CN101273033A

CN101273033A - 4- (iH-indazol-s-yl-amino)-quinazoline compounds as ERBB receptor tyrosine kinase inhibitors for the treatment of cancer

Info

Publication number: CN101273033A
Application number: CNA2006800355341A
Authority: CN
Inventors: R·H·布拉德伯里; B·C·巴拉姆; R·杜克里
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2005-09-20
Filing date: 2006-09-14
Publication date: 2008-09-24

Abstract

A quinazoline derivative of the Formula I: wherein the substituents are as defined in the text for use in the production of an anti proliferative effect which effect is produced alone or in part by inhibiting erbB2 receptor tyrosine kinase in a warm blooded animal such as man.

Description

4-(1H-indazole-5-base-amino as the ERBB receptor tyrosine kinase inhibitors for the treatment of cancer)-quinazoline compound

The present invention relates to some new quinazoline derivant or its pharmacy acceptable salt, these compounds have anti-tumor activity, therefore can be used for the treatment of in the method for human or animal body.The invention still further relates to method, the pharmaceutical composition that contains these derivatives and their purposes in methods of treatment of the described quinazoline derivant of preparation, as the purposes of medicine of the noumenal tumour disease that is used for prevention or treatment warm-blooded animal (as the people) in preparation.

Present multiple treatment suppresses the compound of the synthetic and cell proliferation of DNA because of the scheme of the caused disease of unusual adjusting (as psoriasis and cancer) of cell proliferation has all adopted.Up to now, the compound that is used for this type of treatment is generally all toxic to various cells, but they may be useful for the enhancement of quick noble cells such as tumour cell.Just adopting other method to develop these Cytotoxic antitumor drugs, for example selective depressant of cell signaling approach at present.The inhibitor of these types may have and presents the usefulness that strengthens selectively acting to suppressing tumour cell, thereby may reduce the possibility of the therapy with unwanted side effect.

Eukaryotic cell is constantly reacted to many different extracellular signals, and these signals can make and link up (communication) between intravital each cell of machine.Physical responses widely in these Signal Regulation cells comprises propagation, differentiation, apoptosis and mobility (motility).The extracellular signal is taked the form of various soluble factor, comprises somatomedin and other autocrine factor, paracrine factor and endocrine factor.By combining with the specificity transmembrane receptor, these parts interrelate extracellular signal and the interior signal transduction path of cell, thereby make the signal conduction stride across plasma membrane, and each cell is replied its extracellular signal generation.The conductive process of many these signals utilizes the reversing process of proteic phosphorylation, and proteic phosphorylation participates in promoting these different cell responses.The phosphorylation state of target protein is subjected to the adjusting of specificity kinases and Phosphoric acid esterase, and described kinases and Phosphoric acid esterase are responsible for the proteic adjusting by about 1/3rd in all albumen of mammalian genes group coding.Because phosphorylation is an important regulation mechanism in the signal conductive process, therefore, the distortion in these cells in the approach causes unusual cell growth and differentiation, impel thus cell transformation also with regard to not at all surprising (comment al in Cohen et, Curr Opin Chem Biol, 1999, 3, 459-465).

Know that generally many these type of Tyrosylprotein kinases are the constitutive activity form because of generation suddenlys change and/or cause the various human cell transformation when overexpression.Kinase whose these sudden changes and form overexpression be present in the most human tumor (comment al in Kolibaba et, Biochimica etBiophysica Acta, 1997, 133, F217-F248).Because Tyrosylprotein kinase plays an important role in the hyperplasia of multiple tissue and differentiation, therefore in the new anti-cancer therapies of research, more attention is to concentrate on these enzymes.The enzyme of this family is divided into two groups---and acceptor and non--receptor tyrosine kinase for example are respectively EGF acceptor and SRC family.From great deal of research results (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.These Tyrosylprotein kinases can be divided into 20 kinds of receptor tyrosine kinases and 10 kinds of non--receptor tyrosine kinase subfamilies (Robinson et al, Oncogene, 2000, 19, 5548-5557).

In the mitogenetic signal conduction that activated cell duplicates, these receptor tyrosine kinases have special vital role.These macromole glycoprotein of crossing over cytoplasmic membrane have the born of the same parents of its ligands specific (as the Urogastron EGF of EGF acceptor) outer in conjunction with the territory.The combination of part causes the activation by the kinase enzymatic activity of the acceptor of the intracellular portion coding of this receptor.This activity makes the crucial tyrosine amino acid phosphorylation in the target protein, causes proliferation signal conduction passing through cytoplasmic membrane.

The receptor tyrosine kinase (it comprises: EGFR, erbB2, erbB3 and erbB4) of known erbB family general with the propagation that advances tumour cell and relevant (commentary of surviving in Olayioye Et al., EMBO J., 2000, 19, 3159).The overexpression that mechanism is the acceptor on protein level that can realize is commonly referred to be the result of gene amplification.This point can be observed in many common human cancers and (comment in Klapper Et al., Adv.Cancer Res., 2000, 77, 25), mammary cancer (Sainsbury for example Et Al., Brit.J.Cancer, 1988, 58, 458; Guerin Et Al., Oncogene Res., 1988, 3, 21; Slamon Et al., Science, 1989, 244, 707; Kliin Et Al., Breast Cancer Res.Treat., 1994, 29, 73 and comment al. in Salomon et, Crit. Rev.Oncol.Hematol., 1995, 19, 183), non--small cell lung cancer (NSCLCs) comprises gland cancer (Cerny Et 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.Cancer Res., 2001, 7, 1850) and other lung cancer (Hendler Et Al., Cancer Cells, 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, for example colon, rectum or cancer of the stomach (Bolen Et Al., Oncogene Res., 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., Neoplasma, 2001, 48, 188).Along with the detection that the receptor tyrosine kinase that more people's tumor tissues is carried out erbB family is expressed, people expect that the popularity of this family and importance will further be established future.

Because the imbalance of one or more (particularly erbB2) in these acceptors generally believes that now many tumours have more aggressive clinically, and therefore with the patient's relevant (Brabender of prognosis mala Et al, Clin.Cancer Res., 2001, 7, 1850; Ross Et al, Cancer Investigation, 2001, 19, 554, Yu Et al., Bioessays, 2000, 22.7, 673).

Except these clinical effectivenesses, clinical preceding information resources point out the receptor tyrosine kinase of erbB family relevant with cell transformation.This comprises observes one or more erbB acceptors of many tumor cell line overexpressions, and observes EGFR or erbB2 has the ability that makes these cell modification when transfection is in non--tumour cell.Because tumour spontaneously takes place in mammary gland the transgenic mice of overexpression erbB2, the potentiality of this tumorigenesis is further confirmed.In addition, some preclinical studies confirmed to resist-proliferation function can remove one or more erbB activity with micromolecular inhibitor, dominant negative regulation agent (dominant negatives) or inhibiting antibody and induce and (comment in Mendelsohn Et al., Oncogene, 2000, 19, 6550).Therefore, have recognized that the inhibitor of these receptor tyrosine kinases should have value (the Yaish et al. of the selective depressant of breeding as mammalian cancer cells Science, 1988, 242, 933, Kolibaba et al, Biochimica 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 described clinical preceding data, small molecules EGFR tyrosine kinase inhibitor Iressa

(being also referred to as gefitinib and ZD1839) and Tarceva

(being also referred to as erlotinib and CP-358,774) be approved for the treatment late period non--small cell lung cancer.In addition, also use the inhibiting antibody of anti-EGFR and erbB2 (to be respectively erbitux (c-225/cetuximab) and Trastuzumab (trastuzumab)) the result proof noumenal tumour that is used for the treatment of selection clinically be useful (comment al in Mendelsohn et, 2000, Oncogene, 19, 6550-6565).

Recently, the ATP of the interior catalytic domain of the cell of EGF acceptor has been found in some subgroup of nonsmall-cell lung cancer (NSCLC) in conjunction with the sudden change in the capsule.The existence that suddenlys change in the acceptor demonstrates the EGFR tyrosine kinase inhibitor dependency (Lynch et al, the N Engl J Med2004 that reply of gefitinib for example; 350:2129-2139; Paez et al, Science 2004; 304:1497-1500), be apparent that the clinical benefit of compound such as gefitinib and erlotinib can not be by the EGFR independent inductive that suddenlys change although become.Verified, it is viewed that the phosphorylation pattern in the acceptor that ligand stimulation causes suddenling change is different from wild-type receptor, and this is considered to the remaining signal of mutant EGF receptor-selective ground transduction, and NSCLC becomes dependent for this signal.By compound for example gefitinib suppress these signals and can help these efficiency of drugs (Sordella et al.Science2004; 305:1163-1167).Similarly, the sudden change in the erbB2 kinases district recent findings in some primary tumor for example in NSCLC, glioblastoma and stomach and the ovarian tumor (Stephens et al., Nature 2004; 431; 525-526).Therefore EGF and/or erbB2 receptor tyrosine kinase are important targets to the restraining effect in wild-type and the mutant acceptor, and this will be expected to produce antitumous effect.

Amplification and/or activity to erbB receptor Tyrosylprotein kinase member detects, thereby hints it in some non--neoplasm diseases, for example psoriasis (Ben-Bassat, Curr. Pharm.Des., 2000, 6, 933; Elder Et Al., Science, 1989, 243, 811), benign prostatic hyperplasia (BPH) (Kumar Et al., Int.Urol.Nephrol., 2000, 32, 73), atherosclerosis and restenosis (Bokemeyer Et al., Kidney Int., 2000, 58, 549) in play a role.Therefore, expectation erbB receptor tyrosine kinase inhibitor will be used for the treatment of these and other non--malignant cell excess proliferative disease.

WO 96/09294, WO 96/15118, WO 96/16960, WO 96/30347, WO96/33977, WO 96/33978, WO 96/33979, WO 96/33980, WO 96/33981, WO 97/03069, WO 97/13771, WO 97/30034, WO 97/30035, WO 97/38983, WO 98/02437, WO 98/02434, WO 98/02438, WO 98/13354, WO 99/35132, WO 99/35146, WO 01/21596, WO 00/55141 and WO 02/18372 disclose some separately and have the substituent quinazoline derivant of anilino have receptor tyrosine kinase and suppress active on the 4-position.WO 97/03069 also discloses multiple 4-(indazole-5-base amino) quinazoline derivant, but none is included in substituting group on the quinazoline ring 5-position in these derivatives.

Cockerill et al., Bioorg. ﹠amp; Med.Chem.Lett., 11 (2001), 1401-1405 discloses quinazoline derivant 4-([1-benzyl) indazole-5-yl] amino) quinazoline and 5,6-dimethoxy-4 '-([1-benzyl) indazole-5-yl] amino) quinazoline and they are as the purposes of EGF and erbB2 receptor tyrosine kinase inhibitors.This document is not disclosed in quinazoline ring 5-position and comprises substituent quinazoline derivant.

Lackey et al., Bioorg. ﹠amp; Med.Chem.Lett., 14 (2004), 111-114 discloses and has contained substituent 4-([1-{3-luorobenzyl) indazole-5-yl in quinazoline ring 6-position] amino) quinazoline derivant and they are as the purposes of EGF and erbB2 receptor tyrosine kinase inhibitors.This document is not disclosed in quinazoline ring 5-position and comprises substituent quinazoline derivant.

WO 01/94341 discloses some and has the Src family inhibitor of c-Src, c-Yes and c-Fyn for example that the substituent quinazoline derivant of 5-is non--receptor tyrosine kinase.Disclose unexposed 4-(indazole-5-base is amino) quinazoline derivant in WO 01/94341, the nitrogen-atoms of indazolyl is contained the substituting group replacement of aryl or heteroaryl in this derivative.

WO 02/34744 also discloses some quinazoline derivant and they purposes as the inhibitor of non--receptor tyrosine kinase Src family.This quinazoline derivant contains 7-indyl amino group in the 4-position of quinazoline ring, and contains hydrogen atom in the 5-position at the quinazoline ring.Unexposed 4-in this PCT application (indazole-5-base is amino) quinazoline derivant let alone contains 4-(indazole-5-base amino) quinazoline derivant of the methoxyl group that connects amide group in the 5-position of quinazoline ring.

WO 03/040108 and WO 03/040109 disclose some separately and have inhibitor, particularly EGF and the erbB2 receptor tyrosine kinase inhibitors that the substituent quinazoline derivant of 5-is the erbB family of Tyrosylprotein kinase.WO 03/040108 and WO 03/040109 disclose some 4-(indazole-5-base is amino) quinazoline derivant respectively.There is not a kind of quinazoline derivant that is disclosed on the 5-position of quinazoline ring, to contain the methoxyl group that connects amide group.

It is erbB family's group inhibitor, particularly EGF and the erbB2 receptor tyrosine kinase of tyrosine kinase inhibitor that WO 2004/093880 also discloses some quinazoline derivant with 5-bit substituent.This PCT application discloses some 4-anilino-quinazoline derivatives, and they have the substituent oxyethyl group of the amine of connection in the 5-position of quinazoline ring.Unexposed 4-in this application (indazole-5-base is amino) quinazoline derivant.

WO 2005/118572 (with PCT number of patent application PCT/GB2005/002215 co-pending altogether) also discloses some, and to have the substituent quinazoline derivant of 5-be the inhibitor of tyrosine kinase inhibitor erbB family, particularly EGF and erbB2 receptor tyrosine kinase.This PCT patent application discloses some 4-anilino-quinazoline derivatives, and they have the methoxyl group that connects amide substituents in the 5-position of quinazoline ring.Unexposed 4-in this application (indazole-5-base is amino) quinazoline derivant.

WO 2005/097137 discloses the quinazoline derivant that contains hydroxyl and they purposes as kinases inhibitor.This PCT applies for unexposed 4-(indazole-5-base is amino) quinazoline derivant, let alone also contains 4-(indazole-5-base the is amino) quinazoline derivant of the methoxyl group that connects amide group in the 5-position of quinazoline ring.

Prior art does not disclose 4-(indazole-5-base is amino) quinazoline derivant, this 4-(indazole-5-base amino) quinazoline derivant is connected amide group in the 5-position methoxyl group replaces, and this 4-(indazole-5-base is amino) quinazoline derivant has in the 1-position of indole ring and contains substituent aryl or heteroaryl.

Still need to find other compound, the particularly compound of selectivity erbB2 tyrosine kinase inhibitor of having good activity in vivo and comparing the pharmacological property of improvement with known erbB tyrosine kinase inhibitor.For example, need be for example, but be not limited to the compounds of the advantage of following aspect and/or the character of improvement: (i) physical properties; (ii) good DMPK character is as low clearance rate, high bioavailability and/or favourable transformation period and/or good distribution volume and/or high absorption; (iii) reduce clinical medicine-drug interaction and easily send out factor (for example cytochrome P 450 enzymes restraining effect or inducing action); (iv) have and reduce patient QT interval and prolongs the compound of liability, for example in HERG analyzes non-activity can a little less than active compound.

Surprisingly, we have now found that, are chosen in the 5-position and are contained 4-(indazole-5-base the is amino) quinazoline derivant that the substituting group of some methoxyl group that connects amide group replaces and have the effective antitumour activity.Although do not wish compound disclosed by the invention only is defined as and have pharmacologically active by influencing the effect of a kind of single creature process, but, the applicant thinks that described quinazoline derivant produces antitumor action in the mode of one or more receptor tyrosine kinases of inhibition erbB family, and described kinases is relevant with the signal conduction step of the propagation that causes tumour cell.Especially, the applicant thinks that quinazoline derivant of the present invention produces antitumor action by suppressing EGF and/or erbB2 receptor tyrosine kinase.More particularly, the applicant thinks that quinazoline derivant of the present invention is to produce antitumor action by comparing the mode that optionally suppresses the erbB2 receptor tyrosine kinase with the EGF receptor tyrosine kinase.The applicant thinks that also quinazoline derivant of the present invention has the good character of combination, for example mentioned above those.

For erbB acceptor, particularly erbB2 used herein, will comprise wild-type and mutant acceptor, unless otherwise specified.Term " sudden change " comprises and including, but not limited in one or more coding acceptor for example gene amplification, Nucleotide in-frame deletion or replacements of the exon of erbB2.

Usually, quinazoline derivant of the present invention has effective inhibition activity to erbB receptor tyrosine kinase family, for example they can suppress EGF and/or erbB2 and/or erbB4 receptor tyrosine kinase, simultaneously other kinases are had less inhibition activity.And in general, the effectiveness that quinazoline derivant of the present invention suppresses erbB2 significantly is better than the EGFR Tyrosylprotein kinase, thereby produces effective treatment of the tumour that erbB2 is caused potentially.Therefore, might there be the dosage of obviously effect to give quinazoline derivant of the present invention to EGFR or other Tyrosylprotein kinase to be enough to suppress the erbB2 Tyrosylprotein kinase.The selective inhibitory that is provided by quinazoline derivant of the present invention can provide the treatment by the tyrosine kinase mediated patient's condition of erbB2, alleviate simultaneously may with suppress the relevant unwanted side effect of other Tyrosylprotein kinase.

The quinazoline derivant of formula I is provided according to a first aspect of the invention:

Wherein:

R ¹Be selected from hydrogen, hydroxyl, (1-4C) alkoxyl group and (1-4C) alkoxyl group (1-4C) alkoxyl group;

G ¹, G ², G ³And G ⁴Be selected from hydrogen and halogen independently of one another;

X ¹Be selected from SO ₂, CO, SO ₂N (R ⁶) and C (R ⁶) ₂, each R wherein ⁶Be independently selected from hydrogen and (1-4C) alkyl;

Q ¹Be aryl or heteroaryl, this aryl or heteroaryl be optional to have one or more halogeno-group, cyano group, (1-4C) alkoxyl group and (1-4C) substituting groups of alkyl of being independently selected from;

R ²And R ³, it can be identical or different, is selected from hydrogen, (2-4C) thiazolinyl, (2-4C) alkynyl and (1-4C) alkyl, should (1-4C) alkyl is optional has one or more hydroxyl substituents, perhaps

R ²And R ³Form cyclopropyl rings with the carbon atom that they connected;

R ⁴And R ⁵It can be identical or different, be selected from hydrogen, (3-4C) thiazolinyl, (3-4C) alkynyl and (1-4C) alkyl, should (1-4C) alkyl optional has one or more following substituting groups that are independently selected from: halogeno-group, cyano group, hydroxyl, amino, (1-4C) alkylamino, two-[(1-4C) alkyl] is amino and (1-4C) alkoxyl group, perhaps

R ⁴And R ⁵Form 4,5,6 or 7 yuan of saturated heterocycles with the nitrogen-atoms that they connected, it is chosen wantonly and contains one or more oxygen, S, SO, SO of being independently selected from ₂And N (R ⁷) other heteroatoms, R wherein ⁷Be selected from hydrogen and (1-4C) alkyl,

And wherein by R ⁴, R ⁵The heterocycle that the nitrogen-atoms that is connected with them forms is optional to have one or more following substituting groups that are independently selected from: halogeno-group, cyano group, hydroxyl, (1-4C) alkyl and (1-4C) alkoxyl group,

And wherein by R ⁴, R ⁵The heterocycle that the nitrogen-atoms that is connected with them forms is chosen wantonly has 1 or 2 oxo or sulfo-substituting group;

Or its pharmacy acceptable salt.

According to a second aspect of the invention, provide the quinazoline derivant of formula I, wherein:

R ²And R ³, it can be identical or different, is selected from hydrogen and (1-4C) alkyl, should (1-4C) alkyl is optional has one or more hydroxyl substituents, perhaps

R ²And R ³Form cyclopropyl rings with the carbon atom that they connected;

R ⁴And R ⁵It can be identical or different, be selected from hydrogen and (1-4C) alkyl, should (1-4C) alkyl optional have one or more following substituting groups that are independently selected from: hydroxyl, amino, (1-4C) alkylamino, two-[(1-4C) alkyl] is amino and (1-4C) alkoxyl group, perhaps

Or its pharmacy acceptable salt.

According to a third aspect of the invention we, provide the quinazoline derivant of formula I, wherein:

X ¹Be CH ₂

R ²And R ³Form cyclopropyl rings with the carbon atom that they connected;

Or its pharmacy acceptable salt.

According to a forth aspect of the invention, provide the quinazoline derivant of formula I, wherein:

X ¹Be CH ₂

R ²And R ³Form cyclopropyl rings with the carbon atom that they connected;

Or its pharmacy acceptable salt.

According to a fifth aspect of the invention, provide the quinazoline derivant of formula I, wherein:

R ²Be hydrogen;

R ³It is methyl;

Or its pharmacy acceptable salt.

According to a sixth aspect of the invention, provide the quinazoline derivant of formula I, wherein:

R ²Be hydrogen;

R ³It is methyl;

Or its pharmacy acceptable salt.

In this manual, generic term " alkyl " comprises straight chain and branched-chain alkyl, as propyl group, sec.-propyl and the tertiary butyl.Yet, when relating to the independent alkyl such as " propyl group ", only be to refer in particular to linear form; When relating to the independent branched-chain alkyl such as " sec.-propyl ", only be to refer in particular to the side chain form.Similarly convention is applicable on other generic term that for example (1-4C) alkoxyl group comprises methoxyl group and oxyethyl group, and (1-4C) alkylamino comprises methylamino-, ethylamino and isopropylamino, and two-[(1-4C) alkyl] amino comprise dimethylamino, diethylin, N-sec.-propyl- N-methylamino-.

Should be appreciated that, more than the quinazoline derivant of Ding Yi some formula I is owing to have one or more unsymmetrical carbon, therefore can exist with optically active or racemic form, the present invention comprises any have above-mentioned active such optically active or racemic form in its definition.Especially, if radicals R ²And R ³Inequality, then the quinazoline derivant of formula I is connecting described radicals R ²And R ³Carbon atom on can have chiral centre.The present invention includes active all these steric isomers, for example (2R) and (2S) isomer (particularly (2R) isomer) with this paper definition.Be also to be understood that in the title of chipal compounds (R, S) any ratio (scalemic) or the racemic mixture of expression, and (R) and (S) expression enantiomer.In title, there is not (R, S), (R) or (S) time, should be appreciated that this name refers to any ratio or racemic mixture, wherein the mixed thing comprises the R and the S enantiomer of any relative proportion, and racemic mixture comprises 50: 50 R of ratio and S enantiomer.By standard technique of organic chemistry well known in the art, for example, can carry out the synthetic of optically active form by fractionation synthetic from the optically active initial substance or by racemic form.Similarly, use the standard laboratory technology of mentioning hereinafter, can estimate above-mentioned activity.

Suitable group in the above-mentioned general group comprises those that list below.

When being aryl, suitable Q ¹Be, for example, phenyl or naphthyl, particularly phenyl.

When being heteroaryl, suitable Q ¹Be, for example, have 4 of as many as and be independently selected from the aromatics 5-of ring hetero atom or the 6-unit monocycle of oxygen, nitrogen and sulphur, for example furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl or 1,3, the 5-triazinyl.When being heteroaryl, special Q ¹Be, for example, contain aromatics 5-or 6-unit monocycle that nitrogen and optional 1 or 2 (for example 1) are independently selected from other ring hetero atom of oxygen, nitrogen and sulphur, for example pyrryl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base, thiadiazolyl group, triazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl or 1,3,5-triazinyl (Qi Shi oxazolyl of You, isoxazolyl, imidazolyl, thiazolyl or pyridyl, Qi Shi oxazolyl of Geng You, thiazolyl or pyridyl).

When this paper mentions R ⁴And R ⁵Form 4,5,6 or 7 yuan of saturated heterocycles with the nitrogen-atoms that they connected, it is chosen wantonly and contains one or more oxygen, S, SO, SO of being independently selected from ₂And N (R ⁷) other heteroatoms (R wherein ⁷Definition is as mentioned) time, the described ring of Xing Chenging compatibly contains one or two other heteroatoms thus, and contains an other heteroatoms with being more suitable for.For example, the described ring that forms thus can be selected from azetidine-1-base, tetramethyleneimine-1-base, pyrazolidine-1-base, piperidines-1-base, morpholine-4-base and piperazine-1-base (particularly azetidine-1-base, tetramethyleneimine-1-base, piperidines-1-base, morpholine-4-base and piperazine-1-yl).By R ⁴And R ⁵Any heterocycle that forms with the nitrogen-atoms that they connected is optional have one or more as defined herein can be identical or different substituting group, and/or optionally have 1 or 2 oxo or a sulfo-substituting group.

Should be appreciated that 2-, 6-and the 8-position of the quinazoline group described in the formula I on this quinazoline ring is not substituted separately.

For any ' R ' group (R ¹To R ⁷), for any ' G ' group (R ¹To R ⁴) or for Q ¹Or X ¹Various groups in the group, suitable value comprises :-

For halogeno-group: fluorine, chlorine, bromine and iodine;

For (1-4C) alkyl: methyl, ethyl, propyl group, sec.-propyl and the tertiary butyl;

For (2-4C) thiazolinyl: vinyl, pseudoallyl, allyl group and but-2-ene

Base;

For (2-4C) alkynyl: ethynyl, 2-propynyl and fourth-2-alkynyl;

For (1-4C) alkoxyl group: methoxyl group, oxyethyl group, propoxy-, isopropoxy and

Butoxy;

For (1-4C) alkoxyl group (1-4C) alkoxyl group: oxyethyl group methoxy base, propoxy-methoxyl group, methoxy

Base oxethyl, ethoxy ethoxy, methoxy propyl

Oxygen base, oxyethyl group propoxy-, different third oxygen of methoxyl group

Base and methoxyl group butoxy;

For (1-4C) alkylamino: methylamino-, ethylamino, third amino, isopropylamino

With fourth amino; With

For two-[(1-4C) alkyl] amino: dimethylamino, diethylin, N-ethyl-N-first ammonia

Base and two-isopropylamino.

When mentioning (1-4C) alkyl in this manual, should be appreciated that this group is meant the alkyl that contains 4 carbon atoms of as many as.Similarly, mention that (1-2C) alkyl is meant the alkyl that contains 2 carbon atoms of as many as, for example methyl and ethyl.Similar agreement is applicable to above listed other group.

When as mentioned the definition formula-X ¹-Q ¹Group in, X ¹Be SO for example ₂N (R ⁶) linking group, then SO ₂N (R ⁶) SO of linking group ₂Group is connected with the indazolyl of formula I, and SO ₂N (R ⁶) nitrogen-atoms and the Q of linking group ¹Group connects.

Should be appreciated that the quinazoline derivant of some formula I can exist with solvation and non-solvent form, for example the form of aquation.Should be appreciated that, the present invention includes the erbB receptor tyrosine kinase is demonstrated for example all such solvate form thereof of antiproliferative activity of restraining effect.

The quinazoline derivant that be also to be understood that some formula I can show as polymorph, thereby the present invention includes the erbB receptor tyrosine kinase is demonstrated for example all such forms of antiproliferative activity of restraining effect.

Be also to be understood that all tautomeric forms of the quinazoline derivant that the present invention relates to formula I, they demonstrate for example antiproliferative activity of restraining effect to the erbB receptor tyrosine kinase.

The pharmacy acceptable salt that is fit to of the quinazoline derivant of formula I is, for example, and the acid salt of the quinazoline derivant of formula I, for example acid salt that is become with mineral acid or organic acid.The mineral acid that is fit to comprises, for example, and hydrochloric acid, Hydrogen bromide or sulfuric acid.The organic acid that is fit to comprises, for example, and trifluoroacetic acid, Citric Acid or toxilic acid.The pharmacy acceptable salt that another of the quinazoline derivant of formula I is fit to is, for example, the salt of the quinazoline derivant of enough tart formula I, for example an alkali metal salt or alkaline earth salt, as calcium salt or magnesium salts, perhaps ammonium salt, the perhaps salt that forms with for example following organic bases: methylamine, dimethylamine, Trimethylamine 99, piperidines, morpholine or three-(2-hydroxyethyl) amine.

