CN101659658A

CN101659658A - Quinoline substituted by cyan

Info

Publication number: CN101659658A
Application number: CN200910152099A
Authority: CN
Inventors: 易崇勤; 赵鸿莲
Original assignee: Peking University Founder Group Co Ltd; PKU International Healthcare Group Co Ltd; PKUCare Pharmaceutical R&D Center
Current assignee: 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
Priority date: 2008-08-29
Filing date: 2009-07-28
Publication date: 2010-03-03
Anticipated expiration: 2029-07-28
Also published as: CN101659658B

Abstract

The invention relates to a quinoline substituted by cyan shown in formula 1, wherein R<1>, X<1>, R<2>, R<3>, R<5>, n and m are defined in a specification; and the preparation method thereof comprisesthe medicine compounds and applications thereof in preparation of medicine which is used as an anti-proliferation agent and used for preventing or treating tumor which is sensitive to receptor tyrosine kinase inhibiting EGF and erbB.

Description

The quinoline that cyano group replaces

Technical field

The present invention relates to its methods of treatment that has anti-tumor activity and therefore be applicable to human or animal body of some novel quinoline or its pharmacy acceptable salt.The invention still further relates to the preparation method of described quinoline, the pharmaceutical composition that comprises them and their application in methods of treatment, for example be used for preventing or treating the application of the medicine of solid tumor disease in warm-blooded animal such as the human body in preparation.

Background technology

The disease that present many treatments are caused unusually by cell proliferation regulation and control such as the scheme of psoriasis and cancer have been utilized the compound that suppresses the synthetic and cell proliferation of DNA.So far, the compound that is used for this treatment has cytotoxicity usually, pretends usefulness but they have for quick noble cells such as cancer cells, and this effect is favourable.Developed at present the method for replaceable these cell toxicant antitumour drugs, for example the selective depressant of cell signal approach.The inhibitor of these types can show and strengthen selectively acting in the potentiality of antitumor cell, and therefore can reduce the probability of the adverse side effect that treatment has.

Eukaryotic cell makes like this and can carry out communication between the biological intravital cell constantly to many different extracellular signal reactions.The intracellular many physical responses of these Signal Regulation comprise propagation, differentiation, apoptosis and motion.The extracellular signal shows as various water-soluble factor form, comprises somatomedin and paracrine and endocrine factor.By the binding specificity transmembrane receptor, these parts to the intracellular signal transduction approach, therefore, pass signal transduction the extracellular signal combination plasma membrane and allow cell individual that its extracellular signal is replied.Many signal transduction processes are utilized the reverse process of protein phosphorylation effect, and described albumen participates in promoting above various cell responses.The phosphorylation state of target protein is regulated by specificity kinases and phosphoesterase, and these enzymes proteic about 1/3 are regulated all of mammalian genes group coding.Because phosphorylation is the very important regulation mechanism in the signal transduction process, therefore be understood that the not normal cell that will cause of approach is grown and prosoplasia in these cells, and (summary is referring to Cohen et al. therefore to promote transformation, Curr OpinChem Biol, 1999,3,459-465).

Well-known many Tyrosylprotein kinases sport the constitutive activity form and/or cause various human cells to transform after by overexpression.Kinase whose these sudden changes or overexpression form in accounting for the human tumor of significant proportion, all exist (summary referring to Kolibaba et al., Biochimica et BiophysicaActa, 1997,133, F217-F248).Because the vital role that Tyrosylprotein kinase has in the propagation of various tissues and differentiation has the research of a lot of development of new anti-cancer therapies all to concentrate on these enzymes.This family's enzyme is divided into two groups: receptor tyrosine kinase and nonreceptor tyrosine kinase are respectively for example EGF acceptor and SRC family.From the big quantity research result of (comprising the Human Genome Project), in human genome, identified about 90 kinds of Tyrosylprotein kinases, wherein 58 kinds is receptor type, and 32 kinds is non-receptor type.They can be divided into 20 kinds of receptor tyrosine kinases and 10 kinds of nonreceptor tyrosine kinase subfamilies (Robinson et al., Oncogene, 2000,19,5548-5557).

Receptor tyrosine kinase is to causing the mitogenesis signal transduction particularly important of cellular replication.These big glycoprotein of crossing over cytoplasmic membrane have the extracellular binding domains at its ligands specific (for example Urogastron of EGF acceptor (EGF)).Binding partner causes the kinase whose enzymic activity of activated receptor, and kinase activity is by the intracellular portion coding of acceptor.Crux tyrosine amino acid in this active phosphorus acidifying target protein makes the proliferation signal transduction pass cytoplasmic membrane.

The erbB family of known receptor Tyrosylprotein kinase (comprising EGFR, erbB2, erbB3 and erbB4) usually participates in promoting the propagation and the survival (summary is referring to Olayioye et al., EMBO J., 2000,19,3159) of tumour cell.A kind of mechanism that can finish this effect is the overexpression receptor protein, and overexpression is the result of gene amplification normally.This observes (summary is referring to Klapper et al., Adv.Cancer Res., 2000,77,25), for example mammary cancer (Sainsbury et al., Brit.J.Cancer, 1988,58,458 in a lot of common human cancers; Guerin et al., OncogeneRes., 1988,3,21; Slamon et al., Science, 1989,244,707; Kliin et al., Breast Cancer Res.Treat., 1994,29,73; Summary is referring to Salomon et al., Crit.Rev.Oncol.Hemato., 1995,19,183); Nonsmall-cell lung cancer (NSCLC) comprises gland cancer Cernyet al., Brit.J.Cancer, 1986,54,265; Reubi et al., Int.J.Cancer, 1990,45,269; Rusch et al., Cancer Research, 1993,53,2379; Brabender et al., Clin.Canc Res., 2001,7,1850) and other lung cancer (Hendler et al., CancerCells, 1989,7,347; Ohsaki et al., Oncol.Rep., 2000,7,603), bladder cancer (Neal et al., Lancet, 1985,366; Chow et al, Clin.Cancer Res., 2001,7,1957, Zhau et al., Mol Carcinog., 3,254), esophagus cancer (Mukaida et al., Cancer, 1991,68,142), gastrointestinal cancer colorectal carcinoma, the rectum cancer or cancer of the stomach (Bolen et al., OncogeneRes. for example, 1987,1,149; Kapitanovic et al., Gastroenterology.2000,112,1103; Ross et al., Cancer Invest., 2001,19,554), prostate cancer (Visakorpi et al., Histochem.J., 1992,24,481; Kumar et al., 2000,32,73; Scher et al., J.Natl.Cancer Inst., 2000,92,1866), leukemia (Konaka et al., Cell, 1984,37,1035, Martin-Subero et al., Cancer Genet Cytogenet., 2001,127,174), ovarian cancer (Hellstrom et al., Cancer Res., 2001,61,2420), head and neck cancer (Shiga et al., Head Neck, 2000,22,599) or carcinoma of the pancreas (Ovotny et al., Neoplasm, 2001,48,188).

Along with the expression of more mankind tumor tissue being tested the erbB family of its receptor tyrosine kinase, expection future their ubiquity and importance will further strengthen.

Result as one or more above-mentioned acceptors (particularly erbB2) mistake is regulated generally believes the richer clinically aggressiveness of many tumours, and therefore patient's prognosis poorer (Brabender etal., Clin.Cancer Res., 2001,7,1850; Ross et al., Cancer Investigation, 2001,19,554, Yu et al,, Bioessays, 2000,22.7,673).Except above clinical discovery, a large amount of clinical preceding information illustrates that receptor tyrosine kinase erbB family participates in cell transformation.Comprise following observed result: one or more erbB acceptors of many tumor cell line overexpressions; Behind non-tumor cell, they can transform these cells in transfection for EGFR or erbB2.This carciongenic potency is further confirmed: the transgenic mice of overexpression erbB2 becomes tumour in the mammary gland organic growth. in addition, a large amount of preclinical studies is verified to knock out one or more erbB activity by micromolecular inhibitor, dominance feminine gender or inhibiting antibody, (summary is referring to Mendelsohn et al. can to produce antiproliferative effect, Oncogene, 2000,19,6550).Therefore, the inhibitor of generally acknowledged these receptor tyrosine enzymes will have important value (Yaish et al as the selective depressant of mammalian cancer cells propagation, Science, 1988,242,933, Kolibaba et al., Biochimiea et Biophysica Acta, 1997,133, F217-F248; Al-Obeidi et al, 2000, Oncogene, 19,5690-5701; Mendelsohn et al., 2000, Oncogene, 19,6550-6565).Except these clinical preceding data, (summary is referring to Mendelsohn et al., 2000, Oncogene also to have confirmed to use the inhibition antibody (being respectively c-225 and trastuzumab) of EGFR and erbB2 to be of value to the clinical treatment of selected solid tumor, 19,6550-6565).

After testing the amplification and/or the activity of erbB receptor junket atmosphere acid kinase, therefore and infer this amplification and/or actively in a large amount of non-malignant proliferation diseases, have certain effect, for example following disease: psoriasis (Ben-Bassat, Curr.Pharm.Des., 2000,6,933; Elder et al., Science, 1989,243,811), benign prostate propagation (BPH) (Kumar et al., Int.Urol.Nephrol., 2000,32,73), pulse atherosclerosis and restenosis (Bokemeyer et al., KidneyInt., 2000,58,549).Therefore, expection erbB receptor tyrosine kinase inhibitor will can be used for treating other nonmalignant disease of above disease and excessive cell proliferation.

European patent application EP 566226 discloses some 4-phenylamino quinazoline, and it is a receptor tyrosine kinase inhibitors.

International Patent Application WO 96/33977, WO 96/33978, WO 96/33979, WO96/33980, WO 96/33981, WO 97/30034 and WO 97/38994 disclose some and have contained the phenylamino substituting group in the 4-position and at the quinazoline derivant of 6-and/or 7-substd, they have receptor tyrosine kinase and suppress active.

European patent application EP 837063 discloses the 4-amido quinazoline derivatives that aryl replaces, and its 6-or 7-position at the quinazoline ring has the part that comprises aryl or heteroaryl.It is said that these compounds are applicable to treatment hyper-proliferative sexual disorder.

International Patent Application WO 97/30035 and WO 98/13354 disclose the 4-phenylamino quinazoline that some 7-replaces, and it is the vascular endothelial growth factor receptor receptor tyrosine kinase inhibitors.

WO 00/55141 discloses 6, and the 4-phenylamino quinazoline compound that 7-replaces is characterized in that the substituting group of 6-and/or 7-position has ester connection portion (RO-CO).

WO 00/56720 openly is used for the treatment of 6 of cancer or atopic reaction, 7-dialkoxy-4-phenylamino quinazoline compound.

WO 02/41882 discloses the 4-phenylamino quinazoline compound that 6-and/or 7-position are replaced by pyrrolidyl-alkoxyl group or piperidyl-alkoxyl group.

WO 03/082290 disclose some 6, the 4-phenylamino quinazoline compound that 7-replaces has receptor tyrosine kinase and suppresses active. the object lesson of this compound is 6-{[1-(N-methylamino formyl radical methyl) piperidin-4-yl] the oxygen base-4-(3-chloro-4-fluoroanilino)-7-methoxyl group-quinazoline.

Summary of the invention

The applicant now is surprisingly found out that; increase substituting group and randomly increase other substituting group to formamyl and produced selected compounds group with enhanced activity to phenylamino; wherein compound has double activity; influenced activity especially as the erbB2 kinase inhibitor; but kept the EGF restraining effect simultaneously, made them be particularly suitable for clinically being applied to treatment and relating to this two kinds of kinase whose tumours.

Be not intended to hint that compound disclosed by the invention is only because have pharmaceutical active to a kind of biological procedures effect, but believe that The compounds of this invention provides antitumor action by suppressing one or more receptor tyrosine kinases erbB family, described receptor tyrosine kinase erbB family participates in causing the signal transduction step of tumor cell proliferation.Especially, think that The compounds of this invention provides antitumor action by suppressing EGFR and/or erbB2 receptor tyrosine kinase.

[summary of the invention]

1. the quinoline of formula I

Wherein n is 0,1,2 or 3,

Each R ⁵Independently be selected from halogen, cyano group, nitro, hydroxyl, amino, carboxyl, sulfamyl, trifluoromethyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl group, (1-6C) alkoxyl group, (2-6C) alkenyl oxy, (2-6C) alkynyl group oxygen base, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) alkoxy carbonyl, N-(1-6C) alkylsulfamoyl group and N, N-two-[(1-6C) alkyl] sulfamyl, C (O) NR ⁶R ⁷, R wherein ⁶And R ⁷Independently be selected from hydrogen, optional (1-6C) alkyl that replaces, optional (3-8C) cycloalkyl that replaces or the optional aryl that replaces, or R ⁶And R ⁷Form with the nitrogen that they connected and to comprise other heteroatomic optional substituted heterocycle;

X ¹Be direct key or O;

R ¹Be selected from hydrogen and (1-6C) alkyl, wherein (1-6C) alkyl is optional is replaced by one or more substituting groups, it can be identical or different, be selected from hydroxyl and halogen, and/or be selected from amino, nitro, carboxyl, cyano group, halogen, (1-6C) alkoxyl group, hydroxyl (1-6C) alkoxyl group, (2-8C) alkenyl, (2-8C) alkynyl group, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, formamyl, N-(1-6C) alkyl-carbamoyl, N, N two-[(1-6C) alkyl] formamyl, (2-6C) alkyloyl, (2-6C) alkyloyl oxygen base, (2-6C) alkanoylamino, the alkanoylamino of N-(1-6C) alkyl-(2-6C), (1-6C) alkoxy carbonyl, sulfamyl, N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkylsulfamoyl group, (1-6C) substituting group of alkane sulfuryl amino of alkane sulfuryl amino and N-(1-6C) alkyl-(1-6C);

M is 0,1,2 or 3;

R ²Be hydrogen or (1-6C) alkyl; And

R ³Be (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl group or (1-6C) alkoxyl group, its any group can be chosen wantonly at the carbon atom place by following replacement: (1-6C) alkoxyl group, amino, (1-6C) alkylamino, two-(1-6C) alkylaminos or wherein s be 0,1 or 2 group S (O) s (1-6C) alkyl, or be selected from oxygen, sulphur or NR optional comprising ⁸Other heteroatomic saturated 5 or 6 yuan of heterocycles, wherein R ⁸Be hydrogen, (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl group, (1-6C) alkyl sulphonyl or (1-6C) alkyl-carbonyl;

Or R ²And R ³The nitrogen-atoms that connects with them forms 5 and 6 yuan of saturated heterocycles, and be selected from oxygen, S, SO or S (O) its optional comprising ₂Or NR ⁸Other heteroatoms, R wherein ⁸As above definition;

2. according to the quinoline of project 1, wherein n is 1,2 or 3.

3. according to the quinoline of project 1 or 2, wherein n is 2 or 3.

4. according to each quinoline of project 1-3, wherein n is 2.

5. according to each quinoline of project 1-3, wherein n is 3.

6. according to each quinoline of aforementioned project, wherein each R ⁵Group is a halogen group.

7. according to each quinoline of aforementioned project, wherein each R ⁵Group is selected from chlorine and fluorine.

8. according to each quinoline of aforementioned project, it comprises R ⁵Group, this R ⁵Group is positioned at place, the position of its phenyl ring neighbour who connects-(2-).

9. according to the quinoline of project 8, wherein be positioned at the R at place, position of neighbour-(2-) ⁵Group is a fluorine.

10. according to each quinoline of aforementioned project, inferior formula (i) group among its Chinese style I:

Be (ii) group of inferior formula:

Wherein, (a) R ¹⁰Or R ¹²Be that hydrogen and another are halogens, and R ¹¹Be halogen, perhaps (b) R ¹⁰Be halogen, R ¹¹Be halogen, and R ¹²Be hydrogen or halogen, perhaps (c) R ¹⁰Be fluorine, R ¹¹Be chlorine, and R ¹²Be selected from hydrogen or fluorine.

11. according to the quinoline of project 10, wherein R ¹¹Or R ¹²One of be that hydrogen and another are fluorine, and R ¹¹Be chlorine.

12. according to the quinoline of project 10, wherein R ¹⁰Be fluorine, R ¹¹Be chlorine, and R ¹²Be hydrogen.

13. according to the quinoline of project 10, wherein R ¹¹Be fluorine, R ¹¹Be chlorine, and R ¹²It is fluorine.

14. according to each quinoline of aforementioned project, wherein X ¹Be oxygen.

15. according to each quinoline of aforementioned project, wherein R ¹Be selected from hydrogen, (1-6C) alkyl and (1-6C) alkoxyl group (1-6C) alkyl, wherein R ¹In optional one or more hydroxyls or the halogenic substituent of containing of any (1-6C) alkyl.

16. according to the quinoline of project 15, wherein R ¹Be selected from (1-6C) alkyl, its optional one or more hydroxyls or halogenic substituent of containing.

17. according to each quinoline of project 1-13, wherein R ¹-X ¹-be selected from hydrogen, methoxyl group, oxyethyl group and 2-methoxy ethoxy.

18. according to the quinoline of project 17, wherein R ¹-X ¹-be methoxyl group.

19. formula IA quinoline according to project 1:

R wherein ², R ³With m such as project 1 definition, R ¹⁰, R ¹¹And R ¹²As each definition of project 10-13, and R ¹³Be selected from hydrogen, methoxyl group, oxyethyl group and 2-methoxy ethoxy.

20. formula IB quinoline according to project 1:

R wherein ², R ³With m such as project 1 definition, and R ¹³Be selected from hydrogen, methoxyl group, oxyethyl group and 2-methoxy ethoxy.

21. formula IC quinoline according to project 1:

22. according to each quinoline of project 19-21, wherein R ¹³It is methoxyl group.

23. according to each quinoline of aforementioned project, wherein m is 0 or 1.

24. according to each quinoline of aforementioned project, wherein m is 1.

25. according to each quinoline of aforementioned project, wherein R ²Be hydrogen or (1-3C) alkyl.

26. according to each quinoline of aforementioned project, wherein R ²Be hydrogen or methyl.

27. according to each quinoline of aforementioned project, wherein R ²Be hydrogen.

28. according to each quinoline of aforementioned project, wherein R ³It is (1-6C) alkyl.

29. according to each quinoline of aforementioned project, wherein R ³It is (1-3C) alkyl.

30. according to each quinoline of aforementioned project, wherein R ³It is methyl.

