CN108464981A

CN108464981A - Inhibit purposes of the composition of TIE2 kinases in the drug for preparing treating cancer

Info

Publication number: CN108464981A
Application number: CN201810436668.9A
Authority: CN
Inventors: D·L·弗林; M·D·考夫曼; B·史密斯; M·S·鲁道兹
Original assignee: Deciphera Pharmaceuticals LLC
Current assignee: Deciphera Pharmaceuticals LLC
Priority date: 2013-11-07
Filing date: 2013-11-07
Publication date: 2018-08-31
Anticipated expiration: 2033-11-07
Also published as: AU2019200261A1; WO2015069266A1; AU2013404949A1; JP2017500371A; AU2013404949B2; JP6568093B2; CA2929715A1; CN105873440A; EP3065549A1; AU2021200113A1; KR20160070188A; CN105873440B; EP3065549A4; CN108464981B; KR20210063475A

Abstract

The present invention relates to the method for inhibiting TIE2 kinases, it is suitable for treatment tumour growth, invasion, it is interior ooze, spread, metastasis of cancer and immunosupress.In particular it relates to the method for 1 (3 tertiary butyl 1 (6 base of quinoline) 1H pyrazoles, 5 base) 3 (2 fluorine 4 (2 (methylcarbamoyl) pyridine, 4 base oxygroup) phenyl) urea and its salt using Formulas I.

Description

Inhibit purposes of the composition of TIE2 kinases in the drug for preparing treating cancer

The application be the applying date be on November 7th, 2013, (international application no is application No. is 201380081931.2 PCT/US2013/069005), entitled " inhibiting purposes of the composition of TIE2 kinases in the drug for preparing treating cancer " The divisional application of application for a patent for invention.

The description for the text file electronically submitted

During the content for the text file electronically submitted is specially incorporated herein in a full-text reference way：Sequence table Computer-readable format copies (filename：DECP_066_00WO_SeqList_ST25.txt, record date：In November, 2013 7 days, 6 kilobytes of file size).

Technical field

The present invention relates to the methods for inhibiting TIE2 kinases, and it is suitable in treatment tumour growth, tumor invasiveness, tumour Ooze, tumour diffusion, neoplasm metastasis and tumour immunity tolerance.In particular it relates to use the side of Formulas I composition Method, the Formulas I composition are described herein as the potent inhibitor of TIE2, for treating breast cancer growth, invasion, interior oozing expansion Scattered, metastasis of cancer and immunological tolerance.

Background technology

Inner membrance endothelial cell kinases -2 (TIE2) is basically limited in the endothelial cell of blood vessel and in bone marrow derived It is expressed in the subset of TIE2 expression monocytes (TEM).TIE2 is Ang-1 (ANG1), angiopoietin 2 (ANG2) With the receptor of angiogenin 4 (ANG4), and this signal transducting system is angiogenesis (new blood vessel is sprouted from existing blood vessel) It generates in (from the beginning new blood vessel is formed) the two and plays an important role with blood tubule.TEM is that circulating monocytic cell and tissue macrophage are thin The subset of born of the same parents, in tumor model have Angiogensis and promote Angiogenic activity (De Palma MD et al.,《Cancer is thin Born of the same parents》(Cancer Cell)2005；8:211-226).TIE2 inhibits that the ability (Mazzieri of TEM and blood vessel association can be reduced R,《Cancer cell》2011；19:512-526) and it is substantially reduced Angiogensis activity (the De Palma of this macrophage subset M,《Clinical Cancer Research》(Clin Cancer Res)2011；17(16):5226-5232).

Cytotoxic chemotherapy, radiotherapy and antiangiogenesis therapy can damage the relevant blood vessel of tumour, thus produce Raw hypoxic tumors environment.Hypoxic tumors environment by activating vascular endothelial cell from vascular endothelial growth factor (VEGF)/ The Tumor angiogenesis that the paths VEGFR2 draw backlash to the angiogenic switch in the paths ANG/TIE2.Promote angiogenesis TEM It is raised from marrow to these hypoxic tumors positions by the way that the TEM in tumor microenvironment is promoted this blood with endothelial cell association by Pipe re-forms.TEM and TIE2 expression endothelial cells thereby are thought to rise in the blood vessel of tumour re-forms after these treatments To important function, (De Palma M et al. the Trends Immunol that are in progress are caused due to the growth of residual tumor cells 2007；28:519-524).

TIE2 is also the mediator of osteoclast differentiation, and TIE2 inhibition causes bone resorption to be invaded in 4T1 mouse mammary cancer models It reduces and reduces tumour growth (Dales JP et al. Int J Oncol 2003；22:391-397).Except TIE2 is in tumour micro-loop Other than physiology expression on the endothelial cell in border, monocyte/macrophage and osteoclast, TIE2, which is also exhibited, is present in breast On cancer cell.The risk of the tumor cells expression of TIE2 and metastatic disease improves and to the independent pre- of the prognosis of multi-variables analysis Surveying the factor is associated (Min Y et al.《Cancer research》(Cancer Res)2010；70:2918-2828).

Noteworthy, the subset of TIE2 expression tissues macrophage is located at the tumor microenvironment for being referred to as metastasis of cancer (TMEM) in specific blood vessels structure.TIE2 expression macrophage contacts in TMEM structures are breast by recent observation result In cancer cell extravasation to vascular circulation and be subsequently diffused into necessary to far-end transfer position (Condeelis J, Pollard JW.《Cell》(Cell)2006；124:263-6；Ginter PS et al.《Cancer research》2012；72 (24 increasings Periodical):Make a summary #P6-02-04).Therefore, new metastasis of cancer may be caused to the inhibition of TIE2 and macrophage in TMEM structures It reduces.

