 6H), 2.20-2.50 (m, 6H), 2.69 (m, 4H), 3.11 (s, 3H), 3.23 (s, 3H), 3.43 (m, 2H), 7.47 (t, J=9.2Hz, 1H), 7.80 (m, 1H), 7.84 (s, 1H), 8.13 (s, 1H), 8.44 (s, 1H), 8.67 (s, 1H), 9.57 (s, 1H), 10.08 (s, 1H).
＜embodiment 128 〉
Figure G2009101520977D00742
1cw: productive rate 48%; 1H NMR (270MHz, DMSO-d 6) δ ppm:1.47 (s, 6H), 2.50-2.58 (m, 6H), 2.65-2.70 (m, 6H), 3.12 (s, 3H), 7.47 (t, J=9.2Hz, 1H), 7.81 (m, 1H), 7.84 (s, 1H), 8.14 (s, 1H), 8.45 (s, 1H), 8.62 (s, 1H), 9.61 (s, 1H), 10.10 (s, 1H).
＜embodiment 129 〉
Figure G2009101520977D00743
1cx: productive rate 45%; 1H NMR (270MHz, DMSO-d 6) δ ppm:1.48 (s, 6H), 1.74 (m, 4H), 2.76 (m, 4H), 3.12 (s, 3H), 7.47 (t, J=9.2Hz, 1H), 7.78 (m, 1H), 7.84 (s, 1H), 8.13 (s, 1H), 8.45 (s, 1H), 8.62 (s, 1H), 9.51 (s, 1H), 10.09 (s, 1H).
＜embodiment 130 〉
Figure G2009101520977D00751
1cy: productive rate 42%; 1H NMR (270MHz, DMSO-d 6) δ ppm:1.48 (s, 6H), 2.38 (s, 3H), 2.68 (t, J=6.4Hz, 2H), 2.82 (t, J=6.4Hz, 2H), 3.11 (s, 3H), 7.47 (t, J=9.0Hz, 1H), 7.81 (m, 1H), 7.88 (s, 1H), 8.13 (s, 1H), 8.46 (s, 1H), 8.62 (s, 1H), 9.57 (s, 1H), 10.06 (s, 1H).
＜embodiment 132 〉
Use 4ao (yield 60%) and the 7-bromo-N that is synthesized by 4-oxo tetrahydropyrans with synthesis example 7 identical methods as initial substance 4-(3-chloro-4-fluoro phenyl)-4,6-quinazoline diamines is converted to 2ao and 1ao by the method identical with embodiment 3.
Figure G2009101520977D00752
4ao: productive rate 60%; 1H NMR (270MHz, CDCl 3) δ ppm:1.61-1.93 (m, 4H), 2.29 (s, 3H), 2.41 (s, 1H), 2.48 (m, 4H), 2.66 (m, 4H), 3.64-3.97 (m, 4H).
Figure G2009101520977D00753
2ao: quantitative yield; 1H NMR (270MHz, DMSO-d 6) δ ppm:1.61 (m, 2H), 2.07 (m, 2H), 2.15 (s, 3H), 2.37 (m, 4H), 2.64 (m, 4H), 3.60 (m, 2H), 3.88 (m, 2H), 5.54 (s, 2H), 7.41 (t, J=9.2Hz, 1H), 7.53 (s, 1H), 7.70 (s, 1H), 7.81 (s, 1H), 8.20 (s, 1H), 8.39 (s, 1H), 9.67 (s, 1H).
Figure G2009101520977D00761
1ao: productive rate 31%; 1H NMR (270MHz, DMSO-d 6) δ ppm:1.56 (m, 2H), 2.01 (m, 2H), 2.17 (s, 3H), 2.36 (m, 4H), 2.63 (m, 4H), 3.61 (m, 2H), 3.84 (m, 2H), 5.84 (d, J=10.0Hz, 1H), 6.31 (d, J=17.0Hz, 1H), 6.54 (dd, J=17.0,10.0Hz, 1H), 7.46 (t, J=9.2Hz, 1H), 7.85 (m, 1H), 7.90 (s, 1H), 8.20 (s, 1H), 8.61 (s, 1H), 8.69 (s, 1H), 9.96 (s, 1H), 10.05 (s, 1H).