31. according to the quinoline of project 1, its be selected from following one or more:

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(N-methylamino formyl radical methyl) piperidin-4-yl]-the oxygen base }-3-itrile group quinoline;

4-(3-chloro-2-fluoroanilino)-6-{[1-(N, N-formyl-dimethylamino methyl) piperidin-4-yl] the oxygen base }-7-methoxyl group-3-itrile group quinoline;

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(morpholine-4-base carbonyl methyl) piperidin-4-yl] the oxygen base }-3-itrile group quinoline;

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(tetramethyleneimine-1-base carbonyl) piperidin-4-yl] the oxygen base }-3-itrile group quinoline;

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(N-methylamino formyl radical) piperidin-4-yl] the oxygen base }-3-itrile group quinoline;

4-(3-chloro-2-fluoroanilino)-6-{[1-(N-(2-dimethyl aminoethyl) formamyl) piperidin-4-yl] the oxygen base }-7-methoxyl group-3-itrile group quinoline;

4-(3-chloro-2-fluoroanilino)-6-{[1-(N, N-formyl-dimethylamino) piperidin-4-yl] the oxygen base }-7-methoxyl group-3-itrile group quinoline;

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(beautiful jade-4-base carbonyl) piperidin-4-yl] the oxygen base }-3-itrile group quinoline;

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(N-[2-tetramethyleneimine-1-base ethyl] formamyl) piperidin-4-yl] the oxygen base }-3-itrile group quinoline;

4-(3-chloro-2,4 difluorobenzene amino)-7-methoxyl group-6-{[1-(N-methylamino formyl radical methyl) piperidin-4-yl] the oxygen base }-3-itrile group quinoline;

4-(3-chloro-2-fluoroanilino)-6-{[1-(N-ethylamino formyl radical methyl) piperidin-4-yl] the oxygen base }-7-methoxyl group-3-itrile group quinoline;

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(N-[2-(tetramethyleneimine-1-yl) ethyl] the carbamyl ylmethyl) piperidin-4-yl] the oxygen base)-3-itrile group quinoline;

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(N-(2-methoxy ethyl) carbamyl ylmethyl) piperidin-4-yl] the oxygen base }-3-itrile group quinoline;

4-(3-chloro-2-fluoroanilino)-6-{[1-(N-(2-dimethyl aminoethyl) carbamyl ylmethyl) piperidin-4-yl] the oxygen base }-7-methoxyl group-3-itrile group quinoline;

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-(1-[2-(4-methylpiperazine-1-yl)-2-oxygen ethyl] and piperidin-4-yl } the oxygen base)-3-itrile group quinoline;

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-(1-[2-piperazine-1-yl)-2-oxygen ethyl] piperidin-4-yl } the oxygen base)-3-itrile group quinoline; And

4-(3-chloro-2,4 difluorobenzene amino)-7-methoxyl group-6-(1-[2-(4-methylpiperazine-1-yl)-2-oxygen ethyl] and piperidin-4-yl } the oxygen base)-3-itrile group quinoline;

Or its pharmacy acceptable salt.

32. according to each the preparation method of quinoline of aforementioned project, it comprises, perhaps

Method (a) formula II compound:

R wherein ¹, X ¹, R ⁵Protect any functional group when having any implication as project 1 definition except needs with n,

React with the formula III compound:

R wherein ², R ³Protect any functional group when having any implication as project 1 definition except needs with m, and Lg is replaceable group, wherein this is reflected at suitable alkali and exists down and carry out easily,

Method (b) is modified the substituting group of another kind of formula I quinoline or its pharmaceutically-acceptable salts or is introduced substituting group, and any functional group is protected in compound such as preceding definition during except needs,

Method (c) formula IV compound:

R wherein ¹, X ¹, R ⁵Protect any functional group during except needs suc as formula the related definition of I with n, and formula V or the reaction of V ' compound:

R wherein ²And R ³As above definition and m ' are 0,1,2 or 3, and condition is to work as R ²It is not 0 when being hydrogen, and Lg is replaceable group;

The protecting group that method (d) is removed formula I quinoline or its pharmaceutically-acceptable salts;

The formula II compound of the above-mentioned definition of method (e) and above-mentioned definition except Lg be that the formula III compound of OH reacts under the Mitsunobu condition;

Method (f) is in order to prepare wherein R ¹-X ¹Be the formula I compound of hydroxyl, cracking is R wherein ¹-X ¹It is the formula I quinoline of (1-6C) alkoxyl group;

Method (g) is in order to prepare wherein X ¹Be O and R ¹Not those compounds of hydrogen, make formula VI compound:

R wherein ², R ³, R ⁵, m and n protect any functional group when having any implication as project 1 definition except needs, with formula R ¹The reaction of-Lg compound, wherein R ¹Having as any implication of project 1 definition is not hydrogen and to protect any functional group and Lg during except needs be replaceable group except it;

Method (h) is in order to prepare wherein R ¹Comprise (1-6C) alkoxyl group of (1-6C) alkoxyl group or replacement or (1-6C) the formula I compound of (1-6C) alkylamino of alkylamino or replacement, alkylation R wherein in the time of suitably ¹The formula I quinoline that comprises hydroxyl or primary amine or secondary amine group;

Method (i) is in order to prepare wherein R ¹The formula I compound that is replaced by group T; wherein T is selected from (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (2-6C) alkanoylamino, (1-6C) alkylthio, (1-6C) alkyl sulphinyl and (1-6C) alkyl sulphonyl, makes formula VII compound:

R wherein ², R ³, R ⁵, X ¹, n and m protect any functional group, R when having implication as preceding definition except needs ¹' be the R that defines as herein ¹Group is replaced by Lg except any T group, and Lg is replaceable group (for example chlorine or bromine), with the reaction of formula TH compound, protects any functional group when wherein T as above defines except needs;

Method (j) formula VIII compound:

R wherein ¹, R ², R ³, X ¹Protecting any functional group and Lg when having any implication as project 1 definition except needs with m is replaceable as previously mentioned group,

Aniline reaction with formula IX:

R wherein ⁵Protect any functional group when having any implication as project 1 definition except needs, and wherein this is reflected at suitable acid and exists down and carry out easily with n;

Method (k) is those formulas I compound of 1,2 or 3 in order to prepare m wherein, makes formula X compound:

Wherein m is 1,2 or 3 and R ¹, X ¹, R ⁵With n such as 1 definition of preceding project, protect any functional group during except needs, with formula R ²NHR ³Primary amine or secondary amine coupling, wherein R ²And R ³As project 1 definition;

Method (I) is by protecting the formula IV compound and the formula V of any functional group as defined above when needing " the compound reaction:

Use the reduction amination method;

Method (m) is for R wherein ³Be by amino, (1-6C) alkylamino, two-(1-6C) alkylaminos or comprise NR on carbon atom ⁸The formula I compound of (2-6C) alkyl of saturated 5 or 6 yuan of heterocyclic substituted, R wherein ⁸As definition in the project 1, through type XX compound:

R wherein ^3aBe Lg-(2-6C) alkyl, wherein Lg is foregoing replaceable group and R wherein ¹, R ², X ¹, R ⁵, m and n protect any functional group when having any implication as preceding definition except needs;

With ammonia or with suitable primary amine or secondary amine reaction,

And after any described method, remove any blocking group of existence.

33. a pharmaceutical composition, it contains just like the formula I quinoline of each definition of project 1-31 or its pharmacy acceptable salt and unites by pharmaceutically acceptable diluent or carrier.

34. as the application of the formula I quinoline of each definition of project 1-31 or its pharmacy acceptable salt as medicine.

35. be used in the warm-blooded animal body, producing the purposes of the medicine of antiproliferative effect in preparation as the formula I quinoline of each definition of project 1-31 or its pharmacy acceptable salt.

36. a method that produces antiproliferative effect in the warm-blooded animal body of this treatment of needs comprises the formula I quinoline or its pharmacy acceptable salt that give described animal such as each definition of project 1-31.

37. formula VI, VII, VIII, X or XX compound as project 32 definition.

[detailed Description Of The Invention]

First aspect present invention provides the following formula I quinoline:

Wherein n is 0,1,2 or 3,

Each R ⁵Independently be selected from halogen, cyano group, nitro, hydroxyl, amino, carboxyl, sulfamyl, trifluoromethyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl group, (1-6C) alkoxyl group, (2-6C) alkenyl oxy, (2-6C) alkynyl group oxygen base, (1-6C) alkylthio, (1-6C) alkyl sulphinyl; (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) alkoxy carbonyl, N-(1-6C) alkylsulfamoyl group and N, N-two-[(1-6C) alkyl] sulfamyl, C (O) NR ⁶R ⁷, R wherein ⁶And R ⁷Independently be selected from hydrogen, optional (1-6C) alkyl that replaces, optional (3-8C) cycloalkyl that replaces or the optional aryl that replaces, or R ⁶And R ⁷Form with the nitrogen that they connected and to comprise other heteroatomic optional substituted heterocycle;

X ¹Be directly strong or O;

R ¹Be selected from hydrogen and (1-6C) alkyl, wherein (1-6C) alkyl is optional is replaced by one or more substituting groups, it can be identical or different, be selected from hydroxyl and halogen, and/or be selected from amino, nitro, carboxyl, cyano group, halogen, (1-6C) alkoxyl group, hydroxyl (1-6C) alkoxyl group, (2-8C) alkenyl, (2-8C) alkynyl group, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, formamyl,-(1-6C) alkyl-carbamoyl, N, N two-[(1-6C) alkyl] formamyl, (2-6C) alkyloyl, (2-6C) alkyloyl oxygen base, (2-6C) alkanoylamino, the alkanoylamino of N-(1-6C) alkyl-(2-6C), (1-6C) alkoxy carbonyl, sulfamyl, N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) substituting group of alkane sulfuryl amino of alkane sulfuryl amino and N-(1-6C) alkyl-(1-6C);

M is 0,1,2 or 3;

R ²Be hydrogen or (1-6C) alkyl; And

R ³Be (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl group or (1-6C) alkoxyl group, any above-mentioned group can be chosen wantonly at the carbon atom place by following replacement: (1-6C) alkoxyl group, amino, (1-6C) alkylamino, two-(1-6C) alkylaminos or wherein s be 0,1 or 2 group S (O) s (1-6C) alkyl, or be selected from oxygen, sulphur or NR optional comprising ⁸Other heteroatomic saturated 5 or 6 yuan of heterocycles, wherein R ⁸Be hydrogen, (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl group, (1-6C) alkyl sulphonyl or (1-6C) alkyl-carbonyl;

Or R ²And R ³The nitrogen-atoms that connects with their forms 5 and 6 yuan of saturated heterocycles, and it is optional to comprise other and be selected from oxygen, S, SO or S (O) ₂Or NR ⁸Heteroatoms, R wherein ⁸As above definition;

In this manual, general term " alkyl " comprises straight chain and branched-chain alkyl for example propyl group, sec.-propyl and the tertiary butyl and (3-7C) cycloalkyl (for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl).But only refer to the straight chain type group when mentioning the concrete alkyl such as " propyl group ", only refer to the branched chain type group when mentioning the concrete branched-chain alkyl such as " sec.-propyl ", during the concrete cycloalkyl mentioned, for example " cyclopentyl " only refers to 5-unit ring, similarly agreement is applied to other general term, for example (1-6C) alkoxyl group comprises methoxyl group, oxyethyl group, ring propoxy-and cyclopentyloxy, (1-6C) alkylamino comprises methylamino, ethylamino, amino and the cyclohexyl amino of cyclobutyl, two [(1-6C) alkyl)] amino comprises dimethylamino, diethylamino, N-cyclobutyl-N-methylamino and N-cyclohexyl-N-ethylamino.

Term " aryl " is meant that aromatic hydrocarbon is such as phenyl and tea base.Term " heterocyclic " and " heterocycle " comprise it can being single and dicyclo and the ring structure that comprises 3-15 atom, wherein at least one atom and suitably 1-4 atom be oxygen, sulphur and nitrogen heteroatom.Ring can be fragrant, non-fragrance with part fragrance, a ring that promptly condenses ring system can be fragrance and another right and wrong fragrance.The object lesson of ring system comprises furyl like this, benzofuryl, tetrahydrofuran base, chromanyl, thienyl, benzothienyl, pyridyl, piperidyl, quinolyl, 1,2,3, the 4-tetrahydric quinoline group, isoquinolyl, 1,2,3, the 4-tetrahydro isoquinolyl, pyrazinyl, piperazine, pyrimidyl, pyridazinyl, quinoxalinyl, quinazolyl, the cinnolines base, pyrryl, pyrrolidyl, indyl, indolinyl, imidazolyl, benzimidazolyl-, pyrazolyl, indazolyl oxazolyl, benzoxazolyl isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, morpholinyl, 4H-1, the 4-benzoxazinyl, 4H-1,4-benzothiazine base, 1,2, the 3-triazolyl, 1,2,4-triazolyl oxadiazole base, furazanyl, thiadiazolyl group, tetrazyl, dibenzofuran group, dibenzothiophene basic ring oxirane group, oxetanyl, azetidinyl, THP trtrahydropyranyl, oxa-cyclic group in heptan, oxazepanyl, tetrahydrochysene-1, the 4-thiazinyl, 1,1-dioxo tetrahydrochysene 1, the 4-thiazinyl, homopiperidinyl, high piperazinyl, the dihydropyridine base, tetrahydro pyridyl, the dihydro-pyrimidin base, tetrahydro-pyrimidine base, tetrahydro-thienyl, tetrahydrochysene sulfo-pyranyl and thio-morpholinyl.

The object lesson of heterocyclic radical comprises THP trtrahydropyranyl, tetrahydrofuran base or N-(1-6C) alkyl pyrrolidine or N-alkyl (1-6C) piperidines.

When ring comprised nitrogen-atoms, it can have hydrogen atom or substituting group and can link to each other with other structure by nitrogen-atoms with the strong needs of the valency that satisfies nitrogen or they for (1-6C) alkyl such as if desired the time.Nitrogen-atoms in the heterocyclic group can be oxidized to the N oxide compound.

Usually, the desirable physical properties of this compound exhibits keeps high antiproliferative activity simultaneously such as high resolution.In addition, chemical compound lot of the present invention does not have activity or weak activity is only arranged in hERG measures.

Should be understood that the opticity or the racemic form that may have one or more unsymmetrical carbons in the formula I compound scope that more than some, defines, present invention resides in and have above-mentioned active any such opticity or a racemic form in its definition.Can be by the synthetic opticity form of the well-known standard technique of organic chemistry filed, for example utilize the opticity initial feed or prepare by the resolution of racemic form.Similarly, above-mentioned activity can adopt standard laboratory technological assessment hereinafter.

It is to be further understood that the tautomeric forms that present invention resides in all the formula I compounds in its definition with antiproliferative activity.

It is to be further understood that some formula I compound may exist solvate forms and non-solvent compound form, for example hydrate forms the present invention includes all such solvate forms with antiproliferative activity.

It is to be further understood that may there be polymorphic in some formula I compound, the present invention includes all such forms with antiproliferative activity.

The desired value that more than relates to general group comprises those following values.

In this specification sheets before this or after this defined arbitrary R ¹, R ², R ³Or R ⁵The appropriate value of group comprises:

For halogen: fluorine, chlorine, bromine and iodine;

For (1-6C) alkyl: methyl, ethyl, propyl group, sec.-propyl, uncle

Butyl, amyl group and hexyl;

For (1-4C) alkyl: methyl, ethyl, propyl group, sec.-propyl and uncle

Butyl;

For (1-6C) alkoxyl group: methoxyl group, oxyethyl group, propoxy-, different third

Oxygen base and butoxy;

For (2-8C) alkenyl: vinyl, pseudoallyl, allyl group and fourth

Thiazolinyl;

For (2-8C) alkynyl group: ethynyl, 2-propynyl and fourth-2-alkynyl;

For (2-6C) alkenyl oxygen: vinyloxy group and allyloxy;

For (2-6C) alkynyl group oxygen: second alkynyloxy group and 2-third alkynyloxy group;

For (1-6C) alkylthio: methylthio group, ethylmercapto group and rosickyite base;

For (1-6C) alkyl sulphinyl: methylsulfinyl and ethyl sulfinyl;

For (1-6C) alkyl sulphonyl: methyl sulphonyl and ethylsulfonyl;

For (1-6C) alkylamino: methylamino-, ethylamino, third amino, different third

Amino and fourth amino;

For two-[(1-6C) alkyl] amino: dimethylamino, diethylin, N-ethyl-N-

Methylamino and diisopropylaminoethyl;

For (1-6C) alkoxy carbonyl: methoxycarbonyl, ethoxy carbonyl, third oxygen

Base carbonyl and uncle-butoxy carbonyl;

For N-(1-6C) alkyl carbamoyl N-methylamino formyl radical, N-ethylamino

Base: formyl radical, N-propyl group formamyl and N-

The sec.-propyl formamyl;

For N, N-two-[(1-6C) alkyl] N, N-formyl-dimethylamino, N-ethyl

Formamyl :-N-methylamino formyl radical and N, N-two

The base formamyl;

For (2-6C) alkyloyl: ethanoyl, propionyl and isobutyryl;

For (2-6C) alkyloyl oxygen: acetoxyl group and propionyloxy;

For (2-6C) alkanoylamino: kharophen and propionamido;

For N-(1-6C) alkyl-(2-6C) alkane N-methyl kharophen and N-methyl propionyl ammonia

Acyl amino: base;

For N-(1-6C) alkyl sulphonamide N-methyl sulfamyl, N-ethyl sulphonamide

Base: base and N-sec.-propyl sulfamyl;

For N, N-two-[(1-6C) alkyl] ammonia N, N-dimethylamino alkylsulfonyl and N-methyl

Alkylsulfonyl :-N-ethyl sulfamyl;

For (1-6C) alkane sulfuryl amino: methylsulfonyl amino and ethylsulfonylamino;

Amino and the N-methyl second for the alkane N-methyl methylsulfonyl of N-(1-6C) alkyl-(1-6C)

Sulfuryl amino: sulfuryl amino;

For the alkoxyl group of hydroxyl-(1-6C): hydroxyl methoxyl group, 2-hydroxyl-oxethyl, 1-

Hydroxyl-oxethyl and 3-hydroxyl propoxy-.

Be interpreted as, work as R ¹By for example amino when replacing (1-6C) alkyl and for example being the 2-amino-ethyl, be (1-6C) alkyl and radicals X ¹Link to each other and (perhaps work as X ¹Link to each other with the quinoline ring when being directly strong).

When using (1-4C) alkyl in this manual, be construed as such group and be meant the alkyl that comprises maximum 4 carbon atoms.The representative example that those of skill in the art can understand such group is the example that comprises maximum 4 carbon atoms in above-mentioned (1-6C) alkyl, for example methyl, ethyl, propyl group, sec.-propyl, butyl and the tertiary butyl.Similarly, (1-3C) alkyl is meant that the alkyl that comprises maximum 3 carbon atoms is such as methyl, ethyl, propyl group and sec.-propyl.Similarly agreement is applicable to above-mentioned other group, for example (1-4C) alkoxyl group, (2-4C) alkenyl, (2-4C) alkynyl group and (2-4C) alkyloyl.

In formula I compound, hydrogen atom is present in 2,5 and 8 of quinoline ring.

