CN101074227A

CN101074227A - Phosphine acyloxy quinazoline derivatives and their medicine using

Info

Publication number: CN101074227A
Application number: CN 200710127910
Authority: CN
Inventors: N·M·赫伦; F·H·荣格; G·R·帕斯凯特; A·A·莫尔特洛克
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2002-12-24
Filing date: 2003-12-22
Publication date: 2007-11-21
Anticipated expiration: 2023-12-22
Also published as: UA86470C2; CN100349906C; ZA200504997B; CN1764668A; CN101074227B

Abstract

The present invention relates to particular quinazoline derivatives useful as intermediates in the preparation of compounds of formula (I): wherein A is 5-membered heteroaryl containing a nitrogen atom and one or two further nitrogen atoms.

Description

Phosphonooxy quinazoline derivatives and pharmaceutical use thereof

The application is that international filing date is December 22, international application no in 2003 the dividing an application for the application of " phosphonooxy quinazoline derivatives and pharmaceutical use thereof " that be PCT/GB2003/005613 (national phase application number be 200380109902.9), denomination of invention.

Technical field

The present invention relates to some quinazoline derivant is used for the treatment of the medicine that some disease (especially proliferative disease for example cancer) and preparation are used for the treatment of proliferative disease, relate to new quinazoline compound, they the preparation method and comprise medicinal compositions as the described compound of activeconstituents.

Background technology

The feature of cancer (and other hyperproliferative disease) is uncontrolled cell proliferation.As if the forfeiture of cell proliferation normal regulating is normally owing to the gene damage of cell passage occurs, and cell passage is regulated and control the process of whole cell cycle.

It is believed that in eukaryotic cell the concatenated in order cell cycle regulation of protein phosphorylation.Identified at present the protein kinase that in this cascade, has several families of vital role.Compare with healthy tissues, many above-mentioned kinase whose activity increase in people's tumour.This may occur owing to the expression variation of proteic expression level raising (for example being caused by gene amplification) or co-activator or arrestin.

The cell cycle regulatory factors of identifying at first and being widely studied is cell cycle protein dependent kinase (or CDK).Specific C DK is indispensable in the activity of specified time for causing and coordinating the process of whole cell cycle.By way of example, as if CDK4 albumen enters the cell cycle (G0-G1-S conversion) by phosphorylation retinoblastoma gene product pRb control.This thorn excited transcryption factor E2F discharges from pRb, and E2F works then, increases to enter necessary gene transcription of S phase.CDK4 is by stimulating its catalytic activity in conjunction with pairing albuminous cell cyclin D.Having one of the initial evidence contact directly between cancer and the cell is to observe in many people's tumours that the cyclin D1 gene is amplified and cyclin D concentration increases (so CDK4 is active increase) (summary is referring to Sherr, 1996, Science 274:1672-1677; Pines, 1995, Seminars in Cancer Biology 6:63-72).Other research (Loda etc., 1997, Nature Medicine 3 (2): 231-234; Gemma etc., 1996, International Journal of Cancer 68 (5): 605-11; Elledge etc., 1996, Trends in Cell Biology 6; 388-392) negative regulatory factor that has confirmed the CDK function is usually regulated under the quilt in people's tumour or is eliminated, and causes above-mentioned kinases to be activated irrelevantly once more.

As if identify the protein kinase that is different from CDK family on the structure recently, it has keying action in the adjusting cell cycle, also very important for tumorigenesis.These kinases comprise the Drosophila aurora and the proteic people's homologue of yeast saccharomyces cerevisiae (S.cerevisiae) Ipl1 of new evaluation.The serine-threonine protein kinase enzyme of three-type-person's homologue Aurora-A, the Aurora-B of these genes and Aurora-C (also being called aurora2, aurora1 and aurora3) coding and regulating cell cycle is (at Adams etc., 2001, Trends in Cell Biology.11 (2): sum up among the 49-54).They an expression and kinase activity peak value occur at G2 and mitotic division stage.Some observations show people's aurora albumen and related to cancer.The Aurora-A gene is positioned at karyomit(e) 20q13, a zone that usually is amplified in people's tumour (comprising breast and colon tumor).Aurora-A may be the main target gene of this amplification because in surpassing 50% primary human colorectal cancer the Aurora-A DNA cloning, the mRNA overexpression.Compare with adjacent healthy tissues, the Aurora-A protein level in these tumours raises greatly.In addition, personnel selection Aurora-A transfection rodent inoblast causes transforming, and makes it possible to growing on the soft agar and can form tumour (Bischoff etc., 1998, The EMBOJournal.17 (11): 3052-3065) on nude mice.Other research (Zhou etc., 1998, Nature Genetics.20 (2): 189-93) confirmed that the people causes centrosome quantity to increase for overexpression Aurora-A and dysploidy increases, this is the known procedure during cancer takes place.Further studies confirm that with normal cell and compare, Aurora-B in the tumour cell (Adams etc., 2001, Chromsoma.110 (2): 65-74) and Aurora-C (Kimura etc., 1999, Journal ofBiological Chemistry, 274 (11): 7334-40) expression increases.

Importantly verified: expression and function (WO 97/22702 and WO 99/37788) by antisense oligonucleotide handler tumor cell line elimination Aurora-A, cause the cell cycle to be suppressed, in these tumor cell lines, produce antiproliferative effect.In addition, the micromolecular inhibitor that has confirmed Aurora-A and Aurora-B has antiproliferative effect (Keen etc. in human tumor cells, 2001, Poster#2455, American Association of Cancer studies annual meeting), only siRNA handles the alternative Aurora-B of elimination and expresses (Ditchfield etc., 2003.Journal of Cell Biology, 161 (2): 267-280).The function that this explanation suppresses Aurora-A and/or Aurora-B will produce antiproliferative effect, and this can be used for treating people's tumour and other hyperproliferative disease.In addition, with compare (for example growth factor receptor tyrosine kinase for example the signal transduction path of EGF-R ELISA (EGFR) or other receptor activation) at the signal transduction path of cell cycle upstream, suppress aurora kinase (Aurora kinases) and have remarkable advantages as these treatment of diseases methods.Because the cell cycle is in the downstream of all these unlike signals conduction active, so the therapy (for example suppressing the Aurora kinases) at the cell cycle will be effective to all proliferative tumour cells, and will be only effective to the tumour cell of expressing these acceptors at the method for signal specific transduction molecule (for example EGFR).It is also believed that in these signal transduction paths, to have important " talk ", mean that suppressing a kind of composition may be become the branch compensation by another kind.

So far, there are many quinazoline derivants to be proposed for the kinases that suppresses different.By way of example, WO 96/09294, WO 96/15118 and WO 99/06378 have introduced the purposes of some quinazoline compound as receptor tyrosine kinase inhibitors, it can be used for treating proliferative disease, and WO 00/21955 discloses the inhibitor of some quinazoline derivant as the VEGF effect.

Quinazoline derivant also is disclosed and is used to suppress the Aurora-A kinases.WO 02/00649 discloses the quinazoline derivant that contains 5 yuan of heteroaromatic rings, and wherein said ring especially is the thiazole of replacement or the thiophene of replacement, and pending application application WO 03/055491 discloses the quinazoline derivant that contains the optional pyrazoles ring that replaces simultaneously.But although the compound of WO 02/00649 and WO03/055491 is arranged, still need the compound of the Aurora of having kinase inhibition characteristics more.

Summary of the invention

This application has is through successfully finding the new compound of a series of inhibition Aurora kinases, especially Aurora-A and/or Aurora-B zymogenesis, and some characteristic that they have makes it especially can be used for preparing the medicine of treatment disease.Specifically, the proliferative disease that The compounds of this invention can be used for treating known Aurora zymogenesis is cancer for example, no matter be solid tumor or the form of blood tumour, especially for example colorectal carcinoma, mammary cancer, lung cancer, prostate cancer, carcinoma of the pancreas, bladder cancer and kidney and leukemia and lymphoma.

One aspect of the present invention provides following formula (I) compound or its pharmacy acceptable salt:

Formula (I)

Wherein

A contains a nitrogen-atoms and also optional 5 yuan of heteroaryls that contain one or two nitrogen-atoms;

X is O, S, S (O), S (O) ₂Or NR ¹⁴

M is 0,1,2 or 3;

Z is selected from-NR ¹R ², phosphonato, the C that replaced by phosphonato or phosphonato _1-4The C that alkyl replaces _3-6Cycloalkyl and contain a nitrogen-atoms and the also optional 4-7 unit ring that contains a nitrogen-atoms by what carbon atom connected, described ring can be saturated, fractional saturation or undersaturated, the C that wherein said ring is replaced by phosphonato or phosphonato on carbon or nitrogen _1-4Alkyl replaces, and chooses wantonly on carbon or nitrogen by 1,2 or 3 halogen or C _1-4Alkyl further replaces;

R ¹Be selected from-COR ⁸,-CONR ⁸R ⁹And C _1-6Alkyl, wherein C _1-6Alkyl is replaced by phosphonato and chooses wantonly and further replaced by 1-2 halogen or methoxyl group;

R ²Be selected from hydrogen ,-COR ¹⁰,-CONR ¹⁰R ¹¹And C _1-6Alkyl, wherein C _1-6Alkyl is optional by 1-3 halogen or C _1-4Alkoxyl group or-S (O) _pR ¹¹(p is 0,1 or 2) or phosphonato replace, perhaps R ²Be selected from C _2-6Thiazolinyl, C _2-6Alkynyl, C _3-6Cycloalkyl and C _3-6Cycloalkyl C _1-4Alkyl; Perhaps

R ¹And R ²The nitrogen that connects with them constitutes 4-7 unit ring, and it is also chosen wantonly and contains a nitrogen-atoms, and described ring can be saturated, unsaturated or fractional saturation, and is selected from phosphonato and C on carbon or nitrogen _1-4The group of alkyl replaces, wherein C _1-4Alkyl by phosphonato or-NR ⁸R ⁹Replace, and described ring is chosen wantonly on carbon or nitrogen by 1,2 or 3 halogen or C _1-4Alkyl further replaces;

R ³Be selected from hydrogen, halogen, cyano group, nitro, C _1-6Alkoxyl group, C _1-6Alkyl ,-OR ¹²,-CHR ¹²R ¹³,-OC (O) R ¹²,-C (O) R ¹²,-NR ¹²C (O) R ¹³,-C (O) NR ¹²R ¹³,-NR ¹²SO ₂R ¹³With-NR ¹²R ¹³

R ⁴For hydrogen or be selected from C _1-4Alkyl, heteroaryl, heteroaryl C _1-4Alkyl, aryl and aryl C _1-4Alkyl, they are optional by 1,2 or 3 following substituting group replacement: halogen, methyl, ethyl, cyclopropyl and ethynyl;

R ⁵Be selected from hydrogen, C _1-4Alkyl, C _2-4Thiazolinyl, C _2-4Alkynyl, C _3-6Cycloalkyl and C _3-6Cycloalkyl C _1-4Alkyl;

R ⁶And R ⁷Independently be selected from hydrogen, halogen, C _1-4Alkyl, C _3-6Cycloalkyl, hydroxyl and C _1-4Alkoxyl group;

R ⁸For being replaced by phosphonato and choosing wantonly by 1-2 halogen or the further C that replaces of methoxyl group _1-4Alkyl;

R ⁹Be selected from hydrogen or C _1-4Alkyl;

R ¹⁰Be selected from hydrogen and C _1-4Alkyl, wherein C _1-4Alkyl is optional by halogen, C _1-4Alkoxyl group, S (O) _q(q is 0,1 or 2) or phosphonato replace;

R ¹¹, R ¹², R ¹³And R ¹⁴Independently be selected from hydrogen, C _1-4Alkyl and heterocyclic radical.

In the present invention, should be understood that some formula (I) compound that this paper defines may exist with opticity or racemic form because containing one or more asymmetric carbons or sulphur atom, the present invention's definition comprises any such opticity or racemic form with Aurora kinase inhibiting activity (especially Aurora-A and/or Aurora-B kinase inhibiting activity).Optically active compounds can obtain by organic chemistry standard technique well-known in the art, for example synthetic the or resolution of racemic form with the opticity initial feed.Similarly, above-mentioned activity can be with the standard laboratory technological assessment of hereinafter mentioning.

In the present invention, should be understood that may there be tautomerism in formula (I) compound or its salt, but the molecular formula of drawing in this specification sheets can only be represented wherein a kind of possible tautomer.Should be understood that to the present invention includes any such tautomeric form, and be not limited only to any tautomeric form that molecular formula is drawn with Aurora kinase inhibiting activity (especially Aurora-A and/or Aurora-B kinase inhibiting activity).

It is to be further understood that some formula (I) compound and its salt can exist with solvation or non-solvent form, for example hydrate forms.Should be understood that and the present invention includes any such solvate forms with Aurora kinase inhibiting activity (especially Aurora-A and/or Aurora-B kinase inhibiting activity).

The present invention relates to formula (I) compound and the salt thereof of this paper definition.The salt that uses in the medicinal compositions should be pharmacy acceptable salt, but other salt can be used for preparation formula (I) compound and their pharmacy acceptable salt.Pharmacy acceptable salt of the present invention can comprise for example formed acid salt of the formula with enough alkalescence (I) compound of this paper definition.Such acid salt includes but not limited to fumarate, mesylate, hydrochloride, hydrobromate, Citrate trianion and maleate and the salt that forms with phosphoric acid and sulfuric acid.In addition, salt with enough tart formulas (I) compound is alkali salt, for example includes but not limited to an alkali metal salt (for example sodium salt or sylvite), alkaline earth salt (for example calcium salt or magnesium salts) or organic amine salt (for example triethylamine, thanomin, diethanolamine, trolamine, morpholine, N-methyl piperidine, N-ethylpiperidine, dibenzylamine or amino acid for example the salt of Methionin).

Formula (I) compound can also be hydrolyzable ester in the body.The interior hydrolyzable ester of body that contains formula (I) compound of carboxyl or hydroxyl has for example pharmaceutically acceptable ester, and its cracking in human body or animal body produces parent acid or alcohol.Such ester can followingly be identified: give (for example intravenously) test animal, the body fluid of checkout animal then with institute's test compounds.

The suitable pharmaceutically acceptable ester of carboxyl comprises C _1-6Alkoxy methyl ester (for example methoxymethyl ester), C _1-6Alkanoyloxymethyl ester (for example oxy acid methyl neopentyl ester), 2-benzo [C] furanonyl ester, C _3-8Cycloalkyloxy carbonyl oxygen base C _1-6Alkyl ester (for example 1-cyclohexyl carbonyl oxygen base ethyl ester), 1,3-dioxole-2-ketone group methyl ester (for example 5-methyl isophthalic acid, 3-dioxole-2-ketone group methyl ester) and C _1-6Alkoxyl group carbonyl oxygen base ethyl ester (for example 1-methoxyl group carbonyl oxygen base ethyl ester); And described ester can form at any carboxyl of The compounds of this invention.

The suitable pharmaceutically acceptable ester of hydroxyl draw together inorganic ester for example phosphoric acid ester (comprising the phosphoramidic acid cyclic ester) and alpha-acyloxy alkyl oxide and in vivo hydrolysis obtain the related compound of parent hydroxy.The example of alpha-acyloxy alkyl oxide comprises acetoxyl group methoxyl group and 2,2-dimethyl propylene acyloxy methoxyl group.The group that is used for the interior hydrolyzable ester of hydroxyl organizer can be selected from and comprise C _1-10Alkyloyl, for example benzoyl of formyl radical, ethanoyl, benzoyl, phenyl acetyl, replacement and phenyl acetyl; C _1-10Alkoxy carbonyl (obtaining alkyl carbonate), for example ethoxy carbonyl; Two-C _1-4Alkyl-carbamoyl and N-(two-C _1-4The alkylamino ethyl)-N-C _1-4Alkyl-carbamoyl (obtaining carbamate); Two-C _1-4Alkylamino ethanoyl and carboxyl ethanoyl.The example of the substitution in ring base of phenyl acetyl and benzoyl comprises amino methyl, C _1-4Alkylamino methyl, two-(C _1-4Alkyl) amino methyl and 3 or 4 morpholino or piperazinyl connecting the benzoyl basic ring by theheterocyclic nitrogen atom by methylene radical.Hydrolyzable ester comprises for example R in other useful body ^AC (O) OC _1-6Alkyl-CO-, wherein R ^ABe for example benzyloxy-C _1-4Alkyl or phenyl.In such ester, the suitable substituent of phenyl comprises for example 4-C _1-4Piperazinyl-C _1-4Alkyl, piperazinyl-C _1-4Alkyl and morpholino-C _1-4Alkyl.

In this manual, generic term " alkyl " comprises straight chain and branched-chain alkyl.But when mentioning the specific alkyl such as " propyl group ", only refer to the straight chain type group, mention specific branched-chain alkyl for example when " tertiary butyl ", only refer to the branched chain type group.Similarly agreement is applicable to other generic term, for example " thiazolinyl " and " alkynyl ".

" cycloalkyl " is saturated mono alkyl ring, and " aryl " is aromatic monocyclic or two rings.

Unless other explanation is arranged, " heteroaryl " be contain 5-10 annular atoms and wherein 1,2,3 or 4 annular atoms be selected from the aromatic monocyclic or two rings of nitrogen, sulphur or oxygen, wherein encircling nitrogen or epithio can be oxidized.

" heterocyclic radical " be contain 4-12 annular atoms and wherein 1,2,3 or 4 annular atoms be selected from the monocycle or two rings of saturated, the unsaturated or fractional saturation of nitrogen, sulphur or oxygen, described ring can connect by carbon or nitrogen, wherein-CH ₂-can choose wantonly by-C (O)-substitute; Optional oxidized formation N-oxide compound of ring nitrogen or epithio atom or S-oxide compound; Wherein ring-NH is optional is replaced by ethanoyl, formyl radical, methyl or methylsulfonyl; Wherein ring is optional is replaced by one or more halogens.

" phosphonato " on the one hand be formula-OP (O) (OH) ₂Group.But term " phosphonato " also comprises the salt of this group, for example the salt that forms with alkalimetal ion (for example sodium or potassium ion) or alkaline-earth metal ions (for example calcium or magnesium ion).

When optional substituting group is selected from " 1-2 ", " 1,2 or 3 " or " 1,2,3 or 4 " group, should be understood that such definition comprises that all substituting groups all are selected from a special groups (promptly all substituting groups are identical) and all substituting groups are selected from two or more special groups (being that substituting group is not same group).

The compounds of this invention is by computer software name (ACD/Name 6.6 or ACD NameBatch 6.0).

Any R group (R ¹-R ¹⁴) or any part or the substituent desired value of such group comprise:

C _1-4Alkyl: methyl, ethyl, propyl group, sec.-propyl, butyl, 2-methyl-propyl and the tertiary butyl;

C _1-6Alkyl: C _1-4Alkyl, amyl group, 2,2-dimethyl propyl, 3-methyl butyl and hexyl;

C _2-4Thiazolinyl: vinyl, allyl group and 1-propenyl;

C _2-6Thiazolinyl: C _2-4Thiazolinyl, 1-butylene base, crotyl, 3-butenyl, 2-methyl but-2-ene base, 3-methyl but-1-ene base, 1-pentenyl, 3-pentenyl and 4-hexenyl;

C _2-4Alkynyl: ethynyl, 1-proyl, 2-propynyl and 3-butynyl;

C _2-6Alkynyl: C _2-4Alkynyl, valerylene base, hexin base and 1-methylpent-2-alkynyl;

C _3-6Cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;

C _3-6Cycloalkyl C _1-4Alkyl: cyclopropyl methyl, cyclopropyl ethyl, cyclobutylmethyl, cyclopentyl-methyl and cyclohexyl methyl;

Aryl: phenyl and naphthyl;

Aryl C _1-4Alkyl: benzyl, styroyl, naphthyl methyl and naphthyl ethyl;

Halogen: fluorine, chlorine, bromine and iodine;

C _1-4Alkoxyl group: methoxyl group, oxyethyl group, propoxy-and isopropoxy;

C _1-6Alkoxyl group: C _1-4Alkoxyl group, pentyloxy, 1-ethyl propoxy-and hexyloxy;

Heteroaryl: pyridyl, imidazolyl, quinolyl, cinnolinyl, pyrimidyl, thienyl, pyrryl, pyrazolyl, thiazolyl, triazolyl,  azoles base, different  azoles base and pyrazinyl, preferred thiazolyl, pyridyl, imidazolyl and pyrimidyl;

Heteroaryl C _1-4Alkyl: pyridylmethyl, pyridyl ethyl, pyrimidinylethyl, pyrimidyl propyl group, pyrimidyl butyl, imidazolyl propyl group, imidazolyl butyl, quinolyl propyl group, 1,3,4-triazolyl propyl group and  azoles ylmethyl;

Heterocyclic radical: furyl; thienyl; pyrryl; pyrrolidyl; imidazolyl; triazolyl; thiazolyl; tetrazyl;  azoles base; different  azoles base; pyrazolyl; pyridyl; pyrimidyl; pyrazinyl; pyridazinyl; triazinyl; quinolyl; isoquinolyl; quinoxalinyl; benzothiazolyl; the benzoxazol base; benzothienyl; benzofuryl; piperidyl; N-ethanoyl piperidyl; N-methyl piperidine base; N-formyl piperazine base; N-methylsulfonyl piperazinyl; high piperazinyl; piperazinyl; azetidinyl; oxetanyl; morpholinyl; tetrahydro isoquinolyl; tetrahydric quinoline group; indolinyl; pyranyl; dihydro-2H-pyranyl; tetrahydrofuran base; 2; 5-two oxa-imidazolidyls; 2; 2-dimethyl-1; 3-dioxolanyl and 3,4-two methylenedioxy benzyls.

The example that should be noted that the term that uses in the relevant specification sheets is also nonrestrictive.

Hereinafter introduce A, X, m, Z, R ³, R ⁴, R ⁵, R ⁶And R ⁷Preferred value.Under suitable situation, such value can be used for any definition, claim or the embodiment that this paper defines.

In one aspect of the invention, A is pyrryl, pyrazolyl, imidazolyl or triazolyl.

Aspect another, A is formula (a) and (b), (c), (d) or group (e):

Wherein * be with formula (I) in the tie point of X group, * * be with formula (I) in (CR ⁶R ⁷) tie point of group.One preferred aspect, A is a pyrazolyl.One preferred aspect, A is formula (a) group of above definition.

In one aspect of the invention, X is NR ¹⁴, O or S.On the other hand, X is NR ¹⁴

Aspect another, X is NH.

In one aspect of the invention, m is 1,2 or 3.In one aspect, m is 1 or 2.

On the other hand, m is 0,2 or 3.On the other hand, m is 0,1 or 2.Aspect another, m is 1.Aspect another, m is 2.

In one aspect of the invention, Z is-NR ¹R ²Or contain a nitrogen-atoms and the also optional 5-6 unit saturated rings that contains a nitrogen-atoms by what carbon atom connected, the C that this ring is replaced by phosphonato or phosphonato on carbon or nitrogen _1-4Alkyl replaces.On the other hand, Z is-NR ¹R ²

In one aspect of the invention, R ¹Be the C that is replaced by phosphonato _1-5Alkyl.On the other hand, R ¹Be the C that is replaced by phosphonato and further replaced by 1-2 halogen _1-5Alkyl.

Aspect another, R ¹Be 2-phosphonato ethyl, 2-phosphonato-1,1-dimethyl ethyl, 2-phosphonato-2-methylethyl, 3-phosphonato-1,1-dimethyl propyl, 3-phosphonato propyl group and 4-phosphonato butyl.Aspect another, R ¹Be 2-phosphonato ethyl, 2-phosphonato-1,1-dimethyl ethyl, 3-phosphonato-1,1-dimethyl propyl or 3-phosphonato propyl group.

Aspect another, R ¹Be 2-phosphonato ethyl.

In one aspect of the invention, R ²Be selected from hydrogen and C _1-6Alkyl, wherein C _1-6Alkyl is optional by 1,2 or 3 halogen or C _1-4Alkoxyl group replaces, perhaps R ²Be selected from C _2-6Thiazolinyl, C _2-6Alkynyl, C _3-6Cycloalkyl and C _3-6Cycloalkyl C _1-4Alkyl.On the other hand, R ²Be hydrogen, allyl group, 2-propynyl, methyl, ethyl, propyl group, sec.-propyl, 2-methyl-propyl, butyl, 2,2-dimethyl propyl, cyclopropyl, cyclopropyl methyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentyl-methyl, 3,3,3-trifluoro propyl or 2-methoxy ethyl.

In one aspect of the invention, R ¹And R ²The nitrogen that connects with them constitutes the optional 5-6 unit saturated rings that comprises an extra nitrogen-atoms, and wherein said ring is selected from phosphonato and C on carbon or nitrogen _1-4The group of alkyl replaces, wherein C _1-4Alkyl by phosphonato or-NR ⁸R ⁹Replace, and described ring is chosen wantonly on carbon or nitrogen by 1-2 C _1-4Alkyl further replaces.In the present invention on the other hand, R ¹And R ²The nitrogen that connects with them constitutes piperidine ring, pyrrolidine ring or piperazine ring, described ring is selected from following group and replaces: phosphonato, phosphonato methyl, 2-phosphonato ethyl, N-ethyl-N-(2-phosphonato ethyl) amino methyl and N-(2-phosphonato ethyl) amino methyl, described ring is optional further to be replaced by 1-methyl.In another aspect of the invention, R ¹And R ²The nitrogen that connects with them constitutes 4-(phosphonato methyl) piperidyl, 2-(phosphonato methyl) pyrrolidyl, 4-(2-phosphonato ethyl) piperazinyl, 3-(phosphonato) pyrrolidyl, 3-(phosphonato) piperidyl, 2-[N-ethyl-N-(2-phosphonato ethyl) amino methyl] pyrrolidyl, 4-(phosphonato) piperidyl, 2-[N-(2-phosphonato ethyl) amino methyl] pyrrolidyl, 4-(2-phosphonato ethyl) piperidyl, 2-(2-phosphonato ethyl) pyrrolidyl and 2-(2-phosphonato ethyl) piperidyl.Aspect another, R ¹And R ²The nitrogen that connects with them constitutes 4-(phosphonato methyl) piperidyl, 2-(phosphonato methyl) pyrrolidyl, 2-(2-phosphonato ethyl) pyrrolidyl and 3-(phosphonato) piperidyl.Aspect another, R ¹And R ²The nitrogen that connects with them constitutes 2-(phosphonato methyl) pyrrolidyl.

In one aspect of the invention, R ³Be C _1-4Alkoxyl group, halogen or hydrogen.Aspect another, R ³Be C _1-4Alkoxyl group or hydrogen.On the other hand, R ³Be methoxyl group.On the other hand, R ³Be hydrogen.On the other hand, R ³Be fluorine.

In one aspect, R ⁴Be the optional phenyl that is replaced by 1-2 fluorine or chlorine.On the other hand, R ⁴Be 3-fluorophenyl, 3-chloro-phenyl-, 3,5-difluorophenyl, 3,4-difluorophenyl, 2-fluorophenyl, 2,3-difluorophenyl, 2,4 difluorobenzene base and 2,5-difluorophenyl.Aspect another, R ⁴Be 3-fluorophenyl, 3,5-difluorophenyl and 2,3-difluorophenyl.In one aspect, R ⁴Be the 3-fluorophenyl.Aspect another, R ⁴Be 3, the 5-difluorophenyl.Aspect another, R ⁴Be 2, the 3-difluorophenyl.

In one aspect of the invention, R ⁵Be hydrogen or methyl.On the other hand, R ⁵Be hydrogen.

In one aspect of the invention, R ⁶Be hydrogen, fluorine, chlorine or methyl.On the other hand, R ⁶Be hydrogen.

In one aspect of the invention, R ⁷Be hydrogen, fluorine, chlorine or methyl.On the other hand, R ⁷Be hydrogen.

In one aspect, R ⁸Be 2-phosphonato ethyl.

In one aspect of the invention, R ⁹Be hydrogen, methyl or ethyl.

In one aspect of the invention, R ¹⁰Be hydrogen, methyl or ethyl.

In one aspect of the invention, R ¹¹Be hydrogen, methyl or ethyl.

In one aspect of the invention, R ¹²Be hydrogen or methyl.

In one aspect of the invention, R ¹³Be hydrogen or methyl.

In one aspect of the invention, R ¹⁴Be hydrogen or methyl.

One group of preferred formula (I) compound or its pharmacy acceptable salt, wherein:

A is formula (a) and (b), (c), (d) or the group (e) of above definition;

X is NH;

M is 0,1,2 or 3;

Z is-NR ¹R ²Or contain a nitrogen-atoms and the also optional 5-6 unit saturated rings that contains a nitrogen-atoms by what carbon atom connected, the C that this ring is replaced by phosphonato or phosphonato on carbon or nitrogen _1-4Alkyl replaces;

R ¹Be the C that is replaced by phosphonato _1-5Alkyl;

R ²Be selected from hydrogen and C _1-6Alkyl, wherein C _1-6Alkyl is optional by 1,2 or 3 halogen or C _1-4Alkoxyl group replaces, perhaps R ²Be selected from C _2-6Thiazolinyl, C _2-6Alkynyl, C _3-6Cycloalkyl and C _3-6Cycloalkyl C _1-4Alkyl;

Perhaps, R ¹And R ²The nitrogen that connects with them constitutes the optional 5-6 unit saturated rings that comprises an extra nitrogen-atoms, and wherein said ring is selected from phosphonato and C on carbon or nitrogen _1-4The group of alkyl replaces, described C _1-4Alkyl by phosphonato or-NR ⁸R ⁹Replace, and described ring is chosen wantonly on carbon or nitrogen by 1-2 C _1-4Alkyl further replaces;

R ³Be C _1-4Alkoxyl group, halogen or hydrogen;

R ⁴Be the optional phenyl that is replaced by 1-2 fluorine or chlorine;

R ⁵Be hydrogen or methyl;

R ⁶And R ⁷Independent is hydrogen, fluorine, chlorine or methyl.

A is formula (a) and (b), (c), (d) or the group (e) of above definition;

X is NH;

M is 1,2 or 3;

Z is-NR ¹R ²

R ¹Be the C that is replaced by phosphonato _1-5Alkyl;

R ²Be selected from hydrogen and C _1-6Alkyl, wherein C _1-6Alkyl is optional by 1,2 or 3 halogen or C _1-4Alkoxyl group replaces, perhaps R ²Be selected from C _2-6Thiazolinyl, C _1-6Alkynyl, C _3-6Cycloalkyl and C _3-6Cycloalkyl C _1-4Alkyl;

R ³Be C _1-4Alkoxyl group, halogen or hydrogen;

R ⁴Be the optional phenyl that is replaced by 1-2 fluorine or chlorine;

R ⁵Be hydrogen or methyl;

R ⁶And R ⁷Independent is hydrogen, fluorine, chlorine or methyl.

Another organizes preferred formula (I) compound or its pharmacy acceptable salt, wherein:

A is formula (a) group of above definition;

X is NH;

M is 1,2 or 3;

Z is-NR ¹R ²

R ¹Be the C that is replaced by phosphonato _1-5Alkyl;

R ³Be C _1-4Alkoxyl group, halogen or hydrogen;

R ⁴Be the optional phenyl that is replaced by 1-2 fluorine or chlorine;

R ⁵Be hydrogen;

R ⁶And R ⁷The hydrogen of respectively doing for oneself.

A is formula (a) group of above definition;

X is NH;

M is 1 or 2;

Z is-NR ¹R ²

R ¹Be the C that is replaced by phosphonato _1-5Alkyl;

R ³Be C _1-4Alkoxyl group;

R ⁴Be the optional phenyl that is replaced by 1-2 fluorine or chlorine;

R ⁵Be hydrogen;

R ⁶And R ⁷The hydrogen of respectively doing for oneself.

A is formula (a) group of above definition;

X is NH;

M is 1,2 or 3;

Z is-NR ¹R ²

R ¹Be the C that is replaced by phosphonato _1-5Alkyl;

R ³Be hydrogen;

R ⁴Be the optional phenyl that is replaced by 1-2 fluorine or chlorine;

R ⁵Be hydrogen;

R ⁶And R ⁷The hydrogen of respectively doing for oneself.

A is formula (a) group of above definition;

X is NH;

M is 1 or 2;

Z is-NR ¹R ²

R ¹Be the C that is replaced by phosphonato _1-5Alkyl;

R ³Be fluorine;

R ⁴Be the optional phenyl that is replaced by 1-2 fluorine or chlorine;

R ⁵Be hydrogen;

R ⁶And R ⁷The hydrogen of respectively doing for oneself.

A is formula (a) and (b), (c), (d) or the group (e) of above definition;

X is NH;

M is 0,1 or 2;

Z is-NR ¹R ²

R ¹And R ²The nitrogen that connects with them constitutes the optional 5-6 unit saturated rings that comprises an extra nitrogen-atoms, and described ring is selected from phosphonato and C _1-4The group of alkyl replaces, described C _1-4Alkyl by phosphonato or-NR ⁸R ⁹Replace, and described ring is optional by 1-2 C _1-4Alkyl further replaces;

R ³Be C _1-4Alkoxyl group, halogen or hydrogen;

R ⁴Be the optional phenyl that is replaced by 1-2 fluorine or chlorine;

R ⁵Be hydrogen or methyl;

R ⁶And R ⁷Independent is hydrogen, fluorine, chlorine or methyl;

R ⁸Be 2-phosphonato ethyl;

R ⁹Be hydrogen, methyl or ethyl.

A is formula (a) group of above definition;

X is NH;

M is 0,1 or 2;

Z is-NR ¹R ²

R ¹And R ²The nitrogen that connects with them constitutes the optional 5-6 unit saturated rings that comprises an extra nitrogen-atoms, and wherein said ring is selected from phosphonato and C on carbon or nitrogen _1-4The group of alkyl replaces, described C _1-4Alkyl by phosphonato or-NR ⁸R ⁹Replace, and described ring is chosen wantonly on carbon or nitrogen by 1-2 C _1-4Alkyl further replaces;

R ³Be C _1-4Alkoxyl group, halogen or hydrogen;

R ⁴Be the optional phenyl that is replaced by 1-2 fluorine or chlorine;

R ⁵Be hydrogen or methyl;

R ⁶And R ⁷Independent is hydrogen, fluorine, chlorine or methyl;

R ⁸Be 2-phosphonato ethyl;

R ⁹Be hydrogen, methyl or ethyl.

A is formula (a) group of above definition;

X is NH;

M is 0,1 or 2;

Z is-NR ¹R ²

R ³Be C _1-4Alkoxyl group;

R ⁴Be the optional phenyl that is replaced by 1-2 fluorine or chlorine;

R ⁵Be hydrogen;

R ⁶And R ⁷The hydrogen of respectively doing for oneself;

R ⁸Be 2-phosphonato ethyl;

R ⁹Be hydrogen, methyl or ethyl.

A is formula (a) group of above definition;

X is NH;

M is 0,1 or 2;

Z is-NR ¹R ²

R ³Be hydrogen;

R ⁴Be the optional phenyl that is replaced by 1-2 fluorine or chlorine;

R ⁵Be hydrogen;

R ⁶And R ⁷The hydrogen of respectively doing for oneself;

R ⁸Be 2-phosphonato ethyl;

R ⁹Be hydrogen, methyl or ethyl.

In the present invention on the other hand, a kind of preferred The compounds of this invention is selected from following any compound:

(1) 1-[3-(the 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] piperidin-4-yl } the methyl dihydrogen phosphate ester;

(2) 2-[[3-({ 4-[(5-{2-[(3,5-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] ethyl phosphonic acid two hydrogen esters;

(3) (2S)-1-[3-(4-[(5-{2-[(3,5-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

(4) (2R)-1-[3-(4-[(5-{2-[(3,5-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

(5) (2S)-1-[3-(the 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

(6) 2-[[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (propyl group) amino] ethyl phosphonic acid two hydrogen esters;

(7) 2-[[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (isobutyl-) amino] ethyl phosphonic acid two hydrogen esters;

(8) 2-[[3-({ 4-[(5-{2-[(3,5-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (isobutyl-) amino] ethyl phosphonic acid two hydrogen esters;

(9) 2-[[3-({ 4-[(5-{2-[(3,5-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (propyl group) amino] ethyl phosphonic acid two hydrogen esters;

(10) 2-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (isobutyl-) amino] ethyl phosphonic acid two hydrogen esters;

(11) 2-{ (2, the 2-dimethyl propyl) [3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(12) 1-[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] piperidines-3-base dihydrogen phosphate;

(13) (2R)-1-[3-(4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

(14) 2-[[3-({ 4-[(5-{2-[(3,5-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (third-2-alkynes-1-yl) amino] ethyl phosphonic acid two hydrogen esters;

(15) 2-[[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (sec.-propyl) amino] ethyl phosphonic acid two hydrogen esters;

(16) 2-[[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (third-2-alkynes-1-yl) amino] ethyl phosphonic acid two hydrogen esters;

(17) 2-[[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (2-methoxy ethyl) amino] ethyl phosphonic acid two hydrogen esters;

(18) 2-{[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(19) 2-{ (cyclobutylmethyl) [3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(20) 2-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (3,3, the 3-trifluoro propyl) amino] ethyl phosphonic acid two hydrogen esters;

(21) 2-{ allyl group [3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(22) 2-{ cyclobutyl [3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(23) 2-{ cyclopentyl [3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(24) 2-{ cyclopropyl [3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(25) 2-{ (cyclopropyl methyl) [3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(26) 2-{ cyclobutyl [3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

Or its pharmacy acceptable salt.