＜embodiment 133 〉
To (after 300mg, dichloromethane solution 1.46mmol) (4.5mL) be cooled to 0 ℃-5 ℃, add trifluoroacetate (TFA) (4.5mL) with the synthetic acrylamide body 1z of the method for embodiment 25.Directly stir after 1.5 hours the underpressure distillation desolventizing.Residue is washed with ether is outstanding, and leaching obtains purpose compound 1apnTFA (50mg).
Figure G2009101520977D00762
1ap·nTFA： 1H NMR(270MHz，DMSO-d 6)δppm：1.46(s，6H)，2.21(s，1H)，2.86(m，4H)，3.14(m，4H)，5.87(d，J＝10.0Hz，1H)，6.34(d，J＝17.0Hz，1H)，6.58(dd，J＝17.0，10.0Hz，1H)，7.50(t，J＝9.2Hz，1H)，7.77(m，1H)，7.92(s，1H)，8.19(s，1H)，8.57(s，1H)，8.75(s，1H)，10.01(s，1H)，10.13(s，1H)。
＜embodiment 134 〉
At room temperature with 4-(4-methyl isophthalic acid-piperazinyl)-4-ketone group-butyric acid (0.69g, 10.0mmol), N-methyl propargyl amine (2.00g, 10.0mmol), EDC (2.88g, 15.0mmol), (2.1mL, 15.0mmol) DMF solution (30mL) stirs a night to triethylamine.Add water (40mL) in reaction solution, resultant extracts with methylene dichloride (40mL * 3).Extraction liquid cleans with sodium bicarbonate aqueous solution, saturated aqueous common salt, and concentrating under reduced pressure obtains the DMF solution (10.00g) of N-methyl-4-(4-methyl isophthalic acid-piperazinyl)-4-ketone group-N-(2-propyl group)-butine acid amides (4aq).
Utilize DMF solution and the 7-bromo-N4-(3-chloro-4-fluorophenyl)-4 of this 4aq, 6-quinazoline diamines is converted to 1ag by the method identical with embodiment 3.
Figure G2009101520977D00771
1aq: productive rate 7%; 1H NMR (300MHz, 354K, DMSO-d 6) δ ppm:2.18 (s, 3H), 2.29 (m, 4H), 2.62 (m, 4H), 3.01 (s, 3H), 3.45 (m, 4H), 4.46 (s, 2H), 5.80 (dd, J=10.1,1.5Hz, 1H), 6.33 (dd, J=16.8,1.5Hz, 1H), 6.61 (m, 1H), 7.39 (t, J=9.2Hz, 1H), 7.82 (m, 1H), 7.86 (s, 1H), 8.11 (s, 1H), 8.56 (s, 1H), 8.79 (s, 1H), 9.65 (s, 1H), 9.92 (s, 1H);
＜embodiment 135 〉
By the method identical with synthesis example 7, use the tertiary butyl-4-ketone group-1-piperazine carboxylic acid salt to replace 1,3-diethoxy acetone, use diethylamine to replace the synthetic 4ar (yield 97%) of 1-methylpiperazine, use 4ar and 7-bromo-N 4-(3-chloro-4-fluorophenyl)-4,6-quinazoline diamines carries out the reaction identical with embodiment 3, obtains 2ar (R=H).Make the di-t-butyl dicarboxylate (Boc of itself and 1 equivalent in the methylene dichloride under ice-cold 2O) reaction is 30 minutes, and thick resultant obtains compound 2ar (R=Boc by silica gel column chromatography refinement; Total yield is 85%).Utilize embodiment 3-2) method this compound 2ar (R=Boc) is converted to 1ar.