The concrete new quinazoline derivant of the present invention comprises, for example, the quinazoline derivant of formula I or its pharmacy acceptable salt, wherein except that specializing, R ¹, R ², R ³, R ⁴, R ⁵, G ¹, G ², G ³, G ⁴, Q ¹And X ¹In each have among front or following (a) to (eeee) in all senses defined :-

(a) R ¹Be selected from hydrogen, hydroxyl, methoxyl group, oxyethyl group and methoxy ethoxy;

(b) R ¹Be selected from hydrogen and methoxyl group;

(c) R ¹Be hydrogen;

(d) G ¹, G ², G ³And G ⁴Be selected from hydrogen, chlorine and fluorine (particularly hydrogen and fluorine) separately independently of each other;

(e) G ¹, G ², G ³And G ⁴All be hydrogen;

(f) X ¹Be C (R ⁶) ₂, each R wherein ⁶Be hydrogen or (1-4C) alkyl (for example (1-2C) alkyl) independently;

(g) X ¹Be CH ₂,

(h) Q ¹Be selected from phenyl and 5 or 6 yuan of bicyclic heteroaryl rings, this ring contains 1,2 or 3 heteroatoms that is independently selected from oxygen, nitrogen and sulphur, and this phenyl or heteroaryl be optional to have 1,2 or 3 (for example 1 or 2) and be independently selected from following substituting group: halogeno-group, cyano group, (1-4C) alkyl and (1-4C) alkoxyl group;

(i) Q ¹Be selected from phenyl and 5 or 6 yuan of bicyclic heteroaryl rings, this ring contains 1,2 or 3 heteroatoms that is independently selected from oxygen, nitrogen and sulphur, and this phenyl or heteroaryl be optional to have 1,2 or 3 (for example 1 or 2) and be independently selected from following substituting group: chlorine, fluorine, cyano group, (1-2C) alkyl and (1-2C) alkoxyl group (especially fluorine and methyl);

(j) Q ¹Be selected from phenyl and 5 or 6 yuan of bicyclic heteroaryl rings, this ring contains 1,2 or 3 heteroatoms that is independently selected from oxygen, nitrogen and sulphur, and this phenyl or heteroaryl be optional to have 1,2 or 3 (for example 1 or 2) and be independently selected from following substituting group: fluorine, cyano group, methyl and methoxyl group;

(k) Q ¹Be phenyl, this phenyl is optional to have 1,2 or 3 (for example 1 or 2) (h), (i) or (j) substituting group of definition as mentioned;

(l) Q ¹Be phenyl, this phenyl is chosen wantonly has 1 or 2 substituting group that is independently selected from chlorine and fluorine;

(m) Q ¹Be phenyl, this phenyl has 1 or 2 substituting group that is independently selected from chlorine and fluorine;

(n) Q ¹Be phenyl, this phenyl is optional to have 12 and is independently selected from following substituting group: fluorine, cyano group, methyl and methoxyl group (especially fluorine, cyano group and methoxyl group);

(o) Q ¹Be phenyl, this phenyl has 1 or 2 (particularly 1) fluoro substituents;

(p) Q ¹It is the 3-fluorophenyl;

(q) Q ¹It is the 3-p-methoxy-phenyl;

(r) Q ¹It is the 2-cyano-phenyl;

(s) Q ¹Be 5 or 6 yuan of monocyclic heteroaryl rings, this ring contains 1 nitrogen heteroatom and optional 1 other heteroatoms that is selected from oxygen, nitrogen and sulphur, and this heteroaryl is optional to have 1,2 or 3 (for example 1 or 2) (h), (i) or (j) substituting group of definition as mentioned;

(t) Q ¹Be selected from phenyl, pyridyl, pyrazinyl, 1,3-thiazoles base, 1H-imidazolyl, 1H-pyrazolyl, 1, the 3-oxazolyl is with isoxazolyl, and it is optional to have 1,2 or 3 (for example 1 or 2) (h), (i) or (j) substituting group of definition as mentioned;

(u) Q ¹Be selected from phenyl, pyridyl, pyrazinyl, 1,3-thiazoles base He isoxazolyl (particularly phenyl, pyridyl and 1,3-thiazoles base), it is optional to have 1,2 or 3 (for example 1 or 2) (h), (i) or (j) substituting group of definition as mentioned;

(v) Q ¹Be selected from phenyl, pyridyl, 1,3-thiazolyl, 1H-imidazolyl, 1, the 3-oxazolyl is with isoxazolyl (particularly phenyl, pyridyl and 1,3-thiazoles base), and it is optional to have 1,2 or 3 (for example 1 or 2) (h), (i) or (j) substituting group of definition as mentioned;

(w) Q ¹Be selected from phenyl, pyridyl, 1,3-thiazoles base and 1, the 3-oxazolyl, it is optional to have 1,2 or 3 (for example 1 or 2) (h), (i) or (j) substituting group of definition as mentioned;

(x) Q ¹Be selected from 2-, 3-or 4-pyridyl, 2-pyrazinyl, 1,3-thiazol-2-yl, 1,3-thiazole-4-base, 1,3-thiazole-5-base, 3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, it is optional to have 1,2 or 3 (for example 1 or 2) (h), (i) or (j) substituting group of definition as mentioned;

(y) Q ¹Be selected from 2-, 3-or 4-pyridyl, 1,3-thiazol-2-yl, 1,3-thiazole-4-base, 1,3-thiazole-5-base, 1H-imidazoles-2-base, 1,3-oxazole-2-base, 3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, it is optional to have 1,2 or 3 (for example 1 or 2) (h), (i) or (j) substituting group of definition as mentioned;

(z) Q ¹Be selected from phenyl, 2-or 3-pyridyl, 1,3-thiazoles-2-base, 1,3-thiazoles-4-base, 1,3-thiazoles-5-base and 1,3-oxazole-2-base, it is optional to have 1,2 or 3 (for example 1 or 2) (h), (i) or (j) substituting group of definition as mentioned;

(aa) Q ¹Be selected from phenyl, 2-pyridyl, 1,3-thiazoles-2-base and 1,3-thiazoles-4-base (particularly phenyl, 2-pyridyl and 1,3-thiazoles-4-yl), it is optional to have 1,2 or 3 (for example 1 or 2) (h), (i) or (j) substituting group of definition as mentioned;

(bb) Q ¹Be pyridyl (particularly 2-pyridyl or 3-pyridyl), it is optional to have 1,2 or 3 (for example 1 or 2) (h), (i) or (j) substituting group of definition as mentioned;

(cc) Q ¹Be the 2-pyridyl, it is optional to have 1 or 2 and is independently selected from following substituting group: fluorine, chlorine and (1-2C) alkoxyl group (particularly fluorine);

(dd) Q ¹Be the 3-pyridyl, it is optional to have 1 or 2 and is independently selected from following substituting group: fluorine, chlorine and (1-2C) alkoxyl group (particularly fluorine);

(ee) Q ¹It is the 2-pyridyl;

(ff) Q ¹It is 6-fluoro-pyridin-3-yl;

(gg) Q ¹Be 1,3-thiazoles base (particularly 1,3-thiazoles-2-base, 1,3-thiazoles-4-base or 1,3-thiazoles base-5-yl), it is optional to have 1 or 2 (for example 1) (h), (i) or (j) substituting group of definition as mentioned;

(hh) Q ¹Be 1,3-thiazoles-4-base, it is optional to have 1 or 2 and is independently selected from following substituting group: fluorine, chlorine, (1-2C) alkyl and (1-2C) alkoxyl group (particularly methyl);

(ii) Q ¹Be 1,3-thiazoles-2-base, it is optional to have 1 or 2 and is independently selected from following substituting group: fluorine, chlorine, (1-2C) alkyl and (1-2C) alkoxyl group (particularly methyl);

(jj) Q ¹Be 1,3-thiazoles-5-base, it is optional to have 1 or 2 and is independently selected from following substituting group: fluorine, chlorine, (1-2C) alkyl and (1-2C) alkoxyl group (particularly methyl);

(kk) Q ¹It is 1,3-thiazoles-4-base;

(ll) Q ¹It is 1,3-thiazoles-2-base;

(mm) Q ¹It is 1,3-thiazoles-5-base;

(nn) Q ¹Be the 2-methyl isophthalic acid, 3-thiazole-5-base;

(oo) Q ¹Be 1,3-oxazolyl (particularly 1,3-oxazole-2-yl), it is optional to have 1 or 2 (for example 1) (h), (i) or (j) substituting group of definition as mentioned;

(pp) Q ¹Be 1,3-oxazole-2-base;

(qq) Q ¹Shi isoxazolyl (particularly isoxazole-3-base), it is optional to have 1 or 2 (for example 1) (h), (i) or (j) substituting group of definition as mentioned;

(rr) Q ¹Be 5-methyl-isoxazole-3-bases;

(ss) Q ¹Be 3,5-dimethyl-isoxazole-4-bases;

(tt) Q ¹Be 1H-imidazolyl (particularly 1H-imidazoles-2-yl), it is optional to have 1 or 2 (for example 1) (h), (i) or (j) substituting group of definition as mentioned;

(uu) Q ¹It is 1-methyl-imidazoles-2-base;

(vv) Q ¹Be selected from 3-fluorophenyl, 2-pyridyl, 6-fluoro-pyridin-3-yl, 1,3-thiazole-5-base, 1,3-thiazole-4-base, 1,3-thiazol-2-yl, 2-methyl isophthalic acid, 3-thiazole-5-base, 1,3-oxazole-2-base, 5-methyl-isoxazole-3-bases, 3,5-dimethyl isoxazole-4-base and 1-methyl-imidazoles-2-base;

(ww) Q ¹Be selected from 3-fluorophenyl, 3-p-methoxy-phenyl, 2-cyano-phenyl, 2-pyridyl, 6-fluoro-pyridin-3-yl, 1,3-thiazoles-4-base, 1,3-thiazoles-2-base, 2-methyl isophthalic acid, 3-thiazole-5-base and 1,3-oxazole-2-base;

(xx) Q ¹Be selected from phenyl, pyridyl, 1,3-thiazolyl, 1H-imidazolyl, 1, the 3-oxazolyl is with isoxazolyl (particularly phenyl, pyridyl and 1,3-thiazoles base), and it is optional to have 1,2 or 3 (for example 1 or 2) (h), (i) or (j) substituting group of definition as mentioned; And

X ¹Be C (R ⁶) ₂, each R wherein ⁶Be hydrogen or (1-2C) alkyl (each R particularly independently ⁶Be hydrogen);

(yy) Q ¹Be selected from phenyl, pyridyl, 1,3-thiazoles base and 1, the 3-oxazolyl, it is optional to have 1,2 or 3 (for example 1 or 2) (h), (i) or (j) substituting group of definition as mentioned; And

(zz) Q ¹Be selected from phenyl, pyridyl, 1,3-thiazolyl, 1H-imidazolyl, 1, the 3-oxazolyl is with isoxazolyl (particularly phenyl, pyridyl and 1,3-thiazoles base), and it is optional to have 1,2 or 3 (for example 1 or 2) (h), (i) or (j) substituting group of definition as mentioned;

X ¹Be C (R ⁶) ₂, each R wherein ⁶Be hydrogen or (1-2C) alkyl (each R particularly independently ⁶Be hydrogen); And

G ¹, G ², G ³And G ⁴All be hydrogen;

(aaa) Q ¹Be selected from phenyl, pyridyl, 1,3-thiazoles base and 1, the 3-oxazolyl, it is optional to have 1,2 or 3 (for example 1 or 2) (h), (i) or (j) substituting group of definition as mentioned;

G ¹, G ², G ³And G ⁴All be hydrogen;

(bbb) described group-X ¹-Q ¹Be selected from pyridine-2-ylmethyl, 1,3-thiazoles-2-ylmethyl, 1,3-thiazoles-4-ylmethyl and 3-luorobenzyl (particularly pyridine-2-ylmethyl, 1,3-thiazoles-4-ylmethyl and 3-luorobenzyl);

(ccc) described group-X ¹-Q ¹Be selected from 3-luorobenzyl, 3-methoxy-benzyl, 2-cyano group benzyl, pyridine-2-ylmethyl, (6-fluoro-pyridin-3-yl) methyl, 1,3-thiazole-4-ylmethyl, 1,3-thiazol-2-yl methyl, (2-methyl isophthalic acid, 3-thiazole-5-yl) methyl and 1,3-oxazole-2-ylmethyl;

(ddd) described group-X ¹-Q ¹It is the 3-methoxy-benzyl;

(eee) described group-X ¹-Q ¹It is 2-cyano group benzyl;

(fff) described group-X ¹-Q ¹It is (6-fluoro-pyridin-3-yl) methyl;

(ggg) described group-X ¹-Q ¹It is 1,3-thiazoles-2-ylmethyl;

(hhh) described group-X ¹-Q ¹It is (2-methyl isophthalic acid, 3-thiazole-5-yl) methyl;

(iii) described group-X ¹-Q ¹Be 1,3-oxazole-2-ylmethyl;

(jjj) described group-X ¹-Q ¹It is pyridine-2-ylmethyl;

(kkk) described group-X ¹-Q ¹It is 1,3-thiazoles-4-ylmethyl;

(lll) described group-X ¹-Q ¹It is the 3-luorobenzyl;

(mmm) R ²And R ³Be selected from hydrogen and (1-2C) alkyl (for example methyl) separately independently of each other;

(nnn) R ²And R ³Be selected from hydrogen and (1-2C) alkyl, wherein R separately independently of each other ²And R ³In at least one is (1-2C) alkyl (a for example methyl);

(ooo) R ²Be hydrogen and R ³Be (1-2C) alkyl (for example methyl);

(ppp) R ²And R ³All be hydrogen;

(qqq) R ⁴And R ⁵, it can be identical or different, is selected from hydrogen and (1-4C) alkyl, should (1-4C) alkyl is optional has one or more hydroxyl substituents, perhaps

R ⁴And R ⁵Form saturated 4,5,6 or 7 yuan (particularly 5 or 6) first heterocycles with the nitrogen-atoms that they connected, it is optional to contain one or more oxygen, S, SO, SQ of being independently selected from ₂And N (R ⁷) other heteroatoms, R wherein ⁷Be selected from hydrogen and (1-2C) alkyl,

(rrr) R ⁴And R ⁵, it can be identical or different, is selected from hydrogen and (1-4C) alkyl, should (1-4C) alkyl is optional has one or more hydroxyl substituents, perhaps

R ⁴And R ⁵Form with the nitrogen-atoms that they connected and to be selected from following heterocycle: azetidine-1-base, tetramethyleneimine-1-base, pyrazolidine-1-base, piperidines-1-base, morpholine-4-base and piperazine-1-base, wherein arbitrary heterocycle is optional to have one or more following substituting groups that are independently selected from: halogeno-group, cyano group, hydroxyl, (1-4C) alkyl and (1-4C) alkoxyl group, and wherein arbitrary heterocycle is optional has 1 or 2 oxo or a sulfo-substituting group;

(sss) R ⁴And R ⁵, it can be identical or different, is selected from hydrogen and (1-4C) alkyl, should (1-4C) alkyl is optional has one or more hydroxyl substituents, perhaps

R ⁴And R ⁵Form the heterocycle that is selected from tetramethyleneimine-1-base and morpholine-4-base with the nitrogen-atoms that they connected, wherein arbitrary heterocycle is optional to have one or more following substituting groups that are independently selected from: halogeno-group, cyano group, hydroxyl, (1-4C) alkyl and (1-4C) alkoxyl group, and wherein arbitrary heterocycle is optional has 1 or 2 oxo or a sulfo-substituting group;

(ttt) R ⁴Be hydrogen and R ⁵Be (1-4C) alkyl, this (1-4C) alkyl is chosen wantonly has one or more hydroxyl substituents;

(uuu) R ⁴And R ⁵Be independently selected from hydrogen, methyl, ethyl and 2-hydroxyethyl;

(vvv) R ⁴Be hydrogen and R ⁵Be selected from hydrogen, methyl, ethyl and 2-hydroxyethyl;

(www) R ⁴Be hydrogen and R ⁵Be selected from methyl, ethyl and 2-hydroxyethyl;

(xxx) R ⁴And R ⁵All are (1-4C) alkyl, this (1-4C) alkyl is chosen wantonly has one or more hydroxyl substituents;

(yyy) R ⁴Be methyl and R ⁵Be (1-4C) alkyl, this (1-4C) alkyl is chosen wantonly has one or more hydroxyl substituents;

(zzz) R ⁴Be methyl and R ⁵Be selected from methyl, ethyl and 2-hydroxyethyl;

(aaaa) R ⁴And R ⁵All are methyl;

(bbbb) R ⁴And R ⁵Form the heterocycle that is selected from tetramethyleneimine-1-base and morpholine-4-base with the nitrogen-atoms that they connected, this heterocycle is optional to have one or more following substituting groups that are independently selected from: halogeno-group, cyano group, hydroxyl, (1-4C) alkyl and (1-4C) alkoxyl group, and this heterocycle is optional has 1 or 2 oxo or a sulfo-substituting group;

(cccc) R ⁴And R ⁵Form the heterocycle that is selected from tetramethyleneimine-1-base and morpholine-4-base with the nitrogen-atoms that they connected;

(dddd) Q ¹Be selected from phenyl, 2-pyridyl and 1,3-thiazoles-2-base, it is optional to have 1,2 or 3 (for example 1 or 2) (h), (i) or (j) substituting group of definition as mentioned; And

(eeee) described group-X ¹-Q ¹Be selected from pyridine-2-ylmethyl, 1,3-thiazoles-2-ylmethyl and 3-luorobenzyl.

One embodiment of the invention is the quinazoline derivant of formula I, wherein:

R ¹Be selected from hydrogen and (1-2C) alkoxyl group (R for example ¹Be hydrogen or methoxyl group, particularly hydrogen);

X ¹Be CH ₂

Q ¹Be aryl or heteroaryl, this aryl or heteroaryl be optional to have one or more (for example 1 or 2) and is independently selected from following substituting group: chlorine, fluorine, cyano group, (1-2C) alkyl and (1-2C) alkoxyl group (especially fluorine, cyano group, methyl and methoxyl group);

And G wherein ¹, G ², G ³, G ⁴, R ², R ³, R ⁴And R ⁵Has any value defined above;

Or its pharmacy acceptable salt.

In this embodiment, Q ¹Special value be phenyl, perhaps contain 1 nitrogen heteroatom and optional 1 other heteroatomic 5 or 6 yuan of hetero-aromatic ring that are independently selected from oxygen, nitrogen and sulphur, this phenyl or heteroaryl be optional to have 1,2 or 3 substituting group of definition as mentioned.

Another embodiment of the invention is the quinazoline derivant of formula I, wherein:

X ¹Be CH ₂

Q ¹It is heteroaryl, this heteroaryl is optional to have one or more (for example 1 or 2) and is independently selected from following substituting group: chlorine, fluorine, cyano group, (1-2C) alkyl and (1-2C) alkoxyl group (especially fluorine, cyano group, methyl and methoxyl group, more particularly fluorine and methyl);

Or its pharmacy acceptable salt.

In this embodiment, Q ¹Special value be to contain 1 nitrogen heteroatom and optional 1 other heteroatomic 5 or 6 yuan of hetero-aromatic ring that are independently selected from oxygen, nitrogen and sulphur, this heteroaryl is optional to have 1,2 or 3 substituting group of definition as mentioned.

X ¹Be CH ₂

Q ¹It is phenyl, perhaps contain 1 nitrogen heteroatom and optional 1 other heteroatomic 5 or 6 yuan of hetero-aromatic ring that are independently selected from oxygen, nitrogen and sulphur, this phenyl or heteroaryl ring be optional to have one or more halogeno-group, cyano group, (1-4C) alkoxyl group and (1-4C) substituting groups of alkyl of being independently selected from;

R ⁴And R ⁵, it can be identical or different, is selected from hydrogen and (1-2C) alkyl, should (1-2C) alkyl is optional has one or more hydroxyl substituents, perhaps

And G wherein ¹, G ², G ³, G ⁴, R ²And R ³Has any value defined above;

Or its pharmacy acceptable salt.

In this embodiment, Q ¹Special value be phenyl, pyridyl, 1,3-thiazoles base, 1H-imidazolyl, 1,3-oxazolyl Huo isoxazolyl, wherein Q ¹Choose wantonly and have 1,2 or 3 substituting group of definition as mentioned.

R ¹Be selected from hydrogen and methoxyl group (R particularly ¹Be hydrogen);

X ¹Be CH ₂

Q ¹It is phenyl, perhaps contain 1 nitrogen heteroatom and optional 1 other heteroatomic 5 or 6 yuan of hetero-aromatic ring that are independently selected from oxygen, nitrogen and sulphur (particularly nitrogen and sulphur), this phenyl or heteroaryl ring be optional to have one or more halogeno-group, cyano group, (1-4C) alkoxyl group and (1-4C) substituting groups of alkyl of being independently selected from;

R ⁴And R ⁵Form morpholine-4-basic ring with the nitrogen-atoms that they connected;

And G wherein ¹, G ², G ³, G ⁴, R ²And R ³Has any value defined above;

Or its pharmacy acceptable salt.

In this embodiment, Q ¹Special value be phenyl, pyridyl, 1,3-thiazoles base or 1,3-oxazolyl (particularly phenyl, pyridyl or 1,3-thiazoles base, for example phenyl, pyridine-2-base or 1,3-thiazoles-2-yl), wherein Q ¹Choose wantonly and have 1,2 or 3 substituting group of definition as mentioned.Q ¹Special substituting group comprise fluorine, methyl, methoxyl group and cyano group (especially fluorine).

In this embodiment, R ²And R ³, it can be identical or different, can be selected from hydrogen and (1-2C) alkyl especially.

In this embodiment, G ¹, G ², G ³, G ⁴Hydrogen in particular.

X ¹Be CH ₂

Q ¹Be selected from phenyl, pyridyl and 1,3-thiazoles base (for example phenyl, pyridine-2-base or 1,3-thiazoles-2-yl), wherein Q ¹Choose wantonly to have and be selected from following substituting group: fluorine, methyl, methoxyl group and cyano group (for example fluorine);

R ⁴And R ⁵Be (1-2C) alkyl (R for example independently ⁴And R ⁵All are methyl), perhaps

G ¹, G ², G ³, G ⁴Be hydrogen;

R ²Be (1-2C) alkyl (for example methyl);

And R ³Be hydrogen;

Or its pharmacy acceptable salt.

The concrete quinazoline derivant of the present invention is that for example, one or more are selected from the quinazoline derivant of following formula I:

(2R)-and N-(2-hydroxyethyl)-N-methyl-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide;

5-[(1R)-1-methyl-2-morpholine-4-base-2-oxo oxyethyl group]-N-[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine;

(2R)-and N, N-dimethyl-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide;

(2S)-and N, N-dimethyl-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide;

(2R)-and 2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide;

(2R)-and N-methyl-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide;

(2R)-and N-ethyl-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide;

5-[(1R)-1-methyl-2-oxo-2-tetramethyleneimine-1-base oxethyl]-N-[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine;

(2R)-and N-(2-hydroxyethyl)-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide;

N, N-dimethyl-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] ethanamide;

2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] ethanamide;

N-ethyl-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] ethanamide;

N-(2-hydroxyethyl)-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] ethanamide;

N-methyl-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] ethanamide;

N-(2-hydroxyethyl)-N-methyl-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] ethanamide;

5-(2-oxo-2-tetramethyleneimine-1-base oxethyl)-N-[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine;

5-(2-morpholine-4-base-2-oxo oxyethyl group)-N-[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine;

(2R)-and N, N-dimethyl-2-[(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide;

(2R)-and 2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base]-N, N-dimethyl propylene acid amides;

(2R)-and N, N--two-methyl-2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide;

(2R)-N, N-dimethyl-2-{[4-(1-[(2-methyl isophthalic acid, 3-thiazole-5-yl) methyl]-1H-indazole-5-yl } amino) quinazoline-5-yl] the oxygen base } propionic acid amide;

(2R)-2-{[4-(1-[(6-fluorine pyridin-3-yl) methyl]-1H-indazole-5-yl } amino) quinazoline-5-yl] the oxygen base }-N, N-dimethyl propylene acid amides;

(2R)-and 2-[(4-{[1-(3-methoxy-benzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base]-N, N-dimethyl propylene acid amides;

(2R)-and 2-[(4-{[1-(2-cyano group benzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base]-N, N-dimethyl propylene acid amides;

(2R)-and N, N-dimethyl-2-[(4-{[1-(1,3-oxazole-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide;

(2S)-and 2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base]-N, N-dimethyl propylene acid amides;

N-[1-(3-luorobenzyl)-1H-indazole-5-yl]-5-[(1S)-1-methyl-2-oxo-2-tetramethyleneimine-1-base oxethyl]-quinazoline-4-amine;

(2S)-and 2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide; N-[1-(3-luorobenzyl)-1H-indazole-5-yl]-5-[(1R)-1-methyl-2-oxo-2-tetramethyleneimine-1-base oxethyl]-quinazoline-4-amine;

(2R)-and 2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide; 5-[(1S)-1-methyl-2-oxo-2-tetramethyleneimine-1-base oxethyl]-N-[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine;

(2S)-and 2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide;

5-[(1S)-1-methyl-2-oxo-2-tetramethyleneimine-1-base oxethyl]-N-[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine;

(2S)-and N, N-dimethyl-2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide;

(2S)-and 2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide;

5-[(1R)-1-methyl-2-oxo-2-tetramethyleneimine-1-base oxethyl]-N-[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine;

(2R)-and 2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide;

(2R)-and 2-[(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide;

(2R)-and N-methyl-2-[(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide;

(2R)-and N-ethyl-2-[(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide;

5-[(1R)-1-methyl-2-oxo-2-tetramethyleneimine-1-base oxethyl]-N-[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine;

(2R)-and N-(2-hydroxyethyl)-N-methyl-2-[(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide;

(2R)-and N-(2-hydroxyethyl)-2-[(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide;

5-[(1R)-1-methyl-2-morpholine-4-base-2-oxo oxyethyl group]-N-[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine;

(2S)-and N, N-dimethyl-2-[(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide;

(2S)-and N-methyl-2-[(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide;

5-[(1S)-1-methyl-2-oxo-2-tetramethyleneimine-1-base oxethyl]-N-[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine;

5-[(1S)-1-methyl-2-morpholine-4-base-2-oxo oxyethyl group]-N-[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine;

(2S)-and N-methyl-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide;

5-[(1S)-1-methyl-2-morpholine-4-base-2-oxo oxyethyl group]-N-[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine;

(2R)-and 2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base]-the N-methyl propanamide;

(2R)-and 2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base]-N-ethyl propionic acid amide;

(2R)-and 2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base]-N-(2-hydroxyethyl) propionic acid amide;

(2R)-and 2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base]-N-(2-hydroxyethyl)-N-methyl propanamide;

N-[1-(3-luorobenzyl)-1H-indazole-5-yl]-5-[(1R)-and 1-methyl-2-morpholine-4-base-2-oxo oxyethyl group] quinazoline-4-amine;

(2S)-and 2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base]-the N-methyl propanamide;

N-[1-(3-luorobenzyl)-1H-indazole-5-yl]-5-[(1S)-and 1-methyl-2-morpholine-4-base-2-oxo oxyethyl group] quinazoline-4-amine;

(2R)-and N-(2-hydroxyethyl)-2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide;

(2R)-and N-(2-hydroxyethyl)-N-methyl-2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide;

(2R)-and N-ethyl-2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide;

(2R)-and N-methyl-2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide;

5-[(1R)-1-methyl-2-morpholine-4-base-2-oxo oxyethyl group]-N-[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine;

(2S)-and N-methyl-2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide; With

5-[(1S)-1-methyl-2-morpholine-4-base-2-oxo oxyethyl group]-N-[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine;

Or its pharmacy acceptable salt.

Can be according to known quinazoline derivant or its pharmacy acceptable salt that is used to prepare any suitable method preparation formula I of the relevant compound of chemistry.The method that is fit to comprises, for example, and those methods of explanation among WO 96/15118, WO 01/94341, WO 03/040108 and the WO 03/040109.When being used for the quinazoline derivant of preparation formula I, these methods have constituted another aspect of the present invention, and these methods can be described with the alternative of exemplary process described below, except that specializing, and the symbol R that in these methods, adopts ¹, R ², R ³, R ⁴, R ⁵, X ¹, Q ¹, G ¹, G ², G ³And G ⁴Have above in all senses defined.Necessary initial substance can adopt the organic chemistry standard method to obtain.In conjunction with the alternative of following exemplary process and the embodiment that provides, the preparation of this type of initial substance is described.Perhaps, also can adopt with the similar method of described method and obtain required initial substance, these methods are in the those of ordinary skill ken of organic chemistry filed.

Method (a)The quinazoline of formula II:

R wherein ¹, G ¹, G ², G ³, G ⁴, X ¹And Q ¹Except protecting any functional group where necessary, have any implication defined above, and the acid amides of formula III reaction:

R wherein ², R ³, R ⁴And R ⁵Except protecting any functional group where necessary, have any implication defined above, and L ¹Be the replaced group that is fit to, for example halogeno-group (for example chlorine or bromine), sulfonyloxy group (for example sulfonyloxy methyl oxygen base or toluene-4-sulfonyloxy group) or L ¹It is hydroxyl;

Perhaps

Method (b)In the presence of the alkali that is fit to, with the quinazoline of formula IV (or its suitable salt, for example its alkaline earth salt or an alkali metal salt are as sodium salt or sylvite):

R wherein ¹, R ², R ³, G ¹, G ², G ³, G ⁴, X ¹And Q ¹Except protecting any functional group where necessary, have any implication defined above, and L ²Be the replaced group that is fit to, for example (1-3C) alkoxyl group (for example methoxy or ethoxy) or L ²Be hydroxyl, this hydroxyl combines to produce with the coupling reagent that is fit to easily and can replace group, easily with the amine coupling of formula V:

R wherein ⁴And R ⁵Except protecting any functional group where necessary, has any implication defined above;

Perhaps

Method (c)For R wherein ²Be the quinazoline derivant of the formula I of 2-hydroxyethyl, the quinazoline of formula VI:

R wherein ¹, R ³, G ¹, G ², G ³, G ⁴, X ¹And Q ¹Except protecting any functional group where necessary, has any implication defined above, with the reaction of the amine of the formula V of above definition;

Perhaps

Method (d)The quinazoline of formula VII:

R wherein ¹, R ², R ³, G ¹, G ², G ³, G ⁴, X ¹And Q ¹Except protecting any functional group where necessary, has any implication defined above, with the reaction of the amine of the formula V of above definition;

Perhaps

Method (e)The quinazoline of formula VIII-4 (3H)-ketone:

R wherein ¹, R ², R ³, R ⁴And R ⁵Except protecting any functional group where necessary, have any implication defined above, and the reaction of the amine of activating group that is fit to and formula IX:

G wherein ¹, G ², G ³, G ⁴, X ¹And Q ¹Except protecting any functional group where necessary, has any implication defined above;

Perhaps

Method (f)The quinazoline of formula X:

R wherein ¹, G ¹, G ², G ³, G ⁴, X ¹And Q ¹Except protecting any functional group where necessary, have any implication defined above, and L ³Be for example halogeno-group (for example fluorine) of the replaced group that is fit to, and the compound reaction of formula XI:

R wherein ², R ³, R ⁴And R ⁵Except protecting any functional group where necessary, has any implication defined above;

Perhaps

Method (g)In the presence of the alkali that is fit to, with the quinazoline of formula XII:

R wherein ¹, R ², R ³, R ⁴, R ⁵, G ¹, G ², G ³And G ⁴Except protecting any functional group where necessary, have any implication defined above, easily with the compound coupling of formula XIII:

Q ¹-X ¹-L ⁴

XIII

Q wherein ¹And X ¹Except protecting any functional group where necessary, have any implication defined above, and L ⁴Be the replaced group that is fit to, for example halogeno-group (for example fluorine, chlorine, bromine or iodine) or sulfonyloxy group (for example sulfonyloxy methyl oxygen base or toluene-4-sulfonyloxy group);

Perhaps

Method (h) is for R ¹Be the quinazoline derivant of the formula I of hydrogen, the quinazoline of hydrogenation of formula XIV:

Wherein X is halogeno-group (for example iodine, bromine or chlorine) and R ², R ³, R ⁴, R ⁵, G ¹, G ², G ³, G ⁴, X ¹And Q ¹Except protecting any functional group where necessary, has any implication defined above;

And after this, if necessary:

(i) quinazoline derivant of formula I is changed into the quinazoline derivant of another kind of formula I;

(ii) (pass through ordinary method) and remove any blocking group of existence;

(iii) form pharmacy acceptable salt.

More than Fan Ying actual conditions is as follows:

Method (a)

Work as L ¹Be that for example, when halogeno-group or sulfonyloxy group, the reaction of method (a) is carried out in the presence of the alkali that is fit to easily.The alkali that is fit to is, for example, and the carbonate of basic metal or alkaline-earth metal, for example yellow soda ash, salt of wormwood, cesium carbonate or lime carbonate.This reaction randomly propiodal for example in the presence of sodium iodide or the potassiumiodide or the alkalimetal hydride that is being fit to for example carry out in the presence of sodium hydride or the potassium hydride KH.

Carry out easily under the described existence that is reflected at suitable inert solvent or thinner, this inert solvent or thinner be ester (for example ethyl acetate) for example, halogenated solvent (for example methylene dichloride, chloroform or tetracol phenixin), ether (tetrahydrofuran (THF) or 1 for example, the 4-diox), aromatic solvent (for example toluene), alcohol (for example methyl alcohol or ethanol), or dipolar aprotic solvent is (for example N, N-dimethyl formamide, N, N-N,N-DIMETHYLACETAMIDE, N-methylpyrrolidin-2-ketone or dimethyl sulfoxide (DMSO)).Described reaction is easily for example carrying out in 0 to 120 ℃ the temperature range, easily in envrionment temperature or near carrying out under the envrionment temperature and/or under about 50 ℃.

