CN101298427A

CN101298427A - Diaryl urea compound and use thereof

Info

Publication number: CN101298427A
Application number: CNA2008100290244A
Authority: CN
Inventors: 丁克; 裴端卿; 王德平; 段磊; 任小梅; 周净; 甘继荣; 周凤涛; 张章
Original assignee: Guangzhou Institute of Biomedicine and Health of CAS
Current assignee: Guangzhou Institute of Biomedicine and Health of CAS
Priority date: 2008-06-26
Filing date: 2008-06-26
Publication date: 2008-11-05
Anticipated expiration: 2028-06-26
Also published as: CN101298427B

Abstract

The invention discloses a compound with a general formula I and an acid or alkali salt or solid isomer thereof that is acceptable in medicine as well as the applications of the compound and the acid or alkali salt or solid isomer thereof in preparing the medicines for curing or preventing knub; the definitions for each gene in the general formula can be seen in an instruction.

Description

Diaryl urea compound and application thereof

Technical field

The invention belongs to chemical field of medicaments, relate to a class diaryl urea compound and an application thereof particularly.

Background of invention

Tumour is the No.1 killer of present human health and life, and its sickness rate is only second to cardiovascular disease.And along with the influence of environmental pollution or other factors, the sickness rate of malignant tumour is fast rise trend.According to the data that World Health Organization 2003 announces, the total malignant tumor patient 1,000 ten thousand in the whole world in 2000, because of malignant tumour death person up to 6,200,000, account for 12%～25% of total death toll.Anticipate the year two thousand twenty, global annual new cases will reach 1,500 ten thousand.In recent years, though some novel target new drug developments such as tyrosine protein inhibitor listings are arranged, but still can't satisfy growing clinical cancer patient's needs far away.The antitumor drug research and development also are still the important research direction of present medicament research and development circle.

Recently studies show that some diaryl urea compounds with different structure feature can reach the growth that suppresses tumour cell by the arrestin kinase activity.Proved that the activeconstituents that these diaryl urea compounds can be used as in the pharmaceutical composition is used for the treatment of excess proliferative diseases such as cancer.Diaryl urea Raf inhibitor such as Sorafinib have obtained drugs approved by FDA and have been used for clinical treatment.Pertinent literature is referring to Wang, J.Med.Chem. such as G.T.; 2005; 48 (9); 3118-3121; Tao, J.Med.Chem. such as Z.-F.; 2007; 50; 1514-1527; Dai, J.Med.Chem. such as Y.; 2007; 50 (7); 1584-1597; Regan, J.Med.Chem. such as J.; (Article); 2002; 45 (14); 2994-3008; Dai, J.Med.Chem. such as Y.; 2005; 48 (19); 6066-6083; Tao, Bioorg.Med.Chem.Letts such as Zhi-Fu (2007), 17 (23), 6593-6601; Riedl, US such as Bernd 7235576 (Chemical Abstract 147:118041); Dai, J.Med.Chem. such as Y. (2007), 50 (7), 1584-1597; Bold, PCT Int.Appl.WO 2005051366 such as Guido; Wilhelm, PCT Int.Appl. (2004) such as Scott, WO2004113274; Miller, U.S.Pat.Appl.Publ. such as Scott (2004), US 458,015, abandoned; Busch-Petersen, PCT Int.Appl. (2004) such as Jakob, WO 2004039775; Houghton, Investigational New Drugs (1996) such as Peter J, 14 (3), 271-280; Howbert, J.Med.Chem. such as J.Jeffry (1990), 33 (9), 2393-407; Molecular cancer therapeutics (2006) such as Gable Karissa L, 5 (4), 1079-86.; Hasegawa, J.Med.Chem. such as Masaichi (2007), 50 (18), 4453-4470; Riedl, Bernd etc. (2007), US7235576; Wilhelm, Scott.PCT Int.Appl. (2007), WO 2007053574; Cusack, PCT Int.Appl. (2005) such as Kevin, WO 2005110410; Hoelzemann, PCT Int.Appl. (2005) such as Guente, WO 2005019192; Thaimattam, Bioorganic﹠amp such as Ram; Medicinal Chemistry (2004), 12 (24), 6415-6425; Dumas, PCT Int.Appl. (2004) such as Jacques, WO 2004078748; Khire, Uday R.; Deng Bioorganic﹠amp; MedicinalChemistry Letters (2004), 14 (3), 783-786; Floersheimer, PCT Int.Appl. (2003) such as Andreas, WO2003099771; Riedl, U.S.Pat.Appl.Publ. such as Bernd (2003), US 2003207872; Riedl, Bernd; Deng U.S.Pat.Appl.Publ. (2003), US 2003181442; Riedl, Bernd; Deng U.S.Pat.Appl.Publ. (2003), US2003144278; Dumas, Jacques; Deng U.S.Pat.Appl.Publ. (2002), US 2002165394; Dumas, PCT Int.Appl. (2002) such as Jacques, WO 2002062763; Cheung, PCT Int.Appl. (2002) such as Mui, WO2002044156; Riedl, Bernd; Deng PCT Int.Appl. (2000), WO 2000042012; Riedl, PCT Int.Appl. (2000) such as Bernd, WO 2000041698; Miller, Scott; Deng PCT Int.Appl. (1999), WO 9932436; Springer, PCT Int.Appl. (2006) such as Caroline Joy, WO 2006067466; Wada, PCT Int.Appl. (2008) such as Kunio, WO 2008044688; Chi, PCT Int.Appl. (2008) such as Liguo, WO 2008023235; Aquila, Brian; PCT Int.Appl. (2007) such as Lyne, WO 2007119055; PCT Int.Appl. (2007) such as Alfred, WO2007115670; Hasegawa, J.Med.Chem. such as Masaichi (2007), 50 (18), 4453-4470; Riedl, Bernd etc. (2007), US 7235576; Chen, PCT Int.Appl. (2007) such as Ping, WO 2007061882; Miyazaki, Bioorg.Med.Chem.Letts such as Yasushi (2007), 17 (6), 1773-1778; Ozawa, PCT Int.Appl. (2007) such as Sawako, WO 2007018137; Scott, Aust.Pat.Appl. (2006) such as William J., AU 2006201959; Stieber, PCT Int.Appl. (2006) such as Frank, WO 2006040056; PCT Int.Appl. (2006) such as Vinod F., WO2006039718; Hoelzemann, PCT Int.Appl. (2005) such as Guenter, WO 2005019192; Curtin, U.S.Pat.Appl.Publ. (2005) such as Michael L., US 2005026976; Wilhelm, Scott; Deng PCT Int.Appl. (2004), WO2004113274; Curtin, U.S.Pat.Appl.Publ. (2005) such as Michael L., US 2005026976; Wilhelm, PCT Int.Appl. (2004) such as Scott, WO 2004113274; Curtin, PCT Int.Appl. (2004) such as Michael L, WO2004108672; Michaelides, U.S.Pat.Appl.Publ. (2004) such as Michael R, US 2004014756; Khire, Bioorg.Med.Chem.Letts (2004) such as Uday R, 14 (3), 783-786; Michaelides, U.S.Pat.Appl.Publ. (2003) such as Michacl R., US 2003225273; Riedl, Bernd; Deng U.S.Pat.Appl.Publ. (2003), US2003207872; Michaelides, PCT Int.Appl. (2003) such as Michael R., WO 2003080625; Riedl, U.S.Pat.Appl.Publ. such as Bernd (2003), US 2003181442; Hirst, U.S.Pat.Appl.Publ. (2003) such as Gavin C., US 2003153752; Riedl, U.S.Pat.Appl.Publ. such as Bernd (2003), US 2003144278; Adams, PCT Int.Appl. (2003) such as JerryLeroy, WO 2003022852; Dumas, U.S.Pat.Appl.Publ. such as Jacques (2002), US 2002165394; Dumas, PCT Int.Appl. (2002) such as Jacques, WO 2002062763; Cheung, PCT Int.Appl. (2002) such as Mui, WO 2002044156; Dumas, U.S.Pat.Appl.Publ. such as Jacques (2002), US2002065296; Hirst, PCT Int.Appl. (2001) such as Gavin C., WO 2001072751; Bender, PCT Int.Appl. (2001) such as Steven Lee, WO 2001053274; Riedl, U.S.Pat Appl.Publ. (2003) such as Bernd, US2003144278; Riedl, PCT Int.Appl. (2000) WO 2000042012 such as Bernd; Riedl, PCT Int.Appl (2000) such as Bernd, WO 2000041698; Miller, PCT Int.Appl. (1999) WO 9932463 such as Scott.

But for diaryl urea compound with Chinese style I constitutional features of the present invention and anti-tumor activity thereof, the relevant report of Shang Weijian.

Summary of the invention

One of technical issues that need to address of the present invention provide a kind of new diaryl urea compound.

The technical scheme that solves the problems of the technologies described above is as follows:

Compound in the formula (I) or pharmacy acceptable salt or steric isomer,

Wherein:

A, B are optional separately to be CH or N;

Ar is a phenyl, pyridyl, pyrimidyl or do not contain or contain the aromatic nucleus of nitrogen, sulphur, oxygen heteroatom;

Following a is 0 or 1; B is 0 or 1;

R ₁Be selected from:

1)H；

2)F；

3)CF ₃；

R ₂Be selected from:

1)H；

2) C ₁～C ₈Alkyl;

3) C ₁～C ₈Perfluoroalkyl;

4)C ₁～C ₈NR ₆R ₅；

R ₃Be the substituting group of 1～5 different positions on aromatic ring, certainly optional:

1)H；

2) halogen;

3)NO ₂；

4)C ₀～C ₄NR ₄R ₅；

5) C ₁～C ₃Perfluoroalkyl;

6) O _aC ₁～C ₃Perfluoroalkyl;

7) O _aC ₁～C ₃Alkyl;

8) C ₁～C ₃The N-cycloalkyl;

9) C ₁～C ₃The N-aryl;

10) C ₁～C ₄The N-heterocyclic radical;

11) O _aC ₃～C ₆Cycloalkyl-heterocyclic radical;

12) O _aC ₃～C ₆Cycloalkyl-NR ₄R ₅

13) O _aC ₃～C ₆Cycloalkyl-alkyl;

R ₅And R ₄Independently be selected from separately:

1)H；

2) (C=O) _aO _bC ₁～C ₄Alkyl;

3) (C=O) _aO _bAryl;

4) (C=O) _aO _bC ₂～C ₄Thiazolinyl;

5) (C=O) _aO _bC ₂～C ₄Alkynyl;

6) O _bC ₁～C ₃Perfluoroalkyl;

7) (C=O) _aO _bC ₃～C ₆Cycloalkyl;

8) (C=O) _aO _bHeterocyclic radical;

9) SO ₂C ₁～C ₃Alkyl;

10) (C=O) _aO _bC ₀～C ₃Alkylidene group-aryl;

11) (C=O) _aO _bC ₀～C ₃The alkylidenyl-heterocyclic base;

12)(C＝O) _aO _bC ₀～C ₄-NR ₆R ₇；

13) (C=O) _aO _bC ₃～C ₆Cycloalkyl-COOR ₇

14) (C=O) _aO _bC ₃～C ₆Cycloalkyl-aryl;

15) (C=O) _aO _bC ₃～C ₆Cycloalkyl-heterocyclic radical;

16) (C=O) _aO _bC ₃～C ₆Cycloalkyl-alkyl;

Wherein, described alkyl, aryl, thiazolinyl, alkynyl, cycloalkyl and the heterocyclic radical of listing above is optional to be selected from R by maximum 3 ₆Substituting group replace; Perhaps R ₄With R ₅And the atom that connects them forms the dicyclo that one 4～7 yuan monocycle or each ring are 4～7 yuan, and optionally in the formed ring contains one or 2～3 heteroatomss that are selected from N, O and S; Described monocycle or dicyclo are optional by one or more R that are selected from ₄Substituting group replace;

R ₆And R ₇Independently be selected from separately:

1)H；

2) O _bC ₁～C ₄Alkyl;

3) O _bAryl;

4) O _bC ₂～C ₄Thiazolinyl;

5) O _bC ₂～C ₄Alkynyl;

7) O _bC ₁～C ₃Perfluoroalkyl;

8) O _bC ₃～C ₆Cycloalkyl;

9) O _bHeterocyclic radical;

10) O _bC ₀～C ₃Alkylidene group-aryl;

11) O _bC ₀～C ₃The alkylidenyl-heterocyclic base;

12) O _bC ₃～C ₆Cycloalkyl-aryl;

13) C ₃～C ₆Cycloalkyl-heterocyclic radical;

14) C ₃～C ₆Cycloalkyl-alkyl.

Preferably, another embodiment of the application is formula II compound or its pharmacy acceptable salt or steric isomer:

A, B, Ar and R ₁～R ₃Definition and formula 1 in identical.