A kind of preferred The compounds of this invention is selected from following any compound:

(1) 2-{4-[({4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) methyl] piperidines-1-yl } ethyl phosphonic acid two hydrogen esters;

(2) 2-[[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] ethyl phosphonic acid two hydrogen esters;

(3) 2-[[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (sec.-propyl) amino] ethyl phosphonic acid two hydrogen esters;

(4) 3-{[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) propyl group] amino }-3-methyl butyl dihydrogen phosphate;

(5) 2-{ (2S)-1-[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } ethyl phosphonic acid two hydrogen esters;

(6) (2R)-1-[3-(4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

(7) 2-[[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (propyl group) amino] ethyl phosphonic acid two hydrogen esters;

(8) 2-[[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (butyl) amino] ethyl phosphonic acid two hydrogen esters;

(9) 2-{ cyclopentyl [3-({ 4-[(5-{2-[(2,3-difluorophenyl)-amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(10) (2S)-1-[3-(4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

(11) (2S)-1-[3-(the 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

(12) 2-{ cyclopentyl [3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(13) 2-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] ethyl phosphonic acid two hydrogen esters;

(14) 2-{[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) propyl group] amino }-2-methyl-propyl dihydrogen phosphate;

(15) 2-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (propyl group) amino] ethyl phosphonic acid two hydrogen esters;

(16) (2R)-1-[3-(the 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

(17) 3-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] the propyl group dihydrogen phosphate

(18) 2-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) propyl group] (2-methoxy ethyl) amino] ethyl phosphonic acid two hydrogen esters

(19) 2-[[4-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) butyl] (propyl group) amino] ethyl phosphonic acid two hydrogen esters;

(20) 2-[[4-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) butyl] (ethyl) amino] ethyl phosphonic acid two hydrogen esters;

(21) (2R)-1-[4-(4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) butyl] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

(22) 2-[[4-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) butyl] (methyl) amino] ethyl phosphonic acid two hydrogen esters;

(23) (2S)-1-[4-(4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) butyl] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

Or its pharmacy acceptable salt.

Further preferred compound is:

The 2-{ ethyl [3-(6-fluoro-4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

Or its pharmacy acceptable salt.

A kind of preferred compound is selected from following any compound:

(2) (2S)-1-[3-(the 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

(3) 2-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (isobutyl-) amino] ethyl phosphonic acid two hydrogen esters;

(4) 2-{ (2, the 2-dimethyl propyl) [3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(5) 1-[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] piperidines-3-base dihydrogen phosphate;

(6) 2-{[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(7) 2-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-1 H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (3,3, the 3-trifluoro propyl) amino] ethyl phosphonic acid two hydrogen esters;

(8) 2-{ cyclopropyl [3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(9) 2-{ cyclobutyl [3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(10) (2S)-1-[3-(the 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

(11) 2-{ cyclopentyl [3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(12) 2-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] ethyl phosphonic acid two hydrogen esters;

(13) 2-{[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) propyl group] amino }-2-methyl-propyl dihydrogen phosphate;

(14) 2-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (propyl group) amino] ethyl phosphonic acid two hydrogen esters;

(15) (2R)-1-[3-(the 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

(16) 3-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] the propyl group dihydrogen phosphate;

(17) 2-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) propyl group] (2-methoxy ethyl) amino] ethyl phosphonic acid two hydrogen esters;

(18) 2-{ ethyl [3-({ 6-fluoro-4-[(5-{2-[(3-fluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

Or its pharmacy acceptable salt.

A kind of further preferred compound is selected from following any compound:

(7) 2-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (3,3, the 3-trifluoro propyl) amino] ethyl phosphonic acid two hydrogen esters;

Or its pharmacy acceptable salt.

Other preferred compound is following any compound:

(1) 2-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (isobutyl-) amino] ethyl phosphonic acid two hydrogen esters;

(2) 2-{ (2, the 2-dimethyl propyl) [3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(3) 2-{[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(4) 2-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (3,3, the 3-trifluoro propyl) amino] ethyl phosphonic acid two hydrogen esters;

(5) 2-{ cyclopropyl [3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(6) 2-{ cyclobutyl [3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

Or its pharmacy acceptable salt.

A kind of particularly preferred compound is selected from following any compound:

(1) (2S)-1-[3-(the 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

(2) 2-{ cyclopentyl [3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(3) 2-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] ethyl phosphonic acid two hydrogen esters;

(4) 2-([3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) propyl group] amino }-2-methyl-propyl dihydrogen phosphate;

(5) 2-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (propyl group) amino] ethyl phosphonic acid two hydrogen esters;

(6) (2R)-1-[3-(the 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

(7) 3-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] the propyl group dihydrogen phosphate;

(8) 2-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) propyl group] (2-methoxy ethyl) amino] ethyl phosphonic acid two hydrogen esters;

Or its pharmacy acceptable salt.

A kind of especially preferred The compounds of this invention is selected from following any compound:

(1) 2-{ cyclopentyl [3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(2) 2-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] ethyl phosphonic acid two hydrogen esters;

(3) 2-{[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) propyl group] amino }-2-methyl-propyl dihydrogen phosphate;

(4) 2-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (propyl group) amino] ethyl phosphonic acid two hydrogen esters;

(5) 3-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] the propyl group dihydrogen phosphate;

(6) 2-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) propyl group] (2-methoxy ethyl) amino] ethyl phosphonic acid two hydrogen esters;

Or its pharmacy acceptable salt.

A kind of further preferred compound is selected from following any compound:

(1) 2-[[3-({ 4-[(5-{2-[(3,5-difluorophenyl) amino]-the 2-oxoethyl)-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] ethyl phosphonic acid two hydrogen esters;

(2) (2S)-1-[3-(4-[(5-{2-[(3,5-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

(3) (2R)-1-[3-(4-[(5-{2-[(3,5-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

(4) 2-[[3-({ 4-[(5-{2-[(3,5-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (isobutyl-) amino] ethyl phosphonic acid two hydrogen esters;

(5) 2-[[3-({ 4-[(5-{2-[(3,5-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (propyl group) amino] ethyl phosphonic acid two hydrogen esters;

(6) 2-[[3-({ 4-[(5-{2-[(3,5-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (third-2-alkynes-1-yl) amino] ethyl phosphonic acid two hydrogen esters;

Or its pharmacy acceptable salt.

A kind of further preferred compound is selected from following any compound:

(1) 2-[[3-({ 4-[(5-{2-[(3,5-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] ethyl phosphonic acid two hydrogen esters;

(2) 2-[[3-({ 4-[(5-{2-[(3,5-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (isobutyl-) amino] ethyl phosphonic acid two hydrogen esters;

(3) 2-[[3-({ 4-[(5-{2-[(3,5-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (propyl group) amino] ethyl phosphonic acid two hydrogen esters;

(4) 2-[[3-({ 4-[(5-{2-[(3,5-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (third-2-alkynes-1-yl) amino] ethyl phosphonic acid two hydrogen esters;

Or its pharmacy acceptable salt.

Another kind of preferred compound is selected from following any compound:

(1) 2-[[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (propyl group) amino] ethyl phosphonic acid two hydrogen esters;

(2) 2-[[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (isobutyl-) amino] ethyl phosphonic acid two hydrogen esters;

(3) (2R)-1-[3-(4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

(4) 2-[[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (sec.-propyl) amino] ethyl phosphonic acid two hydrogen esters;

(5) 2-[[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (third-2-alkynes-1-yl) amino] ethyl phosphonic acid two hydrogen esters;

(6) 2-[[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (2-methoxy ethyl) amino] ethyl phosphonic acid two hydrogen esters;

(7) 2-{ (cyclobutylmethyl) [3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(8) 2-{ allyl group [3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(9) 2-(cyclobutyl [3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-2-oxoethyl }-1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(10) 2-{ cyclopentyl [3-({ 4-[(5-(2-[(2,3-difluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(11) 2-{ (cyclopropyl methyl) [3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(12) 2-{4-[({4-[(5-{2-[(2,3-two-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) methyl] piperidines-1-yl } ethyl phosphonic acid two hydrogen esters;

(13) 2-[[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] ethyl phosphonic acid two hydrogen esters;

(14) 2-[[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (sec.-propyl) amino] ethyl phosphonic acid two hydrogen esters;

(15) 3-{[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) propyl group] amino }-3-methyl butyl dihydrogen phosphate;

(16) 2-{ (2S)-1-[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } ethyl phosphonic acid two hydrogen esters;

(17) (2R)-1-[3-(4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

(18) 2-[[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (propyl group) amino] ethyl phosphonic acid two hydrogen esters;

(19) 2-[[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (butyl) amino] ethyl phosphonic acid two hydrogen esters;

(20) 2-{ cyclopentyl [3-({ 4-[(5-{2-[(2,3--difluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(21) (2S)-1-[3-(4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

(22) 2-[[4-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) butyl] (propyl group) amino] ethyl phosphonic acid two hydrogen esters;

(23) 2-[[4-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) butyl] (ethyl) amino] ethyl phosphonic acid two hydrogen esters;

(24) { (2R)-]-[4-(4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) butyl] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

(25) 2-[[4-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) butyl] (methyl) amino] ethyl phosphonic acid two hydrogen esters;

(26) (2S)-1-[4-(4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) butyl] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

Or its pharmacy acceptable salt.

(9) 2-{ cyclobutyl [3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(10) 2-{ cyclopentyl [3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

Or its pharmacy acceptable salt.

Other preferred compound is following any compound:

(3) 2-[[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (sec.-propyl) amino] ethyl phosphonic acid two hydrogen esters;

(4) 2-[[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (third-2-alkynes-1-yl) amino] ethyl phosphonic acid two hydrogen esters;

(5) 2-[[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (2-methoxy ethyl) amino] ethyl phosphonic acid two hydrogen esters;

(6) 2-{ (cyclobutylmethyl) [3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(7) 2-{ allyl group [3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(8) 2-{ cyclobutyl [3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(9) 2-{ cyclopentyl [3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(10) 2-{ (cyclopropyl methyl) [3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

Or its pharmacy acceptable salt.

Other preferred compound is following any compound:

(2) 2-[[3-({ 4-[(5-(2-[(2,3-difluorophenyl) amino]-2-oxoethyl }-1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] ethyl phosphonic acid two hydrogen esters;

(9) 2-{ cyclopentyl [3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(11) 2-[[4-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) butyl] (propyl group) amino] ethyl phosphonic acid two hydrogen esters;

(12) 2-[[4-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) butyl] (ethyl) amino] ethyl phosphonic acid two hydrogen esters;

(13) (2R)-1-[4-(4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) butyl] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

(14) 2-[[4-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) butyl] (methyl) amino] ethyl phosphonic acid two hydrogen esters;

(15) (2S)-1-[4-(4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) butyl] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

Or its pharmacy acceptable salt.

Other preferred compound is following any compound:

(1) 2-[[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] ethyl phosphonic acid two hydrogen esters;

(2) 2-[[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (sec.-propyl) amino] ethyl phosphonic acid two hydrogen esters;

(3) 3-{[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) propyl group] amino }-3-methyl butyl dihydrogen phosphate;

(4) 2-[[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (propyl group) amino] ethyl phosphonic acid two hydrogen esters;

(5) 2-[[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (butyl) amino] ethyl phosphonic acid two hydrogen esters;

(6) 2-{ cyclopentyl [3-({ 4-[(5-(2-[(2,3-difluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters;

(7) 2-[[4-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) butyl] (propyl group) amino] ethyl phosphonic acid two hydrogen esters;

(8) 2-[[4-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) butyl] (ethyl) amino] ethyl phosphonic acid two hydrogen esters;

(9) 2-[[4-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) butyl] (methyl) amino] ethyl phosphonic acid two hydrogen esters;

Or its pharmacy acceptable salt.

Further particularly preferred compound is selected from following any compound:

(4) (2S)-1-[3-(the 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

(6) (2R)-1-[3-(4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

(7) 2-{ (2S)-1-[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } ethyl phosphonic acid two hydrogen esters;

(8) (2R)-1-[3-(4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

(9) (2S)-1-[3-(4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

(11) (2R)-1-[3-(the 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

(12) (2R)-1-[4-(4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) butyl] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

(13) (2S)-1-[4-(4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) butyl] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester;

Or its pharmacy acceptable salt.

The further embodiment of the present invention comprises following any compound:

(1) N-(2, the 3-difluorophenyl)-2-{3-[(7-{[1-(2-hydroxyethyl) piperidin-4-yl] methoxyl group } quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(2) N-(2, the 3-difluorophenyl)-2-{3-[(7-{3-[(3-hydroxyl-1, the 1-dimethyl propyl) amino] propoxy-} quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(3) N-(2, the 3-difluorophenyl)-2-{3-[(7-{3-[(2S)-2-(2-hydroxyethyl) tetramethyleneimine-1-yl] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(4) (butyl) amino N-(2, the 3-difluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(5) 2-{3-[(7-{3-[cyclopentyl (2-hydroxyethyl) amino] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(2, the 3-difluorophenyl) ethanamide;

(6) N-(2, the 3-difluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl) tetramethyleneimine-1-yl] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(7) N-(3-fluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl) tetramethyleneimine-1-yl] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(8) 2-{3-[(7-{3-[cyclopentyl (2-hydroxyethyl) amino] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(3-fluorophenyl) ethanamide;

(9) N-(3-fluorophenyl)-2-{3-[(7-{3-[ethyl (2-hydroxyethyl) amino] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(10) N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyl-1, the 1-dimethyl ethyl) amino] propoxy-} quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(11) (propyl group) amino N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(12) N-(3-fluorophenyl)-2-{3-[(7-{3-[(2R)-2-(hydroxymethyl) tetramethyleneimine-1-yl] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(13) (propyl group) amino N-(2, the 3-difluorophenyl)-2-{3-[(7-{4-[(2-hydroxyethyl)] butoxy }-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(14) N-(3-fluorophenyl)-2-{3-[(7-{4-[ethyl (2-hydroxyethyl) amino] butoxy }-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(15) N-(2, the 3-difluorophenyl)-2-{3-[(7-{4-[(2R)-2-(hydroxymethyl) tetramethyleneimine-1-yl] butoxy }-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(16) (methyl) amino N-(2, the 3-difluorophenyl)-2-{3-[(7-{4-[(2-hydroxyethyl)] butoxy } quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(17) N-(2, the 3-difluorophenyl)-2-{3-[(7-{4-[(2S)-2-(hydroxymethyl) tetramethyleneimine-1-yl] butoxy }-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(18) 2-{3-[(7-{3-[ethyl (3-hydroxypropyl) amino] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(3-fluorophenyl) ethanamide;

(19) (2-methoxy ethyl) amino N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)] propoxy-} quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(20) 2-{3-[(7-{3-[ethyl (2-hydroxyethyl) amino] propoxy-}-6-fluquinconazole quinoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(3-fluorophenyl) ethanamide;

Or its pharmacy acceptable salt.

The route of synthesis of any compound can find in an embodiment.

The preferred compound of this embodiment is selected from following any compound:

(1) N-(3-fluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl) tetramethyleneimine-1-yl] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(2) 2-{3-[(7-{3-[cyclopentyl (2-hydroxyethyl) amino] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(3-fluorophenyl) ethanamide;

(3) N-(3-fluorophenyl)-2-{3-[(7-{3-[ethyl (2-hydroxyethyl) amino] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(4) N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyl-1, the 1-dimethyl ethyl) amino] propoxy-} quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(5) (propyl group) amino N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(6) N-(3-fluorophenyl)-2-{3-[(7-{3-[(2R)-2-(hydroxymethyl) tetramethyleneimine-1-yl] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(7) N-(3-fluorophenyl)-2-{3-[(7-{4-[ethyl (2-hydroxyethyl) amino] butoxy }-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(8) 2-{3-[(7-{3-[ethyl (3-hydroxypropyl) amino] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(3-fluorophenyl) ethanamide;

(9) (2-methoxy ethyl) amino N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl)] propoxy-} quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(10) 2-{3-[(7-{3-[ethyl (2-hydroxyethyl) amino] propoxy-}-6-fluquinconazole quinoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(3-fluorophenyl) ethanamide;

Or its pharmacy acceptable salt.

Other preferred compound is following any compound:

(7) (propyl group) amino N-(2, the 3-difluorophenyl)-2-{3-[(7-{4-[(2-hydroxyethyl)] butoxy }-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(8) N-(2, the 3-difluorophenyl)-2-{3-[(7-{4-[(2R)-2-(hydroxymethyl) tetramethyleneimine-1-yl] butoxy }-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(9) (methyl) amino N-(2, the 3-difluorophenyl)-2-{3-[(7-{4-[(2-hydroxyethyl)] butoxy } quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(10) N-(2, the 3-difluorophenyl)-2-{3-[(7-{4-[(2S)-2-(hydroxymethyl) tetramethyleneimine-1-yl] butoxy }-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

Or its pharmacy acceptable salt.

On the other hand, the invention provides the method for a kind of preparation formula (I) compound or its pharmacy acceptable salt, this method comprises by the suitable hydroxyl of phosphorylation formula (II) compound is converted into formula (I) compound:

Formula (II)

Wherein A, X, m, R ³, R ⁴, R ⁵, R ⁶, R ⁷And R ⁹Be the definition in the formula (I);

Z ' is selected from-NR ^{1 '}R ^{2 '}, hydroxyl, the C that replaced by hydroxyl or hydroxyl _1-4The C that alkyl replaces _3-6Cycloalkyl and contain a nitrogen-atoms and the also optional 4-7 unit ring that contains a nitrogen-atoms by what carbon atom connected, described ring can be for saturated, unsaturated or fractional saturation, the C that wherein said ring is replaced by hydroxyl or hydroxyl on carbon or nitrogen _1-4Alkyl replaces, and described ring is chosen wantonly on carbon or nitrogen by 1,2 or 3 halogen or C _1-4Alkyl further replaces; R ^{1 '}Be selected from-COR ^{8 '},-CONR ^{8 '}R ⁹And C _1-6Alkyl, wherein C _1-6Alkyl is replaced by hydroxyl and chooses wantonly and further replaced by 1-2 halogen or methoxyl group; R ^{2 '}Be selected from hydrogen ,-COR ¹⁰,-CONR ¹⁰R ¹¹With optional by 1-3 halogen or C _1-4Alkoxyl group or-S (O) _pR ¹¹The C that (p is 0,1 or 2) or hydroxyl replace _1-6Alkyl, perhaps R ^{2 '}Be selected from C _2-6Thiazolinyl, C _2-6Alkynyl, C _3-6Cycloalkyl and C _3-6Cycloalkyl C _1-4Alkyl; Perhaps R ^{1 '}And R ^{2 '}The nitrogen that connects with them constitutes 4-7 unit ring, and it is also chosen wantonly and contains a nitrogen-atoms, and described ring can be saturated, unsaturated or fractional saturation, and is selected from hydroxyl and C on carbon or nitrogen _1-4The group of alkyl replaces, wherein C _1-4Alkyl by hydroxyl or-NR ^{8 '}R ⁹Replace, and described ring is chosen wantonly on carbon or nitrogen by 1,2 or 3 halogen or C _1-4Alkyl further replaces; R ^{8 '}C for the hydroxyl replacement _1-4Alkyl, and optional further replaced by 1-2 halogen or methoxyl group:

After this, can carry out following steps if desired:

I) formula (I) compound is converted into another kind of formula (I) compound; And/or

Ii) slough any blocking group; And/or

Iii) generate its pharmacy acceptable salt.

Phosphorylation reaction is fit to following carrying out: under inert atmosphere, handle 30min to 4h with 1-H tetrazolium (or suitable alternative for example S-ethyl tetrazolium or pyridine  hydrochloride) and diethylamino phosphorous acid di tert butyl carbonate or diethylamino phosphorous acid dibenzyl ester at 5-35 ℃, for example metachloroperbenzoic acid (mCPBA) or 30% aqueous hydrogen peroxide solution are handled 2-18h in-10 to 25 ℃ with oxygenant then.Concerning mentioned reagent, final step need be sloughed tertiary butyl blocking group and produce bound phosphate groups, can be easy to the following blocking group of sloughing: with 1 of 4.0N hydrochloric acid, 4-two  alkane solution are handled 12-18h at 10-35 ℃.

This method comprises that further (wherein Z ' is-NR preparation formula (II) compound ^{1 '}R ^{2 '}) method, this method comprises makes formula (III) compound, wherein L is a for example halogen (for example chlorine) of leavings group:

Formula (III)

React with following formula (IV) amine:

Formula (IV).

The suitable reaction conditions of this method comprises: exist or do not exist under the appropriate catalyst (for example tetrabutylammonium iodide or potassiumiodide), formula (III) compound and excessive formula (IV) amine (for example N,N-DIMETHYLACETAMIDE) in inert solvent are heated 12-72h in 50-100 ℃.In an alternative method, leavings group L can be a formaldehyde in the formula (III), with the reaction of amine (IV) can be under reductive condition with reductive agent for example sodium cyanoborohydride finish.

Formula (IV) amine is known in the art, perhaps can be prepared by methods known in the art by those of skill in the art.

Described method may further include preparation formula (III) compound, and (wherein X is NR ¹⁴) method, this method comprises makes the formula V compound, wherein R ' and R " be for example methyl and ethyl of alkyl, L is the definition in the formula (III):

Formula V

With following formula (VI) compound reaction, wherein R can be for hydrogen or such as the group of tert-butoxycarbonyl (Boc) or trityl:

Formula (VI)

Such reaction can realize under the condition of document introduction, for example formula V compound and formula (VI) compound is heated 2-18h in 100-130 ℃ in solvent (for example acetate).

Perhaps, described method may further include preparation formula (III) compound (wherein X is NR ¹⁴, O or S) method, this method comprises makes formula (VII) compound, wherein R ^*Be leavings group halogen (for example chlorine) for example:

Formula (VII)

With the reaction of formula (VI) compound, wherein R can be hydrogen, tert-butoxycarbonyl (Boc) or trityl.Such reaction can realize under the condition of document introduction, for example at acid catalyst for example in the presence of the hydrochloric acid, with formula (VII) compound and formula (VI) compound in solvent (for example Virahol or N,N-DIMETHYLACETAMIDE) in 80-100 ℃ of heating 2-6h.Perhaps, more than reaction can be reacted 2-6h in 50-80 ℃ with for example sodium hydride realization of alkali in inert solvent (for example dimethyl formamide).

The formula V compound can be used formula (VIII) compound, and wherein P is a for example benzyl of hydroxy-protective group:

Formula (VIII)

Make the reaction of formula (VIII) compound and formula (IX) compound, wherein L ' is a for example halogen (for example bromine) of leavings group, and L is the definition in the formula (III):

Formula (IX)

Such reaction can be finished (method of introducing already with document slough blocking group after) under the condition of document introduction; for example in the presence of catalyzer (for example cesium carbonate), formula (VIII) compound and formula (IX) compound are for example heated 1-4h in 80-100 ℃ in the acetonitrile at solvent.

The method of preparation formula (VIII) compound comprises makes formula (X) compound, and wherein P is the definition in the formula (VIII):

Formula (X)

With suitable acetal N for example, the reaction of dinethylformamide dimethylacetal.This reaction be adapted at organic solvent for example in toluene or the benzene in high temperature (being adapted at the reflux temperature of solvent) reaction down.

Formula (X) compound is a known compound, perhaps can be prepared with ordinary method by those of skill in the art.Specifically, formula (X) compound can be by reduction corresponding formula (XI) nitro-compound, and wherein P is the definition in the formula (VIII):

Formula (XI)

Proper reaction conditions illustrates hereinafter.

Formula (XI) compound can pass through nitration (XII) compound and obtain, and wherein P is the definition in the formula (VIII)

Formula (XII)

For example use nitric acid as nitrating agent.Proper reaction conditions also illustrates hereinafter.

Can react according to example explanation hereinafter with corresponding formula (XIII) aldehyde and azanol and obtain formula (XII) nitrile.

Formula (XIII)

Described method may further include the method for preparation formula (VII) compound, and this method comprises makes formula (XIV) compound

Formula (XIV)

L wherein ^*Be hydroxyl, with suitable for example thionyl chloride, phosphoryl chloride or phosphorus pentachloride reaction of chlorizating agent.Proper reaction conditions also illustrates hereinafter.

Formula (XIV) compound is a known compound, perhaps can be prepared with ordinary method by those of skill in the art.Specifically, formula (XIV) compound can through type (XV) compound, wherein L " be for example halogen (fluorine) of leavings group

Formula (XV)

With formula (XVI) compound prepared in reaction, wherein L ^*Be hydroxyl:

Formula (XVI)

Proper reaction conditions illustrates hereinafter.

Formula (XV) compound is a known compound, perhaps can be prepared with ordinary method by those of skill in the art.Specifically, formula (XV) compound can be prepared as follows: make formula (XVII) compound (wherein L " be leavings group halogen (fluorine) for example, L  is alkoxyl group or hydroxyl) and clean methane amide at 140-200 ℃ of reaction 3-6h.

Formula (XVII)

Proper reaction conditions illustrates hereinafter.

Formula (XVII) compound is a known compound, perhaps can be prepared with ordinary method by those of skill in the art.Specifically, formula (XVII) compound can be prepared as follows: with formula (XVIII) compound (wherein L " be leavings group halogen (fluorine) for example, L  is alkoxyl group or hydroxyl) with reductive agent for example V-Brite B at water: in the dichloromethane solvent system in room temperature reduction 1-3h.

Formula (XVIII)

Formula (XVIII) compound can pass through nitration (XIX) compound and obtain, wherein L " and L  be definition in the formula (XVIII)

Formula (XIX)

Described method comprises further that also (wherein X is NR to preparation formula (VI) compound ¹⁴, O or S) method, this method is included in coupler (for example O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea  hexafluorophosphate) and diisopropylethylamine exists down, makes formula (XX) compound, wherein P is suitable blocking group:

Formula (XX)

With formula HNR ⁴R ⁵Amine is reaction under inertia, anhydrous condition in solvent (for example N,N-DIMETHYLACETAMIDE).

(wherein X is NR to formula (XX) compound ¹⁴, P is COOR) and can use formula (XXI) compound:

Formula (XXI)

Itself and formula (XXII) compound are reacted, and wherein L is suitable leavings group:

Formula (XXII)

The suitable agent and the reaction conditions of this reaction comprise: under nitrogen atmosphere, use tert-Butyl dicarbonate and triethylamine in tetrahydrofuran (THF) in 0 ℃ of reaction.

Formula (III) compound can also through type (XX) compound (sloughing the protection back) and formula V compound prepared in reaction under the condition that document is introduced, for example with reaction mixture solvent for example in the acetate in 100-130 ℃ of heating 2-18h.Can exist down at coupler (for example O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea  hexafluorophosphate) and diisopropylethylamine then, with product formula (XXIII) compound:

Formula (XXIII)

In addition; formula (XXIII) compound can also be prepared as follows: formula (XX) compound of deprotection and formula (VII) compound are reacted under the condition of document introduction; for example in the presence of acid catalyst (for example hydrochloric acid), reaction mixture is heated 2-6h in 80-100 ℃ in solvent (for example Virahol or N,N-DIMETHYLACETAMIDE).Perhaps this reaction can with alkali for example sodium hydride finish, inert solvent for example in the dimethyl formamide in 50-80 ℃ of reaction 2-6h.

Formula (XXI) compound that contains heteroaromatic rings prepares according to document.But still illustrate,

When A was the pyrazoles ring, formula (XXI) compound can be according to following flow preparation:

Can be understood that the different ring substituents of The compounds of this invention part can be before or after aforesaid method introduces or can obtain by conventional modified with functional group by the substitution reaction of standard aromatics, this is included in preparation method of the present invention aspect equally.Such reaction and modification for example comprise introduces substituting group, reduction substituting group, alkylation substituting group or oxidation substituting group by the aromatics substitution reaction.The reagent of these steps and reaction conditions are well-known at chemical field.The object lesson of aromatics substitution reaction comprises with concentrated nitric acid introduces nitro, introduces acyl group with for example acyl halide and Lewis acid (for example aluminum chloride) under Friedel Crafts condition; Under Friedel Crafts condition, introduce alkyl with alkylogen and Lewis acid (for example aluminum chloride); Introduce halogen.The object lesson of modifying comprises nitroreduction for amino, for example with the nickel catalyzator catalytic hydrogenation or with iron heat treated in the presence of hydrochloric acid; Alkylthio is oxidized to alkyl sulphinyl or alkyl sulphonyl.

Also accessible is in some reaction mentioned in this article, any sensitive group of the compound that may need protection.Those skilled in the art know and need protection in what situations and suitable guard method.Use GPF (General Protection False group (about illustrating referring to T.W.Green Protective Groups in Organic Synthesis, John Wiley andSons, 1991) according to standard operation.Thus, if reactant comprises for example amino, carboxyl or hydroxyl, then need in some reaction mentioned in this article, protect such group.

The appropriate protection group of amino or alkylamino has for example acyl group, for example alkyloyl (for example ethanoyl); Alkoxy carbonyl, for example methoxycarbonyl, ethoxy carbonyl or tert-butoxycarbonyl; Aryl methoxy carbonyl, for example benzyloxycarbonyl; Or aroyl, for example benzoyl.The deprotection condition of above blocking group must change according to the difference of selected blocking group.Therefore by way of example, such as the acyl group of alkyloyl or alkoxy carbonyl or aroyl can by with suitable alkali for example alkali metal hydroxide (for example lithium hydroxide or sodium hydroxide) hydrolysis slough.Perhaps can slough by for example using suitable acid (example hydrochloric acid, sulfuric acid, phosphoric acid or trifluoroacetic acid) to handle such as the acyl group of tert-butoxycarbonyl, aryl methoxy carbonyl for example benzyloxycarbonyl can be by for example using catalyzer (for example palladium carbon) hydrogenation or sloughing with Lewis acid (for example three (trifluoroacetic acid) boron) processing.Other appropriate protection group of primary amino has for example phthaloyl, can handle with alkylamine (for example dimethylaminopropyl amine) or hydrazine it is sloughed.

The appropriate protection group of hydroxyl for example has acyl group (for example alkyloyl such as ethanoyl, aroyl such as benzoyl) or arylmethyl (for example benzyl).The deprotection condition of above blocking group must change according to the difference of selected blocking group.Therefore by way of example, acyl group for example alkyloyl or aroyl can by with suitable alkali for example alkali metal hydroxide (for example lithium hydroxide or sodium hydroxide) hydrolysis slough.Perhaps, arylmethyl for example benzyl can slough by for example using catalyzer (for example palladium carbon) hydrogenation.

The appropriate protection group of carboxyl has for example esterified group, and for example methyl or ethyl can be sloughed it by for example using alkali (for example sodium hydroxide) hydrolysis; The perhaps tertiary butyl for example can be handled it is sloughed by for example using acid (for example organic acid for example trifluoroacetic acid); Perhaps benzyl for example can be sloughed it by for example using catalyzer (for example palladium carbon) hydrogenation.

Blocking group can be sloughed with the well-known routine techniques of chemical field in any suitable stage of building-up process.

The present invention provides medicinal compositions on the other hand, and said composition comprises formula (I) compound or its pharmacy acceptable salt and the pharmaceutically acceptable diluent or carrier of this paper definition.

The present composition can be the formulation of suitable following application mode: oral (for example is tablet, lozenge, hard or soft balsam wafer, water-based or oiliness suspensoid, emulsion, dispersible powder or granula, syrup or elixir), topical (for example is an emulsifiable paste, ointment, gel, perhaps water-based or butyrous solution or suspensoid), inhalation (for example being fines or liquid aersol), insufflation administration (for example being fines) or parenteral admin (for example are intravenously, the sterile aqueous or the oily solution agent of subcutaneous or intramuscular administration; Or be the suppository of rectal administration).

The present composition can obtain by ordinary method with conventional pharmaceutical excipient well-known in the art.Therefore, the composition that orally uses can comprise for example one or more tinting materials, sweeting agent, seasonings and/or sanitas.

The pharmaceutically acceptable vehicle that is fit to tablet for example comprises inert diluent for example lactose, yellow soda ash, calcium phosphate or lime carbonate, and granulating agent and disintegrating agent for example corn form sediment or alginic acid; Tackiness agent is starch for example; Lubricant is Magnesium Stearate, stearic acid or talcum powder for example; Sanitas is ethyl p-hydroxybenzoate or propylparaben for example, and oxidation inhibitor xitix for example.Tablet is dressing not, perhaps dressing is with the disintegration that changes them and the sorption of activeconstituents in gi tract subsequently, perhaps improve their stability and/or improve outward appearance, in both cases, use conventional Drug coating and method well-known in the art.

Oral compositions can be the hard gelatine capsule agent, and wherein activeconstituents mixes with inert solid diluent (for example lime carbonate, calcium phosphate or kaolin); Perhaps be the hard gelatine capsule agent, wherein activeconstituents and water or oil (for example peanut oil, whiteruss, soya-bean oil, Oleum Cocois or preferably olive oil) or any other acceptable solvent mix.

Aqueous suspension comprises activeconstituents and one or more suspension agents of fines form, for example Xylo-Mucine, methylcellulose gum, HYDROXY PROPYL METHYLCELLULOSE, sodiun alginate, polyvinylpyrrolidone, tragacanth and Sudan Gum-arabic usually; Dispersion agent or wetting agent, for example Yelkin TTS, the condensation product of alkylene oxide and lipid acid (for example polyoxyethylene stearic acid ester), the condensation product of ethylene oxide and long chain aliphatic alcohol (for example 17 carbon vinyloxy group hexadecanols), ethylene oxide and condensation product (for example polyoxyethylene sorbitol monooleate) derived from the part ester of lipid acid and hexitol, the condensation product of ethylene oxide and long chain aliphatic alcohol (for example 17 carbon vinyloxy group hexadecanols), ethylene oxide and condensation product (for example polyoxyethylene sorbitol monooleate) derived from the part ester of lipid acid and hexitol, or ethylene oxide and derived from the condensation product (for example polyethylene anhydro sorbitol monooleate) of the part ester of lipid acid and hexitan.Aqueous suspension can also comprise one or more sanitass (for example ethyl p-hydroxybenzoate or propylparaben), oxidation inhibitor (for example xitix), tinting material, seasonings and/or sweeting agent (for example sucrose, asccharin or aspartame).

The oiliness suspensoid can followingly be prepared: activeconstituents is suspended in vegetables oil (for example peanut oil, sweet oil, sesame oil or Oleum Cocois) or mineral oil (for example whiteruss).The oiliness suspensoid can also comprise thickening material for example beeswax, solid paraffin or hexadecanol.Can add sweeting agent (for example above-mentioned sweeting agent) and seasonings so that agreeable to the taste oral preparations to be provided.Can add oxidation inhibitor (for example xitix) in these compositions preserves.

Being fit to add entry prepares and comprises disperseing of aqueous suspension or solution or cryodesiccated powder or particle activeconstituents and dispersion or wetting agent, suspension agent and one or more sanitass usually.Suitable dispersion or wetting agent and suspension agent are above illustrating.Also can use other vehicle for example sweeting agent, seasonings and tinting material.

Medicinal compositions of the present invention also can be oil-in-water emulsion.Oil phase can be the mixture of vegetables oil (for example sweet oil or peanut oil), mineral oil (for example whiteruss) or any above-mentioned oil.Suitable emulsifying agent can be for for example naturally occurring natural gum (for example Sudan Gum-arabic or tragacanth), naturally occurring phosphatide (for example soybean lecithin), derived from the ester of lipid acid and hexitan or the condensation product (for example polyethenoxy sorbitan monooleate) of part ester (for example anhydro sorbitol monooleate) and described part ester and ethylene oxide.Emulsion also can comprise sweeting agent, seasonings and sanitas.

Syrup and elixir can be used sweeting agent (for example glycerine, propylene glycol, Sorbitol Powder, aspartame or sucrose) preparation, can also comprise negative catalyst, sanitas, seasonings and/or tinting material.

Medicinal compositions also can be water-based or oiliness suspensoid, solution, emulsion or the special system of aseptic injection, and it can be prepared according to currently known methods with one or more above-mentioned suitable dispersant or wetting agent and suspension agent.Aseptic injection preparation can also be aseptic injectable solution or the suspension in nontoxic parenteral acceptable diluent or solvent, for example polyglycol solution.

Suppository can be prepared as follows: with activeconstituents and suitable non-stimulated mixed with excipients, described vehicle is solid at normal temperatures, but is liquid under rectal temperature, therefore will discharge medicine in the rectum fusing.Suitable vehicle comprises for example theobroma oil and polyoxyethylene glycol.

Usually, topical formulations for example emulsifiable paste, ointment, gel and water-based or oily solution agent or suspensoid can followingly obtain: activeconstituents and local acceptable conventional solvent or thinner are prepared according to ordinary method well-known in the art.

The composition that is blown into administration can be the fines form, comprise the mean diameter of particle for for example 30 μ m or below the 30 μ m, preferred 5 μ m or below the 5 μ m, more preferably 5 μ m to 1 μ m, powder itself can only comprise activeconstituents, perhaps with for example lactose dilution of one or more physiologically acceptable carriers.The powder that will be used for insufflation is retained in easily and contains for example capsule of 1-50mg activeconstituents, utilizes the administration of turbine type suction apparatus, for example is used to be blown into the device of known drug Sodium Cromoglicate.

The composition of inhalation can be conventional pressurized aerosol, is used for activeconstituents is assigned as the aerosol that comprises micro-solid or is small droplets.Can use for example volatile hydrocarbon or fluoridize hydro carbons of conventional aerosol propellant, the aerosol device distributes the metered amount activeconstituents easily.

About the further information of preparation, can consult Comprehensive MedicinalChemistry, the 5th volume, 25.2 chapters, (Corwin Hansch director editorial member), Pergamon Press1990.

Therefore, the present invention provides the therepic use of formula (I) compound or its pharmacy acceptable salt on the other hand.Formula (I) compound or its pharmacy acceptable salt purposes as medicine further is provided.Formula (I) compound or its pharmacy acceptable salt also can be used for treatment can benefit from the kinase whose disease of one or more Aurora of inhibition.Specifically, estimate that inhibition Aurora-A kinases and/or Aurora-B kinases may be useful.Preferred inhibition Aurora-B kinases is useful.Formula (I) compound or its pharmacy acceptable salt can be further used for treating hyperproliferative disease for example cancer (especially colorectal carcinoma, mammary cancer, lung cancer, prostate cancer, carcinoma of the pancreas, bladder cancer and kidney) or leukemia or lymphoma.

In addition, formula (I) compound or its pharmacy acceptable salt can be used for treating for example people's method of warm-blooded animal.According to this on the one hand, the invention provides the method that formula (I) compound or its pharmacy acceptable salt are used for the treatment of the people who suffers from disease, described disease can be benefited from and suppress one or more Aurora kinases, and described method comprises formula (I) compound that needs the patient of this treatment significant quantity or the step of its pharmacy acceptable salt.Specifically, estimate that inhibition Aurora-A kinases and/or Aurora-B kinases may be useful.Preferred inhibition Aurora-B kinases is useful.Further provide formula (I) compound or its pharmacy acceptable salt to be used for the treatment of and suffer from for example people's of following hyperproliferative disease method: cancer (especially colorectal carcinoma, mammary cancer, lung cancer, prostate cancer, carcinoma of the pancreas, bladder cancer and kidney) or leukemia or lymphoma, described method comprise formula (I) compound that needs the patient of this treatment significant quantity or the step of its pharmacy acceptable salt.