Figure G2009101520977D00772
4ar: productive rate 97%; 1H NMR (300MHz, CDCl 3) δ ppm:1.04 (t, J=7.2Hz, 6H), 1.46 (s, 9H), 1.57 (m, 2H), 1.92 (m, 2H), 2.32 (s, 1H), 2.67 (q, J=7.2Hz, 4H), 3.11 (m, 2H), 3.89 (m, 2H).
Figure G2009101520977D00781
2ar (R=Boc): productive rate 85%; 1H NMR (300MHz, CDCl 3) δ ppm:1.11 (t, J=7.1Hz, 6H), 1.47 (s, 9H), 1.73 (m, 2H), 2.01 (m, 2H), 2.76 (q, J=7.1Hz, 4H), 3.17 (m, 2H), 3.92 (m, 2H), 4.97 (s, 2H), 6.98 (s, 1H), 7.15 (t, J=8.7Hz, 1H), 7.24 (m, 1H), 7.54 (s, 1H), 7.86 (s, 1H), 7.93 (s, 1H), 8.58 (s, 1H).
1ar: productive rate 63%; 1H NMR (300MHz, CDCl 3) δ ppm:1.11 (t, J=7.0Hz, 6H), 1.47 (s, 9H), 1.73 (m, 2H), 2.01 (m, 2H), 2.76 (q, J=7.0Hz, 4H), 3.17 (m, 2H), 3.92 (m, 2H), 5.82 (d, J=10.2Hz, 1H), 6.31 (d, J=16.9Hz, 1H), 6.51 (dd, 10.2,16.9Hz, 1H), 7.45 (t, J=9.1Hz, 1H), 7.72 (m, 1H), 7.89 (m, 1H), 8.19 (dd, J=2.6,6.8Hz, 1H), 8.61 (s, 1H), 8.74 (s, 1H), 9.98 (s, 1H), 10.07 (s, 1H).
＜embodiment 136 〉
Compound 4cz and 7-bromo-N that use makes proyl amine and isonipecotic acid ethyl ester reaction obtain under ice bath, in acetonitrile and under the condition that salt of wormwood exists 4-(3-chloro-4-fluorophenyl)-4,6-quinazoline diamines, the method by identical with embodiment 3 obtains compound 1-{3-[6-amino-4-(3-chloro-4-fluorophenyl amino)-7-quinazolyl]-the 2-propyl group }-4-piperidine carboxylate (2cz) (yield 73%).To compound 2cz, react by the method identical with embodiment 66, thick resultant passes through silica gel column chromatography, the solid that obtains in ethanol, is carried out room temperature with the 2N aqueous sodium hydroxide solution of 3 equivalent roughly and handled in 2 hours, then, neutralize, generate throw out.The leaching resultant is washed with acetonitrile is outstanding, obtains the faint yellow solid (yield 57%) of compound 1cz.
Figure G2009101520977D00791
4cz: productive rate 78%; 1H NMR (300MHz, CDCl 3) δ ppm:1.26 (t, J=7.1Hz, 3H), 1.73 (m, 2H), 1.96 (m, 2H), 2.17 (m, 4H), 2.31 (s, 1H), 3.30 (s, 2H), 4.13 (q, J=7.1Hz, 2H).
2cz: productive rate 73%.
Figure G2009101520977D00793
1cz： 1H NMR(300MHz，DMSO-d 6)δppm：1.63(m，2H)，1.96(m，2H)，2.17(m，4H)，2.31(s，1H)，3.08(s，3H)，3.30(s，2H)，7.46(t，J＝9.1Hz，1H)，7.72-7.83(m，1H)，7.85(s，1H)，8.11(s，1H)，8.35(s，1H)，8.58(s，1H)，9.57(s，1H)，10.02(s，1H)，11.92(br，1H)。
＜embodiment 137 〉
Use 3-methoxyl group propine and 7-bromo-N 4-(3-chloro-4-fluorophenyl)-4,6-quinazoline diamines, the method by identical with embodiment 3 is converted to N 4-(3-chloro-4-fluorophenyl)-7-(3-methoxyl group-1-proyl) quinazoline-4, the 6-diamines is then according to the method [having used 2-(4-morpholino) ethyl sulfonyl chloride to replace methylsulfonyl chloride] of embodiment 66 record synthetic compound 1caa thus.