Work as L ¹When being hydroxyl, the reaction of method (a) is carried out under the Mitsunobu condition that is fit to easily.The Mitsunobu condition that is fit to comprises, for example, in the presence of tertiary phosphine that is fit to and two-alkyl azo, two carbonic ethers, at organic solvent for example in THF or the suitable methylene dichloride and, but react at ambient temperature easily at 0 ℃ to 60 ℃ temperature range internal reaction.The tertiary phosphine that is fit to comprises for example three-normal-butyl phosphine or three suitable-Phenylphosphine.Two-alkyl azo, two carbonic ethers that are fit to comprise for example azo Ue-5908 (DEAD) or suitable azo tert-Butyl dicarbonate (DTAD).The details of Mitsunobu reaction is contained in Tet.Letts., and 31,699, (1990); TheMitsunobu Reaction, D.L.Hughes, Organic Reactions, 1992, Vol.42,335-656; And Progress in the Mitsunobu Reaction, D.L.Hughes, OrganicPreparations and Procedures International, 1996, Vol.28,127-164.

Method (b)

Work as L ²When being hydroxyl, the reaction of method (b) in the presence of the coupling reagent that is fit to and is randomly being carried out in the presence of suitable catalyzer and/or suitable alkali easily.The coupling reagent that is fit to, for example, the peptide coupling reagent that is fit to, O-(7-azepine benzo triazol-1-yl)-N for example, N, N, N '-tetramethyl-urea hexafluoro-phosphoric acid salt (HATU) or carbodiimide be dicyclohexylcarbodiimide or 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI) for example.The catalyzer that is fit to is, for example, and Dimethylamino pyridine, 4-pyrrolidyl pyridine, 2 hydroxy pyrimidine N-oxide compound (HOPO) or I-hydroxybenzotriazole (HOBT).The alkali that is fit to is, for example, and organic amine alkali such as pyridine, 2,6-lutidine, trimethylpyridine, 4-Dimethylamino pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine or diazabicylo [5.4.0] 11 carbon-7-alkene, the perhaps carbonate of basic metal or alkaline-earth metal, for example yellow soda ash, salt of wormwood, cesium carbonate or lime carbonate.

Work as L ²When being (1-3C) alkoxyl group, do not need coupling reagent, alkali or catalyzer.

Carry out easily under the existence that is reflected at suitable inert solvent or thinner of method (b), this inert solvent or thinner be ether (for example tetrahydrofuran (THF) or 1,4 diox) for example, aromatic solvent (for example toluene), alcohol (for example methyl alcohol or ethanol), or dipolar aprotic solvent is (for example N, N-dimethyl formamide, N, N-N,N-DIMETHYLACETAMIDE, N-methylpyrrolidin-2-ketone or dimethyl sulfoxide (DMSO)).Described reaction is for example being carried out in 0 to 120 ℃ the temperature range easily.Work as L ²When being hydroxyl, this reaction can be easily in envrionment temperature or near carrying out under the envrionment temperature.

Easily, this reaction also can by the heating unit that in sealed vessel, use to be fit to for example microwave heater the reactant heating is finished.

Method (c)

Carry out easily under the existence that is reflected at suitable inert solvent or thinner of method (c), this inert solvent or thinner be ester (for example ethyl acetate) for example, halogenated solvent (for example methylene dichloride, chloroform or tetracol phenixin), ether (tetrahydrofuran (THF) or 1 for example, the 4-diox), aromatic solvent (for example toluene), alcohol (for example ethanol), or dipolar aprotic solvent is (for example N, N-dimethyl formamide, N, N-N,N-DIMETHYLACETAMIDE, N-methylpyrrolidin-2-ketone or dimethyl sulfoxide (DMSO)).Described reaction is easily for example carrying out in 0 to 120 ℃ the temperature range, easily in envrionment temperature or near carrying out under the envrionment temperature.

Method (d)

Carry out easily under the existence that is reflected at suitable inert solvent or thinner of method (d), this inert solvent or thinner be ester (for example ethyl acetate) for example, halogenated solvent (for example methylene dichloride, chloroform or tetracol phenixin), ether (tetrahydrofuran (THF) or 1 for example, the 4-diox), aromatic solvent (for example toluene), alcohol (for example methyl alcohol or ethanol), or dipolar aprotic solvent is (for example N, N-dimethyl formamide, N, N-N,N-DIMETHYLACETAMIDE, N-methylpyrrolidin-2-ketone or dimethyl sulfoxide (DMSO)).Described reaction is easily for example carrying out in 0 to 120 ℃ the temperature range, easily in envrionment temperature or near carrying out under the envrionment temperature.

Method (e)

In method (e), quinazoline-4 (3H)-ketone of formula VIII is reacted with the activating reagent that is fit to easily, so that by the replaced group that is fit to for example halogeno-group (as chlorine) oxo group of 4 of quinazolines-4 (3H)-ketone ring is replaced, and be formed for quinazoline (hereinafter referred to as " quinazoline that is activated ") with the amine reaction of formula IX.Thus the quinazoline that is activated of this of Xing Chenging easily original position use and be not further purified.

The quinazoline of formula VIII-4 (3H)-ketone uses ordinary method to carry out with the reaction of the activating reagent that is fit to easily.For example, the quinazoline of formula VIII-4 (3H)-ketone can with the halide reagent reaction that is fit to, this halide reagent is the mixture of thionyl chloride, phosphoryl chloride or tetracol phenixin and triphenyl phosphine for example.

The reaction of the amine of quinazoline that is activated and formula IX is for example being carried out in the presence of the acid at catalytic amount in the presence of the acid easily.The acid that is fit to comprises, for example hydrogen chloride gas (be dissolved in easily suitable inert solvent for example ether Huo diox in) or hydrochloric acid.

Perhaps, when the quinazoline that is activated contains halogeno-group group (for example chlorine) in the 4-position of quinazoline ring, can when not having acid or alkali, carry out with the reaction of the amine of formula IX.In this reaction, the autocatalytically that the replacement of halogeno-group leavings group causes acid (H-halogeno-group) original position to form and react.

The reaction of the amine of quinazoline that perhaps, is activated and formula IX can be carried out in the presence of the alkali that is fit to.The alkali that is fit to is, for example, and hexamethyl two lithium silicides (LiHMDS) or hexamethyl two silication sodium (NaHMDS).

More than be reflected under the existence of suitable inert solvent or thinner and carry out easily, this inert solvent or thinner be alcohol or ester (for example methyl alcohol, ethanol, Virahol or ethyl acetate) for example, halogenated solvent (for example ethylene dichloride, methylene dichloride, chloroform or tetracol phenixin), ether (for example tetrahydrofuran (THF), ether or 1, the 4-diox), aromatic solvent (for example toluene), or dipolar aprotic solvent is (for example N, N-dimethyl formamide, N, N-N,N-DIMETHYLACETAMIDE, N-methylpyrrolidin-2-ketone or dimethyl sulfoxide (DMSO)).

When handling under the situation that has or do not exist acid, more than reaction is for example being carried out in 0 to 250 ℃ the temperature range easily, in 40 to 80 ℃ temperature range, carry out easily or preferably, carry out at the reflux temperature of solvent for use or under near this reflux temperature.When handling under the situation that has alkali, more than reaction for example-78 is being carried out to 30 ℃ temperature range easily.

Method (f)

Method (f) can be carried out in the presence of the alkali that is fit to easily.The alkali that is fit to is, for example, and alkalimetal hydride, for example sodium hydride.

This is reflected under the existence of suitable inert solvent or thinner and carries out easily, and this inert solvent or thinner be ether (for example tetrahydrofuran (THF) or 1,4 diox) for example, and dipolar aprotic solvent (for example N, N-dimethyl formamide, N, N-N,N-DIMETHYLACETAMIDE, N-methylpyrrolidin-2-ketone or dimethyl sulfoxide (DMSO)).Described reaction is for example being carried out in 0 to 120 ℃ the temperature range easily.

Method (g)

Specific replaced group L ⁴Be bromine, chlorine or sulfonyloxy methyl oxygen base.

The reaction of the compound of the quinazoline of formula XII and formula XIII is carried out in the presence of the alkali that is fit to easily.The alkali that is fit to is, for example, organic amine alkali is pyridine, 2 for example, 6-lutidine, trimethylpyridine, 4-Dimethylamino pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine or diazabicylo [5.4.0] 11 carbon-7-alkene; The perhaps for example carbonate of basic metal or alkaline-earth metal, for example yellow soda ash, salt of wormwood, cesium carbonate, lime carbonate; Perhaps for example alkalimetal hydride, for example sodium hydride.

Carry out easily under the existence that is reflected at suitable inert solvent or thinner of the compound of the quinazoline of formula XII and formula XIII, this inert solvent or thinner be halogenated solvent (for example methylene dichloride, chloroform or tetracol phenixin) for example, ether (tetrahydrofuran (THF) or 1 for example, 4 dioxs), or dipolar aprotic solvent (for example N, N-dimethyl formamide, N, N-N,N-DIMETHYLACETAMIDE, N-methylpyrrolidin-2-ketone or dimethyl sulfoxide (DMSO)).Perhaps, this reaction can be carried out in the presence of inert solvent or thinner.Described reaction is easily for example carrying out in 25 to 100 ℃ the temperature range, easily in envrionment temperature or near carrying out under the envrionment temperature.

Method (h)

It will be understood by those skilled in the art that the hydrogenation in the method (h) can use ordinary method to carry out.For example, the method for Shi Heing comprises with catalyzer (for example platinum or the palladium catalyst) catalytic hydrogenation that is fit to.

Initial substance

The initial substance of method (a)

The quinazoline of formula II can obtain by routine operation, for example described in the reaction process 1:

Reaction process 1

L wherein ⁴, L ⁵And L ⁶Be the replaced group that is fit to, condition is L ⁶Compare L ⁵More unstable, and R ¹, G ¹, G ², G ³, G ⁴, X ¹And Q ¹Except protecting any functional group where necessary, has any implication defined above.

The replaced group L that is fit to ⁴Definition as mentioned.The replaced group L that is fit to ⁵Be that for example, halogeno-group or sulfonyloxy group are as fluorine, chlorine, sulfonyloxy methyl oxygen base or toluene-4-sulfonyloxy, particularly fluorine.The replaced group L that is fit to ⁶Be; for example; halogeno-group or alkoxyl group, aryloxy, sulfydryl, alkylthio, aryl sulfo-, alkyl sulphinyl, aryl sulfonyl kia, alkyl sulphonyl, aryl sulfonyl, alkylsulfonyloxy or aryl-sulfonyl oxygen group, for example chlorine, bromine, methoxyl group, phenoxy group, penta fluoro benzene oxygen base, methyl sulfo-, methane sulfonyl, methanesulfonyloxy group or toluene-4-sulfonyloxy group.Preferred L ⁵And L ⁶Be halogeno-group, for example L ⁵Be fluorine and L ⁶Be chlorine.

The note of reaction process 1:

Step (i)

The quinazoline that it will be appreciated by those skilled in the art that the quinazolone conversion accepted way of doing sth IIb of formula IIa can use ordinary method to carry out, and for example reacts with the activating reagent that is fit to by the compound with formula IIa.For example, work as L ⁵Be fluorine and L ⁶When being halogeno-group (for example chlorine), 5-fluoro-quinazoline-4 (3H)-ketone can with the halide reagent reaction that is fit to, this halide reagent is the mixture of thionyl chloride, phosphoryl chloride or tetracol phenixin and triphenyl phosphine for example.

Step (ii) and (iia)

The reaction of the amine of the quinazoline of formula IIb and formula IX or IXa is for example carried out in the presence of the acid of catalytic amount in the presence of acid easily.The acid that is fit to comprises, for example hydrogen chloride gas (be dissolved in easily suitable inert solvent for example ether Huo diox in) or hydrochloric acid.

Perhaps, this reaction can be carried out in the presence of the alkali that is fit to.The alkali that is fit to is, for example, and hexamethyl two lithium silicides (LiHMDS) or hexamethyl two silication sodium (NaHMDS).

Perhaps, this reaction can be carried out when not having acid or alkali.In this reaction, the autocatalytically that the replacement of halogeno-group leavings group causes acid (H-halogeno-group) original position to form and react.

More than be reflected under the existence of suitable inert solvent or thinner and carry out easily, this inert solvent or thinner be alcohol or ester (for example methyl alcohol, ethanol, Virahol or ethyl acetate) for example, halogenated solvent (for example methylene dichloride, chloroform or tetracol phenixin), ether (for example tetrahydrofuran (THF), ether or 1, the 4-diox), aromatic solvent (for example toluene), or dipolar aprotic solvent is (for example N, N-dimethyl formamide, N, N-N,N-DIMETHYLACETAMIDE, N-methylpyrrolidin-2-ketone or dimethyl sulfoxide (DMSO)).

Step (iii)

Step reaction (iii) can be used easily and be similar to condition used in the aforesaid method (g) and carry out.

Step (iv)

The quinazoline of formula IId can then be removed described blocking group by ordinary method and be carried out by reacting with the shielded oxygen affinity nucleome that is fit to the conversion of the quinazoline of formula II.For example, this conversion can be undertaken by reacting in the presence of the alkali that is fit to the N-acetyl ethanolamine easily.The alkali that is fit to is, for example, and non-by force-nucleophilic alkali such as alkalimetal hydride (for example sodium hydride) or alkali metal amide (for example LDA (LDA)).This is reflected under the existence of suitable inert solvent or thinner and carries out easily, and this inert solvent or thinner be ether (for example tetrahydrofuran (THF) or 1,4 diox) for example, and dipolar aprotic solvent (for example N, N-dimethyl formamide, N, N-N,N-DIMETHYLACETAMIDE, N-methylpyrrolidin-2-ketone or dimethyl sulfoxide (DMSO)).Described reaction for example carrying out in 10 to 250 ℃ the temperature range, is preferably carried out in 100 to 150 ℃ scope easily.

This conversion can be alternatively by with alkali metal alcoholates (for example sodium methylate) reaction that is fit to, then demethylation reaction and carrying out routinely.For example, for example the reaction of sodium methylate can be at the inert solvent that is fit to for example in the presence of the methyl alcohol, carry out in the solvent refluxing temperature or under near this reflux temperature with the alkali metal alcoholates that is fit to.Can use any suitable demethylation reaction condition.For example, can be by in 50 to 180 ℃ of temperature ranges, reacting with pyridine hydrochloride, by in-78 to 30 ℃ of temperature ranges with boron tribromide reaction, perhaps in 50 to 200 ℃ of temperature ranges with for example thiophenol sodium reaction and carry out this demethylation step of the thiolate that is fit to.Especially, can by with pyridine hydrochloride in the presence of the pyridine solvent, carry out this demethylation reaction at the reflux temperature of this solvent or under near this reflux temperature.

The initial substance of reaction process 1

The compound of formula IIa is that commerce can get, and perhaps can use the ordinary method preparation.For example 5-fluoro-quinazoline-4 (3H)-ketone initial substance is that commerce can get, and perhaps can use the ordinary method preparation, for example at J.Org.Chem.1952, and 17, described in the 164-176.

The compound of formula IX and IXa is that commerce can get, and perhaps they are known in the document, and perhaps they can be by standard method preparation known in the art.For example, the compound of formula IX and IXa can prepare according to reaction process 2:

Reaction process 2

L wherein ⁴Be suitable replaced group defined above, and G ¹, G ², G ³, G ⁴, X ¹And Q ¹Except protecting any functional group where necessary, has any implication defined above.

The note of reaction process 2:

Step (i)

The reaction of step (i) can be used easily and be similar to condition used in the aforesaid method (g) and carry out.

Step (ii)

It will be appreciated by those skilled in the art that in the reduction in (ii) of the step of reaction process 2 to use ordinary method to carry out.For example, reduction at the nitro of step in (ii) can be carried out under standard conditions, for example by catalytic hydrogenation with platinum/carbon, palladium/carbon or nickel catalyzator, for example iron, titanium chloride (III), tin chloride (III) or indium are handled perhaps for example V-Brite B or platinum oxide (IV) processing of reductive agent that is fit to another kind with metal.

Step (iii)

Step reaction (iii) can be used easily and be similar to condition used in the aforesaid method (g) and carry out, but between this reaction period, amino (NH ²) group must be protected usually.

The acid amides of formula III is that commerce can get, and perhaps they are known in the document, perhaps can use method preparation well known in the art.

The initial substance of method (b)

The quinazoline of formula IV can obtain by routine operation.L wherein for example ²The quinazoline compound that is the formula IV of (1-3C) alkoxyl group (for example methoxyl group) can prepare by formula II compound defined above or formula IId compound defined above and the reaction of formula IVa compound:

R wherein ⁸Be (1-3C) alkyl group and R ²And R ³Except protecting any functional group where necessary, has any implication defined above.

The reaction of formula II compound and formula Iva compound can be carried out under the Mitsunobu condition that is fit to mentioned above easily.

The reaction of formula IId compound and formula IVa compound is carried out in the presence of the alkali that is fit to easily.The alkali that is fit to is that for example, alkali metal alcoholates is sodium methylate or sodium ethylate for example.

L wherein ²The quinazoline compound (or its salt that is fit to) that is the formula IV of hydroxyl can be by L wherein ²Be that the compound of the formula IV of (1-3C) alkoxyl group at room temperature reacts with the alkali metal hydroxide that is fit to and prepares, this alkali metal hydroxide is sodium hydroxide for example.This is reflected under the existence of suitable inert solvent or thinner and carries out easily, and this inert solvent or thinner be ether (for example tetrahydrofuran (THF) or 1,4 diox) for example, or alcohol (for example methyl alcohol).

L wherein ²It is alternatively through type II compound and halogenation (for example chlorination) alcohol that the is fit to reaction and preparing under the chlorotone reaction conditions that is fit to of quinazoline compound (or its be fit to salt) of the formula IV of hydroxyl, this is that those skilled in the art are intelligible, and for example or WO 03/077847 in reference example 27 described in.

The compound of formula IVa and V is that commerce can get, and perhaps they are known in the document, perhaps can use method preparation well known in the art.

The initial substance of method (c)

Formula VI compound can use method preparation well known in the art.For example formula VI compound can prepare by formula II compound defined above and the reaction of formula VIa compound:

R wherein ³Except protecting any functional group where necessary, has any implication defined above, for example under suitable Mitsunobu condition discussed above.

The compound of formula V and VIa is that commerce can get, and perhaps they are known in the document, perhaps can use method preparation well known in the art.

The initial substance of method (d)

Formula V compound is above being discussed.

Under the reaction conditions that above method (b) is discussed, use suitable coupling reagent and the alkali (for example HATU and diisopropylethylamine) that is fit to mentioned above, formula VII compound can be from L wherein ²The formula IV compound that is hydroxyl prepares by inner coupled reaction.

The initial substance of method (e)

Formula VIII compound can use method preparation well known in the art.Formula VIII compound can, for example, by quinazoline-4 (3H)-ketone compound of the formula VIIIa that is fit to:

L wherein ⁷Be for example halogeno-group or sulfonyloxy group (for example fluorine, chlorine, sulfonyloxy methyl oxygen base or toluene-4-sulfonyloxy group, particularly fluorine) or L of the replaced group that is fit to ⁷Be hydroxyl, and R ¹Except protecting any functional group where necessary, has any implication defined above; Prepare with formula VIII compound reaction defined above.Usually the nitrogen of quinazoline ring 3-position is shielded, for example by the pyvaloyloxymethyl radical protection.

Work as L ⁷When being the replaced group that is fit to, the reaction of formula VIIIa compound and formula VIII compound use easily with the (iv) used conditions of similarity of reaction process 1 step mentioned above and above the conditions of similarity of method (a) carry out.

Work as L ⁷When being hydroxyl, the reaction of formula VIIIa compound and formula VIII compound is above being carried out under the described condition of method (a) easily.

Formula VIIIa compound is that commerce can get, and perhaps they are known in the document, and perhaps they can use method preparation well known in the art (for example, to work as R ¹Be hydrogen and L ⁷When being fluorine, compound 5-fluoro-3,4-dihydroquinazoline initial substance are that commerce can get, and perhaps can use the ordinary method preparation, for example at J.Org.Chem.1952, and 17, described in the 164-176).

The compound of formula IX is that commerce can get, and perhaps they are known in the document, perhaps can use method well known in the art preparation (for example described in the above reaction process 2).

The initial substance of method (f)

The quinazoline of formula X can use method preparation discussed above, for example discusses in reaction process 1.

The compound of formula XI is that commerce can get, and perhaps they are known in the document, perhaps can use method preparation well known in the art.

The initial substance of method (g)

The quinazoline of formula XII can use method preparation discussed above, for example discusses in reaction process 1.

The compound of formula XIII is that commerce can get, and perhaps they are known in the document, perhaps can use standard method preparation known in the art.

The initial substance of method (h)

The quinazoline of formula XIV can use method preparation discussed above.

The quinazoline derivant of formula I can adopt aforesaid method, and with the form acquisition of free alkali, perhaps, as selection, it also can obtain with the form of salt (for example acid salt).When hope obtains free alkali by the salt of the quinazoline derivant of formula I, described salt can be with suitable alkaline purification, for example, the carbonate of basic metal or alkaline-earth metal or oxyhydroxide (such as yellow soda ash, salt of wormwood, lime carbonate, sodium hydroxide or potassium hydroxide), perhaps use ammonia treatment, for example use methyl alcohol system ammonia solution (for example methanol solution of 7N ammonia).

The quinazoline derivant of formula I can use any suitable method to carry out to the conversion of the quinazoline derivant of another kind of formula I, and this is that those of skill in the art understand.For example, the method for the Mitsunobu reaction by above going through, wherein R ¹Be that the quinazoline derivant of the formula I of hydroxyl can change into R wherein ¹It is the quinazoline derivant of the another kind of formula I of (1-4C) alkoxyl group.

Generally speaking, the blocking group that is used for aforesaid method can be selected from that document is described or the skilled known any group that is suitable for protecting functional group to be protected of chemist, and can adopt ordinary method to introduce blocking group.Remove blocking group according to the known any method easily that is suitable for removing blocking group to be removed of chemist that describe in the document or skilled; these class methods are selected, and principle is that this method can remove described blocking group and simultaneously to the minimum that influences of other group in the related molecule.

For simplicity, provide the example of concrete blocking group below, wherein " rudimentary " (as in low alkyl group) representative preferably has the group of 1 to 4 carbon atom.Be appreciated that these examples are not limit.The specific examples of the method that removes blocking group that provides equally, below neither limit.The using method and the removal methods thereof of the blocking group of certainly, specifically not mentioning are also included within the scope of the invention.

Carboxy protective group can be to form the fatty alcohol of ester or the residue of aryl fatty alcohol, or forms the residue (described pure and mild silanol preferably contains 1 to 20 carbon atom) of the silanol of ester.The example of carboxy protective group comprises straight or branched (1-12C) alkyl (as the sec.-propyl and the tertiary butyl); Lower alkoxy-low alkyl group (as methoxymethyl, ethoxyl methyl and isobutoxy methyl); Low-grade acyloxy-low alkyl group (as acetoxy-methyl, propionyl oxygen ylmethyl, butyryl radicals oxygen ylmethyl and pivaloyl group oxygen ylmethyl); Elementary alkoxy carbonyl oxygen base-low alkyl group (as 1-methoxycarbonyl oxygen base ethyl and 1-ethoxy carbonyl oxygen base ethyl); Aryl lower alkyl (as benzyl, 4-methoxy-benzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl-methyl and phthalidyl); Three (low alkyl group) silyl (as trimethyl silyl and t-butyldimethylsilyl); Three (lower alkyl is admired) silyl-low alkyl group (as the trimethyl silyl ethyl); And (2-6C) thiazolinyl (as allyl group).The method that is particularly suitable for removing carboxy protective group comprises, as acid-, alkali-, metal-or enzyme-catalytic scission reaction.

The example of hydroxy-protective group comprises low alkyl group (as the tertiary butyl), low-grade alkenyl (as allyl group); Low-grade alkane acidyl (as ethanoyl); Elementary alkoxy carbonyl (as tert-butoxycarbonyl); Low-grade alkenyl oxygen base carbonyl (as allyl group oxygen base carbonyl); Aryl-lower alkoxy carbonyl (as benzyloxycarbonyl, 4-methoxyl group benzyloxy base carbonyl, 2-nitro benzyloxycarbonyl and 4-nitro benzyloxycarbonyl); Three (low alkyl group) silyl (as trimethyl silyl and t-butyldimethylsilyl) and aryl lower alkyl (as benzyl).

The example of amido protecting group comprises formyl radical, aryl lower alkyl (as benzyl, 4-methoxy-benzyl, the 2-nitrobenzyl and 2 of benzyl and replacement, 4-dimethoxy-benzyl and trityl group); Two-4-anisyl methyl and furyl methyl; Elementary alkoxy carbonyl (as tert-butoxycarbonyl); Low-grade alkenyl oxygen base carbonyl (as allyl group oxygen base carbonyl); Aryl-lower alkoxy carbonyl (as benzyloxycarbonyl, 4-methoxyl group benzyloxy base carbonyl, 2-nitro benzyloxycarbonyl and 4-nitro benzyloxycarbonyl); Low-grade alkane acidyl oxygen base alkyl (for example pivaloyl oxygen ylmethyl); Trialkylsilkl (as trimethyl silyl and t-butyldimethylsilyl); The benzylidene of alkylidene group (as methylene radical) and benzylidene and replacement.

The appropriate means that removes hydroxyl and amido protecting group comprise as acid-, alkali-, metal-or the hydrolysis reaction of enzyme-catalytic group (as 2-nitro benzyloxycarbonyl), the hydrogenation of group (as benzyl) and photolysis of group (as 2-nitro benzyloxycarbonyl).For example, the tert-butoxycarbonyl blocking group can be removed from amino through acid catalyzed hydrolysis with trifluoroacetic acid.

About the general guide of reaction conditions and reagent, the reader can be referring to Advanced OrganicChemistry, and the 4th edition, J.March edits, by John Wiley ﹠amp; Sons publishes in 1992; And about the guide of blocking group, then can be referring to Protective Groups in OrganicSynthesis, the 2nd edition, by editors such as T.Green, it is also by John Wiley ﹠amp; Son publishes.

Should be appreciated that some in the various ring substituents of quinazoline derivant of the present invention can be introduced by the substitution reaction of standard aromatics before or after aforesaid method or generate through conventional modified with functional group at once, these processes are also included within the method for the present invention.Such reaction and modification comprise, for example, introduce substituting group, substituent reduction, substituent alkylation and substituent oxidation by the aromatics substitution reaction.The reagent and the reaction conditions that are used for such operation are that chemical field is known.The specific examples of aromatics substitution reaction comprises with concentrated nitric acid introduces nitro, under Friedel Crafts condition, introduces acyl group with for example carboxylic acid halides and Lewis acid (as aluminum chloride); Under Friedel Crafts condition, introduce alkyl with alkylogen and Lewis acid (as aluminum chloride); With the introducing halogeno-group.

When the pharmacy acceptable salt of the quinazoline derivant that needs formula I, for example during acid salt, it can adopt ordinary method by for example, makes described quinazoline derivant and suitable acid-respons and obtains.

As mentioned above, some compound of the present invention can contain one or more chiral centres, thereby can be used as the steric isomer existence.Steric isomer can adopt routine techniques, separates as chromatography or fractional crystallization.Enantiomer can be passed through the separation of racemic body, for example separates by fractional crystallization, fractionation or HPLC.Diastereomer can separate by the different physical property of diastereomer, for example separates by fractional crystallization, HPLC or flash chromatography.Perhaps, concrete steric isomer can synthesize preparation by the chirality initial substance through chirality by not causing under the condition of racemization or epimerization, or by preparing with the chiral reagent derivatize.When separating a kind of concrete steric isomer, suitablely be separated into this steric isomer that does not have other steric isomer substantially, for example contain and be less than 20%, particularly be less than 10% and more especially be less than other steric isomer of 5% weight.

In the chapters and sections of the preparation of the quinazoline derivant that above relates to formula I, term " inert solvent " refers to not the solvent that reacts in the mode of the yield that influences required product unfriendly with initial substance, reagent, intermediate or product.

Those skilled in the art should understand that, for with alternative and some occasion, mode obtains quinazoline derivant of the present invention more easily, each method steps mentioned above can carry out with different order, and/or each reaction can be carried out (being that chemical transformation can be carried out at the above relevant different intermediates of being correlated with concrete reaction) in the different steps of whole route.

Some intermediate that aforesaid method uses is novel, and constitutes another feature of the present invention.Therefore the invention provides and be selected from formula II, IV, VI, VII, VIII, X, XII and XIV compound or its salt as defined above.

Concrete formula IV compound comprises that one or more are selected from following quinazoline derivant: (2R)-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate, (2R)-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid and [(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl acetate.

Further concrete formula IV compound comprises that one or more are selected from following quinazoline derivant: (2S)-2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate, (2R)-and 2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate, (2S)-and 2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate, (2S)-2-[(4-{[1-(1,3-thiazol-2-yl methyl)-and 1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate and (2R)-2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate.

Further concrete formula IV compound comprises that one or more are selected from following quinazoline derivant again: (2R)-and 2-[(4-{[1-(1,3-thiazole-4-ylmethyl)-and 1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate, (2R)-2-[(4-{[1-(1,3-thiazole-4-ylmethyl)-and 1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid, (2S)-2-[(4-{[1-(1,3-thiazole-4-ylmethyl)-and 1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate, (2S)-2-[(4-{[1-(1,3-thiazole-4-ylmethyl)-and 1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid, (2S)-and 2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid, (2R)-and 2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid, (2S)-and 2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid, (2R)-2-[(4-{[1-(1,3-thiazol-2-yl methyl)-and 1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid and (2S)-2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid.

Concrete formula VII compound is (6R)-6-methyl-4-[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl]-4H-[1,4] Evil azepines are [5,6,7-de] quinazolines-5 (6H)-ketone also.

Concrete formula VIII compound comprises that one or more are selected from following quinazoline derivant: (2R)-and N, N-dimethyl-2-[(4-oxo-3,4-dihydroquinazoline-5-yl) oxygen base] propionic acid amide and (2S)-N, N-dimethyl-2-[(4-oxo-3,4-dihydroquinazoline-5-yl) the oxygen base] propionic acid amide.

Concrete formula II compound comprises that one or more are selected from following quinazoline derivant: 4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-alcohol, 4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } the pure and mild 4-{[1-of quinazoline-5-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-alcohol.Further concrete formula II compound comprises 4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-alcohol.

Concrete formula X compound is following one or more: 5-fluoro-N-[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine, 5-fluoro-N-[1-(3-luorobenzyl)-1H-indazole-5-yl] quinazoline-4-amine and 5-fluoro-N-[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine.Further concrete formula X compound comprises 5-fluoro-N-[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine.

Described intermediate can be the form of the salt of this intermediate.Such salt needs not to be pharmacy acceptable salt.For example it can be used for preparing the pharmaceutically intermediate of unacceptable salt form, if for example, such salt can be used for the quinazoline derivant of preparation formula I.