The present invention provides formula (I) compound or the purposes of its pharmacy acceptable salt in the preparation medicine on the other hand, and described medicine is used for the treatment of can benefit from the kinase whose disease of one or more Aurora of inhibition.Specifically, estimate that inhibition Aurora-A kinases and/or Aurora-B kinases may be useful.Preferred inhibition Aurora-B kinases is useful.The present invention provides formula (I) compound or the purposes of its pharmacy acceptable salt in the preparation medicine on the other hand, and described medicine is used for the treatment of hyperproliferative disease for example cancer (especially colorectal carcinoma, mammary cancer, lung cancer, prostate cancer, carcinoma of the pancreas, bladder cancer and kidney) or leukemia or lymphoma.

For above-mentioned therepic use, dosage will change according to compound used therefor, mode of administration, required treatment, the illness of demonstration and the difference of animal or patient's age or sex.Therefore, dosage need be calculated according to well-known medical science principle.

When formula (I) compound was used for the treatment of or prevents purpose, the per daily dose accepted that gives can give by divided dose if desired for for example 0.05mg/kg-50mg/kg body weight usually.Usually, when adopting the parenteral administration, use lower dosage.Thus, by way of example, for intravenous administration, the dosage range that adopts is for example 0.05mg/kg-25mg/kg body weight usually.Similarly, for the inhalation administration, the dosage of use is for example 0.05mg/1g-25mg/kg body weight.

Methods of treatment defined above can be used as independent therapy and uses, and perhaps except The compounds of this invention, can also relate to routine operation, radiotherapy or chemotherapy.Described chemotherapy can comprise the antitumour drug of one or more following types :-

(i) antiproliferative agents/antitumour drug of using of medical oncology with and combination medicine, for example alkylating agent (for example cis-platinum, carboplatin, endoxan, mustargen, melphalan, Chlorambucil, busulfan and nitrosourea); Metabolic antagonist (antifolate for example, for example fluorine pyrimidine (as 5 FU 5 fluorouracil and Tegafur), thunder are for bent thiophene, methotrexate, cytosine arabinoside and hydroxyurea; Antitumor antibiotics (for example anthracycline such as Zorubicin, bleomycin, Dx, daunorubicin, epirubicin, idarubicin, Mitomycin-C, gengshengmeisu and Plicamycin); Antimitotic drug (for example catharanthus alkaloid such as vincristine(VCR), vincaleucoblastine, vindesine and vinorelbine; Taxanes such as safe element and taxotere); Topoisomerase enzyme inhibitor (for example epipodophyllotoxin (as Etoposide and teniposide), amsacrine, Hycamtin and camptothecine);

(ii) cytostatics estrogen antagonist (tamoxifen for example for example, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogen (bicalutamide for example, flutamide, Nilutamide and acetate cyproterone), lhrh antagonist or LHRH agonist (goserelin for example, Leuprolide and buserelin), progestogen (for example acetate megestrol), aromatase inhibitor (Anastrozole for example, letrozole, vorozole and Exemestane) and 5 inhibitor (for example finasteride);

The (iii) anticancer medicine of invading (for example metalloprotein inhibitors such as Marimastat; The inhibitor of urokinase plasminogen activator function of receptors);

(iv) somatomedin depressant of functions, for example such inhibitor comprise growth factor antibodies, growth factor receptor antibody (anti--erbb2 antibody trastuzumab [Herceptin for example ^TM] and anti--erbb1 antibody Cetuximab [C225]), the Farnesyltransferase inhibitor, tyrosine kinase inhibitor and serine/threonine kinase inhibitor, the inhibitor of epidermal growth factor family (EGFR family tyrosine kinase inhibitor for example for example, N-(3-chloro-4-fluorophenyl)-7-methoxyl group-6-(3-morpholino propoxy-) quinazoline-4-amine (gefitinib for example, AZD1839), N-(3-ethynyl phenyl)-6, two (2-methoxy ethoxy) quinazolines of 7--4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholino propoxy-) quinazoline-4-amine (CI 1033)), for example be derived from the inhibitor of hematoblastic growth factor family and the inhibitor of pHGF family for example;

(v) anti-angiogenic formation medicine for example suppresses medicine (the anti-vascular endothelial cell growth factor antibody rhuMAb-VEGF [Avastin for example of vascular endothelial growth factor effect ^TM], for example International Patent Application WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354 disclosed compound) and the compound (for example linomide, integrin alpha v beta 3 depressant of functions and angiostatin) of other mechanism of action;

(vi) angiolysis medicine, for example disclosed compound among combretastatin A4 and International Patent Application WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and the WO 02/08213;

(vii) antisense therapy, for example at the medicine of above-mentioned target, for example ISIS 2503, a kind of anti--the ras antisense;

(viii) gene therapy, comprise the method for for example replacing aberrant gene (for example unusual p53 or unusual BRCA1 or BRCA2), GDEPT (method of cytosine(Cyt) deaminase, thymidine kinase or bacterium nitroreductase is for example used in the pharmacotherapy of gene targeting enzyme precursor) and increase the method (for example multidrug resistance gene therapy) of patient chemotherapy or radiotherapy tolerance;

(ix) immunotherapy, for example comprise in vitro with body in increase the method for patient tumors cell immunogenicity, for example use cytokine (for example interleukin-22, interleukin 4 or granulocyte-macrophage colony stimutaing factor) transfection; Reduce the method for T-cell incapability; Use the method for the immunocyte (for example dendritic cell of cytokine transfection) of transfection; The method of the tumor cell line of use cytokine transfection and the method for using antiidiotypic antibody.

In addition, The compounds of this invention can be united use with one or more cell cycle inhibitors.Particularly unite use with the cell cycle inhibitor that suppresses bub1, bubR1 or CDK.

Such combination therapy can be simultaneously, sequential or give each component of combination therapy separately.

Such combination medicine product use is above introduced the The compounds of this invention of dosage range and is ratified other medical active medicine of dosage range at it.

Except medical usage, formula (I) compound and pharmacy acceptable salt thereof also can be used as exploitation and standardization body reaches the pharmacological tool of body built-in test system outward, described test macro is used to estimate the cell cycle activity inhibitor in for example effect on cat, dog, rabbit, monkey, rat and the mouse of laboratory animal, and this evaluation is a part of seeking new medicine.

In above other pharmaceutical compositions, step, method, purposes and medication preparation feature, the alternative or preferred embodiment of the The compounds of this invention that this paper introduces is suitable equally.

The compounds of this invention suppresses the serine-threonine kinase activity of Aurora kinases (especially Aurora-A and/or Aurora-B), suppresses cell cycle and cell proliferation thus.These characteristics can be estimated by one or more methods of for example hereinafter introducing.Although do not wish to be subjected to theory, believe that formula (I) compound that this paper introduces can be used as prodrug.In following method (c) with (d), believe in formula (I) compound phosphonato in position cracking obtain hydroxyl and such cracking is essential for the activity in these tests.

(a) external Aurora-A kinase inhibition test

Determine that in this test test-compound suppresses the active ability of serine-threonine kinase.The DNA of coding Aurora-A can synthetic or clone's acquisition by full gene.Then this DNA is expressed in appropriate expression system, obtain having the active polypeptide of serine-threonine kinase.Be under the Aurora-A situation, (PCR) separates encoding sequence from cDNA by polymerase chain reaction, is cloned into BamH1 and the Not1 restriction endonuclease site of rhabdovirus expression vector pFastBac HTc (GibcoBRL/Life technologies).5 ' PCR primer comprise to Aurora-A encoding sequence 5 ' the recognition sequence of restriction endonuclease BamH1.This just allows to press 6 histidine residues, transcribed spacer and the rTEV protease cracking site that frame inserts Aurora-A gene and pFastBacHTc vector encoded.

3 ' PCR primer replaces the Aurora-A terminator codon and has extra encoding sequence, is the recognition sequence of terminator codon and restriction endonuclease Not1 then.This extra encoding sequence (5 ' TAC CCA TAC GAT GTT CCA GAT TAC GCT TCT TAA 3 ') coded polypeptide sequence YPYDVPDYAS.This sequence obtains from influenza virus hemagglutinin, and usually as the marker epitope sequences, this sequence can be identified with monoclonal antibody specific.Therefore, the Aurora-A albumen of 6 histidine marks of reorganization pFastBac vector encoded N-end, influenza virus hemagglutinin epi-position mark C-terminal.The concrete grammar of assembling recombinant DNA molecules can be referring to national textbook, Sambrook etc. for example, 1989, Molecular Cloning-ALaboratory Manual, the 2nd edition, Cold Spring Harbor Laboratory press; Ausubel etc., 1999, Current Protocols in Molecular Biology, John Wileyand Sons Inc.

The preparation of recombinant virus can be carried out according to the scheme of the GibcoBRL of manufacturers.Briefly say, the carrier that carries the Aurora-A gene is transformed into intestinal bacteria (E.coli) the DH10Bac cell that contains baculovirus genome (bacmidDNA), through swivel base, bacmid DNA is directly transferred in the zone that the pFastBac carrier is comprised gentamicin resistant gene and Aurora-A gene (comprising baculovirus polyhedrin body protein promotor) in cell.Select with gentamicin, kantlex, tsiklomitsin and X-gal, gained white colony should comprise the reorganization bacmid DNA of the Aurora-A that encodes.After Bacmid DNA extracted from the small-scale culture of some BH10Bac white colonies, arrive fall army worm (Spodoptera frugiperda) Sf21 cell with CellFECTIN reagent (GibcoBRL) according to the specification sheets transfection of manufacturers, described cell is grown in containing the TC100 substratum (GibcoBRL) of 10% serum.Behind transfection 72h, by collecting cell substratum results virion.Infect the suspension culture that 100ml contains 1 * 107 cell/ml Sf21 with the 0.5ml substratum.After infecting 48h, the harvested cell substratum is determined virus titer with the standard blob analytical method.Virus stocks is used for infecting Sf9 and " High5 " cell to determine the proteic expression of reorganization Aurora-A with infection multiplicity (MOI) 3.

For extensive expression Aurora-A kinase activity, the Sf21 insect cell in 28 ℃ of growths, rolls with 3r.p.m on the Wheaton tourelle in the TC100 substratum that replenishes 10% foetal calf serum (Viralex) and 0.2%F68 Pluronic (Sigma).Cell density reaches 1.2 * 10 ⁶Behind cell/ml, they are infected with infection multiplicity 1 with the pure Aurora-A recombinant virus of plaque, gather in the crops behind the 48h.All purification steps subsequently carry out under 4 ℃.To comprise 2.0 * 10 altogether ⁸The freezing insect cell precipitation of cell thaws per 3 * 10 ⁷Cell is with pH7.44 ℃ of 1.0ml molten born of the same parents' damping fluid (25mM HEPES (N-[2-hydroxyethyl] piperazine-N '-[2 ethane sulfonic aicd]), 100mM KCl, 25mM NaF, 1mM Na ₃VO ₄, 1mM PMSF (phenyl methyl sulfonic acid fluoride), 2mM 2 mercapto ethanol, 2mM imidazoles, 1 μ g/ml Trypsin inhibitor,Trasylol, 1 μ g/ml Gastric inhibitory polypeptide, 1 μ g/ml leupeptin) dilution.Realize lysis with Dounce homogenizer, subsequently with lysate with 41, the centrifugal 35min of 000g.The supernatant liquor of sucking-off is injected the chromatographic column of the diameter 5mm that contains 500 μ l Ni NTA (nitrilo-three-acetate) agaroses (Qiagen, production code member 30250), and chromatographic column has been used molten born of the same parents' damping fluid balance.After using the molten born of the same parents' damping fluid of 12ml, 7ml lavation buffer solution (4 ℃ of 25mM HEPES pH7.4,100mM KCl, 20mM imidazoles, 2mM 2 mercapto ethanol) washing chromatographic column successively, the UV that reaches elutriant absorbs baseline values.Bonded Aurora-A albumen is come out from the chromatographic column wash-out with elution buffer (4 ℃ of 25mM HEPES pH7.4,100mM KCl, 400mM imidazoles, 2mM2-mercaptoethanol).Collection is corresponding to the wash-out part (2.5ml) of UV absorption peak.To comprise the kinase whose wash-out of active A urora-A and partly use fully dialysis of dialysis damping fluid (4 ℃ of 25mM HEPES pH7.4,45% glycerine (v/v), 100mM KCl, 0.25%Nonidet P40 (v/v), 1mM dithiothreitol (DTT)).

With the Aurora-A enzyme of all new lots in analysis by concentration improves constantly with enzyme thinner (25mMTris-HCl pH7.5,12.5mM KCl, 0.6mM DTT) dilution.For typical batch, the mother liquor enzyme to be diluted with 1: 666 with the enzyme diluent, each is analyzed hole and uses 20 μ l dilution enzyme.With test-compound (10mM methyl-sulphoxide (DMSO) solution) dilute with water, add 10 μ l diluted compounds in each hole of analysis plates." fully " and " blank " control wells 2.5%DMSO alternative compounds.Except " blank " hole, add the enzyme of the new dilution of 20 microlitres in porose.Add 20 microlitre enzyme thinners in " blank " hole.To contain 0.2 μ Ci[γ then ³³P] (Amersham Pharmacia is than 20 microlitre reaction mixtures (25mM Tris-HCl, 78.4mM KCl, 2.5mM NaF, 0.6mM dithiothreitol (DTT), the 6.25mM MnCl of work 〉=2500Ci/mmol) for ATP ₂, 6.25mM ATP, 7.5 μ M peptide substrates [vitamin H-LRRWSLGLRRWSLGLRRWSLGLRRWSLG]) add all test holes and begin reaction.With plate at room temperature incubation 60min.For stopped reaction, add 100 μ l20%v/v ortho-phosphoric acid during institute is porose.With 96 orifice plate harvesting devices (TomTek) peptide substrates is captured positively charged Nitrocellulose P30filtermat (Whatman), analyze with Beta plate counter then ³³The keying action of P." blank " (not having enzyme) and " fully " (not having compound) control value are used for determining that test-compound suppresses the dilution range of 50% enzymic activity.

In this test, the concentration that The compounds of this invention suppresses 50% enzymic activity is that the concentration that compound 5 suppresses 50% enzymic activity among the 0.3nM-1000nM, particularly table 1 is 5.5nM.

(b) external Aurora-B kinase inhibition test

Determine that in this test test-compound suppresses the active ability of serine-threonine kinase.The DNA of coding Aurora-B can synthetic or clone's acquisition by full gene.Then this DNA is expressed in appropriate expression system, obtain having the active polypeptide of serine-threonine kinase.Be under the Aurora-B situation, (PCR) separates encoding sequence from cDNA by polymerase chain reaction, is cloned into pFastBac system (promptly directly expressing the Aurora-B albumen of 6-histidine mark) according to the similar approach of the above-mentioned Aurora-A of being used for.

For extensive expression Aurora-B kinase activity, the Sf21 insect cell in 28 ℃ of growths, rolls with 3r.p.m on the Wheaton tourelle in the TC100 substratum that replenishes 10% foetal calf serum (Viralex) and 0.2%F68 Pluronic (Sigma).Cell density reaches 1.2 * 10 ⁶Behind cell/ml, they are infected with infection multiplicity 1 with the pure Aurora-B recombinant virus of plaque, gather in the crops behind the 48h.All purification steps subsequently carry out under 4 ℃.To comprise 2.0 * 10 altogether ⁸The freezing insect cell precipitation of cell thaws per 2 * 10 ⁷The cell molten born of the same parents' damping fluid of 1.0ml (50mM HEPES (the N-[2-hydroxyethyl] piperazine-N '-[2 ethane sulfonic aicd]) 4 ℃ of pH7.5,1mMNa ₃VO ₄, 1mM PMSF (phenyl methyl sulfonic acid fluoride), 1mM dithiothreitol (DTT), 1 μ g/ml Trypsin inhibitor,Trasylol, 1 μ g/ml Gastric inhibitory polypeptide, 1 μ g/ml leupeptin) dilution.Realize lysis with Soniprep, subsequently with lysate with 41, the centrifugal 35min of 000g.The supernatant liquor of sucking-off is injected the chromatographic column of the diameter 5mm that contains 1.0ml CM Sepharose Fast Flow (Amersham Pharmacia Biotech), and chromatographic column has been used molten born of the same parents' damping fluid balance.After using the molten born of the same parents' damping fluid of 12ml, 7ml lavation buffer solution (pH7.44 ℃ of 50mM HEPES, 1mM dithiothreitol (DTT)) washing chromatographic column successively, the UV that reaches elutriant absorbs baseline values.Bonded Aurora-B albumen is come out from the chromatographic column wash-out with gradient elution damping fluid (pH7.44 ℃ of 25mM HEPES, 0.6mM NaCl, 1mM dithiothreitol (DTT) are from 0% elution buffer to 100% elution buffer, 15min, flow velocity 0.5ml/min).Collection is corresponding to the wash-out part (1.0ml) of UV absorption peak.Wash-out is partly used fully dialysis of dialysis damping fluid (pH7.44 ℃ of 25mM HEPES, 45% glycerine (v/v), 100mM KCl, 0.05% (v/v) IGEPAL CA630 (SigmaAldrich), 1mM dithiothreitol (DTT)).Detect the Aurora-B kinase activity of dialysis part.

With the Aurora-B enzyme of all new lots in analysis by concentration improves constantly with enzyme thinner (25mMTris-HCl pH7.5,12.5mM KCl, 0.6mM DTT) dilution.For typical batch, the mother liquor enzyme to be diluted with 1: 40 with the enzyme thinner, each is analyzed hole and uses 20 μ l dilution enzyme.With test-compound (10mM methyl-sulphoxide (DMSO) solution) dilute with water, add 10 μ l diluted compounds in each hole of analysis plates." fully " and " blank " control wells 2.5%DMSO alternative compounds.Except " blank " hole, add the enzyme of the new dilution of 20 microlitres in porose.Add 20 microlitre enzyme thinners in " blank " hole.To contain 0.2 μ Ci[γ then ³³P] (Amersham Pharmacia is than 20 microlitre reaction mixtures (25mM Tris-HCl, 78.4mM KCl, 2.5mM NaF, 0.6mM dithiothreitol (DTT), the 6.25mM MnCl of work 〉=2500Ci/mmol) for ATP ₂, 37.5mM ATP, 25 μ M peptide substrates [vitamin H-LRRWSLGLRRWSLGLRRWSLGLRRWSLG]) add all test holes and begin reaction.With plate at room temperature incubation 60min.For stopped reaction, add 100 μ l20%v/v ortho-phosphoric acid during institute is porose.With 96 orifice plate harvesting devices (TomTek) peptide substrates is captured positively charged Nitrocellulose P30 filtermat (Whatman), analyze with Beta plate counter then ³³The keying action of P." blank " (not having enzyme) and " fully " (not having compound) control value are used for determining that test-compound suppresses the dilution range of 50% enzymic activity.

In this test, the concentration that The compounds of this invention suppresses 50% enzymic activity is that the concentration that compound 5 suppresses 50% enzymic activity among the 0.3nM-1000nM, particularly table 1 is 1.6nM.

(c) body outer cell proliferation analysis

This analytical procedure and other analytical procedure can be used to detect test-compound to the Mammals adherent cell inhibition ability of human tumor cell line SW620 (ATCC CCL-227) growth for example.This analyzing and testing test-compound is attached to the inhibition ability of cell DNA to Thymine deoxyriboside analogue 5 '-bromo-2 '-deoxidation-urine nucleosides (BrdU).Usually, with SW620 or other adherent cell with 1 * 10 ⁵Cells/well is inoculated into 96 orifice plates (Costar), and described orifice plate through handling and wherein having added the L-15 substratum (GIBCO) that contains 5% foetal calf serum, 1%L-glutamine (100 μ l/ hole), allows its adhesion spend the night.Gave cell compound (with L-15 (containing 5%FCS, 1%L-glutamine) dilution 10mM DMSO mother liquor) in second day.Comprise untreated control wells in all plates and contain known the hole of BrdU in conjunction with 100% compound that suppresses.Exist or do not exist under the test-compound behind the 48h, cell detects with the specification sheets of Boehringer (Roche) Cell Proliferation BrdU ELISA test kit (cat.No.1 647 229) according to manufacturers in the ability of 2h mark phase in conjunction with BrdU.Say simply, add 15 μ lBrdU labelled reagents (to be diluted to substratum-L-15,5%FCS, 1%L-glutamine at 1: 100) in each hole, send plate back to moist (+5%CO ₂), 37 ℃ of incubation case 2h.Behind 2h, the labelled reagent decant is shifted out, on paper handkerchief, strike plate gently.Add FixDenat solution (50 μ l/ hole), with plate at room temperature incubation 45min under vibration.FixDenat solution decant is shifted out, on paper handkerchief, rap the plate of upset.Then with phosphate buffered saline buffer (PBS) washing once, add 100 μ l/ hole Anti-BrdU-POD antibody-solutions (diluting with 1: 100) with antibody dilution buffer with plate.Then the vibration under in room temperature incubation plate 90min.Decant is removed unconjugated Anti-BrdU-POD antibody, uses PBS wash plate 4 times, blots then.Add tmb substrate solution (100 μ l/ hole), the about 10min of incubation is up to the color considerable change under room temperature, vibration.Detect the optical density(OD) in each hole at the 690nm wavelength with Titertek Multiscan plate reader.Compound treatment, be untreated and 100% value that suppresses contrast is used for determining that test-compound suppresses the dilution range of 50%BrdU keying action.In this test, The compounds of this invention has activity at 0.3nM-10000nM, and especially, compound 5 has activity at 0.1nM in the table 1.

(d) cell in vitro cycle analysis

This analytical procedure determines that test-compound stops the ability of cell cycle specified phase.Many different mammal cell lines can be used for this to be analyzed, and comprises the SW620 cell that is used as example herein.With the SW620 cell with 7 * 10 ⁵Cell/T25 flask (Costar) is inoculated into 5ml L-15 (5%FCS, 1%L-glutamine).Then with the 37 ℃ incubation case (5%COs of flask in humidity ₂) be incubated overnight.Second day, the 5 μ lL-15 (5%FCS, 1%L-glutamine) that will contain proper concn test-compound (being dissolved in DMSO) added flask.Also comprise a control treatment (0.5%DMSO) that does not have compound.Then cell is used the compound incubation specified time (24h).After this, with substratum sucking-off from cell, cell separates from flask by tryptic of short duration incubation then with the aseptic PBSA washing of 5ml preheating (37 ℃), be suspended in 5ml and contain the aseptic PBSA of 1% bovine serum albumin (BSA, Sigma-Aldrich Co.).With sample with the centrifugal 10min of 2200rpm.The suction supernatant liquor, remaining 200 μ lPBS/BSA solution.To precipitate by 10 pipettings and be suspended in this 200 μ l solution again, produce individual cells suspension.80% ethanol that 1ml is ice-cold slowly adds each cell suspending liquid, and sample spends the night or when needs dye-20 ℃ of storages.Centrifugation cell is extracted ethanol out, will precipitate to be suspended in the 200 μ l PBS that contain 100 μ g/ml RNAse (Sigma Aldrich) and 10 μ g/ml propidium iodides (Sigma Aldrich) again.At 37 ℃ of incubation cell suspending liquid 30min, add 200 μ l PBS again, sample is in the dark spent the night in 4 ℃ of storages.

Then with all samples with No. 21 pin injection treatment 10 times.Then sample transfer is managed to LPS, pass through fluorescent activation cell sorting (FACS) analyzing DNA content/cell with FACScan flow cytometer (Becton Dickinson).Usually, count and write down 30,000 cells with software CellQuestv1.1 (Verity Software).The cell cycle distribution of cell mass is calculated with software Modfit (Verity Software), is expressed as the percentage of cells that contains 2N (G0/G1), 2N-4N (S stage) and 4N (G2/M) DNA.

In this test, The compounds of this invention has activity at 0.3nM-10000nM.

Below by non-limiting example explanation the present invention, wherein can suitably use the known standard technique of skilled chemical technology personnel and be similar to the technology of introducing among the embodiment under the situation, and except as otherwise noted, otherwise:

(i) evaporation operation is finished by rotary evaporation in vacuo, and subsequent processing steps is to carry out after removing by filter residual solid (for example siccative);

(ii) various operations are at room temperature carried out, and are generally 18-25 ℃, and except as otherwise noted, otherwise in air, carry out, unless perhaps those of skill in the art need carry out other operation under inert atmosphere (for example argon);

(iii) column chromatography (by quick operation) and medium pressure liquid chromatography method (MPLC) are carried out on MerckKieselgel silicon-dioxide (Art.9385);

The yield that (iv) provides only is used as and illustrates, not necessarily obtainable maximum yield;

(v) common, the structure of formula (I) end product confirms by nuclear (being generally proton) mr (NMR) and mass-spectrometric technique; Proton resonance chemical displacement value deuterated methyl-sulphoxide (DMSOd ₆, detect except as otherwise noted), with δ scale (apart from the ppm downfield of tetramethylsilane), use one of following four kinds of instruments:

-Varian Gemini 2000 spectrometers, manipulation fields intensity are 300MHz,

-Bruker DPX300 spectrometer, manipulation fields intensity are 300MHz;

-JEOL EX400 spectrometer, manipulation fields intensity are 400MHz

-Bruker Avance 500 spectrometers, manipulation fields intensity are 500MHz

The following expression of the multiplicity at peak: s, unimodal; D, bimodal; Dd, double doublet; T, triplet; Q, quartet; Qu, quintet; M, multiplet; Bs, wide unimodal;

(vi) the machine synthesis method is used Zymate XP automation, uses Zymate MasterLaboratory Station to add solution, uses Stem RS5000 Reacto-Station 25 ℃ of stirrings;

(vii) following subsequent disposal and purification operations of carrying out automatic synthetic reaction mixture: evaporation uses Genevac HT 4 to carry out under vacuum; Column chromatography uses AnachemSympur MPLC system to carry out on silicon-dioxide, uses and fills Merck silicon-dioxide (60 μ m, the post of diameter 27mm 25g); The structure of end product confirms by LCMS in Waters2890/ZMD micromass system according to following condition, and provides retention time (RT), min:

The asymmetric C18 3.5um of post: Waters 4.6 * 50mm

Solvent orange 2 A: H ₂O

Solvent B:CH ₃CN

Solvent C: methyl alcohol+5%HCOOH

Flow velocity: 2.5ml/min

Working time: 5min, wherein the 4.5min gradient is 0-100%C

Wavelength: 254nm, bandwidth 10nm

Mass detector: ZMD micromass

Volume injected 0.005ml

(viii) handle and in Waters Alliance HT system, carry out, and provide retention time (RT), min according to following condition for the analysis mode LCMS that is not the compound of machine synthesis method preparation:

Post: 2.0mm * 5cm Phenomenex Max-RP 80A

Solvent orange 2 A: water

Solvent B: acetonitrile

Solvent C: methyl alcohol/1% formic acid or water/1% formic acid

Flow velocity: 1.1ml/min

Working time: 5min, wherein the 4.5min gradient is constant 5% solvent of 0-95%B+

C

Wavelength: 254nm, bandwidth 10nm

Volume injected 0.005ml

Mass detector: Micromass ZMD

(ix) preparative high performance liquid chromatography (HPLC) carries out under following arbitrary condition :-Waters prepares type LCMS instrument, and the retention time of mensuration (RT) is expressed as min:

Post: β-alkaline Hypercil (21 * 100mm) 5 μ m

Solvent orange 2 A: water/0.1% volatile salt

Solvent B: acetonitrile

Flow velocity: 25ml/min

Working time: 10min, wherein the 7.5min gradient is 0-100%B

Wavelength: 254nm, bandwidth 10nm

Volume injected 1-1.5ml

Mass detector: Micromass ZMD

-Gilson preparation HPLC instrument, the retention time of measurement (RT) is expressed as min:

Post: 21mm * 15cm Phenomenex Luna2 C18

Solvent orange 2 A: water+0.2% trifluoroacetic acid,

Solvent B: acetonitrile+0.2% trifluoroacetic acid

Flow velocity: 21ml/min

Working time: 20min, wherein the 10minute graded is 5-100%B

Wavelength: 254nm, bandwidth 10nm

Volume injected 0.1-4.0ml

(ix) intermediate does not characterize fully usually, and purity is judged by thin-layer chromatography (TLC), HPLC, infrared (IR), MS or NMR analytical method.

Below each tabular lifted the object lesson of formula (I) compound, wherein * represents the tie point of formula (I) compound above group and each table in each table:

Table 1

Table 2

Table 3

Table 4

Table 5

Embodiment 1-prepares compound 1-{1-[3-({ 4-[(5-{2-[(3-fluorophenyl) amino of table 1]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] piperidin-4-yl } the methyl dihydrogen phosphate ester

With two (tertiary butyls) { 1-[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-2-oxoethyl }-1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] piperidin-4-yl } methyl phosphorodithioate (400mg, 0.53mmol) be suspended in two  alkane (20ml), (795 μ l are 3.18mmol) at room temperature treatment 15h with two  alkane solution of hydrochloric acid (4.0N).The filtered and recycled solid with the washing of two  alkane, obtains the compound 1 (360mg, 94% yield) of table 1 50 ℃ of vacuum-dryings:

¹H-NMR(DMSO?d ₆，AcOD)：8.88(s，1H)，8.27(s，1H)，7.61(m，1H)，7.35(m，3H)，6.84(m，1H)，6.81(s，1H)，4.28(m，2H)，3.98(s，3H)，3.83(s，2H)，3.75(t，2H)，3.58(d，2H)，3.26(m，2H)，3.26(m，2H)，2.32(m，2H)，1.85(m，3H)，1.54(m，2H)：

MS(+ve?ESI)：644.5(M+H) ⁺。

Following acquisition is as two (tertiary butyls) of initial feed { 1-[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-2-oxoethyl }-1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] piperidin-4-yl } methyl phosphorodithioate:

A) with 4-benzyloxy-3-methoxybenzaldehyde (157g, 649mmol), sodium acetate (106g, 1.29mol), hydroxylamine hydrochloride (90g, 1.29mol) and the mixture backflow 21h of acetate (500ml).Evaporating solvent will be iced/water (1000ml) and add resistates formation viscous solid.Mixture neutralizes with aqueous sodium hydroxide solution, uses methylene dichloride (2 * 500ml) extractions then.Organic solution is used dried over mgso then with 1.0N sodium hydroxide (100ml), salt solution (100ml) washing.Evaporating solvent, with resistates and hexane: ethyl acetate (3: 1) is ground, and collects solid by vacuum filtration, obtains brown solid 4-benzyloxy-3-anisole formonitrile HCN (123g, 80% yield):

¹H-NMR(DMSO?d ₆)：7.38(m，7H)，7.19(m，1H)，5.18(s，2H)，3.80(s，3H)：

MS(-ve?ESI)：238(M-H) ^-。

B) 5 ℃ with acetate (17ml) slowly add nitric acid (40ml, 440mmol).Add Powdered 4-benzyloxy-3-anisole formonitrile HCN (10g, 42mmol), in 10min with mixture heating up to 23 ℃.Heat release occurs, temperature is controlled at less than 30 ℃ with ice bath.At 23 ℃ of 20h that stir the mixture, then in the impouring ice/water (1000ml).After stirring 2h, suction filtration is collected yellow solid, washes with water, the dry yellow solid 4-benzyloxy-3-methoxyl group-6-nitrobenzonitrile (10-1g, 85% yield) that obtains:

¹H-NMR(DMSO?d ₆)：7.95(s，1H)，7.70(s，1H)，7.40(m，5H)，5.30(s，2H)，3.95(s，3H)：

MS(-ve?ESI)：283(M-H) ^-。

C) with 4-benzyloxy-3-methoxyl group-6-nitrobenzonitrile (46g, 162mmol), sodium bicarbonate (95g, 1.13mol), water (750ml), methylene dichloride (550ml) and tetrabutylammonium chloride (30g, mixture 108mmol) stirs fast at 20 ℃, in 2h by amount add V-Brite B (66g, 379mmol).With mixture restir 1h, separate each phase then.(2 * 200ml) extractions, dried over mgso is used in organic solution water (300ml) washing of merging to water with methylene dichloride.Solution concentration to 250ml, is added 1 of 4.0M hydrochloric acid, and (150ml 0.6mol), uses ether (1000ml) dilution, in cooled on ice to 4-two  alkane solution then.Collect the gained solid by vacuum filtration, wash with ether.Solid is stirred in methyl alcohol (1000ml), add sodium hydrogen carbonate solution (800ml), stir 1h to pH8.Collect solid by vacuum filtration, water, methanol wash successively, vacuum-drying obtains light brown solid 2-amino-4-(benzyl oxygen base)-5-anisole formonitrile HCN (34g, 82% yield):

¹H-NMR(DMSO?d ₆)：7.40(m，5H)，6.90(s，1H)，6.50(s，1H)，5.60(brs，2H)，5.02(s，2H)，3.65(s，3H)：

MS(+ve?ESI)：254(M+H) ⁺

D) with 2-amino-4-(benzyl oxygen base)-5-anisole formonitrile HCN (100g, toluene 394mmol) (1400ml) solution dimethylformamide dimethyl acetal (100ml, 940mmol) handle under refluxing, slowly solvent distillation is 105 ℃ to keep internal temperature simultaneously.Behind 3h, cooling solution removes by filter small amount of solid.Vacuum-evaporation filtrate is ground resistates and ether, collects solid by vacuum filtration, and vacuum-drying obtains brown solid N '-(5-(benzyl oxygen base)-2-cyano group-4-p-methoxy-phenyl)-N, N-dimethyl carbonamidine (110g, 90% yield):

¹H-NMR(DMSO?d ₆)：7.90(s，1H)，7.40(m，5H)，7.10(s，1H)，6.88(s，1H)，5.15(s，2H)，3.70(s，3H)，3.02(s，3H)，2.95(s，3H)：

MS(+ve?ESI)：310(M+H) ⁺

MS(-ve?ESI)：308(M-H) ^-。

E) with N '-(5-(benzyl oxygen base)-2-cyano group-4-p-methoxy-phenyl)-N, and N-dimethyl carbonamidine (110g, 356mmol) and trifluoroacetic acid (600ml) 15min that refluxes together.Grind with ether evaporation back and toluene coevaporation, collects solid by vacuum filtration, and vacuum-drying obtains N1-(2-cyano group-5-hydroxyl-4-p-methoxy-phenyl)-N, the light brown trifluoroacetate of N-dimethyl carbonamidine (112g, 95% yield):

¹H-NMR(DMSOd ₆)：8.39(s，1H)，7.38(s，1H)，6.90(s，1H)，3.80(s，3H)，3.25(s，3H)，3.17(s，3H)：

MS(+ve?ESI)：220(M+H) ⁺

MS(-ve?ESI)：218(M-H) ^-。

F) with N '-(2-cyano group-5-hydroxyl-4-p-methoxy-phenyl)-N, N-dimethyl carbonamidine (21.9g, 66mmol), cesium carbonate (998g, 300mmol), 1-bromo-3-chloropropane (11ml, 110mmol) and the mixture backflow 1h of acetonitrile (300ml).Reaction mixture, vacuum evaporating solvent.(2 * 150ml) extract the water of resistates (200ml) solution with methylene dichloride.Organic solution is used dried over mgso with salt solution (50ml) washing.Vacuum evaporating solvent grinds resistates and ether.Collect solid by vacuum filtration, vacuum-drying obtains white solid N '-(5-(3-chlorine propoxy-)-2-cyano group-4-p-methoxy-phenyl)-N, N-dimethyl carbonamidine (17.7g, 91% yield):

¹H-NMR(DMSO?d ₆)：8.89(s，1H)，7.07(s，1H)，6.75(s，1H)，4.15(t，2H)，3.77(t，2H)，3.70(s，3H)，3.05(s，3H)，2.95(s，3H)，2.18(m，2H)：

MS(+ve?ESI)：296.4(M+H) ⁺。

G) make N '-(5-(3-chlorine propoxy-)-2-cyano group-4-p-methoxy-phenyl)-N, N-dimethyl carbonamidine (230mg, acetate 0.78mmol) (0.7ml) solution and (5-amino-1H-pyrazole-3-yl) methyl acetate (CAS 174891-10-2; WO 95/33724) (110mg 0.74mmol) reacts 1h under refluxing.Cooling mixture, evaporation of acetic acid, resistates is purified with silica gel chromatography, methanol solution (90: 10) wash-out with methylene dichloride/1% ammonia, obtain paste solid (5-((7-(3-chlorine propoxy-)-6-methoxyl group quinazoline-4-yl) amino)-1H-pyrazole-3-yl) methyl acetate (219mg, 69% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.93(s，1H)，8.28(s，1H)，7.32(s，1H)，6.80(s，1H)，4.02(m，2H)，4.00(s，3H)，3.75-3.85(m，s，4H)，3.65(s，3H)，2.30(m，2H)，1.90(s，3H)：

MS(+ve?ESI)：406.5(M+H) ⁺。

H) make (5-((7-(3-chlorine propoxy-)-6-methoxyl group quinazoline-4-yl) amino)-1H-pyrazole-3-yl) methyl acetate (100mg, 0.247mmol) tetrahydrofuran (THF) (1.2ml)/water (0.6ml) solution and lithium hydroxide (21mg 0.493mmol) spends the night at room temperature reaction.To pH4, the filtered and recycled solid washes with water mixture with the 6.0N hcl acidifying, and drying obtains light brown solid (5-((7-(3-chlorine propoxy-)-6-methoxyl group quinazoline-4-yl) amino)-1H-pyrazole-3-yl) acetate (72mg, 75% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.95(s，1H)，8.28(s，1H)，7.32(s，1H)，6.80(s，1H)，4.33(m，2H)，4.00(s，3H)，3.83(m，2H)，3.74(s，2H)，2.40-2.50(m，2H)：

MS(+ve?ESI)：392.5，394.5(M+H) ⁺。

I) make (5-((7-(3-chlorine propoxy-)-6-methoxyl group quinazoline-4-yl) amino)-1H-pyrazole-3-yl) acetate (7.83g, (78ml) solution of dimethyl formamide 20mmol) and 3-fluoroaniline (2.44g, 22mmol) at 1-(3-dimethylamino-propyl group)-3-ethyl-carbodiimide hydrochloride (4.2g, 22mmol), 2 hydroxy pyrimidine-1-oxide compound (2.22g, 20mmol) and diisopropylethylamine (2.8g 22mmol) exists down in 50 ℃ of reaction 1.7h.Remove by vacuum-evaporation and to desolvate, resistates and water are ground (twice), purify by silica gel chromatography and (to use methylene dichloride: methyl alcohol (95: 3 to 85: 15) wash-out), obtain light brown solid 2-(5-((7-(3-chlorine propoxy-)-6-methoxyl group quinazoline-4-yl) amino)-1H-pyrazole-3-yl)-N-(3-fluorophenyl) ethanamide (4.5g, 46% yield):

¹H-NMR(DMSO?d ₆)：8.47(s，1H)，8.02(s，1H)，7.60-7.68(m，1H)，7.30-7.41(m，2H)，7.20(s，1H)，6.88(m，1H)，6.84(s，1H)，4.27(m，2H)，3.96(s，3H)，3.84(m，2H)，3.78(s，2H)，2.26(m，2H)：

MS(+ve?ESI)：485.6(M+H) ⁺。

J) with piperidin-4-yl methyl alcohol (115mg, 1mmol) add 2-(5-((7-(3-chlorine propoxy-)-6-methoxyl group quinazoline-4-yl) amino)-1H-pyrazole-3-yl)-N-(3-fluorophenyl) ethanamide (121mg, 0.25mmol) N,N-DIMETHYLACETAMIDE (1ml) solution, at 90 ℃ of reacting by heating thing 9h.The cooling reactant is to room temperature, and vacuum is removed volatile matter.Reversed-phase HPLC is purified and is obtained Off-white solid N-(3-fluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl) piperidines-1-yl] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (80mg, 57% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.96(s，1H)，8.30(s，1H)，7.63(m，1H)，7.36(m，3H)，6.90(m，1H)，6.84(s，1H)，4.30(t，2H)，4.01(s，3H)，3.85(s，2H)，3.62(d，2H)，3.32(d，2H)，3.27(m，2H)，2.98(t，2H)，2.29(m，2H)，1.90(d，2H)，1.67(m，1H)，1.42(m，2H)：

MS(+ve?ESI)：564.6(M+H) ⁺。

K) with N-(3-fluorophenyl)-2-{3-[(7-{3-[4-(hydroxymethyl) piperidines-1-yl] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (450mg, 1mmol) be dissolved in dimethyl formamide (2ml), with tetrazolium (224mg, 4mmol) with diethylamino phosphorous acid di tert butyl carbonate (479 μ l, 2mmol) add mixture, under argon atmospher, continue to stir 3h in room temperature.Reaction mixture is to-60 ℃, and (297mg, dimethyl formamide 0.6mmol) (1.5ml) solution slowly adds reaction mixture with monoperphthalic acid magnesium.Then this mixture is stirred 1.5h at-60 ℃, add Sodium Pyrosulfite (1.5g, water 10mmol) (2ml) solution, reaction mixture slowly is heated to room temperature, evaporation, resistates is purified by silica gel chromatography, use methylene dichloride: the methanol solution of 3.0N ammonia (100: 0 to 92: 8) wash-out, obtain paste solid two (tertiary butyl) { 1-[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-2-oxoethyl }-1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] piperidin-4-yl } methyl phosphorodithioate (420mg, 70% yield):

¹H-NMR(DMSO?d ₆)：8.46(s，1H)，7.99(s，1H)，7.63(d，1H)，7.36(m，2H)，7.35(s，1H)，7.15(s，1H)，6.90(m，1H)，6.88(s，1H)，4.17(t，2H)，3.95(s，3H)，3.77(s，2H)，3.72(t，2H)，2.91(d，2H)，2.46(t，2H)，1.96(m，4H)，1.65(m，2H)，1.58(m，1H)，1.41(s，18H)，1.25(m，2H)：

MS(+ve?ESI)：756.6(M+H) ⁺。

Embodiment 2-prepares compound 2-2-[[3-({ 4-[(5-{2-[(3, the 5-difluorophenyl) amino of table 1]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin ({ 4-[(5-{2-[(3 with two (tertiary butyl) 2-[[3-, the 5-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] ethyl phosphonic acid ester (320mg, 0.428mmol), obtain compound 2 (260mg, 86% yield) for the table 1 of Off-white solid:

¹H-NMR(DMSO?d ₆，CD ₃COOD)：8.92(s，1H)，8.31(s，1H)，7.41(m，3H)，6.88(t，1H)，6.84(s，1H)，4.32(m，4H)，3.97(s，3H)，3.89(s，2H)，3.42(m，6H)，2.32(m，2H)，1.31(t，3H)：

MS(+ve?ESI)：636.4(M+H) ⁺。

Following acquisition is as two (tertiary butyl) 2-[[3-of initial feed ({ 4-[(5-{2-[(3,5-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] the ethyl phosphonic acid ester:

A) make 3-{[7-(3-chlorine propoxy-)-6-methoxyl group quinazoline-4-yl] amino }-1H-pyrazoles-5-yl) acetate (3.91g, (20ml) suspension of dimethyl formamide 10mmol) and 3,5-difluoroaniline (1.42g, 11mmol) at 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (2.01g, 10.5mmol) and 2 hydroxy pyrimidine-1-oxide compound (1.11g 10mmol) exists down in 60 ℃ of reaction 1.75h.Vacuum evaporating solvent grinds resistates and water twice.