Another embodiment of the application is formula III compound or its pharmacy acceptable salt or steric isomer:

A, B, Ar and R ₁～R ₃Definition and formula 1 in identical.

Another embodiment of the application is formula IV compound or its pharmacy acceptable salt or steric isomer:

A, B, and R ₁～R ₃Definition and formula 1 in identical.

Another embodiment of the invention is formula V compound or its pharmacy acceptable salt or steric isomer:

A, B, and R ₁～R ₃Definition and formula 1 in identical.

Another object of the present invention provides a kind of medicinal compositions.

Described medicinal compositions is made up of above-mentioned described compound or its pharmacy acceptable salt or steric isomer and pharmaceutically acceptable carrier.

Another object of the present invention provides the application of above-claimed cpd.

Technical scheme is as follows:

The application in the medicine of preparation treatment or prophylaxis of tumours of above-claimed cpd and pharmacy acceptable salt thereof or steric isomer.

The application has also related to the above-claimed cpd that utilizes effective dose can be used for the treatment of histocyte lymphatic cancer, nonsmall-cell lung cancer, small cell lung cancer, adenocarcinoma of lung, lung squamous cancer, carcinoma of the pancreas, mammary cancer, prostate cancer, liver cancer, cancer of the stomach, colorectal carcinoma, the rectum cancer, ovarian cancer, palace stem cancer, the cancer of the brain, esophagus cancer, osteocarcinoma, carcinoma of testis, brain, reproductive system, lymphsystems such as melanoma, skin carcinoma, cell carcinoma, prostate cancer, nasopharyngeal carcinoma, leukemia, medium excess proliferative diseases such as Digestive tract, tumor in respiratory system.The application also related to independent use or with estrogenic agents present application or that just locating the development phase; androgen receptor modifier; the retinoid-like receptor modulators; cytotoxin/cytostatics; antiproliferative; protein transferase inhibitor; the HMG-CoA reductase inhibitor; the HIV kinases inhibitor; reverse transcriptase inhibitors; angiogenesis inhibitor; cell proliferation and the agent of existence signal suppressing; the medicine and the cell death inducer at the interference cell cycle outpost of the tax office; cytotoxic drug; the tyrosine protein inhibitor; the EGFR inhibitor; the VEGFR inhibitor; the serine/threonine protein inhibitor; the Bcr-Abl inhibitor; the c-Kit inhibitor; the Met inhibitor; the Raf inhibitor; mek inhibitor; the MMP inhibitor; topoisomerase enzyme inhibitor; the Histidine deacetylase inhibitor; proteasome inhibitor; the CDK inhibitor; the Bcl-2 family protein inhibitor, the MDM2 family protein inhibitor; the IAP family protein inhibitor; the STAT family protein inhibitor; the PI3K inhibitor; the AKT inhibitor; the integrin retarding agent; interferon-' alpha '; il-1 2; cox 2 inhibitor; p53; the p53 activator; VEGF antibody; medication combined medications such as EGF antibody increase its clinical effectiveness.

The invention provides a class new diaryl urea compound with formula I constitutional features and pharmacy acceptable salt or steric isomer, it can be used as the single-activity agent or is used for the treatment of the medicine of transition appreciation type diseases such as cancer in preparation with other activeconstituents laticiferous cell toxitherapy combined utilization, for clinical treatment treatment or prophylaxis of tumours provide new medicament selection.

Description of drawings

Fig. 1 is that explanation Compound D 147 can effectively suppress lung cell A549, L78, the synoptic diagram of the growth of GLC46 and GLC82;

Fig. 2 is the synoptic diagram that explanation Compound D 147 can effectively suppress the growth of kinds of tumor cells such as lung carcinoma cell, mammary cancer, liver cancer, colorectal carcinoma, prostate cancer, melanoma;

Fig. 3 is that explanation D147 suppresses MEK in A431, the phosphorylation of ERK, the synoptic diagram of blocking-up Ras-Raf-Mek-ErK signal path;

Fig. 4 is explanation D147 suppresses the phosphorylation of STAT3 in Du145 a synoptic diagram;

Fig. 5 is explanation D147 suppresses the expression of CyclinD3 and Caspase3 in HepG2 a synoptic diagram;

But Fig. 6 is the synoptic diagram of explanation D-147 oral absorption.

Embodiment

In the chemicals of the present invention, as any variable (R for example ₄, R ₅, R ₆, R ₇Deng) in any component, occur surpassing once, then its each definition that occurs is independent of other each definition that occurs.Equally, allow the combination of substituting group and variable, as long as this combination makes compound stable.The line that puts loop systems from substituting group under represents that the key of indication can be connected on any annular atoms that can replace.If loop systems is many rings, it means that this key only is connected on any suitable carbon atom of adjacent loops.Be appreciated that those of ordinary skills can select the substituting group of The compounds of this invention and substitution pattern and provide chemically stable and can be easy to the synthetic compound from the raw material that can obtain easily by the method for art technology and following proposition.Replace if substituting group self is exceeded a group, should understand these groups can be on the identical carbon atoms or on the different carbon atom, as long as make Stability Analysis of Structures.Phrase " optional replaced " by one or more substituting groups be considered to phrase " optional replaced " by at least one substituting group quite and in the case embodiment preferred will have 0-3 substituting group.

Term used herein " alkyl " and " alkylidene group " mean and comprise saturated fatty alkyl side chain and straight chain with particular carbon atom number.For example, " C ₁-C ₈Alkyl " in " C ₁-C ₈" definition comprise the group of arranging with straight or branched with 1,2,3,4,5,6,7 or 8 carbon atom.For example, " C ₁-C ₈Alkyl " specifically comprise methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group, hexyl, heptyl, octyl group etc.Term " cycloalkyl " refers to have the monocycle saturated fatty alkyl of particular carbon atom number.For example " cycloalkyl " comprises cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl etc.

" alkoxyl group " representative is by the cyclic or the acyclic alkyl of the carbon atom that indicates number of oxo bridge connection.Therefore " alkoxyl group " comprises the definition of abovementioned alkyl and cycloalkyl.

If the number of clear and definite carbon atom not, term " thiazolinyl " refers to straight chain, side chain or cyclic, contains the non-aromatic hydrocarbon base of 2-10 carbon atom and at least one carbon-to-carbon double bond.Carbon-to-carbon of preferred existence is two strong, and can have the most nearly 4 two being good for of nonaromatic carbon carbon.Therefore, " C ₂-C ₆Thiazolinyl " refer to have the thiazolinyl of 2-6 carbon atom.Thiazolinyl comprises vinyl, propenyl, butenyl, 2-methyl butene base and cyclohexenyl.If the straight chain of thiazolinyl, side chain or circular part can contain two keys and indicate the thiazolinyl that replaces then this part can be substituted.

Term " alkynyl " refers to straight chain, ripples or cyclic, contains 2-8 carbon atom and at least one carbon carbon triple-linked non-aromatic hydrocarbon base.Can have that the most nearly 3 carbon carbon three are strong.Therefore, " C ₂-C ₆Alkynyl " refer to have the alkynyl of 2-6 carbon atom.Alkynyl comprises ethynyl, proyl, butynyl, 3-methyl butynyl etc.If the straight chain of alkynyl, side chain or circular part can contain triple bond and indicate the alkynyl that replaces then this part can be substituted.

In some example, substituting group can define with the certain limit carbon atom number that comprises 0, for example (C ₀-C ₆) alkylidene group-aryl.If aryl is considered to phenyl, then this definition comprises phenyl self, also comprises-CH ₂Ph ,-CH ₂CH ₂Ph ,-CH (CH ₃) CH ₂CH (CH ₃) Ph etc.

" aryl " used herein is 7 atom bicyclic carbocyclic nearly in any stable monocycle of 7 atoms or each ring nearly in the finger ring, and wherein at least one ring is aromatic nucleus.The example of this aryl comprises phenyl, naphthyl, tetralyl, indanyl and xenyl.Aryl substituent be dicyclo and a ring be in the nonaromatic example, should understand through aromatic nucleus and connect.

7 atom bicyclic carbocyclic nearly in the stable monocycle of 7 atoms or each ring nearly in term used herein " heteroaryl " the representative ring, wherein at least one ring is for aromatic nucleus and contain 1-4 and be selected from O, the heteroatoms of N and S. the heteroaryl in this range of definition includes but not limited to: bifurcation pyridine base, carbazyl, cinnolines base quinoxalinyl, pyrazolyl (pyrrazolyl), indyl, the benzotriazole base, the base of muttering of barking, thienyl, benzothienyl, the benzo base of muttering of barking, quinolyl, isoquinolyl oxazolyl isoxazolyl, indyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, tetrahydroquinoline.For the definition of following heteroaryl, " heteroaryl " also is interpreted as and comprises any N-oxide derivative that contains the heteroaryl of nitrogen.The heteroaryl substituting group be dicyclo and to contain a ring be non-aromaticity or do not contain in the heteroatomic example, should understand the aromatic nucleus or connect of respectively hanging oneself through containing heteroatomic ring.

Used herein term " heterocycle " or " heterocyclic radical " are meant and contain 1-4 heteroatomic 5 yuan of-10 yuan of aromaticity or non-aromaticity heterocycle that is selected from O, N and S, and comprise bicyclic radicals. " heterocyclic radical " therefore comprises above mentioned heteroaryl, also comprises its dihydro and tetrahydro-analogue." heterocyclic radical " further example includes but not limited to: benzimidazolyl-; benzofuryl; benzopyranyl; the benzopyrazoles base; the benzotriazole base; benzothienyl benzoxazolyl; carbazyl; carbolinyl; the cinnolines base; furyl; imidazolyl; indolinyl; indyl; indolazinyl; indazolyl; the different benzo base of muttering of barking; pseudoindoyl; isoquinolyl; isothiazolyl isoxazolyl; how pyridyl oxadiazole base oxazolyl oxazoline isoxazoline; oxetanyl (oxetanyl); pyranyl; pyrazinyl; pyrazolyl; pyridazinyl; the pyridopyridine base; pyridyl; pyrimidyl; pyrryl; quinazolyl; quinolyl quinoxalinyl; THP trtrahydropyranyl; tetrazyl; the tetrazolo pyridyl; thiadiazolyl group; thiazolyl; thienyl; triazolyl; azetidinyl; 1; the 4-alkyl dioxin; azepan base (hexallydroazepinyl); piperazinyl; piperidyl; the pyridin-2-ones base; pyrrolidyl; morpholinyl; thio-morpholinyl (thiomorpholinyl); the dihydrobenzo imidazolyl; dihydro benzo furyl; the dihydrobenzo thienyl; Er hydrogen benzoxazolyl; the dihydrofuran base; the glyoxalidine base; indolinyl; the dihydro-isoxazole base; dihydro isothiazolyl Er Qing oxadiazole base dihydro-oxazole base; the dihydro pyrazinyl; the pyrazoline base; the dihydropyridine base; the dihydro-pyrimidin base; the pyrrolin base; the dihydroquinoline base; the dihydro tetrazyl; the thiodiazoline base; dihydro-thiazolyl; the dihydro-thiophene base; the dihydro triazolyl; the dihydro azetidinyl; the methylenedioxyphenyl formyl radical; tetrahydrofuran base and tetrahydro-thienyl, and N-oxide compound.The connection of heterocyclic substituent can realize by carbon atom or by heteroatoms.

In one embodiment, heterocycle is selected from 2-azatropylidene (it is tall and erect down to go up grass) ketone, benzimidazolyl-, 2 one diazepines (it is tall and erect down to go up grass) ketone, imidazolyl, 2-imidazolone, indyl, isoquinolyl, morpholinyl, piperidyl, piperazinyl, pyridyl, pyrrolidyl, 2-piperidone, 2-pyrimidone, 2-Pyrrolidone, quinolyl, tetrahydrofuran base, tetrahydro isoquinolyl and thienyl.

As understood by one of ordinary skill in the art, used herein " halogen " (" halo ") or " halogen " mean and comprise chlorine, fluorine, bromine and iodine.

Unless otherwise defined, alkyl, thiazolinyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic radical substituting group can be unsubstituted or replacement.For example, (C ₁-C ₆) alkyl can by one, two or three be selected from OH, oxo, halogen, alkoxyl group, dialkyl amido or heterocyclic radical for example the substituting group of morpholinyl, piperidyl etc. replace.In this case, be OH if substituting group is oxo and another, then comprise following in the definition :-(C=O) CH ₂CH (OH) CH ₃, (C=O) OH ,-CH ₂(OH) CH ₂CH (O) etc.