The suitable pharmacy acceptable salt of formula I compound is the acid salt of formula I compound for example, for example with the inorganic or organic acid acid salt such as hydrochloric acid, Hydrogen bromide, sulfuric acid, trifluoroacetic acid, citric acid or toxilic acid; The salt that enough tart formula I compounds are perhaps for example arranged, for example basic metal or alkaline earth salt such as calcium salt or magnesium salts, ammonium salt or with the salt of organic bases such as methylamine, dimethylamine, Trimethylamine 99, piperidines, morpholine or three-(2-hydroxyethyl) amine.

The object lesson of n is 1,2 or 3, suitably 2 or 3.

Suitably, each R ⁵Independently be selected from halogen, trifluoromethyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl group or C (O) NR ⁶R ⁷Base, wherein R ⁶And R ⁷As above definition.

Especially, each R ⁵Independently be selected from halogen such as chlorine or fluorine.

Work as R ⁶And R ⁷When being not hydrogen; its concrete substituting group comprises halogen; nitro; cyano group; hydroxyl; amino; carboxyl; formamyl; sulfamyl; trifluoromethyl; (2-8C) alkenyl; (2-8C) alkynyl group; (1-6C) alkoxyl group; (2-6C) alkenyl oxy; (2-6C) alkynyl group oxygen base; (1-6C) alkylthio; (1-6C) alkyl sulphinyl; (1-6C) alkyl sulphonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; (1-6C) alkoxy carbonyl; N-(1-6C) alkyl-carbamoyl; N; N-two-[(1-6C) alkyl] formamyl; N-(1-6C) alkylsulfamoyl group; N, N-two-[(1-6C) alkyl] sulfamyl; (3-8C) cycloalkyl; aryl and heterocyclic radical.

R ⁶And R ⁷The object lesson of aryl substituent comprise phenyl or naphthyl, phenyl particularly.

R ⁶And R ⁷The object lesson of heterocyclic substituent comprise that 5 or 6 yuan of heterocycles are such as furyl, tetrahydrofuran base, thienyl, pyridyl, piperidyl, pyrazinyl, piperazinyl, pyrimidyl, pyridazinyl, pyrryl, pyrrolidyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, morpholinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazole base, furazanyl, thiadiazolyl group or tetrazyl.

Work as R ⁶And R ⁷When forming the heterocycle of optional replacement with the nitrogen-atoms that they connected, it for example is 5 or 6 yuan of rings, and it is saturated or unsaturated.Concrete example comprises piperidyl, pyrrolidyl, morpholinyl or thio-morpholinyl.Alternative, R ⁶And R ⁷Form (3-6C) alkenyl together.

R ⁶And R ⁷Can be with the heterocycle that the nitrogen-atoms that they connected forms by above-mentioned and R ⁶And R ⁷Relevant arbitrary group replaces.In addition; these rings can be replaced by one or more (1-6C) alkyl; himself can choose wantonly by one or more and be selected from following group and replace: halogen; nitro; cyano group; hydroxyl; amino; carboxyl; formamyl; sulfamyl; trifluoromethyl; (2-8C) alkenyl; (2-8C) alkynyl group; (1-6C) alkoxyl group; (2-6C) alkenyl oxy; (2-6C) alkynyl group oxygen base; (1-6C) alkylthio; (1-6C) alkyl sulphinyl; (1-6C) alkyl sulphonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; (1-6C) alkoxy carbonyl; N-(1-6C) alkyl-carbamoyl; N; N-two-[(1-6C) alkyl] formamyl; N-(1-6C) alkylsulfamoyl group or N, N-two-[(1-6C) alkyl] sulfamyl.

Work as R ⁶Or R ⁷When being not hydrogen, its exemplary substituting group is cyano group, hydroxyl, (2-8C) alkenyl, (2-8C) alkynyl group, (1-6C) alkoxyl group, (1-6C) alkylthio, (1-6C) alkylamino, aryl such as phenyl or heterocyclic radical such as furyl, in addition, works as R ⁶And R ⁷When forming ring with the nitrogen-atoms that they connected, (1-6C) alkyl is such as methyl.

When n is 1,2 or 3, a R ⁵Group is suitably in the position of phenyl ring neighbour-(2-).

When n is 1,2 or 3, a R ⁵Group suitably between phenyl ring-(3-) position.

Therefore, when n is 1, R ⁵Group suitably in the position of phenyl ring neighbour-(2-) or-(3-) position.

In the present invention on the other hand, when n is 2, first R ⁵Group suitably between phenyl ring-position, second R ⁵Group suitably in phenyl ring neighbour-position or right-position, this ring has substituting group at the 2-of phenyl ring and 3-or 3-and 4-position thus.

In the present invention on the other hand, when n is 2 or 3, first R ⁵Group is suitably in phenyl ring neighbour-position, second R ⁵Group is suitably-, and randomly (when n is 3), the 3rd R ⁵Group suitably phenyl ring right-position.Thus, when n was 2, this ring suitably had substituting group in the 2-and the 3-position of phenyl ring, and when n was 3, this ring suitably had substituting group in 2-, 3-and the 4-position of phenyl ring.

The quinoline that 2-that the applicant has been surprised to find at phenyl ring and 3-position or 2-, 3-and 4-position have a substituting group (for example halogenic substituent) has substituent quinoline than the 3-of phenyl ring and 4-position and has given compound enhanced activity, and these compounds have improved the effectiveness of anti-erbB 2 and/or EGFR (particularly erbB2) in raji cell assay Raji.The quinoline that 2-that it is believed that at phenyl ring and 3-position or 2-, 3-and 4-position have substituting group (for example halogenic substituent) also will improve the effectiveness of anti-erbB 2 and/or EGFR (particularly erbB2) in vivo.

Suitably, when n is 2 or 3, each R ⁵Group is that identical or different halogen atom is such as chlorine or fluorine.Suitably, at least one R ⁵Group is a fluorine, and at least one fluorine suitably is positioned at the position of the neighbour of phenyl ring-(2-).

Suitably, when n is 2, each R ⁵Group is identical or different halogen atom.Especially, R ⁵Group is a chlorine, and be preferably placed at its continuous phenyl ring between-(3-) position, another R ⁵Group is a fluorine, and it is preferably placed at position, the position of the neighbour of phenyl ring-(2-) or right-(4-) (preferred adjacent-(2-) position).

Suitably, when n is 3, each R ⁵Group is identical or different halogen atom.Especially, R ⁵Group is a chlorine, and be preferably placed at its continuous phenyl ring between-(3-) position, other two R ⁵Each fluorine naturally of group, it preferably lays respectively at position, the position of the neighbour of phenyl ring-(2-) and right-(4-).

Formula I Central Asia formula (i) group thus:

Object lesson be (ii) group of inferior formula:

Wherein, (a) R ¹⁰Or R ¹²Be hydrogen and another be halogen such as chlorine or fluorine, particularly fluorine, and R ¹¹Be halogen such as chlorine or fluorine, particularly chlorine, perhaps (b) R ¹⁰Be that halogen is such as chlorine or fluorine, particularly fluorine, R ¹¹Be halogen such as chlorine or fluorine, particularly chlorine, and R ¹²Be hydrogen or halogen such as chlorine or fluorine, particularly fluorine, perhaps (c) R ¹⁰Be fluorine, R ¹¹Be chlorine, and R ¹²Be hydrogen or fluorine.Especially, R ¹⁰, R ¹¹And R ¹²Define as (b) and/or (c).

In one embodiment, when n is 2, each R ⁵Group is identical or different halogen atom (such as fluorine and/or chlorine) and first R ⁵Group is positioned at phenyl ring neighbour-position and second R ⁵Between being positioned at-position, at this moment (i) when m is 0,1,2 or 3, R ³Not (1-6C) alkyl and (ii) when m is 0, R ²And R ³Do not form and optional comprise other and be selected from oxygen, S, SO or S (O) with the nitrogen-atoms that they connected ₂Or NR ⁸Saturated 5 or 6 yuan of heterocycles, wherein R ⁸Be hydrogen, (1-4C) alkyl or (1-4C) alkyl sulphonyl.

Suitably, X ¹Be oxygen.

Especially, R ¹Be selected from hydrogen, (1-6C) alkyl and (1-6C) alkoxyl group (1-6C) alkyl, wherein R ¹In optional one or more (suitably being 1 or 2) hydroxyl or the halogenic substituent that contain of arbitrary (1-6C) alkyl.More particularly, R ¹Be selected from (1-6C) alkyl, preferably (1-4C) alkyl and more preferably (1-2C) alkyl.For example, R ¹It can be methyl.

For example, R ¹-X ¹-be selected from methoxyl group, oxyethyl group, sec.-propyl oxygen base, cyclo propyl methoxy, 2-hydroxyl-oxethyl, 2-fluorine oxyethyl group, 2-methoxy ethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoro ethoxy or 3-hydroxy-3-methyl butoxy.

Especially, R ¹-X-is selected from hydrogen, (1-4C) alkoxyl group and (1-4C) alkoxyl group (1-4C) alkoxyl group.For example, R ¹-X-is selected from hydrogen, methoxyl group, oxyethyl group and 2-methoxy ethoxy.

Suitably, m is 1,2 or 3.Preferably, m is 0 or 1 (more preferably 1).

Work as R ²And R ³Form optionally when comprising other heteroatomic saturated heterocyclic with the nitrogen-atoms that they connected, this heterocycle is 6 yuan of rings particularly.

Work as R ²And R ³Form optionally when comprising other heteroatomic saturated 5 or 6 (preferred 6) first heterocycle with the nitrogen-atoms that they connected, it suitably comprises and is selected from O and NR ⁸Other heteroatoms, R wherein ⁸Related definition suc as formula I.

Work as R ²And R ³Form optionally when comprising other heteroatomic saturated 5 or 6 yuan of heterocycles with the nitrogen-atoms that they connected, it suitably contains pyridine ring, morpholine ring, piperidine ring or piperazine ring, chooses wantonly at possible nitrogen-atoms place by the R suc as formula the I related definition ⁸Replace.

R ⁸The object lesson of group comprises that (1-3C) alkyl is such as methyl; (1-3C) alkyl sulphonyl is such as methyl sulphonyl; (1-3C) alkyl-carbonyl is such as ethanoyl; (2-4C) alkenyl is such as allyl group; Or (2-4C) alkynyl group such as proyl.Especially, R ⁸Be that (1-3C) alkyl is such as methyl.

Thus, work as R ²And R ³Form optionally when comprising other heteroatomic saturated 5 or 6 yuan of heterocycles with the nitrogen-atoms that they connected, it suitably contains the morpholine ring.Other example comprises tetramethyleneimine, piperidines, piperazine or N methyl piperazine, particularly piperazine or N methyl piperazine.

Preferably, R ²Be hydrogen or (1-3C) alkyl.

Especially, R ²Be hydrogen or methyl (preferred hydrogen).

R ³Suitable substituting group comprise (1-6C) alkoxyl group, (1-6C) alkylamino, two-(1-6C) alkylaminos or optionally comprise other and be selected from oxygen, sulphur or NR ⁸Heteroatomic saturated 5 or 6 yuan of heterocycles, wherein R ⁸As above definition.

Especially, R ³Suitable substituting group comprise (1-3C) alkoxyl group such as methoxyl group, amino, (1-3C) alkylamino, two-(1-3C) alkylaminos such as dimethylamino, (1-3C) alkyl sulphonyl, pyrrolidine ring or piperazine ring, its on possible nitrogen-atoms, can comprise (1-3C) alkyl such as methyl, (2-4C) alkenyl such as vinyl, (2-4C) alkynyl group such as proyl, (1-5C) alkyl sulphonyl such as methylsulfonyl or (1-6C) alkyl-carbonyl such as ethanoyl.

Suitably, R ³Be (1-6C) alkyl, (1-3C) alkyl particularly is such as methyl or ethyl.Suitably, R ²Be hydrogen and R ³Be (1-6C) alkyl, particularly (1-3C) alkyl is such as methyl or ethyl.

The object lesson of formula I compound is a formula IA compound:

R wherein ², R ³As above define R with m ¹⁰, R ¹¹And R ¹²As above inferior formula related definition (ii), and R ¹³Be selected from hydrogen, methoxyl group, oxyethyl group and 2-methoxy ethoxy, particularly methoxyl group.

The special example of other of formula I compound is formula IB and IC compound:

R wherein ², R ³As above define and R with m ¹³Be selected from hydrogen, methoxyl group, oxyethyl group and 2-methoxy ethoxy, particularly methoxyl group.

The special example of other of formula I compound is a formula ID compound:

Wherein:

R ^5aAnd R ^5bIndependently be selected from halogen (for example fluorine and/or chlorine);

X ¹Be directly strong or O;

R ¹Be selected from hydrogen and (1-6C) alkyl, wherein (1-6C) alkyl is optional is replaced by one or more substituting groups, it can be identical or different, be selected from hydroxyl and halogen, and/or be selected from following substituting group: amino, nitro, carboxyl, cyano group, halogen, (1-6C) alkoxyl group, hydroxyl (1-6C) alkoxyl group, (2-8C) alkenyl, (2-8C) alkynyl group, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, formamyl, N-(1-6C) alkyl-carbamoyl, N, N two-[(1-6C) alkyl] formamyl, (2-6C) alkyloyl, (2-6C) alkyloyl oxygen base, (2-6C) alkanoylamino, the alkanoylamino of N-(1-6C) alkyl-(2-6C), (1-6C) alkoxy carbonyl, sulfamyl, N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) the alkyl sulfonyl amino of amino and N-(1-6C) alkyl of alkyl sulfonyl-(1-6C);

M is 0,1,2 or 3;

R ²Be hydrogen or (1-6C) alkyl;

R ³It is (1-6C) alkyl, wherein (1-6C) alkyl is chosen wantonly on carbon atom by following replacement: (1-6C) alkyl, amino, (1-6C) alkylamino, two-(1-6C) alkylaminos or wherein s be 0,1 or 2 group S (O) s (1-6C) alkyl, or be selected from oxygen, sulphur or NR optional comprising ⁸Other heteroatomic saturated 5 or 6 yuan of heterocycles, wherein R ⁸Be nitrogen, (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl group, (1-6C) alkyl sulphonyl or (1-6C) alkyl-carbonyl; Or when m is 0, R ²And R ³The nitrogen-atoms that is connected with them forms 5 and 6 yuan of saturated heterocycles together, and it is optional to comprise other and be selected from oxygen, S, SO or S (O) ₂Or NR ⁸Heteroatoms, R wherein ⁸Be hydrogen, (1-4C) alkyl or (1-4C) alkyl sulphonyl.

Or its pharmacy acceptable salt.

In a kind of embodiment of formula ID compound, R ³Group is (1-6C) alkyl, particularly unsubstituted (1-6C) alkyl.R for example ³Group is methyl or ethyl, particularly methyl.

In the another embodiment of formula ID compound, m is 0 and R ²And R ³The nitrogen-atoms that is connected with them forms 5 and 6 yuan of saturated heterocycles together, and it is optional to comprise other and be selected from oxygen, S, SO or S (O) ₂Or NR ⁸Heteroatoms, R wherein ⁸Be hydrogen, (1-4C) alkyl or (1-4C) alkyl sulphonyl.R for example ²And R ³The nitrogen-atoms that is connected with them together forms the morpholine ring.Other example comprises tetramethyleneimine, piperidines, piperazine or N methyl piperazine, particularly piperazine or N methyl piperazine.

Obviously the novel especially compound of the present invention comprises formula I compound (comprising IA, IB, IC and ID) to those skilled in the art, except as otherwise noted, and each R wherein ¹, R ², R ³, R ⁵, X ¹, m and n have aforementioned arbitrary implication.

Formula I quinoline for example comprises one or more:

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(morpholine-4-base carbonyl) piperidin-4-yl] the oxygen base }-3-itrile group quinoline;

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-(1-[2-(piperazine-1-yl)-2-oxygen ethyl] and piperidin-4-yl } the oxygen base)-3-itrile group quinoline; And

Or its pharmacy acceptable salt.

The special example of formula I quinoline comprises one or more:

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(N-[2-(tetramethyleneimine-1-yl) ethyl] the carbamyl ylmethyl) piperidin-4-yl] the oxygen base }-3-itrile group quinoline;

Or its pharmacy acceptable salt.

The special example of formula I quinoline comprises one or more:

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(N-methylamino formyl radical methyl) piperidin-4-yl] the oxygen base }-3-itrile group quinoline; And

Or its pharmacy acceptable salt.

The special example of formula IB quinoline comprises one or more:

4-(3-chloro-2-fluoroanilino)-6-{[1-(N, N-formyl-dimethylamino) piperidin-4-yl] the oxygen base } 7-methoxyl group-3-itrile group quinoline;

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-(1-[2-(4-methylpiperazine-1-yl)-2-oxygen ethyl] and piperidin-4-yl } the oxygen base)-3-itrile group quinoline; And

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-(1-[2-(piperazine-1-yl)-2-oxygen ethyl] and piperidin-4-yl } the oxygen base)-3-itrile group quinoline;

Or its pharmacy acceptable salt.

The special example of formula IC quinoline comprises one or more:

4-(3-chloro-2,4 difluorobenzene amino)-7-methoxyl group-6-{[1-(N-methylamino formyl radical methyl) piperidin-4-yl] the oxygen base }-3-itrile group quinoline; And

Or its pharmacy acceptable salt.

The special example of formula ID quinoline comprises one or more:

4-(3-chloro-2-fluoroanilino)-6-{[1-(N, N-dimethylamino formyl) piperidin-4-yl] the oxygen base }-7-methoxyl group-3-itrile group quinoline;

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(N-(2-methoxy ethyl) carbamyl ylmethyl) piperidin-4-yl] the oxygen base }-3-itrile group quinoline; And

Or its pharmacy acceptable salt.

The special example of formula ID quinoline comprises one or more:

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(morpholine-4-base carbonyl) piperidin-4-yl] the oxygen base }-3-itrile group quinoline; And

Or its pharmacy acceptable salt.

Particularly preferred formula I compound for example is 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(N-methyl rn formyl radical methyl) piperidin-4-yl] the oxygen base }-3-itrile group quinoline, or its pharmacy acceptable salt.

Another particularly preferred formula I compound for example is 4-(3-chloro-2,4 difluorobenzene amino)-7-methoxyl group-6-{[1-(N-methylamino formyl radical methyl]) piperidin-4-yl] the oxygen base }-3-itrile group quinoline, or its pharmacy acceptable salt.

Another particularly preferred formula I compound for example is 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(N-[2-(tetramethyleneimine-1-yl) ethyl] carbamyl ylmethyl) piperidin-4-yl] the oxygen base }-3-itrile group quinoline, or its pharmacy acceptable salt.

Another particularly preferred formula I compound for example is 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-({ 1-[2-(4-methylpiperazine-1-yl)-2-oxygen ethyl] piperidin-4-yl } oxygen base)-3-itrile group quinoline, or its pharmacy acceptable salt.

Another particularly preferred formula I compound for example is 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-({ 1-[2-(piperazine-1-yl)-2-oxygen ethyl] piperidin-4-yl } oxygen base)-3-itrile group quinoline, or its pharmacy acceptable salt.