Biology is measured

Before by their activity in vivo of xenotransplantation research evaluation, in non-protein tyrosine kinase mensuration and proliferation assay test, the inhibition activity of compound is estimated based on cell based on cell.

A) protein tyrosine kinase phosphorylation assay

A kind of test compound of this test determination suppresses to comprise the ability of phosphorylation of the tyrosine of peptide substrate by EGFR, erbB2 and erbB4 Tyrosylprotein kinase.

The reconstitution cell internal fragment of EGFR, erbB2 and erbB4 (registration number is respectively X00588, X03363 and L07868) is cloned and is expressed in baculovirus (baculovirus)/Sf21 system.By with ice-cold dissolving damping fluid (20mM N-2-hydroxyethyl piperazine-N '-2-ethanesulfonic acid (HEPES) pH7.5,150mM NaCl, 10% glycerine, 1%Triton X-100,1.5mM MgCl ₂, 1mM ethylene glycol-two (beta-amino ether) N ', N ', N ', N '-tetraacethyl (EGTA)), add that proteinase inhibitor handles these cells, remove by centrifuging then, by these cell preparation lysates.

(by L-glutamic acid, L-Ala and the tyrosine interpolymer cco-polynler at random with 6: 3: 1 ratio) forms by a kind of synthetic peptide of its phosphorylation) ability measure the kinase whose activity of the formation of these recombinant proteins.Especially, with synthetic peptide (0.2 μ g peptide in 100 μ l phosphate buffered saline (PBS) (PBS) solution, and 4 ℃ down hatching spend the night) apply Maxisorb ^TM96 hole enzyme plates.At 50mM HEPES, among the pH 7.4, at room temperature wash each plate to remove any unnecessary uncombined synthetic peptide.By at room temperature, in the plate of peptide coating, at room temperature with 50mMHEPES, the Triphosaden (ATP) of the Km concentration of pH7.4, each corresponding enzyme, 10mMMnCl ₂, 0.05mM Na ₃VO ₄, in the 0.1mM DL-dithiothreitol (DTT) (DTT), 0.05%TritonX-100, hatched 20 minutes with the test compound in DMSO (final concentration 2.5%), with the activity of assessment EGFR or erbB2.The termination reaction by the liquid component of removing this test, and wash this plate succeeded by PBS-T (phosphate buffered saline (PBS) adds 0.05%Tween 20).

Detect immobilized (immobilised) phosphorylated peptide product of this reaction by immunization method.At first, at room temperature, each plate and the anti-Tyrosine O-phosphate primary antibody (4G10 is from Upstate Biotechnology) that derives from mouse were hatched 90 minutes together.After the washing, at room temperature, each plate was handled 60 minutes with horseradish peroxidase (HRP) bonded goat-anti mouse secondary antibody (NXA 931, from Amersham) up hill and dale.After the washing, use 22 '-Lian nitrogen-two [3-ethyl benzo thiazole phenanthroline sulfonic acid (6)] di-ammonium salts crystal (ABTS further ^TM, from Roche) and as a kind of substrate, by the HRP activity of colorimetry measurement in each hole of this plate.

By reading to measure in the light absorption ratio at 405nm place on the plate device, and will develop the color quantitatively, and obtain the activity of corresponding enzyme at Molecular Devices ThermoMax microplate.Use IC ₅₀Value is represented a kind of kinase inhibitory activity of given compound.This can measure out by calculating the required compound concentrations of inhibition that obtains 50% phosphorylated in this test.Calculate the scope of phosphorylated by positive control value (carrier adds ATP) and negative control value (carrier deducts ATP).

B) mensuration of the KB cell proliferation that impels of EGFR

This measures the ability that the experiment with measuring compound suppresses human tumor cell line KB (deriving from U.S. germplasm preservation center (ATCC)) propagation.

In Eagle ' the s substratum (DMEM) of Dulbecco ' the s improvement that contains 10% foetal calf serum, 2mM glutamine and non-essential amino acid, at 37 ℃, 7.5%CO ₂Air incubator in cultivate the KB cell.Use trypsinase/ethylenediamine tetraacetic acid (EDTA) (EDTA) harvested cell from stock (stock) flask.Use hematimeter and measure cell density, and use trypan blue solution and calculate its viability, then at 37 ℃, 7.5%CO ₂Down, with every hole 1.25 * 10 ³The density of cell contains 2.5% with cell inoculation in the DMEM of serum, 1mM glutamine and the non-essential amino acid of charcoal absorption in 96 orifice plates, make its precipitation (settle) 4 hours then.

After being adsorbed on the plate, with described cell with or without epidermal growth factor (EGF) (final concentration 1ng/ml) and with or not be used in compound (final concentration 0.1%) processing of a kind of concentration range in the dimethyl sulfoxide (DMSO) (DMSO), hatched then 4 days.After incubation period, by the 3-(4,5-dimethylthiazole-2-yl)-2 that adds 50 μ l, 5-phenylbenzene tetrazolium bromide (MTT) (storing solution 5mg/ml) was measured cell quantity in 2 hours.Clean then MTT solution beats this plate gently, makes cytolysis in the DMSO of the 100 μ l that add.

Use Molecular Devices ThermoMax microplate and read the plate device, read the light absorption ratio of dissolved cell at 540nm.Use IC ₅₀Value is represented inhibition of proliferation.This can obtain the required compound concentrations of 50% inhibition of proliferation in this test by calculating and calculate.Calculate the scope of propagation by positive (carrier adds EGF) and negative (carrier deducts EGF) control value.

C) clone's 24 phosphoric acid-erbB2 raji cell assay Raji

This immunofluorescence terminal point method of inspection determination test compound suppresses the ability of the phosphorylated of erbB2 in MCF7 (mammary cancer) deutero-clone; this clone be by the application standard method with total length erbB2 gene transfection MCF7 cell, obtain a kind of mistake and express the proteic clone of total length wild-type erbB2 and obtain (be called hereinafter ' clone 24 ' cell).

Under 37 ℃, at 7.5%CO ₂In the air incubator, in growth medium (GrowthMedium) (Eagle ' the s substratum (DMEM) that contains no phenol red Dulbecco ' the s modification of 10% foetal calf serum, 2mM glutamine and 1.2mg/ml G418), cultivate clone's 24 cells.By at PBS (phosphate buffered saline (PBS), pH7.4, Gibco No.10010-015) in washing once, harvested cell from T 75 deposit flasks is used 2ml trypsin 1.25mg/ml then)/(0.8mg/ml) solution harvested cell of ethylenediamine tetraacetic acid (EDTA) (EDTA).The described cell of resuspending in growth medium.Use hematimeter and measure cell density, use trypan blue solution then and calculate its viability, then with the cell redilution in growth medium, and with every hole 1 * 10 ⁴The density of cell (among the 100ul), with its be inoculated in clear bottom 96 orifice plates (Packard, No.6005182) in.

After 3 days, from each hole, remove growth medium, replace the 100 μ l test media (Assay Medium) (the no phenol red DMEM that contains 2mM glutamine, 1.2mg/ml G418) that have or do not have the erbB inhibitor compound.Plate was put back to incubator 4 hours, and the formaldehyde solution among 20% of adding 20 μ l the PBS in every hole placed room temperature following 30 minutes with plate then.Remove this stationary liquid with the multiple tracks transfer pipet, in every hole, add the PBS of 100 μ l, remove with the multiple tracks transfer pipet then, in every hole, add 50 μ l PBS again.Closure plate and under 4 ℃, be stored to many 2 weeks then.

At room temperature carry out immunostaining.Use a kind of plate washing device, with 200 μ d PBS/Tween20 (by (Sigma No.P3563) joins the double distilled H of 1L with 1 bag of PBS/Tween dry mash ₂Make among the O) wash each hole once, the 0.5%Triton X-100/PBS that adds 100 μ l then is to soak into (permeabalise) cell.After 10 minutes, with 200 μ l PBS/Tween, 20 wash plate, every then hole adds 100 μ l lock solution (the 5%Marvel skim-milk (Nestle) in PBS) and hatched 15 minutes.After removing this lock solution with plate washing device, (epi-position phosphoric acid-Tyr1248, SantaCruz No.SC-12352-R), were hatched 2 hours then with the anti-phosphoric acid erbB2IgG of the rabbit polyclonal antibody of dilution in 1: 250 in lock solution to add 30 μ l in each hole.Use plate washing device then and remove this trie primary antibody solutions, use plate washing device again with 200 μ l PBS/Tween, 20 washed twice.Every hole adds 100 μ l lock solution, plate is hatched 10 minutes again.In every hole, add then 30 μ l be diluted at 1: 750 Alexa-Fluor 488 goat anti-rabbit igg secondary antibody in the lock solution (Molecular Probes, No.A-11008)., in this stage with black tail band seal, with plate lucifuge protection as far as possible from now on.Hatched each plate 45 minutes, and from the hole, removed secondary antibody solution then, use plate washing device again with 200 μ l PBS/Tween, 20 washings three times.In each plate, add 100 μ l PBS then, hatched 10 minutes, use plate washing device again and remove.In every hole, add 50 μ l of PBS then, plate is resealed with the black tail band, before analyzing, store down at 4 ℃.In 6 hours of the immunostaining of finishing the work, plate is measured.

Use Acumen Explorer instrument (Acumen Bioscience Ltd.), its for a kind of can by laser scanning quantitative determination characteristics of image read the plate device, be determined at the fluorescent signal in every hole.Set this instrument and surpass the quantity of the fluorescent target of predetermined threshold value, thereby a kind of erbB2 of measurement is provided the method for proteic phosphorylated state with measurement.To import a suitable software package (as Origin) with the analysis that carries out curve fitting by the fluorescence dose response data that every kind of compound obtains.Use IC ₅₀Value is represented the inhibition of erbB2 phosphorylated.This can be by calculating 50% phosphorylated obtain erbB2 in this test the required compound concentrations of signal of inhibition measure out.

D) BT-474 xenotransplantation is measured in the body

This measures the experiment with measuring compound at female Swiss thymic mouse (Alderley Park, the nu/nu genotype) suppresses the ability (Baselga of growth that the BT-474 tumor cell line is grown to the specific mutation of heterograft in, J.et al. (1998) Cancer Research, 58,2825-2831).

This BT-474 tumor cell line (human breast carcinoma) be from Dr Baselga (at LaboratorioRecerca Oncologica, Paseo Vall D ' Hebron 119-129, Barcelona 08035, Spam) obtains.With this clone subclone, and obtain some population (being called " BT474C " hereinafter).

Female Swiss athymic mouse (nu/nu genotype) is bred and fed in Alderley Park negative pressure disrupter (PFI Systems Ltd.).The mouse pass is supported in a kind of Fencing system with 12 hours illumination/dark cycle, and quantity-unlimiting sterilization meals and water of searching for food is provided.Whole experimental procedures is all carried out with the mouse in 8 ages in week at least.

Flank after being tried mouse, by give each animal subcutaneous injection in 100 μ l serum free mediums and 50%Matrigel 1 * 10 ⁷The fresh culture cell is finished the xenotransplantation of BT474C tumour cell.Replenish progynon B (Mesalin, Intravet UK 0.2mg/ml) to animal, subcutaneous injection the day before yesterday 100 a μ g/ animal of cell implantation are then appended 50 a μ g/ animal weekly; Perhaps implant the release estradiol sheets (InnovativeResearch of America) on the 21st of 0.5mg in the day before yesterday of cell implantation.As an example, be chosen in and implanted the back the 14th, mouse is weaved into 10 groups at random, give compound with the 0.1ml/10g body weight once a day then or vehicle Control is treated.By twice bilateral weekly with the vernier caliper measurement tumour, application of formula (length x width) x √ (length x width) x (π/6) and determine its volume, wherein length is this tumour diameter longitudinally, width is corresponding vertical line.By the average change of compare group and treatment group gross tumor volume, calculate growth inhibiting situation from when beginning treatment, and use the statistical significance between two groups of Students t test evaluations.

E) BT474C cell proliferating determining

The BT474C cell is the subclone population of above-mentioned body enteroception attitude cell.

It is that (3-(4 for a kind of MTS that BT474C measures, 5-dimethylthiazole-2-yl)-5-(3-carboxyl p-methoxy-phenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt-Promega G1111) based on the cell proliferating determining of terminal point, its determination test compound suppressed the ability of cell proliferation during 4 days.At 7.5%CO ₂In the air incubator, under 37 ℃, cell in growth medium is grown into logarithmic phase, this growth medium is no phenol red Dulbecco ' s improvement Eagle ' s substratum (DMEM), wherein contains 10% foetal calf serum, 10%M1 additive (the inner supply of AstraZeneca), 1% oxaloacetic acid.By in PBS (phosphate buffered saline (PBS), pH7.4, Gibco No.10010-015) washing once and with 2ml trypsin 1.25mg/ml)/ethylenediamine tetraacetic acid (EDTA) (EDTA) (0.8mg/ml) solution remove and from lay in flask collecting cell.Cell is suspended in the mensuration medium once more, and this medium is phenol red Dulbecco ' s improvement Eagle ' s substratum (DMEM), wherein contains foetal calf serum, 10%M1 additive, 1% oxaloacetic acid that 10% carbon/dextran decomposes (stripped).Use haemocytometer to measure cell density, and use trypan blue solution to calculate viability, then further be diluted in and measure in the substratum, again with 1 * 10 ⁴The density inoculation (100ul) of cells/well is in 96 orifice plates (Costar 3598) of clear bottom.The another one plate is set as 0 day control board.After 4 hours, join the mode of passing triplicate plate with dose response, the mensuration substratum serial dilution that will contain test compound is in 100%DMSO (Sigma D5879).Plate was handled with MTS solution (tetrazole compound-prepared in etherosulfuric acid trilafon (PES-Sigma P4544)/PBS by the MTS powder) in 0 day, cultivated 2 hours, then by adding 10%SDS with the stopping of reaction.On spectrophotometer, read plate in the 490nm place.

Assay plate was placed 4 days down at 37 ℃, use MTS solution (as above) to handle then, it is transformed into the solubility first moon for (formazan) product by active cells.After plate cultivation 2 hours, by adding 10%SDS (sodium lauryl sulphate), on spectrophotometer, read plate in the 490nm place with the stopping of reaction, obtain with respect to the absorption value that transforms dye strength.

The optical density dose response data that obtains with each compound is output in the suitable software package (for example Origin), and analysis carries out curve fitting.

The restraining effect of BT474C cell proliferation is with IC ₅₀Value (, calculating GI50) expression by using the data of 0 day absorption value more than the log/lin tracing analysis.This is to measure by calculating the compound concentration that needs the 50% cell inhibitory effect effect that produces.

F) potassium channel of hERG-coding suppresses to measure

IonWorks ^TMThe cell cultures of HT:

At 37 ℃ and humidification environment (5%CO ₂) under, Chinese hamster ovary K1 (CHO) cell of expressing hERG (is described by people such as Persson, Persson, F., Carlsson, L., Duker, G., andJacobson, I., Blocking characteristics of hERG, hNav1.5, andhKvLQT1/hminK after administration of the novel anti-arrhythmiccompound AZD7009., J Cardiovasc.Electrophysiol., 16,329-341.2005) in the F-12Ham substratum, grow into half fusion, contain L-glutaminate in this F-12Ham substratum, 10% tire calf serum (FCS) and 0.6mg/ml Totomycin (being the Sigma product).Before the use, with Versene (Invitrogen) washing in 1: 5000 of this monolayer with (37 ℃) 3ml part of pre-temperature.After this solution of sucking-off, under 37 ℃, in the incubator, the Versene with other 2ml cultivates 6 minute at 1: 5000 with flask.By beaing gently cell is separated from drag then, again with Dulbecco ' s-PBS (calcic 0.9mM and magnesium 0.5mM) (PBS of 10ml; Invitrogen) join in this flask, be drawn in the 15ml centrifuge tube, centrifugal (50g, 4 minutes).Abandon the supernatant liquor of generation, pellet is suspended among the PBS of 3ml lightly again.Shift out the cell suspension of 0.5ml part, discharge according to Trypan Blue and measure survivaling cell number (Cedex; Innovatis), regulate cell resuspending volume, obtain the final cell concentration that needs with PBS.The CHO-Kv1.5 cell of keeping and preparing to use in the same manner, it is used to regulate IonWorks ^TMThe voltage compensation of HT.

IonWorks ^TMThe HT electrophysiology:

The principle of this device and operation are described (Schroeder, K., Neagle by people such as Schroeder, B., Trezise, D.J., and Worley, J., Ionworks HT:a new high-throughputelectrophysiology measurement platform, J Biomol Screen, 8,50-64,2003).In brief, this technology is based on 384-orifice plate (PatchPlate ^TM), in this plate, in each hole, use to be drawn to the position and to keep cell in aperture, to be separated into two separating liquid chambers and attempt writing down.In case seal, will be at PatchPlate ^TMThe solution of downside change into a solution that contains amphotericin B.Seen through the cell patch that covers the cave in each hole like this, and in fact cell patch pincers perforation, complete made in record.

At room temperature (～21 ℃) operate IonWorks in the following manner ^TMHT (a kind of β-tester) from EssenInstruments.Will be at pack into the PBS of 4ml of the tank of " Buffer " position, and the above-mentioned CHO-hERG cell suspension of packing in " Cells " position.96 orifice plates (at the bottom of the V-arrangement, Greiner Bio-one) that will contain test compound (3X of its final experimental concentration) place " Plate 1 " position, and with PatchPlate ^TMBe clamped in this PatchPlate ^TMOn the device.Each compound plate is placed on 12 row, makes it to constitute 10 8-point concentration-effect curves; All the other 2 row on the plate are placed the cisapride (final concentration 10 μ M, its definite inhibition level) of carrier (attempt 0.33% DMSO eventually, it determines to analyze baseline) and super large sealing concentration.Use IonWorks then ^TMThe jet head (F-Head) of HT adds to PatchPlate with the PBS of 3.5 μ l ^TMEach hole in, " inside " solution is injected in its bottom, this solution has following composition (mM): K-Gluconate 100, KCl 40, MgCl ₂3.2, EGTA3 and HEPES 5 (being the Sigma product) (pH 7.25-7.30 regulates with 10M KOH).Start after the also deaeration, electronics head (E-head) is centered on PatchPlate ^TMMove with the test of getting into the cave (hole test) (be in each hole of applied voltage pulse measurement cave whether open).With the F-head the above-mentioned cell suspension of 3.5 μ l is injected into PatchPlate then ^TMEach hole in, give cell 200 seconds and arrive, seal the cave in each hole again.Then, with the E-head circumference around PatchPlate ^TMMove sealing resistance to obtain in each hole.And then, with PatchPlate ^TMThe solution of bottom changes over " access " solution,, this solution has following composition (mM): KCl 140, EGTA 1, MgCl ₂1 and HEPES20 (pH 7.25-7.30, with 10M KOH regulate) add the amphotericin B (being the Sigma product) of 100 μ g/ml.Fragment perforation 9 minutes takes place after, with the E-head circumference around PatchPlate ^TMCertain hour is moved in 48 holes, obtains pre-chemical combination hERG current measurement result.To join PatchPlate from the 3.5 μ l solution in each hole of compound plate with the F-head then ^TMOn 4 holes in (in each hole, final DMSO concentration be 0.33%).This is by finishing from the rarest moving to the denseest chemical combination plate hole, so that inferior limit influences the continuity (carry-over) of any compound.Approximately cultivate after 3 fens halfs, with the E head at PatchPlate ^TMWhole 384 holes around move, to obtain back compound hERG current measurement result.By this way, can form non-cumulative concentration-effect curve, as long as the standard of accepting reaches enough percentage of cells (seeing the following form), the influence of each concentration of test compound is by 1 to 4 cell record.

Before-and back-compound hERG electric current bring out by the univoltage pulse, this voltage pulse consists of :-70mV keeps at place the 20s time, 160ms goes to-60mV (the acquisition estimation is leaked electricity), 100ms travels back to-70mV, 1s goes to+40mV, and 2s goes to-30mV, and last 500ms goes to-70mV.Preceding-and back-compound voltage pulse between, do not have the clamp (clamping) of membrane potential.According to the voltage pulse scheme begin+the electric current estimated value of bringing out between 10mV step is the electric leakage of electric current deduction.With 2.5k Hz current signal is taken a sample.

According to the spike of electric leakage deduction, pass through IonWorks ^TMHT software, by obtain the initial maintenance phase-40ms of 70mV place mean current (base current) and by tail current response peak deduction it, before measuring automatically-and back-scanning hERG strength of current.The standard of accepting of the electric current that brings out in each hole is: preceding-scanning sealing resistance＞60M Ω, preceding-scanning hERG tail current amplitude＞150pA; Back-scanning sealing resistance＞60M Ω.The inhibition degree of hERG electric current by with before each hole-after scanning hERG electric current removes-scanning hERG electric current estimates.

Although the pharmacological properties of the quinazoline derivant of formula I changes with structural changes as expected, but usually, test (a) and (b) more than one or more are planted, (c), (d) and (e) in, under following concentration or dosage, the quinazoline derivant of susceptible of proof formula I has activity :-

Test (a) :-IC ₅₀Scope, 0.001-1 μ M for example;

Test (b)-IC ₅₀Scope, 0.001-5 μ M for example;

Test (c) :-IC ₅₀Scope, 0.001-5 μ M for example;

Test (d) :-active scope, for example 1-200mg/kg/ days;

Test (e) :-IC ₅₀Scope, 0.001-5 μ M for example;

Tried in the present invention under the effective dose of quinazoline derivant, in test (d), do not observed unacceptable toxicity on the physiology.Test (f) has shown the safety limit between target and hERG activity, and showing to have the hERG passage to suppress the irregular pulse that causes.Therefore, when the quinazoline derivant that gives formula I defined above in the dosage range with hereinafter qualification or its pharmacy acceptable salt, expection can not produce the toxic action of trouble.

By embodiment, Table A illustrates the activity of representative compounds of the present invention.The 2nd hurdle of Table A shows the IC that derives from the test (a) that is used to suppress the effect of EGFR Tyrosylprotein kinase protein phosphorylation ₅₀Data; The 3rd hurdle shows the IC derive from the test (a) that is used to suppress the effect of erbB2 Tyrosylprotein kinase protein phosphorylation ₅₀Data; The 4th hurdle is presented in the above-mentioned test (c), the inhibiting IC of erbB2 phosphorylation in MCF7 deutero-clone ₅₀Data:

Table A

Embodiment number	IC ₅₀(μ M) tests (a): the inhibition of EGFR Tyrosylprotein kinase protein phosphorylation effect	IC ₅₀(μ M) tests (a): the inhibition of erbB2 Tyrosylprotein kinase protein phosphorylation effect	IC ₅₀(μ M) tests (c): the inhibition of erbB2 Tyrosylprotein kinase protein phosphorylation effect
Embodiment number				1	0.21	0.012	-
2	0.032	0.003	0.035	1	0.21	0.012	-

According to a further aspect in the invention, provide medicinal compositions, this medicinal compositions comprises quinazoline derivant 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 (for example be tablet for the form that is applicable to oral administration, lozenge, hard or soft capsule, water-based or oily suspensions, emulsion, but dispersion powder or granule, syrup or elixir), the form that is applicable to topical is (as ointment, ointment, jelling agent, water-based or oily solution or suspension), be applicable to the form (as fine powder or liquid aerosol) of inhalation, be applicable to the form (as pulvis subtilis) 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 or intramuscular administration are perhaps as the suppository that is used for rectal administration).

Can adopt various conventional pharmaceutical excipient well known in the art to prepare composition of the present invention through conventional method.Therefore, being used for liquid preparations for oral administration can contain, for example, and one or more tinting materials, sweeting agent, correctives and/or sanitas.

Combine with one or more vehicle and must adjust according to host who is treated and concrete route of administration with the amount of the active ingredient that obtains single formulation.For example, the preparation that is used for the human oral administration contains usually that (be more suitable for is 0.5 to 100mg just like 0.5mg to 0.5g active ingredient, as be 1 to 30mg), and also contain the vehicle of suitable convention amount in the said preparation, the amount of vehicle can be about 5 to about 98% of composition total weight.

Certainly, according to the known principle of medical field, when being used for the treatment of or prevent purpose, the dosage size of the quinazoline derivant of formula I should change according to the character of animal or patient's the patient's condition and severity, age and sex and route of administration.

When the quinazoline derivant with formula I is used for the treatment of or prevents purpose, generally be mode administration with the per daily dose that can accept certain limit, be 0.1mg/kg to 75mg/kg body weight as the per daily dose scope, can divide administration for several times in case of necessity.Usually, when adopting the parenteral administration, should give lower dosage.Therefore, when intravenously administrable, the dosage range that adopts is as 0.1mg/kg to 30mg/kg body weight usually.Similarly, when inhalation, the dosage range that adopts is as 0.05mg/kg to 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 to 0.5g that has an appointment quinazoline derivant of the present invention in the unit dosage.

We find that quinazoline derivant of the present invention has antiproliferative properties, and for example anticancer property it is believed that this specific character from its erbB, particularly EGF, and more especially the erbB2 receptor tyrosine kinase suppresses active.In addition, some quinazoline derivant of the present invention has the erbB2 of inhibition receptor tyrosine kinase than obvious better effectiveness of other Tyrosylprotein kinase of inhibition (for example EGFR Tyrosylprotein kinase).Such quinazoline derivant has the effectiveness of enough inhibition erbB2 receptor tyrosine kinases, they can be to be enough to suppress the amount use of erbB2 receptor tyrosine kinase, demonstrate simultaneously few, or obviously low other Tyrosylprotein kinase of inhibition such as the activity of EGFR.The selectivity that can be used for such quinazoline derivant suppresses the erbB2 receptor tyrosine kinase, and can be used for effectively treating the tumour that erbB2 for example causes.

Therefore, expect that compound of the present invention is used for the treatment of separately or part by by erbB, the particularly disease or the medical condition of erbB2 receptor tyrosine kinase mediation, promptly described quinazoline derivant can be used for producing erbB (particularly erbB2) receptor tyrosine kinase restraining effect the warm-blooded animal of the such treatment of needs.Therefore, quinazoline derivant of the present invention provides the method for treatment malignant cell, it is characterized in that receptor tyrosine kinase carries out by suppressing erbB, particularly erbB2.Quinazoline derivant particularly of the present invention can be used for producing and resists-propagation and/or short-apoptosis (pro-apoptotic) and/or anti--invasion and attack effect, and it is to mediate by suppressing erbB (particularly erbB2) receptor tyrosine kinase separately or partly.Particularly, expect that quinazoline derivant of the present invention is used for prevention or treats those to suppressing the tumour of erbB (particularly erbB2) receptor tyrosine kinase sensitivity, described kinases participates in making the signal transduction step of these tumor cell proliferations and survival.Therefore expect that quinazoline derivant of the present invention is by providing antiproliferative effect and be used for the treatment of and/or prevent some excess proliferative diseases.These diseases comprise, for example psoriasis, benign prostatic hyperplasia (BPH), atherosclerosis and restenosis, and particularly, erbB is erbB2 more especially, the tumour that receptor tyrosine kinase causes.Optimum or malignant tumour like this can influence any tissue, comprise non-noumenal tumour, for example leukemia, multiple myeloma or lymphoma, also comprise noumenal tumour, for example the tumour of bile duct, bone, bladder, brain/CNS, breast, colorectum, uterine cervix, uterine endometrium, stomach, head and neck, liver, lung, muscle, neuron, esophagus, ovary, pancreas, pleura/peritonaeum, prostate gland, kidney, skin, testis, Tiroidina, uterus and vulva.

According to this respect of the present invention, quinazoline derivant or its pharmacy acceptable salt are provided as the formula I of medicine.

Therefore, according to this aspect of the invention, provide the quinazoline derivant of formula I defined above or its pharmacy acceptable salt preparation be used for warm-blooded animal for example the people produce purposes in the medicine of antiproliferative effect.

Another feature according to this aspect of the present invention, the method of antiproliferative effect is provided among warm-blooded animal that provides in the treatment of this kind of needs such as the people, and this method comprises quinazoline derivant or its pharmacy acceptable salt of the I of formula as defined above that gives described animal effective dose.

Another aspect of the present invention provides the quinazoline derivant of formula I, or its pharmacy acceptable salt, its be used for warm-blooded animal for example the people produce antiproliferative effect.

According to a further aspect in the invention, provide the quinazoline derivant of the formula I of definition as mentioned or its pharmacy acceptable salt preparation be used for warm-blooded animal for example the people produce purposes in the medicine of antiproliferative effect, described antiproliferative effect be separately or part produce by suppressing the erbB2 receptor tyrosine kinase.

Another feature according to this aspect of the present invention, the warm-blooded animal that provides in the treatment of this kind of needs for example produces the method for antiproliferative effect among the people, described antiproliferative effect is to produce by suppressing the erbB2 receptor tyrosine kinase separately or partly, and this method comprises quinazoline derivant or its pharmacy acceptable salt of the I of formula as defined above that gives described animal effective dose.

According to a further aspect in the invention, provide be used for warm-blooded animal for example the people produce quinazoline derivant or its pharmacy acceptable salt of the formula I of antiproliferative effect, described antiproliferative effect be separately or part produce by suppressing the erbB2 receptor tyrosine kinase.

According to a further aspect in the invention, provide the quinazoline derivant of formula I as defined above or its pharmacy acceptable salt preparation be used for the treatment of separately or part by the erbB purposes in the medicine of the disease of erbB2 receptor tyrosine kinase mediation or medical conditions (cancer for example as herein described) particularly.

Another feature according to this aspect of the present invention, the warm-blooded animal that provides in the treatment of this kind of needs for example among the people treatment separately or part by the erbB particularly disease of erbB2 receptor tyrosine kinase mediation or the method for medical conditions (cancer for example as herein described), this method comprises quinazoline derivant or its pharmacy acceptable salt of the formula I of definition as mentioned that gives described animal effective dose.

According to a further aspect in the invention, provide quinazoline derivant or its pharmacy acceptable salt of formula I, its be used for the treatment of separately or part by the erbB particularly disease or the medical conditions (cancer for example as herein described) of the mediation of erbB2 receptor tyrosine kinase.

According to a further aspect in the invention, the quinazoline derivant of the formula I that defines as mentioned or its pharmacy acceptable salt is used for preventing or treating the medicine of these tumours in preparation purposes are provided, described tumour is to suppress participating in the signal transduction step, thereby for example EGF and/or erbB2 and/or erbB4 (especially erbB2) receptor tyrosine kinase are responsive to one or more erbB receptor tyrosine kinases that cause tumor cell proliferation.

Another feature according to this aspect of the present invention, provide be used for the warm-blooded animal of this kind of needs treatment for example people's prevention or treatment to suppressing for example method of those tumours of EGF and/or erbB2 and/or erbB4 (especially erbB2) receptor tyrosine kinase sensitivity of one or more erbB receptor tyrosine kinases, described kinases participates in causing the signal transduction step of tumor cell proliferation and/or survival, and this method comprises quinazoline derivant or its pharmacy acceptable salt of the formula I of definition as mentioned that gives described animal effective dose.