1caa: productive rate 10%; 1H NMR (300MHz, CDCl 3) δ ppm:2.39 (m, 4H), 2.89 (t, J=6.9Hz, 2H), 3.38 (t, J=7.0Hz, 2H), 3.50 (s, 3H), 3.65 (m, 4H), 4.34 (s, 2H), 7.20 (t, J=9.0Hz, 1H), 7.54 (m, 1H), 7.93 (m, 1H), 8.05 (s, 1H), 8.07 (s, 1H), 8.73 (s, 1H), 9.57 (s, 1H), 10.02 (s, 1H).
＜embodiment 138 〉
Method [having used 4-(4-morpholino)-2-butyric acid to replace vinylformic acid] according to embodiment 1 record is converted to 1as with compound 2t (embodiment 20).
Figure G2009101520977D00801
1as: productive rate 17%; 1H NMR (300MHz, DMSO-d 6) δ ppm:1.47 (s, 6H), 1.74 (m, 4H), 2.76 (m, 8H), 3.72 (t, J=4.7Hz, 4H), 4.06 (s, 2H), 7.45 (t, J=9.0Hz, 1H), 7.72 (m, 1H), 7.83 (m, 1H), 8.18 (s, 1H), 8.58 (s, 1H), 8.61 (s, 1H), 9.62 (s, 1H), 9.98 (s, 1H).
Test example 1: the evaluation of tyrosine kinase inhibitor of the present invention
(1) EGFR tyrosine kinase inhibitory activity
(method) used and carry out the refining EGF acceptor of part from the A431 cell strain that comes from people's squamous cell carcinoma, improved tyrosine kinase activity assay method (the proceedings of theNational Academy of Science of the U.S.A. of Linda J.Pike etc., 1982,79,1433), and carried out determination of activity.Detailed method is as follows:
In containing the Dalbeck political reform EAGLE substratum (DMEM) of cowboy's serum (FBS) 10%, under 37 ℃, the condition of 5% carbon dioxide, cultivate the A431 cell, with the homogenate in the solution that contains N-2-hydroxyethyl piperidine subbase-N ' of 10mM-2-ethanesulfonic acid (Hepes) damping fluid (pH 7.4), 0.25M sucrose, 0.1mM EDTA of this cell, with 3000G centrifugal 5 minutes then, and then with 100000G centrifuged supernatant 30 minutes, obtain A431 cytolemma part, the refining EGF acceptor of its part as the enzyme source is supplied and determination of activity.
Be dissolved in above-mentioned A431 cytolemma part (10～15 μ g), 30mM Hepes damping fluid (pH7.7), 2mM MnCl 2, 100mM Na 3After adding the EGF of 100ng in the reaction mixture (ultimate density 1%DMSO) of the analyte in VO4 and the dimethyl sulfoxide (DMSO) (DMSO), add synthetic substrate Angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe) 50 μ g, adenosine triphosphate (contains Y- 32P-marked body 37KBq) ultimate density 10mM makes the reaction beginning.The capacity of this moment is 60 μ L.
Reaction is 30 minutes in ice, adds 10mg/mL bovine serum albumin 6 μ L, 20% Tricholroacetic Acid, 25 μ L, and reaction is stopped, and directly places 30 minutes in ice then.
Then, after centrifugal 2 minutes, get supernatant liquor 40 μ L with 5000G, be adsorbed on the P81 phosphorus cellulose paper.Be immersed in 0.75% phosphate aqueous solution 5 minutes, clean, repeats four dippings, cleaning operation after, taking-up paper is measured by the scintiscanning counter 32The counting of p is set at A with this value.