In some example, definition R ₆And R ₅Make it form 4-7 unit monocycle jointly or each ring be the bicyclic heterocycle of 4-7 unit with the nitrogen that is connected them, and optional containing denitrogenate outer one or two and be selected from the other heteroatoms of N, O and S, described heterocycle is chosen wantonly by one or more R that are selected from ₅Substituting group replace.The heterocyclic example that can so form includes but not limited to following heterocycle, must keep that heterocycle is optional to be selected from R by one or more (and preferred one, two or three) firmly in mind ₅Substituting group replace:

R in one embodiment ₁Be selected from: hydrogen, fluorine, trifluoromethyl.

In one embodiment, R ₂Be selected from optional by hydrogen, alkyl, fluoro-alkyl and by R ₅Any alkyl that replaces.

In one embodiment, a is 0, and b is 1.

In one embodiment, a is 0, and b is 0.

The present invention includes the free form of formula I～V compound, also comprise its pharmacy acceptable salt and steric isomer.Some specific exemplary compounds are the protonated salt of aminated compounds herein.Term " free form " refers to the aminated compounds with salt-independent shape.The pharmaceutically-acceptable salts that is included not only comprises the exemplary salt of specific compound described herein, also comprises the typical pharmacy acceptable salt of all formula I compound free forms.Can use the free form of technical point known in the art from described compound specific salts.For example, can be by for example NaOH dilute aqueous soln, salt of wormwood dilute aqueous soln, weak ammonia and sodium bicarbonate dilute aqueous soln are handled this salt and made free form regeneration with suitable alkali dilute aqueous soln.Free form some physical properties for example in polar solvent on the solubleness with its separately salt form more or less distinguish, but for the invention this hydrochlorate of purpose and alkali salt aspect other pharmacy with its free form is suitable separately.

Can be by the conventional chemical method from the synthetic pharmacy acceptable salt of the present invention of the The compounds of this invention that contains basic moiety or acidic moiety.Usually, the salt by ion-exchange chromatography or the inorganic or organic acid prepared in reaction basic cpd in the combination of appropriate solvent or multiple solvent by free alkali and stoichiometric quantity or excessive required salt form.Similarly, by reacting the salt that forms acidic cpd with suitable inorganic or organic bases.

Therefore, the pharmacy acceptable salt of The compounds of this invention comprises by alkaline The compounds of this invention and conventional the non-toxic salt inorganic or The compounds of this invention that organic acid reaction forms.For example, conventional non-toxic salt comprises and derives from for example salt of hydrochloric acid, Hydrogen bromide, sulfuric acid, thionamic acid, phosphoric acid, nitric acid etc. of mineral acid, also comprise from organic acid for example acetate, propionic acid, succsinic acid, oxyacetic acid, stearic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, xitix, pounce on the salt of preparations such as acid, toxilic acid, hydroxymaleic acid, toluylic acid, L-glutamic acid, phenylformic acid, Whitfield's ointment, Sulphanilic Acid, 2-acetoxyl group-phenylformic acid, fumaric acid, toluenesulphonic acids, methylsulfonic acid, ethane disulfonic acid, oxalic acid, hydroxyethylsulfonic acid, trifluoroacetic acid.

If The compounds of this invention is a tart, then suitable " pharmacy acceptable salt " refers to comprise by pharmaceutically acceptable nontoxic alkali the salt of mineral alkali and organic bases preparation. the salt that derives from mineral alkali comprises aluminium salt, ammonium salt, calcium salt, mantoquita, molysite, ferrous salt, lithium salts, magnesium salts, manganese salt, manganous salt, sylvite, sodium salt, zinc salt etc.Preferred especially ammonium salt, calcium salt, magnesium salts, sylvite and sodium salt.Derive from the salt of pharmaceutically acceptable organic nontoxic alkali, described alkali comprises primary amine, the salt of secondary amine and tertiary amine, the amine that replaces comprises naturally occurring replacement amine, cyclic amine and deacidite be arginine for example, trimethyl-glycine, caffeine, choline, N, N '-dibenzyl-ethylenediamin, diethylamine, the 2-DEAE diethylaminoethanol, the 2-dimethylaminoethanol, monoethanolamine, thanomin, quadrol, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, Histidine, hydroxocobalamin, isopropylamine, Methionin, methyl glucoside amine, morpholine, piperazine, piperidines, the croak smack one's lips, the polyamines resin, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, tromethane etc.

Berg etc., " Pharmaceutical Salts, " J.Pharm.Sci. ' 1977:66:1-19 more detailed description the preparation of pharmacy acceptable salt mentioned above and other typical pharmacy acceptable salt.

Because the acidic moiety of deprotonation is for example completed base and be can be anionic in the compound under physiological condition, and this electric charge that has can be had for example former quantum balancing counteracting of quaternary nitrogen of cationic protonated or alkylating basic moiety by inside then, is potential inner salt or zwitter-ion so should note The compounds of this invention.

Except that standard method known or illustration in experimental arrangement in the literature, can adopt prepared in reaction The compounds of this invention as showing in the following scheme.Therefore, following illustrative approach is for illustrative purposes rather than is confined to listed compound or any specific substituting group.The substituting group number that shows in the scheme must not meet number used in the claim, and for clarity sake, shows that single substituting group is connected under the definition of formula I～V hereinbefore to allow on the compound of multi-substituent.

Scheme

As shown in option A among I～V compound can be that starting raw material passes through 6 step reactions by 2-trifluoromethyl-4-hydroxy phenylformic acid synthetic.

Option b has illustrated that with p-fluorophenol be starting raw material, synthetic compound I～V, totally 8 steps.

Option A

Option b

Diaryl urea compound that the present invention relates to and pharmacy acceptable salt thereof can effectively suppress the growth of kinds of tumor cells, and growth factor signal paths such as Ras-Raf-MEK-ERK are produced restraining effect.Be used to prepare antitumor drug.As skilled in the art to understand, related compound and the pharmacologically acceptable salts thereof of the application is used for excess proliferative diseases such as the preparation treatment mankind and other mammiferous tumour.

In one embodiment, the application provides compound and excess proliferative disease or the symptoms such as pharmacologically acceptable salts treatment people or other mammal tumor that a kind of utilization has formula I～V.

In one embodiment, designed compound and the pharmacologically acceptable salts thereof of the application can be used for the treatment of or control excess proliferative diseases such as histocyte lymphatic cancer, nonsmall-cell lung cancer, small cell lung cancer, adenocarcinoma of lung, lung squamous cancer, carcinoma of the pancreas, mammary cancer, prostate cancer, liver cancer, skin carcinoma, cell carcinoma, prostate cancer, nasopharyngeal carcinoma, leukemia.

In one embodiment; compound that the application is designed and pharmacologically acceptable salts thereof can with estrogenic agents present application or that just locating the development phase; androgen receptor modifier; the retinoid-like receptor modulators; cytotoxin/cytostatics; antiproliferative; protein transferase inhibitor; the HMG-CoA reductase inhibitor; the HIV kinases inhibitor; reverse transcriptase inhibitors; angiogenesis inhibitor; cell proliferation and the agent of existence signal suppressing; the medicine and the cell death inducer at the interference cell cycle outpost of the tax office; cytotoxic drug; the tyrosine protein inhibitor; the EGFR inhibitor; the VEGFR inhibitor; the serine/threonine protein inhibitor; the Bcr-Abl inhibitor; the c-Kit inhibitor; the Met inhibitor; the Raf inhibitor; mek inhibitor; the MMP inhibitor; topoisomerase enzyme inhibitor; the Histidine deacetylase inhibitor; proteasome inhibitor; the CDK inhibitor; the Bcl-2 family protein inhibitor, the MDM2 family protein inhibitor; the IAP family protein inhibitor; the STAT family protein inhibitor; the PI3K inhibitor; the AKT inhibitor; the integrin retarding agent; interferon-' alpha '; il-1 2; cox 2 inhibitor; p53; the p53 activator; VEGF antibody; medication combined medications such as EGF antibody increase its clinical effectiveness.

Compound that the application is related and pharmacologically acceptable salts thereof can be used for the treatment of following disease and following other disease of not listing according to following method:

1) a kind of utilization comprises the application's method related, that have the formula I～compound of V structure and the medicinal compositions of pharmacologically acceptable salts treatment people or other mammiferous mammary cancer.Including, but not limited to aggressive duct carcinoma, aggressive lobular carcinoma, DCIS be lobular carcinoma originally.

2) a kind of utilization comprise the application related, have a method of the formula I～compound of V structure and the medicinal compositions of pharmacologically acceptable salts thereof treatment people or other mammiferous respiratory cancer.Including, but not limited to Xiao Xibao ﹠amp; Nonsmall-cell lung cancer and bronchial adenoma and pleura pulmonary blastoma.

3) a kind of utilization comprises the application's method related, that have the formula I～compound of V structure and the medicinal compositions of pharmacologically acceptable salts treatment people or other mammiferous cancer of the brain.Including, but not limited to brain stem and neurospongioma, cerebellum and big cerebral astrocytoma, ependymoma and neuroderm and pine nut knurl body now.

4) a kind of utilization comprises the application's method related, that have the formula I～compound of V structure and the medicinal compositions of pharmacologically acceptable salts thereof treatment people or other mammiferous hero, female reproductive organ's tumour.The tumour of male reproductive organ includes but not limited to prostate gland and carcinoma of testis.Female reproductive organ's tumour includes but not limited to carcinoma of endometrium, cervical cancer, ovarian cancer, carcinoma of vagina and carcinoma vulvae and intrauterine knurl.

5) a kind of utilization comprises the application's method related, that have the formula I～compound of V structure and the medicinal compositions of pharmacologically acceptable salts treatment people or other mammiferous gastral tumour.Include but not limited to anus cancer, colorectal carcinoma, colon straight way cancer, esophagus cancer, cancer of the stomach, the carcinoma of the pancreas rectum cancer, carcinoma of small intestine or glandula cancer.

6) a kind of utilization comprises the application's method related, that have the tumour of the formula I～compound of V structure and the medicinal compositions of pharmacologically acceptable salts treatment people or other mammiferous urethra.Include but not limited to bladder cancer, penile cancer, kidney, carcinoma of renal pelvis, carcinoma of ureter or urethral carcinoma.

7) a kind of utilization comprises the application's method related, that have the formula I～compound of V structure and the medicinal compositions of pharmacologically acceptable salts treatment people or other mammiferous cancer eye.Include but not limited to intraocular melanoma and retinocytoma.

8) plant utilization and comprise the application's method related, that have the formula I～compound of V structure and the medicinal compositions of pharmacologically acceptable salts treatment people or other Mammals liver cancer.Include but not limited to hepatoma (having or do not have the stem cell cancer that fiberboard changes) ÷ cholangiocarcinoma (stones in intrahepatic bile duct cancer) and blended liver cell property cholangiocarcinoma.

9) plant utilization and comprise the application's method related, that have the formula I～compound of V structure and the medicinal compositions of pharmacologically acceptable salts treatment people or other mammal skin cancer.Include but not limited to squamous cell carcinoma, Kaposi, malignant melanoma, Merck Schwann Cells skin carcinoma and non-melanoma cells cancer.

10) plant utilization and comprise the application's method related, that have the formula I～compound of V structure and the medicinal compositions of pharmacologically acceptable salts treatment people or other Mammals head and neck cancer.Include but not limited to larynx, hypopharynx, nasopharynx, oropharynx cancer and lip and oral carcinoma.

11) plant to utilize comprise the application related, have the formula I～compound of V structure and the medicinal compositions of pharmacologically acceptable salts treatment people or a lymphadenomatous method of other Mammals.Include but not limited to AIDS be correlated with lymphoma, non Hodgkin lymphoma, cutaneous T cell lymphoma, He Jiesen disease and central nervous system lymphoma.

12) plant utilization and comprise the application's method related, that have the formula I～compound of V structure and the medicinal compositions of pharmacologically acceptable salts treatment people or other Mammals sarcoma.Include but not limited to that soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, woods are sarcoma and rhabdosarcoma.

13) plant to utilize comprise the application related, have the formula I～compound of V structure and a medicine of pharmacologically acceptable salts thereof

With combination treatment people or the leukemic method of other Mammals.Include but not limited to acute myeloid leukemia,

Acute woods chronic myeloid leukemia, chronic lymphocyte leukemia, chronic lymphocytic leukemia and hairy cell leukemia.Take mode and dosage range

According to the standard pharmaceutical technology, The compounds of this invention can give Mammals, preferred people with pharmaceutically acceptable acceptor, auxiliary material or thinner combination separately or in medicinal compositions.Can be oral or subcutaneous, intramuscular injection, intraperitoneal, vein, rectum and part, eyes, lung, nasal cavity, parenteral give compound.

In one embodiment, when utilizing formula I～V compounds for treating or patient such as control cancer etc., the taking dose scope is in oral 0.1～500 mg/day/kg body weight.Suitable administering mode is a single dose administration or every day secondary, three times, four inferior multiple dosings or utilize slow release method administration every day.For multiple large mammal, its preferred dosage scope is 0.1～1500 mg/day/kg body weight, is preferable over 0.5～100 mg/day/kg body weight.For mean body weight is 70 kilograms patient, and its, dosage was 1～500 milligram every day.For some property invigorated compounds especially, adult patient's dosage every day can hang down and reach 0.1 mg/day.