According to a further aspect in the invention, quinazoline derivant or its pharmacy acceptable salt of formula I are provided, it is used for prevention or treatment to suppressing for example those tumours of EGF and/or erbB2 and/or erbB4 (especially erbB2) receptor tyrosine kinase sensitivity of one or more erbB receptor tyrosine kinases, and described kinases participates in causing the signal transduction step of tumor cell proliferation and/or survival.

According to a further aspect in the invention, the quinazoline derivant of the formula I that defines as mentioned or its pharmacy acceptable salt is used for providing EGF and/or erbB2 and/or erbB4 (especially erbB2) the inhibiting medicine of receptor tyrosine kinase in preparation purposes are provided.

Another feature according to this aspect of the present invention, provide be used for the warm-blooded animal of this kind of needs treatment for example the people EGF and/or erbB2 and/or the inhibiting method of erbB4 (especially erbB2) receptor tyrosine kinase are provided, this method comprises quinazoline derivant or its pharmacy acceptable salt of the formula I of definition as mentioned that gives described animal effective dose.

Another aspect of the present invention provides quinazoline derivant or its pharmacy acceptable salt of formula I, and it is used to provide EGF and/or erbB2 and/or erbB4 (especially erbB2) receptor tyrosine kinase restraining effect.

According to a further aspect in the invention, provide the quinazoline derivant of the formula I of definition as mentioned or its pharmacy acceptable salt to be used for providing the purposes of the medicine of selectivity erbB2 kinase inhibitory activity in preparation.

Another feature according to this aspect of the present invention, provide be used for the warm-blooded animal of this kind of needs treatment for example the people selectivity erbB2 is provided the method for kinase inhibitory activity, this method comprises quinazoline derivant or its pharmacy acceptable salt of the formula I of definition as mentioned that gives described animal effective dose.

According to a further aspect in the invention, provide quinazoline derivant or its pharmacy acceptable salt of formula I, it is used to provide selectivity erbB2 kinase inhibitory activity.

It is more effective that " selectivity erbB2 kinase inhibitory activity " is meant that the quinazoline derivant inhibition erbB2 receptor tyrosine kinase of formula I suppresses other kinases than it.Some compound particularly of the present invention suppresses the erbB2 receptor kinase and suppresses other Tyrosylprotein kinase than it, and for example other erbB receptor tyrosine kinase (particularly EGFR Tyrosylprotein kinase) is more effective.For example, according in suitable analysis to relative IC ₅₀The mensuration of value (for example derives from Clone 24 phosphines-erbB2 cell analysis IC of (a kind of cell erbB2 Tyrosylprotein kinase suppresses active assay method) with aforesaid given test compound ₅₀Value with derive from the KB cell analysis IC of (a kind of cell EGFR Tyrosylprotein kinase suppresses active assay method) ₅₀Value compares), the effectiveness that selectivity erbB2 kinase inhibitor of the present invention suppresses the erbB2 receptor tyrosine kinase suppresses at least 5 times by force of EGFR Tyrosylprotein kinases, preferably at least 10 times than it.

According to a further aspect in the invention, provide the quinazoline derivant of the formula I of definition as mentioned or its pharmacy acceptable salt to be used for the treatment of purposes in the medicine of cancer in preparation, described cancer for example is selected from leukemia, multiple myeloma, lymphoma, the cancer of bile duct, bone, bladder, brain/CNS, breast, colorectum, uterine cervix, uterine endometrium, stomach, head and neck, liver, lung, muscle, neuron, esophagus, ovary, pancreas, pleura/peritonaeum, prostate gland, kidney, skin, testis, Tiroidina, uterus and vulva.

Another feature according to this aspect of the present invention, provide the warm-blooded animal of this kind of needs treatment and for example treated method for cancer among the people, described cancer for example is selected from leukemia, multiple myeloma, lymphoma, bile duct, bone, bladder, brain/CNS, breast, colorectum, uterine cervix, uterine endometrium, stomach, head and neck, liver, lung, muscle, neuron, esophagus, ovary, pancreas, pleura/peritonaeum, prostate gland, kidney, skin, testis, Tiroidina, the cancer of uterus and vulva, this method comprise quinazoline derivant or its pharmacy acceptable salt of the formula I of definition as mentioned that gives described animal effective dose.

According to a further aspect in the invention, quinazoline derivant or its pharmacy acceptable salt of formula I are provided, it is used for the treatment of cancer, described cancer for example is selected from leukemia, multiple myeloma, lymphoma, the cancer of bile duct, bone, bladder, brain/CNS, breast, colorectum, uterine cervix, uterine endometrium, stomach, head and neck, liver, lung, muscle, neuron, esophagus, ovary, pancreas, pleura/peritonaeum, prostate gland, kidney, skin, testis, Tiroidina, uterus and vulva.

As indicated above, be used for the treatment of or dosage size that the prophylactic treatment disease specific is required must change according to other situation, the host who is treated, route of administration and the severity of disease for the treatment of.

Can give quinazoline derivant of the present invention with the form of prodrug, according to the inventor's definition, described prodrug is illustrated in warm-blooded animal and for example decomposes in the human body, discharges the compound of quinazoline derivant of the present invention.Available prodrug changes the physical properties and/or the pharmacokinetic property of The compounds of this invention.When quinazoline derivant of the present invention contains the group that is fit to that can be connected with the group of characteristic changing or substituting group, can form prodrug.The example of prodrug comprises in vivo can dissociated ester derivative (it can form on the hydroxyl of the quinazoline derivant of formula I), and in vivo can dissociated amide derivatives (it can form on the amino of the quinazoline derivant of formula I).

Therefore, the present invention includes can obtain by organic synthesis and can be by the quinazoline derivant of those formulas I of definition as mentioned that obtains at its prodrug of human or animal body internal disintegration.Therefore, the present invention includes quinazoline derivant by those formulas I of methodology of organic synthesis preparation, and this type of quinazoline derivant that in human or animal body, produces by the precursor compound metabolism, promptly the quinazoline derivant of formula I can be the quinazoline derivant of synthetic preparation or the quinazoline derivant that metabolism produces.

The prodrug of the quinazoline derivant of the pharmaceutically acceptable formula I that is fit to is to judge according to rational medicine, is fit to give the prodrug of human or animal body, but the toxicity that does not have unwanted pharmacologically active and do not know to work as.

Various forms of prodrugs are described in for example following document :-

a) Methods in Enzymology，Vol. 42，p.309 to 396，edited by K. Widder，etal.(Academic Press，1985)；

b)Design of Pro-drugs，edited by H.Bundgaard，(Elsevier，1985)；

c)A Textbook of Drug Design and Development，edited byKrogsgaard-Larsen and H.Bundgaard，Chapter 5“Design and ApplicationofPro-drugs”，edited by H.Bundgaard，p.113to 191(1991)；

D) H.Bundgaard, Advanced Drug Delivery Reviews, 8, 1 to 38 (1992); With

e)H.Bundgaard，et al.， Journal of Pharmaceutical Sciences， 77，285(1988).

Antiproliferative treatment defined above can be used separately as the single therapy method, perhaps except that quinazoline derivant of the present invention, 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) other antiproliferative/antitumour drug and the combination thereof adopted in medical oncology are as alkylating agent (for example cis-platinum, oxaliplatin, carboplatin, endoxan, mustargen, melphalan, Chlorambucil, busulfan, Temozolomide and Nitrosourea); Antimetabolite (for example gemcitabine and anti-folic acid class such as fluorine pyrimidines (as 5 FU 5 fluorouracil and Tegafur), Raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea; Antitumor antibiotics (as anthracyclines, as Zorubicin, bleomycin, Dx, daunorubicin, epirubicin, darubicin, Mitomycin-C, actinomycin and Plicamycin); Antimitotic agent (vinca alkaloids for example, as vincristine(VCR), vinealeucoblastine(VLB), vindesine and vinorelbine, and taxanes such as taxol and Docetaxel and polokinase inhibitor); And topoisomerase enzyme inhibitor (as the Etoposide class, as Etoposide and teniposide, amsacrine, Hycamtin and camptothecine);

(ii) cytostatics, anti-estrogens (as tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene) for example, anti-androgens (as bicalutamide, flutamide, Nilutamide and acetate cyproterone), lhrh antagonist or LHRH agonist (as goserelin, Leuprolide and buserelin), progestogens (as the acetate megestrol), aromatase inhibitor (as Anastrozole, letrozole, fluorine chlorazol (vorazole) and Exemestane) and 5 inhibitor such as finasteride;

(iii) anti-invasion agent (for example c-Src kinases man's group inhibitor such as 4-(6-chloro-2,3-methylenedioxyphenyl amido)-7-[2-(4-methylpiperazine-1-yl) oxyethyl group]-5-tetrahydropyran-4-base oxygen base quinazoline (AZD0530; International Patent Application WO 01/94341) and N-(2-chloro-6-aminomethyl phenyl)-2-{6-[4-(2-hydroxyethyl) piperazine-1-yl]-2-methylpyrimidine-4-base is amino thiazole-5-carboxylic acid amides (dasatinib; BMS-354825; J.Med.Chem., 2004, 47, 6658-6661), and inhibitors of metalloproteinase such as Marimastat, upar depressant of functions, perhaps heparanase antibody);

(iv) somatomedin depressant of functions: for example this type of inhibitor comprises growth factor antibodies, growth factor receptor antibody (for example, anti--erbB2 antibody trastuzumab [Herceptin ^TM] and anti--erbB1 antibody Cetuximab [Erbitux, C225]); This type of inhibitor also comprises for example epidermal growth factor family inhibitor (EGFR family tyrosine kinase inhibitor for example of tyrosine kinase inhibitor, as N-(3-chloro-4-fluorophenyl)-7-methoxyl group-6-(3-morpholino propoxy-) quinazoline-4-amine (gefitinib, ZD1839), N-(3-ethynyl phenyl)-6,7-two (2-methoxy ethoxy) quinazoline-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholino propoxy-)-quinazoline-4-amine (CI 1033), erbB2 tyrosine kinase inhibitor such as lapatinib, pHGF man group inhibitor, platelet-derived growth factor family inhibitor such as imatinib, serine/threonine kinase inhibitor (for example Ras/Raf communication inhibitor such as farnesyl transferase inhibitor, sorafenib (BAY 43-9006) for example), through MEK and/or the kinase whose cell communication of AKT inhibitor, pHGF man group inhibitor, c-box (c-kit) inhibitor, the abl kinase inhibitor, IGF acceptor (rhIGF-1) kinase inhibitor; Aurora kinase inhibitor (for example AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459), and cell cycle protein dependent kinase inhibitor such as CDK2 and/or CDK4 inhibitor;

(v) anti-angiogenic agent [for example resists-blood vessel pork skin cell growth factor antibody rhuMAb-VEGF (Avastin as those medicines that suppress the vascular endothelial growth factor effect ^TM) and vegf receptor tyrosine kinase inhibitor such as 4-(4-bromo-2-fluoroanilino)-6-methoxyl group-7-(1-methyl piperidine-4-ylmethoxy) quinazoline (zD6474; Embodiment 2 among the WO 01/32651), 4-(4-fluoro-2 methyl indole-5-base oxygen base)-6-methoxyl group-7-(3-tetramethyleneimine-1-base propoxy-) quinazoline (AZD2171; Embodiment 240 among the WO 00/47212), vatalanib (PTK787; WO 98/35985) and SU11248 (sunitinib; WO 01/60814), those disclosed compound in International Patent Application WO 97/22596, WO 97/30035, WO97/32856 and WO 98/13354, and those compounds that work by other mechanism (for example linomide, beta 2 integrin alpha v β 3 depressant of functions and angiostatin (angiostatin))];

(vi) blood vessel injury agent, as combretastatin A4, and in International Patent Application WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO02/08213 disclosed compound;

(vii) antisense therapy agent for example relates to those therapeutical agents of top listed target, as ISIS 2503, a kind of anti--agent of ras antisense therapy;

(viii) gene therapy, comprise the method, GDEPT (gene-pacemaker enzyme prodrug therapy) method that for example replace aberrant gene (as unusual p53 or unusual BRCA1 or BRCA2), as use those methods of Isocytosine deaminase, thymidine kinase or bacterium nitroreductase, and increase the method (as multidrug resistance gene therapy) of patient to chemotherapy or radiotherapy tolerance; With

(ix) immunotherapy, comprise the immunogenic method that increases the patient tumors cell in for example external and the body, as using cytokine (as interleukin-22, interleukin 4 or granulocyte-macrophage colony stimutaing factor) transfection, reduce the anergic method of T-cell, use the method for the dendritic cells of transfection immunocyte such as cytokine-transfection, use cytokine-transfection tumor cell line method and use anti-spy to answer the method for antibody.

By simultaneously, order or each component of separately treating, can carry out this type of combination therapy.This type of joint product uses other interior medical active agent of amount ranges of interior quinazoline derivant of the present invention of dosage range mentioned above and approval.

According to an aspect of the present invention, provide medicinal product, other antitumour drug defined above that this product comprises the quinazoline derivant of formula I defined above and is used for the cancer combination therapy.

Although the quinazoline derivant of formula I mainly is the medicine as warm-blooded animal (comprising the people), when needing, they also can be used to suppress the effect of erbB receptor tyrosine protein kinase.Therefore, these compounds can be as new biological test exploitation and the pharmaceutical standards product in the new pharmacology drug research.

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

(i) temperature with degree centigrade provide (℃); Operation is to carry out under room temperature or envrionment temperature, promptly carries out in 18-25 ℃ temperature range;

(ii) organic solution is through anhydrous magnesium sulfate or anhydrous sodium sulfate drying; The evaporation of solvent is decompression (600-4000 pascal; 4.5-30mmHg) and be up under 60 ℃ the bath temperature, use rotatory evaporator to carry out;

(iii) chromatography refers to the flash chromatography on silica gel method; Tlc (TLC) is carried out on silica-gel plate;

(iv) in general, reaction process is by TLC and/or analysis mode LC-MS monitoring, and the reaction times that provides only is used for explanation; Retention time (t _R) be that (C18,3.5 μ M carry out in 4.6 * 50mm) the LC/MS Waters 2790/ZMD Micromass system being equipped with Waters Symmetry post; Detect UV 254nM and MS; Wash-out: flow velocity 2.5ml/min, linear gradient go through 3 minutes from 95% water-5% methyl alcohol that contains 5% formic acid to 40% water-55% acetonitrile-5% methyl alcohol that contains 5% formic acid; Linear gradient is gone through 1 minute to 95% acetonitrile-5% methyl alcohol that contains 5% formic acid then;

(v) final product has satisfied proton magnetic resonance (PMR) (NMR) spectrum and/or mass-spectrometric data;

(productive rate that vi) provides only is used for explanation, might not be can reach productive rate by improving one's methods of effort; More if desired material then repeats preparation;

(vii) when providing, the NMR data are the form of delta (δ) value of main feature proton, provide as interior mark with the every ppm (ppm) with respect to tetramethylsilane (TMS), except as otherwise noted, use full deuterated dimethyl sulfoxide (DMSO-d ₆) as solvent, measure at the 400MHz place; Use following abbreviation: s representative unimodal; The d representative is bimodal; T represents triplet; Q represents quartet; M represents multimodal; Br represents broad peak;

(viii) chemical symbol has its common implication; Adopt SI units and symbol;

(ix) solvent ratio is with volume: volume (v/v) relation provides; With

(x) mass spectrum with 70 electron-volts electron energy, uses direct contact probe to carry out in chemi-ionization (CI) pattern; The ionization of wherein pointing out is undertaken by electron impact (EI), fast atom bombardment(FAB) (FAB) or electron spray(ES) (ESP); Provide the m/z value; In general, only report the ion of indication gross (parent mass); Except as otherwise noted, the mass ion of quoting is (MH) ⁺, it refers to protonated mass ion; As for M ⁺For losing the mass ion that the electron institute generates; And as for M-H ⁺For losing the mass ion that proton produces;

(xi) except as otherwise noted, containing the carbon of asymmetric replacement and/or the compound of sulphur atom is not split;

(xii) wherein synthetic as with synthesizing described in the previous examples, described similarly, used amount is the mmole ratio with respect to amount used in the previous examples;

(xiii) all microwave reactions are at Personal Chemistry EMRYS ^TMCarry out in the Optimizer EXP microwave synthesizer;

(xiv) preparative high performance liquid chromatography (HPLC) adopts following condition to carry out on the Waters instrument:

Post: 30mm * 15cm Xterra Waters, C18,5mm

Solvent orange 2 A: the water that contains 1% acetate or 2g/l volatile salt

Solvent B: acetonitrile

Flow velocity: 40ml/min

Working time: 15 minutes, comprise 10 minutes gradients of 5-95%B

Wavelength: 254nm

Injection rate: 2.0-4.0ml;

(xv) use following abbreviation:

HATU O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea is defeated

Hexafluoro-phosphoric acid salt; With

The THF tetrahydrofuran (THF);

DMF N, dinethylformamide;

The DMA N,N-dimethylacetamide;

The DCM methylene dichloride;

The DMSO dimethyl sulfoxide (DMSO);

DTAD azoformic acid di-t-butyl ester;

The DIPEA diisopropylethylamine;

The IPA Virahol;

Ether (Ether) ether; With

The TFA trifluoroacetic acid.

Embodiment 1

(2R)-and N-(2-hydroxyethyl)-N-methyl-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide

With (2R)-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] (200mg, 0.44mmol) suspension of the stirring in 2-(methylamino-)-ethanol (2ml) heated 30 minutes down at 100 ℃ in microwave reactor methyl propionate.2-(methylamino-)-ethanol is evaporated under high vacuum, again resistates is distributed between water and DCM.With organic phase salt water washing, drying flashes to jelly.After the ether grinding, title compound is separated (silica gel, 5%2M NH by chromatography ₃-methyl alcohol/DCM) is white solid (126mg, 58%); The NMR spectrum(393K) 1.65 (d, 3H), 3.07 (s, 2H), 3.39-3.66 (m, 5H), 4.40 (s, 1H), 5.71 (s, 2H), 5.76-5.83 (m, 1H), 7.05 (d, 1H), 7.20 (d, 1H), 7.23-7.28 (m, 1H), 7.35 (d, 1H), 7.58 (d, 1H), 7.65-7.73 (m, 2H), 7.84 (dd, 1H), 8.07 (s, 1H), 8.45 (s, 1H), 8.48 (s, 1H), 8.52 (d, 1H), 10.86 (s, 1H); Mass spectrumMH ⁺498.

As (2R)-2-[(4-{[1-(pyridine-2-the ylmethyl)-1H-indazole-5-yl of initial substance] amino } quinazoline-5-yl) the oxygen base] methyl propionate is prepared as follows:

DMF (0.2ml) is joined 5-fluoro-3, in the 4-dihydro-suspension of 3H-quinazoline-4-one (1.64g) in thionyl chloride (10ml), this mixture is stirred, and heated 6 hours down at 80 ℃.Remove volatile matter by evaporation, again with resistates methylbenzene azeotropic (20ml).The gained solid is added drop-wise in the mixture of saturated sodium bicarbonate (50ml), trash ice (50g) and DCM (50ml) of vigorous stirring in batches, makes temperature keep below 5 ℃ like this.Separate organic phase, drying concentrates, and obtaining 4-chloro-5-fluquinconazole quinoline is solid, its not purified promptly be used (1.82g, 99%); NMR Spectrum(300MHz, CDCl ₃) 7.35-7.45 (m, 1H), 7.85-7.95 (m, 2H), 9.0 (s, 1H).

(10.95g, 60mmol) (7.98g, 60mmol) the part solution of the stirring in Virahol (300ml) heated 3 hours under refluxing with the 5-Aminoindazole with 4-chloro-5-fluquinconazole quinoline.Be cooled to envrionment temperature, leach the product hydrochloride, with Virahol and ether washing.With salt and water (400ml)/ethanol (100ml) heating, and with the ammoniacal liquor acidifying of part solution.Precipitated solid is leached, wash with water again, obtain 5-fluoro-N-1H-indazole-5-base quinazoline-4-amine (14.91g, 89%); The NMR spectrum(300MHz) 7.42 (dd, 1H), 7.53 (s, 2H), 7.60 (d, 1H), 7.83 (m, 1H), 8.08 (d, 2H), 8.50 (s, 1H), 9.20 (d, 1H), 13.05 (s, 1H); Mass spectrumMH ⁺280.

To 5-fluoro-N-1H-indazole-5-base quinazoline-4-amine (3.35g, 12mmol) and 2-picolyl chlorination thing hydrochloride (2.07g, 12.6mmol) add in the part solution of the stirring in DMF (60ml) in batches sodium hydride (60%, be scattered in the mineral oil, 1.01g, 25.2mmol).By slight cooling reaction is kept at ambient temperature, and stirred 18 hours.By adding saturated aqueous ammonium chloride (5ml), under high vacuum, evaporate again the reaction mixture quencher.Resistates is distributed the organic phase anhydrous Na between the 2.5MNaOH aqueous solution and DCM ₂SO ₄Drying, evaporation.This product by chromatography (5% methanol/ethyl acetate) purifying, by grinding crystallization with ether, is obtained 5-fluoro-N-[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl again] quinazoline-4-amine (1.8g, 41%); NMR Spectrum(300MHz) 5.75 (s, 2H), 6.97 (d, 1H), 7.27 (m, 1H), 7.41 (dd, 1H), 7.54-7.75 (m, 4H), 7.84 (q, 1H), 8.12 (d, 2H), 8.50 (m, 2H), 9.23 (d, 1H); Matter SpectrumMH ⁺371.

To sodium hydride (60%, in mineral oil, 1.68g, 42mmol) slowly add in the suspension of the stirring in DMA (25ml) N-(2-hydroxyethyl) ethanamide (1.80g, 17.5mmol).When effervesce disappears, adding 5-fluoro-N-[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] (2.60g 7.0mmol), heats this mixture 18 hours down at 120 ℃ quinazoline-4-amine again.Reaction is passed through to add saturated NH ₄The Cl aqueous solution (5ml) quencher, evaporation (high vacuum).Resistates and water (100ml) stir, and obtain gelatinous precipitate, and it is leached and washes with water.With this product by chromatography (silica gel do to be loaded, and the purifying of 5 to 10% methyl alcohol/DCM) by grinding crystallization with ether, obtains 4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl again] amino quinazoline-5-alcohol (928mg, 32%); The NMR spectrum(373K) 5.72 (s, 2H), 6.77 (m, 3H), 7.03 (d, 1H), 7.23 (dd, 1H), 7.44 (t, 1H), 7.50 (d, 1H), 7.59 (d, 1H), 7.70 (t, 1H), 8.07 (s, 1H), 8.13 (s, 1H), 8.27 (s, 1H), 8.52 (d, 1H), 11.87 (br s, 1H); Mass spectrumMH ⁺369.

To 4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-alcohol (870mg, 2.36mmol), (2S)-2 hydroxy propanoic acid methyl esters (368mg, 3.54mmol) and triphenyl phosphine (927mg, 3.54mmol) add in the part solution of stirring in DCM (20ml) DTAD (814mg, 3.54mmol).This mixture was stirred 1 hour, become settled solution.This solution with the extraction of 2N hydrochloride aqueous solution, is abandoned organic phase.Water alkalizes with ammoniacal liquor, extracts with DCM.With organic phase salt water washing, drying flashes to oil, and it grinds crystallization with ether, obtains (2R)-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (789mg, 74%); NMRSpectrum (300MHz) 1.70 (d, 3H), 3.78 (s, 3H), 5.51 (q, 1H), 5.76 (s, 2H), 6.95 (d, 1H), 7.16 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.69 (m, 4H), 8.16 (s, 1H), 8.43 (s, 1H), 8.52 (s, 2H), 10.48 (s, 1H); Mass spectrumMH ⁺455.

Embodiment 2

5-[(1R)-1-methyl-2-morpholine-4-base-2-oxo oxyethyl group]-N-[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine

In the solution of the stirring of morpholine (2ml) in methyl alcohol (10ml), add 4A molecular sieve powder (2g).After stirring 10 minutes, add (6R)-6-methyl-4-[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl]-4H-[1,4] Evil azepines also [5,6,7-de] quinazolines-5 (6H)-ketone (125mg 0.3mmol), stirs this mixture 3 days again.Reaction mixture is filtered, and evaporating solvent.Resistates is placed DCM, use ammoniacal liquor and salt water washing again, drying flashes to jelly.(silica gel, the purifying of 5% methyl alcohol/DCM) by grinding crystallization with ether, obtain title compound (75mg, 50%) again by chromatography with this product; The NMR spectrum(373K) 1.63 (d, 3H), 3.58-3.66 (m, 8H), 5.72 (s, 2H), 5.81 (q, 1H), 7.04 (d, 1H), 7.22 (d, 1H), 7.26 (dd, 1H), 7.36 (d, 1H), 7.59 (d, 1H), 7.67-7.73 (m, 2H), 7.83 (dd, 1H), 8.08 (d, 1H), 8.45 (d, 1H), 8.49 (s, 1H), 8.52 (d, 1H), 10.90 (s, 1H); Mass spectrumMH ⁺510.

(6R)-6-methyl-4-[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl as initial substance]-4H-[1,4] Evil azepines also [5,6,7-de] quinazolines-5 (6H) ketone are prepared as follows:

To (2R)-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (520mg, 1.15mmol) add 2.5M aqueous sodium hydroxide solution (2ml in the solution of (as acquisition as described in the preparation of initial substance among the embodiment 1) stirring in methyl alcohol (10ml), 5mmol), again with this solution stirring 3 hours.Evaporating solns places water with resistates, is acidified with acetic acid to about pH4, restir 15 minutes.Leach throw out, wash with water, drying obtains (2R)-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid (435mg, 86%); The NMR spectrum(300MHz) 1.69 (d, 3H), 5.36 (q, 1H), 5.75 (s, 2H), 6.94 (d, 1H), 7.14 (d, 1H), 7.27 (t, 1H), 7.35 (d, 1H), 7.71 (m, 4H), 8.12 (s, 1H), 8.43 (s, 1H), 8.52 (s, 2H), 1076 (s, 1H), do not observe one tradable; Mass spectrumMH ⁺441.

To (2R)-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid (415mg, 0.94mmol) add DIPEA (1ml) and HATU (447mg in the solution in DMA (8ml), 1.18mmol), again this solution was heated 90 minutes down at 80 ℃.(223mg 0.59mmol), heats this reaction mixture other 60 minutes down at 70 ℃ again to add more HATU.Evaporation (high vacuum) solvent places DCM with resistates again.Product ammoniacal liquor and salt water washing, drying flashes to jelly.This jelly is passed through chromatography (silica gel, 2% methanol/ethyl acetate) purifying, again by grinding crystallized product with ether, obtain (6R)-6-methyl-4-[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl]-4H-[1,4] Evil azepines also [5,6,7-de] quinazoline-5 (6H)-ketone (316mg, 80%); The NMR spectrum(300MHz) 1.55 (d, 3H), 5.25 (q, 1H), 5.75 (s, 2H), 7.17 (d, 1H), 7.30 (m, 3H), 7.68 (m, 4H), 7.91 (t, 1H), 8.10 (s, 1H), 8.50 (d, 1H), 8.75 (s, 1H); Mass spectrumMH ⁺423.

Embodiment 3

(2R)-and N, N-dimethyl-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide

With (2R)-N, N-dimethyl-2-[(4-oxo-3,4-dihydroquinazoline-5-yl) the oxygen base] propionic acid amide (783mg, 3mmol), triphenyl phosphine (2.35g, 9mmol) and tetracol phenixin (8.62ml, 90mmol) 1, the mixture in the 2-ethylene dichloride (20ml) stirred 2 hours down at 45 ℃.Cool off this mixture, again the vaporising under vacuum solvent.Add 1-(pyridine-2-ylmethyl)-1H-indazole-5-amine (706mg, 3.15mmol) and acetonitrile (15ml).This mixture was stirred 1 hour down at 75 ℃.After the cooling, the vaporising under vacuum solvent.Resistates is diluted among the DCM, uses the 2N hcl as extraction agent again.Water layer by adding the neutralization of 6N ammoniacal liquor, is extracted with DCM again.DCM layer dried over mgso., vaporising under vacuum solvent again.With resistates by chromatography with silica gel purification twice (first elutriant: 3%6N methyl alcohol system ammonia solution/DCM; Second elutriant: 3% methyl alcohol/DCM), obtaining title compound is white foam (600mg, 43%); The NMR spectrum(CDCl ₃) 1.72 (d, 3H), 3.06 (s, 3H), 3.14 (s, 3H), 5.43 (q, 1H), 5.75 (s, 2H), 6.81 (m, 2H), 7.17 (m, 1H), 7.41 (d, 1H), 7.48 (d, 1H), 7.62-7.53 (m, 2H), 7.81 (dd, 1H), 8.10 (s, 1H), 8.44 (d, 1H), 8.58 (d, 1H), 8.62 (s, 1H); Mass spectrum468.

As (the 2R)-N of initial substance, N-dimethyl-2-[(4-oxo-3,4-dihydroquinazoline-5-yl) the oxygen base] propionic acid amide is prepared as follows:

With sodium hydride (124g, 60%, in oil, 31mmol) join 5-methoxyl group quinazoline-4 (3H)-ketone (5g, 28.4mmol in batches; As acquisition as described in the WO-96/09294) in the solution in dry DMF (50ml), simultaneously with temperature maintenance at 25 ℃.This mixture was at room temperature stirred 30 minutes.At room temperature added through 3 hours chloromethyl pivalate (4.45ml, 31mmol).Add other sodium hydride (0.12g, 3mmol) and chloromethyl pivalate (0.67ml 4.5mmol), stirs this mixture other 1 hour again.After the evaporating solvent,, wash under the high vacuum with DCM with this mixture dilute with water.After dried over mgso and evaporating solvent, with resistates by chromatography with silica gel (elutriant: ethyl acetate-sherwood oil, 6: 4 to 8: 2) purifying, obtain that (5-methoxyl group-4-oxo quinazoline-3 (4H)-yl) methyl pivalate is white solid (7.4g, 90%); HPLC t _R: 2.69min; Mass spectrumMH ⁺291.

(7g joins 38mmol) that ((7.4g is 25.5mmol) in the solution in pyridine (25ml) for 5-methoxyl group-4-oxo quinazoline-3 (4H)-yl) methyl pivalate with magnesium bromide.This mixture was stirred 1 hour down at 120 ℃.After the cooling, evaporating solvent under high vacuum.Add acetic acid,diluted (15ml is in 100ml water).Precipitated solid is filtered, washes with water, again under vacuum at P ₂O ₅Exist dryly down, obtain that (5-hydroxyl-4-oxo quinazoline-3 (4H)-yl) methyl pivalate is white solid (6.33g, 90%); The NMR spectrum(CDCl ₃) 1.23 (s, 9H), 5.93 (s, 2H), 6.99 (d, 1H), 7.22 (d, 1H), 7.68 (t, 1H), 8.21 (s, 1H); Mass spectrumMH ⁺277.