Also measure simultaneously the counting of the reaction that the reaction, measured matter and the EGF that do not add measured matter do not add, be set at B, C respectively.
Calculate the tyrosine-kinase enzyme inhibition rate by these values according to following formula.
Inhibiting rate (%)=100-{ (A-C)/(B-C) } * 100
According to the inhibiting rate of the interpolation concentration gained that changes measured matter, calculate IC 50Value (50% inhibition concentration).
Table 11
The compound sequence number IC 50nM The compound sequence number IC 50nM The compound sequence number IC 50nM
1a 1.1 1ac 3.0 1ca 1.2
1b 1.8 1ad 2.9 1cb 1.7
1c 2.2 1ae ＞10 1cc 2.2
1d 8.1 1af 2.2 1cd 6.2
1e 5.1 1ag 8.1 1ce 3.2
1f ＜1 1ah 3.3 1cf 2.8
1g ＜1 1ai ＞10 1cg 4.5
1h 2.9 1aj 2.9 1ch 6.0
1i ＞10 1ak ＜1 1ci ＜1
1j 6.5 1al 6.0 1cj ＜1
1k 4.3 1am 6.3 1ck 6.5
1l 8.8 1an 5.9 1cl 1.2
1m ＞10 1ao 2.8 1cm 9.8
1n ＜1 1ap 9.3 1cn 3.2
1o 6.6 1aq 5.6 1co 1.8
1p 5.9 1as 1.8 1cp 2.9
1q 1.8 1ba ＜1 1cq 3.0
1r 5.4 1bb 2.7 1cr 8.7
1s 6.2 1bc 6.1 1cs 1.9
1t 3.3 1bd 5.5 1ct 3.2
1u 2.7 1be 7.7 1cu 5.4
1v 3.5 1bf 8.1 1cv 6.1
1x 4.4 1bg 7.4 1cw ＞10
1y 3.6 1bh 9.2 1cx 2.1
1z ＜1 1bi 2.8 1cy ＜1
1aa ＜1 1bj ＞10 1cz ＜1
1ab 2.8
(2) HER2 tyrosine kinase inhibitory activity
(method)
Cell uses by the 659th Xie Ansuan being substituted by the NIH3T3 mouse fibroblast strain that variation c-erbB2 that L-glutamic acid has stabilizing active is out of shape.Below be designated as the A4 cell.Utilize to add the DMEM/F12 mixed culture medium (hereinafter referred to as collective media) of 10%FBS, with 37 ℃, 5%CO2,95%Air condition, in plastic ware, keep and cultivate this cell strain.
Outstanding turbid A4 cell in collective media is dispersed in 12 orifice plates with 3 * 105/ holes, the cell that becomes fusion was cultivated 2 hours at 37 ℃ with compound.After cleaning cell once with PBS, outstanding turbid at molten born of the same parents' damping fluid (60mM Tris (pH6.8) again, 2%SDS, 10% glycerine, 5% beta-mercaptoethanol, 0.001% tetrabromophenol sulfonphthalein) in, uses ultrasonication, be used for western protein as WCL and shift seal (Western blot) method of inhaling.
After the WCL of protein content 25 μ g parts is used for 7.5%SDS-polypropylene phthalein amine electrophoresis, be replicated on the pvdf membrane.Behind this membrane closure, in the Tris damping fluid that adds 0.1%Tween20, hatch with Tyrosine O-phosphate, mouse monoclonal antibody, then, with 2 antibody treatment of the anti-mouse of HRP mark.Handle film with chemical illuminating reagent, carry out the chemoluminescence shooting with luminous ccd video camera, be recorded in the electronic medium.The optical density meter carries out quantification to the phosphoric acid signal of gained, and the signal when not adding compound is made as 100% to be suppressed, and background signal is made as 0%, and the phosphorylation that suppresses to estimate based on compound with % suppresses.