Synthesizing of formula I quinoline

The present invention provides the preparation method of formula I quinoline or its pharmaceutically-acceptable salts on the other hand.To be interpreted as that some substituting group may need protection to take precautions against the reaction that they do not need in some following method.When skilled chemist needs this protection if will understanding, how such protecting group is placed correct position and amiable how sloughing.

The example of relevant protecting group can be referring to the common teaching material of many relevant these contents, ' Protective Groups in Organic Synthesis ' (the John Wiley﹠amp that for example TheodoraGreen showed; Sons publishes).Removing of protecting group can be undertaken by the method that being fit to known to any ordinary method described in the document or the chemist that is skilled in technique removed the protecting group of being discussed; selected these class methods should be able to be removed protecting group, and the interference to other group of molecule simultaneously reduces to minimum.

Therefore, if reactant comprises for example groups such as amino, carboxyl or hydroxyl, described group may need protection in some reaction mentioned above.

The blocking group that is fit to amino or alkylamino is for example acyl group, and for example alkyloyl is (as ethanoyl, alkoxy carbonyl (as methoxycarbonyl, ethoxy carbonyl or tert-butoxycarbonyl, aryl methoxy carbonyl (as benzyloxycarbonyl or aroyl (for example benzyl acyl group).The deprotection condition of above-mentioned protecting group must change with selected protecting group.Therefore, for example can be such as the acyl group of alkyloyl or alkoxy carbonyl or aroyl by removing with suitable alkali such as alkali metal hydroxide (as lithium hydroxide or sodium) hydrolysis.Perhaps; acyl group such as uncle-butoxy carbonyl for example can be removed by handling with suitable acid (example hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid), for example can be by removing through catalyzer (as by palladium carbon) hydrogenation or by handling with Lewis acid (as three (trifluoroacetic acid) boron) such as the fragrant methoxycarbonyl of benzyloxycarbonyl.The protecting group that other of primary amino is fit to is for example phthaloyl, and it can be by handling with alkylamine (as dimethylaminopropylamine) or removing with the hydrazine processing.

The appropriate protection group of hydroxyl is for example acyl group, and for example the alkane acyl is such as ethanoyl, aroyl (for example benzyl acyl group) or arylmethyl (as benzyl).The deprotection condition of above-mentioned protecting group must change with selected protecting group.Therefore, for example can remove such as the acyl group of alkyloyl or aroyl by separating with suitable alkali such as alkali metal hydroxide (as lithium hydroxide or sodium) or ammoniacal liquor.Perhaps, for example can be such as the arylmethyl of benzyl by removing through catalyzer (as by palladium carbon) hydrogenation.

The appropriate protection group of carboxyl is for for example becoming the group of ester; for example methyl or ethyl; it can be by removing with alkali such as sodium hydroxide hydrolysis; the perhaps tertiary butyl for example; it can be removed by handling as organic acid (as trifluoroacetic acid) with acid; perhaps benzyl for example, it can be by removing through catalyzer (as by palladium carbon) hydrogenation.

Also usable resins is as protecting group.

The routine techniques that can adopt chemical field to know is removed protecting group in any step easily of described synthetic.

Can be by being applicable to quinoline or its pharmacy acceptable salt of the known any method preparation formula I for preparing the chemofacies related compounds.Being used for the quinoline of preparation formula I or these methods of its pharmacy acceptable salt provides another feature of the present invention, and these methods are illustrated by following representative embodiment.Necessary raw material can obtain by the organic chemistry standard method (referring to, Advanced Organic Chemistry (Wiley-Interscience) for example, Jerry March).The preparation of these raw materials is described in subsidiary non-limiting example.In addition, can obtain necessary raw material by the similar approach with those explanations, these methods are within organic chemist's ordinary skill ability.About the information of essential raw material of preparation or related compound (can adopt it to form essential raw material) also can and apply in following patent in discovery, the content of its methods involving part is attached among the present invention by introducing at this: WO 94/27965, WO 95/03283, WO 96/33977, WO 96/33978, WO96/33979, WO 96/33980, WO 96/33981, WO 97/30034, WO 97/38994, WO 01/66099, US 5,252,586, EP 520722, EP 566226, EP 602851 and EP635507.

The present invention also provides by the following method (a) to (m) preparation formula I quinoline or its pharmaceutically-acceptable salts (wherein except as otherwise noted, each variable-definition is as above):

Step (a) through type II compound:

R wherein ¹, X ¹, R ⁵Protect any functional group when having any as defined above implication except needs, react with the formula III compound with n:

R wherein ², R ³Protect any functional group when having any as defined above implication except needs with m, and Lg is replaceable group, wherein this is reflected at suitable alkali and exists down and carry out easily, and after this removes existing protecting group by ordinary method.

The group L g that is easy to replace for example is halogen, alkane alkylsulfonyl oxygen base or arylsulfonyl oxygen groups, for example chlorine, bromine, methylsulfonyl oxygen base, 4-oil of mirbane alkylsulfonyl oxygen base or toluene-4-alkylsulfonyl oxygen base (suitable is methylsulfonyl oxygen base, 4-oil of mirbane alkylsulfonyl oxygen or toluene-4-alkylsulfonyl oxygen base).

This is reflected under the alkali existence has advantage.Suitable alkali for example is organic amine alkali such as diisopropyl ethyl amine, pyridine, 2,6-lutidine, trimethylpyridine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine or diazabicyclo [5.4.0] 11-7-alkene, or for example basic metal or alkaline earth metal carbonate or oxyhydroxide, for example yellow soda ash, salt of wormwood, cesium carbonate, lime carbonate, nitrogen sodium oxide or potassium hydroxide.Alternatively, this alkali for example is alkalimetal hydride such as sodium hydride, basic metal or alkaline-earth metal acid amides, for example acid amides sodium or two (trimethyl silyl) acid amides sodium or enough alkali metal halide such as the cesium fluoride and the sodium iodide of alkalescence.This is reflected at inert solvent or the thinner existence is suitably carried out down, solvent or thinner be alcohol or ester such as methyl alcohol, ethanol, 2-propyl alcohol or ethyl acetate for example, halogenated solvent such as methylene dichloride, trichloromethane or tetracol phenixin, ether such as tetrahydrofuran (THF) or 1, the 4-dioxane, aromatic hydrocarbon solvent such as toluene, or suitable dipolar aprotic solvent such as N, dinethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-ketone or dimethyl sulfoxide (DMSO).This is reflected in a certain temperature range and carries out easily as 10-150 ℃ (or solvent boiling point), suitably at 20-90 ℃.

Suitable especially alkali is cesium fluoride.This is reflected at inertia dipolar aprotic solvent such as N,N-dimethylacetamide or N, suitably carries out in the dinethylformamide.

This reaction is suitably carried out under 25-85 ℃ of temperature.

Method (b) by modification formula I quinoline or its pharmaceutically-acceptable salts substituting group or introduce substituting group, compound such as preceding definition are protected any functional group during except needs, and are after this removing any protecting group by ordinary method.

Known in the art substituting group is converted into other substituent method.For example alkylthio can be oxidized to alkyl sulphinyl or alkyl sulphonyl; cyano reduction is amino; nitroreduction is amino; hydroxyl turns to methoxyl group through alkyl; bromo is converted into alkylthio, and amino can generate alkanoylamino (for example with suitable acyl chlorides or anhydride reaction) or alkyloyl oxygen based hydrolysable is hydroxyl (for example the acetoxyl group ethanoyl can be converted into hydroxyacetyl) through acidylate.Easily, can be as the final step of preparation I compound with a R ¹Groups converted is another R ¹Group.

Method (c) through type IV compound:

R wherein ²And R ³Protect any functional group when as above defining except needs, and m ' is 0,1,2 or 3, condition is to work as R ²It is not 0 when being hydrogen, and Lg is replaceable group (for example halogen such as a chlorine or bromine).

Above-mentioned be reflected at suitable alkali (such as describe in the method (a) those, for example salt of wormwood, triethylamine, 4-dimethylaminopyridine or two-sec.-propyl ethamine) exist down and in the presence of inert solvent or thinner (for example inert solvent and thinner such as N-methylpyrrolidin-2-ketone, acetonitrile, N,N-dimethylacetamide, methyl alcohol, ethanol or the methylene dichloride of description in method (a)), carry out easily easily.

When m ' was 1,2 or 3, this was reflected at propiodal such as sodium iodide or potassiumiodide and exists down, suitably suitably carries out in 10-90 ℃ of temperature range at for example 10-150 ℃ (or solvent boiling point).For example, when m was 1, this reaction can use triethylamine as suitably alkali, potassiumiodide carry out under about 80 ℃ of temperature as appropriate solvent or thinner as suitable propiodal and N,N-dimethylacetamide.

When m is 0, the typical temperature that does not need propiodal and this reaction be 0 ℃ to room temperature.

The reaction of formula IV compound and formula V ' compound is applicable to and prepares wherein R ²Formula hydrogen and m are 0 compounds.

Method (d) is by removing the protecting group of formula I quinoline or its pharmaceutically-acceptable salts.

The known proper method of removing protecting group is also discussed in this article.For example in order to generate wherein R ¹Comprise the formula I compound of primary amine or secondary amine, cracking is R wherein ¹The corresponding formula I compound that comprises protected primary amine or secondary amine group.

Suitable amino protecting group for example is disclosed before this arbitrary amino protecting group.The proper method of these amino protecting groups of cracking is disclosed before this.Especially, suitable protecting group be than lower alkoxycarbonyl such as tert-butoxycarbonyl, it can be in the popular response condition such as cracking under the acid-catalyzed hydrolysis, for example in the presence of trifluoroacetic acid.

Method (e) is reacted under the Mitsunobu condition by the formula II compound of above-mentioned definition and the formula III compound of above-mentioned definition, except Lg is OH, after this removes the protecting group of any existence by ordinary method.

Suitable Mitsunobu condition comprises, for example, in the presence of suitable three grades of phosphines and the two-alkyl azodicarboxylate, suitably reaction at ambient temperature in organic solvent such as THF or suitable methylene dichloride and 0 ℃ of-60 ℃ of temperature range.Three grades of suitable phosphines for example comprise three-just-butyl phosphine or suitably are three-Phenylphosphine.Suitable two-alkyl azodicarboxylate for example comprises diethylazodicarboxylate (DEAD) or suitably is azo-2-carboxylic acid's two-tert-butyl ester.The details of Mitsunobu reaction is included in Tet.Letts., and 31,699, (1990); The Mitsunobu Reaction, D.L.Hughes, Organic Reactions, 1992, Vol.42,335-656 and Progress in the MitsunobuReaction, D.L.Hughes, Organic Preparations and ProceduresInternational, 1996, Vol.28 is among the 127-164.

Method (f) is by cracking R wherein ¹-X ¹The formula I quinoline that is (1-6C) alkoxyl group prepares wherein R ¹-X ¹It is the formula I compound of hydroxyl.

This scission reaction can be by known this conversion of realization one of many methods finish.R wherein ¹The scission reaction that is the formula I compound of (1-6C) alkyl for example handles or uses basic metal diaryl phosphides such as diphenylphosphine lithium to handle and can finish by use basic metal (1-6C) alkyl sulfur compounds such as sulfur alcohol sodium.Alternatively, this scission reaction is for example by using boron or aluminium trihalid such as boron tribromide processing quinoline or finishing by reacting with mineral acid such as trifluoroacetic acid.These are reflected at above-mentioned suitable inert solvent or the thinner existence is suitably carried out down.Preferred scission reaction is to use pyridine hydrochloride to handle the quinoline of formula I.This scission reaction for example 10-150 ℃ for example suitably finish in 25-80 ℃ of temperature range.

R wherein ², R ³, R ⁵, m and n protect any functional group when having any as defined above implication except needs, with formula R ¹The reaction of-Lg compound, wherein R ¹Protecting any functional group, Lg when having any as defined above implication except needs is replaceable group, and wherein this is instead suitably carrying out in the presence of the alkali easily;

Remove any protecting group of existence subsequently by any ordinary method.

Suitable replaceable group, Lg as definition in the preceding method (a), for example is a chlorine or bromine.This is reflected at suitable alkali existence and suitably carries out down.Appropriate solvent, thinner or alkali for example comprise those that preceding method (a) is relevant.Alternatively, Lg is a hydroxyl, and this reaction can be carried out under the Mitsunobu condition, as preceding method (e) associated description.

Method (h) is in order to prepare wherein R ¹Comprise (1-6C) alkoxyl group of (1-6C) alkoxyl group or replacement or (1-6C) the formula I compound of (1-6C) alkylamino of alkylamino or replacement, in the time of suitably, as the described suitable alkali of preceding method (a) in the presence of alkylation R wherein ¹The formula I quinoline that comprises hydroxyl or primary amine or secondary amine group.

Suitable alkylating reagent alkylate hydroxyl for example known in the art forms the alkoxyl group or the amino any reagent that forms the alkylamino of alkylamino or replacement of alkylation of alkoxyl group or replacement, the halogenide of alkyl or substituted alkyl for example, for example (1-6C) alkyl chloride, bromide, iodide, easily as defined above suitably in the presence of the alkali, suitable inert solvent or thinner as defined above and in 10-140 ℃ of temperature range for example easily in envrionment temperature or near under the envrionment temperature.Can use similar approach will choose wantonly (2-6C) alkyloyl oxygen base of replacement, (2-6C) alkanoylamino and (1-6C) the alkane sulfuryl amino introduce R ¹

In order to prepare wherein R easily ¹The formula I compound that comprises (1-6C) alkylamino of (1-6C) alkylamino or replacement, can use formaldehyde or (2-6C) alkyl aldehydes (for example acetaldehyde or propionic aldehyde) implement reduction amination.For example, in order to prepare wherein R ¹Those formulas I compound that comprises the N-methyl, the respective compound that comprises the N-H group can suitably reacted in the presence of the reductive agent with formaldehyde.Suitable reductive agent for example is for example formic acid, aluminum hydride basic metal thing such as a lithium aluminum hydride or suitably for alkali metal borohydride such as sodium borohydride, trimethoxy sodium borohydride and sodium triacetoxy borohydride of hydride reducer.This is reflected at suitable inert solvent or thinner and for example is used for than the tetrahydrofuran (THF) and the ether of strong reductant such as lithium aluminum hydride or is used for carrying out easily than the methylene dichloride of weak reductant such as sodium triacetoxy borohydride and sodium cyanoborohydride or protic solvent such as methyl alcohol or ethanol.When reductive agent was formic acid, this reaction used aqueous formic acid to carry out easily.This is reflected at 10-100 ℃ such as in the 70-90 ℃ of temperature range or near carrying out under the envrionment temperature.Easily, when reductive agent is formic acid, prevent on the NH group that alkylating protecting group from can remove on the spot such as tert-butoxycarbonyl (for example from synthetic starting raw material time just exist) reaction process.

R wherein ², R ³, R ⁵, X ¹, n and m protect any functional group, R when having implication as preceding definition except needs ¹' be R as defined herein ¹Group is replaced by Lg except any T group, and Lg is replaceable group (for example chlorine or bromine, or methanesulfonates),

With the reaction of formula TH compound, protect any functional group when wherein T as above defines except needs;

Remove any blocking group of existence subsequently by ordinary method.

This is reflected at suitable alkali existence and carries out easily down.This is reflected in suitable inert solvent or the thinner and can carries out easily.Suitably alkali, solvent and thinner for example are described in the method (a).This is reflected under the temperature of for example 10-150 ℃, for example 30-60 ℃ and suitably carries out.

Method (j) through type VIII compound:

R wherein ¹, R ², R ³, X ¹Protecting any functional group and Lg when having foregoing implication except needs with m is replaceable as previously mentioned group,

Aniline reaction with formula IX:

R wherein ⁵Protect any functional group when having foregoing any implication except needs, and wherein this is reflected at suitable acid and exists down and carry out easily, removes any blocking group of existence subsequently by ordinary method with n.

The suitable replaceable group of Lg representative as previously mentioned, particularly halogen such as chlorine.

This is reflected at suitable inert solvent or thinner for example alcohol or ester such as methyl alcohol, ethanol, Virahol or ethyl acetate, halogenated solvent such as methylene dichloride, chloroform or tetracol phenixin, ether such as tetrahydrofuran (THF) or 1, the 4-diox, aromatic solvent such as toluene or dipolar aprotic solvent such as N, carry out easily in dinethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-ketone acetonitrile or the dimethyl sulfoxide (DMSO).This for example is reflected at 10-250 ℃ and carries out easily in 40-120 ℃ of temperature range or under the reflux temperature of solvent or thinner easily.Easily, formula VIII compound and formula IX compound at polar solvent such as Virahol, easily for example in the presence of the catalytic amount acid, react under these conditions in acid.Suitable acid comprises the ether Huo dioxane solution and the spirit of salt of hydrogen chloride gas, for example the hydrogenchloride dioxane solution of 4M.Alternative, this is reflected in non-polar solvent such as diox or dipolar aprotic solvent such as N,N-dimethylacetamide or the acetonitrile in acid and for example can carries out easily in the presence of the ether Huo dioxane solution of hydrogen chloride gas or the spirit of salt.

Lg is the formula VIII compound of halogen, can react in the presence of acid with formula IX compound.In this reaction, replace halogen leavings group Lg and cause forming on the spot HLg acid and this reaction of autocatalysis.Easily, this is reflected at suitable inert organic solvents and for example carries out in Virahol, diox or the N,N-dimethylacetamide.The suitable condition of this reaction as mentioned above.

Alternative, formula VIII compound can suitably react in the presence of the alkali with formula IX compound.Be applicable to described in the alkali such as preceding method (a) of this reaction.For example, suitable alkali is that the alkaline-earth metal acid amides is as two (trimethyl silyl) acid amides sodium.This is reflected in for example above-mentioned those relevant with method (j) of inert solvent or thinner and carries out easily;

Wherein m is 1,2 or 3 and R ¹, X ¹, R ⁵Protect any functional group during except needs with n such as preceding definition,

With formula R ²NHR ³Primary amine or secondary amine coupling, wherein R ²And R ³As preceding definition; Remove any blocking group of existence subsequently by ordinary method.

This coupled reaction is at suitable coupling reagent such as carbodiimide (for example 1-[3-(dimethylamino) propyl group]-3-ethyl carbodiimide) or suitable peptide coupling reagent O-(7-azepine benzo triazol-1-yl)-N for example, N, N ', N '-tetramethyl-urea positively charged ion hexafluoro-phosphoric acid salt (HATU) carries out under existing easily.This reaction also can be united in the presence of suitable coupling reagent such as the carbodiimide at I-hydroxybenzotriazole and carried out.This coupled reaction is carried out in dinethylformamide, N,N-dimethylacetamide or the N-methylpyrrolidin-2-ketone at inert solvent such as halogenated solvent such as methylene dichloride or dipolar aprotic solvent such as N.Suitably, this coupled reaction is for example carried out in the presence of two-sec.-propyl ethylamine or the 4-dimethylaminopyridine at suitably alkali such as organic amine.This coupled reaction is suitably carried out under-25 ℃-150 ℃ easily at ambient temperature.