The wetting mashed prod of gained is dissolved in methylene dichloride: the mixture of water (80: 20), be adsorbed onto on the silica gel, purify by silica gel chromatography, use methylene dichloride: methyl alcohol (95: 5 to 85: 15) wash-out, obtain light brown solid 2-(5-((7-(3-chlorine propoxy-)-6-methoxyl group quinazoline-4-yl) amino)-1H-pyrazole-3-yl)-N-(3, the 5-difluorophenyl) ethanamide (2.45g, 49% yield):

¹H-NMR(DMSO?d ₆)：8.47(s，1H)，8.02(s，1H)，7.36(m，2H)，7.20(s，1H)，6.94(t，1H)，6.84(s，1H)，4.27(m，2H)，3.96(s，3H)，3.83(m，2H)，3.79(s，2H)，2.27(m，2H)：

MS(+ve?ESI)：503.5，505.5(M+H) ⁺。

B) response class of introducing with embodiment 1j seemingly, but begin with 2-(ethylamino) ethanol (89mg, 1mmol) and 2-(5-((7-(3-chlorine propoxy-)-6-methoxyl group quinazoline-4-yl) amino)-1H-pyrazole-3-yl)-N-(3, the 5-difluorophenyl) ethanamide (130mg, 0.26mmol), obtain Off-white solid N-(3, the 5-difluorophenyl)-and 2-{3-[(7-{3-[ethyl (2-hydroxyethyl) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (124mg, 86% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.96(s，1H)，8.30(s，1H)，7.35(m，2H)，7.33(s，1H)，6.90(m，1H)，6.84(s，1H)，4.30(m，2H)，4.01(s，3H)，3.86(s，2H)，3.78(t，2H)，3.30(m，6H)，2.29(m，2H)，1.27(t，3H)：

MS(+ve?ESI)：556.5(M+H) ⁺。

C) response class of introducing with embodiment 1k seemingly, but begin with N-(3, the 5-difluorophenyl)-and 2-{3-[(7-{3-[ethyl (2-hydroxyethyl) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (400mg, 0.72mmol), obtain Off-white solid two (tertiary butyl) 2-[[3-({ 4-[(5-{2-[(3, the 5-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] ethyl phosphonic acid ester (320mg, 60% yield):

¹H-NMR(DMSO?d ₆)：8.36(s，1H)，7.88(s，1H)，7.26(m，2H)，7.04(s，1H)，6.83(t，2H)，6.73(s，1H)，4.07(m，2H)，3.85(s，3H)，3.77(q，2H)，2.68(s，2H)，2.55(m，4H)，2.43(m，2H)，1.81(m，2H)，0.88(t，3H)：

MS(+ve?ESI)：748.5(M+H) ⁺。

Embodiment 3-prepares compound 3-{ (2S)-1-[3-({ 4-[(5-{2-[(3,5-difluorophenyl) amino of table 1]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester

The response class of introducing with embodiment 1 seemingly, but begin with two (tertiary butyls) (2S)-1-[3-({ 4-[(5-{2-[(3, the 5-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } methyl phosphorodithioate (130mg, 0.171mmol), obtain the compound 3 (91mg, 74% yield) of table 1:

¹H-NMR(DMSO?d ₆，CD ₃COOD)：8.91(s，1H)，8.29(s，1H)，7.40(m，3H)，6.89(t，1H)，6.82(s，1H)，4.31(m，2H)，4.20(m，2H)，4.00(s，3H)，3.88(s，2H)，3.80(m，1H)，3.70(m，1H)，3.60(m，1H)，3.28(m，1H)，3.23(m，1H)，2.30(m，2H)，2.20(m，1H)，2.03(m，1H)，1.95(m，1H)，1.82(m，1H)：

MS(+ve?ESI)：648.3(M+H) ⁺。

Following acquisition as two (tertiary butyls) of initial feed (2S)-1-[3-({ 4-[(5-{2-[(3,5-difluorophenyl) amino]-the 2-oxoethyl-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl the oxygen base) propyl group] tetramethyleneimine-2-yl methyl phosphorodithioate:

A) response class of introducing with embodiment 2b seemingly, but begin with L-dried meat ammonia alcohol (101mg, 1mmol), obtain Off-white solid N-(3, the 5-difluorophenyl)-2-{3-[(7-{3-[(2S)-and 2-(hydroxymethyl) tetramethyleneimine-1-yl] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (85mg, 57% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.96(s，1H)，8.30(s，1H)，7.30-7.40(m，3H)，6.85-6.95(m，1H)，6.84(s，1H)，4.30(m，2H)，4.01(s，3H)，3.86(s，2H)，3.72-3.82(m，1H)，3.50-3.70(m，4H)，3.15-3.30(m，2H)，2.25-2.40(m，2H)，1.95-2.20(m，2H)，1.85-1.95(m，1H)，1.70-1.85(m，1H)：

MS(+ve?ESI)：568.6(M+H) ⁺。

B) with N-(3, the 5-difluorophenyl)-2-{3-[(7-{3-[(2S)-and 2-(hydroxymethyl) tetramethyleneimine-1-yl] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } (650mg 1.14mmol) is dissolved in N,N-DIMETHYLACETAMIDE (4ml) to ethanamide.(160mg, 2.3mmol) (637 μ l 2.3mmol) add mixture, continuously stirring 3h under room temperature, argon atmospher with diethylamino phosphorous acid di tert butyl carbonate with tetrazolium.Then reaction mixture is diluted with methylene dichloride (50ml), wash with saturated solution of sodium bicarbonate.Reclaim organic phase, use dried over mgso, filter the back and concentrate.Crude product is dissolved in tetrahydrofuran (THF) (18ml) at 0 ℃, hydrogen peroxide (30%, 335 μ l) is added solution, at stirring at room 15h.Cooling mixture to 0 ℃ at 0 ℃ of water (5ml) solution that adds Sodium Pyrosulfite (1.08g), is heated to room temperature with reactant.Mixture washs with saturated solution of sodium bicarbonate with ethyl acetate (50ml) dilution.Reclaim organic phase, use dried over mgso, filter vacuum concentration.Crude product is purified with silica gel chromatography, use methylene dichloride: methyl alcohol: the methanol solution of 3.0N ammonia (95: 5: 0 to 95: 0: 5) wash-out, obtain Off-white solid two (tertiary butyl) (2S)-1-[3-({ 4-[(5-{2-[(3, the 5-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } methyl phosphorodithioate (133mg, 15% yield):

¹H-NMR(DMSO?d ₆)：8.44(s，1H)，7.96(s，1H)，7.35(m，2H)，7.13(s，1H)，6.92(m，1H)，6.82(s，1H)，4.18(m，2H)，3.93(s，3H)，3.75(m，3H)，3.56(m，1H)，3.08(m，1H)，2.92(m，1H)，2.67(m，1H)，2.46(m，1H)，2.20(q，1H)，1.95(m，2H)，1.83(m，1H)，1.68(m，2H)，1.59(m，1H)，1.38(s，18H)：

MS(+ve?ESI)：760.5(M+H) ⁺。

Embodiment 4-prepares compound 4-{ (2R)-1-[3-({ 4-[(5-{2-[(3,5-difluorophenyl) amino of table 1]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester

The response class of introducing with embodiment 1 seemingly, but begin with two (tertiary butyls) (2R)-1-[3-({ 4-[(5-{2-[(3, the 5-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } methyl phosphorodithioate (350mg, 0.46mmol), obtain compound 4 (305mg, 92% yield) for the table 1 of Off-white solid:

¹H-NMR(DMSO?d ₆)：8.90(s，1H)，8.29(s，1H)，7.40(m，3H)，6.87(t，1H)，6.81(s，1H)，4.31(m，2H)，4.20(m，2H)，4.00(s，3H)，3.88(s，2H)，3.80(m，1H)，3.70(m，1H)，3.60(m，1H)，3.28(m，1H)，3.23(m，1H)，2.32(m，2H)，2.20(m，1H)，2.04(m，1H)，1.95(m，1H)，1.84(m，1H)：

MS(+ve?ESI)：648.4(M+H) ⁺。

Following acquisition as two (tertiary butyls) of initial feed (2R)-1-[3-({ 4-[(5-{2-[(3,5-difluorophenyl) amino]-the 2-oxoethyl-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl the oxygen base) propyl group] tetramethyleneimine-2-yl methyl phosphorodithioate:

A) response class of introducing with embodiment 2b seemingly, but begin with D-dried meat ammonia alcohol (101mg, 1mmol), obtain Off-white solid N-(3, the 5-difluorophenyl)-2-{3-[(7-{3-[(2R)-and 2-(hydroxymethyl) tetramethyleneimine-1-yl] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (85mg, 57% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.96(s，1H)，8.30(s，1H)，7.35(m，2H)，7.33(s，1H)，6.91(m，1H)，6.84(s，1H)，4.31(m，2H)，4.01(s，3H)，3.86(s，2H)，3.78(m，1H)，3.63(m，4H)，3.22(m，2H)，2.30(m，2H)，2.13(m，1H)，2.03(m，1H)，1.80(m，1H)，1.78(m，1H)：

MS(+ve?ESI)：568.5(M+H) ⁺。

B) response class of introducing with embodiment 3b seemingly, but begin with N-(3, the 5-difluorophenyl)-2-{3-[(7-{3-[(2R)-and 2-(hydroxymethyl) tetramethyleneimine-1-yl] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (600mg, 1.06mmol), acquisition Off-white solid two (tertiary butyl) (2R)-1-[3-({ 4-[(5-{2-[(3, the 5-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } methyl phosphorodithioate (361mg, 45% yield):

¹H-NMR(DMSO?d ₆)：8.45(s，1H)，7.96(s，1H)，7.35(m，2H)，7.13(s，1H)，6.93(m，1H)，6.82(s，1H)，4.18(m，2H)，3.95(s，3H)，3.75(m，3H)，3.58(m，1H)，3.08(m，1H)，2.93(m，1H)，2.67(m，1H)，2.46(m，1H)，2.22(q，1H)，1.96(m，2H)，1.86(m，1H)，1.69(m，2H)，1.61(m，1H)，1.38(s，18H)：

MS(+ve?ESI)：760.5(M+H) ⁺。

Embodiment 5-prepares compound 5-{ (2S)-1-[3-({ 4-[(5-{2-[(3-fluorophenyl) amino of table 1]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester

The response class of introducing with embodiment 1 seemingly, but begin with two (tertiary butyls) (2S)-1-[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl the oxygen base) propyl group] tetramethyleneimine-2-yl methyl phosphorodithioate (282mg, 0.38mmol), obtain compound 5 (265mg, 97% yield) for the table 1 of Off-white solid:

¹H-NMR(DMSO?d ₆)：8.90(s，1H)，8.30(s，1H)，7.66(d，1H)，7.46(s，1H)，7.40(m，2H)，6.90(m，1H)，6.81(s，1H)，4.31(m，2H)，4.20(m，2H)，4.00(s，3H)，3.88(s，2H)，3.80(m，1H)，3.70(m，1H)，3.60(m，1H)，3.28(m，1H)，3.22(m，1H)，2.32(m，2H)，2.20(m，1H)，2.04(m，1H)，1.95(m，1H)，1.84(m，1H)：

MS(+ve?ESI)：630.6(M+H) ⁺。

Following acquisition as two (tertiary butyls) of initial feed (2S)-1-[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl the oxygen base) propyl group] tetramethyleneimine-2-yl methyl phosphorodithioate:

A) response class of introducing with embodiment 1j seemingly, but begin with L-dried meat ammonia alcohol (121mg, 0.25mmol), obtain Off-white solid N-(3-fluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl) tetramethyleneimine-1-yl] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (86mg, 62% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.95(s，1H)，8.29(s，1H)，7.60-7.70(m，1H)，7.28-7.40(m，3H)，6.85-6.92(m，1H)，6.82(s，1H)，4.31(m，2H)，4.00(s，3H)，3.84(s，2H)，3.70-3.80(m，1H)，3.50-3.70(m，4H)，3.10-3.30(m，2H)，2.20-2.40(m，2H)，2.05-2.20(m，1H)，1.95-2.10(m，1H)，1.85-1.95(m，1H)，1.70-7.85(m，1H)：

MS(+ve?ESI)：549.6(M+H) ⁺。

B) response class of introducing with embodiment 1k seemingly, but begin with N-(3-fluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl) tetramethyleneimine-1-yl] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (275mg, 0.5mmol), acquisition Off-white solid two (tertiary butyl) (2S)-1-[3-((4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } methyl phosphorodithioate (255mg, 69% yield):

¹H-NMR(DMSO?d ₆)：8.46(s，1H)，7.98(s，1H)，7.64(d，1H)，7.36(m，2H)，7.15(s，1H)，6.89(m，1H)，6.81(s，1H)，4.18(m，2H)，3.93(s，3H)，3.75(m，3H)，3.58(m，1H)，3.11(m，1H)，2.97(m，1H)，2.67(m，1H)，2.46(m，1H)，2.22(m，1H)，1.98(m，2H)，1.82(m，1H)，1.71(m，2H)，1.62(m，1H)，1.38(s，18H)：

MS(+ve?ESI)：742.7(M+H) ⁺

Embodiment 6-prepares compound 6-2-[[3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino of table 1]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (propyl group) amino] ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin ({ 4-[(5-{2-[(2 with two-tertiary butyl 2-[[3-, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (propyl group) amino] ethyl phosphonic acid ester (316mg, 0.41mmol), obtain the compound 6 (300mg, 100% yield) of table 1:

¹H-NMR(DMSO?d ₆，TFA)：8.96(s，1H)，8.31(s，1H)，7.75(m，1H)，7.36(s，1H)，7.20(m，2H)，6.84(s，1H)，4.31(t，2H)，4.24(m，2H)，4.01(s，3H)，3.94(s，2H)，3.50(m，2H)，3.38(m，2H)，3.19(m，2H)，2.32(m，2H)，1.74(m，2H)，0.95(t，3H)：

MS(+ve?ESI)：650.3(M+H) ⁺。

Following acquisition is as two-tertiary butyl 2-[[3-of initial feed ({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (propyl group) amino] the ethyl phosphonic acid ester:

A) under argon atmospher, 0 ℃, with 5-{[7-(3-chlorine propoxy-)-6-methoxyl group quinazoline-4-yl] amino }-the 1H-pyrazole-3-yl) (3.91g 10mmol) is suspended in and contains 2,3-difluoroaniline (1.55g, pyridine 12mmol) (20ml) acetate.0 ℃ slowly add phosphoryl chloride (1.53g, ethyl acetate 10mmol) (2ml) solution, with the gained mixture at the 1.5h internal heating to room temperature.Reaction mixture produces the red solid precipitation with ethyl acetate (150ml) and ether (50ml) dilution.Reclaim solid by suction filtration, be suspended in water (100ml) after the drying again.Cooling mixture to 0 ℃ adds the 1.5N ammonium hydroxide aqueous solution and regulates pH to 7.After stirring 15min, reclaim solid, dry, purify with silica gel chromatography, use methylene dichloride: methyl alcohol (95/5) and strengthen polarity to methylene dichloride: the methanol solution of ammonia (95: 2) wash-out, obtain pink solid 2-(3-{[7-(3-chlorine propoxy-)-6-methoxyl group quinazoline-4-yl] amino }-1H-pyrazoles-5-yl)-N-(2, the 3-difluorophenyl) ethanamide (2.55g, 50% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.94(s，1H)，8.28(s，1H)，7.73(m，1H)，7.33(s，1H)，7.15-7.22(m，1H)，6.84(s，1H)，4.30(m，2H)，4.00(s，3H)，3.94(s，2H)，3.84(m，2H)，2.30(m，2H)：

MS(+ve?ESI)：503.9(M+H) ⁺。

B) with 2-(propyl group amino) ethanol (700mg, 68mmol) and potassiumiodide (564mg, 34mmol) add 2-(3-{[7-(3-chlorine propoxy-)-6-methoxyl group quinazoline-4-yl] amino }-1H-pyrazoles-5-yl)-N-(2, the 3-difluorophenyl) ethanamide (855mg, N,N-DIMETHYLACETAMIDE 17mmol) (8ml) solution heats 5h with reactant at 85 ℃.Vacuum evaporating solvent grinds resistates and ether, and suction filtration is collected solid.Purify with silica gel chromatography, with methylene chloride (90: 10) to methylene chloride/ammoniacal liquor (7.0N) wash-out, obtain N-(2, the 3-difluorophenyl)-and the 2-{3-[(7-{3-[(2-hydroxyethyl) (propyl group) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (650mg, 67% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.96(s，1H)，8.30(s，1H)，7.75(m，1H)，7.33(s，1H)，7.18-7.22(m，2H)，6.84(s，1H)，4.30(m，2H)，4.00(s，3H)，3.94(s，2H)，3.78(m，2H)，3.30-3.45(m，2H)，3.28(m，2H)，3.15-3.20(m，2H)，2.28(m，2H)，1.73(m，2H)，0.95(t，3H)：

MS(+ve?ESI)：570.3(M+H) ⁺。

C) under room temperature, argon atmospher, with diethylamino phosphorous acid di tert butyl carbonate (417 μ m, 1.5mmol) contain tetrazolium (210mg slow the adding, N-(2 3mmol), the 3-difluorophenyl)-and the 2-{3-[(7-{3-[(2-hydroxyethyl) (propyl group) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (569mg, dimethyl formamide 1mmol) (2.5ml) solution.At stirring at room mixture 1.5h, be cooled to-10 ℃, slowly add hydrogen peroxide (134 μ m9.0N solution, 1.2mmol).At stirring at room gained mixture 2h.(570mg, water 3mmol) (2ml) solution is at stirring at room mixture 0.5h to add Sodium Pyrosulfite at 0 ℃ then.Enriched mixture adds methylene chloride (8: 2), leaches solid then, washs with methylene chloride.Vacuum concentrated filtrate, purify with silica gel chromatography then, with methylene chloride (90: 10) to methylene chloride/ammoniacal liquor (7.0N) (90: 10: 1) wash-out, obtain Off-white solid two-tertiary butyl 2-[[3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (propyl group) amino] ethyl phosphonic acid ester (319mg, 42% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.95(s，1H)，8.29(s，1H)，7.72(m，1H)，7.33(s，1H)，7.18(m，2H)，6.84(s，1H)，4.20-4.35(m，4H)，4.00(s，3H)，3.94(s，2H)，3.53(m，2H)，3.39(m，2H)，3.20(m，2H)，2.30(m，2H)，1.73(m，2H)，1.44(s，18H)，0.95(t，3H)：

MS(+ve?ESI)：762.5(M+H) ⁺。

Compound 6 (above synthetic is its dihydrochloride) also can be prepared as its free alkali in accordance with the following methods:

D) with 2-[[3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (propyl group) amino] ethyl phosphonic acid two hydrogen ester dihydrochloride (10g, 13mmol) be dissolved in methyl alcohol (300ml), with cyclohexane oxide (12,7g 130mmol) adds solution.At stirring at room solution 48h, separate out white solid during this period.Mixture dilutes with ether (100ml), the filtered and recycled solid, wash with ether, vacuum-drying obtains yellow powder powder 2-[[3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (propyl group) amino] ethyl phosphonic acid two hydrogen esters (7.65g, 88% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.96(s，1H)，8.30(s，1H)，7.74(m，1H)，7.34(s，1H)，7.19(m，2H)，6.84(s，1H)，4.31(m，2H)，4.24(m，2H)，4.01(s，3H)，3.94(s，2H)，3.51(m，2H)，3.38(m，2H)，3.18(m，2H)，2.29(m，2H)，1.73(m，2H)，0.96(t，3H)：

MS(+ve?ESI)：650(M+H) ⁺。

C ₂₈H ₃₄F ₂N ₇O ₇P+1.04 H ₂O+0.03 Et ₂O theoretical value C, 50.37%; H, 5.47%; N, 14.62%; Measured value C, 50.02%; H, 5.54%; N, 14.48%.

Embodiment 7-prepares compound 7-2-[[3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino of table 1]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (isobutyl-) amino] ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin ({ 4-[(5-{2-[(2 with two-tertiary butyl 2-[[3-, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (isobutyl-) amino] ethyl phosphonic acid ester (465mg, 0.6mmol), obtain the compound 7 (480mg, 100% yield) of table 1:

¹H-NMR(DMSO?d ₆，TFA)：8.95(s，1H)，8.34(s，1H)，7.76(m，1H)，7.43(s，1H)，7.18(m，2H)，6.86(s，1H)，4.33(m，4H)，4.02(s，3H)，3.97(s，2H)，3.54(m，2H)，3.40(m，2H)，3.12(d，2H)，2.35(m，2H)，2.17(m，1H)，1.05(d，6H)。

Following acquisition is as two-tertiary butyl 2-[[3-of initial feed ({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (isobutyl-) amino] the ethyl phosphonic acid ester:

A) under-65 ℃, argon atmospher, (5.28g, methyl alcohol 120mmol) (14ml) cold soln (60 ℃) slowly add isobutylamine (30.7g, methyl alcohol 420mmol) (100ml) solution with oxyethane.With mixture at the 14h internal heating to room temperature, vacuum concentration, remaining oily matter by distillation purify (b.p.130 ℃/0.5mmHg) obtain 2-(isobutylamino) ethanol (11g, 78% yield):

¹H-NMR(DMSO?d ₆)：4.40(m，1H)，3.42(m，2H)，2.50(m，2H)，2.30(d，2H)，1.63(m，1H)，0.85(d，6H)。

B) response class of introducing with embodiment 6b seemingly, but begin with 2-(isobutylamino) ethanol (936mg, 80mmol), at 90C heating 3.5h, obtain Off-white solid N-(2, the 3-difluorophenyl)-and the 2-{3-[(7-{3-[(2-hydroxyethyl) (isobutyl-) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (810mg, 69% yield):

¹H-NMR?(DMSO?d ₆，TFA)：8.96(s，1H)，8.30(s，1H)，7.45(m，1H)，7.34(s，1H)，7.21(m，2H)，6.84(s，1H)，4.31(m，2H)，4.00(s，3H)，3.95(s，2H)，3.81(m，2H)，3.36(m，2H)，3.30(m，2H)，3.12(m，1H)，3.06(m，1H)，2.31(m，2H)，2.13(m，1H)，1.01(d，6H)：

MS(+ve?ESI)：584.3(M+H) ⁺。

C) response class of introducing with embodiment 6c seemingly, but begin with N-(2, the 3-difluorophenyl)-and the 2-{3-[(7-{3-[(2-hydroxyethyl) (isobutyl-) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (4.96mg, 8.5mmol), obtain two-tertiary butyl 2-[[3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (isobutyl-) amino] ethyl phosphonic acid ester (4.7g, 71% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.96(s，1H)，8.30(s，1H)，7.74(m，1H)，7.34(s，1H)，7.19(m，2H)，6.84(s，1H)，4.30(m，4H)，4.00(s，3H)，3.94(s，2H)，3.54(m，2H)，3.39(m，2H)，3.12(d，2H)，2.32(m，2H)，2.14(m，1H)，1.45(s，18H)，1.02(d，6H)：

MS(+ve?ESI)：776.8(M+H) ⁺。

Embodiment 8-prepares compound 8-2-[[3-({ 4-[(5-{2-[(3, the 5-difluorophenyl) amino of table 1]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (isobutyl-) amino] ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin ({ 4-[(5-{2-[(3 with two-tertiary butyl 2-[[3-, the 5-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (isobutyl-) amino] ethyl phosphonic acid ester (325mg, 0.42mmol), obtain the compound 8 (315mg, 98% yield) of table 1:

¹H-NMR(DMSO?d ₆，TFA)：8.95(s，1H)，8.32(s，1H)，7.39(d，1H)，7.38(s，1H)，7.36(d，1H)，6.91(t，1H)，6.84(s，1H)，4.30(m，2H)，4.01(s，3H)，3.87(s，2H)，3.53(m，2H)，3.39(m，2H)，3.11(d，1H)，2.32(m，2H)，2.14(m，1H)，1.02(d，6H)：

MS(+ve?ESI)：664.3(M+H) ⁺。

Following acquisition as two-tertiary butyl 2-[[3-of initial feed ((4-[(5-{2-[(3,5-difluorophenyl) amino]-the 2-oxoethyl-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl the oxygen base) propyl group] (isobutyl-) amino] the ethyl phosphonic acid ester:

A) under argon atmospher, make 2-(3-{[7-(3-chlorine propoxy-)-6-methoxyl group quinazoline-4-yl] amino }-1H-pyrazoles-5-yl)-N-(3, the 5-difluorophenyl) ethanamide (2.0g, 4.0mmol) at 1-Methyl-2-Pyrrolidone (20ml), potassiumiodide (1.33g, 8.0mmol) in 2-(isobutylamino) ethanol (1.88g, 16mmol) 60 ℃ the reaction 8h.Vacuum evaporating solvent, resistates is purified with silica gel chromatography, with methylene chloride (95: 5) to methylene chloride/ammoniacal liquor (7.0N) (95: 5: 1) wash-out, obtain N-(3, the 5-difluorophenyl)-and the 2-{3-[(7-{3-[(2-hydroxyethyl) (isobutyl-) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (1.05g, 45% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.95(s，1H)，8.29(s，1H)，7.35(d，2H)，7.34(s，1H)，6.92(t，1H)，6.83(s，1H)，4.30(m，2H)，4.00(s，3H)，3.86(s，2H)，3.82(t，2H)，3.89(m，2H)，3.29(m，2H)，2.17-2.98(m，2H)，2.30(m，2H)，2.13(m，1H)，1.01(d，6H)：

MS(+ve?ESI)：584.3(M+H) ⁺。

B) with diethylamino phosphorous acid di tert butyl carbonate (1.25ml, 4.18mmol) contain tetrazolium (431mg slow the adding, 6.16mmol) N-(3, the 5-difluorophenyl)-and the 2-{3-[(7-{3-[(2-hydroxyethyl) (isobutyl-) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (1.03g, dimethyl formamide 1.73mmol) (6ml) solution.At stirring at room mixture 2h, add methylene dichloride (30ml) then.(3 * 25ml) extract drying, vacuum concentration to the gained mixture with methylene dichloride with saturated solution of sodium bicarbonate (15ml) washing, water.Crude product is dissolved in tetrahydrofuran (THF) (25ml), is cooled to 0 ℃, (30%w/w, 0.40ml 3.9mmol) slowly add solution with hydrogen peroxide.At stirring at room reactant 2h, be cooled to 0 ℃, with Sodium Pyrosulfite (1.08g, water 5.7mmol) (2ml) solution-treated.At stirring at room mixture 0.5h, with ethyl acetate (30ml) dilution, with sodium bicarbonate aqueous solution (15ml) washing, with ethyl acetate (20ml) extracting twice.Vacuum evaporating solvent, then purify with silica gel chromatography, with methylene chloride (98: 2) to methylene chloride/ammoniacal liquor (7.0N) (95: 5: 1) wash-out, obtain two-tertiary butyl 2-[[3-({ 4-[(5-{2-[(3, the 5-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (isobutyl-) amino] ethyl phosphonic acid ester (335mg, 25% yield):

¹H-NMR(DMSO?d ₆，TFA)：12.35(s，1H)，10.64(s，1H)，10.16(s，1H)，8.45(s，1H)，7.99(s，1H)，7.36(d，2H)，7.13(s，1H)，6.94(t，1H)，6.84(s，1H)，4.19(t，2H)，3.95(s，3H)，3.87(q，2H)，3.79(s，2H)，2.65(m，4H)，2.21(d，2H)，1.91(m，2H)，1.70(m，1H)，1.39(s，18H)，0.83(d，6H)：

MS(+ve?ESI)：776.4(M+H) ⁺。

Embodiment 9-prepares compound 9-2-[[3-({ 4-[(5-{2-[(3, the 5-difluorophenyl) amino of table 1]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (propyl group) amino] ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin ({ 4-[(5-{2-[(3 with two-tertiary butyl 2-[[3-, the 5-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (propyl group) amino] ethyl phosphonic acid ester (510mg, 0.67mmol), obtain the compound 9 (503mg, 42% yield) of table 1:

¹H-NMR(DMSO?d ₆，TFA)：8.94(s，1H)，8.31(s，1H)，7.38(d，1H)，7.37(s，2H)，7.36(d，1H)，6.92(t，1H)，6.83(s，1H)，4.30(t，2H)，4.24(t，2H)，4.00(s，3H)，3.87(s，2H)，3.49(t，2H)，3.36(t，2H)，3.18(t，2H)，2.26-2.36(m，2H)，1.68-1.79(m，2H)，0.94(t，3H)：

MS(+ve?ESI)：649.9(M+H) ⁺。

Following acquisition is as two-tertiary butyl 2-[[3-of initial feed ({ 4-[(5-{2-[(3,5-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl) the oxygen base) propyl group] (propyl group) amino] the ethyl phosphonic acid ester:

A) response class of introducing with embodiment 8a seemingly, but begin ethanol (1.83ml with 2-(propyl group amino), 16mmol), obtain N-(3, the 5-difluorophenyl)-and the 2-{3-[(7-{3-[(2-hydroxyethyl) (propyl group) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (900mg, 39% yield):

¹H-NMR(DMSO?d ₆)：10.63(s，1H)，10.17(s，1H)，8.46(s，1H)，8.00(s，1H)，7.36(d，2H)，7.14(s，1H)，6.94(t，1H)，6.85(s，1H)，4.35(br?s，1H)，4.20(t，2H)，3.95(s，3H)，3.79(s，2H)，3.46(m，2H)，2.63(m，2H)，2.52(m，2H)，2.42(m，2H)，1.92(m，2H)，1.42(m，2H)，0.83(t，3H)：

MS(+ve?ESI)：570.3(M+H) ⁺。

B) response class of introducing with embodiment 8b seemingly, but begin with N-(3, the 5-difluorophenyl)-and the 2-{3-[(7-{3-[(2-hydroxyethyl) (propyl group) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (880mg, 1.54mmol), obtain two-tertiary butyl 2-[[3-({ 4-[(5-{2-[(3, the 5-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (propyl group) amino] ethyl phosphonic acid ester (525mg, 45% yield):

¹H-NMR(DMSO?d ₆，TFA)：12.35(s，1H)，10.63(s，1H)，10.16(s，1H)，8.45(s，1H)，7.99(s，1H)，7.37(d，1H)，7.34(d，1H)，7.13(s，1H)，6.94(t，1H)，6.84(s，1H)，4.17(t，2H)，3.94(s，3H)，3.87(q，2H)，3.79(s，2H)，2.67(t，2H)，2.63(t，2H)，2.43(t，2H)，1.91(t，2H)，1.39(s，18H)，0.83(t，3H)：

MS(+ve?ESI)：762.6(M+H) ⁺。

Embodiment 10-prepares compound 10-2-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino of table 1]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (isobutyl-) amino] ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin amino with two-tertiary butyl 2-[[3-({ 4-[(5-{2-[(3-fluorophenyl)]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (isobutyl-) amino] ethyl phosphonic acid ester (450mg, 0.59mmol), obtain the compound 10 (420mg, 99% yield) of table 1:

¹H-NMR(DMSO?d ₆，TFA)：8.90(s，1H)，8.30(s，1H)，7.64(m，1H)，7.36(m，3H)，6.85(m，2H)，4.30(m，4H)，4.00(s，3H)，3.86(s，2H)，3.53(m，2H)，3.37(m，2H)，3.09(m，2H)，2.34(m，2H)，2.14(m，1H)，1.05(m，6H)：

MS(+ve?ESI)：646.6(M+H) ⁺。

Following acquisition is as two-tertiary butyl 2-[[3-of initial feed ({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (isobutyl-) amino] the ethyl phosphonic acid ester:

A) response class of introducing with embodiment 5a seemingly, but begin with 2-(isobutylamino) ethanol (181mg, 1.55mmol), obtain N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl) (isobutyl-) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (101mg, 57% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.96(s，1H)，8.30(s，1H)，7.63(d，1H)，7.32-7.41(m，2H)，7.34(s，1H)，6.90(t，1H)，6.83(s，1H)，4.30(t，2H)，4.00(s，3H)，3.84(s，2H)，3.80(t，2H)，3.37(t，2H)，3.28(t，2H)，3.15-3.00(m，2H)，2.29(m，2H)，2.12(m，2H)，1.00(d，6H)：

MS(+ve?ESI)：566.3(M+H) ⁺。

B) response class of introducing with embodiment 5b seemingly, but begin with N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl) (isobutyl-) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (565mg, 1mmol), acquisition two-tertiary butyl 2-[[3-(the 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl) the oxygen base) propyl group] (isobutyl-) amino] ethyl phosphonic acid ester (420mg, 55% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.37(s，1H)，7.88(s，1H)，7.55(m，1H)，7.26(m，2H)，7.04(s，1H)，6.81(m，2H)，4.09(t，2H)，3.82(s，3H)，3.76(m，2H)，3.67(m，2H)，2.57(m，4H)，2.11(m，2H)，1.82(m，2H)，1.60(m，1H)，1.29(s，18H)，0.74(d，6H)：

MS(+ve?ESI)：758.5(M+H) ⁺。

Embodiment 11-prepares compound 11-2-{ (2, the 2-dimethyl propyl) [3-({ 4-[(5-{2-[(3-fluorophenyl) the amino]-2-oxoethyl of table 1 }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin with two-tertiary butyl 2-{ (2, the 2-dimethyl propyl) [3-(the 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid ester (350mg, 0.45mmol), obtain the compound 11 (325mg, 100% yield) of table 1:

¹H-NMR(DMSO?d ₆，TFA)：8.94(s，1H)，8.3(s，1H)，7.63(d，1H)，7.36(s，1H)，7.34(m，2H)，6.88(m，1H)，6.82(s，1H)，4.30(m，4H)，3.99(s，3H)，3.84(s，2H)，3.54(m，2H)，3.38(m，2H)，3.19(m，2H)，2.37(m，2H)，1.09(s，9H)：

MS(+ve?ESI)：660.4(M+H) ⁺。

Following acquisition is as two-tertiary butyl 2-{ (2, the 2-dimethyl propyl) of initial feed [3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } the ethyl phosphonic acid ester:

A) under-30 ℃, argon atmospher, (2.5ml 5.0mmol) slowly adds (2, the 2-dimethyl propyl) amine (13g, methyl alcohol 150mmol) (15ml) solution with the oxyethane that is cooled to-20 ℃.At stirring at room mixture 16h.Vacuum evaporating solvent, resistates by distillation purify (b.p.132 ℃/9mmHg) obtain 2-((2, the 2-dimethyl propyl) amino) ethanol (6.4g, 97% yield):

¹H-NMR(DMSO?d ₆，TFA)：3.70(m，2H)，3.02(m，2H)，2.81(m，2H)，0.98(s，9H)。

B) response class of introducing with embodiment 5a seemingly, but begin with 2-(2, the 2-dimethyl propyl) ethanol (203mg amino), 1.55mmol), obtain 2-{3-[(7-{3-[(2, the 2-dimethyl propyl) (2-hydroxyethyl) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(3-fluorophenyl) ethanamide (111mg, 61% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.96(s，1H)，8.30(s，1H)，7.64(d，1H)，7.32-7.41(m，2H)，7.34(s，1H)，6.90(t，1H)，6.83(s，1H)，4.31(t，2H)，3.99(s，3H)，3.84(s，2H)，3.83(t，2H)，3.42(t，2H)，3.32(t，2H)，3.20(dd，2H)，2.35(m，2H)，1.07(s，9H)：

MS(+ve?ESI)：580.3(M+H) ⁺。

C) response class of introducing with embodiment 5b seemingly, but begin to use 2-{3-[(7-{3-[(2, the 2-dimethyl propyl) (2-hydroxyethyl) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(3-fluorophenyl) ethanamide (1.33g, 2.3mmol), obtain two-tertiary butyl 2-{ (2, the 2-dimethyl propyl) [3-(the 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid ester (620mg, 40% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.95(s，1H)，8.3(s，1H)，7.64(d，1H)，7.28-7.40(m，2H)，7.34(s，1H)，6.88(m，1H)，6.84(s，1H)，4.31(m，4H)，4.00(s，3H)，3.85(s，2H)，3.56(m，2H)，3.39(m，2H)，3.21(m，2H)，2.32(m，2H)，1.43(s，9H)，1.10(s，9H)：

MS(+ve?ESI)：716.4(M+H) ⁺。

Embodiment 12-prepares compound 12-1-[3-({ 4-[(5-{2-[(3-fluorophenyl) amino of table 1]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] piperidines-3-base dihydrogen phosphate

The response class of introducing with embodiment 1 seemingly, but begin amino with two-tertiary butyl 1-[3-({ 4-[(5-{2-[(3-fluorophenyl)]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] piperidines-3-base phosphoric acid ester (540mg, 0.72mmol), obtain the compound 12 (500mg, 98% yield) of table 1:

¹H-NMR(DMSO?d ₆，TFA)：8.92(s，1H)，8.28(s，1H)，7.62(d，1H)，7.32(m，3H)，6.82(m，2H)，4.45-4.66(m，2H)，4.27(m，2H)，3.99(s，3H)，3.84(s，2H)，3.55(m，2H)，3.30(m，2H)，3.00(m，2H)，2.30(m，2H)，2.05(m，2H)，1.65(m，2H)：

MS(+ve?ESI)：630.2(M+H) ⁺。

Following acquisition is as two-tertiary butyl 1-[3-of initial feed ({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] piperidines-3-base phosphoric acid ester:

A) response class of introducing with embodiment 5a seemingly, but begin with piperidines-3-phenol (101mg, 1mmol), acquisition N-(3-fluorophenyl)-2-[3-(7-[3-(3-hydroxy piperidine-1-yl) propoxy-]-6-methoxyl group quinazoline-4-yl } amino)-1H-pyrazoles-5-yl] ethanamide (65mg, 47% yield):

¹H-NMR(DMSO?d ₆，IFA)：8.96(s，1H)，8.29(s，1H)，7.62(d，1H)，7.38(m，2H)，7.34(m，2H)，7.34(s，1H)，6.90(m，1H)，6.84(s，1H)，4.28(m，2H)，4.10(m，1H)，4.00(s，3H)，3.85(s，2H)，2.80-3.50(m，6H)，1.30-2.40(m，6H)：

MS(+ve?ESI)：550.6(M+H) ⁺。

B) response class of introducing with embodiment 5b seemingly, but begin with N-(3-fluorophenyl)-2-[3-({ 7-[3-(3-hydroxy piperidine-1-yl) propoxy-]-6-methoxyl group quinazoline-4-yl } amino)-1H-pyrazoles-5-yl] ethanamide (604mg, 1.1mmol), acquisition two-tertiary butyl 1-[3-(the 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] piperidines-3-base phosphoric acid ester (550mg, 67% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.38(s，1H)，7.90(s，1H)，7.55(d，1H)，7.30(m，2H)，7.06(s，1H)，6.80(m，2H)，4.09(m，3H)，3.86(s，3H)，3.68(s，2H)，2.80(m，1H)，2.55(m，1H)，2.03(m，2H)，1.87(m，3H)，1.60(m，1H)，1.35(m，22H)：

MS(+ve?ESI)：742.5(M+H) ⁺。

Embodiment 13-prepares compound 13-{ (2R)-1-[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino of table 1]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester

The response class of introducing with embodiment 1 seemingly, but begin with two-tertiary butyl (2R)-1-[3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } methyl phosphorodithioate (445mg, 0.59mmol), obtain the compound 13 (440mg, 94% yield) of table 1:

¹H-NMR(DMSO?d ₆，TFA)：8.94(s，1H)，8.31(s，1H)，7.73(m，1H)，7.40(s，1H)，7.19(m，2H)，6.83(s，1H)，4.31(t，2H)，4.20(m，2H)，4.01(s，3H)，3.94(s，2H)，3.82(m，1H)，3.70(m，1H)，3.60(m，1H)，3.31(m，1H)，3.23(m，1H)，2.32(m，2H)，2.19(m，1H)，2.04(m，1H)，1.95(m，1H)，1.85(m，1H)：

MS(+ve?ESI)：648.3(M+H) ⁺。

Following acquisition as two-tertiary butyl of initial feed (2R)-1-[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl the oxygen base) propyl group] tetramethyleneimine-2-yl methyl phosphorodithioate:

A) response class of introducing with embodiment 6b seemingly, but begin with (2R)-tetramethyleneimine-2-base methyl alcohol (101mg, 1mmol), obtain N-(2, the 3-difluorophenyl)-2-{3-[(7-{3-[(2R)-and 2-(hydroxymethyl) tetramethyleneimine-1-yl] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (134mg, 79% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.95(s，1H)，8.29(s，1H)，7.75(m，1H)，7.32(s，1H)，7.16(m，2H)，6.84(s，1H)，4.30(m，2H)，4.00(s，3H)，3.94(s，2H)，3.70-3.85(m，1H)，3.52-3.70(m，4H)，3.15-3.30(m，2H)，2.25-2.35(m，2H)，1.75-2.20(m，4H)：

MS?ES+：568.2(M+H) ⁺

MS(+ve?ESI)：568.2(M+H) ⁺。

B) response class of introducing with embodiment 6c seemingly, but begin with N-(2, the 3-difluorophenyl)-2-{3-[(7-{3-[(2R)-and 2-(hydroxymethyl) tetramethyleneimine-1-yl] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (1.1g, 1.9mmol), acquisition two-tertiary butyl (2R)-1-[3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } methyl phosphorodithioate (453mg, 31% yield):

¹H-NMR(DMSO?d ₆，TFA)：10.24(s，1H)，10.15(s，1H)，8.44(s，1H)，7.98(s，1H)，7.72(t，1H)，7.19(m，2H)，7.13(s，1H)，6.83(s，1H)，4.17(br?s，2H)，3.93(s，3H)，3.85(s，1H)，3.77(m，1H)，3.56(t，1H)，3.54(t，1H)，3.08(t，1H)，2.94(m，1H)，2.66(m，1H)，2.47(m，1H)，2.20(q，1H)，1.94(m，2H)，1.86(m，1H)，1.69(m，2H)，1.60(m，1H)，1.37(s，9H)，1.36(s，9H)：

MS(+ve?ESI)：758.5(M+H) ⁺。

Compound 13 (above synthetic is its dihydrochloride) also can be prepared as its free alkali in accordance with the following methods:

C) response class of introducing with embodiment 6d is the free alkali of the compound 13 of light yellow solid but begin with compound 13 acquisitions seemingly:

¹H-NMR(DMSO?d ₆)：10.30(s，1H)，10.20(s，1H)，8.50(s，1H)，8.00(s，1H)，7.70-7.80(m，1H)，7.20-7.30(m，3H)，6.70(s，1H)，4.30-4.40(m，2H)，4.10-4.20(m，1H)，3.90(s，3H)，3.80(s，2H)，3.70-3.75(m，1H)，3.40-3.50(m，1H)，3.30-3.35(m，1H)，3.20-3.25(m，1H)，3.05-3.15(m，1H)，2.90-3.00(m，1H)，2.10-2.20(m，2H)，1.90-2.00(m，1H)，1.70-1.80(m，3H)：

MS(+ve?ESI)：648(M+H) ⁺。

C ₂₈H ₃₂F ₂N ₇O ₇P+2.3H ₂O theoretical value C, 48.8%; H, 5.35%; N, 14.23%; Measured value C, 48.95%; H, 5.03%; N, 14.15%

Embodiment 14-prepares compound 14-2-[[3-({ 4-[(5-{2-[(3, the 5-difluorophenyl) amino of table 1]-the 2-oxoethyl--the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (third-2-alkynes-1-yl) amino] ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin ({ 4-[(5-{2-[(3 with two-tertiary butyl 2-[[3-, the 5-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (third-2-alkynes-1-yl) amino] ethyl phosphonic acid ester (400mg, 0.53mmol), obtain the compound 14 (290mg, 77% yield) of table 1:

¹H-NMR(DMSO?d ₆，TFA)：8.94(s，1H)，8.34(s，1H)，7.42(m，3H)，6.89(m，2H)，4.37(m，6H)，4.04(s，3H)，3.92(s，2H)，3.87(s，1H)，3.57(m，2H)，3.47(m，2H)，2.39(m，2H)：

MS(+ve?ESI)：646.4(M+H) ⁺。

Following acquisition is as two-tertiary butyl 2-[[3-of initial feed ({ 4-[(5-{2-[(3,5-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (third-2-alkynes-1-yl) amino] the ethyl phosphonic acid ester:

A) under argon atmospher, (3.3g, methyl alcohol 75mmol) (10ml) cold soln (40 ℃) slowly add propargylamine (16.5g, methyl alcohol 300mmol) (60ml) solution that is cooled to-65 ℃ with oxyethane.With mixture at the 16h internal heating to room temperature, vacuum evaporating solvent, resistates purified by distillation obtains 2-(third-2-alkynes-1-base is amino) ethanol (5.0g, 67% yield):

¹H-NMR(DMSO?d ₆，TFA)：3.91(m，2H)，3.65(m，3H)，3.06(m，2H)。

B) response class of introducing with embodiment 8a seemingly, but begin ethanol (99mg with 2-(third-2-alkynes-1-base is amino), 1mmol), at 105 ℃ of heating 12h, obtain N-(3, the 5-difluorophenyl)-and the 2-{3-[(7-{3-[(2-hydroxyethyl) (third-2-alkynes-1-yl) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (50mg, 31% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.95(s，1H)，8.29(s，1H)，7.34(m，2H)，7.31(s，1H)，6.91(m，1H)，6.83(s，1H)，4.29(m，4H)，4.00(s，3H)，3.89(m，1H)，3.86(s，2H)，3.80(m，2H)，3.43(m，2H)，3.36(m，2H)，2.30(m，2H)：

MS(+ve?ESI)：566.2(M+H) ⁺。

C) response class of introducing with embodiment 8b seemingly, but begin with N-(3, the 5-difluorophenyl)-and the 2-{3-[(7-{3-[(2-hydroxyethyl) (third-2-alkynes-1-yl) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (734mg, 1.3mmol), obtain two-tertiary butyl 2-[[3-({ 4-[(5-{2-[(3, the 5-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (third-2-alkynes-1-yl) amino] ethyl phosphonic acid ester (400mg, 41% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.51(s，1H)，7.99(s，1H)，7.35(m，2H)，7.28(s，1H)，6.93(m，1H)，6.72(s，1H)，4.21(m，2H)，3.95(m，5H)，3.75(m，2H)，3.60(m，2H)，3.28(s，1H)，2.85(m，2H)，2.79(m，2H)，1.97(m，2H)，1.37(s，9H)。

Embodiment 15-prepares compound 15-2-[[3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino of table 1]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (sec.-propyl) amino] ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin ({ 4-[(5-{2-[(2 with two-tertiary butyl 2-[[3-, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (sec.-propyl) amino] ethyl phosphonic acid ester (450mg, 0.59mmol), obtain the compound 15 (405mg, 95% yield) of table 1:

¹H-NMR(DMSO?d ₆)：8.90(s，1H)，8.32(s，1H)，7.69(m，1H)，7.51(s，1H)，7.21(m，2H)，6.81(s，1H)，4.33(m，2H)，4.26(m，2H)，4.00(s，3H)，3.92(s，2H)，3.72(m，1H)，3.40(m，2H)，3.29(m，2H)，2.32(m，2H)，1.31(m，6H)：

MS(+ve?ESI)：650.3(M+H) ⁺。

Following acquisition is as two-tertiary butyl 2-[[3-of initial feed ({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (sec.-propyl) amino] the ethyl phosphonic acid ester:

A) response class of introducing with embodiment 6b seemingly, but begin ethanol (103mg with 2-(sec.-propyl amino), 1mmol), obtain N-(2, the 3-difluorophenyl)-and the 2-{3-[(7-{3-[(2-hydroxyethyl) (sec.-propyl) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (84mg, 49% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.97(s，1H)，8.33(s，1H)，7.79(m，1H)，7.35(s，1H)，7.18(m，2H)，6.88(s，1H)，4.34(t，2H)，4.03(s，3H)，3.98(s，2H)，3.81(m，3H)，3.40(m，3H)，3.20(m，1H)，2.35(m，2H)，1.33(m，6H)：

MS(+ve?ESI)：570.2(M+H) ⁺。

B) response class of introducing with embodiment 6c seemingly, but begin with N-(2, the 3-difluorophenyl)-and the 2-{3-[(7-{3-[(2-hydroxyethyl) (sec.-propyl) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (650mg, 1.14mmol), obtain two-tertiary butyl 2-[[3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (sec.-propyl) amino] ethyl phosphonic acid ester (520mg, 60% yield):

¹H-NMR(DMSO?d ₆)：8.44(s，1H)，7.98(s，1H)，7.73(m，1H)，7.19(m，2H)，7.12(s，1H)，6.83(s，1H)，4.16(t，2H)，3.93(s，3H)，3.85(s，2H)，3.77(m，2H)，2.90(m，1H)，2.60(m，4H)，1.86(m，2H)，1.36(s，18H)，0.94(m，6H)：

MS(+ve?ESI)：762.7(M+H) ⁺。

Embodiment 16-prepares compound 16-2-[[3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino of table 1]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (third-2-alkynes-1-yl) amino] ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin ({ 4-[(5-{2-[(2 with two-tertiary butyl 2-[[3-, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (third-2-alkynes-1-yl) amino] ethyl phosphonic acid ester (630mg, 0.84mmol), the compound 16 of acquisition table 1 ((540mg, 86% yield):

¹H-NMR(DMSO?d ₆，AcOD)：8.89(s，1H)，8.29(m，1H)，7.70(m，1H)，7.37(m，1H)，7.16(m，2H)，6.81(m，1H)，4.29(m，6H)，3.99(m，3H)，3.92(m，2H)，3.82(m，1H)，3.52(m，2H)，3.43(m，2H)，2.32(m，2H)：

MS(+ve?ESI)：646.3(M+H) ⁺。

Following acquisition is as two-tertiary butyl 2-[[3-of initial feed ({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (third-2-alkynes-1-yl) amino] the ethyl phosphonic acid ester:

A) response class of introducing with embodiment 6b seemingly, but begin ethanol (99mg with 2-(third-2-alkynes-1-base is amino), 1mmol), obtain N-(2, the 3-difluorophenyl)-and the 2-{3-[(7-{3-[(2-hydroxyethyl) (third-2-alkynes-1-yl) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (128mg, 75% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.95(s，1H)，8.29(s，1H)，7.74(m，1H)，7.31(s，1H)，7.18(m，2H)，6.83(s，1H)，4.30(m，4H)，4.00(s，3H)，3.94(s，2H)，3.87(m，1H)，3.80(m，2H)，3.44(m，2H)，3.35(m，2H)，2.30(m，2H)：

MS(+ve?ESI)：566.2(M+H) ⁺。

B) response class of introducing with embodiment 6c seemingly, but begin with N-(2, the 3-difluorophenyl)-and the 2-{3-[(7-{3-[(2-hydroxyethyl) (third-2-alkynes-1-yl) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (680mg, 1.2mmol), obtain two-tertiary butyl 2-[[3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (third-2-alkynes-1-yl) amino] ethyl phosphonic acid ester (630mg, 70% yield):

¹H-NMR(DMSO?d ₆)：8.45(s，1H)，7.98(s，1H)，7.72(m，1H)，7.17(m，3H)，6.83(s，1H)，4.16(m，2H)，3.85(m，7H)，3.45(m，2H)，3.13(m，1H)，2.69(m，4H)，1.90(m，2H)，1.35(m，18H)：

MS(+ve?ESI)：758.5(M+H) ⁺。

Embodiment 17-prepares compound 17-2-[[3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino of table 1]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (2-methoxy ethyl) amino] ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin ({ 4-[(5-{2-[(2 with two-tertiary butyl 2-[[3-, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (2-methoxy ethyl) amino] ethyl phosphonic acid ester (500mg, 0.64mmol), obtain the compound 17 (450mg, 94% yield) of table 1:

¹H-NMR(DMSO?d ₆，AcOD)：8.91(s，1H)，8.33(s，1H)，7.74(m，1H)，7.43(s，1H)，7.18(m，2H)，6.85(s，1H)，4.32(m，4H)，4.02(s，3H)，3.96(s，2H)，3.77(m，2H)，3.56(m，2H)，3.49(m，2H)，3.44(m，2H)，3.34(s，3H)，2.34(m，2H)：

MS(+ve?ESI)：666.2(M+H) ⁺。

Following acquisition is as two-tertiary butyl 2-[[3-of initial feed ({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (2-methoxy ethyl) amino] the ethyl phosphonic acid ester:

A) response class of introducing with embodiment 6b seemingly, but begin ethanol (119mg with 2-((2-methoxy ethyl) amino), 1mmol-is according to A.A.Santilli etc., J. Heterocycl.Chem.1972,9, the 309-13 preparation), obtain N-(2, the 3-difluorophenyl)-and the 2-{3-[(7-{3-[(2-hydroxyethyl) (2-methoxy ethyl) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (124mg, 71% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.97(s，1H)，8.31(s，1H)，7.76(m，1H)，7.33(s，1H)，7.19(m，2H)，6.85(s，1H)，4.31(t，2H)，4.02(s，3H)，3.95(s，2H)，3.80(t，2H)，3.73(t，2H)，3.45(m，4H)，3.36(m，5H)，2.31(m，2H)：

MS(+ve?ESI)：586.2(M+H) ⁺。

B) response class of introducing with embodiment 6c seemingly, but begin with N-(2, the 3-difluorophenyl)-and the 2-{3-[(7-{3-[(2-hydroxyethyl) (2-methoxy ethyl) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (800mg, 1.4mmol), obtain two-tertiary butyl 2-[[3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (2-methoxy ethyl) amino] ethyl phosphonic acid ester (560mg, 53% yield):

¹H-NMR(DMSO?d ₆)：8.44(s，1H)，7.99(s，1H)，7.72(m，1H)，7.20(m，2H)，7.12(s，1H)，6-84(s，1H)，4.16(t，2H)，3.93(t，3H)，3-85(m，4H)，3.38(m，2H)，3.20(s，3H)，2.74(m，2H)，2.67(m，4H)，1.90(m，2H)，1.39(m，18H)：

MS(+ve?ESI)：778.6(M+H) ⁺。

Embodiment 18-prepares compound 18-2-{[3-({ 4-[(5-{2-[(3-fluorophenyl) amino of table 1]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin amino with two-tertiary butyl 2-{[3-({ 4-[(5-{2-[(3-fluorophenyl)]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid ester (729mg, 1.04mmol), obtain the compound 18 (505mg, 72% yield) of table 1:

¹H-NMR(DMSO?d ₆，AcOD)：8.85(s，1H)，8.25(s，1H)，7.60(d，1H)，7.33(m，3H)，6.83(m，1H)，6.80(s，1H)，4.27(m，2H)，4.15(m，2H)，3.97(s，3H)，3.83(s，2H)，3.26(m，2H)，3.15(m，2H)，2.24(m，2H)：

MS(+ve?ESI)：590.1(M+H) ⁺。

Following acquisition is as two-tertiary butyl 2-{[3-of initial feed ({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } the ethyl phosphonic acid ester:

A) response class of introducing with embodiment 5a seemingly, but begin ethanol (156mg with 2-(cyclopropyl amino), 1.55mmol), obtain 2-{3-[(7-{3-[cyclopropyl (2-hydroxyethyl) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(3-fluorophenyl) ethanamide (22mg, 13% yield):

¹H-NMR (DMSO d ₆, TFA): 8.97 (s, 1H), 8.31 (s, 1H), 7.65 (d, 1H), 7.33-7.42 (m, 2H), 7.37 (s, 1H), 6.92 (t, 1H), 6.85 (s, 1H), 4.33 (m, 2H), 4.02 (s, 3H), 3.86 (s, 2H), 3.79 (t, 2H), 3.48 (m, 2H), 3.42 (t, 2H), 2.97 (m, 1 seal, 2.36 (m, 2H), 1.04 (m, 2H), 0.94 (m, 2H):

MS(+ve?ESI)：550.2(M+H) ⁺。

B) response class of introducing with embodiment 5b seemingly, but begin with 2-{3-[(7-{3-[cyclopropyl (2-hydroxyethyl) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(3-fluorophenyl) ethanamide (1.1g, 2.0mmol), acquisition two-tertiary butyl 2-{ cyclopropyl [3-(the 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid ester (150mg, 10% yield) and two-tertiary butyl 2-{[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl the oxygen base) propyl group] amino ethyl phosphonic acid ester (730mg, 52% yield) mixture is directly used in next step with it:

¹H-NMR(DMSO?d ₆，TFA)：8.97(s，1H)，8.32(s，1H)，7.78(d，1H)，7.36(m，2H)，7.34(s，1H)，6.87(m，2H)，4.33(m，2H)，4.16(m，2H)，4.03(s，3H)，3.88(s，2H)，3.33(m，2H)，3.24(m，2H)，2.38(m，2H)，1.47(s，18H)：

MS(+ve?ESI)：702.5(M+H) ⁺。

Embodiment 19-prepares compound 19-2-{ (cyclobutylmethyl) [3-({ 4-[(5-{2-[(2,3-difluorophenyl) the amino]-2-oxoethyl of table 1 }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin [3-({ 4-[(5-{2-[(2 with two-tertiary butyl 2-{ (cyclobutylmethyl), the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid ester (400mg, 0.508mmol), obtain the compound 19 (365mg, 96% yield) of table 1:

¹H-NMR(DMSO?d ₆，AcOD)：8.92(s，1H)，8.33(s，1H)，7.71(m，1H)，7.44(s，1H)，7.19(m，2H)，6.82(s，1H)，4.30(m，4H)，4.00(s，3H)，3.94(s，2H)，3.42(m，2H)，3.29(m，4H)，2.82(m，1H)，2.31(m，2H)，2.13(m，2H)，1.87(m，4H)：

MS(+ve?ESI)：676.4(M+H) ⁺。

Following acquisition is as two-tertiary butyl 2-{ (cyclobutylmethyl) of initial feed [3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } the ethyl phosphonic acid ester:

A) (5ml 43.8mmol) slowly adds glycine ethyl ester (5.86g, methylene dichloride 42mmol) (100ml) and triethylamine (14.6ml, 105mmol) solution with tetramethylene carbonyl chlorine at 0 ℃.Then with mixture at stirring at room 14h.Reaction mixture is isolated organic phase with dilute hydrochloric acid (1.0N) washing, and dry final vacuum evaporation obtains yellow solid.Obtain white solid N-(cyclobutyl carbonyl) glycine ethyl ester (7.78g, 100% yield) with methylene dichloride/sherwood oil recrystallization:

¹H-NMR(DMSO?d ₆)：8.08(t，1H)，4.09(q，2H)，3.79(s，2H)，3.07(m，1H)，2.00-2.18(m，4H)，1.89(m，1H)，1.78(m，1H)，1.20(t，3H)。

B) (7.6g, tetrahydrofuran (THF) 41mmol) (40ml) solution add diborane solution, and (100ml 1.0N tetrahydrofuran solution 100mmol), heats 24h at 60 ℃ with N-(cyclobutyl carbonyl) glycine ethyl ester.(20ml 1.0N tetrahydrofuran solution 20mmol) adds mixture, reheat 8h with other diborane.The careful methyl alcohol (20ml) that adds at stirring at room reactant 30min, slowly adds hydrochloric acid (6ml 6.0N solution) then.The vacuum concentration reactant adds methylene dichloride, shifts out solid matter by suction filtration.With organic filtrate drying, purify by silica gel chromatography behind the vacuum concentration, to methylene chloride/ammoniacal liquor (7.0N) (94: 5: 1) wash-out, obtain 2-((cyclobutylmethyl) amino) ethanol (4.16g, 78% yield) with methylene chloride (96: 4):

¹H-NMR(DMSO?d ₆，TFA)：8.38(brs，1H)，3.65(t，2H)，2.98(m，4H)，2.62(m，2H)，2.06(m，2H)，1.72-1.94(m，4H)。

C) response class of introducing with embodiment 6b seemingly, but begin ethanol (129mg with 2-((cyclobutylmethyl) amino), 1mmol), obtain the 2-{3-[(7-{3-[(cyclobutylmethyl) (2-hydroxyethyl) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(2, the 3-difluorophenyl) ethanamide (134mg, 75% yield):

¹H-NMR(DMSO?d ₆)：8.49(s，1H)，8.00(s，1H)，7.74(m，1H)，7.15-7.30(m，3H)，6.75(m，1H)，4.25(m，2H)，3.96(s，3H)，3.86(s，2H)，3.60-3.80(m，2H)，3.30-3.40(m，4H)，2.50-2.80(m，4H)，1.60-2.40(m，7H)：

MS(+ve?ESI)：596.2(M+H) ⁺。

D) response class of introducing with embodiment 6c seemingly, but begin to use the 2-{3-[(7-{3-[(cyclobutylmethyl) (2-hydroxyethyl) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(2, the 3-difluorophenyl) ethanamide (773mg, 1.3mmol), obtain two-tertiary butyl 2-{ (cyclobutylmethyl) [3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid ester (400mg, 40% yield):

¹H-NMR(DMSO?d ₆)：8.45(s，1H)，7.99(s，1H)，7.72(m，1H)，7.20(m，3H)，6.83(s，1H)，4.15(s，2H)，3.94(s，3H)，3.85(m，4H)，2.60(m，4H)，2.47(m，3H)，1.88(m，4H)，1.75(m，2H)，1.60(m，2H)，1.36(s，18H)：

MS(+ve?ESI)：788.8(M+H) ⁺。

Embodiment 20-prepares compound 20-2-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino of table 1]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (3,3, the 3-trifluoro propyl) amino] ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin amino with two-tertiary butyl 2-[[3-({ 4-[(5-{2-[(3-fluorophenyl)]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (3,3, the 3-trifluoro propyl) amino] ethyl phosphonic acid ester (450mg, 0.56mmol), obtain the compound 20 (405mg, 46% yield) of table 1:

¹H-NMR(DMSO?d ₆，TFA)：8.95(s，1H)，8.32(s，1H)，7.65(d，1H)，7.39(s，1H)，7.36(m，1H)，6.89(m，1H)，6.83(s，1H)，4.31(t，2H)，4.27(m，2H)，4.01(s，2H)，3.86(s，2H)，3.57(br?s，2H)，3.54(m，2H)，3.43(t，2H)，2.97(m，2H)，2.33(m，2H)：

MS(+ve?ESI)：686.4(M+H) ⁺。

Following acquisition is as two-tertiary butyl 2-[[3-of initial feed ({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (3,3, the 3-trifluoro propyl) amino] the ethyl phosphonic acid ester:

A) (14.2g 102mmol) exists down, and with 3-bromo-1,1, (5.5ml, (3ml is 51.25mmol) at 60 ℃ of heating 36h for two  alkane (50ml) solution 51.6mmol) and thanomin for 1-trifluoro propane at salt of wormwood.Vacuum evaporating solvent, resistates is purified with silica gel chromatography, to methylene chloride/ammoniacal liquor (7.0N) (95: 5: 1) wash-out, obtains 2-((3,3, the 3-trifluoro propyl) amino) ethanol (4.47g, 55% yield) with methylene chloride (95: 5):

¹H-NMR(DMSO?d ₆，TFA)：3.56(t，2H)，2.97(t，2H)，2.82(t，2H)，2.57(m，2H)。

B) response class of introducing with embodiment 5a seemingly, but begin with 2-((3,3, the 3-trifluoro propyl) ethanol (221mg amino), 1.55mmol), obtain N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl) (3,3, the 3-trifluoro propyl) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (77mg, 41% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.96(s，1H)，8.29(s，1H)，7.63(d，1H)，7.31-7.40(m，2H)，7.33(s，1H)，6.89(t，1H)，6.83(s，1H)，4.29(t，2H)，3.99(s，3H)，3.84(s，2H)，3.79(t，2H)，3.51(m，2H)，3.38(m，2H)，2.91(m，2H)，2.29(m，2H)：

MS(+ve?ESI)：606.2(M+H) ⁺。

C) response class of introducing with embodiment 5b seemingly, but begin with N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl) (3,3, the 3-trifluoro propyl) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (651mg, 1.07mmol), acquisition two-tertiary butyl 2-[[3-(the 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] (3,3, the 3-trifluoro propyl) amino] ethyl phosphonic acid ester (455mg, 53% yield):

¹H-NMR(DMSO?d ₆)：10.45(s，1H)，10.15(s，1H)，8.44(s，1H)，7.98(s，1H)，7.62(d，1H)，7.35(m，1H)，7.33(s，1H)，7.13(s，1H)，6.89(t，1H)，6.82(s，1H)，4.16(t，2H)，3.93(s，3H)，3.87(q，2H)，3.76(s，2H)，2.73(m，4H)，2.66(t，2H)，2.42(m，2H)，1.90(m，2H)，1.37(s，18H)：

MS(+ve?ESI)：797.9(M+H) ⁺

Embodiment 21-prepares compound 21-2-{ allyl group [3-({ 4-[(5-{2-[(2,3-difluorophenyl) the amino]-2-oxoethyl of table 1 }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin with 2-{ allyl group [3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl two-tertiary butyl phosphoric acid ester (310mg, 0.408mmol), obtain the compound 21 (293mg, 100% yield) of table 1:

¹H-NMR(DMSO?d ₆，AcOD)：8.92(s，1H)，8.32(s，1H)，7.70(m，1H)，7.43(s，1H)，7.19(m，2H)，6.82(s，1H)，6.05(m，1H)，5.63(m，1H)，5.56(m，1H)，4.30(m，4H)，4.00(s，3H)，3.93(m，4H)，3.45(m，2H)，3.33(m，2H)，2.33(m，2H)：

MS(+ve?ESI)：648.3(M+H) ⁺。

Following acquisition is as the 2-{ allyl group of initial feed [3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl two-tertiary butyl phosphoric acid ester:

A) oxyethane (2.5ml, 50mmol-are cooled to-20 ℃) is added allyl amine (14g, methyl alcohol 250mmol) (20ml) solution (20 ℃).At stirring at room mixture 14h, vacuum evaporating solvent, remaining oily matter by distillation purify (b.p.140 ℃/14mmHg) obtain 2-(allyl amino) ethanol (4.2g, 84% yield):

¹H-NMR(DMSO?d ₆)：5.83(m，1H)，5.14(m，1H)，5.02(m，1H)，3.43(m，2H)，3.14(m，2H)，2.50(m，2H)。

B) response class of introducing with embodiment 6b seemingly, but begin with 2-(allyl amino) ethanol (101mg, 1mmol), obtain 2-{3-[(7-{3-[allyl group (2-hydroxyethyl) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(2, the 3-difluorophenyl) ethanamide (99mg, 58% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.97(s，1H)，8.32(s，1H)，7.77(m，1H)，7.33(s，1H)，7.18(m，2H)，6.87(s，1H)，6.01(m，1H)，5.60(m，2H)，4.31(t，2H)，4.02(s，3H)，3.94(m，4H)，3.82(t，2H)，3.35(m，4H)，2.34(m，2H)：

MS(+ve?ESI)：568.2(M+H) ⁺。

C) response class of introducing with embodiment 6c seemingly, but begin with 2-{3-[(7-{3-[allyl group (2-hydroxyethyl) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(2, the 3-difluorophenyl) ethanamide (1.0g, 1.76mmol), obtain 2-{ allyl group [3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl two-tertiary butyl phosphoric acid ester (310mg, 23% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.97(s，1H)，8.30(s，1H)，7.75(m，1H)，7.32(s，1H)，7.20(m，2H)，6.85(s，1H)，6.00(m，1H)，5.74(m，2H)，4.30(m，4H)，4.01(s，3H)，3.95(m，4H)，3.50(m，2H)，3.37(m，2H)，2.30(m，2H)，1.45(s，18H)：

MS(+ve?ESI)：760.5(M+H) ⁺。

Embodiment 22-prepares compound 22-2-{ cyclobutyl [3-({ 4-[(5-{2-[(2,3-difluorophenyl) the amino]-2-oxoethyl of table 1 }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin with two-tertiary butyl 2-{ cyclobutyl [3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid ester (450mg, 0.58mmol), obtain the compound 22 (420mg, 98% yield) of table 1:

¹H-NMR(DMSO?d ₆，AcOD)：8.91(s，1H)，8.31(s，1H)，7.72(m，1H)，7.42(s，1H)，7.20(m，2H)，6.82(s，1H)，4.28(m，4H)，4.00(s，3H)，3.94(s，3H)，3.35(m，2H)，3.25(m，2H)，2.41(m，2H)，2.25(m，4H)，1.70(m，2H)：

MS(+ve?ESI)：662.5(M+H) ⁺。

Following acquisition is as two-tertiary butyl 2-{ cyclobutyl of initial feed [3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } the ethyl phosphonic acid ester:

A) response class of introducing with embodiment 6b seemingly, but begin ethanol (117mg with 2-(cyclobutyl amino), 1mmol-is according to D.F.Morrow etc., J.Med.Chem.1973,16,736-9 prepares) and potassiumiodide (103mg, 0.62mmol) N,N-DIMETHYLACETAMIDE (2ml) solution at argon atmospher, 95 ℃ reaction 4h down, obtain 2-{3-[(7-{3-[cyclobutyl (2-hydroxyethyl) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(2, the 3-difluorophenyl) ethanamide (97mg, 56% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.92(s，1H)，8.27(s，1H)，7.74(m，1H)，7.29(s，1H)，7.15-7.20(m，2H)，6.83(s，1H)，4.30(m，2H)，3.98(s，3H)，3.98(m，3H)，3.68-3.80(m，2H)，3.20-3.30(m，2H)，3.15(m，2H)，2.30(m，2H)，2.22(m，4H)，1.65-1.82(m，2H)：

MS(+ve?ESI)：582.2(M+H) ⁺。

B) response class of introducing with embodiment 6c seemingly, but begin with 2-{3-[(7-{3-[cyclobutyl (2-hydroxyethyl) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(2, the 3-difluorophenyl) ethanamide (668mg, 1.15mmol), obtain two-tertiary butyl 2-{ cyclobutyl [3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid ester (450mg, 51% yield):

¹H-NMR(DMSO?d ₆)：8.44(s，1H)，7.98(s，1H)，7.70(m，1H)，7.18(m，3H)，6.83(s，1H)，4.15(t，2H)，3.90(s，3H)，3.85(m，4H)，3.15(m，1H)，2.62(m，4H)，1.90(m，4H)，1.75(m，2H)，1.53(m，2H)，1.39(s，18H)：

MS(+ve?ESI)：774.8(M+H) ⁺。

Embodiment 23-prepares compound 23-2-{ cyclopentyl [3-({ 4-[(5-{2-[(2,3-difluorophenyl) the amino]-2-oxoethyl of table 1 }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin with two-tertiary butyl 2-{ cyclopentyl [3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid ester (360mg, 0.46mmol), obtain the compound 23 (330mg, 95% yield) of table 1:

¹H-NMR(DMSO?d ₆，AcOD)：8.91(s，1H)，8.32(s，1H)，7.70(m，1H)，7.43(s，1H)，7.20(m，2H)，6.82(s，1H)，4.31(m，4H)，4.00(s，3H)，3.94(s，2H)，3.80(m，1H)，3.48(m，2H)，3.36(m，2H)，2.33(m，2H)，2.08(m，2H)，1.75(m，4H)，1.58(m，2H)：

MS(+ve?ESI)：676.5(M+H) ⁺。

Following acquisition is as two-tertiary butyl 2-{ cyclopentyl of initial feed [3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } the ethyl phosphonic acid ester:

A) response class of introducing with embodiment 6b seemingly, but begin ethanol (129mg with 2-(cyclopentyl amino), 1mmol-is according to D.F.Morrow etc., J.Med.Chem.1973,16, the 736-9 preparation), obtain 2-{3-[(7-{3-[cyclopentyl (2-hydroxyethyl) amino] and propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(2, the 3-difluorophenyl) ethanamide (86mg, 48% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.93(s，1H)，8.28(s，1H)，7.73(m，1H)，7.30(s，1H)，7.14(m，2H)，6.83(s，1H)，4.29(m，2H)，3.98(s，3H)，3.93(s，2H)，3.78(m，3H)，3.37(m，2H)，3.26(m，2H)，2.30(m，2H)，2.09(m，2H)，1.74(m，4H)，1.72(m，2H)：

MS(+ve?ESI)：596.2(M+H) ⁺。

B) response class of introducing with embodiment 6c seemingly, but begin with 2-{3-[(7-{3-[cyclopentyl (2-hydroxyethyl) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(2, the 3-difluorophenyl) ethanamide (654mg, 1.1mmol), obtain two-tertiary butyl 2-{ cyclopentyl [3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid ester (364mg, 42% yield):

¹H-NMR(DMSO?d ₆)：8.44(s，1H)，7.99(s，1H)，7.70(m，1H)，7.18(m，3H)，6.83(s，1H)，4.15(m，2H)，3.90(s，3H)，3.83(m，4H)，3.07(m，1H)，2.68(m，4H)，1.90(m，2H)，1.72(m，2H)，1.55(m，2H)，1.48(m，2H)，1.35(m，20H)：

MS(+ve?ESI)：789.0(M+H) ⁺。

Embodiment 24-prepares compound 24-2-{ cyclopropyl [3-({ 4-[(5-{2-[(3-fluorophenyl) the amino]-2-oxoethyl of table 1 }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters

With hydrochloric acid (1.05ml 4.0N two  alkane solution, 4.2mmol) two-tertiary butyl 2-{ cyclopropyl under add stirring [3-(the 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid ester (519mg, 0.7mmol) methylene dichloride (15ml) and two  alkane (30ml) suspension, mix reactant 7h at 45 ℃.Reclaim precipitation by suction filtration, resistates is dissolved in methylene chloride (8: 2), by the solids removed by filtration material.The organic filtrate of vacuum-evaporation, resistates and ether are ground the compound 24 (430mg, 88% yield) that obtains table 1:

¹H-NMR(DMSO?d ₆，ACOH)：8.91(s，1H)，8.32(s，1H)，7.64(m，1H)，7.39(m，3H)，6.90(m，1H)，6.80(s，1H)，4.32(m，4H)，4.00(s，3H)，3.87(s，2H)，3.57(m，2H)，3.48(m，2H)，2.95(m，1H)，2.40(m，2H)，1.18(m，2H)，0.92(m，2H)：

MS(+ve?ESI)：630.4(M+H) ⁺。

Following acquisition is as two-tertiary butyl 2-{ cyclopropyl of initial feed [3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } the ethyl phosphonic acid ester:

A) under room temperature, argon atmospher, with diethylamino phosphorous acid di tert butyl carbonate (523 μ l, 2.1mmol) in 5min, add and contain tetrazolium (245mg, 3.5mmol) 2-{3-[(7-{3-[cyclopropyl (2-hydroxyethyl) amino] propoxy--6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl-N-(3-fluorophenyl) ethanamide (793mg, 1.4mmol) dimethyl formamide (8ml) solution, 1.5h stirs the mixture.Cooling solution to 5 ℃, slowly add cumene hydroperoxide (426mg, 2.8mmol), at 50 ℃ of 1h that stir the mixture, at room temperature restir 1h.Cooling mixture to 5 ℃, add triethyl-phosphite (415mg, 2.5mmol), at stirring at room reactant 1h.Ethyl acetate extraction is used in the solution with water dilution, isolates organic phase, and dry back concentrates.Gained oily matter is purified with silica gel chromatography, with methylene chloride (98: 2) to methylene chloride/ammoniacal liquor (7.0N) (95: 5: 1) wash-out, obtain Off-white solid two-tertiary butyl 2-{ cyclopropyl [3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid ester (630mg, 59% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.97(s，1H)，8.32(s，1H)，7.65(d，1H)，7.35(m，3H)，6.86(m，2H)，4.33(m，4H)，4.03(s，3H)，3.87(s，2H)，3.66(m，2H)，3.53(m，2H)，3.00(m，1H)，2.38(m，2H)，1.45(s，18H)，1.07(m，2H)，0.96(m，2H)：

MS(+ve?ESI)：759.7(M+H) ⁺。

Embodiment 25-prepares compound 25-2-{ (cyclopropyl methyl) [3-({ 4-[(5-{2-[(2,3-difluorophenyl) the amino]-2-oxoethyl of table 1 }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin [3-({ 4-[(5-{2-[(2 with two-tertiary butyl 2-{ (cyclopropyl methyl), the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid ester (725mg, 0.94mmol), obtain the compound 25 (661mg, 90% yield) of table 1:

¹H-NMR(DMSO?d ₆，TFA)：8.95(s，1H)，8.32(s，1H)，7.74(m，1H)，7.39(s，1H)，7.21(m，2H)，6.84(s，1H)，4.32(t，2H)，4.28(m，2H)，4.01(s，3H)，3.95(s，2H)，3.56(br?s，2H)，3.46(t，2H)，3.19(d，2H)，2.32(m，2H)，1.18(m，1H)，0.68(m，2H)，0.47(m，2H)：

MS(+ve?ESI)：662.4(M+H) ⁺。

Following acquisition is as two-tertiary butyl 2-{ (cyclopropyl methyl) of initial feed [3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } the ethyl phosphonic acid ester:

A) at 0 ℃, with Vinyl chloroformate (4.2ml, 37mmol) in 30min, add the cyclopropyl methylamine (3.00ml, 34.6mmol) and methylene dichloride (35ml) stirred solution of triethylamine (7ml).At stirring at room reactant 2h, water (20ml) is added mixture, add 2.0N hydrochloric acid and regulate pH to 3.Isolate organic phase, drying, vacuum concentration obtains (cyclopropyl methyl) urethanum (5.9g, 100% yield):

¹H-NMR(CDCl ₃)：7.24(br?s，1H)，3.24(m，2H)，1.43(t，3H)，1.04(m，1H)，0.59(m，2H)，0.29(m，2H)：

MS(+ve?ESI)：172(M+H) ⁺。

B) with (cyclopropyl methyl) urethanum (5.90g, 34.6mmol) tetrahydrofuran (THF) (30ml) solution add diborane (130ml 1.0N tetrahydrofuran solution in room temperature, 130mmol) (34ml, 268mmol) solution is at stirring at room mixture 48h with the chloro trimethyl silane.Add methyl alcohol (20ml), at stirring at room reactant 30min.Add successively methylene dichloride (25ml), hydrochloric acid (4ml 6.0N solution, 24mmol), at stirring at room reactant 30min.The methanol solution (7.0N) that adds ammonia is collected white solid, the organic filtrate of vacuum-evaporation by suction filtration.Purify with silica gel chromatography, with methylene dichloride to methylene chloride (95: 5) to methylene fluoride/methyl alcohol/ammoniacal liquor (7.0N) (90: 9: 1) wash-out, obtain light yellow liquid 2-((cyclopropyl methyl) amino) ethanol (2.99g, 75% yield):

¹H-NMR(DMSO?d ₆，TFA)：3.66(t，2H)，3.02(t，2H)，2.84(d，2H)，1.06(m，1H)，0.58(m，2H)，0.35(m，2H)。

C) response class of introducing with embodiment 6b seemingly, but begin amino with 2-(cyclopropyl methyl)) ethanol (115mg, 1mmol), obtain 2-{3-[(7-{3-[(cyclopropyl methyl) (2-hydroxyethyl) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(2, the 3-difluorophenyl) ethanamide (6mg, 3% yield):

¹H-NMR(DMSO?d ₆)：10.23(s，1H)，10.16(s，1H)，8.44(s，1H)，7.98(s，1H)，7.72(m，1H)，7.18(m，2H)，7.14(s，1H)，6.84(s，1H)，4.32(s，1H)，4.18(t，2H)，3.93(s，3H)，3.85(s，2H)，3.45(m，2H)，2.69(t，2H)，2.58(t，2H)，2.35(d，2H)，1.90(m，2H)，0.83(m，1H)，0.41(m，2H)，0.08(m，2H)：

MS(+ve?ESI)：582.2(M+H) ⁺。

D) response class of introducing with embodiment 6c seemingly, but begin with 2-{3-[(7-{3-[(cyclopropyl methyl) (2-hydroxyethyl) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(2, the 3-difluorophenyl) ethanamide (673mg, 1.16mmol), obtain two-tertiary butyl 2-{ (cyclopropyl methyl) [3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid ester (110mg, 12% yield):

¹H-NMR(DMSO?d ₆)：10.23(s，1H)，10.15(s，1H)，8.44(s，1H)，7.98(s，1H)，7.72(t，1H)，7.19(m，2H)，7.13(s，1H)，6.83(s，1H)，4.17(t，2H)，3.93(s，3H)，3.88(q，2H)，3.85(s，2H)，2.76(t，2H)，2.72(t，2H)，2.38(d，2H)，1.91(m，2H)，1.37(s，18H)，0.83(m，1H)，0.42(m，?2H)，0.09(m，2H)：

MS(+ve?ESI)：774.7(M+H) ⁺

Embodiment 26-prepares compound 26-2-{ cyclobutyl [3-({ 4-[(5-{2-[(3-fluorophenyl) the amino]-2-oxoethyl of table 1 }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin with two-tertiary butyl 2-{ cyclobutyl [3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-2-oxoethyl-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid ester (416mg, 0.55mmol), obtain the compound 26 (455mg, 100% yield) of table 1:

¹H-NMR(DMSO?d ₆，TFA)：8.94(s，1H)，8.31(s，1H)，7.65(d，1H)，7.38(m，2H)，7.36(s，1H)，6.90(m，1H)，6.83(s，1H)，4.30(t，2H)，4.22(m，2H)，4.01(s，3H)，3.94(m，1H)，3.86(s，2H)，3.37(s，2H)，3.27(br?s，2H)，2.35(t，2H)，2.26(m，4H)，1.77(m，1H)，1.68(m，1H)：

MS(+ve?ESI)：644.2(M+H) ⁺。

Following acquisition is as two-tertiary butyl 2-{ cyclobutyl of initial feed [3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } the ethyl phosphonic acid ester:

A) response class of introducing with embodiment 5a seemingly, but begin with 2-(cyclobutyl amino) ethanol (178 mg, 1.55mmol), obtain 2-{3-[(7-{3-[cyclobutyl (2-hydroxyethyl) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(3-fluorophenyl) ethanamide (42 mg, 24% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.96(s，1H)，8.29(s，1H)，7.64(d，1H)，7.36(m，2H)，7.34(s，1H)，6.90(t，1H)，6.83(s，1H)，4.29(t，2H)，4.00(s，3H)，3.94(m，1H)，3.85(s，2H)，3.75(m，2H)，3.25(m，2H)，3.17(m，2H)，2.08-2.39(m，6H)，1.76(m，1H)，1.69(m，1H)：

MS(+ve?ESI)：564.2(M+H) ⁺。

B) response class of introducing with embodiment 5b seemingly, but begin with 2-{3-[(7-{3-[cyclobutyl (2-hydroxyethyl) amino] propoxy-}-6-methoxyl group quinazoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(3-fluorophenyl) ethanamide (474mg, 0.84mmol), acquisition two-tertiary butyl 2-{ cyclobutyl [3-(the 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-6-methoxyl group quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid ester (109mg, 17% yield):

¹H-MR(DMSO?d ₆)：10.46(s，1H)，10.16(s，1H)，8.44(s，1H)，7.98(s，1H)，7.62(d，1H)，7.34(m，1H)，7.33(s，1H)，7.13(s，1H)，6.89(t，1H)，6.82(s，1H)，4.15(t，2H)，3.93(s，3H)，3.84(q，2H)，3.76(s，2H)，3.16(m，1H)，2.64(t，2H)，2.59(t，2H)，1.96(m，2H)，1.88(m，2H)，1.77(m，2H)，1.55(m，2H)，1.38(s，18H)：

MS(+ve?ESI)：756.7(M+H) ⁺。

Embodiment 27-prepares the compound 27-2-{4-[({4-[(5-{2-[(2 of table 2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) methyl] piperidines-1-yl } ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin with two-tertiary butyl 2-{4-[({4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) methyl] piperidines-1-yl } ethyl phosphonic acid ester (230mg, 0.32mmol), obtain compound 27 (230mg, 95% yield) for the table 2 of white solid:

¹H-NMR(DMSO?d ₆)：12.00(s，1H)，10.40(s，1H)，8.95(s，1H)，8.80(d，1H)，7.70-7.80(m，1H)，7.40(d，1H)，7.35(s，1H)，7.15-7.25(m，2H)，6.70(s，1H)，4.20-4.30(m，2H)，4.05-4.15(m，2H)，3.90(s，2H)，3.50-3.60(m，2H)，3.10-3.25(m，2H)，2.27(m，1H)，2.10-2.20(m，2H)，1.70-1.90(m，2H)，1.20(t，2H)：

MS(+ve?ESI)：618(M+H) ⁺，

MS(-ve?ESI)：616(M-H) ^-。

Following acquisition is as two-tertiary butyl 2-{4-[({4-[(5-{2-[(2 of initial feed, 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) methyl] piperidines-1-yl } the ethyl phosphonic acid ester:

A) (4.00g, thionyl chloride 15.9mmol) (25ml) suspension heat 1h with reactant at 85 ℃ with 7-(the benzyl oxygen base) quinazoline-4 (3H)-ketone under dimethyl formamide (0.1ml) the adding stirring.The cooling reactant, the vacuum-evaporation excessive thionyl chloride, (2 * 25ml) azeotropic are dissolved in N,N-DIMETHYLACETAMIDE (20ml) then with resistates and toluene.Adding 5-amino-1H-pyrazole-3-yl acetate (2.27g, 15.9mmol), at 90 ℃ of reacting by heating thing 2.5h.The cooling reactant is to room temperature, in the impouring ice-water (200ml), by the solid that suction filtration collection is separated out, obtain the light orange solid (3-{[7-(benzyl oxygen base) quinazoline-4-yl] amino }-1H-pyrazoles-5-yl) acetate (3.92g, 60% yield):

¹H-NMR(DMSO?d ₆)：12.70(br?s，1H)，8.75(s，1H)，8.70(d，1H)，7.57(m，2H)，7.35-7.50(m，4H)，7.30(s，1H)，6.70(s，1H)，5.35(s，2H)，3.70(s，2H)：

MS(+ve?ESI)：376(M+H) ⁺，

MS(-ve?ESI)：374(M-H) ^-。

B) at 0 ℃ with phosphoryl chloride (1.00ml, 11.6mmol) 2 under add stirring, the 3-difluoroaniline (1.44g, 11.6mmol), (3-{[7-(benzyl oxygen base) quinazoline-4-yl] amino }-1H-pyrazoles-5-yl) and acetate (3.82g, 9.30mmol) and the suspension of pyridine (40ml).At stirring at room reactant 1h, be cooled to 0 ℃ then, add other phosphoryl chloride (0.5ml), in 1h, allow it rise to room temperature then.With reactant impouring 20% aqueous hydrochloric acid, collect the gained solid by suction filtration.Long-time vacuum-drying, acquisition orange solids 2-(3-{[7-(benzyl oxygen base) quinazoline-4-yl] amino }-1H-pyrazoles-5-yl)-N-(2, the 3-difluorophenyl) ethanamide (4.90g, 100% yield), it contains portion water:

¹H-NMR?(DMSO?d ₆)：11.30(s，1H)，10.30(s，1H)，8.80(s，1H)，8.70(d，1H)，7.80-7.80(m，1H)，7.50-7.60(m，2H)，7.35-7.45(m，5H)，7.30(s，1H)，7.10-7.20(m，2H)，6.80(s，1H)，5.40(s，2H)，3.90(s，2H)：

MS(+ve?ESI)：487(M+H) ⁺，

MS(-ve?ESI)：485(M-H) ^-。

C) with 2-(3-{[7-(benzyl oxygen base) quinazoline-4-yl] amino }-1H-pyrazoles-5-yl)-(4.90g 9.30mmol) adds trifluoroacetic acid (75ml), at 90 ℃ of reacting by heating thing 4h to N-(2, the 3-difluorophenyl) ethanamide.The cooling reactant, vacuum is removed excessive trifluoroacetic acid, and resistates is dissolved in methyl alcohol (30ml).Above methanol solution is added drop-wise to sodium bicarbonate aqueous solution (100ml), makes to produce the orange solids precipitation.Collect solid, wash with water then, after vacuum-drying, obtain filbert solid N-(2, the 3-difluorophenyl)-2-{3-[(7-hydroxyl quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (3.60g, 97% yield):

¹H-NMR(DMSO?d ₆)：12.50(br?s，1H)，10.30(s，1H)，8.70(s，1H)，8.60(d，1H)，7.70-7.80(m，1H)，7.30-7.40(m，2H)，7.10(d，1H)，7.00(s，1H)，6.80(br?s，1H)，3.80(s，2H)：

MS(+ve?ESI)：397(M+H) ⁺，

MS(-ve?ESI)：395(M-H) ^-。

D) at 0 ℃ with methane sulfonyl chloride (864mg, 7.58mmol) be added drop-wise to N-(tert-butoxycarbonyl) piperidin-4-yl methyl alcohol (1.63g, 7.58mmol) and triethylamine (1.40ml, anhydrous tetrahydro furan 10.0mmol) (15ml) solution is at this temperature reaction stirred 1h.The filtering reaction thing, resistates washs with ether, and the organic phase that vacuum-evaporation merges obtains colorless oil.Oily matter is dissolved in N,N-DIMETHYLACETAMIDE (10ml), add N-(2, the 3-difluorophenyl)-2-{3-[(7-hydroxyl quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } and ethanamide (2.00g, 5.07mmol) and salt of wormwood (1.39g, 10.0mmol), reactant is heated 16h at 70 ℃.The vacuum concentration reaction mixture, purify with the fast silica gel chromatogram method, with 0-5% ethanol/methylene wash-out, obtain yellow solid 4-[({4-[(5-(2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) methyl] piperidines-1-base t-butyl formate (1.11g, 38% yield):

¹H-NMR(DMSO?d ₆)：12.50(s，1H)，10.30(d，2H)，8.60-8.70(m，2H)，7.70-7.80(m，1H)，7.30-7.40(m，4H)，6.90(s，1H)，4.00-4.10(m，4H)，3.90(s，2H)，2.80-2.90(m，2H)，2.00-2.10(m，1H)，1.80-1.90(m，2H)，1.50(s，9H)，1.30-1.40(m，2H)：

MS(+ve?ESI)：594(M+H) ⁺，

MS(-ve?ESI)：592(M-H) ^-。

E) trifluoroacetic acid (5ml) is added 4-[({4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) methyl] piperidines-1-base t-butyl formate (1.11g, 1.897mmol) methylene dichloride (25ml) solution, at stirring at room reactant 30min.Vacuum is removed volatile matter, and product is purified with reversed-phase HPLC.Hplc is obtained partial vacuum be concentrated into 20% of original volume,, produce the orange solids precipitation with the yellow soda ash alkalization.Suction filtration is collected solid, and be dissolved in methylene dichloride: methyl alcohol (1: 9) washes with water.Vacuum evaporating solvent acquisition orange powder shape solid N-(2, the 3-difluorophenyl)-2-(3-([7-(piperidin-4-yl methoxyl group) quinazoline-4-yl] amino }-1H-pyrazoles-5-yl) ethanamide (612mg, 66% yield):

¹H-NMR(DMSO?d ₆)：12.40(s，1H)，10.20(br?s，2H)，8.50-8.60(m，2H)，7.70-7.80(m，1H)，7.00-7.20(m，4H)，6.70(brs，1H)，4.20(br?s，1H)，4.00(d，2H)，3.90(s，2H)，3.10-3.20(m，2H)，2.90-3.00(m，2H)，1.90-2.00(m，1H)，1.70-1.80(m，2H)，1.20-1.30(m，2H)：

MS(+ve?ESI)：494(M+H) ⁺，

MS(-ve?ESI)：492(M-H) ^-。

F) with acetoxyl group sodium borohydride (392mg, 1.86mmol) adding t-butyldimethylsilyloxy ethylhexanal (324mg, 1.86mmol), N-(2, the 3-difluorophenyl)-2-(3-{[7-(piperidin-4-yl methoxyl group) quinazoline-4-yl] amino }-1H-pyrazoles-5-yl) ethanamide (612mg, 1.24mmol), acetate (0.42ml, 7.4mmol) methyl alcohol (10ml) and tetrahydrofuran (THF) (30ml) solution, at stirring at room reactant 18h.Add other acetoxyl group sodium borohydride (392mg, 1.86mmol) and the t-butyldimethylsilyloxy ethylhexanal (324mg, 1.86mmol), reaction stirred 10min, vacuum concentration then.Resistates is purified by Biotage 40M post flash chromatography and (is used methyl alcohol successively: methylene dichloride (7: 93), 7.0N ammoniacal liquor: methyl alcohol (1: 99) wash-out), after evaporating solvent and vacuum-drying, obtain light orange solid 2-{3-[(7-{[1-(the 2-{[tertiary butyl (dimethyl) silyl] oxygen base } ethyl) piperidin-4-yl] methoxyl group } quinazoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(2, the 3-difluorophenyl) ethanamide (410mg, 51% yield):

¹H-NMR(DMSO?d ₆)：12.40(s，1H)，10.15(s，1H)，10.10(s，1H)，8.50(s，1H)，8.45(d，1H)，7.60-7.70(m，1H)，7.00-7.20(m，4H)，6.70(s，1H)，3.90(d，2H)，3.70(s，2H)，3.60(t，2H)，2.80-2.90(m，2H)，2.40(t，2H)，1.90-2.00(m，2H)，1.70-1.80(m，3H)，1.20-1.30(m，2H)，0.80(s，9H)，0.00(s，6H)：

MS(+ve?ESI)：652(M+H) ⁺，

MS(-ve?ESI)：650(M-H) ^-。

G) with tetra-n-butyl Neutral ammonium fluoride (0.69ml 1.0N tetrahydrofuran solution, 0.69mmol) adding 2-{3-[(7-{[1-(the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl) piperidin-4-yl] methoxyl group } quinazoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(2, the 3-difluorophenyl) ethanamide (410mg, tetrahydrofuran (THF) 0.63mmol) (10ml) solution.At stirring at room reactant 18h, add 2 parts of tetra-n-butyl Neutral ammonium fluorides (0.69mmol) during this period in addition.With the reactant vacuum concentration, resistates is purified by Biotage 40S post flash chromatography and (is used methyl alcohol successively: methylene dichloride (25: 75), 7.0N ammoniacal liquor: methyl alcohol (1: 99) wash-out), obtain light orange solid N-(2, the 3-difluorophenyl)-and 2-{3-[(7-{[1-(2-hydroxyethyl) piperidin-4-yl] methoxyl group } quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (258mg, 76% yield):

¹H-NMR(DMSO?d ₆)：12.30(s，1H)，10.30(br?s，1H)，8.50(br?s，2H)，7.76(m，1H)，7.10-7.40(m，4H)，6.90(br?s，1H)，4.40(br?s，1H)，4.10(d，2H)，3.80(br?s，2H)，3.40-3.50(m，2H)，2.90-3.00(m，2H)，2.50(t，2H)，2.00-2.10(m，2H)，1.70-1.80(m，3H)，1.30-1.40(m，2H)：

MS(+ve?ESI)：538(M+H) ⁺，

MS(-ve?ESI)：536(M-H) ^-。

H) response class of introducing with embodiment 6c seemingly, but begin with N-(2, the 3-difluorophenyl)-and 2-{3-[(7-{[1-(2-hydroxyethyl) piperidin-4-yl] methoxyl group } quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (235mg, 0.44mmol), obtain white solid two-tertiary butyl 2-{4-[({4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) methyl] piperidines-1-yl } ethyl phosphonic acid ester (232mg, 73% yield):

¹H-NMR(DMSO?d ₆)：12.30(s，1H)，10.20(d，2H)，8.40(br?s，2H)，7.60-7.70(m，1H)，7.30-7.40(m，4H)，6.80(br?s，1H)，4.05(d，2H)，3.92(m，2H)，3.80(br?s，2H)，2.80-2.90(m，2H)，2.50(t，2H)，2.00-2.10(m，2H)，1.60-1.70(m，3H)，1.40(s，18H)，1.20-1.30(m，2H)：

MS(+ve?ESI)：730(M+H) ⁺，

MS(-ve?ESI)：728(M-H) ^-。

Embodiment 28-prepares compound 28-2-[[3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino of table 3]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin ({ 4-[(5-{2-[(2 with two (tertiary butyl) 2-[[3-, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] ethyl phosphonic acid ester (302mg, 0.422mmol), obtain compound 28 (300mg, 100% yield) for the table 3 of white solid:

¹H-NMR(DMSO?d ₆)：12.00(s，1H)，10.30(s，1H)，8.90(d，1H)，7.65-7.75(m，1H)，7.50-7.60(m，2H)，7.10-7.25(m，2H)，6.70(s，1H)，4.35(t，2H)，4.20-4.30(m，2H)，3.90(s，2H)，3.40-3.50(m，2H)，3.25-3.35(m，2H)，3.10-3.20(m，2H)，2.20-2.40(M，2H)，1.30(t，3H)：

MS(+ve?ESI)：606(M+H) ⁺，

MS(-ve?ESI)：604(M-H) ^-。

Following acquisition is as two (tertiary butyl) 2-[[3-of initial feed ({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] the ethyl phosphonic acid ester:

A) (15g 96mmol) is dissolved in 2-methyl cellosolve (97ml) with 2-amino-4-fluorobenzoic acid.Add the acetate carbonamidine (20.13g, 193.4mmol), with mixture heating up to the 18h that refluxes.The cooling reactant concentrates, and (0.01N stirs 1h in 250ml) at ammonium hydroxide aqueous solution with resistates.Filtering suspension liquid washes with water, obtains Off-white solid 7-fluquinconazole quinoline-4 (3H)-ketone (10.35g, 65% yield) with the Vanadium Pentoxide in FLAKES drying:

¹H-NMR(DMSO?d ₆)：12.32(br?s，1H)，8.19(dd，1H)，8.14(s，1H)，7.45(dd，1H)，7.39(m，1H)：

MS(-ve?ESI)：163(M-H) ^-，

MS(+ve?ESI)：165(M+H) ⁺。

B) (14.6g 365mmol) adds 1, ammediol (27.8g, dimethyl formamide 365mmol) (70ml) solution with sodium hydride at 0 ℃.(10g 60.9mmol), at 60 ℃ of reacting by heating mixtures, heats 3h at 110 ℃ then to add 7-fluquinconazole quinoline-4 (3H)-ketone by amount.Cooling reactant to 0 ℃, water (280ml) quencher is adjusted to pH5.9.Filter gained suspension, water, ether washing successively obtains white powder 7-(3-hydroxyl propoxy-) quinazoline-4 (3H)-ketone (12.41g, 92% yield) with the Vanadium Pentoxide in FLAKES drying:

¹H-NMR(DMSO?d ₆)：11.90(br?s，1H)，8.04(s，1H)，8.00(d，1H)，7.10(m，2H)，4.17(t，2H)，3.58(t，2H)，1.92(m，2H)：

MS(+ve?ESI)：221(M+H) ⁺。

C) with 7-(3-hydroxyl propoxy-) quinazoline-4 (3H)-ketone (10.5g, 47.7mmol) and thionyl chloride (100ml 137mmol) mixes.Add dimethyl formamide (1ml), reaction mixture is heated to 85 ℃ of 1h.Cooling mixture is used dilution with toluene to room temperature, is evaporated to dried.Repeat this operation until removing all thionyl chloride.Resistates is dissolved in methylene dichloride, washs with saturated sodium bicarbonate solution.The water layer dichloromethane extraction.Organism is merged, and dry (sal epsom) is concentrated into remaining yellow solid.Remove a small amount of soluble impurity with the ether grinding, concentrate ether filtrate to being left Off-white solid 4-chloro-7-(3-chlorine propoxy-) quinazoline (8.5g, 70% yield):

¹H-NMR(DMSO?d ₆)：13.25(br?s，1H)，8.34(s，1H)，8.06(d，1H)，7.17(m，2H)，4.21(t，2H)，3.83(t，2H)，2.23(m，2H)：

MS(+ve?ESI)：257，259(M+H) ⁺。

D) (2.5g, 9.72mmol) (1.37g 9.72mmol) mixes in dimethyl formamide (25ml) with (3-amino-1H-pyrazoles-5-yl) acetate with 4-chloro-7-(3-chlorine propoxy-) quinazoline.(1.25ml 4.8mmol), is heated to 90 ℃ of 40min with reactant to the two  alkane solution of adding 4M HCl.Cooling solution is to room temperature, and diatomite filtration is passed through in water (250ml) dilution.Acidic solution is alkalized to pH4.9, leach yellow powder.(at pH3, the red solid of separating out is separated, suspend in water, alkalize to pH12.Carefully regulate back pH4.8, cause separating out yellow powder, itself and first product is merged).Solid washs with ether, with the Vanadium Pentoxide in FLAKES drying obtain the light orange solid (3-{[7-(3-chlorine propoxy-) quinazoline-4-yl] amino }-1H-pyrazoles-5-yl) acetate (2.88g, 82% yield):

¹H-NMR(DMSO?d ₆)：12.60(br?s，2H)，10.78(br?s，1H)，8.65(s，m)，8.60(d，1H)，7.26(d，1H)，7.22(s，1H)，6.67(s，1H)，4.28(t，2H)，3.83(t，2H)，3.67(s，2H)，2.24(m，2H)：

MS(-ve?ESI)：360，362(M-H) ^-，

MS(+ve?ESI)：362，364(M+H) ⁺。

E) with 2, the 3-difluoroaniline (1.15g, 8.95mmol) add (3-{[7-(3-chlorine propoxy-) quinazoline-4-yl] amino }-1H-pyrazoles-5-yl) acetate (2.70g, pyridine 7.46mmol) (30ml) suspension, cooling reactant to 0 ℃.The dropping phosphoryl chloride (1.14g, 7.46mmol), at 0 ℃ of reaction stirred 1h.Reactant is heated to room temperature, adds phosphoryl chloride (0.5ml) once more.Reaction stirred 4.5h.The reaction mixture ethyl acetate: ether (100ml: 37ml) dilution, stir 18h.Leach precipitation, suspend in water, and usefulness ammonium hydroxide (7%, 15ml) neutralization.Leach the gained yellow suspension, wash with water, dry (Vanadium Pentoxide in FLAKES) obtain orange powder shape 2-(3-{[7-(3-chlorine propoxy-) quinazoline-4-yl] amino }-1H-pyrazoles-5-yl)-N-(2, the 3-difluorophenyl) ethanamide (3.15g, 89% yield):

¹H-NMR(DMSO?d ₆)：10.64(br?s，1H)，10.27(s，1H)，8.60(s，1H)，8.55(d，1H)，7.70(m，1H)，7.20(m，6H)，6.68(s，1H)，4.27(t，2H)，3.83(m，4H)，2.25(m，2H)：

MS(-ve?ESI)：471，473(M-H) ^-，

MS(+ve?ESI)：473，475(M+H) ⁺。

F) with 2-(3-{[7-(3-chlorine propoxy-) quinazoline-4-yl] amino }-1H-pyrazoles-5-yl)-N-(2, the 3-difluorophenyl) ethanamide (300mg, 0.634mmol), potassiumiodide (210mg, 1.27mmol), dimethyl amine (2ml) and 2-(ethylamino) ethanol (226mg, 2.54mmol) mix, be heated to 50 ℃ of 72h.Reactant is filled into 40S silicon-dioxide biotage post with methylene dichloride (20ml) dilution.Use earlier the methylene dichloride wash-out, strengthen polarity then to methylene dichloride: methyl alcohol (9: 1) wash-out, use methylene dichloride again: methyl alcohol: ammoniacal liquor (9: 1: 0.8) wash-out, obtain baby pink solid N-(2, the 3-difluorophenyl)-and 2-{3-[(7-{3-[ethyl (2-hydroxyethyl) amino] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (181mg, 54% yield):

¹H-NMR(DMSO?d ₆)：12.35(s，1H)，10.25(s，2H)，8.52(s，2H)，7.71(m，1H)，7.16(m，4H)，6.78(s，1H)，4.33(t，1H)，4.17(t，2H)，3.84(s，2H)，3.43(m，2H)，2.60(t，2H)，2.49(m，4H)，1.88(m，2H)，0.96(t，3H)：

MS(-ve?ESI)：524(M-H) ^-，

MS(+ve?ESI)：526(M+H) ⁺。

G) response class of introducing with embodiment 6c seemingly, but begin with N-(2, the 3-difluorophenyl)-and 2-{3-[(7-{3-[ethyl (2-hydroxyethyl) amino] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (372mg, 0.71mmol), obtain light yellow solid two (tertiary butyl) 2-[[3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] ethyl phosphonic acid ester (304mg, 60% yield):

¹H-NMR(DMSO?d ₆)：12.30(s，1H)，10.20(d，2H)，8.60-8.70(m，2H)，7.70-7.80(m，1H)，7.05-7.25(m，4H)，6.80(brs，1H)，4.20(t，2H)，3.80-3.90(m，4H)，2.60-2.70(m，4H)，2.40-2.50(m，2H)，1.80-1.90(m，2H)，1.40(s，18H)，0.95(t，3H)：

MS(+ve?ESI)：718(M+H) ⁺，

MS(-ve?ESI)：716(M-H) ^-。

Embodiment 29-prepares compound 29-2-[[3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino of table 3]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (sec.-propyl) amino] ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin ({ 4-[(5-{2-[(2 with two-tertiary butyl 2-[[3-, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (sec.-propyl) amino] ethyl phosphonic acid ester (372mg, 0.51mmol), obtain compound 29 (342mg, 92% yield) for the table 3 of light yellow solid:

¹H-NMR(DMSO?d ₆)：12.00(s，1H)，10.30(s，1H)，8.90(s，1H)，8.80(d，1H)，7.60-7.70(m，1H)，7.40-7.50(m，2H)，7.10-7.20(m，2H)，6.70(s，1H)，4.40(t，2H)，4.20-4.30(m，2H)，3.90(s，2H)，3.70-3.80(m，1H)，3.40-3.50(m，2H)，3.20-3.30(m，2H)，2.30-2.40(m，2H)，1.35(d，6H)：

MS(+ve?ESI)：620(M+H) ⁺，

MS(-ve?ESI)：618(M-H) ^-。

Following acquisition is as two-tertiary butyl 2-[[3-of initial feed ({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (sec.-propyl) amino] the ethyl phosphonic acid ester:

A) response class of introducing with embodiment 28f seemingly, but begin ethanol (262mg with 2-(sec.-propyl amino), 2.54mmol), obtain Off-white solid N-(2, the 3-difluorophenyl)-and 2-{3-[(7-{3-[sec.-propyl (2-hydroxyethyl) amino] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (182mg, 53% yield):

¹H-NMR(DMSO?d ₆)：12.35(s，1H)，10.20(s，1H)，8.50(s，2H)，7.71(m，1H)，7.20(m，4H)，6.78(s，1H)，4.29(br?s，1H)，4.19(t，2H)，3.85(s，2H)，3.38(dt，2H)，2.88(m，1H)，2.55(t，2H)，2.45(t，2H)，1.82(m，2H)，0.93(d，6H)：

MS(-ve?ESI)：538(M-H) ^-，

MS(+ve?ESI)：540(M+H) ⁺。

B) response class of introducing with embodiment 6c seemingly, but begin with N-(2, the 3-difluorophenyl)-and 2-{3-[(7-{3-[sec.-propyl (2-hydroxyethyl) amino] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (414mg, 0.77mmol), obtain white solid two-tertiary butyl 2-[[3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (sec.-propyl) amino] ethyl phosphonic acid ester (374mg, 67% yield):

¹H-NMR(DMSO?d ₆)：12.40(s，1H)，10.20(d，2H)，8.50-8.60(m，2H)，7.60-7.80(m，1H)，7.10-7.30(m，4H)，6.80(br?s，1H)，4.15-4.25(m，2H)，3.80-3.90(m，4H)，2.85-3.00(m，1H)，2.50-2.65(m，4H)，1.80-1.90(m，2H)，1.40(s，18H)，1.00(s，3H)，0.98(s，3H)：

MS(+ve?ESI)：732(M+H) ⁺，

MS(-ve?ESI)：730(M-H) ^-。

Embodiment 30-prepares compound 30-3-{[3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino of table 3]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) propyl group] amino }-3-methyl butyl dihydrogen phosphate

The response class of introducing with embodiment 1 seemingly, but begin ({ 4-[(5-{2-[(2 with two-tertiary butyl 3-{[3-, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) propyl group] amino }-3-methyl butyl phosphoric acid ester (490mg, 0.67mmol), obtain the light yellow dihydrochloride (480mg, 99% yield) of the compound 30 of table 3:

¹H-NMR(DMSO?d ₆)：12.00(s，1H)，10.35(s，1H)，9.20(br?s，1H)，8.90(s，1H)，8.80(d，1H)，7.72(m，1H)，7.50(d，2H)，7.40(s，1H)，7.20-7.30(m，2H)，6.70(s，1H)，4.30(t，2H)，3.90-4.00(m，2H)，3.85(s，2H)，3.10-3.20(m，2H)，2.20-2.30(m，2H)，2.00-2.10(m，2H)，1.40(d，6H)：

MS(+ve?ESI)：620(M+H) ⁺。

MS(-ve?ESI)：618(M-H) ^-。

Following acquisition is as two-tertiary butyl 3-{[3-of initial feed ({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) propyl group] amino }-3-methyl butyl phosphoric acid ester:

A) response class of introducing with embodiment 28f seemingly, but begin with 3-amino-3-methyl fourth-1-alcohol (655mg, 6.36mmol), obtain Off-white solid N-(2, the 3-difluorophenyl)-2-{3-[(7-{3-[(3-hydroxyl-1, the 1-dimethyl propyl) amino] propoxy-} quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (450mg, 39% yield):