Table 12
Compound % suppresses (0.1 μ M) % suppresses (1 μ M)
1a 79 18
1h 64 11
1ah 83 7
1as 46 2
1cp 39 6
(3) effect of inhibition cancer in the body
Method: at the outstanding turbid human epidermal cancer cells A4315 * 106/100 μ l in PBS of the back subcutaneous transplantation of the female nude mice of Balb/c (when buying 5 week ages), before and after 7 days, reach 100mm in the average-volume of transplantation tumor 3The time, divide into groups, 4 every group, make the mean tumour volume value of each group certain.Measure major diameter and minor axis with gauge, with [(minor axis) 2 * major diameter/2]=gross tumor volume [mm 3] as the gross tumor volume value.Give medicine from grouping day once-a-day continuous 14 days pressure per os, mice in control group is not given medicine.Calculate gross tumor volume that administration is begun day with control group and drug treating group as 1 relative tumor control rate.Suppress cancer effect %=(last day relative tumor proliferation rate-1 of medicine control group)/(last day relative tumor control rate-1 of control group) * 100
The result: compare with the control group that does not give any active compound, the compound in the table 11 is under the dosage of 0.05～10mg/kg, and tumor killing effect is all between 0.7%～63.7%.As seen The compounds of this invention is effective as carcinostatic agent.
2: two kinds of compounds of experimental example suppress specific activity to protein tyrosine kinase
Disclosed compound N among compound 1a among the comparative study this patent preferred compound embodiment 1 and the patent WO2000018740-[4-[(3-chloro-4-fluorophenyl) amino]-3-cyano group-7-(4-methyl isophthalic acid-piperazinyl)-6-quinolyl]-2-butyne acid amides (N-[4-[(3-chloro-4-fluorophenyl) amino]-3-cyano-7-(4-methyl-1-piperazinyl)-6-quinolinyl]-2-Butynamide), (the CAS registration number: 263149-44-6) to the tyrosine-kinase enzyme inhibition activity.
Test method sees " evaluation of tyrosine kinase inhibitor of the present invention " (1) and (2) in the experimental example 1 for details, and test is studied EGFR Tyrosylprotein kinase and HER2 respectively.Test-results shows that the EGFR Tyrosylprotein kinase of the compound 1a inhibition among this patent embodiment 1 significantly is better than WO2000018740 compound (p=0.009), and HER2 tyrosine-kinase enzyme inhibition activity does not have significant difference, sees Table 13.
Table 13 this patent preferred compound and WO2000018740 compound suppress specific activity to Tyrosylprotein kinase
Figure G2009101520977D00831

Claims (10)

1. the quinoline shown in general formula (I) or its pharmacy acceptable salt,
Figure FSB00001010848000011
In the formula (I):
N represents 1 or 2 integer,
R 1Expression halogen atom, cyano group, C 1-C 5Alkyl, C 1-C 5Alkoxyl group ,-NR 14R 15, wherein: R 14And R 15Independently represent C separately 1-C 5Alkyl,
R 2Expression
Figure FSB00001010848000012
In the formula: X represents-C (O)-or-SO 2-, R 4, R 5And R 6Independently represent hydrogen atom separately, or
Figure FSB00001010848000013
In the formula: R 7The expression morpholino replaces or unsubstituted C 1-C 5Alkyl,
R 3Expression
Figure FSB00001010848000014
In the formula: R 8, R 9Independently represent hydrogen atom, C separately 1-C 5Alkoxyl group replaces or unsubstituted C 1-C 5Alkyl, perhaps R 8And R 9Form ring and expression together and exist or do not exist-O-,-NR 10-C 3-C 8Ring alkylidene group, wherein R 10Expression hydrogen atom or C 1-C 5Alkyl, m are represented 0 or 1 integer, R 11, R 12Independently represent hydrogen atom separately, Y represents C 1-C 5Alkoxyl group, N-methyl-(N-methyl piperidine-4-yl) be amino ,-N (R 16)-(CO) u-(CR 17R 18) v-(CO) j-R 19, R wherein 16Expression C 1-C 5Alkoxyl group replaces or unsubstituted C 1-C 5Alkyl, R 17, R 18Independent expression hydrogen atom separately, u and j represent 0 or 1, v represent 1 or 2 integer, R 19Expression hydrogen atom, cyano group, C 1-C 5Alkoxyl group, morpholino, 4-C 1-C 5Alkylpiperazine-1-base or two (C 1-C 5Alkyl) amino, wherein, 1) u and j represent simultaneously at 0 o'clock, and v represents 2,2) R 19During expression cyano group, j represents 0,
Figure FSB00001010848000021
Figure FSB00001010848000022
Figure FSB00001010848000023
In the formula: r and t independently represent 1 or 2 integer separately, and k represents that 0, W represents hydrogen atom, hydroxyl, C 1-C 5Alkoxyl group, carboxyl, two (C 1-C 5Alkyl) amino.