Formulation

This medicinal compositions that contains activeconstituents can be made into and is suitable for the oral administration form, but for example tablet, lozenge, lozenge, water or oil suspension dispersion powder or granule, emulsion, hard capsule or soft capsule or syrup or elixir.Can be according to the composition of any currently known methods preparation expection orally give in the medicinal compositions manufacturing field, and for pharmaceutically purified and agreeable to the taste preparation are provided, this composition can contain one or more medicaments that is selected from sweeting agent, seasonings, tinting material and sanitas.Tablet contains activeconstituents and the nontoxic acceptable accessories that is applicable to the manufacturing tablet.These auxiliary materials for example can be, and inert diluent is lime carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate for example; Granulation agent (granulating) and disintegrating agent be Microcrystalline Cellulose, cross-linked carboxymethyl cellulose sodium (sodium crosscarmellose), W-Gum or Lalgine for example; Tackiness agent is starch, gelatin, polyvinylpyrrolidone or gum arabic for example; Reach lubricant for example Magnesium Stearate, stearic acid or talcum powder.Thereby tablet is dressing or cover the undesirable taste of medicine or prolong in gi tract disintegration and absorption and thereby provide the drug effect of last much longer by the known technology dressing not.For example, the raw material that can adopt water-soluble taste masking is hydroxyl Nei Ji-methylcellulose gum or hydroxypropylcellulose for example, or adopts time-delay raw material for example ethyl cellulose, cellulose acetate butyrate.Tabules can be 0.1 milligram/sheet, 0.2 milligram/sheet, 0.25 milligram/sheet, 0.5 milligram/sheet, and 1 milligram/sheet, 2 milligrams/sheet, 5 milligrams/sheet, 10 milligrams/sheet, 25 milligrams/sheet, 50 milligrams/sheet, 100 milligrams/sheet, 250 milligrams/sheet of and.Other formulation such as capsule etc. can be done similar dosage reference.

The preparation that orally uses also can be made into hard-gelatin capsules, and wherein activeconstituents is mixed in inert solid diluent, for example in lime carbonate, calcium phosphate or the white bole; Or make Gelseal, wherein activeconstituents is mixed in water-soluble carrier for example in macrogol or oil medium such as peanut oil, whiteruss or the sweet oil.

Aqueous suspension contains and the auxiliary material blended active material that is suitable for making aqueous suspension.This auxiliary material is for example Xylo-Mucine, methylcellulose gum, Vltra tears, sodium alginate, polyvinylpyrrolidone, tragakanta and a gum arabic of suspending agent; Dispersion agent or wetting agent can be for example Yelkin TTS of naturally occurring phosphatide, or the condensation product of alkylene oxide and lipid acid polyoxyethylene stearic acid ester for example, or the condensation product of alkylene oxide and long chain aliphatic alcohol 17 carbon vinyloxy group hexadecanols (heptadecaethyleneoxycetanol) for example, or alkylene oxide and derive from lipid acid and the condensation product of the partial ester of hexitol polyoxyethylene sorbitol monooleate for example, or alkylene oxide and derive from lipid acid and the condensation product of the partial ester of hexitan polyethylene dehydrated sorbitol mono-fatty acid ester for example.This aqueous suspension also can contain one or more sanitass for example ethyl p-hydroxybenzoate or P-hydroxybenzoic acid n-propyl ester, one or more tinting materials, and one or more seasoningss and one or more sweeting agents be sucrose, asccharin or aspartame for example.

Can be by activeconstituents being suspended in vegetables oil for example in peanut oil, sweet oil, sesame oil or the Oleum Cocois, or mineral oil for example prepares oil-based suspension in the whiteruss.This oil-based suspension can contain thickening material for example beeswax, solid paraffin or hexadecanol.Can add sweeting agent mentioned above and seasonings and be fit to oral preparation to provide.Can for example Butylated Hydroxyanisole (butylated hydroxyanisol) or alpha-tocopherol store these compositions by adding antioxidant.

But dispersion powder or granule are suitable for preparing aqueous suspension and providing and dispersion agent or wetting agent, suspending agent and one or more sanitas blended activeconstituentss by adding entry.Suitable dispersion agent or wetting agent and suspending agent be the example explanation by above relating to.Also can there be other auxiliary materials for example sweeting agent, seasonings and tinting material.These compositions can by add antioxidant for example xitix store.

The present composition also can be made into the form of water external emulsion.Oil phase can be vegetables oil for example sweet oil or peanut oil, or mineral oil for example whiteruss or its mixture.Suitable emulsifying agent can be for example soybean lecithin of naturally occurring phosphatide, reach the ester class or derive from lipid acid and the partial ester of hexitan mixture, the condensation product of for example sorbitan monooleate, and described partial ester and alkylene oxide is the polyoxyethylene sorbitan monooleate for example.This emulsion also can contain sweeting agent, seasonings, sanitas and antioxidant.

For example glycerine, propylene glycol, sorbyl alcohol or sucrose prepare syrup and elixir can to use sweeting agent.This preparation also can contain wetting agent, sanitas, seasonings and tinting material and antioxidant.

Medicinal compositions can be made into the aqueous solution of sterile injectable.In acceptable carrier and solvent, can adopt water, ringer's solution and isotonic sodium chlorrde solution.

This sterile injectable preparation also can be made into activeconstituents and is dissolved in sterile injectable oil-in-water microemulsion in the oil phase.For example, at first activeconstituents is dissolved in the mixture of soya-bean oil and Yelkin TTS, then oil solution is put into the mixture of water and glycerine and handled and make microemulsion.

This injectable solution or microemulsion can pass through local bolus injection (local bolus injection) and import in patient's blood flow.Selectable, in this way give the constant circulation concentration that solution or micro emulsion help keeping compound.For keeping this constant density, can utilize the continuous intravenous injection delivery apparatus.An embodiment of this device is DeltecCADD-PLUS ^TMModel 5400 intravenous injection pumps.

This medicinal compositions can be made into sterile injectable solution or the oily suspension form that is used for intramuscular or subcutaneous administration.Can use the dispersion agent above mention or wetting agent and suspending agent to prepare this suspension according to known technology.Sterile injectable preparation also can be made into sterile injectable solution or the suspension in nontoxic parenteral acceptable diluent or solvent, for example as the solution in 1,3 butylene glycol.In addition, the conventional fixed oil that adopts is as solvent or suspension medium.For this purpose, can adopt any non-irritating fixed oil to comprise synthetic monoglyceride or triglyceride.In addition, find in injectable formulation, to use for example oleic acid of lipid acid.

Formula I～V compound also can rectal administration the suppository form administration.Can prepare these compositions by hybrid medicine and suitable nonirritant auxiliary material, thus its be at normal temperatures solid but under rectal temperature for liquid and therefore in rectum fusing discharge medicine.This raw material comprises the mixture and the cithrol of theobroma oil, glycogelatin, hydrogenant vegetables oil, various molecular weight polyisoprene ethylene glycol.

Use for the part, adopt emulsifiable paste, ointment, gelifying agent, solution or the suspension etc. (be this application purpose, topical application comprises mouth wass and mouth wash shua) that contain formula I～V compound.

The compounds of this invention can be in suitable nose the part of carrier and delivery apparatus use with nose in form administration, or use the form administration of the skin patch that those of ordinary skills know through skin.After the administration of transdermal delivery system form, the dosage of whole dosage regimen is naturally than intermittently administration is continuous.The compounds of this invention also can be sent by suppository, and the matrix of employing is the mixture and the cithrol of theobroma oil, glycogelatin, hydrogenant vegetables oil, various molecular weight polyisoprene ethylene glycol for example.

If give the experimenter The compounds of this invention, normally by the doctor that prescribes usually according to each patient's age, body weight, sex and reaction, and the corresponding change dosage of patient's serious symptom and determine per daily dose.

Drug metabolite and prodrug

The compound that the application is related and the meta-bolites of pharmacologically acceptable salts thereof, and the prodrug that can change the structure of related compound of the application and pharmacologically acceptable salts thereof in vivo into are also contained in the application's the claim.

Drug combination

Formula I～V compound can or improve the other medicines coupling of similar symptom to known treatment.During Combined Preparation, the original Gei Yaofangshi ﹠amp of medicine; Dosage remains unchanged, and simultaneously or take formula I～V compound subsequently.When formula I～V compound and other one or more medicines were taken simultaneously, preferred use contained the medicinal compositions of one or more known drugs and formula I～V compound simultaneously.Drug combination is also included within the eclipsed time period and takes formula I～V compound and other one or more known drugs.When formula I compound and other one or more medicines carried out drug combination, the dosage the when dosage of formula I～V compound or known drug may be than their independent medications was lower.

Can carry out the medicine of drug combination or activeconstituents with formula I～V compound comprises but is not limited to:

Estrogenic agents; androgen receptor modifier; the retinoid-like receptor modulators; cytotoxin/cytostatics; antiproliferative; protein transferase inhibitor; the HMG-CoA reductase inhibitor; the HIV kinases inhibitor; reverse transcriptase inhibitors; angiogenesis inhibitor; cell proliferation and the agent of existence signal suppressing; the medicine and the cell death inducer at the interference cell cycle outpost of the tax office; cytotoxic drug; the tyrosine protein inhibitor; the EGFR inhibitor; the VEGFR inhibitor; the serine/threonine protein inhibitor; the Bcr-Abl inhibitor; the c-Kit inhibitor; the Met inhibitor; the Raf inhibitor; mek inhibitor; the MMP inhibitor; topoisomerase enzyme inhibitor; the Histidine deacetylase inhibitor; proteasome inhibitor; the CDK inhibitor; the Bcl-2 family protein inhibitor, the MDM2 family protein inhibitor; the IAP family protein inhibitor; the STAT family protein inhibitor; the PI3K inhibitor; the AKT inhibitor; the integrin retarding agent; interferon-' alpha '; il-1 2; cox 2 inhibitor; p53; the p53 activator; VEGF antibody; EGF antibody etc.