Use the reduction amination method.Those skilled in the art obviously will know or obviously can know appropriate reaction conditions according to document.

Method (m) is for R wherein ³Be by amino, (1-6C) alkylamino, two (1-6C) alkylaminos or comprise NR on carbon atom ⁸The formula I compound of (2-6C) alkyl of saturated 5 or 6 yuan of heterocyclic substituted, R wherein ⁸As relevant formula I definition, through type XX compound:

R wherein ^3aBe Lg-(2-6C) alkyl, wherein Lg is foregoing replaceable group, and R wherein ¹, R ², X ¹, R ⁵, m and n protect any functional group when having foregoing any implication except needs;

React with ammonia or with suitable primary amine or secondary amine such as tetramethyleneimine, remove any blocking group of existence subsequently by ordinary method.

Method (m) be reflected at inert solvent or thinner (for example method (a) and (c) described in inert solvent and thinner, as acetonitrile, N,N-dimethylacetamide, methyl alcohol, ethanol or methylene dichloride) exist down and carry out easily.This is reflected at iodide source such as sodium iodide or potassiumiodide exists down and in 10-150 ℃ of temperature range for example (or under solvent boiling point) suitably in 20-90 ℃ of scope, suitably carry out.

To be interpreted as that before aforesaid method or can introduce by the fragrant substitution reaction of standard following closely or can generate some different ring substituents in the The compounds of this invention by conventional modified with functional group, these methods are also included within method of the present invention aspect.These reactions and modification for example comprise by fragrant substitution reaction introduces substituting group, reduction substituting group, alkylation substituting group and oxidation substituting group.The reagent of these methods and reaction are known for chemical field.The concrete ion of fragrance substitution reaction comprises use concentrated nitric acid introducing nitro, for example uses carboxylic acid halides and lewis' acid (as aluminum chloride) to introduce acyl group under Friedel Crafts condition; Use haloalkane and lewis' acid (as aluminum chloride) under Friedel Crafts condition, to introduce alkyl; And introducing halogen group.

It will be appreciated by those skilled in the art that, for obtaining The compounds of this invention in mode more easily in other situation and some occasion, order that can be different carries out above-described each process step, and/or carries out each reaction (promptly adopting the intermediate relevant with being different from above-mentioned concrete reaction to carry out each chemical conversion) with the different stages in whole route.

When the pharmacy acceptable salt (for example acid salt) of the quinoline that needs formula I, can adopt conventional method, for example by making described quinoline and suitable acid-respons acquisition.For in preparation process, being easy to separate described compound, can prepare the compound of the form of non-pharmacy acceptable salt.Modify resulting salt by routine techniques then, generate the pharmacy acceptable salt of described compound.These technology comprise ion exchange technique for example or the technology of the described compound of redeposition in the presence of pharmaceutically acceptable counter ion.For example, redeposition in the presence of the acid (as HCl) that is fit to obtains the salt acid salt.

In this part, above-mentioned wording " inert solvent " is meant not can be with the mode that influences the desired product yield unfriendly and the solvent of starting raw material, reagent, intermediate or product reaction.

The preparation of starting raw material

Formula II compound be commercially available or can adopt routine techniques or with similar method preparation described in the prior.Especially above listed those patents and application, as WO96/15118, WO 01/66099 and EP 566226.For example, can be according to reaction process 1 preparation formula II compound:

Reaction process 1

R wherein ¹, X ¹, R ⁵, Lg and n such as preceding definition and Pg be hydroxyl protecting group.

(i) reaction be suitable for inertia protonic solvent (as alkanol, for example Virahol), aprotic solvent (as dioxane) or dipolar aprotic solvent (as N, N-N,N-DIMETHYLACETAMIDE) in, in the presence of acid (as hydrogen chloride gas in ether or the dioxane or hydrochloric acid), under the conditions of similarity described in the aforesaid method (j), carries out.

Perhaps, described reaction can be carried out in the presence of alkali (as salt of wormwood) in one of above-mentioned inert solvent expediently.The scope that more than is reflected at is for for example in 0-150 ℃, suitably or near the reflux temperature of reaction solvent under carry out expediently.

The (ii) Pg of these reactions of cracking under standard conditions.For example, when Pg be alkyloyl (during as ethanoyl, can be by in the presence of methyl alcohol system ammonia solution, heating with its cracking.

Formula XI compound is known compound or the currently known methods preparation that can adopt the preparation similar compound.If commercially available can not providing, formula XI compound can the method for described step be prepared by being selected from the standard chemical technology, being similar to the technology of synthetic known structure analogue compounds or being similar in an embodiment.For example, the standard chemical technology of describing among the Houben Weyl.For example, but adopt the method preparation formula XI compound of explanation in the reaction process 2, wherein R ¹-X ¹Be methoxyl group, Lg is that chlorine and Pg are ethanoyl:

Reaction process 2

Compound in this specification sheets that the technician can be applied to reaction process 2 not specify (for example on the 7-position of described quinoline ring, introducing the substituting group of non-methoxyl group).

The formula III compound be commercially available or can adopt standard technique preparation, the technology of explanation among US5252586 and the WO 94/27965 for example.

But formula IV compound through type II compound and XVa or XVb compound react and prepare:

Wherein Lg is that replaceable group and Pg as preceding definition are suitable blocking groups.For example, Lg can be that alkane alkylsulfonyl oxygen can be carboxylic acid tert-butyl ester such as methylsulfonyl oxygen base and Pg.

The condition that the reaction of formula II compound and formula XV compound can be described in the method (a) above being similar to is carried out, and removes protecting group subsequently under standard conditions.For example, this reaction can be used the suitable alkali of salt of wormwood conduct, the suitable thinner of N-methylpyrrolidin-2-ketone conduct and carry out under about 105 ℃.

The reaction of formula II compound and formula XVb compound can be removed protecting group subsequently carrying out as under the Mitsunobu condition of above-mentioned method (a) under standard conditions.

But formula IV compound is through type IX compound and formula XVc compound also:

Prepared in reaction, wherein Lg, X ¹And R ¹As preceding definition and Pg is the due care base.

The condition that the reaction of formula IX compound and formula XVc compound can be described in the method (j) above being similar to is carried out, and removes protecting group subsequently under standard conditions.

Formula VI compound can be through the preparation of top method (a) or method (e), for example uses compound through reaction process 1 preparation as starting raw material.

Formula VII compound can be through for example method (a) or method (d) method (e) preparation, wherein R ¹The group of representative is suitably by suitable replaceable group L g such as chlorine or bromine functionalization.

Formula VIII compound can be through ordinary method preparation well known in the art.For example remove the hydroxyl protecting group in the above-mentioned reaction process 1 formula XI compound, Pg, with production XIII compound:

The Pg protecting group can be removed from formula XI compound through conventional technology.

Then, formula XIII compound can with the coupling of aforementioned formula III compound, use the condition of describing in method (a) or the method (e) that is similar to.

Formula XX compound can method (a) or method (c) method (k) above for example prepare.

Formula V, V ' and IX compound can be buied or can prepare through standard technique.Formula V " compound can prepare through standard technique, Synthesis for example, 1993,12,1233 and Tetrahedron, 1992,48,5557 illustrated.

Wherein m is that 1,2 or 3 formula X compound for example can be by formula IV compound and R ¹O ₂C (CH ₂) preparation of m-Lg alkanisation, wherein Lg and R ¹The condition of describing in the method (c) above being similar to is also used in as above definition in the presence of alkali, subsequently ester is converted into carboxylic acid (for example through saponification reaction or sour deprotection).

Alternatively, wherein m is that 1,2 or 3 formula X compound can be by formula IV compound and R ¹O ₂C (CH ₂) condition preparation that m-OH describes in method (e) above being similar to through Mitsunobu reaction, subsequently ester is converted into carboxylic acid (for example through saponification reaction or sour deprotection).

Used some novel intermediates is provided as further feature of the present invention with their preparation method in the top method.

According to a further general feature of the present invention, provide as above-mentioned formula VI, VII, VIII, X and XX compound or its salt (comprising its pharmacy acceptable salt).These compounds for example are 6-{[1-(N-(2-chloroethyl) formamyl) piperidin-4-yls] the oxygen base }-4-(3-chloro-2-fluoroanilino)-7-methoxyl group-3-itrile group-quinoline, [4-({ 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-3-itrile group-quinoline-6-yl } oxygen base) piperidines-1-yl] acetate and [4-({ 4-(3-chloro-2,4 difluorobenzene amino)-7-methoxyl group-3-itrile group-quinoline-6-yl } oxygen base) piperidines-1-yl] acetate.

Biological assay

In the inhibition activity that the protein tyrosine kinase that is not based on cell is measured and measured compound in the proliferation assay based on cell, transplant the activity in vivo of having estimated them in the research in xenotransplantation afterwards.

A) protein tyrosine kinase phosphorylation assay

This test determination test compound contains the ability of the peptide substrate phosphorylation of tyrosine by EGFR or the inhibition of ErbB2 Tyrosylprotein kinase.

Reconstitution cell internal fragment EGFR, erbB2 and erbB4 (catalog number (Cat.No.) is respectively X00588, X03363 and L07868) are cloned and are expressed in baculovirus/Sf21 system.By with these cells with ice-cooled molten born of the same parents' damping fluid (20mM N-2-hydroxyethyl piperazine-N '-2-ethanesulfonic acid (HEPES) pH7.5,150mM NaCl, 10% glycerine, 1%TritonX-100,1.5mM MgC1 ₂, 1mM ethylene glycol-two (beta-amino ether) N ', N ', N ', N '-tetraacethyl (EGTA) add that proteinase inhibitor handles, and prepare lysate by centrifugal clarification then.

Make phosphorylation takes place a kind of synthetic peptide (is that the randomcopolymer of 6: 3: 1 L-glutamic acid, L-Ala and tyrosine is formed by ratio) ability measure the formation kinase activity of described recombinant protein by it.Specifically, with Maxisorb ^TM96 hole immunization test boards are coated with (0.2 μ g peptide is in 100Ld phosphate-buffered saline (PBS) and 4 ℃ of overnight incubation) with synthetic peptide.Under the room temperature, each plate is washed to remove any excessive unconjugated synthetic peptide with 50mM HEPES pH 7.4 then with PBS-T (phosphate-buffered saline that has 0.5% polysorbas20).By under 22 ℃, at 100mM HEPES pH7.4, be used for adenosine triphosphate (ATP), 10mM MnCl under the Km concentration of each enzyme ₂, 0.1mmNa ₃VO ₄, in the 0.2mM DL-sulphur threitol (DTT), 0.1%TritonX-100, the assay plate of peptide bag quilt was hatched 20 minutes with the DMSO solution (final concentration 2.5%) of test compound, measure the tyrosine kinase activity of EGFR, ErbB2 or ErbB4.By removing the liquid ingredient of measuring in the liquid, wash each plate termination reaction with PBS-T then.

Immobilized phosphoric acid-peptide (phospho-peptide) product by the described reaction of determination of immunological methods.At first, at room temperature, each plate was hatched 90 minutes with the anti-Tyrosine O-phosphate primary antibody of cultivating in mouse (deriving from the 4G10 of Upstate Biotechnology).Behind the thorough washing, under the room temperature, each plate used (horseradish peroxidase (HRP) that derives from the NXA931 of Amersham was handled 60 minutes in conjunction with goat-anti mouse secondary antibodies.Further after the washing, adopt as 2 of substrate 2 '-azino-two-[3-ethyl benzo thiazole phenanthroline sulfonic acid (6)] di-ammonium salts crystal (ABTS1 ^TM, available from Roche) and the HRP activity in every hole in the colorimetric estimation plate.

By under 405nm, measuring absorbancy,, measure enzymic activity thus to developing the color quantitatively with Molecular Devices ThermoMax microplate.The kinase inhibitory activity of given compound is with IC ₅₀Value representation.Measure IC by calculating the required compound concentration of 50% restraining effect that in this mensuration, provides phosphorylated ₅₀Value.From positive (medium adds ATP) and negative (medium subtracts ATP) control value, calculate the phosphorylated scope.

B) the KB cell proliferation test of EGFR driving

This test determination test compound suppresses the ability of KB cell (KB cell is obtained by AmericanType Culture Collection (ATCC)) propagation.

At 7.5%CO ₂In the air incubator, under 37 ℃, in containing the DulbeccoShi improvement EagleShi substratum (DMEM) of 10% foetal calf serum, 2mM glutamine and non-essential amino acid, cultivate KB cell (KB cell is provided by ATCC).Adopt trypsinase/ethylenediamine tetraacetic acid (EDTA) (EDTA), harvested cell from the deposit bottle.Adopt hematimeter to measure cell density, then with every hole 1.25 * 10 ³The density of individual cell is inoculated in 7.5%CO ₂, among the DMEM that contains 2.5% activated carbon decolorizing blood plasma (stripped serum), 1mm glutamine and non-essential amino acid in 96 orifice plates under 37 ℃, fix 4 hours, adopt trypan blue solution to calculate vigor then.

Cell adhesion with (or need not) EGF (final concentration 1ng/ml) with methyl-sulphoxide (DMSO) (final concentration 0.1%) processing of the compound in (or need not) finite concentration scope, was hatched cell 4 after on the plate then.After hatching end, and the bromination 3-by adding 50 μ l (4,5-dimethylthiazole-2-base-2,5-phenylbenzene four quinolines (storing solution 5mg/ml) are measured cell count 2 hours.Then MTT solution is inclined to, culture plate is rapped drying, add 100 μ l DMSO then and dissolve described cell.

By adopting Molecular Devices ThermoMax microplate, the absorbancy of under 540nm, reading the dissolved cell.With inhibition of proliferation effect IC ₅₀Value representation.By calculating the required compound concentration of 50% restraining effect that produces propagation is measured IC ₅₀Value.From positive (medium adds EGP) and negative (medium subtracts EGP) control value, calculate multiplication nursery.

C) xenotransplantation is measured in the body

(i)LOVO

This test detects test compound suppresses LoVo tumour (rectum cancer is derived from ATCC) growth in female Swiss athymic mouse (AlderleyPark, nu/nu genotype) ability.

Raise female Swiss nude mouse (nu/nu genotype), remain on then among the Aldefiey Park among the negative pressure Isolator (shield retaining) (PFI Systems Ltd.).Mouse closed support in having 12 little time/dark round-robin barrier apparatus, aseptic food and water freely are provided.all adopt the mouse at least 8 ages in week to carry out in steps.By giving 1 * 10 of the fresh culture of every mouse subcutaneous injection in 100 μ l serum free mediums ⁷Individual cell is set up the xenotransplantation of LoVo tumour cell (the rectum adenocarcinoma of colon is derived from ATCC) at the rear side belly of donor mice.After transplanting the 5th day, mouse is divided into 7 groups at random, then amount every day of 0.1ml/10g body weight to give compound 1 time or control media is handled.Pass through two-sided vernier caliper measurement gross tumor volume 2 times weekly, adopt following formula to calculate: (length x width) * √ (length x width) * (л/6), wherein length is the longest diameter by this tumour, width is corresponding perpendicular diameter.The mean change of the gross tumor volume by compare group and treatment group is calculated from studying initial growth-inhibiting, adopts the statistical significance between two groups of the Students t check assessments.

(ii) BT-474 xenotransplantation is measured in the body

This test detects test compound at female Swiss athymic mouse (Alderley Park, the nu/nu genotype) suppresses BT-474 tumour cell xenotransplantation (human breast cancer in, be derived from DrVaselga, Laboratorio Recerca Oncologica, Paseo Vall D ' Hebron 119-129, Barcelona 08035, Spain) Sheng Chang ability (Baselga, J.et al. (1998) CancerResearch, 58,2825-2831).

Raise female Swiss nude mouse (nu/nu genotype), remain on then among the Aldefiey Park among the negative pressure Isolator (shield retaining) (PFI Systems Ltd.).Mouse closed support in having 12 little time/dark round-robin barrier apparatus, aseptic food and water freely are provided.all adopt the mouse at least 8 ages in week to carry out in steps.By giving 1 * 10 of the fresh culture of every mouse subcutaneous injection in containing 100 μ l serum free mediums of 50% matrigel ⁷Individual cell, the xenotransplantation of setting up the BT-474 tumour cell at the rear side belly of donor mice.After transplanting the 14th day, mouse is divided into 10 groups at random, then amount every day of 0.1ml/10g body weight to give compound 1 time or control media is handled.Pass through two-sided vernier caliper measurement gross tumor volume 2 times weekly, adopt following formula to calculate: (length x width) * √ (length x width) * (л/6), wherein length is the longest diameter by this tumour, width is corresponding perpendicular diameter. the mean change of the gross tumor volume by compare group and treatment group is calculated from studying initial growth-inhibiting, adopts the statistical significance between two groups of the Students t check assessments.

D) the potassium channel inhibition test of hERG-coding

This test determination test compound suppresses tail current mobile ability by the potassium channel of people's ether-a-go-go-genes involved (hERG)-coding.

Human embryo kidney (HEK) (HEK) cell of expressing the hERG--coding pass is grown in add 10% foetal calf serum (Labtech International; Production number 4-101-500), the 10%M1 serum-free replenishes liquid (EggTechnologies; Production number 70916) and 0.4mg/ml Geneticin G418 (Sigma-Aldrich; Catalog number (Cat.No.) G7034) Eagle minimum essential medium (EMEM; Sigma-Aldrich; Catalog number (Cat.No.) M2279) in.Before each on-test 1 or 2 day, adopt the normal structure cultural method, with Accutase (TCS Biologicals) isolated cell from tissue culture flasks.Then they are placed on the glass cover slide in each hole of 12 well culture plates, cover with the 2ml growth medium.

For writing down every porocyte, the glass cover slide that cell is housed is placed the bottom, Perspex chamber of containing body lotion (seeing below) under the room temperature (20 ℃).This chamber is fixed on the platform of an inverted phase contrast microscope.Cover glass is placed this chamber, from gravity supply storehouse (gravity-fed reservoir), in described chamber, poured into body lotion 2 minutes with the speed of about 2ml/min immediately.Stop perfusion then.

To pull out device (Sutter Instrument Co.) with P-97 trace pipette is full of with pipette solution (seeing below) from the membranaceous pipette that borosilicate glass tube (GC120F, Harvard Apparatus) makes.By silver/silver chloride line, described pipette is connected in the top of patch clamp augmentor (Axopatch200B, Axon Instruments).This bottom, top is connected the earth polar.It is made up of the side silver chloride line that is inserted in 3% agar of being made up of 0.85% sodium-chlor.