2. quinoline according to claim 1 or its pharmacy acceptable salt is characterized in that, in general formula (I), n represents 1, R 1Expression C 1-C 5Alkoxyl group.
3. quinoline according to claim 1 or its pharmacy acceptable salt is characterized in that, in general formula (I), and R 3Expression
Figure FSB00001010848000024
In the formula: R 8, R 9Independent a) expression hydrogen atom, b separately) expression C 1-C 5Alkoxyl group replaces or unsubstituted C 1-C 5Alkyl, m represent 0 or 1, R 11, R 12Represent hydrogen atom respectively, Y represents
Figure FSB00001010848000025
In the formula: p and q represent that 2, Z represents-NR 20-, wherein: R 20Expression is by cyano group or C 1-C 5Alkoxyl group replaces or unsubstituted C 1-C 5Alkyl.
4. compound according to claim 1 or its pharmacy acceptable salt is characterized in that, in general formula (I), n represents 2, R 1The expression halogen atom, R 2Expression
Figure FSB00001010848000031
In the formula: X represents-C (O)-, R 4, R 5And R 6The expression hydrogen atom,
R 3Expression
Figure FSB00001010848000032
In the formula: R 8, R 9Expression C 1-C 5Alkoxyl group replaces or unsubstituted C 1-C 5Alkyl, m represent 0 or 1, Y represent N-methyl-(N-methyl piperidine 4-yl) amino ,-N (R 16)-(CO) u-(CR 17R 18) v-(CO) j-R 19, R wherein 16Expression C 1-C 5Alkyl, R 17, R 18Independently represent hydrogen atom separately, u and j represent that 0, v represents 2, R 19Expression two (C 1-C 5Alkyl) amino, or
Figure FSB00001010848000033
In the formula: p and q represent 2, Z represent-CO-,-NR 20-, wherein: R 20Expression hydrogen atom, C 1-C 5Alkyl.
5. the quinoline shown in following formula 1a or the 1f, or its pharmacy acceptable salt,
Figure FSB00001010848000034
6. pharmaceutical composition, it contains each described quinoline of claim 1～5 or its pharmacy acceptable salt and pharmaceutically acceptable carrier.
7. each described quinoline of claim 1～5 or its pharmacy acceptable salt purposes in the medicine of preparation TSPK inhibitor.
8. the described purposes of claim 7, described TSPK is selected from epidermal growth factor recipient tyrosine specificity protein kinase and human epidermal growth factor receptor 2's TSPK.
9. each described quinoline of claim 1～5 or its pharmacy acceptable salt are for the preparation of the purposes in the medicine of the active hyperfunction disease that causes that treats and/or prevents TSPK.
10. each described quinoline of claim 1～5 or its pharmacy acceptable salt are for the preparation of the purposes in the medicine of the disease that treats and/or prevents cancer, arteriosclerosis and chronic eczema.
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