In one embodiment, can carry out the medicine of drug combination or activeconstituents with formula I～V compound comprises but is not limited to: rIL-2, clinic effect of alendronate, Interferon, rabbit, Ah Qu Nuoying, allopurinol, epidermal growth factor, the Palonosetron hydrochloride, altretamine, amino glutethimide, amifostine, amrubicin, SN-11841, anastrozole, dolasetron, aranesp, arglabin, white arsenic, Arnold is new, U-18496, azathioprine, bacille Calmette-Guerin vaccine or tice bacille Calmette-Guerin vaccine, bestatin, betamethasone acetate, betamethasone sodium phosphate preparation, bexarotene, bleomycin sulfate, broxuridine, bortezomib, busulfan, thyrocalcitonin, A Laizuo monoclonal antibody injection, capecitabine, carboplatin, Kang Shide, cefesone, celmoleukin, daunorubicin, Chlorambucil, cis-platinum, CldAdo, CldAdo, chlorine is bent phosphoric acid, endoxan, arabinose born of the same parents former times, Dacarbazine, dactinomycin, daunorubicin liposome, dexamethasone, Wymesone, Estradiol Valerate, denileukin diftitox, Di Bomei, deslorelin, ground La Zuosheng, stilboestrol, Fluconazole, many Xi Taqi, doxifluridine, Zorubicin, dronabinol, admire-the 166-chitosan complexes, eligard, rasburicase, epirubicin hydrochloride, aprepitant, pidorubicin, Epoetin Alfa, erythropoietin, according to platinum, Ergamisole, estradiol preparation, 17-, estramustine phosphate sodium, ethinylestradiol, amifostine, hydroxyl phosphoric acid, Etopophos, etoposide, fadrozole, the tamoxifen preparation, filgrastim, Fei Nasi carries, Fei Leisi replaces, floxuridine, fluconazole, fludarabine, the 5-fluorodeoxyuridine monophosphate, 5 FU 5 fluorouracil, Fluoxymesterone, flutamide, formestane, 1-β-D-arabinofuranosylcytosine-5 '-stearyl phosphoric acid ester, fotemustine, fulvestrant, gamma-globulin, gemcitabine, WAY-CMA 676, imatinib mesylate, Gliadel, goserelin, Graniseeron Hydrochloride, histrelin, new with U.S., hydrocortisone, erythro-hydroxyl nonyl VITAMIN B4, hydroxyurea, replace not monoclonal antibody of smooth different shellfish, idarubicin, ifosfamide, interferon alpha, interferon-' alpha ' 2, interferon A, interferon B, interferon alfa-n1, Alferon N, interferon beta, interferon-gamma-1a, interleukin II, intron A, Iressa, Rinotecan, Kytril, the sulfuric acid lentinan, letrozole, formyl tetrahydrofolic acid, Leuprolide, leuprolide acetate, L-tetramisole, the levo leucovorin calcium salt, levothyroxine sodium, levothyroxine sodium preparation, lomustine, lonidamine, dronabinol, mustargen, mecobalamin, medroxyprogesterone acetate, Magace, melphalan, esterified estriol, 6-coloured glaze base purine, mesna, methotrexate, the amino-laevulic acid methyl esters, miltefosine, Minomycin, ametycin, mitotane, rice holder green onion quinone, Win-24540, the citric acid Evacet, S 254, the Pegylation filgrastim, oprelvekin, neupogen, Nilutamide, tamoxifen, NSC-631570, recombination human interleukins-11-β, Sostatin, Ondansetron Hydrochloride, the dehydrohydro-cortisone oral solution, oxaliplatin, taxol, Pediapred, pegaspargase, Pai Luoxin, pentostatin, Picibanil, the hydrochloric acid pilocarpine, adjoin the gentle star that compares, Plicamycin, porfimer sodium, prednimustine, prednisolone steaglate, prednisone, premarin, the third kappa navel, the epoetin, Raltitrexed, Libiee, etidronic acid rhenium-186, Mabthera, Redoxon-A, romurtide, Salagen, Sostatin, sargramostim, semustine, sizofiran, sobuzoxane, bluff the sodium prednisolone, Paphos acid, stem-cell therapy, streptozocin, Metastron, levothyroxine sodium, tamoxifen, YM-617, Ta Suonaming, tastolactone, taxotere, Ro 23-6019, Temozolomide, teniposide, testosterone propionate, Synrotabs, Tioguanine, thio-tepa, thyrotropic hormone, tiludronic acid, topotecan, toremifene, tositumomab, Herceptin, Treosulfan, tretinoin, the Rheumatrex tablet, the trimethylammonium melamine, trimetrexate, the acetate triptorelin, triptorelin pamoate, Youfuding, uridine, valrubicin, vesnarinone, vinealeucoblastine(VLB), vincristine(VCR), vindesine, vinorelbine, virulizin, ADR-529, Zinostatin stimalamer, Zudan, the taxol protein stabilization formulations, acolbifene, Interferon, rabbit r-lb, affinitak, aminopterin-induced syndrome, arzoxifene, asoprisnil, Atamestane, atrasentan, BAY 43-9006, Avastin, CCI-779, CDC-501, celecoxib, Cetuximab, crisnatol, cyproterone acetate, Decitabine, DN-101, Zorubicin-MTC, dSLIM, the dutasteride, edotecarin, eflornithine, Exatecan, fenretinide, histamine dihydrochloric acid, the histrelin hydrogel implant, holmium-166DOTMP, Ibandronic acid, interferon-gamma, intron-PEG, ixabepilone, keyhole shape hemocyanin, L-651582, lanretide, Lasofoxifene, libra, lonafamib, Miproxifene, minot is bent acid esters, MS-209, liposome MTP-PE, MX-6, nafarelin, Nemorubicin, Neovastat, Nola Qu Te, Ao Limosen, onco-TCS, osidem, taxol polyglutamic acid esters, pamidronate disodium injection, PN-401, QS-21, overstate the West, R-1549, raloxifene, leopard moth enzyme, 13-is along tretinoin, husky platinum, seocalcitol, T-138067, tarceva, the docosahexenoic acid taxol, thymosin, loud, high-pitched sound azoles furan woods, tipifarnib, Win-59075, TLK-286, toremifene, trans MID-lo7R, valspodar, vapreotide, vatalanib, Visudyne, Vinflunine, Z-100 and azoles come unicorn acid or their combination.

The purpose of the embodiment that is provided is to help further to understand the present invention.Adopting specific raw material, species is for describing the present invention rather than limiting its reasonable range.

Embodiment 1

Compound (1 * 10 with different concns ^-8～1 * 10 ^-5M) handle A549 (adenocarcinoma of lung), L-78 (lung squamous cancer), Du145 (prostate cancer), KB (mouth epithelial cells cancer), OS-RC-2 (kidney), colorectal carcinoma tumour cells such as (HT-29) respectively, MTT after 72 hours, hatched again 4 hours, and measured its light absorption value with microplate reader then at 570nm.Found that compound treatment can obviously reduce the absorption of various cells to MTT, illustrate that compound can significantly suppress the propagation of these cells, inhibiting rate becomes positive correlation with drug level.According to the growth-inhibiting effect of compound to these tumour cells, we calculate the half-inhibition concentration (IC of compound to the tumour cell cell ₅₀) be 1 * 10 ^-8～1 * 10 ^-5M.Referring to Fig. 1, Fig. 2 and table 1.(compound used therefor is respectively the prepared compound of embodiment 3-36, represents with the embodiment label in table 1).

The IC that table 1. part diaryl urea compound suppresses different growth of tumour cell ₅₀(μ M)

Embodiment compiles

A431 (epidermal carcinoma)

A549 (lung cancer)

HT-2 9 (colons

Du14 5 (prostate glands

KB (oral carcinoma)

L-78 (lung cancer)

MCF-7 (mammary cancer)

OS-RC-2 (kidney)

Hela (cervical cancer)

PG (lung cancer)

Number			Cancer)	Cancer)
Number			Cancer)	Cancer)							3	4.2	2.0	8.4	2.5	4.1	8.3	6.2	3.0	6.7	3.2
4		12.5	28.4	17.1	＞50		＞50		11.6	16.5	3	4.2	2.0	8.4	2.5	4.1	8.3	6.2	3.0	6.7	3.2
4		12.5	28.4	17.1	＞50		＞50		11.6	16.5	5		＞50	18.3	27.3	＞50	28.1	＞50		13	10.6
6		＞50	14	51	＞50		38.3		18.2	10.5	5		＞50	18.3	27.3	＞50	28.1	＞50		13	10.6
6		＞50	14	51	＞50		38.3		18.2	10.5	7		11.6	14.4	11.9	10.6	16	11		17	10.8
8		14.4	12.5	12.6	21.2	12.8	12.4		39.1	16.1	7		11.6	14.4	11.9	10.6	16	11		17	10.8
8		14.4	12.5	12.6	21.2	12.8	12.4		39.1	16.1	9	＞50	＞50	＞50	＞50	＞50	＞50	＞50		＞50	12.9
10		11.2	＞50	17.3	＞50	＞50	15.3		＞50	11	9	＞50	＞50	＞50	＞50	＞50	＞50	＞50		＞50	12.9
10		11.2	＞50	17.3	＞50	＞50	15.3		＞50	11	11		＞50	＞50	＞50	＞50	＞50	＞50	＞50	13.8	11.3
12		24.5	＞50	13.6	12.6	47.4	12.5			74	11		＞50	＞50	＞50	＞50	＞50	＞50	＞50	13.8	11.3
12		24.5	＞50	13.6	12.6	47.4	12.5			74	13		＞50	＞50	19.8	40	25.1	16.3		24.8
14		12.5	9.5	2.8	4.7	8.0	6.3		5.2		13		＞50	＞50	19.8	40	25.1	16.3		24.8
14		12.5	9.5	2.8	4.7	8.0	6.3		5.2		15	51			40		42		59
16				31		43					15	51			40		42		59
16				31		43					17	25	＞50	24.5	11	10	0.9	＞50	2.5
18		8		10.9	9.3	8					17	25	＞50	24.5	11	10	0.9	＞50	2.5
18		8		10.9	9.3	8					19		33.8	9.7	11.2	28.7	19.5	44.5	39.8	26.7
20		33.9	19.8	15	19.7	16.8	23.1	18.9	17.9		19		33.8	9.7	11.2	28.7	19.5	44.5	39.8	26.7
20		33.9	19.8	15	19.7	16.8	23.1	18.9	17.9		21		17.6	47.7	16.1	31.5		37.7
22		＞50	＞50	＞50				＞50	12		21		17.6	47.7	16.1	31.5		37.7
22		＞50	＞50	＞50				＞50	12		23		＞50	＞50	13.7				40	51
24		＞50	18	2.8				7.3	17.2		23		＞50	＞50	13.7				40	51
24		＞50	18	2.8				7.3	17.2		25	43			＞50		67	＞50	＞50	＞50
26	＞50			38		43					25	43			＞50		67	＞50	＞50	＞50
26	＞50			38		43					27	78	8.5		8.7	3.1	3.2		0.8
28	35	＞50		＞50		46		6	64		27	78	8.5		8.7	3.1	3.2		0.8
28	35	＞50		＞50		46		6	64		29		3.3	7.7	2.8				9.5
31		9.1	4.8		1.8			6.2			29		3.3	7.7	2.8				9.5

33	＞50	10.6	1.8				8.9	12.6
33	＞50	10.6	1.8				8.9	12.6		34	28.5	10.9	5.4				15.9
35	2.7	9.3	3.0	8.2	7.	6		10.6	9.3	34	28.5	10.9	5.4				15.9
35	2.7	9.3	3.0	8.2	7.	6		10.6	9.3	36	4.5			5.5	7.3	4.0

Embodiment 2

Tumour cell A431 or HepG2 cultivate in six orifice plates by the standard cell lines cultural method, and used substratum is that ATCC recommends to use substratum, contains 10%FCS.

When cell grows to 80-90%, change substratum into corresponding serum free medium, after serum starvation 16-24 hour, add the D147 or the solvent contrast of different concns in the substratum.After the drug treating two hours, adding EGF (final concentration is 100ng/ml) in substratum handled after 30 minutes, substratum is removed in suction, 1XPBS (pH7.2) with 4 ℃ of precoolings cleans, the 1XSDS sample buffer lysing cell that in culture hole, adds 0.1ml, sweep cell with cell rapidly, the collecting cell lysate is in the Eppendorf pipe of 1ml, the pair cell lysate carries out supersound process to reduce the viscosity of lysate, subsequently cell pyrolysis liquid is boiled 5 minutes at 95 ℃, makes the thorough sex change of albumen, put cold after, cell pyrolysis liquid is centrifugal, supernatant is transferred in another E ppenforf pipe, as cell sample liquid.30 μ l cell sample liquid separate through 12.5% SDS-polyacrylamide gel electrophoresis, and the albumen with separator well is transferred on the pvdf membrane through wet method through gel subsequently.After transfer finishes, film with the 1XTBST room temperature sealing that contains 5% skim-milk one hour, please be washed 3 times 5 minutes/time with 1XTBST, with anti-(MEK, pMEK, Erk, the pErK of film with suitable dilution, STAT3, pSTAT3, CyclinD3, CyclinE, CyclinB1, Caspase3, Caspase9, GAPDH) diluent applies and to educate, and room temperature or 4 ℃ spend the night, and film are cleaned 3 times with 1XTBST again, 5 minutes/time, subsequently film is hatched room temperature 1 hour with two anti-diluents of the HRP mark that suitably dilutes.Subsequently film is cleaned 3 times with 1XTBS, 5 minutes/time, press on the handbook of Apharmsham ECL PLUS DETECTION SYSTEM bonded albumen on the ECL detection method detection film then.Referring to Fig. 3,4,5.

1XSDS sample buffer: 62.5mM Tris-HCl (pH6.8), 2%w/v SDS, 10%glycerol, 50mM DTT, 0.01%bromophenol blue

1XTBST：50mM Tris-HCl，pH7.4，150mMNaCl，0.1％Tween-20.

One anti-diluent: 1XTBST contains 0.05%Tween-20,5%BSA.

Two anti-diluents: 1XTBS T, 5% skim-milk

Embodiment 3

4-(4-{3-[4-chloro-3-(trifluoromethyl) phenyl] urea groups } phenoxy group) N-methylbenzene-1-fluoro-2-benzamide (D147) (4-[4-[3-[4-Chloro-3-(trifluoromethyl) phenyl] ureido] phenoxy]-N-methylphenyl-1-fluoro-2-carboxamide) (D147)

Step 1.2-fluoro-5-hydroxy benzaldehyde (2-fluoro-5-hydroxybenzaldehyde)

Under the room temperature with 4-fluorophenol (4-fluorophenol, 5.6 gram, 50mmol), imidazoles (8.5 grams, 125mmol) be dissolved among the 50mLDMF, add altogether in three batches TBSCl (9.05 the gram, 60mmol), stirred overnight at room temperature, add water 100mL, petroleum ether extraction (50mLx3), organic phase washes twice with 10%NaOH solution, dry decompression revolve desolvate an oily matter.Gained oily matter is dissolved among the 60mL THF,-78 ℃ slowly drip tBuLi (37mL, 1.5mol/L, 55mmol), dropwise afterreaction 30min, drip DMF 4mL (50mmol), continue reaction 20min, THF solution (the 60mL that adds TBAF, 60mmol), with reaction mixture dislocation room temperature reaction 1h, THF is revolved in decompression, the NaOH solution 100mL that adds 1M, (2 * 30mL), water is transferred pH value to 5～6, extracted with diethyl ether (5 * 50mL) with concentrated hydrochloric acid to extracted with diethyl ether, drying, steaming are removed ether and are got product 5.6 grams (80%).