Whole-cell configuration record cell with patch clamp technique.Keep current potential-80mV (by the augmentor setting) carry out " swarming into (break-in) " and carry out series resistance and the suitable debugging of electric capacity control after, adopt electric physiology software (Clampex, Axon Instruments) current potential (80mV) is kept in setting, transmits an agreement voltage (voltage protocol) then.Per 15 seconds of this agreement is used once, by 1 second to+40mV step and subsequently 1s extremely-the 50mV step forms.Under 1kHz, by the low electric current of augmentor by each application protocol voltage of filtering response.Then by with similar quanxtizer with similarly signal digitalized in the augmentor, the filtering signal of online acquisition.On the computer of operation Clampex software (Axon Instruments), catch digitized signal afterwards.Keep voltage and to+40mV step process, under 1kHz, surveying sample electric current.Sample rate with remaining voltage protocol is made as 5kHz then.

List the penetration degree of described composition, pH and described body lotion and pipette solution in the following table.

Salt	Suction pipe (mM)	Body lotion (mM)
Salt	Suction pipe (mM)	Body lotion (mM)	??NaCl	??-	??137
??KCl	??130	??4	??NaCl	??-	??137
??KCl	??130	??4	??MgCl ₂	??1	??1
??CaCl ₂	??-	??1.8	??MgCl ₂	??1	??1
??CaCl ₂	??-	??1.8	??HEPES	??10	??10
Glucose	??-	??10	??HEPES	??10	??10
Glucose	??-	??10	??Na ₂ATP	??5	??-
??EGTA	??5	??-	??Na ₂ATP	??5	??-

Parameter	Suction pipe	Body lotion
Parameter	Suction pipe	Body lotion	??pH	??7.18-7.22	??7.40
The pH regulator agent	??1M?KOH	??1M?NaOH	??pH	??7.18-7.22	??7.40
The pH regulator agent	??1M?KOH	??1M?NaOH	Penetration degree (mOsm)	??275-285	??285-295

By Clampex software (Axonlnstruments) online record voltage from+40mV to-50mV step after the amplitude of potassium channel tail current of hERG-coding.Behind the amplitude stability of this tail current, in cell, add the body lotion that contains the medium that is tried material.The adding medium does not have obvious influence to the amplitude of tail current, sets up the accumulative total mass action curve to compound then.

By expressing the amplitude of tail current down in the given concentration (percentage concentration that in medium, exists) of test compound, quantitative to the effect of each concentration of test compound.

By adopting normal data match software package, will fit to the usefulness (IC that equation comes the determination test compound that deletes of quaternary parameter by the percentage restraining effect value that concentration-effect constitutes ₅₀).If being seen inhibition level is no more than 50% under the highest experimental concentration, does not promptly produce efficiency value and quote percent inhibition under this concentration.

E) clone 24 phosphoric acid-erbB2 (phospho-erbB2) measures

This immunofluorescence endpoint determination has been measured test compound suppresses the erbB2 phosphorylation in the clone of source MCF7 (mammary cancer) ability, and clone is wherein crossed expression whole audience wild-type erbB2 proteic clone (after this be called " clone 24 " cell) through standard method transfection MCF7 cell with what produce by using total length erbB2 gene.

Under 37 ℃ in 7.5%CO ₂To clone 24 cell cultures in the air incubator in growth medium (do not contain the improved Eagle ' of phenol red Dulbecco ' s s substratum (DMEM), comprise 10% foetal calf serum, 2mM L-glutamic acid and 1.2mg/ml G418).By washing in the PVS (phosphate-buffered saline, pH7.4, Gibco No.10010-015) once and use 2ml trypsin 1.25mg/ml)/(0.8mg/ml) solution results of ethylenediamine tetraacetic acid (EDTA) (EDTA), thereby from T75 deposit bottle harvested cell.Cell is suspended in the growth medium once more.Further in growth medium, before the dilution, use hemocytometer to measure cell density and also use trypan blue solution to calculate vitality, with cell with 1 * 10 ⁴The density in the every hole of individual cell (among the 100 μ l) be inoculated in clarification have in 96 orifice plates at the end (Packard, No.6005182).

After 3 days, from each hole, remove growth medium and replacement, contain or do not contain the erbB inhibitor compound with 100 μ l mensuration substratum (not containing phenol red DMEM, 2mM L-glutamic acid, 1.2mg/ml G418).This plate sent back in the incubator to place in each hole, added the PBS solution of 20 μ l, 20% formaldehyde in 4 hours then and each plate was placed room temperature 30 minutes.Use multichannel pipettor to remove this fixative solution, in each hole, add 100 μ l PBS and use multichannel pipettor to remove then, and then add 50 μ l PBS to each hole.Seal each plate and reached for 2 weeks in 4 ℃ of storages.

Carry out immunostaining under the room temperature.(adding 1 bag PBS/ tween dry powder (Sigma No.P3563) prepares) in the 1L distilled water washs each hole and adds 200 μ l retardance liquid (Blocking Solution) (the PBS/ polysorbas20 solution of 5% Marvel exsiccant skimming milk (Nestle)) then and hatched 10 minutes to use 200 μ l PBS/ polysorbas20s through plate washing device.Use plate washing device to remove retardance liquid, add 200 μ l0.5%Triton X-100/PBS permeation cells.After 10 minutes, use 200 μ l PBS/ polysorbas20s to wash this plate and add 200 μ l retardance liquid once more and hatched 15 minutes.After using plate washing device to remove retardance liquid, in each hole, add through 30 μ l rabbit polyclonals of 1: 250 retardance liquid dilution anti--phosphoric acid ErbB2 IgG antibody (epitope phosphoric acid-Tyr 1248, SantaCruz, No.SC-12352-R) and hatched 2 hours.Use plate washing device from each hole, to remove this trie primary antibody solutions then, with after plate washing device uses 200 μ lPBS/ polysorbas20 washed twice.Then to each hole add 30 μ lAlexa-Fluor, 488 goat anti-rabbit igg secondary antibody through the dilution of 1: 750 retardance liquid (Molecular Probes, No.A-11008).From now on, as possible, the plate that keeps in Dark Place, this moment is by sealing with the black tape base.Hatch these plates and from each hole, removed secondary antibody solution in 45 minutes then, with after plate washing device uses 200 μ l PBS/ polysorbas20 washed twice.Adding 100 μ l PBS then in each hole hatched 10 minutes after plate washing device is removed.And then in each plate, add 100 μ l PBS, and need not to hatch for a long time, remove through plate washing device.In each hole, add 50 μ l PBS then, seal these plates and before analyzing, reach 2 days with the black tape base once more in 4 ℃ of storages.

Use Acumen Explorer Instrument (Acumen Bioscience Ltd.) to measure the fluorescent signal in each hole, this instrument is the plate count device that can be used for fast quantification laser scanning image feature.Set thereby the fluorescence number that this apparatus measures is higher than predetermined threshold of measurement to(for) the erbB2 phosphorylation state of protein is provided.The fluorescence dose response data that each compound is obtained is applied to appropriate software bag (such as Origin) to carry out the curve The matching analysis.The inhibition of erbB2 phosphorylation is expressed as IC ₅₀Value.It is determined by the required compound concentration of erbB2 phosphorylation signal that calculates inhibition 50%.

Although the pharmacological properties of formula I compound is as changing with structural changes of estimating, usually, in the test, under following concentration or dosage, susceptible of proof formula I compound has activity more than one or more are planted:

Test (a) :-IC ₅₀In 0.001-10 μ M scope for example;

Test (b) :-IC ₅₀In 0.001-10 μ M scope for example;

Test (e) :-IC ₅₀In 0.001-10 μ M scope for example;

Test (c) :-for example have activity in 1-200mg/kg/ days the dosage range;

By the mode of embodiment, Table A is for example understood the activity of representative compounds of the present invention.Table A the 2nd hurdle shows that test (a) suppresses the IC of EGFR Tyrosylprotein kinase protein phosphorylation ₅₀Value; The 3rd hurdle shows that test (a) suppresses the IC of erbB2 Tyrosylprotein kinase protein phosphorylation ₅₀Value; The 4th hurdle shows the IC that suppresses KB cell proliferation in the above-mentioned test (b) ₅₀Value; The 5th hurdle shows the IC of erbB2 Tyrosylprotein kinase protein phosphorylation in the clone that suppresses to derive from MCF7 in the above-mentioned test (e) ₅₀Value:

Table A

Embodiment number	?IC ₅₀(μ M) tests (a): suppress EGFR Tyrosylprotein kinase protein phosphorylation	?IC ₅₀(μ M) tests (a): suppress erbB2 Tyrosylprotein kinase protein phosphorylation	?IC ₅₀(μ M) tests (b): suppress KB cell proliferation	?IC ₅₀(μ M) tests (e): suppress erbB2 Tyrosylprotein kinase protein phosphorylation
Embodiment number			?IC ₅₀(μ M) tests (b): suppress KB cell proliferation		??5	??0.014	??0.037	??0.008	??0.016
??7	??0.012	??0.023	??0.013	??0.024	??5	??0.014	??0.037	??0.008	??0.016
??7	??0.012	??0.023	??0.013	??0.024	??10	??0.007	??0.011	??0.021	??0.033

Two kinds of compounds suppress specific activity to the protein tyrosine kinase phosphorylation

Disclosed compound 4-[(2-bromo-4-chloro-phenyl-among preferred compound embodiment 5 and the patent WO2000018740 in the comparative study this patent) amino]-7-[2-(4-hydroxyl-piperidino) oxyethyl group]-6-methoxyl group-3-quinolinecarbonitriles

(4-[(2-bromo-4-chlorophenyl) amino]-7-[2-(4-hydroxy-1-piperidinyl) ethoxy]-6-methoxy-3-Quinolinecarbonitrile) (CAS:263149-66-2's) suppresses active to the protein tyrosine kinase phosphorylation.

Test method sees " a) protein tyrosine kinase phosphorylation assay " under the biological assay item for details, test is adopted reconstitution cell internal fragment EGFR and erbB2 clone and is expressed in baculovirus/sf21 system, measures compound contains the peptide substrate of tyrosine to the protein tyrosine kinase phosphorylation inhibition ability.Test-results shows that this patent embodiment 5 medicines significantly are better than the documentation compound to EGFR (p＜0.01) and erbB2 (p＜0.05) protein tyrosine kinase phosphorylation inhibition effect, the results are shown in Table B.Table B this patent embodiment 5 compounds and documentation compound suppress the protein tyrosine kinase phosphorylation

Specific activity

Invention a kind of medicinal compositions is provided on the other hand, this medicinal compositions comprises quinoline or its pharmacy acceptable salt and the pharmaceutically acceptable diluent or carrier of the formula I of definition as mentioned.

Composition of the present invention can be for being applicable to the form that orally uses (tablet for example, lozenge, hard or soft capsule, water-based or oily suspensions, emulsion, but dispersion powder or granule, syrup or elixir), be applicable to that the local form of using is (as creme, paste, jelling agent, water-based or oily solution or suspension), be applicable to the form (as finely divided powder or liquid aerosol) of inhalation, be applicable to the form (as finely divided powder agent) that is blown into administration or be the form that is applicable to parenterai administration (for example sterile aqueous or oily solution, can be used for vein, subcutaneous, intramuscular administration is perhaps for being used for the suppository of rectal administration).

Can adopt various conventional pharmaceutical excipient well known in the art, prepare composition of the present invention by ordinary method.Therefore, being intended for use liquid preparations for oral administration can contain just like one or more tinting materials, sweeting agent, correctives and/or sanitas.

The amount that one or more vehicle combine with the active ingredient that obtains single formulation must change according to host who is treated and concrete route of administration.For example, the preparation that is intended for use the human oral administration is fit to usually contain just like the 0.5mg-0.5g active medicine and (is more suitable for being 0.5-100mg, as be 1-30mg), and also contain an amount of vehicle in the said preparation, the amount of vehicle can be about 5%-98% of composition total weight.

Certainly, according to the known principle of medical field, when formula I compound was used for the treatment of or prevents purpose, its dosage size should change according to animal or disease of patient character and severity, age and sex and route of administration.

When formula I compound being used for the treatment of or preventing purpose, generally be to be the scope administration of 0.1mg/kg-75mg/kg body weight with for example per daily dose, in case of necessity can be with several divided dose administrations.Usually, when adopting the parenteral administration, should give lower dosage.Therefore, for example when intravenously administrable, the dosage range that adopts is as the 0.1mg/kg-30mg/kg body weight usually.Similarly, when inhalation, the dosage range that adopts is for example 0.05mg/kg-25mg/kg body weight usually.But the preferred oral administration is particularly with the form oral administration of tablet.Generally speaking, contain the 0.5mg-0.5g that has an appointment compound of the present invention in the unit dosage.

We find that The compounds of this invention has anti proliferative properties such as anticancer character, and this character is considered to be caused by the active particularly blended erbB2/EGF character of its erbB family receptors junket atmosphere acid kinase inhibition.

Therefore, the expectation The compounds of this invention can be used for treating the disease or the illness of or part mediation independent by the erbB receptor tyrosine kinase, and promptly described compound is used in and produces erbB receptor tyrosine kinase restraining effect in the warm-blooded animal that needs this kind treatment.Therefore, The compounds of this invention provides a kind of method for the treatment of malignant cell, and this method feature is to suppress one or more erbB family of receptor tyrosine kinase.Specifically, The compounds of this invention can be used for producing by suppressing antiproliferative and/or proapoptosis and/or the anti-erosion effect that the erbB receptor tyrosine kinase is independent or part mediates.Especially expect that The compounds of this invention can be used for preventing or treats suppressing those tumours of one or more erbB receptor tyrosine kinase sensitivity, these receptor tyrosine kinases are relevant with the signal conduction step that drives these tumor cell proliferations and existence.Therefore, the expectation The compounds of this invention can be used for treating psoriasis, benign prostate (BPH), atherosclerosis and restenosis and/or cancer by antiproliferative effect is provided, in particular for the cancer of treatment erbB receptor tyrosine kinase sensitivity.These optimum or malignant tumours can influence any tissue, comprise non-solid tumour, as leukemia, multiple myeloma or lymphatic cancer, and solid tumor, as bile duct, bone, bladder, brain/CNS, breast, colorectum, uterine endometrium, stomach, head and neck, liver, lung, neurone, oesophagus, ovary, pancreas, prostate gland, kidney, skin, testis, Tiroidina, uterus and the carcinoma of vulva.

One aspect of the present invention provides as the formula I compound of medicine or its pharmacy acceptable salt.

Another aspect of the present invention provides formula I compound or its pharmacy acceptable salt to produce the purposes of antiproliferative effect in such as the people warm-blooded animal.

Therefore, one aspect of the present invention provides formula I quinoline or its pharmacy acceptable salt as preceding definition to be used for warm-blooded animal such as the purposes in the medicine of people's generation antiproliferative effect in preparation.

Another feature according to this aspect of the present invention, the warm-blooded animal that the invention provides in this type of treatment of needs produces the method for antiproliferative effect in such as the people, and this method comprises quinoline or its pharmacy acceptable salt of the formula I of the aforementioned definitions that gives described animal effective dose.

Another aspect of the present invention provides the quinoline of formula I of aforementioned definitions or its pharmacy acceptable salt to be used for preventing or to treat suppressing the purposes of erbB receptor tyrosine kinase such as the medicine of those tumours of the associating sensitivity of EGFR and erbB2 in preparation, and it is relevant that described receptor tyrosine kinase and the signal that causes tumor cell proliferation conduct step.

This another feature on the one hand of the present invention provides a kind of prevention or the methods of treatment such as those tumours of the associating sensitivity of EGFR and erbB2 to the erbB family that suppresses one or more receptor tyrosine kinase, described acceptor junket atmosphere acid kinase is relevant with the signal conduction step that causes tumor cell proliferation and/or existence, and this method comprises quinoline or its pharmacy acceptable salt of the formula I of the aforementioned definitions that gives described animal effective dose.

Another feature according to this aspect of inventing, the invention provides formula I compound or its pharmacy acceptable salt and preventing or treating suppressing the erbB receptor tyrosine kinase such as the purposes in those tumours of the associating sensitivity of EGFR and erbB2, described receptor tyrosine kinase is relevant with the signal conduction step that causes tumor cell proliferation.

According to another aspect of the present invention, the invention provides the quinoline of formula I of aforementioned definitions or its pharmacy acceptable salt are used for providing the medicine of the EGFR of associating and erbB2 tyrosine kinase inhibitory activity in preparation purposes.

Another feature according to this aspect of the present invention, the invention provides a kind of method that the EGFR and the erbB2 tyrosine kinase inhibitory activity of associating are provided, this method comprises quinoline or its pharmacy acceptable salt of the formula I of the aforementioned definitions that gives described animal effective dose.

According to another feature of this aspect of the present invention, the invention provides and be used to provide the EGFR of associating and formula I compound or its pharmacy acceptable salt of erbB2 tyrosine kinase inhibitory activity.

According to another feature of this aspect of the present invention, the invention provides the quinoline of formula I of aforementioned definitions or its pharmacy acceptable salt and be used for the treatment of purposes in the medicine of cancer (for example be selected from following cancer: leukemia, multiple myeloma, lymphatic cancer, bile duct, bone, bladder, brain/CNS, breast, colorectum, uterine endometrium, stomach, head and neck, liver, lung, neurone, oesophagus, ovary, pancreas, prostate gland, kidney, skin, testis, Tiroidina, uterus and the carcinoma of vulva) in preparation.

Another feature according to this aspect of the present invention, the invention provides a kind of warm-blooded animal in the treatment of this kind of needs treats cancer in such as the people and (for example is selected from following cancer: leukemia, multiple myeloma, lymphatic cancer, bile duct, bone, bladder, brain/CNS, breast, colorectum, uterine endometrium, stomach, head and neck, liver, lung, neurone, oesophagus, ovary, pancreas, prostate gland, kidney, skin, testis, Tiroidina, the uterus and the carcinoma of vulva) method, this method comprises quinoline or its pharmacy acceptable salt of the formula I of the aforementioned definitions that gives described animal effective dose.

According to another feature of this aspect of the present invention, the invention provides a kind of formula I compound or its pharmacy acceptable salt that is used for the treatment of cancer (for example be selected from following cancer: leukemia, multiple myeloma, lymphatic cancer, bile duct, bone, wing indulge in, brain/CNS, breast, colorectum, uterine endometrium, stomach, head and neck, liver, lung, neurone, oesophagus, ovary, pancreas, prostate gland, kidney, skin, testis, Tiroidina, uterus and the carcinoma of vulva).

As mentioned above, treatment or the big young pathbreaker of the needed dosage of a kind of disease specific of prophylactic treatment must change according to the severity of other factors, the host who is treated, route of administration and the disease for the treatment of.