With DTAD (13.34g, 58mmol) join in batches (5-hydroxyl-4-oxo quinazoline-3 (4H)-yl) methyl pivalate (and 8g, 29mmol), triphenyl phosphine (15.2g, 58mmol) and (S)-N, N-dimethyl lactic amide (5.1g, 43.5mmol; As Larcheveque M., Synthesis 1986,1,60 described acquisitions) in the ice-cold solution in DCM (300ml).This mixture was at room temperature stirred 1 hour.After the evaporating solvent, resistates is diluted with 6N methyl alcohol system ammonia solution (100ml) under the vacuum.This mixture was at room temperature stirred 18 hours.After the evaporating solvent, grinding residues in ether.With the gained solid filtering, more further by chromatography with silica gel (elutriant: the purifying of 3 to 5% methyl alcohol/DCM) obtains (2R)-N, N-dimethyl-2-[(4-oxo-3,4-dihydroquinazoline-5-yl) oxygen base] propionic acid amide is white solid (5.4g, 71%); The NMR spectrum(CDCl ₃) 1.77 (d, 3H), 2.94 (s, 3H), 3.19 (s, 3H), 5.10 (q, 1H), 6.92 (d, 1H), 7.35 (d, 1H), 7.63 (t, 1H), 8.00 (s, 1H); Mass spectrumMH ⁺262.

1-(pyridine-2-ylmethyl)-1H-indazole-5-amine as initial substance is prepared as follows:

With the 5-nitro indazole (40.75g, 250mmol), picolyl chlorination thing hydrochloride (45.1g, 275mmol) and salt of wormwood (72.4g, 525mmol) mixture in DMF (400ml) is 75 ℃ of down heating 3 hours.Add other picolyl chlorination thing hydrochloride (4.1g, 25mmol) and salt of wormwood (3.45g, 25mmol), again with this mixture 75 ℃ of down other 2 hours of heating.After the cooling, with this mixture water (800ml) dilution.Filtering precipitate washes with water, drying.With the solid that generates by chromatography with silica gel (elutriant: 50% ethyl acetate/petroleum ether) purifying, obtaining 5-nitro-1-(pyridine-2-ylmethyl)-1H-indazole is solid (34.5g, 55%); The NMR spectrum(CDCl ₃) 5.77 (s, 2H), 7.03 (d, 1H), 7.23 (m, 1H), 7.55 (d, 1H), 7.63 (m, 1H), 8.27-8.23 (m, 2H), 8.58 (m, 1H), 8.74 (d, 1H); Mass spectrumMH ⁺255.

Further wash-out obtains 5-nitro-2-(pyridine-2-ylmethyl)-2H-indazole; The NMR spectrum(CDCl ₃) 5.76 (s, 2H), 7.26 (m, 2H), 7.77-7.69 (m, 2H), 8.10 (dd, 1H), 8.42 (s, 1H), 8.61 (m, 1H), 8.74 (d, 1H); Mass spectrumMH ⁺255.

With 5-nitro-1-(pyridine-2-ylmethyl)-1H-indazole (34g, 134mmol) and (1g) the mixture hydrogenation under 1bar pressure in methyl alcohol (500ml) of platinum oxide (IV).(stop to absorb hydrogen this moment) after 4 hours, with this mixture of diatomite filtration.Reduction vaporization filtrate.Resistates is ground in ether, and obtaining 1-(pyridine-2-ylmethyl)-1H-indazole-5-amine is pale solid (28.6g, 95%); The NMR spectrum(CDCl ₃) 3.61 (m, 2H), 5.67 (m, 2H), 6.78 (d, 1H), 6.82 (dd, 1H), 6.95 (d, 1H), 7.16 (m, 1H), 7.20 (d, 1H), 7.53 (m, 1H), 7.87 (s, 1H), 8.57 (d, 1H); Mass spectrumMH ⁺225.

Embodiment 4

(2S)-and N, N-dimethyl-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide

With (2S)-N, N-dimethyl-2-[(4-oxo-3,4-dihydroquinazoline-5-yl) the oxygen base] propionic acid amide (200mg, 0.77mmol), triphenyl phosphine (603mg, 2.3mmol) and tetracol phenixin (2.2ml, 23mmol) 1, the mixture in the 2-ethylene dichloride (5ml) stirred 2 hours down at 45 ℃.Add 1-(pyridine-2-ylmethyl)-1H-indazole-5-amine (179mg, 0.8mmol), vaporising under vacuum solvent again.Add acetonitrile (5ml).This mixture was stirred 2 hours down at 75 ℃.After the cooling, add 6N methyl alcohol system ammonia solution (3ml).The vaporising under vacuum solvent.With resistates by chromatography with silica gel (elutriant: the purifying of 3% to 5% methyl alcohol/DCM), obtaining title compound is white foam (208mg, 58%); The NMR spectrum(CDCl ₃) 1.72 (d, 3H), 3.06 (s, 3H), 3.14 (s, 3H), 5.43 (q, 1H), 5.75 (s, 2H), 6.81 (m, 2H), 7.17 (m, 1H), 7.41 (d, 1H), 7.48 (d, 1H), 7.62-7.53 (m, 2H), 7.81 (dd, 1H), 8.10 (s, 1H), 8.44 (d, 1H), 8.58 (d, 1H), 8.62 (s, 1H); Mass spectrum468.

(2S)-N as initial substance, N-dimethyl-2-[(4-oxo-3,4-dihydroquinazoline-5-yl) oxygen base] propionic acid amide is from (5-hydroxyl-4-oxo quinazoline-3 (4H)-yl) methyl pivalate and (R)-N, N-dimethyl lactic amide (5.1g, 43.5mmol; According to LarchevequeM., Synthesis 1986,1 from (R)-methyl lactate, 60 preparations), use the operation preparation be similar to embodiment 3 initial substances.(the 2S)-N that obtains, N-dimethyl-2-[(4-oxo-3,4-dihydroquinazoline-5-yl) the oxygen base] propionic acid amide is white solid (5g, 66%); The NMR spectrum1.49 (d, 3H), 2.82 (s, 3H), 3.07 (s, 3H), 5.21 (q, 1H), 6.74 (d, 1H), 7.17 (d, 1H), 7.62 (t, 1H), 7.96 (s, 1H); Mass spectrumMH ⁺262.

Embodiment 5

(2R)-and 2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide

With (2R)-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] (250mg, 0.55mmol) solution in methyl alcohol (3ml) is saturated by ammonia being blown in this solution several minutes with ammonia for methyl propionate.Sealing contains the pipe of this solution, at room temperature this mixture is stirred 48 hours again.Filtering precipitate, with ether washing, drying, obtaining title compound is white solid (165mg, 65%); The NMR spectrum1.66 (d, 3H), 5.14 (q, 1H), 5.77 (s, 2H), 6.94 (d, 1H), 7.02 (d, 1H), 7.30 (m, 1H), 7.36 (d, 1H), 7.55 (br s, 1H), 7.78-7.67 (m, 4H), 7.89 (br s, 1H), 8.15 (s, 1H), 8.52 (m, 3H), 10.80 (br s, 1H); Mass spectrumMH ⁺440.

As (2R)-2-[(4-{[1-(pyridine-2-the ylmethyl)-1H-indazole-5-yl of initial substance] amino } quinazoline-5-yl) the oxygen base] methyl propionate is prepared as follows.

With 4N hydrogenchloride/diox (9.6ml, 38.4mmol) add to 1-(pyridine-2-ylmethyl)-1H-indazole-5-amine (8.78g, 39.2mmol) and 4-chloro-5-fluquinconazole quinoline (7g, 38.4mmol; As preparation as described in the WO2001/094341) in the mixture in acetonitrile (100ml).This mixture was stirred 1.5 hours down at 75 ℃.After the cooling, this mixture is evaporated to drying.Resistates is diluted in the 6N methyl alcohol system ammonia solution.This mixture is evaporated to drying, and redilution is in DCM.Cross after the filter solid, filtrate is evaporated to drying.With resistates by chromatography with silica gel (elutriant: the purifying of methyl alcohol/DCM) obtains 5-fluoro-N-[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine is beige solid (10.2g, 72%); The NMR spectrum(CDCl ₃) 5.76 (s, 2H), 6.89 (d, 1H), 7.22-7.18 (m, 2H), 7.58-7.45 (m, 3H), 7.72 (m, 2H), 8.11 (s, 1H), 8.21 (s, 1H), 8.47 (m, 1H), 8.60 (d, 1H), 8.68 (s, 1H); Mass spectrumMH ⁺371.

With 5-fluoro-N-[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] and quinazoline-4-amine (10.2g, 27.5mmol) and sodium methylate (4.46g, the 82.6mmol) heating 24 hours under refluxing of the mixture in methyl alcohol (250ml).After the cooling, evaporating solvent is dissolved in resistates among the DCM.MgSO is used in this solution liquid water and salt water washing again ₄Dry.Evaporating solvent obtains 5-methoxyl group-N-[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine is beige solid (10.5g, 100%); The NMR spectrum(CDCl ₃) 4.11 (s, 3H), 5.75 (s, 2H), 6.87 (d, 1H), 6.91 (d, 1H), 7.19 (m, 1H), 7.57-7.42 (m, 4H), 7.64 (t, 1H), 8.09 (s, 1H), 8.22 (m, 1H), 8.59 (m, 2H), 9.83 (br s, 1H); Mass spectrumMH ⁺383.

With 5-methoxyl group-N-[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] and quinazoline-4-amine (10.1g, 27.4mmol) and pyridine hydrochloride (15.8g, the 137mmol) heating 3 hours under refluxing of the mixture in pyridine (150ml).After the cooling, evaporating solvent grinds resistates in 5% sodium bicarbonate aqueous solution, and the gained mixture was stirred 30 minutes.Filter little yellow mercury oxide, water and ether washing are used P again under high vacuum ₂O ₅Drying obtains 4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-alcohol is solid (10.1g, 100%); The NMR spectrum5.76 (s, 2H), 6.67 (m, 2H), 6.96 (d, 1H), 7.29 (m, 1H), 7.42 (m, 1H), 7.52 (dd, 1H), 7.74-7.66 (m, 2H), 8.13 (s, 1H), 8.33 (s, 2H), 8.52 (d, 1H); Mass spectrumMH ⁺369.

With DTAD (11.48g, 49.9mmol) join 4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino quinazoline-5-alcohol (7.36g in batches, 20mmol), (S)-methyl lactate (2.29ml, 24mmol) and triphenyl phosphine (13.1g is 49.9mmol) in the ice-cold solution in DCM (200ml).This mixture was at room temperature stirred 1 hour.(2 * 50ml) extract with 2N hydrochloric acid with this mixture.Merge the hydrochloric acid layer, wash with DCM again.Under cooling by slowly add strong aqua with the pH regulator of this solution to pH 9.(2 * 100ml) extract this aqueous solution with DCM.Merge these DCM layers, MgSO is used in water and salt water washing again ₄Dry.After the evaporating solvent, with resistates by chromatography with silica gel (elutriant: the purifying of 4% methyl alcohol/DCM), obtain (2R)-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate is little yellow solid (7.35g, 80%); The NMR spectrum(CDCl ₃) 1.80 (d, 3H), 3.85 (s, 3H), 5.15 (q, 1H), 5.76 (s, 2H), 6.79 (d, 1H), 6.85 (d, 1H), 7.18 (m, 1H), 7.43 (d, 1H), 7.50 (d, 1H), 7.63-7.54 (m, 2H), 7.70 (dd, 1H), 8.11 (s, 1H), 8.38 (s, 1H), 8.59 (br d, 1H), 8.63 (s, 1H); Mass spectrumMH ⁺455.

Embodiment 6

(2R)-and N-methyl-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide

Use and embodiment 5 identical operations, with (2R)-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (250mg, 0.55mmol) react with methylamine, obtaining title compound is beige solid (213mg, 86%); The NMR spectrum1.65 (d, 3H), 2.67 (d, 3H), 5.16 (q, 1H), 5.77 (s, 2H), 6.96 (d, 1H), 7.00 (d, 1H), 7.29 (m, 1H), 7.36 (d, 1H), 7.72 (m, 4H), 8.17 (s, 1H), 8.38 (m, 1H), 8.53 (m, 3H), 10.68 (br s, 1H); Mass spectrumMH ⁺454.

Embodiment 7

(2R)-and N-ethyl-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide

Use and embodiment 5 identical operations, with (2R)-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (250mg, 0.55mmol) react with ethamine, obtaining title compound is beige solid (160mg, 62%), in addition, with the HPLC post (C18 of this thick material in preparation HPLC-MS system, 5 microns, diameter 19mm, long 100mm) goes up purifying, with containing the water of 2g/l volatile salt and the mixture wash-out (gradient) of acetonitrile. The NMR spectrum1.04 (t, 3H), 1.65 (d, 3H), 3.17 (m, 2H), 5.15 (q, 1H), 5.77 (s, 2H), 6.95 (d, 1H), 7.01 (d, 1H), 7.29 (m, 1H), 7.36 (d, 1H), 7.72 (m, 4H), 8.17 (s, 1H), 8.44 (br t, 1H), 8.53 (m, 3H), 10.70 (br s, 1H); Mass spectrumMH ⁺468.

Embodiment 8

5-[(1R)-1-methyl-2-oxo-2-tetramethyleneimine-1-base oxethyl]-N-[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine

Use and embodiment 5 identical operations, with (2R)-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (200mg, 0.44mmol) and tetramethyleneimine (0.22ml, 2.6mmol) reaction, obtaining title compound is beige solid (152mg, 70%), in addition, adds Molecular sieve is gone up purifying with this thick material at the HPLC post (C18,5 microns, diameter 19mm, long 100mm) of preparation HPLC-MS system, again with containing the water of 2g/l volatile salt and the mixture wash-out (gradient) of acetonitrile. The NMR spectrum1.60 (d, 3H), 1.81 (m, 2H), 1.94 (m, 2H), 3.47-3.30 (m, 3H), 3.77 (m, 1H), 5.62 (q, 1H), 5.77 (s, 2H), 6.95 (d, 1H), 7.28 (m, 2H), 7.35 (d, 1H), 7.74-7.68 (m, 3H), 7.82 (dd, 1H), 8.15 (s, 1H), 8.53 (m, 3H), 11.07 (br s, 1H); Mass spectrumMH ⁺494.

Embodiment 9

(2R)-and N-(2-hydroxyethyl)-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide

Use and embodiment 5 identical operations, with (2R)-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (250mg, 0.55mmol) and thanomin (0.332ml, 5.5mmol) reaction, obtaining title compound is white solid (164mg, 62%); The NMR spectrum1.64 (d, 3H), 3.21 (m, 2H), 3.43 (m, 2H), 4.75 (t, 1H), 5.22 (q, 1H), 5.77 (s, 2H), 6.95 (d, 1H), 7.01 (d, 1H), 7.29 (m, 1H), 7.36 (d, 1H), 7.72 (m, 4H), 8.16 (s, 1H), 8.48 (br t, 1H), 8.53 (m, 3H), 10.73 (br s, 1H); Mass spectrumMH ⁺484.

Embodiment 10

N, N-dimethyl-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] ethanamide

Use and embodiment 5 identical operations, will [(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl acetate (250mg, 0.55mmol) react with dimethylamine, obtaining title compound is white solid (183mg, 73%); The NMR spectrum2.97 (s, 3H), 3.04 (s, 3H), 5.17 (s, 2H), 5.77 (s, 2H), 6.96 (d, 1H), 7.22 (d, 1H), 7.29 (m, 1H), 7.36 (d, 1H), 7.76-7.69 (m, 3H), 7.91 (m, 1H), 8.15 (s, 1H), 8.53 (m, 2H), 8.57 (s, 1H), 11.21 (br s, 1H); Mass spectrumMH ⁺454.

[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino as initial substance } quinazoline-5-yl) the oxygen base] methyl acetate is prepared as follows:

With DTAD (2.51g, 10.9mmol) join 4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino quinazoline-5-alcohol (2g in batches, 5.43mmol), methyl glycolate (0.629ml, 8.15mmol) and triphenyl phosphine (2.86g is 10.9mmol) in the solution in DCM (50ml).This mixture was at room temperature stirred 2 hours.The vaporising under vacuum solvent.Resistates grinds with ethyl acetate.Filter the precipitation that generates, dry under vacuum with the ethyl acetate washing, obtain title compound, obtain [(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl acetate (1.4g, 59%); The NMR spectrum3.82 (s, 3H), 5.15 (s, 2H), 5.78 (s, 2H), 6.97 (d, 1H), 7.14 (d, 1H), 7.29 (m, 1H), 7.39 (d, 1H), 7.73 (m, 4H), 8.17 (s, 1H), 8.52 (m, 3H), 10.56 (br s, 1H); Mass spectrumMH ⁺441.

Embodiment 11

2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] ethanamide

Use and embodiment 5 identical operations, will [(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl acetate (250mg, 0.55mmol) and ammonia react, obtaining title compound is white solid (210mg, 90%); The NMR spectrum4.87 (s, 2H), 5.77 (s, 2H), 6.97 (m, 2H), 7.29 (m, 1H), 7.37 (d, 1H), 7.59 (br s, 1H), 7.76-7.66 (m, 3H), 7.84 (br s, 1H), 7.91 (m, 1H), 8.14 (s, 1H), 8.57-8.52 (m, 3H), 10.98 (br s, 1H); Mass spectrumMH ⁺426.

Embodiment 12

N-ethyl-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] ethanamide

Use and embodiment 5 identical operations, will [(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl acetate (250mg, 0.55mmol) react with ethamine, obtaining title compound is beige solid (140mg, 56%); The NMR spectrum1.09 (t, 3H), 3.23 (m, 2H), 4.87 (s, 2H), 5.77 (s, 2H), 6.97 (m, 2H), 7.29 (m, 1H), 7.37 (d, 1H), 7.76-7.69 (m, 3H), 7.83 (m, 1H), 8.16 (s, 1H), 8.38 (br t, 1H), 8.56-8.53 (m, 3H), 10.85 (br s, 1H); Mass spectrumMH ⁺454.

Embodiment 13

N-(2-hydroxyethyl)-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] ethanamide

Use and embodiment 5 identical operations, will [(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl acetate (250mg, 0.55mmol) and thanomin (0.333ml, 5.5mmol) reaction, obtaining title compound is white solid (220mg, 85%), in addition, this is reflected at carried out under 45 ℃ 2 days. The NMR spectrum3.30 (m, 2H), 3.49 (m, 2H), 4.79 (m, 1H), 4.89 (s, 2H), 5.77 (s, 2H), 6.96 (m, 2H), 7.29 (m, 1H), 7.37 (d, 1H), 7.77-7.69 (m, 3H), 7.84 (m, 1H), 8.16 (s, 1H), 8.42 (br t, 1H), 8.57-8.53 (m, 3H), 10.87 (br s, 1H); Mass spectrumMH ⁺470.

Embodiment 14

N-methyl-2-[(4-{[-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] ethanamide

Use and embodiment 5 identical operations, will [(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl acetate (250mg, 0.55mmol) react with methylamine, obtaining title compound is white solid (185mg, 76%), in addition, with resistates by chromatography with silica gel (elutriant: the purifying of 5% to 6% methyl alcohol/DCM). The NMR spectrum2.73 (d, 3H), 4.88 (s, 2H), 5.77 (s, 2H), 6.97 (m, 2H), 7.29 (m, 1H), 7.37 (d, 1H), 7.76-7.69 (m, 3H), 7.84 (m, 1H), 8.16 (s, 1H), 8.32 (m, 1H), 8.54 (m, 3H), 10.84 (br s, 1H); Mass spectrumMH ⁺440.

Embodiment 15

N-(2-hydroxyethyl)-N-methyl-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] ethanamide

Use and embodiment 5 identical operations, will [(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl acetate (200mg, 0.45mmol) and 2-(methylamino-) ethanol (0.219ml, 2.73mmol) reaction, obtaining title compound is white solid (130mg, 59%), in addition, this is reflected at carried out under 45 ℃ 18 hours. The NMR spectrum(2 rotational isomers, ratio 2/1) 2.97 and 3.08 (s, 3H), 3.62-3.43 (m, 4H), 4.73 and 4.99 (t, 1H), 5.16 and 5.23 (s, 2H), 5.77 (s, 2H), 6.96 (d, 1H), 7.37-7.18 (m, 3H), 7.75-7.69 (m, 3H), 7.90 (m, 1H), 8.15 (s, 1H), 8.53 (m, 2H), 8.57 (s, 1H), 11.20 and 11.21 (br s, 1H); Mass spectrumMH ⁺484.

Embodiment 16

5-(2-oxo-2-tetramethyleneimine-1-y1 oxyethyl group)-N-[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine

Use and embodiment 5 identical operations, will [(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl acetate (180mg, 0.41mmol) and tetramethyleneimine (0.205ml, 2.45mmol) reaction, obtaining title compound is light brown solid (160mg, 82%), in addition,

Under molecular sieve exists this is reflected at and carried out under 45 ℃ 18 hours. NMR Spectrum1.83 (m, 2H), 1.95 (m, 2H), 3.45 (t, 2H), 3.50 (t, 2H), 5.09 (s, 2H), 5.77 (s, 2H), 6.96 (d, 1H), 7.18 (d, 1H), 7.29 (m, 1H), 7.37 (d, 1H), 7.77-7.69 (m, 3H), 7.91 (m, 1H), 8.15 (s, 1H), 8.53 (s, 2H), 8.57 (s, 1H), 11.16 (br s, 1H); Mass spectrumMH ⁺480.

Embodiment 17

5-(2-morpholine-4-base-2-oxo oxyethyl group)-N-[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine

Use and embodiment 5 identical operations, will [(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl acetate (180mg, 0.40mmol) and morpholine (0.346ml, 3.96mmol) reaction, obtaining title compound is solid (115mg, 59%), in addition,

Under molecular sieve exists this is reflected at and carried out under 60 ℃ 32 hours. The NMR spectrum3.68-3.52 (m, 8H), 5.20 (s, 2H), 5.77 (s, 2H), 6.96 (d, 1H), 7.23 (d, 1H), 7.30 (m, 1H), 7.37 (d, 1H), 7.77-7.68 (m, 3H), 7.90 (m, 1H), 8.15 (s, 1H), 8.53 (s, 2H), 8.56 (s, 1H), 11.18 (br s, 1H); Mass spectrumMH ⁺496.

Embodiment 18

(2R)-and N, N-dimethyl-2-[(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide

With (2R)-N, N-dimethyl-2-[(4-oxo-3,4-dihydroquinazoline-5-yl) the oxygen base] propionic acid amide (200mg, 0.77mmol), triphenyl phosphine (603mg, 2.3mmol) and tetracol phenixin (2.2ml, 23mmol) 1, the mixture in the 2-ethylene dichloride (5ml) stirred 2 hours down at 45 ℃.Add 1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-amine (184mg, 0.8mmol), vaporising under vacuum solvent again.Add acetonitrile (5ml).This mixture was stirred 2 hours down at 75 ℃.After the cooling, the vaporising under vacuum solvent.Resistates is diluted in 6N methyl alcohol system ammonia solution, vaporising under vacuum solvent again.With resistates by chromatography with silica gel (elutriant: the purifying of 3% to 5% methyl alcohol/DCM), obtaining title compound is beige foam (215mg, 60%); The NMR spectrum(CDCl ₃) 1.73 (d, 3H), 3.06 (s, 3H), 3.14 (s, 3H), 5.43 (q, 1H), 5.80 (s, 2H), 6.81 (d, 1H), 6.93 (s, 1H), 7.48 (m, 2H), 7.60 (t, 1H), 7.84 (dd, 1H), 8.08 (s, 1H), 8.43 (s, 1H), 8.62 (s, 1H), 8.78 (s, 1H); Mass spectrum474.

According to the described operation of embodiment 3 initial substances, 1-(1,3-thiazoles-4-the ylmethyl)-1H-indazole-5-amine that is used as initial substance prepares from 5-nitro indazole and 4-(chloromethyl)-1,3-thiazoles hydrochloride:

5-nitro-1-(1,3-thiazoles-4-ylmethyl)-1H-indazole: productive rate: 1.31g, 55%; NMR Spectrum(CDCl ₃) 5.82 (s, 2H), 7.16 (s, 1H), 7.63 (d, 1H), 8.27 (m, 2H), 8.73 (s, 1H), 8.79 (s, 1H).

1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-amine: the beige solid, 505mg, 57%, in addition, carry out in the ethanol in the reaction. The NMR spectrum(CDCl ₃) 5.72 (s, 2H), 6.95-6.85 (m, 3H), 7.29 (d, 1H), 7.85 (s, 1H), 8.77 (s, 1H); Mass spectrumMH ⁺231.

Embodiment 19

(2R)-and 2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base]-N, N-dimethyl propylene acid amides

Use and embodiment 18 identical operations, with (2R)-N, N-dimethyl-2-[(4-oxo-3,4-dihydroquinazoline-5-yl) oxygen base] propionic acid amide (200mg, 0.77mmol) and 1-(3-luorobenzyl)-1H-indazole-5-amine (193mg, 0.8mmol) to obtain title compound be shallow white solid (272mg, 74%) in reaction; The NMR spectrum(CDCl ₃) 1.72 (d, 3H), 3.06 (s, 3H), 3.14 (s, 3H), 5.43 (q, 1H), 5.59 (s, 2H), 6.81 (d, 1H), 6.87 (d, 1H), 6.96 (m, 2H), 7.25 (m, 1H), 7.34 (d, 1H), 7.47 (d, 1H), 7.60 (t, 1H), 7.84 (dd, 1H), 8.07 (s, 1H), 8.42 (s, 1H), 8.62 (s, 1H); Mass spectrum485.

According to the described operation of embodiment 3 initial substances, 1-(3-the luorobenzyl)-1H-indazole-5-amine that is used as initial substance prepares from 5-nitro indazole and 3-luorobenzyl bromination thing:

1-(3-luorobenzyl)-5-nitro-1H-indazole: 1.31g, 55%, in addition, add potassiumiodide (1.05 equivalent); The NMR spectrum(CDCl ₃) 5.82 (s, 2H), 7.16 (s, 1H), 7.63 (d, 1H), 8.27 (m, 2H), 8.73 (s, 1H), 8.79 (s, 1H).

1-(3-luorobenzyl)-1H-indazole-5-amine: beige solid, 804mg, 95%; The NMR spectrum(CDCl ₃) 5.52 (s, 2H), 6.83 (m, 2H), 6.95 (m, 3H), 7.13 (d, 1H), 7.25 (m, 1H), 7.85 (s, 1H).

Embodiment 20

(2R)-and N, N-dimethyl-2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide

Use and embodiment 18 identical operations, with (2R)-N, N-dimethyl-2-[(4-oxo-3,4-dihydroquinazoline-5-yl) oxygen base] propionic acid amide (150mg, 0.57mmol) and 1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-amine (138mg, 0.6mmol) reaction, obtaining title compound is white solid (208mg, 77%); The NMR spectrum(CDCl ₃) 1.73 (d, 3H), 3.06 (s, 3H), 3.14 (s, 3H), 5.43 (q, 1H), 5.92 (s, 2H), 6.82 (d, 1H), 7.26 (m, 1H), 7.50 (d, 2H), 7.61 (t, 1H), 7.75 (d, 1H), 7.87 (dd, 1H), 8.11 (s, 1H), 8.45 (s, 1H), 8.62 (s, 1H); Matter Spectrum474.

According to the described operation of embodiment 3 initial substances, 1-(1,3-thiazoles-2-the ylmethyl)-1H-indazole-5-amine that is used as initial substance is from 5-nitro indazole and 2-(chloromethyl)-1, the 3-thiazole is (as DondoniA.et al, Tetrahedron, 1988, preparation described in 44,2021) prepare:

5-nitro-1-(1,3-thiazoles-2-ylmethyl)-1H-indazole: productive rate: 724mg, 65%; NMR Spectrum(CDCl ₃) 5.96 (s, 2H), 7.32 (d, 1H), 7.62 (d, 1H), 7.77 (d, 2H), 8.28 (m, 2H), 8.74 (s, 1H).

1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-amine: shallow white solid; 578mg, 90%; The NMR spectrum(CDCl ₃) 3.48 (m, 2H), 5.84 (s, 2H), 6.86 (dd, 1H), 6.94 (s, 1H), 7.29-7.23 (m, 2H), 7.73 (s, 1H), 7.88 (s, 1H).

Embodiment 21

(2R)-N, N-dimethyl-2-{[4-(1-[(2-methyl isophthalic acid, 3-thiazole-5-yl) methyl]-1H-indazole-5-yl } amino) quinazoline-5-yl] the oxygen base } propionic acid amide

Use and embodiment 18 identical operations, with (2R)-N, N-dimethyl-2-[(4-oxo-3,4-dihydroquinazoline-5-yl) oxygen base] propionic acid amide (261mg, 1mmol) with the 1-[(2-methyl isophthalic acid, 3-thiazole-5-yl) methyl]-1H-indazole-5-amine (269mg, 1.1mmol) reaction, obtaining title compound is white solid (300mg, 61%); The NMR spectrum(CDCl ₃) 1.73 (d, 3H), 2.62 (s, 3H), 3.07 (s, 3H), 3.15 (s, 3H), 5.43 (q, 1H), 5.71 (s, 2H), 6.82 (d, 1H), 7.43 (d, 1H), 7.49 (d, 1H), 7.61 (m, 2H), 7.86 (dd, 1H), 8.05 (s, 1H), 8.42 (s, 1H), 8.62 (s, 1H); Mass spectrum488.

According to the described operation of embodiment 3 initial substances, 1-[(2-methyl isophthalic acid as initial substance, 3-thiazole-5-yl) methyl]-1H-indazole-5-amine is from 5-nitro indazole and 5-(chloromethyl)-2-methyl isophthalic acid, the 3-thiazole is (as Mashraqi S.H.et al, J.Am.Chem.Soc., 1982,104, preparation described in 4461) preparation:

The 1-[(2-methyl isophthalic acid, 3-thiazole-5-yl) methyl]-5-nitro-1H-indazole: productive rate: 1.5g, 59%; The NMR spectrum(CDCl ₃) 2.64 (s, 3H), 5.76 (s, 2H), 7.50 (d, 1H), 7.62 (d, 1H), 8.25 (s, 1H), 8.29 (dd, 1H), 8.74 (s, 1H).

The 1-[(2-methyl isophthalic acid, 3-thiazole-5-yl) methyl]-1H-indazole-5-amine: shallow white solid, 1.2g, 93%; The NMR spectrum(CDCl ₃) 2.61 (s, 3H), 3.62 (m, 2H), 5.63 (s, 2H), 6.86 (dd, 1H), 6.93 (s, 1H), 7.23 (d, 1H), 7.54 (s, 1H), 7.82 (s, 1H).