¹HNMR(400MHz，d-DMSO)，δ10.14(s，1H)，9.88(br，1H)；7.22～7.17(m，1H)，7.12～7.06(m，2H)

MS(ESI)，m/z：141(M ⁺+H ⁺).

Step 2.2-fluoro-5-(4-oil of mirbane oxygen ether) phenyl aldehyde (2-fluoro-5-(4-nitrophenoxy) benzaldehyde)

With above-mentioned gained compound (5.6 the gram, 40mmol), 4-nitro fluorine this (1-fluoro-4-nitrobenzene, 6.2 the gram, 44mmol), K ₂CO ₃(11.2 grams 80mmol) are mixed among the 50mL DMF, 80 ℃ of reaction 5h.Reaction finishes reaction mixture is poured in the 100 gram water, and ethyl acetate extraction is through column chromatography purification (sherwood oil: ethyl acetate=5: 1) get product 8.4 grams (faint yellow solid, 80%).

¹HNMR(400MHz，d-DMSO)，δ10.356(s，1H)，8.22(d，J＝7.2Hz，2H)；7.58～7.56(m，1H)，7.38～7.34(m，1H)，7.02(d，J＝7.2Hz，2H).

MS(ESI)，m/z：261(M ⁺+H ⁺).

Step 2.2-fluoro-5-(4-oil of mirbane oxygen ether) phenylformic acid (2-fluoro-5-(4-nitrophenoxy) benzoic acid)

Step 2 gained compound 2.61g (10mmol) is dissolved in the 30mL acetone, with 6.84g (50mmol) KH ₂PO ₄The 50mL aqueous solution and the H of 8mL 30% ₂O ₂Mix, be cooled to 5 ℃, drip 4.7g (50mmol) NaClO ₂The 4mL aqueous solution, after dropwising, continue reaction 5h, room temperature reaction 5h again.The most acetone of concentrating under reduced pressure, filtration drying get product (2.3 gram faint yellow solids, 83%).

¹HNMR(400MHz，d-DMSO)，δ8.26(d，J＝9.2Hz，2H)，7.59～7.57(m，1H)；7.52～7.43(m，2H)，7.18，(d，J＝9.2Hz，2H).

MS(ESI)，m/z：278(M ⁺+H ⁺).

Step 3.5-(the amino phenylate of 4-)-2-fluoro-N-methyl-benzamide (5-(4-aminophenoxy)-2-fluoro-N-methylbenzamide)

Add 20mL SOCl in step 2 gained compound 2.21g (8mmol) ₂And 0.1mL DMF, backflow 3h removes SOCl under reduced pressure ₂Raffinate dissolves with THF20mL, in 0 ℃ of aqueous methylamine solution that is added drop-wise to 4.1mL 30%, and 0 ℃ of reaction 3h, remove most THF under reduced pressure, filter, use the 30mL dissolve with methanol behind the gained solid drying, add 10% palladium carbon catalytic hydrogenation 5h, the TLC detection reaction is complete, filter, filtrate decompression revolve steam product (1.9g white solid, 75%).

¹HNMR(400MHz，d-DMSO)，δ8.20(br，1H)，7.26～7.21(m，1H)；7.03～7.00(m，2H)，6.78，(d，J＝8.8Hz，2H)，6.60，(d，J＝8.8Hz，2H)，5.02(s，2H).

MS(ESI)，m/z：261(M ⁺+H ⁺).

Step 4.4-(4-{3-[4-chloro-3-(trifluoromethyl) phenyl] urea groups } phenoxy group) N '-methylbenzene-1-fluoro-2-benzamide (4-[4-[3-[4-Chloro-3-(trifluoromethyl) phenyl] ureido] phenoxy]-N-methylphenyl-1-fluoro-2-carboxamide)

Triphosgene 99mg (0.3mmol) is dissolved in 5mL CH ₂Cl ₂In, in 0 ℃ of about 6ml CH that will dissolve 4-chloro-3-5-trifluoromethylaniline 195mg (1mmol) and triethylamine 606mg (6mmol) ₂Cl ₂Mixing solutions slowly be added drop-wise in the above-mentioned triphosgene solution, after dropwising, the reaction 1h; Gained compound in the step 3 is got 130mg (0.5mmol) be dissolved in 3ml CH ₂Cl ₂, being added drop-wise under the room temperature in the above-mentioned solution, stirring at room reaction 12h is spin-dried for reaction mixture, gets product III (120mg, 50%) through column chromatography.

¹HNMR(400MHz，d-DMSO)，δ9.15(s，1H)，8.87(s，1H)，8.24(br，1H)，8.11(s，1H)，7.66～7.60(m，2H)；7.49(d，J＝8.8Hz，2H)，7.29，(t，1H)，7.15～7.12(m，2H)，7.01(d，J＝8.8Hz，2H)，2.75(d，J＝4.4Hz，3H)，

MS(ESI)，m/z：482(M ⁺+H ⁺).

Embodiment 4

5-(4-(3-(4-chloro-phenyl-) urea) phenoxy group)-2-fluoro-N-methyl-benzamide

(5-(4-(3-(4-chlorophenyl)ureido)phenoxy)-2-fluoro-N-methylbenzamide)

Synthetic method such as embodiment 3.

¹HNMR(400MHz，d-DMSO)，δ8.80(s，1H)，8.74(s，1H)，8.26(br，1H)，7.47(d，J＝8.8Hz，4H)，7.33～7.27(m，3H)，7.14～7.11(m，2H)，7.01，(d，J＝9.2Hz，2H)，2.74(d，J＝4.4Hz，3H)，

MS(ESI)，m/z：414(M ⁺+H ⁺).

Embodiment 5

5-(4-(3-(2-chloro-phenyl-) urea) phenoxy group)-2-fluoro-N-methyl-benzamide

(5-(4-(3-(2-chloro-phenyl)ureido)phenoxy)-2-fluoro-N-methylbenzamide)

Synthetic method such as embodiment 3.

¹HNMR(400MHz，d-DMSO)，δ9.45(s，1H)，8.30(s，1H)，8.26(br，1H)，8.16(dd，J＝8.0，1.2Hz，1H)，7.49(d，J＝9.2Hz，2H)；7.45(dd，J＝8.0，1.2Hz，1H)，7.30，(t，2H)，7.15～7.13(m，2H)，7.03～7.00(m，3H)，2.74(d，J＝4.8Hz，3H)，

MS(ESI)，m/z：414(M ⁺+H ⁺).

Embodiment 6

5-(4-(3-(3-chloro-phenyl-) urea) phenoxy group)-2-fluoro-N-methyl-benzamide

(5-(4-(3-(3-chlorophenyl)ureido)phenoxy)-2-fluoro-N-methylbenzamide)

Synthetic method such as embodiment 3.

¹HNMR(400MHz，d-DMSO)，δ8.88(s，1H)，8.79(s，1H)，8.26(br，1H)，7.71(s，1H)，7.48(d，J＝8.8Hz，2H)；7.32～7.27(m，3H)，7.15～7.11，(m，2H)，7.02～6.99(m，3H)，2.74(d，J＝4.8Hz，3H)，

MS(ESI)，m/z：414(M ⁺+H ⁺).

Embodiment 7

5-(4-(3-(3-chloro-4 fluorophenyls) urea) phenoxy group)-2-fluoro-N-methyl-benzamide

(5-(4-(3-(3-chloro-4-fluorophenyl)ureido)phenoxy)-2-fluoro-N-methylbenzamide)

Synthetic method such as embodiment 3.

¹HNMR(400MHz，d-DMSO)，δ8.86(s，1H)，8.79(s，1H)，8.25(br，1H)，7.79(dd，J＝5.6，0.8Hz，1H)，7.48(d，J＝9.2Hz，2H)；7.33～7.27(m，3H)，7.14～7.11，(m，2H)，7.01(d，J＝8.0Hz 3H)，2.74(d，J＝4.8Hz，3H)，

MS(ESI)，m/z：432(M ⁺+H ⁺).

Embodiment 8

5-(4-(3-(3-fluorophenyl) urea) phenoxy group)-2-fluoro-N-methyl-benzamide

(5-(4-(3-(3-fluoro phenyl)ureido)phenoxy)-2-fluoro-N-methylbenzamide)

Synthetic method such as embodiment 3.

¹HNMR(400MHz，d-DMSO)，δ8.89(s，1H)，8.77(s，1H)，8.25(br，1H)，7.48(d，J＝8.8Hz，3H)，7.29(t，2H)，7.13(t，3H)，7.01，(d，J＝8.8Hz，2H)，6.77(t，1H)，2.74(d，J＝4.0Hz，3H)，

MS(ESI)，m/z：398(M ⁺+H ⁺).

Embodiment 9

5-(4-(3-(2-fluorophenyl) urea) phenoxy group)-2-fluoro-N-methyl-benzamide

(5-(4-(3-(2-fluoro phenyl)ureido)phenoxy)-2-fluoro-N-methylbenzamide)

Synthetic method such as embodiment 3.

¹HNMR(400MHz，d-DMSO)，δ9.09(s，1H)，8.52(s，1H)，8.24(br，1H)，8.14(t，1H)，7.50～7.48(t，2H)，7.29～7.21(m，2H)，7.15～7.12，(m，3H)，7.02(t，3H)，2.74(d，J＝1.6Hz，3H)，

MS(ESI)，m/z：398(M ⁺+H ⁺).

Embodiment 10

5-(4-(3-(4-fluorophenyl) urea) phenoxy group)-2-fluoro-N-methyl-benzamide

(5-(4-(3-(4-fluoro phenyl)ureido)phenoxy)-2-fluoro-N-methylbenzamide)

Synthetic method such as embodiment 3.

¹HNMR(400MHz，d-DMSO)，δ8.68(s，2H)，8.24(br，1H)，7.49～7.44(m，4H)，7.29(t，1H)，7.13～7.09(m，4H)，7.01～6.98，(m，2H)，2.74(t，3H)，

MS(ESI)，m/z：398(M ⁺+H ⁺).

Embodiment 11

5-(4-(3-(4-p-methoxy-phenyl) urea) phenoxy group)-2-fluoro-N-methyl-benzamide

(5-(4-(3-(4-methoxy phenyl)ureido)phenoxy)-2-fluoro-N-methylbenzamide)

Synthetic method such as embodiment 6.

¹HNMR(400MHz，d-DMSO)，δ8.60(s，1H)，8.44(s，1H)，8.24(br，1H)，7.46(d，J＝8.0Hz，2H)，7.36～7.26(M，3H)，7.13～7.10(m，2H)，6.98(d，J＝8.4Hz，2H)，6.86(d，J＝8.0Hz，2H)，3.71(s，3H)，2.74(d，J＝4.4Hz，3H)，

MS(ESI)，m/z：410(M ⁺+H ⁺).

Embodiment 12

5-(4-(3-(2-p-methoxy-phenyl) urea) phenoxy group)-2-fluoro-N-methyl-benzamide

(5-(4-(3-(2-methoxy phenyl)ureido)phenoxy)-2-fluoro-N-methylbenzamide)

Synthetic method such as embodiment 6.

¹HNMR(400MHz，d-DMSO)，δ9.36(s，1H)，8.26(br，1H)，8.21(s，1H)，8.13(d，J＝7.6Hz，1H)，7.49(d，J＝8.8Hz，2H)，7.30(t，1H)，7.13(t，2H)，6.96～6.87(m，5H)，3.88(s，3H)，2.74(d，J＝4.4Hz，3H)，

MS(ESI)，m/z：410(M ⁺+H ⁺).

Embodiment 13

5-(4-(3-(3-p-methoxy-phenyl) urea) phenoxy group)-2-fluoro-N-methyl-benzamide

(5-(4-(3-(3-methoxy phenyl)ureido)phenoxy)-2-fluoro-N-methylbenzamide)

Synthetic method such as embodiment 6.

¹HNMR(400MHz，d-DMSO)，δ8.68(d，2H)，8.25(br，1H)，7.47(d，J＝8.86Hz，2H)，7.31(t，1H)，7.19～7.11(m，4H)，6.99(d，J＝8.86Hz，2H)，6.94(d，J＝8.0Hz，1H)，6.55(dd，J＝8.4，2.0Hz，1H)，3.73(s，3H)，2.74(d，J＝4.4Hz，3H)，

MS(ESI)，m/z：410(M ⁺+H ⁺).