The antiproliferative treatment of above-mentioned definition can be used as the single therapy method and uses separately, perhaps removes quinoline derivatives beyond the region of objective existence of the present invention, and use can also combine with therapeutic method of surgery, radiotherapy or the chemical therapeutic method of routine.This type of chemical therapeutic method can comprise one or more following all kinds of antitumour drugs:

(i) antiproliferative/antitumour drug that adopts in the medical oncology is as alkylating agent (for example cis-platinum, carboplatin, endoxan, mustargen, melphalan, Chlorambucil, busulfan and Nitrosourea); Antimetabolite (as anti-folic acid class (antifolates), for example fluoropyrimidines (as 5 FU 5 fluorouracil and Tegafur), Raltitrexed, the cry of certain animals of first ammonia butterfly, cytarabin and hydroxyurea; Antitumor antibiotics (as green onion cyclamycin class, as Zorubicin, bleomycin, Dx, daunorubicin, epirubicin, darubicin, Mitomycin-C, actinomycin and duomycin); Antimitotic agent (as vinca alkaloids, as vincristin, vinealeucoblastine(VLB), vindesine and vinorelbine, and taxanes (taxoids) are as taxol and taxotere); And topoisomerase enzyme inhibitor (as the Etoposide class, as Etoposide and teniposide, amsacrine, the special willing and camptothecine of topology);

(ii) born of the same parents' inhibitor, as anti-estrogens (as tamoxifen, Toremitene, raloxifene, droloxifene and iodoxyfene), estrogen receptor reduces conditioning agent (as fulvestrant), anti-androgens is (as bicalutamide, flutamide, Nilutamide and acetate cyproterone), LHRT antagonist or LHRT agonist are (as goserelin, Leuprolide and buserelin), progestogens (as the acetate megestrol), arimedex is (as Anastrozole, letrozole, fluorine chlorazol (vorazole) and Exemestane) and the 5a-reductase inhibitor, as finasteride;

(iii) anticancer is invaded agent (as inhibitors of metalloproteinase (as Marimastat) and black kinases Profibrinolysin activator function of receptors inhibitor);

(iv) long factor depressant of functions is drawn together growth factor antibodies, growth factor receptor antibody (as anti-erbb2 antibody trastuzumab [Herceptin as this type of inhibitor packages ^TM] and anti-erbbl antibody Cetuximab [C225]), farnesyl transferase inhibitor, tyrosine kinase inhibitor and silk ammonia are expected the threonine kinase enzyme inhibitors, for example the inhibitor of epidermal growth factor family is (as the tyrosine kinase inhibitor N-of EGIR family (3-chloro-4-fluorophenyl)-7-methoxyl group-6-(3-morpholino propoxy-) quinazoline-4-amine (gefitinib, AZD1839), N-(3-ethynyl phenyl-6, two (2-methoxy ethoxy) quinazolines of 7--4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl-7-(3-morpholino propoxy-) quinazoline-4-amine (CI1033)), for example inhibitor of the inhibitor of thrombocyte class growth factor family and pHGF family;

(v) anti-angiogenic agent suppresses the compound of vascular endothelial growth factor as those, (anti-vascular endothelial cell growth factor antibody rhuMAb-VEGF [Avastin for example ^TM], disclosed compound in International Patent Application WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and those compounds that work by other mechanism (as linomide, integral protein av β 3 depressant of functions and angiostatin);

(vi) vascular damaging agents is as disclosed compound among combretastatin A4 and International Patent Application WO 99/02166, WO00/40529, WO 00/41669, WO 01/92224, W002/04434 and the WO 02/08213;

(Vii) antisense therapy agent, for example relate to above listed target medicine (as ISIS 2503, a kind of anti--the ras antisense drug);

(viii) gene therapy approach, comprise as replacing the aberrant gene approach, as unusual p53 or unusual BRCA1 or BRCA2, GDEPT (therapy that relates to the enzyme precursor medicine of gene) approach, as adopt those approach of Isocytosine deaminase, thymidine kinase or bacterium nitroreductase, and strengthen the approach of patient to chemotherapy or radiotherapeutic tolerance, as multiple drug resistance gene therapy; With

(ix) immunotherapy approach, comprise as approach in the immunogenic external and body that strengthens the patient tumors cell, as using cytokine (as interleukin II, interleukin-4 or rHuGM-CSF) transfection, reduce T-cell anergia approach, adopt transfection immunocyte (as the dendritic cell of cytokine transfection) approach, adopt the approach of the tumor cell line of cytokine transfection, and the approach that adopts anti-atopic antibody.

By simultaneously, order or each component of separately treating, can carry out this type of combination therapy.This type of joint product can use compound of the present invention in aforesaid dosage range, other medical active agent is also used in the amount ranges of its approval.

A kind of medicinal product is provided according to an aspect of the present invention, and this product comprises the quinoline of formula I of aforementioned definitions and other antitumour drug that is used for the aforementioned definitions of cancer combination therapy.

Although formula I compound mainly is the medicine as warm-blooded animal (comprising the people), when needing, they also can be used to suppress the effect of erbB acceptor junket atmosphere pka acid.Therefore, these compounds can also be as new biological test exploitation and the medicinal standard product in the new pharmacology drug research.

Now the present invention is further specified by following non-limiting example, wherein, unless otherwise indicated, otherwise:

(i) degree be degree centigrade (℃); All operations promptly carries out in 18-25 ℃ temperature range all in room temperature or envrionment temperature;

(ii) organic solvent is through anhydrous magnesium sulfate drying; Adopt rotatory evaporator, at decompression (600-4000; 4.5-30mmHg) under, be not higher than the evaporation of carrying out solvent under 60 ℃ the bath temperature;

(iii) chromatography refers to flash chromatography on silica gel; Thin-layer chromatography (TLC) carries out on silica-gel plate;

(iv) carry out TLC and/or analytical LCMS after the reaction process usually, the reaction times that provides only supplies the usefulness of explanation;

(v) end product all has gratifying proton magnetic resonance (PMR) (NMR) spectrum and/or mass-spectrometric data;

(vi) the productive rate of being given for the usefulness of explanation, might not be by conscientiously studying the yield that flow process obtains only; More if desired product can repeat preparation;

(vii) when providing the NMR data, unless otherwise indicated, the NMR data provide with the δ value form of main diagnosis proton, with respect to ppm (ppm) expression as the tetramethylsilane (TMS) of internal standard substance, adopt full deuterium for dimethyl (DMSO-d ₆) be solvent, under 400MHz, measure; Adopt following abbreviation: s, unimodal; D, bimodal; T, triplet; Q, quartet; M, multimodal; B, broad peak;

(viii) chemical symbol has common meaning; Use SI units and symbol;

(ix) the solvent ratio that provides is a volume: volume (v/v); With

(x) mass spectrum (MS) adopts 70 electron-volts of electron energies under chemi-ionization (CI) mode, uses the direct probe that exposes and detects, and ionization is undertaken by electron spray(ES); Provide the m/z value; The common only proton of report expression parent quality; Unless otherwise indicated, mass ion is expressed as (MH) ⁺

(xi) unless otherwise indicated, contain the compound of the carbon of asymmetric replacement and/or sulphur atom without fractionation;

(xii) when describing described in a certain synthetic and previous embodiment when similar, the mmole ratio of institute's usage quantity is equal to the ratio that uses among the described previous embodiment;

(xiii) adopt following abbreviation:

The DCM methylene dichloride;

DMF N, dinethylformamide;

The DMA N,N-dimethylacetamide;

The THF tetrahydrofuran (THF);

(xiv) one synthetic when obtaining acid salt (as HCl salt) when describing, do not confirm the concrete stoichiometry of this salt;

(xv) in embodiment 1-12, unless otherwise indicated, all NMR data of report are free base material, and it is converted into the form of free alkali by isolating salt before evaluation.

Embodiment

Embodiment 1

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(N-methylamino formyl radical methyl) piperidines -4-yl] the oxygen base }-preparation of 3-itrile group-quinoline

With 2-chloro-N-methylacetamide (32mg, 0.3mmol) dropwise add 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(piperidin-4-yl) the oxygen base]-3-itrile group-quinoline (0.3mmol), potassiumiodide (16mg, 0.1mmol) and salt of wormwood (50mg is 0.36mmol) in the acetonitrile of mixture (5ml) solution.Reflux and heated this mixture 1 hour down.Behind the evaporating solvent, residue is in dichloromethane extraction under the vacuum.Make water and salt water washing organic solution, through dried over mgso.Behind the evaporating solvent, (eluent: the generation title compound dichloromethane solution of 1%-2%7N ammonium formiate (methanolicammonia)) is white solid (78mg) residue through chromatography purification on silica gel under the vacuum.

¹H NMR (300MHz, DMSO-d ₆) δ ppm:1.98 (m, 2H), 2.08 (m, 2H), 2.46 (m, 2H), 2.85 (m, 2H), 2.87 (d, 3H), 3.07 (s, 2H), 4.02 (s, 3H), 4.49 (m, 1H), 7.21 (m, 3H), 7.46 (m, 2H), 8.53 (m, 1H), 9.72 (s, 1H); Mass spectrum: MH ⁺498.

As 4-(3-chloro-2-the fluoroanilino)-7-methoxyl group-6-[(piperidin-4-yl of starting raw material) the oxygen base]-3-itrile group-quinoline is prepared as follows:

Step 1

6-acetoxyl group-4-(3-chloro-2-fluoroanilino)-7-methoxyl group-3-itrile group-quinoline hydrochloride

(3.46g 23.8mmol) is suspended in the Virahol (200ml) with 6-acetoxyl group-4-chloro-7-methoxyl group-3-itrile group-quinoline (23.8mmol) and 3-chloro-2-fluoroaniline.With this mixture heating up to 80 ℃ backflow 3 hours.Evaporating solvent, residue is crystallization from acetonitrile, generates hydrochloride product, is lightpink crystalline solid (8.12g);

¹H NMR (300MHz, DMSO-d ₆) δ ppm:2.37 (s, 3H), 4.00 (s, 3H), 7.34 (m, 3H), 7.61 (m, 2H), 8.62 (s, 1H), 9.76 (s, 1H); Mass spectrum: 386.4,388.4.

Step 2

4-(3-chloro-2-fluoroanilino)-6-hydroxyl-7-methoxyl group-3-itrile group-quinoline

To be dissolved in (200ml) in the methyl alcohol from 6-acetoxyl group-4-(3-chloro-2-the fluoroanilino)-7-methoxyl group-3-itrile group-quinoline hydrochloride (21.9mmol) of step 1.Add strong aqua (15ml), stir down, produce milk oil sample hydrochloric acid solid precipitation in 50 ℃ of heated solutions 2 hours.Collect solid after filtration, (3 * 200ml) washings, and exist under the Vanadium Pentoxide in FLAKES vacuum-drying to generate product in 60 ℃ are pale solid (5.26g) through ether;

¹H NMR (300MHz, DMSO-d ₆) δ ppm:3.95 (s, 3H), 7.33 (m, 3H), 7.50 (s, 1H), 7.64 (s, 1H), 8.32 (s, 1H), 9.23 (brs, 1H), 9.77 (s, 1H); Mass spectrum: 344.4,346.4.

Step 3

Uncle 6-{[(1--butoxy carbonyl) piperidin-4-yl] the oxygen base }-4-(3-chloro-2-fluoroanilino)-7-methoxyl group-3-itrile group-quinoline

To be dissolved among the DMA (50ml) from 4-(3-chloro-2-the fluoroanilino)-6-hydroxyl-7-methoxyl group-3-itrile group-quinoline (5.85mmol) of step 2.Add (4-methylsulfonyl oxygen base) piperidines-1-hydroxy acid tert-butyl ester (as Chemical﹠amp; Pharmaceutical Bulletin 2001,49 (7), the 822-829 preparation; 490mg, 1.76mmol) and cesium fluoride (890mg 5.85mmol), stirs down this mixture to 85 of heating ℃.2 hours, 4 hours and 6 hours intermittences, in reaction mixture, add (4-methylsulfonyl oxygen base) piperidines-1-carboxylic acid tert-butyl ester and cesium fluoride of above-mentioned amount.Continue again in 85 ℃ of heating 6 hours after last the adding.Evaporating solvent, residue is at DCM (150ml) and H ₂Distribute among the O (150ml).Water layer is through DCM (4 * 100ml) extractions, combining extraction liquid and DCM layer.The DCM part that merges is through MgSO ₄Dry also evaporation.Residue is through chromatography purification, through 0-2.5% (7: the dense NH of 1MeOH/ ₄The OH aqueous solution) DCM eluant solution.Merge suitable part and evaporation, generate product, be the shallow look foam (2.30g) of taking off;

¹H NMR (300MHz, DMSO-d ₆) δ ppm:1.40 (s, 9H), 1.60-1.65 (m, 2H), 1.95-2.00 (m, 2H), and 3.20-3.25 (m, 2H), 3.65-3.70 (m, 2H), 3.92 (s, 3H), 4.68 (m, 1H), 7.21 (s, 1H), 7.27 (dd, 1H), 7.47 (ddd, 1H), 7.51 (dd, 1H), 7.85 (s, 1H), 8.56 (s, 1H), 9.77 (s, 1H); Mass spectrum: 527.5,529.5.

Step 4

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(piperidin-4-yl) oxygen base]-3-itrile group-quinoline

Will be from the uncle 6-{[(1--butoxy carbonyl of step 3) piperidin-4-yl] the oxygen base }-4-(3-chloro-2-fluoroanilino)-7-methoxyl group-3-itrile group-quinoline (0.70mmol) is dissolved in the trifluoroacetic acid (5ml), and placed this solution 2 hours.Evaporate excessive trifluoroacetic acid, residue is through twice of DCM azeotropic.Residue uses 0-4% (7: the dense NH of 1MeOH/ through chromatography purification ₄The OH aqueous solution) DCM eluant solution.Evaporate suitable part and generate product, be pale solid (257mg);

¹H NMR (300MHz, DMSO-d ₆) δ ppm:1.53-1.64 (m, 2H), 2.00-2.05 (m, 2H), 2.64-2.72 (m, 2H), 3.00-3.07 (m, 2H), 3.92 (s, 3H), 4.60 (m, 1H), 7.20 (s, 1H), 7.26 (ddd, 1H), 7.47 (dd, 1H), 7.50 (dd, 1H), 7.82 (s, 1H), 8.43 (s, 1H), 9.77 (s, 1H); Mass spectrum: 427.2,429.2.

Embodiment 2

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(N-methylamino formyl radical) piperidin-4-yl] The oxygen base }-preparation of 3-itrile group-quinoline

Under the room temperature, with methyl isocyanate (20.4 μ l 0.33mmol) dropwise add 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(piperidin-4-yl) oxygen base]-3-itrile group-quinoline (0.3mmol) is in the mixture of methylene dichloride (5ml).This mixture of stirring at room 4 hours.Behind the vacuum evaporating solvent, (eluent: the generation title compound dichloromethane solution of 2%7N ammonium formiate) is white solid (100mg) residue through chromatography purification on silica gel.

¹H NMR (300MHz, DMSO-d ₆) δ ppm:1.98 (m, 2H), 2.09 (m, 2H), 2.83 (d, 3H), 3.32 (m, 2H), 3.72 (m, 2H), 4.01 (s, 3H), 4.43 (m, 1H), 4.64 (m, 1H), 7.11 (m, 2H), 7.23 (s, 1H), 7.31 (s, 1H), 7.45 (s, 1H), 8.46 (s, 1H), 9.70 (s, 1H); Mass spectrum: MH ⁺484.

Embodiment 3

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(N-(2-tetramethyleneimine-1-base ethyl) amino Formyl radical) piperidin-4-yl] the oxygen base }-3-itrile group-quinoline

In 80 ℃ of heating 6-{[1-(N-(2-chloroethyl) formamyl) piperidin-4-yls] the oxygen base }-4-(3-chloro-2-fluoroanilino)-7-methoxyl group-3-itrile group-quinoline (0.4mmol), tetramethyleneimine (0.14ml; 1.6mmol) and potassiumiodide (134mg, the mixture in N,N-DIMETHYLACETAMIDE 0.8mmol) (3ml) 4 hours.Cooling final vacuum evaporating solvent, residue distribute in water, methylene dichloride and through dichloromethane extraction.Organic layer is through water and salt water washing, dried over mgso.Behind the vacuum evaporating solvent, (eluent: the generation title compound dichloromethane solution of 4%7N ammonium formiate) is white solid (75mg) residue through chromatography purification on silica gel.

¹H NMR (300MHz, DMSO-d ₆) δ ppm:1.78 (m, 4H), 1.95 (m, 2H), 2.04 (m, 2H), 2.53 (m, 4H), 2.63 (t, 2H), 3.33 (m, 4H), 3.76 (m, 2H), 4.01 (s, 3H), 4.64 (m, 1H), 5.27 (m, 1H), 7.16 (m, 2H), 7.22 (s, 1H), 7.30 (s, 1H), 7.47 (s, 1H), 8.45 (s, 1H), 9.72 (s, 1H); Mass spectrum: MH ⁺567.

By 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(piperidin-4-yl) the oxygen base]-3-itrile group-quinoline (0.4mmol) and isocyanic acid 2-chloroethene ester (34 μ l, 0.4mmol) response class is similar to 6-{[1-N-(2-chloroethyl) formamyl of embodiment 2 preparations as starting raw material) piperidin-4-yl] the oxygen base }-4-(3-chloro-2-fluoroanilino)-7-methoxyl group-3-itrile group-quinoline.Yield: 192mg.Mass spectrum: MH ⁺532,534.

Embodiment 4

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(morpholine-4-base carbonyl) piperidin-4-yl] the oxygen base } The preparation of-3-itrile group-quinoline

With 4-morpholinyl carbonyl chlorine (35 μ l, 0.3mmol) dropwise add ice-cold 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(piperidin-4-yl) the oxygen base]-3-itrile group-quinoline (0.3mmol) and diisopropylethylamine (63 μ l, 0.36mmol) in the mixture of methylene dichloride (5ml), this mixture of stirring at room 18 hours.This mixture dilutes through methylene dichloride, water and salt water washing and through dried over mgso.Behind the vacuum evaporating solvent, (eluent: the generation title compound dichloromethane solution of 1-2%7N ammonium formiate) is white solid (92mg) residue through chromatography purification on silica gel.

¹H NMR (300MHz, DMSO-d ₆) δ ppm:1.93 (m, 2H), 2.05 (m, 2H), 3.20 (m, 2H), 3.29 (m, 4H), 3.62 (m, 2H), 3.71 (m, 4H), 4.02 (s, 3H), 4.64 (m, 1H), 7.16 (m, 2H), 7.20 (s, 1H), 7.31 (m, 2H), 8.49 (s, 1H), 9.71 (s, 1H); Mass spectrum: MH ⁺540.

Embodiment 5

4-(3-chloro-2,4 difluorobenzene amino)-7-methoxyl group-6-{[1-(N-methylamino formyl radical methyl) piperazine Pyridine-4-yl] the oxygen base }-3-itrile group-quinoline

With 2-chloro-N-methylacetamide (51mg, 0.47mmol) dropwise add 4-(3-chloro-2,4-two fluoroanilino)-and 7-methoxyl group-6-[(piperidin-4-yl) the oxygen base]-3-itrile group-quinoline (0.47mmol), potassiumiodide (79mg, 0.47mmol) and salt of wormwood (79mg is 0.57mmol) in the mixture of N,N-DIMETHYLACETAMIDE (5ml).Heated these mixtures 1 hour in 70 ℃.Cooled and filtered solid, filtrate use to comprise 2g/l ammonium formiate water and acetonitrile mixture (gradient) wash-out generation title compound (46mg) through the HPLC column purification (C18,5 microns, 19mm diameter, 100mm length) of preparation HPLC-MS system, are white solid.