¹H-NMR(DMSO?d ₆)：12.40(s，1H)，10.20(br?s，2H)，8.60-8.70(m，2H)，7.70-7.80(m，1H)，7.25-7.35(m，4H)，6.80(br?s，1H)，4.20(t，2H)，3.90(s，2H)，3.60(t，2H)，2.70(t，2H)，1.90-2.00(m，2H)，1.50(t，2H)，1.00(s，6H)：

MS(+ve?ESI)：540(M+H) ⁺，

MS(-ve?ESI)：538(M-H) ^-。

B) response class of introducing with embodiment 6c seemingly, but begin with N-(2, the 3-difluorophenyl)-2-{3-[(7-{3-[(3-hydroxyl-1, the 1-dimethyl propyl) amino] propoxy-} quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (212mg, 0.38mmol), obtain light yellow solid two-tertiary butyl 3-{[3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) propyl group] amino }-3-methyl butyl phosphoric acid ester (204mg, 72% yield):

¹H-NMR(DMSO?d ₆)：12.40(s，1H)，10.20(d，2H)，8.50-8.60(m，2H)，7.65-7.75(m，1H)，7.20-7.30(m，4H)，6.80(s，1H)，4.30(t，2H)，3.90-4.00(m，2H)，3.85(s，2H)，2.70-2.80(m，2H)，1.90-2.00(m，2H)，1.60-1.70(m，2H)，1.40(s，18H)，1.10(s，6H)：

MS(+ve?ESI)：732(M+H) ⁺，

MS(-ve?ESI)：730(M-H) ^-。

Embodiment 31-prepares compound 31-2-{ (2S)-1-[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino of table 3]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin with two (tertiary butyl) 2-{ (2S)-1-[3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } ethyl phosphonic acid ester (204mg, 0.27mmol), obtain the light yellow dihydrochloride (198mg, 97% yield) of the compound 31 of table 3:

¹H-NMR(DMSO?d ₆)：12.00(s，1H)，10.80(s，1H)，10.50(s，1H)，8.95(s，1H)，8.80(d，1H)，7.60-7.80(m，1H)，7.50(d，1H)，7.40(s，1H)，7.20-7.30(m，2H)，6.70(s，1H)，4.35(t，2H)，3.90-4.00(m，1H)，3.85(s，2H)，3.60-3.70(m，1H)，3.30-3.50(m，2H)，3.00-3.25(m，2H)，2.20-2.40(m，4H)，1.90-2.10(m，3H)，1.70-1.80(m，1H)：

MS(+ve?ESI)：632(M+H) ⁺，

MS(-ve?ESI)：630(M-H) ^-。

Following acquisition is as two (tertiary butyl) 2-{ (the 2S)-1-[3-of initial feed ({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the ethyl phosphonic acid ester:

A) response class of introducing with embodiment 28f seemingly, but begin tetramethyleneimine (731mg with (2S)-2-(2-hydroxyethyl), 6.36mmol), obtain white solid N-(2, the 3-difluorophenyl)-2-{3-[(7-{3-[(2S)-and 2-(2-hydroxyethyl) tetramethyleneimine-1-yl] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (260mg, 22% yield):

¹H-NMR(DMSO?d ₆)：12.30(s，1H)，10.20(s，2H)，8.40-8.70(m，2H)，7.70-7.80(m，1H)，7.10-7.30(m，4H)，6.80(br?s，1H)，4.30-4.50(m，1H)，4.20(t，2H)，3.80-3.90(m，2H)，3.30-3.50(m，2H)，3.10-3.20(m，1H)，2.90-3.00(m。1H)，2.30-2.40(m，1H)，2.10-2.20(m，1H)，1.90-2.00(m，1H)，1.75-1.85(m，3H)，1.68(m，1H)，1.50-1.60(m，2H)，1.30-1.40(m，2H)：

MS(+ve?ESI)：520(M+H) ⁺，

MS(-ve?ESI)：550(M-H) ^-。

B) response class of introducing with embodiment 6c seemingly, but begin with N-(2, the 3-difluorophenyl)-2-{3-[(7-{3-[(2S)-and 2-(2-hydroxyethyl) tetramethyleneimine-1-yl] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (212mg, 0.38mmol), obtain light yellow solid two (tertiary butyl) 2-{ (2S)-1-[3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } ethyl phosphonic acid ester (204mg, 72% yield):

¹H-NMR(DMSO?d ₆，373K)：12.00(s，1H)，9.90(s，2H)，9.80(s，1H)，8.50(s，1H)，8.40(d，1H)，7.70-7.80(m，1H)，7.20-7.30(m，4H)，6.70(br?s，1H)，4.30(t，2H)，3.90-4.00(m，2H)，3.80(s，2H)，3.00-3.10(m，1H)，2.40-2.50(m，1H)，2.20-2.30(m，1H)，1.80-2.00(m，4H)，1.70-1.80(m，2H)，1.62(m，1H)，1.40-1.50(m，1H)，1.40(s，18H)，0.90-1.00(m，1H)：

MS(+ve?ESI)：742(M+H) ⁺，

MS(-ve?ESI)：740(M-H) ^-。

Embodiment 32-prepares compound 32-{ (2R)-1-[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino of table 3]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester

The response class of introducing with embodiment 1 seemingly, but begin with two (tertiary butyls) (2R)-1-[3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } methyl phosphorodithioate (355mg, 0.49mmol), obtain the light yellow dihydrochloride (being dihydrate) of the compound 32 (355mg, 100% yield) of table 3:

¹H-NMR(DMSO?d ₆)：12.00(br?s，1H)，10.40(s，1H)，8.93(s，1H)，8.82(d，1H)，7.68(m，1H)，7.40-7.50(m，2H)，7.15-7.25(m，2H)，6.75(s，1H)，4.35(t，2H)，4.10-4.30(m，1H)，3.92(s，2H)，3.81(m，1H)，3.55-3.70(m，2H)，3.27(m，1H)，3.18(m，1H)，2.10-2.35(m，4H)，1.85-2.10(m，3H)，1.75-1.85(m，1H)：

MS(+ve?ESI)：618(M+H) ⁺。

Following acquisition as two (tertiary butyls) of initial feed (2R)-1-[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl the oxygen base) propyl group] tetramethyleneimine-2-yl methyl phosphorodithioate:

A) response class of introducing with embodiment 28f seemingly, but begin with D-dried meat ammonia alcohol (257mg, 2.54mmol), obtain pink solid N-(2, the 3-difluorophenyl)-2-{3-[(7-{3-[(2R)-and 2-(hydroxymethyl) tetramethyleneimine-1-yl] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (206mg, 60% yield):

¹H-NMR(DMSO?d ₆)：11.60(br?s，7H)，10.25(s，1H)，8.52(m，2H)，7.75(m，1H)，7.16(m，4H)，6.67(s，1H)，4.22(t，2H)，3.84(s，2H)，3.50(d，2H)，3.35(m，1H)，3.28(m，1H)，3.07(m，1H)，2.86(m，1H)，2.72(m，1H)，2.05(m，2H)，1.95(m，1H)，1.60-1.90(m，4H)：

MS(-ve?ESI)：536(M-H) ^-，

MS(+ve?ESI)：538(M+H) ⁺。

B) response class of introducing with embodiment 6c seemingly, but begin with N-(2, the 3-difluorophenyl)-2-{3-[(7-{3-[(2R)-and 2-(hydroxymethyl) tetramethyleneimine-1-yl] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (437mg, 0.81mmol), acquisition light yellow solid two (tertiary butyl) (2R)-1-[3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } methyl phosphorodithioate (355mg, 60% yield):

¹H-NMR(DMSO?d ₆)：12.30(br?s，1H)，10.20(s，2H)，8.50(s，2H)，7.68(m，1H)，7.10-7.20(m，4H)，6.78(brs，1H)，4.15(t，2H)，3.80(m，3H)，3.65(m，1H)，3.10(m，1H)，2.93(m，1H)，2.64(m，1H)，2.19(m，1H)，1.80-1.95(m，3H)，1.68(m，2H)，1.60(m，1H)，1.33(s，18H)：

MS(-ve?ESI)：728(M-H) ^-，

MS(+ve?ESI)：730(M+H) ⁺。

Embodiment 33-prepares compound 33-2-[[3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino of table 3]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (propyl group) amino] ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin ({ 4-[(5-{2-[(2 with two-tertiary butyl 2-[[3-, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (propyl group) amino] ethyl phosphonic acid ester (271mg, 0.37mmol), obtain the dihydrochloride (266mg, 98% yield) of the compound 33 of table 3:

¹H-NMR(DMSO?d ₆，)：12.02(br?s，1H)，10.40(s，1H)，9.95(s，1H)，9.85(s，1H)，7.70(s，1H)，7.47(m，2H)，7.20(m，2H)，6.73(s，1H)，4.23-4.37(m，4H)，3.92(s，2H)，3.43(m，2H)，3.32(m，2H)，3.13(m，2H)，2.28(m，2H)，1.76(m，2H)，0.95(t，3H)：

MS(+ve?ESI)：618.4(M+H) ⁺，

MS(-ve?ESI)：620.4(M-H) ^-。

Following acquisition is as two-tertiary butyl 2-[[3-of initial feed ({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (propyl group) amino] the ethyl phosphonic acid ester:

A) response class of introducing with embodiment 28f seemingly, but begin ethanol (262mg with 2-(propyl group amino), 2.54mmol), obtain pink solid N-(2, the 3-difluorophenyl)-and the 2-{3-[(7-{3-[(2-hydroxyethyl) (propyl group) amino] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (168mg, 49% yield):

¹H-NMR(DMSO?d ₆：12.35(s，1H)，10.22(s，2H)，8.51(s，2H)，7.71(m，1H)，7.20(m，4H)，6.78(s，1H)，4.30(t，1H)，4.17(t，2H)，3.85(s，2H)，3.43(m，2H)，2.59(t，2H)，2.49(m，2H)，2.39(t，2H)，1.87(m，2H)，1.39(m，2H)，0.82(t，3H)：

MS(-ve?ESI)：538(M-H) ^-，

MS(+ve?ESI)：540(M+H) ⁺。

B) response class of introducing with embodiment 6c seemingly, but begin with N-(2, the 3-difluorophenyl)-and the 2-{3-[(7-{3-[(2-hydroxyethyl) (propyl group) amino] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (690mg, 1.28mmol), obtain light yellow solid two-tertiary butyl 2-[[3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (propyl group) amino] ethyl phosphonic acid ester (271mg, 29% yield):

MS(-ve?ESI)：730(M-H) ^-，

MS(+ve?ESI)：732(M+H) ⁺。

Embodiment 34-prepares compound 34-2-[[3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino of table 3]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (butyl) amino] ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin ({ 4-[(5-{2-[(2 with two (tertiary butyl) 2-[[3-, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (butyl) amino] ethyl phosphonic acid ester (400mg, 0.54mmol), obtain the light yellow dihydrochloride (360mg, 95% yield) of the compound 34 of table 3:

¹H-NMR(DMSO?d ₆)：12.00(s，1H)，10.34(s，1H)，8.93(s，1H)，8.85(d，1H)，7.68(m，1H)，7.47(d，1H)，7.44(s，1H)，7.20(m，2H)，6.74(s，1H)，4.33(t，2H)，4.28(m，2H)，3.93(s，2H)，3.44(m，2H)，3.36(m，2H)，3.16(m，2H)，2.30(m，2H)，1.71(m，2H)，1.34(m，2H)，0.93(t，3H)：

MS(+ve?ESI)：634(M+H) ⁺。

Following acquisition is as two (tertiary butyl) 2-[[3-of initial feed ({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (butyl) amino] the ethyl phosphonic acid ester:

A) response class of introducing with embodiment 28f seemingly, but begin ethanol (891mg with 2-(butyl amino), 7.61mmol), obtain light yellow solid N-(2, the 3-difluorophenyl)-and the 2-{3-[(7-{3-[(2-hydroxyethyl) (butyl) amino] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (625mg, 45% yield):

¹H-NMR(DMSO?d ₆)：12.65(s，1H)，12.32(s，1H)，10.17(m，2H)，8.52(m，2H)，7.72(m，1H)，7.05-7.30(m，4H)，6.78(br?s，1H)，4.30(m，1H)，4.20(t，2H)，3.85(br?s，2H)，3.44(m，2H)，2.63(m，2H)，2.54(m，2H)，2.45(m，2H)，1.90(m，2H)，1.38(m，2H)，1.26(m，2H)，0.84(t，3H)：

MS(+ve?ESI)：554(M+H) ⁺。

B) response class of introducing with embodiment 6c seemingly, but begin with N-(2, the 3-difluorophenyl)-and the 2-{3-[(7-{3-[(2-hydroxyethyl) (butyl) amino] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (605mg, 1.09mmol), obtain light yellow solid two (tertiary butyl) 2-[[3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (butyl) amino] ethyl phosphonic acid ester (400mg, 50% yield):

¹H-NMR(CDCl ₃)：12.80(br?s，1H)，9.47(br?s，1H)，9.40(br?s，1H)，8.72(s，1H)，8.13(d，1H)，8.05(m，1H)，7.22(s，1H)，7.18(d，1H)，7.03(m，1H)，6.86(m，1H)，6.15(br?s，1H)，4.15(t，2H)，4.00(q，2H)，3.83(s，2H)，2.73(t，2H)，2.64(t，2H)，2.47(t，2H)，1.93(m，2H)，1.48(s，18H)，1.44(m，2H)，1.29(m，2H)，0.89(t，3H)：

MS(+ve?ESI)：746(M+H) ⁺。

Embodiment 35-prepares compound 35-2-{ cyclopentyl [3-({ 4-[(5-{2-[(2,3-difluorophenyl) the amino]-2-oxoethyl of table 3 }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin with two-tertiary butyl 2-{ cyclopentyl [3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid ester (405mg, 0.53mmol), obtain the light yellow dihydrochloride (388mg, 100% yield) of the compound 35 of table 3:

¹H-NMR(DMSO?d ₆)：12.00(s，1H)，10.33(s，1H)，8.93(s，1H)，8.83(d，1H)，7.69(m，1H)，7.49(d，1H)，7.41(s，1H)，7.20(m，2H)，6.74(s，1H)，4.32(t，2H)，4.29(m，2H)，3.93(s，2H)，3.77(m，1H)，3.46(m，2H)，3.35(m，2H)，2.31(m，2H)，2.08(m，2H)，1.83(m，2H)，1.74(m，2H)，1.57(m，2H)：

MS(+ve?ESI)：646(M+H) ⁺。

Following acquisition is as two-tertiary butyl 2-{ cyclopentyl of initial feed [3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] amino } the ethyl phosphonic acid ester:

A) response class of introducing with embodiment 28f seemingly, but begin ethanol (1.00g with 2-(cyclopentyl amino), 7.75mmol), obtain light yellow solid N-(2, the 3-difluorophenyl)-the 2-{3-[(7-{3-[cyclopentyl (2-hydroxyl second. base) amino] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (533mg, 37% yield):

¹H-NMR(DMSO?d ₆)：12.66(s，1H)，12.30(s，1H)，10.16(m，2H)，8.52(m，2H)，7.72(m，1H)，7.06-7.40(m，4H)，6.80(s，1H)，4.32(m，1H)，4.19(t，2H)，3.85(brs，2H)，3.43(m，2H)，3.06(m，1H)，2.66(m，2H)，2.56(m，2H)，1.90(m，2H)，1.73(m，2H)，1.58(m，2H)，1.48(m，2H)，1.32(m，2H)：

MS(+ve?ESI)：566(M+H) ⁺。

B) response class of introducing with embodiment 6c seemingly, but begin with 2-{3-[(7-{3-[cyclopentyl (2-hydroxyethyl) amino] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(2, the 3-difluorophenyl) ethanamide (482mg, 0.85mmol), obtain light yellow solid two-tertiary butyl 2-{ cyclopentyl [3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid ester (411mg, 64% yield):

¹H-NMR(CDCl ₃)：12.70(br?s)，1H)，9.35(m，2H)，8.71(s，1H)，8.05(m，2H)，7.20(s，1H)，7.12(d，1H)，7.01(m，1H)，6.86(m，1H)，6.17(br?s)，1H)，4.11(t，2H)，3.98(q，2H)，3.83(s，2H)，3.08(m，1H)，2.80(t，2H)，2.72(t，2H)，1.95(m，2H)，1.78(m，2H)，1.69(m，2H)，1.62(m，2H)，1.50(s，18H)，1.35(m，2H)：

MS(+ve?ESI)：758(M+H) ⁺。

Embodiment 36-prepares compound 36-{ (2S)-1-[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino of table 3]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester

The response class of introducing with embodiment 1 seemingly, but begin with two (tertiary butyls) (2S)-1-[3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } methyl phosphorodithioate (425mg, 0.58mmol), obtain compound 36 (400mg, 99% yield) for the table 3 of Off-white solid:

¹H-NMR(DMSO?d ₆)：12.00(s，1H)，10.35(s，1H)，8.94(s，1H)，8.85(d，1H)，7.67(m，1H)，7.47(d，1H)，7.43(s，1H)，7.20(m，2H)，6.74(s，1H)，4.34(t，2H)，4.15-4.32(m，2H)，3.92(s，2H)，3.78(m，1H)，3.52-3.72(m，2H)，3.30(m，1H)，3.19(m，1H)，2.24-2.42(m，2H)，2.20(m，1H)，2.02(m，1H)，1.96(m，1H)，1.82(m，1H)：

MS(+ve?ESI)：618(M+H) ⁺。

Following acquisition as two (tertiary butyls) of initial feed (2S)-1-[3-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl the oxygen base) propyl group] tetramethyleneimine-2-yl methyl phosphorodithioate:

A) response class of introducing with embodiment 28f seemingly, but begin with L-dried meat ammonia alcohol (770mg, 7.62mmol), obtain light yellow solid N-(2, the 3-difluorophenyl)-2-{3-[(7-{3-[(2S)-and 2-(hydroxymethyl) tetramethyleneimine-1-yl] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (547mg, 40% yield):

¹H-NMR(DMSO?d ₆)：12.66(s，1H)，12.35(s，1H)，10.20(m，2H)，8.51(m，2H)，7.72(m，1H)，7.20(m，4H)，6.77(br?s，1H)，4.21(t，2H)，3.81(br?s，2H)，3.47(m，1H)，2.90-3.42(m，6H)，2.05(m，2H)，1.90(m，1H)，1.72(m，2H)，1.62(m，1H)：

MS(+ve?ESI)：538(M+H) ⁺。

B) response class of introducing with embodiment 6c seemingly, but begin with N-(2, the 3-difluorophenyl)-2-{3-[(7-{3-[(2S)-and 2-(hydroxymethyl) tetramethyleneimine-1-yl] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (485mg, 0.90mmol), acquisition light yellow solid two (tertiary butyl) (2S)-1-[3-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } methyl phosphorodithioate (430mg, 65% yield):

¹H-NMR(CDCl ₃)：12.70(br?s，1H)，9.52(brs，1H)，9.37(br?s，1H)，8.10(s，1H)，8.06(m，1H)，7.18(s，1H)，7.11(d，1H)，7.02(m，1H)，6.85(m，1H)，6.22(br?s，1H)，4.12(m，2H)，3.92(m，1H)，3.84(s，2H)，3.68(m，1H)，3.12(m，1H)，2.97(m，1H)，2.73(m，1H)，2.48(m，1H)，2.25(q，1H)，1.85-2.05(m，3H)，1.55-1.85(m，3H)，1.45(s，18H)：

MS(+ve?ESI)：730(M+H) ⁺。

Embodiment 37-prepares compound 37-{ (2S)-1-[3-({ 4-[(5-{2-[(3-fluorophenyl) amino of table 3]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester

The response class of introducing with embodiment 1 seemingly, but begin with two (tertiary butyls) (2S)-1-[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl the oxygen base) propyl group] tetramethyleneimine-2-yl methyl phosphorodithioate (654mg, 0.92mmol), obtain compound 37 (596mg, 97% yield) for the table 3 of oyster white dihydrochloride:

¹H-NMR(DMSO?d ₆)：11.95(s，1H)，10.73(s，1H)，8.94(s，1H)，8.82(d，1H)，7.65(d，1H)，7.46(d，1H)，7.38(m，3H)，6.90(m，1H)，6.74(s，1H)，4.32(t，2H)，4.21(m，2H)，3.85(s，2H)，3.78(m，1H)，3.64(m，2H)，3.29(m，1H)，3.19(q，1H)，2.31(m，3H)，2.20(m，1H)，2.00(m，3H)，1.81(m，1H)：

MS(+ve?ESI)：599.8(M+H) ⁺。

Following acquisition as two (tertiary butyls) of initial feed (2S)-1-[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl the oxygen base) propyl group] tetramethyleneimine-2-yl methyl phosphorodithioate:

A) response class of introducing with embodiment 28f seemingly, but begin with L-dried meat ammonia alcohol (0.89ml, 8.80mmol) and 2-(3-{[7-(3-chlorine propoxy-) quinazoline-4-yl] amino }-1H-pyrazoles-5-yl)-N-(3-fluorophenyl) ethanamide (1.00g, 2.20mmol), obtain paste solid N-(3-fluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl) tetramethyleneimine-1-yl] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (795mg, 70% yield):

¹H-NMR(DMSO?d ₆)：12.35(m，1H)，10.42(s，1H)，10.19(m，1H)，8.50(s，2H)，7.63(d，1H)，7.35(m，2H)，7.16(m，2H)，6.90(t，1H)，6.73(m，1H)，4.28(t，1H)，4.18(t，2H)，3.73(s，2H)，3.40(m，1H)，3.20(m，1H)，3.07(m，1H)，2.97(m，1H)，2.43(m，2H)，2.15(q，1H)，1.94(m，2H)，1.81(m，1H)，1，64(m，2H)，1.55(m，1H)：

MS(+ve?ESI)：520.1(M+H) ⁺。

B) response class of introducing with embodiment 6c seemingly, but begin with N-(3-fluorophenyl)-2-{3-[(7-{3-[(2S)-2-(hydroxymethyl) tetramethyleneimine-1-yl] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (730mg, 1.41mmol), acquisition light yellow solid two (tertiary butyl) (2S)-1-[3-(the 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } methyl phosphorodithioate (654mg, 65% yield), it is directly used in next step and need not further sign.

Following acquisition as the 2-of initial feed (3-{[7-(3-chlorine propoxy-) quinazoline-4-yl] amino }-1H-pyrazoles-5-yl)-N-(3-fluorophenyl) ethanamide:

C) with trifluoroacetic acid pentafluorophenyl group ester (23.25g, 83mmol) be added drop-wise to (3-{[7-(3-chlorine propoxy-) quinazoline-4-yl] amino }-1H-pyrazoles-5-yl) acetate (15.0g, 41mmol) and pyridine (6.7ml, dimethyl formamide 83mmol) (150ml) solution, cooling simultaneously maintains less than 23 ℃ solution temperature.At stirring at room solution 30min, add then the 3-fluoroaniline (9.22g, 83mmol).At stirring at room reactant 2.5h, and then add 3-fluoroaniline (2ml), mixture is heated 3h at 90 ℃.In reaction mixture impouring dilute hydrochloric acid (0.1M) and ice (about 500ml), leach the gained solid, water, ether washing successively, then drying obtain brown solid 2-(3-{[7-(3-chlorine propoxy-) quinazoline-4-yl] amino }-1H-pyrazoles-5-yl)-N-(3-fluorophenyl) ethanamide (17.7g, 94% yield):

¹H-NMR (DMSO d ₆): 12.50 (br s, 1H), 10.42 (s, 1H), 8.59 (s, 1H), 8.54 (d, 1H), 7.62 (m, 1H), 7.35 (m, 2H), 7.24 (m, 1H), 7.19 (m, 1H), 6.90 (m, 1H), 6.67 (br s, 1H), 4.28 (t, 2H), 3.84 (t, 2H), 3.76 (s, 2H), 2.27 (quintet, 2H).

MS(+ve?ESI)：455(M+H) ⁺。

Embodiment 38-prepares compound 38-2-{ cyclopentyl [3-({ 4-[(5-{2-[(3-fluorophenyl) the amino]-2-oxoethyl of table 3 }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin with two-tertiary butyl 2-{ cyclopentyl [3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-2-oxoethyl-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid ester (572mg, 0.77mmol), obtain the compound 38 (568mg, 100% yield) of table 3:

¹H-NMR(DMSO?d ₆)：11.95(s，1H)，10.73(s，1H)，8.94(s，1H)，8.82(d，1H)，7.65(d，1H)，7.48(d，1H)，7.38(m，3H)，6.89(m，1H)，6.75(s，1H)，4.30(m，4H)，3.85(s，2H)，3.78(t，1H)，3.47(m，2H)，3.37(m，2H)，2.60(m，2H)，2.08(m，2H)，1.78(m，4H)，1.56(m，2H)：

MS(+ve?ESI)：628.4(M+H) ⁺。

Following acquisition is as two-tertiary butyl 2-{ cyclopentyl of initial feed [3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] amino } the ethyl phosphonic acid ester:

A) response class of introducing with embodiment 37a seemingly, but begin ethanol (1.13ml with 2-(cyclopentyl amino), 8.80mmol), obtain paste solid 2-{3-[(7-{3-[cyclopentyl (2-hydroxyethyl) amino] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(3-fluorophenyl) ethanamide (620mg, 51% yield):

¹H-NMR?(DMSO?d ₆)：12.31(m，1H)，10.39(s，1H)，10.16(m，1H)，8.50(s，2H)，7.62(d，1H)，7.35(m，2H)，7.16(m，2H)，6.90(t，1H)，6.78(m，1H)，4.29(m，1H)，4.16(t，2H)，3.74(s，2H)，3.40(m，2H)，3.05(t，1H)，2.66(t，2H)，2.54(obs?m，2H)，1.86(t，2H)，1.72(m，2H)，1.54(m，2H)，1.45(m，2H)，1.31(m，2H)：

MS(+ve?ESI)：548.1(M+H) ⁺。

B) response class of introducing with embodiment 6c seemingly, but begin with 2-{3-[(7-{3-[cyclopentyl (2-hydroxyethyl) amino] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(3-fluorophenyl) ethanamide (580mg, 1.06mmol), acquisition light yellow solid two-tertiary butyl 2-{ cyclopentyl [3-(the 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid ester (572mg, 72% yield), it is directly used in next step and need not further sign.

Embodiment 39-prepares compound 39-2-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino of table 3]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin amino with two (tertiary butyl) 2-[[3-({ 4-[(5-{2-[(3-fluorophenyl)]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] ethyl phosphonic acid ester (539mg, 0.77mmol), obtain compound 39 (504mg, 99% yield) for the table 3 of light yellow dihydrochloride:

¹H-NMR(DMSO?d ₆)：11.98(s，1H)，10.79(s，1H)，8.93(s，1H)，8.83(d，1H)，7.65(d，1H)，7.47(d，1H)，7.38(m，3H)，6.89(t，1H)，6.74(s，1H)，4.32(t，2H)，4.28(m，2H)，3.85(s，2H)，3.42(m，2H)，3.34(m，2H)，3.27(q，2H)，2.29(m，2H)，1.28(t，3H)：

MS(+ve?ESI)：587.8(M+H) ⁺。

Following acquisition is as two (tertiary butyl) 2-[[3-of initial feed ({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] the ethyl phosphonic acid ester:

A) response class of introducing with embodiment 37a seemingly, but begin with N-(ethylamino) ethanol (1.07ml, 11.0mmol), obtain yellow solid N-(3-fluorophenyl)-2-{3-[(7-{3-[ethyl (2-hydroxyethyl) amino] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (660mg, 59% yield):

¹H-NMR(DMSO?d ₆)：12.31(m，1H)，10.39(s，1H)，10.15(m，1H)，8.51(s，2H)，7.62(d，1H)，7.35(m，2H)，7.16(m，2H)，6.90(t，1H)，6.78(m，1H)，4.29(m，1H)，4.20(t，2H)，3.76(s，2H)，3.45(m，2H)，3.30(m，4H)，2.61(t，2H)，1.89(t，2H)，0.95(t，3H)：

MS(+ve?ESI)：508.4(M+H) ⁺。

B) response class of introducing with embodiment 6c seemingly, but begin with N-(3-fluorophenyl)-2-{3-[(7-{3-[ethyl (2-hydroxyethyl) amino] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (620mg, 1.22mmol), acquisition light yellow solid two (tertiary butyl) 2-[[3-(the 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] ethyl phosphonic acid ester (539mg, 63% yield), it is directly used in next step and need not further sign.

Compound 39 (above synthetic is its dihydrochloride) also can be prepared as its free alkali in accordance with the following methods:

C) response class of introducing with embodiment 6d is the free alkali of the compound 39 of light yellow solid but begin with compound 39 acquisitions seemingly:

¹H-NMR?(DMSO?d ₆)：10.53(s，1H)，8.57(s，1H)，8.54(d，1H)，7.62(d，1H)，7.37(m，2H)，7.27(s，1H)，7.21(d，1H)，6.88(m，1H)，6.65(s，1H)，4.27(t，2H)，4.05(m，2H)，3.75(s，2H)，3.24(m，2H)，3.21(t，2H)，3.13(q，2H)，2.18(m，2H)，1.24(t，3H)：

MS(+ve?ESI)：588(M+H) ⁺。

C ₂₆H ₃₁FN ₇O ₆P+3.0 H ₂O theoretical value C, 48.7%; H, 5.8%; N, 15.3%;

Measured value C, 48.8%; H, 5.35%; N, 15.15%.

Embodiment 40-prepares compound 40-3-{[3-({ 4-[(5-{2-[(3-fluorophenyl) amino of table 3]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) propyl group] amino }-3-methyl butyl dihydrogen phosphate

The response class of introducing with embodiment 1 seemingly, but begin amino with two-tertiary butyl 3-{[3-({ 4-[(5-{2-[(3-fluorophenyl)]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) propyl group] amino }-3-methyl butyl phosphoric acid ester (247mg, 0.35mmol), obtain compound 40 (235mg, 100% yield) for the table 3 of light yellow dihydrochloride:

¹H-NMR(DMSO?d ₆)：11.98(s，1H)，10.76(s，1H)，8.94(s，1H)，8.83(d，1H)，7.65(d，1H)，7.48(d，1H)，7.37(m，3H)，6.89(t，1H)，6.75(s，1H)，4.35(t，2H)，4.00(q，2H)，3.85(s，2H)，3.11(m，2H)，2.26(m，2H)，2.05(t，2H)，1.35(s，6H)：

MS(+ve?ESI)：601.8(M+H) ⁺。

Following acquisition is as two-tertiary butyl 3-{[3-of initial feed ({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) propyl group] amino }-3-methyl butyl phosphoric acid ester:

A) response class of introducing with embodiment 37a seemingly, but begin with 3-amino-3-methyl fourth-1-alcohol (1.15ml, 11.0mmol), obtain light yellow solid N-(3-fluorophenyl)-2-{3-[(7-{3-[(3-hydroxyl-1, the 1-dimethyl propyl) amino] propoxy-} quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (310mg, 27% yield):

¹H-NMR(DMSO?d ₆)：12.31(m，1H)，10.40(m，1H)，8.50(m，2H)，7.62(d，1H)，7.35(m，2H)，7.11(m，2H)，6.89(t，1H)，6.56(m，1H)，4.18(t，2H)，3.71(s，2H)，3.52(t，2H)，2.65(t，2H)，1.86(m，2H)，1.52(t，2H)，1.04(s，6H)：

MS(+ve?ESI)：522.5(M+H) ⁺。

B) response class of introducing with embodiment 6c seemingly, but begin with N-(3-fluorophenyl)-2-{3-[(7-{3-[(3-hydroxyl-1, the 1-dimethyl propyl) amino] propoxy-} quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (310mg, 0.59mmol), acquisition light yellow solid two-tertiary butyl 3-{[3-(the 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) propyl group] amino }-3-methyl butyl phosphoric acid ester (247mg, 58% yield), it is directly used in next step and need not further sign.

Embodiment 41-prepares compound 41-2-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino of table 3]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (propyl group) amino] ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin amino with two-tertiary butyl 2-[[3-({ 4-[(5-{2-[(3-fluorophenyl)]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (propyl group) amino] ethyl phosphonic acid ester (270mg, 0.38mmol), obtain the dihydrochloride (248mg, 96% yield) of the compound 41 of table 3:

¹H-NMR(DMSO?d ₆)：11.98(s，1H)，10.77(s，1H)，8.96(s，1H)，8.84(d，1H)，7.65(d，1H)，7.46(d，1H)，7.32-7.41(m，3H)，6.88(m，1H)，6.73(s，1H)，6.73(s，1H)，4.32(t，2H)，4.27(t，2H)，3.87(s，2H)，3.43(t，2H)，3.14(m，2H)，2.28(m，2H)，1.75(m，2H)，0.94(t，3H)：

MS(+ve?ESI)：602(M+H) ⁺，

MS(-ve?ESI)：600(M-H) ^-。

Following acquisition is as two-tertiary butyl 2-[[3-of initial feed ({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (propyl group) amino] the ethyl phosphonic acid ester:

A) response class of introducing with embodiment 37a seemingly, but begin ethanol (0.89g with 2-(propyl group amino), 8.6mmol), obtain light yellow solid N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl) (propyl group) amino] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (480mg, 32% yield):

¹H-NMR(DMSO-d ₆)：12.30(br?s，1H)，10.38(s，1H)，10.15(brs，1H)，8.50(s，2H)，7.60(d，1H)，7.34(m，2H)，7.15(br?s，2H)，6.90(dd，1H)，6.78(br?s，1H)，4.30(br?s，1H)，4.18(t，2H)，3.75(s，2H)，3.45(s，2H)，2.33-2.75(m，6H)，1.90(t，2H)，1.40(m，2H)，0.80(m，3H)：

MS(+ve?ESI)：522(M+H) ⁺，

MS(-ve?ESI)：520(M-H) ^-。

B) response class of introducing with embodiment 6c seemingly, but begin with N-(3-fluorophenyl)-2-(3-[(7-{3-[(2-hydroxyethyl) (propyl group) amino] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (470mg, 0.90mmol), acquisition light yellow solid two-tertiary butyl 2-[[3-(the 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (propyl group) amino] ethyl phosphonic acid ester (271mg, 42% yield):

¹H-NMR(DMSO?d ₆)：12.08(br?s，1H)，10.00(s，1H)，9.89(br?s，1H)，8.53(s，1H)，8.42(d，1H)，7.59(d，1H)，7.34(m，2H)，7.17(m，2H)，6.84(m，1H)，6.56(br?s，1H)，4.25(t，2H)，3.94(m，2H)，3.76(s，2H)，2.79(t，2H)，2.71(t，2H)，2.50(t，2H)，1.93(m，2H)，1.48(m，20H)，0.89(t，3H)：

MS(+ve?ESI)：714(M+H) ⁺，

MS(-ve?ESI)：712(M-H) ^-。

Embodiment 42-prepares compound 42-{ (2R)-1-[3-({ 4-[(5-{2-[(3-fluorophenyl) amino of table 3]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester

The response class of introducing with embodiment 1 seemingly, but begin with two (tertiary butyls) (2R)-1-[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl the oxygen base) propyl group] tetramethyleneimine-2-yl methyl phosphorodithioate (280mg, 0.39mmol), obtain the light yellow dihydrochloride (268mg, 100% yield) of the compound 42 of table 3:

¹H-NMR(DMSO?d ₆)：11.96(s，1H)，10.75(s，1H)，8.94(s，1H)，8.82(d，1H)，7.65(d，1H)，7.43(d，1H)，7.28-7.41(m，3H)，6.91(m，1H)，6.71(s，1H)，4.31(t，2H)，4.20(m，2H)，3.86(s，2H)，3.77(m，1H)，3.55-3.69(m，2H)，3.29(m，1H)，3.17(m，1H)，2.22-2.37(m，2H)，2.17(m，1H)，2.04(m，1H)，1.90(m，1H)，1.79(m，1H)：

MS(+ve?ESI)：600(M+H) ⁺，

MS(-ve?ESI)：598(M-H) ^-。

Following acquisition as two (tertiary butyls) of initial feed (2R)-1-[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl the oxygen base) propyl group] tetramethyleneimine-2-yl methyl phosphorodithioate:

A) response class of introducing with embodiment 37a seemingly, but begin with D-dried meat ammonia alcohol (0.87g, 8.6mmol), obtain light yellow solid N-(3-fluorophenyl)-2-{3-[(7-{3-[(2R)-2-(hydroxymethyl)-tetramethyleneimine-1-yl] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (530mg, 35% yield):

¹H-NMR(DMSO-d ₆)：12.33(br?s，1H)，10.38(s，1H)，10.20(brs，1H)，8.50(s，2H)，7.60(d，1H)，7.35(m，2H)，7.15(s，2H)，6.89(dd，1H)，6.75(br?s，1H)，4.30(br?s，1H)，4.16(t，2H)，3.73(s，2H)，3.39(m，1H)，3.19(m，1H)，3.08(m，1H)，2.98(m，1H)，2.17(m，1H)，1.95(m，2H)，1.80(m，1H)，1.49-1.73(m，4H)：

MS(+ve?ESI)：520(M+H) ⁺，

MS(-ve?ESI)：518(M-H) ^-。

B) response class of introducing with embodiment 6c seemingly, but begin with N-(3-fluorophenyl)-2-{3-[(7-{3-[(2R)-2-(hydroxymethyl) tetramethyleneimine-1-yl] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (530mg, 1.02mmol), acquisition light yellow solid two (tertiary butyl) (2R)-1-[3-(the 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] tetramethyleneimine-2-yl } methyl phosphorodithioate (280mg, 39% yield):

MS(+ve?ESI)：712(M+H) ⁺，

MS(-ve?ESI)：710(M-H) ^-。

Embodiment 43-prepares compound 43-3-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino of table 3]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] the propyl group dihydrogen phosphate

The response class of introducing with embodiment 1 seemingly, but begin amino with two-tertiary butyl 3-[[3-({ 4-[(5-{2-[(3-fluorophenyl)]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] propyl phosphate (45mg, 0.06mmol), obtain the light yellow dihydrochloride (36mg, 95% yield) of the compound 43 of table 3:

¹H-NMR(DMSO?d ₆)：10.35(br?s，1H)，8.78-9.10(m，2H)，7.55-7.62(m，1H)，7.42-7.50(m，2H)，7.28-7.40(m，2H)，6.80-6.87(m，1H)，6.65-6.79(br?m，1H)，4.35(t，2H)，3.95-4.02(m，2H)，3.85(s，2H)，3.28(t，2H)，3.15-3.25(m，4H)，2.25-2.35(m，2H)，2.05-2.15(m，2H)，1.31(t，3H)：

MS(+ve?ESI)：602(M+H) ⁺。

Following acquisition is as two-tertiary butyl 3-[[3-of initial feed ({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] propyl phosphate:

A) response class of introducing with embodiment 37a seemingly, but begin with 3-amino third-1-alcohol (247mg, 3.3mmol), obtain light yellow solid N-(3-fluorophenyl)-2-(3-[(7-{3-[(3-hydroxypropyl) amino] propoxy-} quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (295mg, 54% yield):

¹H-NMR(DMSO?d ₆)：10.42(br?s，1H)，8.43-8.54(m，2H)，7.58-7.63(m，1H)，7.29-7.38(m，2H)，7.11-7.18(m，2H)，6.84-6.91(m，1H)，6.56-6.78(br?m，1H)，4.18(t，2H)，3.72(s，2H)，3.45(t，2H)，2.67(t，2H)，2.58(t，2H)，1.84-1.95(m，2H)，1.51-1.61(m，2H)：

MS(+ve?ESI)：494(M+H) ⁺。

B) with three (acetoxyl group) hydroborate (750mg, 1.48mmol) add N-(3-fluorophenyl)-2-{3-[(7-{3-[(3-hydroxypropyl in room temperature) amino] propoxy-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (290mg, 0.59mmol) and acetaldehyde (39mg, 0.88mmol) dimethyl formamide (3ml) solution, reaction stirred 2h.Reaction mixture is filtered,, purify, use 3-12% methyl alcohol: the methylene dichloride wash-out with the fast silica gel chromatogram method with methylene dichloride (10ml) dilution.The required part of vacuum-evaporation obtains white solid 2-{3-[(7-{3-[ethyl (3-hydroxypropyl) amino] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(3-fluorophenyl) ethanamide (105mg, 34% yield):

¹H-NMR(DMSO?d ₆)：10.41(br?s，1H)，10.13-10.30(br?s，1H)，8.43-8.55(m，2H)，7.57-7.65(m，1H)，7.28-7.39(m，2H)，7.09-7.21(m，2H)，6.83-6.92(m，1H)，6.65-6.81(m，1H)，4.15(t，2H)，3.73(s，2H)，3.41(t，2H)，2.41-2.58(m，6H?under?DMSO)，1.82-1.93(m，2H)，1.48-1.58(m，2H)，0.94(t，3H)：

MS(+ve?ESI)：522(M+H) ⁺。

C) response class of introducing with embodiment 6c seemingly, but begin amino with 2-{3-[(7-(3-[ethyl (3-hydroxypropyl) amino] propoxy-} quinazoline-4-yl)]-1H-pyrazoles-5-yl }-N-(the 3-fluorine is lifted base) ethanamide (90mg, 0.17mmol), acquisition light yellow solid two-tertiary butyl 3-[[3-(the 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) propyl group] (ethyl) amino] propyl phosphate (45mg, 37% yield):

MS(+ve?ESI)：714(M+H) ⁺，

MS(-ve?ESI)：712(M-H) ^-。

Embodiment 44-prepares compound 44-2-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino of table 3]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) propyl group] (2-methoxy ethyl) amino] ethyl phosphonic acid two hydrogen esters

With two-tertiary butyl 2-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) propyl group] (2-methoxy ethyl) amino] ethyl phosphonic acid ester (200mg, 0.3mmol) be dissolved in two  alkane (7ml), (4.0N 0.5ml) spends the night 20 ℃ of processing with the mixture of two  alkane/hydrochloric acid.The filtered and recycled light yellow solid, (55 ℃ of vacuum-dryings, 12h) obtain light yellow solid 2-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) propyl group] (2-methoxy ethyl) amino] ethyl phosphonic acid two hydrogen esters (200mg, 85% yield):

¹H-NMR(DMSO?d ₆，CH ₃COOD)：8.95(s，1H)，8.82(d，1H)，7.65(d，1H)，7.46(d，1H)，7.37(m，3H)，6.88(m，1H)，6.78(s，1H)，4.33(m，2H)，4.28(m，2H)，3.86(s，2H)，3.76(m，2H)，3.53(m，2H)，3.45(m，4H)，3.34(s，3H)，2.30(m，2H)：

MS(+ve?ESI)：618(M+H) ⁺。

Following acquisition is as two-tertiary butyl 2-[[3-of initial feed ({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) propyl group] (2-methoxy ethyl) amino] the ethyl phosphonic acid ester:

A) with 2-((2-methoxy ethyl) amino) ethanol (750mg, 6.29mmol) adding 2-(3-{[7-(3-chlorine propoxy-) quinazoline-4-yl] amino }-1H-pyrazoles-5-yl)-N-(3-fluorophenyl) ethanamide (960mg, 2.11mmol) and potassiumiodide (700mg, 1-Methyl-2-Pyrrolidone 4.22mmol) (8ml) solution.At 80 ℃ of 1.5h that stir the mixture, cooling, be loaded into silicagel column, (use methylene dichloride, methylene dichloride successively: 96: 4 to 92: 8 wash-outs of methyl alcohol) by chromatographic purification, obtain Off-white solid N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl) (2-methoxy ethyl) amino] propoxy-} quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (600mg, 53% yield).