Embodiment 14

5-(5-(3-(4-chloro-3-trifluoromethyl) urea) pyridine-2-phenoxy group)-2-fluoro-N-methyl-benzamide

(5-(5-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)pyridin-2-yloxy)-2-fluoro-N-methylbenzamide)

Synthetic method such as embodiment 6.

¹HNMR(400MHz，d-DMSO)，δ9.26(s，1H)，8.94(s，1H)，8.25(br，1H)，8.19(d，J＝24Hz，1H)，8.08(d，J＝2.0Hz，1H)，8.01(dd，J＝8.8，2.4Hz，1H)，7.66～7.60(m，2H)，7.32～7.27(m，3H)，7.05(d，J＝8.8Hz，1H)，2.76(d，J＝4.4Hz，3H)，

MS(ESI)，m/z：483(M ⁺+H ⁺).

Embodiment 15

5-(4-(3-(4-(4-methylpiperazine-1-replaces) phenyl) urea) benzyloxy)-2-fluoro-N-methyl-benzamide

(2-fluoro-N-methyl-5-(4-(3-(4-(4-methylpiperazin-1-yl)phenyl)ureido)phenoxy)benzamide)

Synthetic method such as embodiment 6.

¹HNMR(400MHz，d-DMSO)，δ8.68(s，1H)，8.47(s，1H)，8.25(br，1H)，7.47(d，J＝8.8Hz，2H)，7.31～7.28(m，3H)，7.12(br，2H)，7.98(d，J＝8.4Hz，2H)，6.88(d，J＝8.4Hz，2H)，3.09(br，4H)，2.76(d，J＝4.0Hz，3H)，2.51(br，4H)，2.33(s，3H).

MS(ESI)，m/z：478(M ⁺+H ⁺).

Embodiment 16

5-(4-(3-(3-chloro-4-(3-(4-methylpiperazine-1-replaces) propoxy-) phenyl) urea groups) benzyloxy)-2-fluoro-N-methyl-benzamide

(5-(4-(3-(3-chloro-4-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)ureido)phenoxy)-2-fluoro-N-methylbenzamide)

Synthetic method such as embodiment 6.

¹HNMR(400MHz，d-DMSO)，δ8.74(s，1H)，8.68(s，1H)，8.25(br，1H)，7.64(s，1H)，7.47(d，J＝8.8Hz，2H)，7.29～7.22(m，2H)，7.14～7.06(m，2H)，6.98(d，J＝8.4Hz，2H)，4.01(t，2H)，2.74(d，J＝4.8，3H)，2.33(br，10H)，2.15(s，3H)，1.85(t，2H).

MS(ESI)，m/z：570(M ⁺+H ⁺).

Embodiment 17

5-(4-(3-(3-chloro-4-(4-fluorine benzyloxy) phenyl) urea groups) phenoxy group)-2-fluoro-N-methyl-benzamide

(5-(4-(3-(3-chloro-4-(4-fluorobenzyloxy)phenyl)ureido)phenoxy)-2-fluoro-N-methylbenzamide)

Synthetic method such as embodiment 6.

¹HNMR(400MHz，d-DMSO)，δ8.67(s，1H)，8.61(s，1H)，8.21(br，1H)，7.67(s，1H)，7.52～7.46(m，4H)，7.31～7.11(m，7H)，7.00(d，J＝8.8Hz，2H)，5.13(s，2H)，2.74(d，J＝4.4，3H).

MS(ESI)，m/z：538(M ⁺+H ⁺).

Embodiment 18

5-(4-(3-(4-chloro-3-(chloromethyl) phenyl) urea groups) phenoxy group)-2-fluoro-N-methyl-benzamide

(5-(4-(3-(4-chloro-3-(chloromethyl)phenyl)ureido)phenoxy)-2-fluoro-N-methylbenzamide)

Synthetic method such as embodiment 6.

¹HNMR(400MHz，d-DMSO)，δ8.89(s，1H)，8.78(s，1H)，8.26(br，1H)，7.74(s，1H)，7.52～7.38(m，4H)，7.29(t，1H)，7.15～7.01(m，2H)，7.01(dd，J＝9.6，2.8Hz，2H)，4.78(s，2H)，2.74(d，J＝4.8Hz，3H)，

MS(ESI)，m/z：462(M ⁺+H ⁺).

Embodiment 19

5-(4-(3-(4-chloro-3-((4-methylpiperazine-1-replaces) methyl) phenyl) urea groups) phenoxy group)-2-fluoro-N-methyl-benzamide

(5-(4-(3-(4-chloro-3-((4-methylpiperazin-1-yl)methyl)phenyl)ureido)phenoxy)-2-fluoro-N-methylbenzamide)

Synthetic method such as embodiment 6.

¹HNMR(400MHz，d-DMSO)，δ9.09(s，1H)，8.99(s，1H)，8.28(br，1H)，7.57(s，1H)，7.47(d，J＝8.8Hz，2H)，7.43(d，J＝8.8Hz，1H)，7.37～7.27(m，2H)，7.14～7.11(m，2H)，7.01(d，J＝8.8，2H)，3.54(s，2H)，2.74(d，J＝4.4Hz，3H)，2.64(br，4H)，2.37(s，3H).

MS(ESI)，m/z：526(M ⁺+H ⁺).

Embodiment 20

5-(4-(3-(4-chloro-3-(piperidines-1-substituted benzyl) phenyl) urea groups) phenoxy group)-2-fluoro-N-methyl-benzamide

(5-(4-(3-(4-chloro-3-(piperidin-1-ylmethyl)phenyl)ureido)phenoxy)-2-fluoro-N-methylbenzamide)

Synthetic method such as embodiment 6.

¹HNMR(400MHz，d-DMSO)，δ9.76(br，1H)，9.42(br，2H)，8.24(s，1H)，7.86(s，1H)，7.55～7.47(m，5H)，7.28(t，1H)，7.13～7.09(m，2H)，7.00(d，J＝8.8，2H)，4.35(s，2H)，3.01(br，2H)，2.73(d，J＝4.4，3H)，1.67(br，6H)，1.45(br，2H).

MS(ESI)，m/z：511(M ⁺+H ⁺).

Embodiment 21

5-(4-(3-(4-chloro-3-(morphine woods benzyl) phenyl) urea groups) phenoxy group)-2-fluoro-N-methyl-benzamide

(5-(4-(3-(4-chloro-3-(morpholinomethyl)phenyl)ureido)phenoxy)-2-fluoro-N-methylbenzamide)

Synthetic method such as embodiment 6.

¹HNMR(400MHz，d-DMSO)，δ8.81(s，1H)，8.67(s，1H)，8.24(br，1H)，7.54(s，1H)，7.47～7.41(m，3H)，7.31～7.26(m，2H)，7.13～7.09(m，2H)，6.98(d，J＝8.8，2H)，3.58(br，4H)，3.49(s，2H)，2.73(d，J＝4.4，3H)，2.41(br，4H).

MS(ESI)，m/z：513(M ⁺+H ⁺).

Embodiment 22

5-(6-(3-(4-(4-methylpiperazine-1-replaces) phenyl) urea groups) pyridine-3-phenoxy group)-2-fluoro-N-methyl-benzamide

(2-fluoro-N-methyl-5-(6-(3-(4-(4-methylpiperazin-1-yl)phenyl)ureido)pyridin-3-yloxy)benzamide)

Synthetic method such as embodiment 6.

¹HNMR(400MHz，d-DMSO)，δ8.69(s，1H)，8.51(s，1H)，8.28(br，1H)，8.17(s，1H)，8.01(d，J＝8.8Hz，1H)，7.34～7.27(m，5H)，7.04(d，J＝8.8，1H)，6.88(d，J＝8.0，2H)，3.33(br，4H)，3.05(br，4H)，2.77(d，J＝4.0Hz，3H)，2.64(br，4H)，2.24(s，3H).

MS(ESI)，m/z：479(M ⁺+H ⁺).

Embodiment 23

5-(5-(3-(3-ethylphenyl) urea groups) pyridine-2-phenoxy group)-2-fluoro-N-methyl-benzamide

(5-(5-(3-(3-ethylphenyl)ureido)pyridin-2-yloxy)-2-fluoro-N-methylbenzamide)

Synthetic method such as embodiment 6.

¹HNMR(400MHz，d-DMSO)，δ8.76(s，1H)，8.71(s，1H)，8.28(br，1H)，8.18(s，1H)，8.01(d，J＝8.4Hz，1H)，7.35～7.18(m，6H)，7.04(d，J＝8.8，1H)，6.84(d，J＝7.2，1H)，2.77(d，J＝4.0Hz，3H)，2.64(m，2H)，1.18(t，3H).

MS(ESI)，m/z：409(M ⁺+H ⁺).

Embodiment 24

5-(6-(3-(3-chloro-4-fluorophenyl) urea groups) pyridine-3-phenoxy group)-2-fluoro-N-methyl-benzamide

(5-(6-(3-(3-chloro-4-fluorophenyl)ureido)pyridin-3-yloxy)-2-fluoro-N-methylbenzamide)

Synthetic method such as embodiment 6.

¹HNMR(400MHz，d-DMSO)，δ9.05(s，1H)，8.92(s，1H)，8.28(br，1H)，8.19(d，J＝4.0Hz，1H)，8.01(dd，J＝8.8，2.4Hz，1H)，7.79～7.77(m，1H)，7.35～7.27(m，5H)，7.05(d，J＝8.8，1H)，2.77(d，J＝4.4Hz，3H).

MS(ESI)，m/z：433M ⁺+H ⁺).

Embodiment 25

5-(6-(3-(3-((2-bromo thiazole-4-replaces) inferior methoxyl group)-4-chloro-phenyl-) urea groups) pyridine-3-phenoxy group)-2-fluoro-N-methyl-benzamide

(5-(6-(3-(3-((2-bromothiazol-4-yl)methoxy)-4-chlorophenyl)ureido)pyridin-3-yloxy)-2-fluoro-N-methylbenzamide)

Synthetic method such as embodiment 6.

¹HNMR(400MHz，d-DMSO)，δ8.83(d，2H)，8.28(br，1H)，8.18(d，J＝2.4Hz，1H)，8.00(dd，J＝8.8，2.4Hz，1H)，7.77(d，J＝13.2，1H)，7.67(d，J＝1.6，1H)，7.34～7.19(m，5H)，7.03(d，J＝8.8，1H)，5.18(d，J＝11.2，2H)，2.77(d，J＝4.4Hz，3H).

MS(ESI)，m/z：607(M ⁺+H ⁺).

Embodiment 26

5-(5-(3-(3-chloro-4-(2-(N ' N '-dimethyl amine) oxyethyl group) phenyl) urea groups) pyridine-2-phenoxy group)-2-fluoro-N-methyl-benzamide

(5-(5-(3-(3-chloro-4-(2-(dimethylamino)ethoxy)phenyl)ureido)pyridin-2-yloxy)-2-fluoro-N-methylbenzamide)

Synthetic method such as embodiment 6.

¹HNMR(400MHz，d-DMSO)，δ9.20(s，2H)，8.33(br，1H)，8.29(s，1H)，8.22(d，J＝12.4Hz，1H)，7.66(s，1H)，7.34～7.27(m，4H)，7.14(d，J＝8.8，1H)，7.03(d，J＝8.4，1H)，4.26(s，2H)，2.76(d，J＝3.2Hz，3H)，2.62(br，6H).

MS(ESI)，m/z：502(M ⁺+H ⁺).

Embodiment 27

5-(5-(3-(3-chloro-4-(3-morphine quinoline propoxy-) phenyl) urea groups) phenoxy group)-2-fluoro-N-methyl-benzamide

(5-(4-(3-(3-chloro-4-(3-morpholinopropoxy)phenyl)ureido)phenoxy)-2-fluoro-N-methylbenzamide)

Synthetic method such as embodiment 6.

¹HNMR(400MHz，d-DMSO)，δ8.67(s，1H)，8.60(s，1H)，8.23-8.24(m，1H)，7.63(s，1H)，7.46(d，J＝8.4Hz，2H)，7.21-7.30(m，3H)，7.05-7.12(m，3H)，6.98(d，J＝8.4Hz，2H)，4.01-4.07(m，2H)，3.55-3.56(m，4H)，2.73(d，J＝4.4Hz，3H)，2.41-2.45(m，2H)，2.32-2.34(m，4H)，1.84-1.87(m，2H).

MS(ESI)，m/z：557(M ⁺+H ⁺).

Embodiment 28

5-(4-(3-(4-(benzyloxy) 3-chlorobenzene) urea groups) phenoxy group)-2-fluoro-N-methyl-benzamide

(5-(4-(3-(4-(benzyloxy)-3-chlorophenyl)ureido)phenoxy)-2-fluoro-N-methylbenzamide)

Synthetic method such as embodiment 6.