¹H NMR (300MHz, DMSO-d ₆) δ ppm:1.98 (m, 2H), 2.07 (m, 2H), 2.45 (m, 2H), 2.86 (m, 2H), 2.87 (d, 3H), 3.06 (s, 2H), 4.01 (s, 3H), 4.48 (m, 1H), 7.06 (m, 1H), 7.15 (m, 1H), 7.20 (s, 1H), 7.32 (m, 2H), 8.36 (s, 1H), 9.76 (s, 1H); Mass spectrum: MH ⁺516.

As 4-(3-chloro-2,4 difluorobenzene the amino)-7-methoxyl group-6-[(piperidin-4-yl of raw material) the oxygen base]-3-itrile group-quinoline is prepared as follows:

With 3-chloro-2,4 difluorobenzene amine (1.7g, 10.1mmol) and Virahol (2ml) solution of 5N hydrogenchloride add 4-[(4-chloro-7-methoxyl group-3-itrile group-quinoline-6-yl) the oxygen base] in Virahol (50ml) solution of piperidines-1-carboxylic acid tert-butyl ester (10.1mmol).Stirred this mixture 3 hours in 89 ℃.Behind the evaporating solvent, residue on silica gel through chromatography purification (eluent: the dichloromethane solution of 5-10%7N ammonium formiate) generate 4-(3-chloro-2,4-two fluoroanilino)-7-methoxyl group-6-[(piperidines-two-yl) oxygen base]-3-itrile group-quinoline (3.57g), be white solid.

¹H NMR (300MHz, DMSO-d ₆) δ ppm:2.15 (m, 2H), 2.30 (m, 2H), 3.34 (m, 2H), 3.47 (m, 2H), 4.01 (s, 3H), 4.91 (m, 1H), 7.13 (m, 2H), 7.58 (m, 2H), 8.31 (s, 1H), 9.65 (s, 1H); Mass spectrum: MH ⁺445.

Embodiment 6-10

Stir [4-({ 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-3-itrile group-quinoline-6-yl } oxygen base) piperidines-1-yl] acetate dihydrochloride (0.4mmol), I-hydroxybenzotriazole (66mg, 0.48mmol), diisopropylethylamine (0.14ml, 0.8mmol), suitable amine (0.48mmol) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (92mg, methylene dichloride suspension (5ml) 0.48mmol) 2 hours.This mixture is through water, 10% sodium bicarbonate aqueous solution and salt water washing and through dried over mgso.Behind the evaporating solvent, residue on the silica gel through chromatography purification (eluent: grind the dichloromethane solution of 2-3%7N ammonium formiate) and in acetonitrile and generate title compound.

Embodiment 6

4-(3-chloro-2-fluoroanilino)-6-{[1-(N-ethylamino formyl radical methyl) piperidin-4-yl] oxygen Base }-7-methoxyl group-3-itrile group-quinoline

Used amine is ethamine.

Yield: 37mg; ¹H NMR (300MHz, DMSO-d ₆) δ ppm:1.17 (t, 3H), 1.98 (m, 2H), 2.09 (m, 2H), 2.45 (m, 2H), 2.87 (m, 2H), 3.05 (s, 2H), 3.33 (m, 2H), 4.02 (s, 3H), 4.49 (m, 1H), 7.16 (m, 3H), 7.30 (s, 1H), 7.43 (s, 1H), 8.48 (s, 1H), 9.71 (s, 1H); Mass spectrum: MH ⁺510.

Embodiment 7

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(N-[2-(tetramethyleneimine-1-yl) ethyl] amino Formyl radical) piperidin-4-yl] the oxygen base }-3-itrile group-quinoline

Used amine is 1-(2-amino-ethyl) tetramethyleneimine.

Yield: 53mg; ¹H NMR (300MHz, DMSO-d ₆) δ ppm:1.80 (m, 4H), 1.98 (m, 2H), 2.07 (m, 2H), 2.45 (m, 2H), 2.53 (m, 4H), 2.62 (t, 2H), 2.87 (m, 2H), 3.07 (s, 2H), 3.40 (m, 2H), 4.02 (s, 3H), 4.48 (m, 1H), 7.16 (m, 3H), 7.31 (m, 1H), 7.54 (s, 1H), 8.51 (s, 1H), 9.71 (s, 1H); Mass spectrum: MH ⁺581.

Embodiment 8

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-{[1-(N-(2-methoxy ethyl) formamyl Methyl) piperidin-4-yl] the oxygen base }-3-itrile group-quinoline

Used amine is the 2-methoxyethyl amine.

Yield: 58mg; ¹H NMR (300MHz, DMSO-d ₆) δ ppm:1.98 (m, 2H), 2.09 (m, 2H), 2.45 (m, 2H), 2.87 (m, 2H), 3.07 (s, 2H), 3.38 (s, 3H), 3.48 (s, 4H), 4.02 (s, 3H), 4.49 (m, 1H), 7.16 (m, 3H), 7.31 (m, 1H), 7.48 (s, 1H), 8.49 (s, 1H), 9.71 (s, 1H); Mass spectrum: MH ⁺542.

Embodiment 9

4-(3-chloro-2-fluoroanilino)-6-{[1-(N-(2-dimethyl aminoethyl) carbamyl ylmethyl) Piperidin-4-yl] the oxygen base }-7-methoxyl group-3-itrile group-quinoline

Used amine is N, the N-dimethyl-ethylenediamine.

Yield: 69mg; ¹H NMR (300MHz, DMSO-d ₆) δ ppm:1.98 (m, 2H), 2.10 (m, 2H), 2.26 (s, 6H), 2.43 (m, 4H), 2.88 (m, 2H), 3.07 (s, 2H), 3.37 (m, 2H), 3.48 (s br, 1H), 4.03 (s, 3H), 4.49 (m, 1H), 7.16 (m, 3H), 7.31 (m, 1H), 7.50 (s, 1H), 8.48 (s, 1H), 9.72 (s, 1H); Mass spectrum: MH ⁺555.

Embodiment 10

4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-(1-[2-(4-methylpiperazine-1-yl)-2-oxygen ethyl] Piperidin-4-yl } the oxygen base)-3-itrile group-quinoline

Used amine is N methyl piperazine.

Yield: 67mg; ¹H NMR (300MHz, DMSO-d ₆) δ ppm:1.97 (m, 2H), 2.11 (m, 2H), 2.32 (s, 3H), 2.40 (m, 6H), 2.87 (m, 2H), 3.22 (s, 2H), 3.65 (m, 4H), 4.02 (s, 3H), 4.46 (m, 1H), 7.16 (m, 3H), 7.30 (m, 1H), 7.33 (s, 1H), 8.46 (s, 1H), 9.70 (s, 1H); Mass spectrum: MH ⁺567.

Embodiment 11

4-(3-ammonia-2-fluoroanilino)-7-methoxyl group-6-(1-[2-(piperazine-1-yl)-2-oxygen ethyl] piperidines -4-yl } the oxygen base)-3-itrile group-quinoline

The method of using embodiment 6-10 except with 1-tert-butoxycarbonyl piperazine as amine and after aqueous solution operation, stirring residue 90 minutes is then through the HPLC purifying in 1: 1 mixture (3ml) of methylene dichloride-trifluoroacetic acid.

Yield: (obtaining 140mg) from the 0.56mmol scale; ¹H NMR (300MHz, DMSO-d ₆) δ ppm:1.96 (m, 2H), 2.11 (m, 2H), 2.42 (m, 2H), 2.88 (m, 6H), 3.23 (s, 2H), 3.59 (m, 4H), 4.01 (s, 3H), 4.46 (m, 1H), 7.15 (m, 3H), 7.29 (s, 1H), 7.41 (s, 1H), 8.45 (s, 1H), 9.70 (s, 1H); Mass spectrum: MH ⁺553.

[4-({ 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-3-itrile group-quinoline-6-yl } oxygen base) piperidines-1-yl] acetate dihydrochloride as starting raw material is prepared as follows:

With chloroacetic acid tert-butyl ester (1.43ml, 10mmol) dropwise add 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-6-[(piperidin-4-yl) the oxygen base]-3-itrile group-quinoline (10mmol), potassiumiodide (1.66g, 10mmol) and salt of wormwood (1.66g is 12mmol) in the mixture of N,N-DIMETHYLACETAMIDE (50ml).Heated these mixtures one hour in 70 ℃.Behind the vacuum evaporating solvent, residue grinds in water.Filter the gained solid, through water washing and through silica gel chromatography purifying (eluent: the dichloromethane solution of 2%7N ammonium formiate) generate [4-({ 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-3-itrile group-quinoline-6-yl } oxygen base) piperidines-1-yl] tert.-butyl acetate, be white solid (3.0g).

¹H NMR (300MHz, DMSO-d ₆) δ ppm:1.48 (s, 9H), 2.01 (m, 2H), 2.10 (m, 2H), 2.56 (m, 2H), 2.89 (m, 2H), 3.19 (s, 2H), 4.01 (s, 3H), 4.49 (m, 1H), 7.16 (m, 3H), 7.29 (m, 2H), 8.48 (s, 1H), 9.70 (s, 1H); Mass spectrum: MH ⁺541.

Will [4-((4-(3-chloro-2-fluoroanilino)-7-methoxyl group-3-itrile group-quinoline-6-yl } oxygen base) piperidines-1-yl] tert.-butyl acetate (5.8mmol) under the room temperature in the dioxane (40ml) of 4N hydrogenchloride suspension 3 hours.The high vacuum evaporation solvent.Residue grinds in ether, filters and generates [4-({ 4-(3-chloro-2-fluoroanilino)-7-methoxyl group-3-itrile group-quinoline-6-yl } oxygen base) piperidines-1-yl] acetate through the ether washing, is dihydrochloride (2.9g).Mass spectrum: MH ⁺485.

Embodiment 12

4-(3-chloro-2,4 difluorobenzene amino)-7-methoxyl group-6-({ 1-[2-(4-methyl piperidine-1-yl)-2- Oxygen base ethyl] piperidin-4-yl } the oxygen base)-3-itrile group-quinoline

Use the method for embodiment 6-10, [4-({ 4-(3-chloro-2,4 difluorobenzene amino)-7-methoxyl group-3-itrile group-quinoline-6-yl } oxygen base) piperidines-1-yl] acetate dihydrochloride and N methyl piperazine are converted into title compound (121mg).

¹H NMR (300MHz, DMSO-d ₆) δ ppm:1.94 (m, 2H), 2.09 (m, 2H), 2.31 (s, 3H), 2.40 (m, 6H), 2.84 (m, 2H), 3.23 (s, 2H), 3.65 (m, 4H), 4.01 (s, 3H), 4.45 (m, 1H), 7.06 (m, 1H), 7.22 (m, 1H), 7.29 (m, 1H), 7.36 (s, 1H), 8.29 (s, 1H), 9.67 (s, 1H); Mass spectrum: MH ⁺585.

Use the same procedure of describing as among the embodiment 11, by 4-(3-chloro-2,4-two fluoroanilino)-and 7-methoxyl group-6-[(piperidin-4-yl) the oxygen base]-preparation of 3-itrile group-quinoline is as [4-({ 4-(3-chloro-2,4 difluorobenzene amino)-7-methoxyl group-3-itrile group-quinoline-6-yl } oxygen base) piperidines-1-yl] acetate dihydrochloride of starting raw material:

[4-({ 4-(3-chloro-2,4 difluorobenzene amino)-7-methoxyl group-3-itrile group-quinoline-6-yl } oxygen base) piperidines-1-yl] tert.-butyl acetate (2.26g): mass spectrum: MH+559.

[4-({ 4-(3-chloro-2,4 difluorobenzene amino)-7-methoxyl group-3-itrile group-quinoline-6-yl } oxygen base) piperidines-1-yl] acetate (dihydrochloride, 2.35g): mass spectrum: MH ⁺503.

Embodiment 13

Pharmaceutical composition

For example understand exemplary pharmaceutical dosage form of the present invention (activeconstituents is called as " compounds X ") as described herein below, be used for intravital treatment of people or prophylactic applications:

(a) tablet I mg/ sheet

Compounds X 100

Lactose Ph.Eur. 182.75

Croscarmellose sodium 12.0

Corn starch paste (5%w/v paste) 2.25

Magnesium Stearate 3.0

(b) injection I (50mg/ml)

Compounds X 5.0%w/v

1M sodium hydroxide solution 15.0%v/v

0.1M hydrochloric acid (regulating pH to 7.6)

Poly(oxyethylene glycol) 400 4.5%w/v

Water for injection to 100%

Can obtain above-mentioned preparation by the known ordinary method of pharmaceutical field.For example tablet can prepare in flakes by being mixed together each component and pressing mixt.

Claims

1. the quinoline of formula I

Wherein n is 0,1,2 or 3,

X ¹Be direct key or O;

M is 0,1,2 or 3;

R ²Be hydrogen or (1-6C) alkyl; And

Or R ²And R ³The nitrogen-atoms that connects with them forms 5 and 6 yuan of saturated heterocycles, and be selected from oxygen, S, SO or S (O) its optional comprising ₂Or NR ⁸Other heteroatoms, R wherein ⁸As above definition.

2. according to the quinoline of claim 1, each R wherein ⁵Group is a halogen group.

3. according to the quinoline of claim 2, each R wherein ⁵Group is selected from chlorine and fluorine.

4. according to the quinoline of claim 1, it comprises R ⁵Group, this R ⁵Group is positioned at place, the position of its phenyl ring neighbour who connects-(2-).

5. according to the quinoline of claim 4, wherein be positioned at the R at place, position of neighbour-(2-) ⁵Group is a fluorine.

6. according to the quinoline of claim 1, inferior formula (i) group among its Chinese style I:

Be (ii) group of inferior formula:

7. according to the quinoline of claim 6, R wherein ¹¹Or R ¹²One of be that hydrogen and another are fluorine, and R ¹¹Be chlorine.

8. according to the quinoline of claim 6, R wherein ¹⁰Be fluorine, R ¹¹Be chlorine, and R ¹²Be hydrogen.

9. according to the quinoline of claim 6, R wherein ¹¹Be fluorine, R ¹¹Be chlorine, and R ¹²It is fluorine.

10. according to the quinoline of claim 1, X wherein ¹Be oxygen.

11. according to the quinoline of claim 1, wherein R ¹Be selected from hydrogen, (1-6C) alkyl and (1-6C) alkoxyl group (1-6C) alkyl, wherein R ¹In optional one or more hydroxyls or the halogenic substituent of containing of any (1-6C) alkyl.

12. according to the quinoline of claim 11, wherein R ¹Be selected from (1-6C) alkyl, its optional one or more hydroxyls or halogenic substituent of containing.

13. according to the quinoline of claim 1, wherein R ¹-X ¹-be selected from hydrogen, methoxyl group, oxyethyl group and 2-methoxy ethoxy.

14. formula IA quinoline according to claim 1:

R wherein ², R ³With m such as claim 1 definition, R ¹⁰, R ¹¹And R ¹²As each definition of claim 6-9, and R ¹³Be selected from hydrogen, methoxyl group, oxyethyl group and 2-methoxy ethoxy.

15. formula IB quinoline according to claim 1:

R wherein ², R ³With m such as claim 1 definition, and R ¹³Be selected from hydrogen, methoxyl group, oxyethyl group and 2-methoxy ethoxy.

16. formula IC quinoline according to claim 1:

17. according to the quinoline of claim 1, wherein R ²Be hydrogen or (1-3C) alkyl.

18. according to the quinoline of claim 17, wherein R ²Be hydrogen or methyl.

19. according to the quinoline of claim 1, wherein R ³It is (1-6C) alkyl.

20. according to the quinoline of claim 19, wherein R ³It is (1-3C) alkyl.

21. according to the quinoline of claim 20, wherein R ³It is methyl.

22. according to the quinoline of claim 1, its be selected from following one or more:

Or its pharmacy acceptable salt.

23. each the preparation method of quinoline of claim 1-22, it comprises, perhaps

Method (a) formula II compound:

R wherein ¹, X ¹, R ⁵Protect any functional group when having any implication as claim 1 definition except needs with n,

React with the formula III compound:

R wherein ², R ³Protect any functional group when having any implication as claim 1 definition except needs with m, and Lg is replaceable group, wherein this is reflected at suitable alkali and exists down and carry out easily,

Method (c) formula IV compound:

R wherein ², R ³, R ⁵, m and n protect any functional group when having any implication as claim 1 definition except needs, with formula R ¹The reaction of-Lg compound, wherein R ¹Having as any implication of claim 1 definition is not hydrogen and to protect any functional group and Lg during except needs be replaceable group except it;

R wherein ², R ³, R ⁵, X ¹, n and m protect any functional group, R when having implication as preceding definition except needs ¹, be the R that defines as herein ¹Group is replaced by Lg except any T group, and Lg is replaceable group (for example chlorine or bromine), with the reaction of formula TH compound, protects any functional group when wherein T as above defines except needs;

Method (j) formula VIII compound:

R wherein ¹, R ², R ³, X ¹Protecting any functional group and Lg when having any implication as claim 1 definition except needs with m is replaceable as previously mentioned group,

Aniline reaction with formula IX:

R wherein ⁵Protect any functional group when having any implication as claim 1 definition except needs, and wherein this is reflected at suitable acid and exists down and carry out easily with n;

Wherein m is 1,2 or 3 and R ¹, X ¹, R ⁵With n such as the definition of preceding claim 1, protect any functional group during except needs, with formula R ²NHR ³Primary amine or secondary amine coupling, wherein R ²And R ³Define as claim 1;

Use the reduction amination method;

Method (m) is for R wherein ³Be by amino, (1-6C) alkylamino, two-(1-6C) alkylaminos or comprise NR on carbon atom ⁸The formula I compound of (2-6C) alkyl of saturated 5 or 6 yuan of heterocyclic substituted, R wherein ⁸As definition in the claim 1, through type XX compound:

With ammonia or with suitable primary amine or secondary amine reaction,

And after any described method, remove any blocking group of existence.

24. a pharmaceutical composition, it contains just like the formula I quinoline of each definition of claim 1-22 or its pharmacy acceptable salt and unites by pharmaceutically acceptable diluent or carrier.

25. as the application of the formula I quinoline of each definition of claim 1-22 or its pharmacy acceptable salt as medicine.

26. be used in the warm-blooded animal body, producing the purposes of the medicine of antiproliferative effect in preparation as the formula I quinoline of each definition of claim 1-22 or its pharmacy acceptable salt.

27. a method that produces antiproliferative effect in the warm-blooded animal body of this treatment of needs comprises the formula I quinoline or its pharmacy acceptable salt that give described animal such as each definition of claim 1-22.

28. formula VI, VII, VIII, X or XX compound as claim 23 definition.