Embodiment 22

(2R)-2-{[4-(1-[(6-fluorine pyridin-3-yl) methyl]-1H-indazole-5-yl } amino) quinazoline-5-yl] the oxygen base }-N, N-dimethyl propylene acid amides

Use and embodiment 18 identical operations, with (2R)-N, N-dimethyl-2-[(4-oxo-3,4-dihydroquinazoline-5-yl) oxygen base] propionic acid amide (200mg, 0.77mmol) and 1-[(6-fluorine pyridin-3-yl) methyl]-1H-indazole-5-amine (204mg, 0.84mmol) reaction, obtaining title compound is white solid (225mg, 60%); The NMR spectrum(CDCl ₃) 1.73 (d, 3H), 3.07 (s, 3H), 3.15 (s, 3H), 5.44 (q, 1H), 5.59 (s, 2H), 6.84 (m, 2H), 7.37 (d, 1H), 7.8-7.45 (m, 3H), 7.87 (dd, 1H), 8.07 (s, 1H), 8.21 (s, 1H), 8.44 (s, 1H), 8.62 (s, 1H); Mass spectrum486.

According to the described operation of embodiment 3 initial substances, 1-[(6-fluorine pyridin-3-yl as initial substance) methyl]-1H-indazole-5-amine is from 5-nitro indazole and 5-(chloromethyl)-2-fluorine pyridine (Pesti J.A.et al, J.Org.Chem., 2000,65,7718) prepare:

1-[(6-fluorine pyridin-3-yl) methyl]-5-nitro-1H-indazole: productive rate: 672mg, 54%; NMR Spectrum(CDCl ₃) 5.64 (s, 2H), 6.90 (dd, 1H), 7.45 (d, 1H), 7.67 (m, 1H), 8.22 (s, 1H), 8.28 (m, 2H), 8.76 (s, 1H).

1-[(6-fluorine pyridin-3-yl) methyl]-1H-indazole-5-amine: shallow white solid, 490mg, 93%; The NMR spectrum(CDCl ₃) 3.63 (m, 2H), 5.51 (s, 2H), 6.83 (m, 2H), 6.94 (s, 1H), 7.15 (d, 1H), 7.57 (m, 1H), 7.84 (s, 1H), 8.15 (s, 1H).

Embodiment 23

(2R)-and 2-[(4-{[1-(3-methoxy-benzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base]-N, N-dimethyl propylene acid amides

Use and embodiment 18 identical operations, with (2R)-N, N-dimethyl-2-[(4-oxo-3,4-dihydroquinazoline-5-yl) oxygen base] propionic acid amide (220mg, 0.84mmol) and 1-(3-methoxy-benzyl)-1H-indazole-5-amine (1.1 equivalent) reaction, obtaining title compound is beige foam (242mg, 58%); The NMR spectrum(CDCl ₃) 1.72 (d, 3H), 3.05 (s, 3H), 3.14 (s, 3H), 3.73 (s, 3H), 5.42 (q, 1H), 5.57 (s, 2H), 6.74 (s, 1H), 6.78-6.81 (m, 3H), 7.20 (t, 1H), 7.36 (d, 1H), 7.46 (d, 1H), 7.59 (t, 1H), 7.80 (d, 1H), 8.06 (s, 1H), 8.40 (s, 1H), 8.61 (s, 1H), 10.85 (br s, 1H); Mass spectrumMH ⁺497.

According to the described operation of embodiment 3 initial substances, 1-(3-the methoxy-benzyl)-1H-indazole-5-amine that is used as initial substance prepares from 5-nitro indazole and 3-methoxy-benzyl muriate:

1-(3-methoxy-benzyl)-5-nitro-1H-indazole: productive rate: 2.22g, 43%; The NMR spectrum(CDCl ₃) 3.74 (s, 3H), 5.61 (s, 2H), 6.73 (s, 1H), 6.78 (d, 1H), 6.83 (d, 1H), 7.23 (d, 1H), 7.39 (d, 1H), 8.22 (d, 1H), 8.25 (s, 1H), 8.73 (s, 1H); Mass spectrumMH ⁺284.

1-(3-methoxy-benzyl)-1H-indazole-5-amino: productive rate: 364mg, 94%; The NMR spectrum(CDCl ₃) 3.72 (s, 3H), 5.50 (s, 2H), 6.70 (s, 1H), 6.76-6.82 (m, 3H), 6.93 (s, 1H), 7.15 (d, 1H), 7.19 (t, 1H), 7.83 (s, 1H); Mass spectrumMH ⁺254.

Embodiment 24

(2R)-and 2-[(4-{[1-(2-cyano group benzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base]-N, N-dimethyl propylene acid amides

Use and embodiment 18 identical operations, with (2R)-N, N-dimethyl-2-[(4-oxo-3,4-dihydroquinazoline-5-yl) oxygen base] propionic acid amide (220mg, 0.84mmol) and 2-[(5-amino-1H-indazole-1-yl) methyl] benzonitrile (1.1 equivalent) reaction, obtaining title compound is beige foam (334mg, 81%); The NMR spectrum(CDCl ₃) 1.72 (d, 3H), 3.06 (s, 3H), 3.14 (s, 3H), 5.43 (q, 1H), 5.83 (s, 2H), 6.81 (d, 1H), 7.01 (d, 1H), 7.37 (t, 1H), 7.42-7.47 (m, 3H), 7.60 (t, 1H), 7.70 (d, 1H), 7.86 (d, 1H), 8.10 (s, 1H), 8.47 (s, 1H), 8.62 (s, 1H), 10.92 (br s, 1H); Mass spectrumMH ⁺492.

According to the described operation of embodiment 3 initial substances, as the 2-[(5-amino-1H-indazole-1-yl of initial substance) methyl] benzonitrile is from 5-nitro indazole and the preparation of 2-brooethyl benzonitrile:

2-[(5-nitro-1H-indazole-1-yl) methyl] benzonitrile: productive rate: 3.12g, 61%; The NMR spectrum(CDCl ₃) 5.95 (s, 2H), 7.20 (d, 1H), 7.53 (t, 1H), 7.65 (t, 1H), 7.90 (d, 1H), 8.01 (d, 1H), 8.29 (d, 1H), 8.48 (s, 1H), 8.87 (s, 1H); Mass spectrumMH ⁺277.

2-[(5-amino-1H-indazole-1-yl) methyl] benzonitrile: productive rate: 212mg, 68%; The NMR spectrum(CDCl ₃) 5.74 (s, 2H), 6.86 (d, 1H), 6.95 (s, 1H), 7.01 (d, 1H), 7.23 (d, 1H), 7.35 (t, 1H), 7.44 (t, 1H), 7.68 (d, 1H), 7.87 (s, 1H); Mass spectrumMH ⁺249.

Embodiment 25

(2R)-and N, N-dimethyl-2-[(4-{[1-(1,3-oxazole-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide

Use and embodiment 18 identical operations, with (2R)-N, N-dimethyl-2-[(4-oxo-3,4-dihydroquinazoline-5-yl) oxygen base] propionic acid amide (212mg, 0.81mmol) and 1-(1,3-oxazole-2-ylmethyl)-and 1H-indazole-5-amine (1 equivalent) reaction, obtaining title compound is beige foam (295mg, 80%); The NMR spectrum(CDCl ₃) 1.73 (d, 3H), 3.06 (s, 3H), 3.14 (s, 3H), 5.43 (q, 1H), 5.71 (s, 2H), 6.81 (d, 1H), 7.09 (s, 1H), 7.48-7.53 (m, 2H), 7.58-7.62 (m, 2H), 7.88 (d, 1H), 8.07 (s, 1H), 8.41 (s, 1H), 8.61 (s, 1H), 10.92 (br s, 1H); Mass spectrumMH ⁺458.

1-(1,3-oxazole-2-ylmethyl)-1H-indazole-5-amine as initial substance is prepared as follows:

(in ethane, (10.5g is 152mmol) in the solution in THF (200ml) 167mmol) to drip oxazole for 66.8ml, 2.5N with n-BuLi under-70 ℃.After at room temperature 2 hours, this mixture is cooled to-60 ℃, drip again DMF (12.8ml, 167mmol).After 1 night at room temperature, with this mixture hydrolysis, use dichloromethane extraction again with cold 1N hydrochloric acid.(5 arrive 10%Et to resistates with silica gel ₂O/CH ₂Cl ₂) purifying, obtain yellow oil (4.57g), with its dissolving methyl alcohol (100ml).In this solution, adding NaBH under 0 ℃ in batches ₄(3.16g 83mmol), at room temperature spends the night this mixture stirring.Add salt solution, regulate pH to 7 with HCl 6N again.After the filtration, with EtOAc extraction, evaporation organic layer, (3 arrive 5%MeOH/CH to resistates with silica gel ₂Cl ₂) purifying, obtaining 1,3-oxazole-2-base methyl alcohol is water white oil (2.95g); The NMR spectrum(CDCl ₃) 4.75 (s, 2H), 7.10 (s, 1H), 7.64 (s, 1H).

With 1,3-oxazole-2-base methyl alcohol (2.68g, 27mmol) and triphenyl phosphine (10.6g 40.6mmol) is dissolved in CCl ₄(44ml) and in the benzene (50ml), this mixture was refluxed 6 hours, cooling is filtered, evaporation again.Resistates obtains 2-(chloromethyl)-1 with silica gel (50%Et2O/ sherwood oil) purifying, and the 3-oxazole is water white oil (1.5g); The NMR spectrum(CDCl ₃) 4.63 (s, 2H), 7.13 (s, 1H), 7.68 (s, 1H).

At room temperature with the 5-nitro indazole (500mg, 3.07mmol), (889mg, 6.44mmol) and 2-(chloromethyl)-1, (396mg, 3.37mmol) mixture in DMF (3ml) stirred 3 hours the 3-oxazole salt of wormwood.Add saturated NH ₄Cl is again with this mixture dichloromethane extraction.After the evaporation, resistates with silica gel (30 to 35%EtOAc/ sherwood oil) purifying, is obtained 5-nitro-1-(1,3-oxazole-2-ylmethyl)-1H-indazole (474mg, 63%); The NMR spectrum(CDCl ₃) 5.76 (s, 2H), 7.11 (s, 1H), 7.60 (d, 1H), 7.62 (s, 1H) 8.26 (s, 1H), 8.31 (d, 1H), 8.74 (s, 1H).

With dense HCl (2.5ml) join 5-nitro-1-(1,3-oxazole-2-ylmethyl)-1H-indazole (456mg, 1.87mmol) and SnCl ₂(1.42g 7.47mmol) in the solution in ethanol (10ml), heats this mixture 4 hours down at 50 ℃ again.With this mixture cooling, be neutralized to pH 8 with 2N sodium hydroxide, use ethyl acetate extraction again.Resistates with silica gel (EtOAc) purifying, is obtained 1-(1,3-oxazole-2-ylmethyl)-1H-indazole-5-amine (182mg, 46%); The NMR spectrum(CDCl ₃) 5.55 (s, 2H), 6.79 (d, 1H), 6.86 (s, 1H), 7.00 (s, 1H), 7.24 (d, 1H), 7.50 (s, 1H), 7.77 (s, 1H); Mass spectrumMH ⁺215.

Embodiment 26

(2S)-and 2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base]-N, N-dimethyl propylene acid amides

With (2S)-2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] (200mg, 0.42mmol) solution stirring in 6N methyl alcohol system dimethylamine (10ml) is 18 hours for methyl propionate.After the evaporating solvent, with resistates by chromatography with silica gel (elutriant: 2% ethanol/methylene) purifying, obtaining title compound is beige solid (115mg, 56%); NMR Spectrum1.59 (d, 3H), 2.94 (s, 3H), 3.15 (s, 3H), 5.71 (s, 2H), 5.86 (q, 1H), 7.07 (m, 3H), 7.30 (d, 1H), 7.36 (m, 2H), 7.74 (m, 2H), 7.84 (m, 1H), 8.17 (s, 1H), 8.51 (s, 1H), 8.55 (s, 1H); Mass spectrum485.

As (2S)-2-[(4-{[1-(3-the luorobenzyl)-1H-indazole-5-yl of initial substance] amino } quinazoline-5-yl) the oxygen base] methyl propionate is prepared as follows:

With 4-chloro-5-fluquinconazole quinoline (1.82g, 10mmol), 1-(3-luorobenzyl)-1H-indazole-5-amine (2.41g, 10mmol is as acquisition as described in the WO 98/02438) and diisopropylethylamine (1.74ml, 10mmol) mixture in Virahol (20ml) is 80 ℃ of heating 45 minutes down.Be cooled to envrionment temperature, leach product, with Virahol and ether washing.Precipitated solid is dry under high vacuum, obtain 5-fluoro-N-[1-(3-luorobenzyl)-1H-indazole-5-yl] quinazoline-4-amine (3.2g, 83%); NMR Spectrum(CDCl ₃) 5.61 (s, 2H), 6.88 (d, 1H), 6.98 (m, 2H), 7.25 (m, 2H), 7.37 (d, 1H), 7.53 (dd, 1H), 7.73 (m, 2H), 8.09 (s, 1H), 8.19 (s, 1H), 8.49 (d, 1H), 8.69 (s, 1H); Mass spectrumMH ⁺388.

5-fluoro-N-[1-(3-luorobenzyl)-1H-indazole-5-yl] quinazoline-4-amine (2.4g, 6.48mmol) react as embodiment 5 initial substances, in addition, use (R)-methyl lactate and need not (S)-methyl lactate, obtain (2S)-2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate:

N-[1-(3-luorobenzyl)-1H-indazole-5-yl]-5-methoxyl group-quinazoline-4-amine: beige solid, productive rate: 2.4g, 97%; The NMR spectrum(CDCl ₃) 4.11 (s, 3H), 5.59 (s, 2H), 7.00-6.85 (m, 4H), 7.27 (m, 1H), 7.34 (d, 1H), 7.48 (d, 1H), 7.53 (d, 1H), 7.65 (t, 1H), 8.06 (s, 1H), 8.19 (s, 1H), 8.61 (s, 1H), 9.82 (br s, 1H); Mass spectrum400.

4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-alcohol: solid, productive rate: 2.8g, 100%; Mass spectrum386.

(2S)-and 2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate: productive rate: 875mg, 60%; Mass spectrum472.

Embodiment 27

N-[1-(3-luorobenzyl)-1H-indazole-5-yl]-5-[(1S)-1-methyl-2-oxo-2-tetramethyleneimine-1-base oxethyl]-quinazoline-4-amine

Use and embodiment 26 identical operations, with (2S)-2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (200mg, 0.42mmol) and tetramethyleneimine (0.35ml, 4.2mmol) reaction, obtaining title compound is solid (135mg, 62%), in addition, with this mixture 55 ℃ of down heating 20 hours, again by chromatography with silica gel (elutriant: the purifying of 3% methyl alcohol/DCM); The NMR spectrum1.60 (d, 3H), 1.82 (m, 2H), 1.94 (m, 2H), 3.5-3.3 (m, 3H), 3.76 (m, 1H), 5.62 (q, 1H), 5.70 (s, 2H), 7.07 (m, 3H), 7.27 (d, 1H), 7.36 (m, 2H), 7.74 (m, 2H), 7.85 (m, 1H), 8.16 (s, 1H), 8.51 (s, 1H), 8.56 (s, 1H), 11.07 (br s, 1H); Mass spectrum511.

Embodiment 28

(2S)-and 2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide

Use and embodiment 5 identical operations, with (2S)-2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (200mg, 0.42mmol) and ammonia react, obtaining title compound is solid (150mg, 77%); The NMR spectrum1.66 (d, 3H), 5.14 (q, 1H), 5.70 (s, 2H), 7.12-7.01 (m, 4H), 7.36 (m, 2H), 7.54 (s, 1H), 7.75 (m, 3H), 7.89 (s, 1H), 8.16 (s, 1H), 8.52 (s, 2H), 10.80 (s, 1H); Mass spectrum457.

Embodiment 29

N-[1-(3-luorobenzyl)-1H-indazole-5-yl]-5-[(1R)-1-methyl-2-oxo-2-tetramethyleneimine-1-base oxethyl]-quinazoline-4-amine

Use and embodiment 26 identical operations, with (2R)-2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (250mg, 0.53mmol) and tetramethyleneimine (0.44ml, 5.3mmol) reaction, obtaining title compound is white solid (210mg, 77%), in addition, with this mixture 55 ℃ of down heating 20 hours, again by chromatography with silica gel (elutriant: the purifying of 3% methyl alcohol/DCM); The NMR spectrum1.60 (d, 3H), 1.82 (m, 2H), 1.94 (m, 2H), 3.5-3.3 (m, 3H), 3.76 (m, 1H), 5.62 (q, 1H), 5.70 (s, 2H), 7.07 (m, 3H), 7.27 (d, 1H), 7.36 (m, 2H), 7.74 (m, 2H), 7.85 (m, 1H), 8.16 (s, 1H), 8.51 (s, 1H), 8.56 (s, 1H), 11.08 (br s, 1H); Mass spectrum511.

(2R)-2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl as initial substance] amino } quinazoline-5-yl) the oxygen base] the following acquisition of methyl propionate:

As described in embodiment 5 initial substances, with 4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino quinazoline-5-alcohol with (S)-the methyl lactate reaction, obtain (2R)-2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (760mg, 69%); Mass spectrum472.

Embodiment 30

(2R)-and 2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide

Use and embodiment 5 identical operations, with (2R)-2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (250mg, 0.53mmol) and ammonia react, obtaining title compound is shallow white solid (220mg, 91%); The NMR spectrum1.66 (d, 3H), 5.14 (q, 1H), 5.70 (s, 2H), 7.12-7.01 (m, 4H), 7.36 (m, 2H), 7.54 (s, 1H), 7.75 (m, 3H), 7.90 (s, 1H), 8.16 (s, 1H), 8.52 (s, 2H), 10.80 (s, 1H); Mass spectrum457.

Embodiment 31

5-[(1S)-1-methyl-2-oxo-2-tetramethyleneimine-1-base oxethyl]-N-[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine

Use and embodiment 26 identical operations, with (2S)-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (250mg, 0.55mmol) and tetramethyleneimine (0.46ml, 5.5mmol) reaction, obtaining title compound is beige solid (140mg, 50%), in addition, with this mixture 55 ℃ of down heating 20 hours, again by chromatography with silica gel (elutriant: the purifying of 4% methyl alcohol/DCM); The NMR spectrum1.60 (d, 3H), 1.82 (m, 2H), 1.94 (m, 2H), 3.49-3.30 (m, 3H), 3.76 (m, 1H), 5.62 (q, 1H), 5.77 (s, 2H), 6.95 (d, 1H), 7.28 (m, 2H), 7.35 (d, 1H), 7.74-7.68 (m, 3H), 7.82 (dd, 1H), 8.15 (s, 1H), 8.53 (m, 3H), 11.08 (br s, 1H); Mass spectrumMH ⁺494.

Use embodiment 5 initial substance identical operations, as (2S)-2-[(4-{[1-(pyridine-2-the ylmethyl)-1H-indazole-5-yl of initial substance] amino } quinazoline-5-yl) the oxygen base] methyl propionate is from 4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-alcohol (1.2g, 3.3mmol) and (R)-methyl lactate (0.37ml 3.9mmol) prepares:

(2S)-and 2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate: white solid, productive rate: 870mg, 59%, The NMR spectrum(CDCl ₃) 1.80 (d, 3H), 3.86 (s, 3H), 5.15 (q, 1H), 5.76 (s, 2H), 6.80 (d, 1H), 6.85 (d, 1H), 7.18 (m, 1H), 7.43 (d, 1H), 7.50 (d, 1H), 7.63-7.54 (m, 2H), 7.70 (dd, 1H), 8.11 (s, 1H), 8.38 (s, 1H), 8.59 (br d, 1H), 8.63 (s, 1H); Mass spectrumMH ⁺455.

Embodiment 32

(2S)-and 2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide

Use and embodiment 5 identical operations, with (2S)-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (250mg, 0.55mmol) and ammonia react, obtaining title compound is shallow white solid (210mg, 84%); The NMR spectrum1.67 (d, 3H), 5.14 (q, 1H), 5.77 (s, 2H), 6.94 (d, 1H), 7.02 (d, 1H), 7.30 (m, 1H), 7.36 (d, 1H), 7.55 (br s, 1H), 7.76-7.67 (m, 4H), 7.90 (br s, 1H), 8.15 (s, 1H), 8.52 (m, 3H), 10.80 (br s, 1H); Mass spectrumMH ⁺440.

Embodiment 33

5-[(1S)-1-methyl-2-oxo-2-tetramethyleneimine-1-base oxethyl]-N-[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine

Use and embodiment 26 identical operations, with (2S)-2-[(4-{[1-(1,3-thiazol-2-yl methyl)-and 1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (250mg, 0.54mmol) (0.45ml 5.4mmol) reacts, and obtains title compound (189mg with tetramethyleneimine, 70%) is solid, in addition, with this mixture 55 ℃ of down heating 20 hours, again by chromatography with silica gel (elutriant: the purifying of 1-5% methyl alcohol/DCM); The NMR spectrum1.61 (d, 3H), 1.82 (m, 2H), 1.94 (m, 2H), 3.47-3.30 (m, 3H), 3.77 (m, 1H), 5.63 (q, 1H), 6.04 (s, 2H), 7.27 (d, 1H), 7.35 (d, 1H), 7.65 (d, 1H), 7.74 (m, 3H), 7.88 (dd, 1H), 8.20 (s, 1H), 8.52 (s, 1H), 8.56 (s, 1H), 11.09 (br s, 1H); Mass spectrum500.

Use the described operation of embodiment 26 initial substances, (2S)-2-[(4-{[1-(1 as initial substance, 3-thiazol-2-yl methyl)-and 1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate is from 1-(1,3-thiazol-2-yl methyl)-1H-indazole-5-amine, 4-chloro-5-fluquinconazole quinoline and (R)-methyl lactate preparation:

5-fluoro-N-[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine: beige solid, productive rate: 3.6g, 77%; The NMR spectrum(CDCl ₃) 5.93 (s, 2H), 7.29-7.21 (m, 2H), 7.55 (m, 2H), 7.74 (m, 3H), 8.12 (s, 1H), 8.23 (s, 1H), 8.48 (br d, 1H), 8.69 (s, 1H); Mass spectrum377.

5-methoxyl group-N-[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine: beige solid, productive rate: 3.7g, 100%; Mass spectrum389.

4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-alcohol: solid, productive rate: 3.4g, 98%; The NMR spectrum(DMSOd ₆And CF ₃CO ₂D) 6.10 (s, 2H), 7.24 (m, 2H), 7.65 (m, 2H), 7.78 (m, 1H), 7.88 (m, 2H), 8.14 (m, 1H), 8.27 (s, 1H), 8.80 (m, 1H); Mass spectrum375.

(2S)-and 2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate: white solid, productive rate: 1.6g, 77%, use (R)-methyl lactate; NMR Spectrum1.72 (d, 3H), 3.80 (s, 3H), 5.54 (q, 1H), 6.05 (s, 2H), 7.18 (d, 1H), 7.38 (d, 1H), 7.80-7.66 (m, 5H), 8.21 (s, 1H), 8.48 (s, 1H), 8.54 (s, 1H), 10.53 (brs, 1H); Mass spectrum461.

Embodiment 34

(2S)-and N, N-dimethyl-2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide

Use and embodiment 26 identical operations, with (2S)-2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] (250mg is 0.54mmol) with the dimethylamine reaction for methyl propionate, obtaining title compound is white solid (195mg, 76%); The NMR spectrum1.59 (d, 3H), 2.93 (s, 3H), 3.14 (s, 3H), 5.85 (q, 1H), 6.04 (s, 2H), 7.30 (d, 1H), 7.35 (d, 1H), 7.65 (d, 1H), 7.74 (m, 3H), 7.87 (dd, 1H), 8.20 (s, 1H), 8.51 (s, 1H), 8.55 (s, 1H), 11.15 (br s, 1H); Mass spectrum474.

Embodiment 35

(2S)-and 2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide

Use and embodiment 5 identical operations, with (2S)-2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (250mg, 0.54mmol) and ammonia react, obtaining title compound is white solid (216mg, 89%); The NMR spectrum1.67 (d, 3H), 5.14 (q, 1H), 6.04 (s, 2H), 7.02 (d, 1H), 7.36 (d, 1H), 7.56 (br s, 1H), 7.66 (d, 1H), 7.83-7.72 (m, 4H), 7.90 (br s, 1H), 8.19 (s, 1H), 8.53 (s, 2H), 10.82 (br s, 1H); Mass spectrum446.

Embodiment 36

5-[(1R)-1-methyl-2-oxo-2-tetramethyleneimine-1-base oxethyl]-N-[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine

Use and embodiment 26 identical operations, with (2R)-2-[(4-{[1-(1,3-thiazol-2-yl methyl)-and 1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (250mg, 0.54mmol) (0.45ml 5.4mmol) reacts, and obtains title compound (160mg with tetramethyleneimine, 59%) is solid, in addition, with this mixture 55 ℃ of down heating 20 hours, again by chromatography with silica gel (elutriant: the purifying of 1-5% methyl alcohol/DCM); The NMR spectrum1.61 (d, 3H), 1.82 (m, 2H), 1.94 (m, 2H), 3.47-3.30 (m, 3H), 3.77 (m, 1H), 5.63 (q, 1H), 6.04 (s, 2H), 7.27 (d, 1H), 7.35 (d, 1H), 7.65 (d, 1H), 7.74 (m, 3H), 7.88 (dd, 1H), 8.20 (s, 1H), 8.52 (s, 1H), 8.56 (s, 1H), 11.09 (br s, 1H); Mass spectrum500.

Use the described operation of embodiment 26 initial substances, (2R)-2-[(4-{[1-(1 as initial substance, 3-thiazol-2-yl methyl)-and 1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate is from 4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } pure and mild (the S)-methyl lactate preparation of quinazoline-5-:

(2R)-and 2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate: white solid, productive rate: 1.4g, 76%; The NMR spectrum1.72 (d, 3H), 3.80 (s, 3H), 5.54 (q, 1H), 6.05 (s, 2H), 7.18 (d, 1H), 7.38 (d, 1H), 7.80-7.66 (m, 5H), 8.21 (s, 1H), 8.48 (s, 1H), 8.54 (s, 1H), 10.53 (br s, 1H); Mass spectrum461.

Embodiment 37

(2R)-and 2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide

Use and embodiment 5 identical operations, with (2R)-2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (250mg, 0.54mmol) and ammonia react, obtaining title compound is white solid (212mg, 88%); The NMR spectrum1.67 (d, 3H), 5.14 (q, 1H), 6.04 (s, 2H), 7.02 (d, 1H), 7.36 (d, 1H), 7.56 (br s, 1H), 7.66 (d, 1H), 7.83-7.72 (m, 4H), 7.90 (br s, 1H), 8.19 (s, 1H), 8.53 (s, 2H), 10.82 (br s, 1H); Mass spectrum446.

Embodiment 38

(2R)-and 2-[(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide

Use and embodiment 5 identical operations, with (2R)-2-[(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (200mg, 0.43mmol) and ammonia react, obtaining title compound is white solid (170mg, 88%); The NMR spectrum1.67 (d, 3H), 5.14 (q, 1H), 5.79 (s, 2H), 7.02 (d, 1H), 7.36 (d, 1H), 7.50 (s, 1H), 7.56 (br s, 1H), 7.79-7.72 (m, 3H), 7.90 (br s, 1H), 8.10 (s, 1H), 8.51 (m, 2H), 9.04 (s, 1H), 10.80 (br s, 1H); Mass spectrumMH ⁺446.

Use the described operation of embodiment 26 initial substances, (2R)-2-[(4-{[1-(1 as initial substance, 3-thiazole-4-ylmethyl)-and 1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate is from 1-(1,3-thiazole-4-ylmethyl)-1H-indazole-5-amine, 4-chloro-5-fluquinconazole quinoline and (S)-methyl lactate preparation:

5-fluoro-N-[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine (solid): productive rate: 13g, 90%; Mass spectrumMH ⁺377.

5-methoxyl group-N-[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine (beige solid): productive rate: 13.4g, 100%; Mass spectrumMH ⁺389.

4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-alcohol (solid): productive rate: 12.5g, 100%; Mass spectrumMH ⁺375.

(2R)-and 2-[(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (white solid): productive rate: 2.6g, 70%, use (S)-methyl lactate; NMR Spectrum(CDCl ₃) 1.80 (d, 3H), 3.86 (s, 3H), 5.16 (q, 1H), 5.80 (s, 2H), 6.80 (d, 1H), 6.97 (s, 1H), 7.52 (m, 2H), 7.62 (t, 1H), 7.73 (m, 1H), 8.08 (s, 1H), 8.36 (s, 1H), 8.63 (s, 1H), 8.79 (s, 1H); Mass spectrumMH ⁺461.

Embodiment 39

(2R)-and N-methyl-2-[(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide

Use and embodiment 5 identical operations, with (2R)-2-[(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] (200mg is 0.43mmol) with the methylamine reaction for methyl propionate, obtaining title compound is white solid (156mg, 78%); The NMR spectrum1.65 (d, 3H), 2.68 (d, 3H), 5.16 (q, 1H), 5.80 (s, 2H), 7.00 (d, 1H), 7.36 (d, 1H), 7.51 (s, 1H), 7.79-7.71 (m, 3H), 8.12 (s, 1H), 8.39 (m, 1H), 8.52 (m, 2H), 9.05 (s, 1H), 10.68 (br s, 1H); Mass spectrumMH ⁺460.

Embodiment 40

(2R)-and N-ethyl-2-[(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide

Use and embodiment 5 identical operations, with (2R)-2-[(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] (200mg is 0.43mmol) with the ethamine reaction for methyl propionate, obtaining title compound is white solid (188mg, 91%); The NMR spectrum1.04 (t, 3H), 1.65 (d, 3H), 3.17 (m, 2H), 5.15 (q, 1H), 5.80 (s, 2H), 7.01 (d, 1H), 7.36 (d, 1H), 7.51 (s, 1H), 7.79-7.72 (m, 3H), 8.12 (s, 1H), 8.44 (m, 1H), 8.53 (m, 2H), 9.04 (s, 1H), 10.69 (br s, 1H); Mass spectrumMH ⁺474.

Embodiment 41

5-[(1R)-1-methyl-2-oxo-2-tetramethyleneimine-1-base oxethyl]-N-[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine

Use and embodiment 26 identical operations, with (2R)-2-[(4-{[1-(1,3-thiazole-4-ylmethyl)-and 1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (200mg, 0.43mmol) (obtaining title compound is solid (130mg for 0.36ml, 4.3mmol) reaction with tetramethyleneimine, 60%), in addition, with this mixture 45 ℃ of down heating 20 hours, again by chromatography with silica gel (elutriant: the purifying of 3% methyl alcohol/DCM). The NMR spectrum1.60 (d, 3H), 1.81 (m, 2H), 1.94 (m, 2H), 3.47-3.38 (m, 3H), 3.77 (m, 1H), 5.62 (q, 1H), 5.79 (s, 2H), 7.26 (d, 1H), 7.35 (d, 1H), 7.51 (s, 1H), 7.77-7.71 (m, 2H), 7.83 (m, 1H), 8.11 (s, 1H), 8.53 (m, 2H), 9.04 (s, 1H), 11.07 (br s, 1H); Mass spectrumMH ⁺500.