¹HNMR(400MHz，d-DMSO)，δ8.69(s，1H)，8.62(s，1H)，8.25(br，1H)，7.67(d，J＝2.4Hz，1H)，7.46(d，J＝8.8Hz，2H)，7.40(t，2H)，7.22-7.35(m，3H)，7.10-7.16(m，3H)，6.99(d，J＝8.8Hz，2H)，5.15(s，2H)，2.74(d，J＝4.4Hz，3H).

MS(ESI)，m/z：520，(M ⁺+H ⁺).

Embodiment 29

5-(4-(3-(3-chloro-4-morphine quinoline base phenyl) urea groups) phenoxy group)-2-fluoro-N-methyl-benzamide

(5-(4-(3-(3-chloro-4-morpholinophenyl)ureido)phenoxy)-2-fluoro-N-methylbenzamide)

Synthetic method such as embodiment 6.

¹HNMR(400MHz，d-DMSO)，δ8.70(s，2H)，8.29-8.23(m，1H)，7.67(d，J＝1.6Hz，1H)，7.47(d，J＝8.8Hz，2H)，7.25-7.31(m，2H)，7.10-7.14(m，3H)，7.00(d，J＝8.8Hz，2H)，3.73(t，4H)，2.91(t，4H)，2.75(d，J＝4.4Hz，3H).

MS(ESI)，m/z：499.0.(M ⁺+H ⁺).

Embodiment 30

5-(4-(3-(3-chloro-4-(piperidines-1-replaces) phenyl) urea groups) phenoxy group)-2-fluoro-N-methyl-benzamide

(5-(4-(3-(3-chloro-4-(piperidin-1-yl)phenyl)ureido)phenoxy)-2-fluoro-N-methylbenzamide)

Synthetic method such as embodiment 6.

¹HNMR(400MHz，d-DMSO)，δ8.65(s，1H)，8.69(s，1H)，8.24(br，1H)，7.64(d，J＝2.0Hz，1H)，7.47(d，J＝8.8Hz，2H)，7.23-7.31(m，2H)，7.06-7.14(m，3H)，7.00(d，J＝8.8Hz，2H)，2.85(t，4H)，2.75(d，J＝4.8Hz，3H)，1.62-1.66(m，4H)，1.51-1.53(m，2H).MS(ESI)，m/z：497.0，(M ⁺+H ⁺).

Embodiment 31

5-(4-(3-(3-chloro-4-(4-methylpiperazine-1-replaces) phenyl) urea groups) phenoxy group)-2-fluoro-N-methyl-benzamide

(5-(4-(3-(3-chloro-4-(4-methylpiperazin-1-yl)phenyl)ureido)phenoxy)-2-fluoro-N-methylbenzamide)

Synthetic method such as embodiment 6.

¹HNMR(400MHz，d-DMSO)，δ8.79(s，1H)，8.78(s，1H)，8.25(br，1H)，7.67(d，J＝2.0Hz，1H)，7.47(d，J＝8.8Hz，2H)，7.2-7.29(m，2H)，7.10-7.14(m，3H)，7.00(d，J＝8.8Hz，2H)，3.16-3.18(m，4H)，2.97-2.97(m，4H)，2.75(d，J＝4.4Hz，3H).2.39(s，3H).

MS(ESI)，m/z：512(M ⁺+H ⁺).

Embodiment 32

5-(4-(3-(3-chloro-4-(2-(4-methylpiperazine-1-replaces) oxyethyl group) phenyl) urea groups) phenoxy group)-2-fluoro-N-methyl-benzamide

(5-(4-(3-(3-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)ureido)phenoxy)-2-fluoro-N-methylbenzamide)

Synthetic method such as embodiment 6.

¹HNMR(400MHz，d-DMSO)，δ8.97(s，1H)，8.97(s，1H)，8.24(br，1H)，7.65(d，J＝2.4Hz，1H)，7.47(d，J＝9.2Hz，2H)，7.31-7.23(m，2H)，7.14-7.05(m，3H)，6.99(d，J＝9.2Hz，2H)，4.13-4.11(m，2H)，2.78(br，2H)，2.75(d，J＝4.4Hz，3H)，2.71-2.69(m，8H)，2.45(s，3H).

MS(ESI)，m/z：556(M ⁺+H ⁺).

Embodiment 33

5-(4-(3-(3-chloro-4-(2-methylene oxygen yl pyridines) phenyl) urea groups) phenoxy group)-2-fluoro-N-methyl-benzamide

(5-(4-(3-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)ureido)phenoxy)-2-fluoro-N-methylbenzamide)

Synthetic method such as embodiment 6.

¹HNMR(400MHz，d-DMSO)，δ8.71(s，1H)，8.66(s，1H)，8.25(br，1H)，7.86-7.85(m，1H)，7.70(d，J＝2.4Hz，1H)，7.56-7.54(m，1H)，7.48-7.42(m，2H)，7.37-7.21(m，3H)，7.14-7.10(m，2H)，6.99(d，J＝8.8Hz，2H)，6,79-6.74(m，1H)，5.12(s，2H)，2.74(d，J＝4.8Hz，3H).

MS(ESI)，m/z：521(M ⁺+H ⁺).

Embodiment 34

5-(4-(3-(3-chloro-4-(2-oxyethyl group morphine quinoline) phenyl) urea groups) phenoxy group)-2-fluoro-N-methyl-benzamide

5-(4-(3-(3-chloro-4-(2-morpholinoethoxy)phenyl)ureido)phenoxy)-2-fluoro-N-methylbenzamide

Synthetic method such as embodiment 6.

¹HNMR(400MHz，d-DMSO)，δ8.68(s，1H)，8.61(s，1H)，8.25(br，1H)，7.64(d，J＝1.6Hz，1H)，7.48(d，J＝8.4Hz，2H)，7.31-7.23(m，2H)，7.14-7.09(m，3H)，6.99(d，J＝8.8Hz，2H)，4.12(br，2H)，3.58(br，4H)，3.17(d，J＝5.2，4H)，2.75(d，J＝4.4Hz，3H)，2.71(br，2H).

MS(ESI)，m/z：543(M ⁺+H ⁺).

Embodiment 35

5-(4-(3-(4-chloro-3-(trifluoromethyl) urea groups) phenoxy group)-2-(trifluoromethyl)-N-methyl-benzamide

5-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methyl-2-(trifluoromethyl)benzamide

Synthetic method such as embodiment 6.

¹HNMR(400MHz，d-DMSO)，δ9.19(s，1H)，8.95(s，1H)，8.39(d，J＝4.8Hz，1H)，8.11(d，J＝2.0Hz，1H)，7.75(d，J＝8.8Hz，1H)，7.64-7.55(m，5H)，7.12(d，J＝8.8Hz，2H)，6.96(d，J＝2.0Hz，1H)，2.71(d，J＝4.4Hz，3H).

MS(ESI)，m/z：532(M ⁺+H ⁺).

Embodiment 36

4-(4-(3-(4-chloro-3-(trifluoromethyl) urea groups) phenoxy group)-2-(trifluoromethyl)-N-methyl-benzamide

4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methyl-2-(trifluoromethyl)benzamide

Synthetic method such as embodiment 6.

¹HNMR(400MHz，d-DMSO)，δ9.19(s，1H)，8.93(s，1H)，8.34(d，J＝4.4Hz 1H)，8.11(d，J＝2.0Hz，1H)，7.66～7.50(m，5H)，7.26(d，J＝2.0Hz，1H)，7.20(dd，J＝2.4，8.4Hz，1H)，7.09(d，J＝8.6Hz，1H)，7.23(d，J＝4.8Hz，3H).

MS(ESI)，m/z：532(M ⁺+H ⁺)。

Claims

1. compound or its pharmacy acceptable salt or the steric isomer in the formula (I):

A, B are optional separately to be CH or N;

Following a is 0 or 1; B is 0 or 1;

R ₁Be selected from:

1)H；

2)F；

3)CF ₃；

R ₂Be selected from:

1)H；

2) C ₁～C ₆Alkyl;

3) C ₁～C ₆Perfluoroalkyl;

4)C ₁～C ₆NR ₄R ₅；

1)H；

2) halogen;

3)NO ₂；

4)C ₀～C ₄NR ₄R ₅；

5) C ₁～C ₃Perfluoroalkyl;

6) O _aC ₁～C ₃Perfluoroalkyl;

7) O _aC ₁～C ₃Alkyl;

8) C ₁～C ₃The N-cycloalkyl;

9) C ₁～C ₃The N-aryl;

10) C ₁～C ₄The N-heterocyclic radical;

11) O _aC ₃～C ₆Cycloalkyl-heterocyclic radical;

12) O _aC ₃～C ₆Cycloalkyl-NR ₄R ₅

13) O _aC ₃～C ₆Cycloalkyl-alkyl;

R ₅And R ₄Independently be selected from separately:

1)H；

2) (C=O) _aO _bC ₁～C ₄Alkyl;

3) (C=O) _aO _bAryl;

4) (C=O) _aO _bC ₂～C ₄Thiazolinyl;

5) (C=O) _aO _bC ₂～C ₄Alkynyl;

6) O _bC ₁～C ₃Perfluoroalkyl;

7) (C=O) _aO _bC ₃～C ₆Cycloalkyl;

8) (C=O) _aO _bHeterocyclic radical;

9) SO ₂C ₁～C ₃Alkyl;

10) (C=O) _aO _bC ₀～C ₃Alkylidene group-aryl;

11) (C=O) _aO _bC ₀～C ₃The alkylidenyl-heterocyclic base;

12)(C＝O) _aO _bC ₀～C ₄-NR ₆R ₇；

13) (C=O) _aO _bC ₃～C ₆Cycloalkyl-COOR ₆

14) (C=O) _aO _bC ₃～C ₆Cycloalkyl-aryl;

15) (C=O) _aO _bC ₃～C ₆Cycloalkyl-heterocyclic radical;

16) (C=O) _aO _bC ₃～C ₆Cycloalkyl-alkyl;

Wherein, described alkyl listed above, aryl, thiazolinyl, alkynyl, cycloalkyl and heterocyclic radical are optional is selected from R by maximum 3 ₆Substituting group replace; Perhaps R ₄With R ₅And the atom that connects them forms the dicyclo that one 4～7 yuan monocycle or each ring are 4～7 yuan, and optionally in the formed ring contains one or 2～3 heteroatomss that are selected from N, O and S; Described monocycle or dicyclo are optional by one or more R that are selected from ₄Substituting group replace;

R ₆And R ₇Independently be selected from separately:

1)H；

2) O _bC ₁～C ₄Alkyl;

3) O _bAryl;

4) O _bC ₂～C ₄Thiazolinyl;

5) O _bC ₂～C ₄Alkynyl;

6) O _bC ₁～C ₃Perfluoroalkyl;

7) O _bC ₃～C ₆Cycloalkyl;

8) O _bHeterocyclic radical;

9) O _bC ₀～C ₃Alkylidene group-aryl;

10) O _bC ₀～C ₃The alkylidenyl-heterocyclic base;

11) O _bC ₃～C ₆Cycloalkyl-aryl;

12) C ₃～C ₆Cycloalkyl-heterocyclic radical;

13) C ₃～C ₆Cycloalkyl-alkyl.

2. according to the described compound of claim 1 or its pharmacy acceptable salt or steric isomer, it has formula II structure:

A, B, Ar and R ₁～R ₃Definition and claim 1 in identical.

3. according to the described compound of claim 1 or its pharmacy acceptable salt or steric isomer, it has the formula III structure:

A, B, Ar and R ₁～R ₃Definition and claim 1 in identical.

4. compound according to claim 2 or its pharmacy acceptable salt or steric isomer, it has formula IV structure:

A, B, and R ₁～R ₃Definition and claim 1 in identical.

5. compound according to claim 3 or its pharmacy acceptable salt or steric isomer, it has formula V structure:

V

A, B, and R ₁～R ₃Definition and claim 1 in identical.

6. medicinal compositions, it is made up of each described compound of claim 1-5 or its pharmacy acceptable salt or steric isomer and pharmaceutically acceptable carrier.

7. each described compound of claim 1-5 and pharmacy acceptable salt thereof or the steric isomer application in the medicine of preparation treatment or prophylaxis of tumours.

8. application according to claim 7, it is characterized in that: described tumour is histocyte lymphatic cancer, nonsmall-cell lung cancer, small cell lung cancer, adenocarcinoma of lung, lung squamous cancer, carcinoma of the pancreas, mammary cancer, prostate cancer, liver cancer, cancer of the stomach, colorectal carcinoma, the rectum cancer, ovarian cancer, palace stem cancer, the cancer of the brain, esophagus cancer, osteocarcinoma, carcinoma of testis, melanoma, skin carcinoma, cell carcinoma, prostate cancer, nasopharyngeal carcinoma, kidney, oral carcinoma, leukemia and brain, reproductive system, lymphsystem, any in Digestive tract, respiratory system and the dermatoma.