¹H-NMR(DMSO?d ₆，TFA)：9.0(s，1H)，8.83(d，1H)，7.65(d，1H)，7.48(d，1H)，7.36(m，2H)，7.28(s，1H)，6.88(m，1H)，6.80(s，1H)，4.32(m，2H)，3.86(s，2H)，3.80(m，2H)，3.73(m，2H)，3.48(m，4H)，3.37(m，2H)，3.34(s，3H)，2.28(m，2H)：

MS(+ve?ESI)：538(M+H) ⁺。

B) at 20 ℃, with diethylamino phosphorous acid di tert butyl carbonate (0.56ml, 2mmol) slowly add N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyethyl) (2-methoxy ethyl) amino] propoxy-} quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (540mg, 1mmol), tetrazolium (200mg, 3mmol) and the mixture 2h of dimethyl formamide (5ml).Cooling mixture to 0 ℃, slowly add hydrogen peroxide (9.0N, 0.33ml, 2.93mmol), at room temperature continuously stirring 12h.(1.14g, water 6mmol) (12ml) solution adds reaction mixture, allows it slowly rise to room temperature with Sodium Pyrosulfite at 0 ℃ then.Evaporating solvent then, resistates is purified by silica gel chromatography, use methylene dichloride: 96: 4 to 94: 6 wash-outs of the methanol solution of ammonia (3.0N), obtain two-tertiary butyl 2-[[3-({ 4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) propyl group] (2-methoxy ethyl) amino] ethyl phosphonic acid ester (220mg, 30% yield):

¹H-NMR(DMSO?d ₆，TFA)：8.98(s，1H)，8.81(d，1H)，7.63(d，1H)，7.48(d，1H)，7.36(m，2H)，7.27(s，1H)，6.90(t，1H)，6.77(s，1H)，4.30(m，2H)，4.26(m，2H)，3.84(s，2H)，3.72(m，2H)，3.55(m，2H)，3.48(m，2H)，3.42(m，2H)，3.34(s，3H)，2.26(m，2H)，1.44(s，18H)：

MS(+ve?ESI)：730(M+H) ⁺。

Embodiment 45-prepares compound 45-2-[[4-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino of table 4]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) butyl] (propyl group) amino] ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin ({ 4-[(5-{2-[(2 with two-tertiary butyl 2-[[4-, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) butyl] (propyl group) amino] ethyl phosphonic acid ester (550mg, 0.74mmol), obtain the dihydrochloride (504mg, 96% yield) of the compound 45 of table 4:

¹H-NMR(DMSO?d ₆)：11.95(s，1H)，10.34(s，1H)，8.90(s，1H)，8.83(d，1H)，7.68(m，1H)，7.45(m，2H)，7.22(m，2H)，6.72(s，1H)，4.23(m，4H)，3.91(s，2H)，3.40(m，2H)，3.20(m，2H)，3.08(m，2H)，1.88(m，4H)，1.71(m，2H)，0.90(t，3H)：

MS(+ve?ESI)：634(M+H) ⁺，

MS(-ve?ESI)：632(M-H) ^-。

Following acquisition is as two-tertiary butyl 2-[[4-of initial feed ({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) butyl] (propyl group) amino] the ethyl phosphonic acid ester:

A) 0 ℃ with 1,4-dihydroxyl butane (33.0ml, 366mmol) sodium hydride under in 10min, add stirring (14.6g 60% is scattered in the oil, N,N-DIMETHYLACETAMIDE 366mmol) (200ml) suspension, reaction stirred 15min is heated to 60 ℃ then.In 5min, add 7-fluquinconazole quinoline-4 (3H)-ketone (10.0g, N,N-DIMETHYLACETAMIDE 61.0mmol) (60ml) solution, with reactant at 110 ℃ of restir 5h.The cooling reactant is poured on the ice (500g), with salt solution (500ml) and 5.0N salt acid treatment (up to pH＜6).Collect the gained solid by suction filtration, water and ether washing are dissolved in N,N-DIMETHYLACETAMIDE (100ml) then.The filtering reaction thing, vacuum-evaporation filtrate obtains white solid 7-(4-hydroxyl-butoxy) quinazoline-4 (3H)-ketone (5.88g, 41% yield) after vacuum-drying:

¹H-NMR(DMSO?d ₆)：8.15(s，1H)，8.10(m，1H)，7.18(m，2H)，4.22(m，2H)，3.58(m，2H)，1.90(m，2H)，1.70(m，2H)：

MS(+ve?ESI)：235(M+H) ⁺，

MS(-ve?ESI)：233(M-H) ^-。

B) (4.86g, thionyl chloride 20.0mmol) (50ml) suspension is with reactant reflux 1h with 7-(4-hydroxyl-butoxy) quinazoline-4 (the 3H)-ketone under dimethyl formamide (0.5ml) the adding stirring.The cooling reactant, the vacuum-evaporation excessive thionyl chloride, (2 * 50ml) azeotropic are dissolved in N,N-DIMETHYLACETAMIDE (50ml) then with resistates and toluene.Add 5-amino-1H-pyrazoles-3-acetate (2.82g, 20mmol) and two  alkane solution of 4.0N hydrochloric acid (5.0ml, 20mmol), at 90 ℃ of reaction stirred 40min.The cooling reactant in the impouring ice-water (500ml), is acidified to pH＞12 with 40% aqueous sodium hydroxide solution to room temperature.Filtering reaction thing, acidifying filtrate be to pH＜4.8, collects the solid of separating out by suction filtration, obtain the light orange solid (3-{[7-(4-chlorine butoxy) quinazoline-4-yl] amino }-1H-pyrazoles-5-yl) acetate (7.07g, 91% yield):

¹H-NMR(DMSO?d ₆)：12.45(br?s，2H)，8.57(s，1H)，8.50(d，1H)，7.17(m，2H)，6.60(s，1H)，4.18(m，2H)，3.75(m，2H)，3.65(s，2H)，1.90(m，4H)：

MS(+ve?ESI)：376(M+H) ⁺，

MS(-ve?ESI)：374(M-H) ^-。

C) at 0 ℃ with phosphoryl chloride (1.8ml, 19.5mmol) 2 under add stirring, the 3-difluoroaniline (2.88g, 22.3mmol), (3-{[7-(4-chlorine butoxy) quinazoline-4-yl] amino }-1H-pyrazoles-5-yl) and acetate (6.97g, 18.6mmol) and pyridine (100ml) suspension.At 0 ℃ of reaction stirred 2.5h, add phosphoryl chloride (0.3ml) once more, allow reactant in 18h, rise to room temperature.Add ethyl acetate (200ml) and ether (100ml), reaction stirred is filtered and is collected viscous solid, then it is suspended in water (300ml).Add dilute ammonia solution up to pH＞7, collect the gained solid by suction filtration.With the washing of gained solid water successively, acetonitrile, follow long-time vacuum-drying, obtain filbert solid 2-(3-{[7-(4-chlorine butoxy) quinazoline-4-yl] amino }-1H-pyrazoles-5-yl)-N-(2, the 3-difluorophenyl) ethanamide (7.6g, 84% yield):

¹H-NMR(DMSO?d ₆)：10.20(s，1H)，8.63(s，1H)，8.58(d，1H)，7.69(m，1H)，7.23(m，1H)，7.15(m，3H)，6.68(s，1H)，4.14(m，2H)，3.81(8，2H)，3.70(m，2H)，1.88(m，4H)：

MS(+ve?ESI)：487(M+H) ⁺

MS(-ve?ESI)：485(M-H) ^-。

D) response class of introducing with embodiment 28f seemingly, but begin ethanol (765mg with 2-(propyl group amino), 7.40mmol) and 2-(3-{[7-(4-chlorine butoxy) quinazoline-4-yl] amino }-1H-pyrazoles-5-yl)-N-(2, the 3-difluorophenyl) ethanamide (1.20g, 2.47mmol), obtain brown solid N-(2, the 3-difluorophenyl)-and 2-{3-[(7-{4-[propyl group (2-hydroxyethyl) amino] butoxy }-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (625mg, 46% yield):

¹H-NMR(DMSO?d ₆)：10.3(br?s，1H)，8.49(s，1H)，8.45(m，1H)，7.70(m，1H)，7.15(m，3H)，7.1(s，1H)，6.58(br，s，1H)，4.1(m，2H)，3.80(s，2H)，3.42(m，2H)，2.45(m，4H)，2.33(m，2H)，1.77(m，2H)，1.55(m，2H)，1.35(m，2H)，0.81(t，3H)：

MS(+ve?ESI)：554(M+H) ⁺

MS(-ve?ESI)：552(M-H) ^-。

E) response class of introducing with embodiment 6c seemingly, but begin with N-(2, the 3-difluorophenyl)-and the 2-{3-[(7-{4-[(2-hydroxyethyl) (propyl group) amino] butoxy }-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (540mg, 0.98mmol), obtain light yellow solid two-tertiary butyl 2-[[4-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) butyl] (propyl group) amino] ethyl phosphonic acid ester (566mg, 78% yield):

¹H-NMR(DMSO?d ₆)：12.3(s，1H)，10.18(m，2H)，8.51(m，2H)，7.72(m，1H)，7.15(m，4H)，6.77(s，1H)，4.15(m，2H)，3.85(m，4H)，2.65(m，2H)，2.40(m，2H)，1.78(m，2H)，1.56(m，2H)，1.4(m，2H)，1.39(s，18H)，0.85(t，3H)：

MS(+ve?ESI)：746(M+H) ⁺

MS(-ve?ESI)：744(M-H) ^-。

Embodiment 46-prepares compound 46-2-[[4-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino of table 4]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) butyl] (ethyl) amino] ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin ({ 4-[(5-{2-[(2 with two (tertiary butyl) 2-[[4-, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) butyl] (ethyl) amino] ethyl phosphonic acid ester (386mg, 0.53mmol), obtain the white dihydrochloride (340mg, 93% yield) of the compound 46 of table 4:

¹H-NMR(DMSO?d ₆)：11.97(s，1H)，10.35(s，1H)，8.92(s，1H)，8.85(d，1H)，7.67(m，1H)，7.45(m，2H)，7.18(m，2H)，6.75(s，1H)，4.23(m，4H)，3.90(s，2H)，3.39(m，2H)，3.20(m，4H)，1.87(m，4H)，1.25(t，3H)：

MS(+ve?ESI)：619(M+H) ⁺

MS(-ve?ESI)：617(M-H) ^-。

Following acquisition is as two (tertiary butyl) 2-[[4-of initial feed ({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) butyl] (ethyl) amino] the ethyl phosphonic acid ester:

A) response class of introducing with embodiment 45d seemingly, but begin with 2-(ethylamino) ethanol (468mg, 5.25mmol), obtain Off-white solid N-(2, the 3-difluorophenyl)-and 2-{3-[(7-{4-[ethyl (2-hydroxyethyl) amino] butoxy }-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (443mg, 47% yield):

¹H-NMR(DMSO?d ₆)：10.25(br?s，1H)，8.45(m，2H)，7.70(m，1H)，7.12(m，4H)，658(br?s，1H)，4.25(br?s，1H)，4.13(m，2H)，3.80(s，2H)，3.42(m，2H)，1.76(m，2H)，1.55(m，2H)，0.95(t，3H)：

MS(+ve?ESI)：540(M+H) ⁺

MS(-ve?ESI)：538(M-H) ^-。

B) response class of introducing with embodiment 6c seemingly, but begin with N-(2, the 3-difluorophenyl)-and 2-{3-[(7-{4-[ethyl (2-hydroxyethyl) amino] butoxy }-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (385mg, 0.71mmol), obtain light yellow solid two (tertiary butyl) 2-[[4-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) butyl] (ethyl) amino] ethyl phosphonic acid ester (393mg, 75% yield):

¹H-NMR(DMSO?d ₆)：12.30(s，1H)，10.18(br?s，1H)，8.50(m，2H)，7.71(m，1H)，7.15(m，4H)，6.78(s，1H)，4.3(m，2H)，3.85(m，4H)，2.68(m，2H)，1.78(m，2H)，1.58(m，2H)，1.40(s，18H)，0.97(t，3H)：

MS(+ve?ESI)：732(M+H) ⁺

MS(-ve?ESI)：730(M-H) ^-。

Embodiment 47-prepares compound 47-{ (2R)-1-[4-({ 4-[(5-{2-[(2,3-difluorophenyl) amino of table 4]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) butyl] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester

The response class of introducing with embodiment 1 seemingly, but begin with two (tertiary butyls) (2R)-1-[4-({ 4-[(5-(2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) butyl] tetramethyleneimine-2-yl } methyl phosphorodithioate (464mg, 0.62mmol), obtain the oyster white dihydrochloride (400mg, 91% yield) of the compound 47 of table 4:

¹H-NMR(DMSO?d ₆)：11.95(s，1H)，10.35(s，1H)，8.92(s，1H)，8.83(d，1H)，7.68(m，1H)，7.45(m，2H)，7.18(m，2H)，6.71(s，1H)，4.2(m，4H)，3.92(s，2H)，3.72(m，1H)，3.60(m，1H)，3.45(m，1H)，3.15(m，2H)，2.15(m，1H)，1.7-2.1(m，7H)：

MS(+ve?ESI)：631(M+H) ⁺

MS(-ve?ESI)：630(M-H) ^-。

Following acquisition as two (tertiary butyls) of initial feed (2R)-1-[4-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl the oxygen base) butyl] tetramethyleneimine-2-yl methyl phosphorodithioate:

A) response class of introducing with embodiment 45d seemingly, but begin with D-dried meat ammonia alcohol (530mg, 5.25mmol), obtain Off-white solid N-(2, the 3-difluorophenyl)-2-{3-[(7-{4-[(2R)-and 2-(hydroxymethyl) tetramethyleneimine-1-yl] butoxy }-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (516mg, 54% yield):

¹H-NMR(DMSO?d ₆)：10.25(br?s，1H)，8.45(m，2H)，7.7(m，1H)，7.15(m，4H)，6.6(br?s，1H)，4.30(br?s，1H)，4.21(m，2H)，3.80(s，2H)，3.40(m，1H)，3.20(m，1H)，3.05(m，1H)，2.85(m，1H)，2.40(m，1H)，2.30(m，1H)，2.10(m，1H)，1.77(m，3H)，1.6(m，5H)：

MS(+ve?ESI)：552(M+H) ⁺

MS(-ve?ESI)：550(M-H) ^-。

B) response class of introducing with embodiment 6c seemingly, but begin with N-(2, the 3-difluorophenyl)-2-{3-[(7-{4-[(2R)-and 2-(hydroxymethyl) tetramethyleneimine-1-yl] butoxy }-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (450mg, 0.82mmol), acquisition light yellow solid two (tertiary butyl) (2R)-1-[4-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) butyl] tetramethyleneimine-2-yl } methyl phosphorodithioate (470mg, 77% yield):

¹H-NMR(DMSO?d ₆)：12.3(s，1H)，10.18(s，1H)，8.50(m，2H)，7.71(m，1H)，7.18(m，4H)，6.77(s，1H)，4.15(m，2H)，3.80(m，3H)，3.62(m，1H)，3.05(m，1H)，2.80(m，1H)，2.65(m，1H)，2.37(m，1H)，2.18(m，1H)，1.80(m，3H)，1.62(m，5H)，1.38(s，18H)：

MS(+ve?ESI)：744(M+H) ⁺

MS(-ve?ESI)：742(M-H) ^-。

Embodiment 48-prepares compound 48-2-[[4-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino of table 4]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) butyl] (methyl) amino] ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin ({ 4-[(5-{2-[(2 with two-tertiary butyl 2-[[4-, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) butyl] (methyl) amino] ethyl phosphonic acid ester (250mg, 0.35mmol), obtain the oyster white dihydrochloride (263mg, 100% yield) of the compound 48 of table 4:

¹H-NMR(DMSO?d ₆)：11.95(s，1H)，10.35(s，1H)，8.92(s，1H)，8.83(d，1H)，7.69(m，1H)，7.45(m，2H)，7.29(m，2H)，6.75(s，1H)，4.22(m，4H)，3.81(s，2H)，3.39(m，2H)，3.20(m，2H)，2.80(s，3H)，1.85(m，4H)：

MS(+ve?ESI)：605(M+H) ⁺

MS(-ve?ESI)：603(M-H) ^-。

Following acquisition is as two-tertiary butyl 2-[[4-of initial feed ({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) butyl] (methyl) amino] the ethyl phosphonic acid ester:

A) response class of introducing with embodiment 45d seemingly, but begin with 2-(methylamino) ethanol (394mg, 5.25mmol), obtain Off-white solid N-(2, the 3-difluorophenyl)-and the 2-{3-[(7-{4-[(2-hydroxyethyl) (methyl) amino] butoxy } quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (536mg, 58% yield):

¹H-NMR(DMSO?d ₆)：10.25(br?s，1H)，8.45(m，2H)，7.71(m，1H)，7.15(m，4H)，6.58(br?s，1H)，4.3(br?s，1H)，4.12(m，2H)，3.80(s，2H)，3.45(m，2H)，2.39(m，4H)，2.15(s，3H)，1.79(m，2H)，1.58(m，2H)：

MS(+ve?ESI)：526(M+H) ⁺

MS(-ve?ESI)：524(M-H) ^-。

B) response class of introducing with embodiment 6c seemingly, but begin with N-(2, the 3-difluorophenyl)-and the 2-{3-[(7-{4-[(2-hydroxyethyl) (methyl) amino] butoxy } quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (460mg, 0.88mmol), obtain light yellow solid two-tertiary butyl 2-[[4-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) butyl] (methyl) amino] ethyl phosphonic acid ester (368mg, 59% yield):

¹H-NMR(DMSO?d ₆)：12.30(s，1H)，10.17(m，2H)，8.50(m，2H)，7.70(m，1H)，7.18(m，4H)，6.77(s，1H)，4.15(m，2H)，3.9(m，2H)，3.85(s，2H)，2.60(m，2H)，2.43(m，2H)，2.20(s，3H)，1.8(m，2H)，1.58(m，2H)，1.40(s，18H)：

MS(+ve?ESI)：718(M+H) ⁺

MS(-ve?ESI)：716(M-H) ^-。

Embodiment 49-prepares compound 49-{ (2S)-1-[4-({ 4-[(5-{2-[(2,3-difluorophenyl) amino of table 4]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) butyl] tetramethyleneimine-2-yl } the methyl dihydrogen phosphate ester

The response class of introducing with embodiment 1 seemingly, but begin with two (tertiary butyls) (2S)-1-[4-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) butyl] tetramethyleneimine-2-yl } methyl phosphorodithioate (386mg, 0.53mmol), obtain the oyster white dihydrochloride (340mg, 93% yield) of the compound 49 of table 4:

¹H-NMR(DMSO?d ₆)：11.7(br?s，1H)，10.30(s，1H)，8.87(s，1H)，8.75(d，1H)，7.68(m，1H)，7.40(m，2H)，7.19(m，2H)，6.71(s，1H)，4.20(m，2H)，4.18(m，2H)，3.90(s，2H)，3.7(m，1H)，3.58(m，1H)，3.42(m，1H)，3.1(m，2H)，2.15(m，1H)，1.75-2.1(m，7H)：

MS(+ve?ESI)：630(M+H) ⁺

MS(-ve?ESI)：632(M-H) ^-。

Following acquisition as two (tertiary butyls) of initial feed (2S)-1-[4-({ 4-[(5-{2-[(2,3-difluorophenyl) amino]-the 2-oxoethyl-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl the oxygen base) butyl] tetramethyleneimine-2-yl methyl phosphorodithioate:

A) response class of introducing with embodiment 45d seemingly, but begin with L-dried meat ammonia alcohol (530mg, 5.25mmol), obtain Off-white solid N-(2, the 3-difluorophenyl)-2-{3-[(7-{4-[(2S)-and 2-(hydroxymethyl) tetramethyleneimine-1-yl] butoxy }-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (550mg, 57% yield):

¹H-NMR(DMSO?d ₆)：12.38(br?s，1H)，10.20(br?s，1H)，8.47(m，2H)，7.70(m，1H)，7.15(m，4H)，6.62(br?s，1H)，4.28(br?s，1H)，4.15(m，2H)，3.81(s，2H)，3.40(m，1H)，3.20(m，1H)，3.02(m，1H)，2.81(m，1H)，2.38(m，1H)，2.30(m，1H)，2.10(m，1H)，1.78(m，3H)，1.58(m，5H)：

MS(+ve?ESI)：552(M+H) ⁺

MS(-ve?ESI)：550(M-H) ^-。

B) response class of introducing with embodiment 6c seemingly, but begin with N-(2, the 3-difluorophenyl)-2-{3-[(7-{4-[(2S)-and 2-(hydroxymethyl) tetramethyleneimine-1-yl] butoxy }-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide (340mg, 0.62mmol), acquisition light yellow solid two (tertiary butyl) (2S)-1-[4-({ 4-[(5-{2-[(2, the 3-difluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino]-quinazoline-7-yl } the oxygen base) butyl] tetramethyleneimine-2-yl } methyl phosphorodithioate (328mg, 71% yield):

¹H-NMR(DMSO?d ₆)：12.30(br?s，1H)，10.15(s，2H)，8.48(m，2H)，7.68(m，1H)，7.15(m，4H)，6.75(br?s，1H)，4.12(m，2H)，3.80(m，2H)，3.61(m，1H)，3.05(m，1H)，2.80(m，1H)，2.62(m，1H)，2.35(m，1H)，2.15(m，1H)，1.81(m，3H)，1.60(m，5H)，1.38(s，18H)：

MS(+ve?ESI)：744(M+H) ⁺

MS(-ve?ESI)：742(M-H) ^-。

Embodiment 50-prepares compound 50-2-{ ethyl [3-({ 6-fluoro-4-[(5-{2-[(3-fluorophenyl) the amino]-2-oxoethyl of table 5 }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid two hydrogen esters

The response class of introducing with embodiment 1 seemingly, but begin with two-tertiary butyl 2-{ ethyl [3-({ 6-fluoro-4-[(5-{2-[(3-fluorophenyl) amino]-2-oxoethyl-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid ester (275mg, 0.38mmol), obtain the oyster white dihydrochloride (260mg, 100% yield) of the compound 50 of table 5:

¹H-NMR(DMSO?d ₆)：12.0(br?s，1H)，10.87(s，1H)，8.96(s，1H)，8.87(d，1H)，7.65(m，2H)，7.38(m，2H)，6.89(m，2H)，6.77(s，1H)，4.42(t，2H)，4.26(m，2H)，3.86(s，2H)，3.44(t，2H)，3.35(m，2H)，3.28(m，2H)，2.33(m，2H)，1.31(t，3H)：

MS(+ve?ESI)：606(M+H) ⁺。

Following acquisition is as two-tertiary butyl 2-{ ethyl of initial feed [3-({ 6-fluoro-4-[(5-{2-[(3-fluorophenyl) amino]-2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) propyl group] amino } the ethyl phosphonic acid ester:

A) (4.27g, (1.6g 60% is scattered in the mineral oil, dimethyl formamide 40.0mmol) (50ml) suspension 39.5mmol) to be added drop-wise to sodium hydride under stirring with benzyl alcohol at 0 ℃.At 0 ℃ of reaction stirred 1h, add 6, (3.60g 19.8mmol), is heated to reactant 60 ℃ of 2h to 7-difluoro quinazoline-4 (1H)-ketone then.The cooling reactant in the impouring water (200ml), is collected gained solid by suction filtration to room temperature.The vacuum-drying solid obtains filbert solid 7-(benzyl oxygen base)-6-fluquinconazole quinoline-4 (1H)-ketone (4.45 g, 83% yield):

¹H-NMR(DMSO?d ₆)：12.24(br?s，1H)，8.05(s，1H)，7.80(d，1H)，7.52(m，2H)，7.44(m，3H)，7.38(t，1H)，5.35(s，2H)。

B) (2.00g 7.41mmol) is dissolved in phosphoryl chloride (20ml), reflux reactant 90min with 7-(benzyl oxygen base)-6-fluquinconazole quinoline-4 (1H)-ketone.The cooling reactant, (2 * 50ml) azeotropic are dissolved in methylene dichloride (5ml) then with toluene.Organic phase is washed with saturated aqueous solution of sodium bicarbonate, uses dried over mgso then.Vacuum evaporating solvent final vacuum drying solid obtains light yellow solid 7-(benzyl oxygen base)-4-chloro-6-fluquinconazole quinoline (1.50g, 71% yield):

¹H-NMR(CDCl ₃)：8.93(s，1H)，7.89(d，1H)，7.51(m，3H)，7.35-7.46?(m，3H)，5.32(s，2H)。

C) with 7-(benzyl oxygen base)-4-chloro-6-fluquinconazole quinoline (1.20g, 4.16mmol) and 2-(3-amino-1H-pyrazoles-5-yl)-(0.97g, mixture 4.15mmol) is reflux 2h in 2-propyl alcohol (20ml) for N-(3-fluorophenyl) ethanamide.The cooling reactant is collected gained solid with ether dilution back by suction filtration to room temperature.Long-time vacuum-drying acquisition light yellow solid 2-(3-{[7-(benzyl oxygen base)-6-fluquinconazole quinoline-4-yl] amino }-1H-pyrazoles-5-yl)-N-(3-fluorophenyl) ethanamide (2/.00g, 92% yield):

¹H-NMR(DMSO?d ₆)：11.72(br?s，1H)，10.71(s，1H)，8.90(s，1H)，8.82(d，1H)，7.65(m，2H)，7.55(m，2H)，7.32-7.50(m，5H)，6.89(m，1H)，6.76(s，1H)，5.42(s，2H)，3.84(s，2H)：

MS(+ve?ESI)：487(M+H) ⁺。

D) with 2-(3-{[7-(benzyl oxygen base)-6-fluquinconazole quinoline-4-yl] amino }-1H-pyrazoles-5-yl)-N-(3-fluorophenyl) ethanamide (hydrochloride) (1.95g, trifluoroacetic acid 3.74mmol) (20ml) solution reflux 7h.The cooling reactant is to room temperature, and vacuum is removed trifluoroacetic acid.With resistates and ether (2 * 25ml) grind, and obtain light yellow solid 2-{3-[(6-fluoro-7-hydroxyl quinazoline-4-yl)-amino]-1H-pyrazoles-5-yl }-N-(3-fluorophenyl) ethanamide (2.00g, 100% yield):

MS(+ve?ESI)：397(M+H) ⁺。

E) with cesium carbonate (2.67g, 8.2mmol) adding 2-{3-[(6-fluoro-7-hydroxyl quinazoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(3-fluorophenyl) ethanamide (2.09g, 4.10mmol) and 3-bromo-n-propyl chloride (0.44ml, 4.5mmol) dimethyl formamide (20ml) stirred solution, with reactant 70 ℃ the heating 1h.The cooling reactant in the impouring water (150ml), is collected gained solid by suction filtration to room temperature.Purify with the flash chromatography on silica gel method and (to use 3-8% methyl alcohol: the methylene dichloride wash-out), acquisition light yellow solid 2-behind vacuum evaporating solvent (3-{[7-(3-chlorine propoxy-)-6-fluquinconazole quinoline-4-yl] amino }-1H-pyrazoles-5-yl)-N-(3-fluorophenyl) ethanamide (1.10g, 57% yield):

MS(+ve?ESI)：473(M+H) ⁺。

F) response class of introducing with embodiment 45d seemingly, but begin with 2-(ethylamino) ethanol (282mg, 3.17mmol) and 2-(3-{[7-(3-chlorine propoxy-)-6-fluquinconazole quinoline-4-yl] amino }-1H-pyrazoles-5-yl)-N-(3-fluorophenyl) ethanamide (500mg, 1.06mmol), obtain Off-white solid 2-{3-[(7-{3-[ethyl (2-hydroxyethyl) amino] propoxy-}-6-fluquinconazole quinoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(3-fluorophenyl) ethanamide (408mg, 73% yield):

¹H-NMR(DMSO?d ₆)：12.40(s，1H)，10.40(s，1H)，10.15(s，1H)，8.53(s，1H)，8.50(br?s，1H)，7.62(d，1H)，7.35(m，3H)，6.89(m，1H)，6.78(br?s，1H)，4.28(m，3H)，3.75(br?s，2H)，3.45(m，2H)，2.62(t，2H)，2.50(m，4H?under?DMSO)，1.91(m，2H)，0.98(t，3H)：

MS(+ve?ESI)：526(M+H) ⁺。

G) response class of introducing with embodiment 6c seemingly, but begin with 2-{3-[(7-{3-[ethyl (2-hydroxyethyl) amino] propoxy-}-6-fluquinconazole quinoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(3-fluorophenyl) ethanamide (266mg, 0.51mmol), acquisition light yellow solid two-tertiary butyl 2-{ ethyl [3-(6-fluoro-4-[(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) amino] quinazoline-7-yl } the oxygen base) propyl group] amino } ethyl phosphonic acid ester (288mg, 79% yield):

¹H-NMR(CDCl ₃)：12.70(br?s，1H)，9.90(br?s，1H)，9.40(s，1H)，8.60(s，1H)，7.98(d，1H)，7.56(d，1H)，7.15-7.30(m，3H)，6.76(m，1H)，6.24(br?s，1H)，4.14(t，2H)，4.03(q，2H)，3.83(s，2H)，2.79(t，2H)，2.70(t，2H)，2.61(m，2H)，1.95(m，2H)，1.48(s，18H)，1.05(t，3H)：

MS(+ve?ESI)：718(M+H) ⁺。

2-(3-amino-1H-pyrazoles-5-yl)-N-(3-fluorophenyl) ethanamide that step 50c uses prepares in accordance with the following methods:

H) 0 ℃ with trifluoroacetic acid pentafluorophenyl group ester (11.9g, 42.5mmol) be added drop-wise to (3-amino-1H-pyrazoles-5-yl) acetate (3.00g, 21.3mmol) and pyridine (3.80ml, dimethyl formamide 46.7mmol) (25ml) solution.Allow reactant in 90min, rise to room temperature, add then the 3-fluoroaniline (4.10ml, 42.5mml).At stirring at room reactant 2.5h, then in the impouring 0.2N hydrochloric acid, with methylene dichloride (3 * 50ml) extractions.Add excessive ether and cause being settled out 2,2,2-three fluoro-N-(5-{2-[(3-fluorophenyl) amino]-the 2-oxoethyl }-the 1H-pyrazole-3-yl) ethanamide (2.08 g, 30% yield), isolate the light orange solid:

MS(+ve?ESI)：331(M+H) ⁺。

I), 2-three fluoro-N-(5-{2-[(3-fluorophenyl) amino with 2,2]-the 2-oxoethyl-the 1H-pyrazole-3-yl) ethanamide (3.10g, 9.4mmol) methyl alcohol (25ml) and 2.0N aqueous hydrochloric acid (20ml, 40mml) in 50 ℃ of heating 2.5h.The cooling reactant is to room temperature, and with the solid sodium bicarbonate alkalization, vacuum concentration is up to beginning to separate out solid then.Collect the gained solid by suction filtration, long-time then vacuum-drying obtains filbert solid 2-(3-amino-1H-pyrazoles-5-yl)-N-(3-fluorophenyl) ethanamide (1.05g, 48% yield):

¹H-NMR(DMSO?d ₆)：11.25(br?s，1H)，10.30(br?s?1H)，7.60(d，1H)，7.32(m，2H)，6.86(m，1H)，5.31(s，1H)，4.62(br?s，2H)，3.48(s，2H)。

Claims

1. compound, it is following any compound:

(3) N-(2, the 3-difluorophenyl)-2-{3-[(7-{3-[(2 S)-and 2-(2-hydroxyethyl) tetramethyleneimine-1-yl] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(10) N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyl-1, the 1-dimethyl propyl) amino] propoxy-} quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(14) N-(2, the 3-difluorophenyl)-2-{3-[(7-{4-[ethyl (2-hydroxyethyl) amino] butoxy }-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(20) 2-{3-[(7-{3-[ethyl (2-hydroxyethyl) amino] propoxy-}-6-fluquinconazole quinoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(3-fluorophenyl) ethanamide or its pharmacy acceptable salt.

2. the compound of claim 1, it is to be selected from following any compound:

(4) N-(3-fluorophenyl)-2-{3-[(7-{3-[(2-hydroxyl-1, the 1-dimethyl propyl) amino] propoxy-} quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(6) N-(3-fluorophenyl)-2-{3-[(7-{3-[(2R)-2-(hydroxymethyl) tetramethyleneimine-1-yl] propoxy-}-quinazoline-4-yl) amino]-1 H-pyrazoles-5-yl } ethanamide;

(7) N-(2, the 3-difluorophenyl)-2-{3-[(7-{4-[ethyl (2-hydroxyethyl) amino] butoxy }-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide;

(10) 2-{3-[(7-{3-[ethyl (2-hydroxyethyl) amino] propoxy-}-6-fluquinconazole quinoline-4-yl) amino]-1H-pyrazoles-5-yl }-N-(3-fluorophenyl) ethanamide or its pharmacy acceptable salt.

3. the compound of claim 1, it is:

N-(3-fluorophenyl)-2-{3-[(7-{3-[ethyl (2-hydroxyethyl) amino] propoxy-}-quinazoline-4-yl) amino]-1H-pyrazoles-5-yl } ethanamide.