Embodiment 42

(2R)-and N-(2-hydroxyethyl)-N-methyl-2-[(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide

Use and embodiment 26 identical operations, with (2R)-2-[(4-{[-(1,3-thiazole-4-ylmethyl)-and 1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (200mg, 0.43mmol) (obtaining title compound is solid (160mg for 0.35ml, 4.3mmol) reaction with 2-(methylamino-) ethanol, 73%), in addition, with this mixture 45 ℃ of down heating 20 hours, again by chromatography with silica gel (elutriant: the purifying of 3% methyl alcohol/DCM). The NMR spectrum(2 rotational isomers) 1.60 (m, 3H), 3.18 and 2.93 (s, 3H), 3.65-3.40 (m, 4H), 5.00 and 4.73 (t, 1H), 5.79 (s, 2H), 5.90 and 5.81 (q, 1H), 7.35-7.30 (m, 2H), 7.51 (s, 1H), 7.85-7.70 (m, 3H), 8.11 (s, 1H), 8.51 (m, 2H), 9.04 (s, 1H), 11.09 (br s, 1H); Mass spectrumMH ⁺504.

Embodiment 43

(2R)-and N-(2-hydroxyethyl)-2-[(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide

Use and embodiment 26 identical operations, with (2R)-2-[(4-{[1-(1,3-thiazole-4-ylmethyl)-and 1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (200mg, 0.43mmol) and thanomin (0.26ml, 4.3mmol) reaction, obtaining title compound is solid (170mg, 80%), in addition, this mixture was heated 20 hours down at 45 ℃. The NMR spectrum1.65 (d, 3H), 3.22 (m, 2H), 3.43 (m, 2H), 4.75 (t, 1H), 5.23 (q, 1H), 5.79 (s, 2H), 7.02 (d, 1H), 7.36 (d, 1H), 7.51 (s, 1H), 7.79-7.72 (m, 3H), 8.11 (s, 1H), 8.48 (m, 1H), 8.51 (s, 2H), 9.04 (s, 1H), 10.72 (br s, 1H); Mass spectrumMH ⁺490.

Embodiment 44

5-[(1R)-1-methyl-2-morpholine-4-base-2-oxo oxyethyl group]-N-[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine

With (2R)-2-[(4-{[1-(1,3-thiazole-4-ylmethyl)-and 1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid (250mg, 0.56mmol), 2 hydroxy pyrimidine-N-oxide compound (124mg, 1.1mmol), morpholine (0.098ml, 1.1mmol), diisopropylethylamine (0.195ml, 1.1mmol) and EDCI (214mg, 1.1mmol) mixture in DMF (2ml) at room temperature stirred 18 hours.Add other coupling reagent (1 equivalent), stir this mixture more than 2 hours again.This reaction mixture is directly injected HPLC post (C18,5 microns, the diameter 20mm of preparation HPLC-MS system, long 100mm) in, with the mixture wash-out (gradient) of water that contains the 2g/l volatile salt and acetonitrile, obtaining title compound is white solid (180mg, 62%); NMR spectrum 1.58 (d, 3H), 3.70-3.40 (m, 8H), 5.79 (s, 2H), 5.88 (q, 1H), 7.29 (d, 1H), 7.35 (s, 1H), 7.51 (s, 1H), 7.75 (m, 2H), 7.84 (m, 1H), 8.10 (s, 1H), 8.51 (s, 2H), 9.04 (s, 1H), 11.12 (br s, 1H); Mass spectrum: MH ⁺516.

As (2R)-2-[(4-{[1-(1,3-thiazoles-4-the ylmethyl)-1H-indazole-5-yl of initial substance] amino } quinazoline-5-yl) the oxygen base] propionic acid is prepared as follows:

With aqueous sodium hydroxide solution (2N, 1ml, 2mmol) join (2R)-2-[(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] (480mg is 1mmol) in the solution in THF (3ml) and methyl alcohol (3ml) for methyl propionate.This mixture was at room temperature stirred 2 hours.After the evaporating solvent, by adding the pH regulator to 3 of 2N hydrochloric acid with this mixture.Filter the precipitation that forms, wash with water, dry under high vacuum again, obtain (2R)-2-[(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid (435mg, 97%); Mass spectrumMH ⁺447.

Embodiment 45

(2S)-and N, N-dimethyl-2-[(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide

Use and embodiment 5 identical operations, with (2S)-2-[(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] (200mg is 0.43mmol) with the dimethylamine reaction for methyl propionate, obtaining title compound is solid (120mg, 58%); The NMR spectrum1.59 (d, 3H), 2.93 (s, 3H), 3.14 (s, 3H), 5.79 (s, 2H), 5.85 (q, 1H), 7.29 (d, 1H), 7.34 (d, 1H), 7.51 (s, 1H), 7.77-7.72 (m, 2H), 7.83 (m, 1H), 8.11 (s, 1H), 8.52 (m, 2H), 9.04 (s, 1H), 11.12 (br s, 1H); Mass spectrumMH ⁺474.

In in embodiment 38 initial substances, use (R)-lactic acid methyl alcohol, (2S)-2-[(4-{[1-(1 as initial substance, 3-thiazole-4-ylmethyl)-and 1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate is from 4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-alcohol preparation.

(2S)-and 2-[(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (white solid): productive rate: 3g, 81%; The NMR spectrum(CDCl ₃) 1.80 (d, 3H), 3.86 (s, 3H), 5.16 (q, 1H), 5.80 (s, 2H), 6.80 (d, 1H), 6.97 (s, 1H), 7.52 (m, 2H), 7.62 (t, 1H), 7.73 (m, 1H), 8.08 (s, 1H), 8.36 (s, 1H), 8.63 (s, 1H), 8.79 (s, 1H); Mass spectrumMH ⁺461.

Embodiment 46

(2S)-and N-methyl-2-[(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide

Use and embodiment 5 identical operations, with (2S)-2-[(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] (200mg is 0.43mmol) with the methylamine reaction for methyl propionate, obtaining title compound is white solid (170mg, 85%); The NMR spectrum1.65 (d, 3H), 2.68 (d, 3H), 5.16 (q, 1H), 5.80 (s, 2H), 7.00 (d, 1H), 7.36 (d, 1H), 7.51 (s, 1H), 7.79-7.71 (m, 3H), 8.12 (s, 1H), 8.39 (m, 1H), 8.52 (m, 2H), 9.05 (s, 1H), 10.68 (br s, 1H); Mass spectrumMH ⁺460.

Embodiment 47

5-[(1S)-1-methyl-2-oxo-2-tetramethyleneimine-1-base oxethyl]-N-[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine

Use and embodiment 26 identical operations, with (2S)-2-[(4-{[1-(1,3-thiazole-4-ylmethyl)-and 1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] (200mg, 0.43mmol) (obtaining title compound is solid (130mg for 0.36ml, 4.3mmol) reaction with tetramethyleneimine, 60%), in addition, with this mixture 45 ℃ of down heating 20 hours, again by chromatography with silica gel (elutriant: the purifying of 3% methyl alcohol/DCM). The NMR spectrum1.60 (d, 3H), 1.81 (m, 2H), 1.94 (m, 2H), 3.47-3.38 (m, 3H), 3.77 (m, 1H), 5.62 (q, 1H), 5.79 (s, 2H), 7.26 (d, 1H), 7.35 (d, 1H), 7.51 (s, 1H), 7.77-7.71 (m, 2H), 7.83 (m, 1H), 8.11 (s, 1H), 8.53 (m, 2H), 9.04 (s, 1H), 11.07 (br s, 1H); Mass spectrumMH ⁺500.

Embodiment 48

5-[(1S)-1-methyl-2-morpholine-4-base-2-oxo oxyethyl group]-N-[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine

Use and embodiment 44 identical operations, with (2S)-2-[(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] (250mg is 0.56mmol) with the morpholine reaction for propionic acid, obtaining title compound is white solid (160mg, 55%); NMR spectrum 1.58 (d, 3H), 3.70-3.40 (m, 8H), 5.79 (s, 2H), 5.88 (q, 1H), 7.29 (d, 1H), 7.35 (s, 1H), 7.51 (s, 1H), 7.75 (m, 2H), 7.84 (m, 1H), 8.10 (s, 1H), 8.51 (s, 2H), 9.04 (s, 1H), 11.12 (br s, 1H); Mass spectrum MH ⁺516.

According to the described operation of embodiment 44 initial substances, (2S)-2-[(4-{[1-(1 as initial substance, 3-thiazole-4-ylmethyl)-and 1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid is from (2S)-2-[(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] the methyl propionate preparation:

(2S)-and 2-[(4-{[1-(1,3-thiazoles-4-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid (white solid): productive rate: 448mg, 100%; Mass spectrumMH ⁺447.

Embodiment 49

(2S)-and N-methyl-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide

Use and embodiment 5 identical operations, with (2S)-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (250mg, 0.55mmol) react with methylamine, obtaining title compound is beige solid (110mg, 46%); The NMR spectrum1.65 (d, 3H), 2.67 (d, 3H), 5.16 (q, 1H), 5.77 (s, 2H), 6.96 (d, 1H), 7.00 (d, 1H), 7.29 (m, 1H), 7.36 (d, 1H), 7.72 (m, 4H), 8.17 (s, 1H), 8.38 (m, 1H), 8.53 (m, 3H), 10.68 (br s, 1H); Mass spectrumMH ⁺454.

Embodiment 50

5-[(1S)-1-methyl-2-morpholine-4-base-2-oxo oxyethyl group]-N-[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine

Use and embodiment 44 identical operations, with (2S)-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid (300mg, 0.68mmol) react with morpholine, obtaining title compound is white solid (120mg, 34%); The NMR spectrum1.58 (d, 3H), 3.67-3.58 (m, 8H), 5.77 (s, 2H), 5.88 (q, 1H), 6.95 (d, 1H), 7.29 (m, 2H), 7.35 (d, 1H), 7.75-7.67 (m, 3H), 7.83 (m, 1H), 8.15 (s, 1H), 8.52 (m, 3H), 11.12 (s, 1H); Mass spectrumMH ⁺510.

According to the described operation of embodiment 44 initial substances, (2S)-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid is from (2S)-2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] the methyl propionate preparation:

(2S)-and 2-[(4-{[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid (solid): productive rate: 440mg, 100%; Mass spectrumMH ⁺441.

Embodiment 51

(2R)-and 2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base]-the N-methyl propanamide

Use and embodiment 26 identical operations, with (2R)-2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (200mg, 0.42mmol) react with methylamine, obtaining title compound is white solid (110mg, 55%), in addition, with HPLC post (C18,5 micron, the diameter 19mm of this thick material in preparation HPLC-MS system, long 100mm) goes up purifying, with containing the water of 2g/l volatile salt and the mixture wash-out (gradient) of acetonitrile. The NMR spectrum1.65 (d, 3H), 2.67 (d, 3H), 5.16 (q, 1H), 5.71 (s, 2H), 7.00 (d, 1H), 7.04-7.10 (m, 3H), 7.36 (dd, 2H), 7.71-7.77 (m, 3H), 8.17 (s, 1H), 8.37 (m, 1H), 8.53 (s, 1H), 8.55 (s, 1H), 10.68 (br s, 1H); Mass spectrumMH ⁺471.

Embodiment 52

(2R)-and 2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base]-N-ethyl propionic acid amide

Use and embodiment 5 identical operations, with (2R)-2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (250mg, 0.53mmol) react with ethamine, obtaining title compound is white solid (195mg, 76%); The NMR spectrum1.04 (t, 3H), 1.65 (d, 3H), 3.14-3.20 (m, 2H), 5.16 (q, 1H), 5.71 (s, 2H), 7.01 (d, 1H), 7.04-7.12 (m, 3H), 7.36 (dd, 2H), 7.72-7.78 (m, 3H), 8.17 (s, 1H), 8.44 (m, 1H), 8.53 (s, 1H), 8.56 (s, 1H), 10.68 (br s, 1H); Mass spectrumMH ⁺485.

Embodiment 53

(2R)-and 2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base]-N-(2-hydroxyethyl) propionic acid amide

Use and embodiment 26 identical operations, with (2R)-2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (200mg, 0.42mmol) and thanomin (0.15ml, 2.5mmol) reaction, obtaining title compound is white solid (170mg, 80%); The NMR spectrum1.65 (d, 3H), 3.22 (q, 2H), 3.41-3.45 (m, 2H), 4.75 (t, 1H), 5.22 (q, 1H), 5.70 (s, 2H), 7.01-7.12 (m, 4H), 7.36 (dd, 2H), 7.72-7.76 (m, 3H), 8.17 (s, 1H), 8.47 (m, 1H), 8.53 (s, 1H), 8.56 (s, 1H), 10.73 (br s, 1H); Mass spectrumMH ⁺501.

Embodiment 54

(2R)-and 2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base]-N-(2-hydroxyethyl)-N-methyl propanamide

Use and embodiment 26 identical operations, with (2R)-2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (205mg, 0.43mmol) and 2-methylethylolamine (326mg, 4.3mmol) reaction, obtaining title compound is white solid (124mg, 56%), in addition, this reaction mixture was heated 24 hours down at 45 ℃, with HPLC post (C18,5 micron, the diameter 19mm of this thick material in preparation HPLC-MS system, long 100mm) goes up purifying, with containing the water of 2g/l volatile salt and the mixture wash-out (gradient) of acetonitrile. The NMR spectrum(2 rotational isomers) 1.59-1.62 (m, 3H), 3.18 and 2.93 (s, 3H), 3.53-3.65 (m, 4H), 5.00 and 4.74 (t, 1H), 5.71 (s, 2H), 5.90 and 5.81 (q, 1H), 7.05-7.07 (m, 3H), 7.30-7.37 (m, 3H), and 7.71-7.77 (m, 2H), 7.82-7.88 (m, 1H), 8.17 (s, 1H), 8.51 (s, 1H), 8.55 and 8.58 (s, 1H), 11.10 (br s, 1H); Mass spectrumMH ⁺515.

Embodiment 55

N-[1-(3-luorobenzyl)-1H-indazole-5-yl]-5-[(1R)-and 1-methyl-2-morpholine-4-base-2-oxo oxyethyl group] quinazoline-4-amine

Use and embodiment 44 identical operations, with (2R)-2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid (300mg, 0.66mmol) react with morpholine, obtaining title compound is white solid (144mg, 42%); The NMR spectrum1.58 (d, 3H), 3.46-3.73 (m, 8H), 5.70 (s, 2H), 5.88 (q, 1H), 7.04-7.12 (m, 3H), 7.29 (d, 1H), 7.34-7.37 (m, 2H), 7.72-7.75 (m, 2H), 7.86 (d, 1H), 8.16 (s, 1H), 8.51 (s, 1H), 8.54 (s, 1H), 11.13 (br s, 1H); Mass spectrumMH ⁺527.

According to the described operation of embodiment 44 initial substances, (2R)-2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid is from (2R)-2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] the methyl propionate preparation:

(2R)-and 2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid (solid): productive rate: 477mg, 98%; Mass spectrumMH ⁺458.

Embodiment 56

(2S)-and 2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base]-the N-methyl propanamide

Use and embodiment 26 identical operations, with (2S)-2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (200mg, 0.42mmol) react with methylamine, obtaining title compound is white solid (126mg, 63%), in addition, with HPLC post (C18,5 micron, the diameter 19mm of this thick material in preparation HPLC-MS system, long 100mm) goes up purifying, with containing the water of 2g/l volatile salt and the mixture wash-out (gradient) of acetonitrile. The NMR spectrum1.65 (d, 3H), 2.67 (d, 3H), 5.16 (q, 1H), 5.71 (s, 2H), 7.00 (d, 1H), 7.04-7.10 (m, 3H), 7.36 (dd, 2H), 7.71-7.77 (m, 3H), 8.17 (s, 1H), 8.37 (m, 1H), 8.53 (s, 1H), 8.55 (s, 1H), 10.68 (br s, 1H); Mass spectrumMH ⁺471.

Embodiment 57

N-[1-(3-luorobenzyl)-1H-indazole-5-yl]-5-[(1S)-and 1-methyl-2-morpholine-4-base-2-oxo oxyethyl group] quinazoline-4-amine

Use and embodiment 44 identical operations, with (2S)-2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid (400mg, 0.87mmol) react with morpholine, obtaining title compound is white solid (120mg, 26%); The NMR spectrum1.58 (d, 3H), 3.46-3.73 (m, 8H), 5.70 (s, 2H), 5.88 (q, 1H), 7.04-7.12 (m, 3H), 7.29 (d, 1H), 7.34-7.37 (m, 2H), 7.72-7.75 (m, 2H), 7.86 (d, 1H), 8.16 (s, 1H), 8.51 (s, 1H), 8.54 (s, 1H), 11.13 (br s, 1H); Mass spectrumMH ⁺527.

According to the described operation of embodiment 44 initial substances, (2S)-2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid is from (2S)-2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] the methyl propionate preparation:

(2S)-and 2-[(4-{[1-(3-luorobenzyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid (solid): productive rate: 231mg, 79%; Mass spectrumMH ⁺458.

Embodiment 58

(2R)-and N-(2-hydroxyethyl)-2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide

Use and embodiment 26 identical operations, with (2R)-2-[(4-{[1-(1,3-thiazol-2-yl methyl)-and 1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (210mg, 0.46mmol) and thanomin (0.17ml, 2.7mmol) reaction, obtaining title compound is solid (185mg, 83%), in addition, this mixture was heated 2 hours down at 65 ℃. The NMR spectrum1.65 (d, 3H), 3.21-3.25 (m, 2H), 3.42-3.46 (m, 2H), 4.75 (t, 1H), 5.23 (q, 1H), 6.04 (s, 2H), 7.02 (d, 1H), 7.37 (d, 1H), 7.66 (s, 1H), 7.73 (t, 1H), 7.77-7.79 (m, 3H) 8.21 (s, 1H), 8.48 (m, 1H), 8.54 (s, 1H), 8.57 (s, 1H), 10.75 (br s, 1H); Mass spectrumMH ⁺490.

Embodiment 59

(2R)-and N-(2-hydroxyethyl)-N-methyl-2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide

Use and embodiment 26 identical operations, with (2R)-2-[(4-{[1-(1,3-thiazol-2-yl methyl)-and 1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] methyl propionate (200mg, 0.43mmol) and 2-(methylamino-) ethanol (0.35ml, 4.3mmol) reaction, obtaining title compound is solid (173mg, 79%), in addition, with this mixture 45 ℃ of down heating 24 hours hours, again at the HPLC post (C18 of preparation HPLC-MS system, 5 microns, diameter 19mm, long 100mm) go up purifying, with containing the water of 2g/l volatile salt and the mixture wash-out (gradient) of acetonitrile. The NMR spectrum(2 rotational isomers) 1.60-1.63 (m, 3H), 3.18 and 2.93 (s, 3H), 3.41-3.65 (m, 4H), 5.01 and 4.75 (br s, 1H), 5.81 and 5.91 (q, 1H), 6.04 (s, 2H), 7.30-7.36 (m, 2H), 7.66 (s, 1H), and 7.71-7.78 (m, 3H), 8.84-8.90 (m, 1H), 8.20 (s, 1H), 8.52 (s, 1H), 8.55 and 8.58 (s, 1H), 11.12 (br s, 1H); Mass spectrumMH ⁺504.

Embodiment 60

(2R)-and N-ethyl-2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide

Use and embodiment 5 identical operations, with (2R)-2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] (200mg is 0.43mmol) with the ethamine reaction for methyl propionate, obtaining title compound is white solid (158mg, 77%); The NMR spectrum1.04 (t, 3H), 1.65 (d, 3H), 3.17 (m, 2H), 5.15 (q, 1H), 6.04 (s, 2H), 7.01 (d, 1H), 7.37 (d, 1H), 7.66 (s, 1H), 7.72-7.80 (m, 4H), 8.21 (s, 1H), 8.44 (m, 1H), 8.54 (s, 1H), 8.56 (s, 1H), 10.71 (br s, 1H); Mass spectrumMH ⁺474.

Embodiment 61

(2R)-and N-methyl-2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide

Use and embodiment 5 identical operations, with (2R)-2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] (210mg is 0.46mmol) with the methylamine reaction for methyl propionate, obtaining title compound is white solid (181mg, 86%); The NMR spectrum1.66 (d, 3H), 2.68 (d, 3H), 5.16 (q, 1H), 6.04 (s, 2H), 7.01 (d, 1H), 7.37 (d, 1H), 7.66 (s, 1H), 7.72-7.80 (m, 4H), 8.21 (s, 1H), 8.39 (m, 1H), 8.54 (s, 1H), 8.56 (s, 1H), 10.70 (br s, 1H); Mass spectrumMH ⁺460.

Embodiment 62

5-[(1R)-1-methyl-2-morpholine-4-base-2-oxo oxyethyl group]-N-[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine

Use and embodiment 44 identical operations, with (2R)-2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] (390mg is 0.87mmol) with the morpholine reaction for propionic acid, obtaining title compound is white solid (148mg, 33%); The NMR spectrum1.58 (d, 3H), 3.40-3.75 (m, 8H), 5.88 (q, 1H), 6.04 (s, 2H), 7.29 (d, 1H), 7.36 (d, 1H), 7.66 (s, 1H), 7.73-7.78 (m, 3H), 7.88-7.90 (m, 1H), 8.20 (s, 1H), 8.52 (s, 1H), 8.55 (s, 1H), 11.15 (br s, 1H); Mass spectrumMH ⁺516.

According to the described operation of embodiment 44 initial substances, (2R)-2-[(4-{[1-(1 as initial substance, 3-thiazol-2-yl methyl)-and 1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid is from (2R)-2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] the methyl propionate preparation:

(2R)-and 2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid (white solid); Productive rate: 393mg, 99%; Mass spectrumMH ⁺447.

Embodiment 63

(2S)-and N-methyl-2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide

Use and embodiment 5 identical operations, with (2S)-2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] (210mg is 0.46mmol) with the methylamine reaction for methyl propionate, obtaining title compound is white solid (178mg, 84%); The NMR spectrum1.66 (d, 3H), 2.68 (d, 3H), 5.16 (q, 1H), 6.04 (s, 2H), 7.01 (d, 1H), 7.37 (d, 1H), 7.66 (s, 1H), 7.72-7.80 (m, 4H), 8.21 (s, 1H), 8.39 (m, 1H), 8.54 (s, 1H), 8.56 (s, 1H), 10.70 (br s, 1H); Mass spectrumMH ⁺460.

Embodiment 64

5-[(1S)-1-methyl-2-morpholine-4-base-2-oxo oxyethyl group]-N-[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine

Use and embodiment 44 identical operations, with (2S)-2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] (380mg is 0.84mmol) with the morpholine reaction for propionic acid, obtaining title compound is white solid (158mg, 37%); The NMR spectrum1.58 (d, 3H), 3.40-3.75 (m, 8H), 5.88 (q, 1H), 6.04 (s, 2H), 7.29 (d, 1H), 7.36 (d, 1H), 7.66 (s, 1H), 7.73-7.78 (m, 3H), 7.88-7.90 (m, 1H), 8.20 (s, 1H), 8.52 (s, 1H), 8.55 (s, 1H), 11.15 (br s, 1H); Mass spectrumMH ⁺516.

According to the described operation of embodiment 44 initial substances, (2S)-2-[(4-{[1-(1 as initial substance, 3-thiazol-2-yl methyl)-and 1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid is from (2S)-2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] the methyl propionate preparation:

(2S)-and 2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid (white solid): productive rate: 389mg, 100%; Mass spectrumMH ⁺447.

Claims

1, the quinazoline derivant of formula I:

Wherein:

R ²And R ³Form cyclopropyl rings with the carbon atom that they connected;

Or its pharmacy acceptable salt.

2, the quinazoline derivant of claim 1, wherein:

R ²And R ³Form cyclopropyl rings with the carbon atom that they connected;

Or its pharmacy acceptable salt.

3, claim 1 or 2 quinazoline derivant, wherein R ¹Be selected from hydrogen and methoxyl group.

4, the quinazoline derivant of claim 3, wherein R ¹Be hydrogen.

5, aforesaid right requires any one or multinomial quinazoline derivant, wherein G ¹, G ², G ³And G ⁴Be selected from hydrogen, chlorine and fluorine separately independently of each other.

6, the quinazoline derivant of claim 5, wherein G ¹, G ², G ³And G ⁴All be hydrogen.

7, aforesaid right requires any one or multinomial quinazoline derivant, wherein X ¹Be C (R ⁶) ₂, each R wherein ⁶Be independently selected from hydrogen and (1-4C) alkyl.

8, the quinazoline derivant of claim 7, wherein X ¹Be CH ₂

9, aforesaid right requires any one or multinomial quinazoline derivant, wherein Q ¹Be selected from phenyl and 5 or 6 yuan of bicyclic heteroaryl rings, this ring contains 1,2 or 3 heteroatoms that is independently selected from oxygen, nitrogen and sulphur, and this phenyl or heteroaryl be optional to have 1,2 or 3 and be independently selected from following substituting group: halogeno-group, cyano group, (1-4C) alkyl and (1-4C) alkoxyl group.

10, the quinazoline derivant of claim 9, wherein Q ¹Be selected from phenyl, pyridyl, 1,3-thiazoles base and 1, the 3-oxazolyl, it is optional to have 1,2 or 3 and is independently selected from following substituting group: halogeno-group, cyano group, (1-4C) alkyl and (1-4C) alkoxyl group.

11, the quinazoline derivant of claim 10, wherein Q ¹Be selected from 3-fluorophenyl, 3-p-methoxy-phenyl, 2-cyano-phenyl, 2-pyridyl, 6-fluoro-pyridin-3-yl, 1,3-thiazoles-4-base, 1,3-thiazoles-2-base, 2-methyl isophthalic acid, 3-thiazole-5-base and 1,3-oxazole-2-base.

12, aforesaid right requires any one or multinomial quinazoline derivant, wherein R ²And R ³Be selected from hydrogen and (1-2C) alkyl separately independently of each other.

13, the quinazoline derivant of claim 12, wherein R ²Be hydrogen and R ³It is (1-2C) alkyl.

14, the quinazoline derivant of claim 12, wherein R ²And R ³All be hydrogen.

15, aforesaid right requires any one or multinomial quinazoline derivant, wherein R ⁴And R ⁵, it can be identical or different, is selected from hydrogen and (1-4C) alkyl, should (1-4C) alkyl is optional has one or more hydroxyl substituents, perhaps

R ⁴And R ⁵Form with the nitrogen-atoms that they connected and to be selected from following heterocycle: azetidine-1-base, tetramethyleneimine-1-base, pyrazolidine-1-base, piperidines-1-base, morpholine-4-base and piperazine-1-base, wherein arbitrary heterocycle is optional to have one or more following substituting groups that are independently selected from: halogeno-group, cyano group, hydroxyl, (1-4C) alkyl and (1-4C) alkoxyl group, and wherein arbitrary heterocycle is optional has 1 or 2 oxo or a sulfo-substituting group.

16, the quinazoline derivant of claim 15, wherein R ⁴Be hydrogen and R ⁵Be (1-4C) alkyl, this (1-4C) alkyl is chosen wantonly has one or more hydroxyl substituents.

17, the quinazoline derivant of claim 15, wherein R ⁴And R ⁵All are (1-4C) alkyl, this (1-4C) alkyl is chosen wantonly has one or more hydroxyl substituents.

18, the quinazoline derivant of claim 15, wherein R ⁴And R ⁵Form the heterocycle that is selected from tetramethyleneimine-1-base and morpholine-4-base with the nitrogen-atoms that they connected, this heterocycle is optional to have one or more following substituting groups that are independently selected from: halogeno-group, cyano group, hydroxyl, (1-4C) alkyl and (1-4C) alkoxyl group, and this heterocycle is optional has 1 or 2 oxo or a sulfo-substituting group.

19, be selected from following one or more the quinazoline derivant of formula I:

5-(2-oxo-2-tetramethyleneimine-1-y1 oxyethyl group)-N-[1-(pyridine-2-ylmethyl)-1H-indazole-5-yl] quinazoline-4-amine;

(2R)-and N, N-dimethyl-2-[(4-{[1-(1,3-thiazoles-2-ylmethyl)-1H-indazole-5-yl] amino } quinazoline-5-yl) the oxygen base] propionic acid amide;

Or its pharmacy acceptable salt.

20, a kind of pharmaceutical composition, it comprises quinazoline derivant or its pharmacy acceptable salt and the pharmaceutically acceptable diluent or carrier of any or multinomial formula I of claim 1-19.

21, a kind of medicament production, it comprise the quinazoline derivant of claim 1-19 any one or multinomial formula I or its pharmacy acceptable salt and other be used for the combination therapy cancer antineoplastic agent.

22, as quinazoline derivant or its pharmacy acceptable salt of any or multinomial formula I of the claim 1-19 of medicine.

23, the quinazoline derivant of any or multinomial formula I of claim 1-19 or its pharmacy acceptable salt are used for producing purposes in the medicine of antiproliferative effect warm-blooded animal in preparation.

24, produce the method for antiproliferative effect in the warm-blooded animal of this kind of needs treatment, this method comprises quinazoline derivant or its pharmacy acceptable salt of any or multinomial formula I of the claim 1-19 that gives described animal effective dose.

25, the quinazoline derivant of any or multinomial formula I of claim 1-19 or its pharmacy acceptable salt preparation be used for the treatment of separately or part by the purposes in the medicine of the disease of erbB receptor tyrosine kinase mediation or medical conditions.

26, in the warm-blooded animal of this kind of needs treatment treatment separately or part by the disease of erbB receptor tyrosine kinase mediation or the method for medical conditions, this method comprises quinazoline derivant or its pharmacy acceptable salt of any or multinomial formula I of the claim 1-19 that gives described animal effective dose.

27, the quinazoline derivant of any or multinomial formula I of claim 1-19 or its pharmacy acceptable salt are used in the warm-blooded animal prevention or treat purposes in the medicine of these tumours in preparation, described tumour participates in the signal transduction step to suppressing, and is responsive thereby cause one or more erbB receptor tyrosine kinases of tumor cell proliferation and/or survival.

28, in the warm-blooded animal of this kind of needs treatment prevention or treatment to the method for those tumours of suppressing one or more erbB receptor tyrosine kinase sensitivities, described kinases participates in causing the signal transduction step of tumor cell proliferation and/or survival, and this method comprises quinazoline derivant or its pharmacy acceptable salt of any or multinomial formula I of the claim 1-19 that gives described animal effective dose.

29, the quinazoline derivant of any or multinomial formula I of claim 1-19 or its pharmacy acceptable salt are used for the treatment of purposes in the medicine of cancer in preparation.

30, treat method for cancer in the warm-blooded animal of this kind of needs treatment, this method comprises quinazoline derivant or its pharmacy acceptable salt of any or multinomial formula I of the claim 1-19 that gives described animal effective dose.