TIE2 expression tissues macrophage (TEM) has shown that out and works in breast cancer immunological tolerance recently.From breast The TEM of room tumour can inhibit tumor-specific immunity to react.Specifically, the inhibition function of TEM similarly by TIE2 and VEGFR kinase activities drive.The TEM detached from breast carcinoma tissue may act as antigen presenting cells, only cause the faint of T cells Proliferation.TIE2 and VEGFR kinase activities induction TEM is blocked to become its phenotype with bone marrow dendritic cells feature with firm The cell that antigen is presented.The immunosuppressive activity of TEM also in mammary tumor T adjust cell high CD86 surface expressions and extensively It is general to participate in being associated.TIE2 and VEGFR kinase activities are to maintain high CD86 surface expression levels and be converted to T cell to exempt from Epidemic disease inhibition adjusts required (the Ibberson M et al. of cell《Clinical Cancer Research》2013；19:3439-3449).

T antigens (PyMT) homogenic type mouse mammary cancer model is opened using mouse mammary tumor virus (MMTV) in polyomavirus Mover, specific breast promoter in mouse mammary tissue to express PyMT.In this model, PyMT breast cancer cells are planted Enter mouse mammary fat pad, and these cancer metastasis and causes dead mouse.Different from heteroplastic transplantation model, PyMT models make With complete immunocompetent mouse.Metastasis of cancer in this known model is expressed huge by the TIE2 in TMEM blood vessel structures Phagocyte is adjusted.Therefore, it is necessary to the novel treatments with the relevant diseases of TIE2.

Invention content

The method of the present invention is for inhibiting TIE2 kinases.Due to this inhibition, the present invention is suitable for for tumour growth, invades Attacking property, it is interior ooze, spread, the treatment or prevention of metastasis of cancer and tumour immunity tolerance.In particular it relates to use Formulas I The method of composition, the Formulas I composition are the potent inhibitor of TIE2 as described below, grown for treating breast cancer, is aggressive, It inside oozes, spread, metastasis of cancer and immunological tolerance：

Wherein

The integer that n is 0 to 7；

X is the basic group of pharmaceutically acceptable salt；

Its restrictive condition is when n is 0, and the Formulas I composition is parent free alkali.In some embodiments, HX is not deposited , whereby the structure of Formulas I be parent free alkali.

Formulas I composition is additionally operable to other cancers, and the TIE2 expression wherein in tumour cell or in tumor microenvironment passes through Jie Lead primary tumor growth, primary tumor invasion, be seeped into blood flow in tumour, tumour cell diffusion, neoplasm metastasis arrive The mechanism of remote organization or tumour immunity tolerance causes tumour progression.Therefore, Formulas I composition uses the inhibition of TIE2 kinases In by inhibit include primary tumor growth, primary tumor invasion, be seeped into blood flow in tumour, tumour cell is spread, Neoplasm metastasis is used for treating cancer to the process of remote organization or tumour immunity tolerance.

TIE2 kinases has shown that out the reason of cancer progression that can become the following：Glioma (Liu et al. people, Oncotarget(2010)1:700-709；Brunckhorst et al.,《Cancer research》(2010)70:7283-7293), melanocyte Tumor (Helfrich et al.,《Clinical Cancer Research》(2009)15:1384-1392), oophoroma (Karlan et al.,《Clinical tumor Learn magazine》(J.Clinical Oncology)(2012)30:362-370), colorectal cancer (Ahmad et al.,《Cancer》 (Cancer)(2001)92:1138-1143；Hashizume et al.,《Cancer research》(2010)70:2213-2223), liver cell Cancer (Matsubara et al.,《Hepatology》(Hepatology)(2013)57:1416-1425；Mitsuhashi et al.,《Liver Popular name for》(2003)37:1105-1113；Tanaka et al.,《Journal of Clinical Investigation》(J.Clin Invest) (1999)103: 341-345) and hematologic cancers (Muller et al.,《Leukaemia research》(Leukemia Research) (2002)26:163- 168；Hou et al.,《Leukaemia research》(2008)32:904-912).

Description of the drawings

Fig. 1 is shown inhibits primary PyMT tumour growths using Formula II composition, Paclitaxel or combinations thereof.

Fig. 2 is shown inhibits PyMT tumour macrophages to build up using Formula II composition, Paclitaxel or combinations thereof.

Fig. 3 is shown inhibits PyMT tumour TIE2 expression cells using Formula II composition, Paclitaxel or combinations thereof It builds up.

Fig. 4 shows the lung cancer inhibited using Formula II composition, Paclitaxel or combinations thereof in PyMT breast cancer models Transfer.

Fig. 5 shows the active PyMT for comparing Paclitaxel and the combination of Paclitaxel and Formula II composition The inhibition of lung cancer metastasis in breast cancer model.

Fig. 6 shows using eribulin as single medicament or inhibits in PyMT breast cancer models with Formula II combination of compositions Lung cancer metastasis.

Fig. 7 shows enzymatic and activity in vivo of the eribulin as single medicament or with Formula II combination of compositions.

Specific implementation mode

Definition：

Term " basic group of the pharmaceutically acceptable salt in Formulas I composition " include but is not limited to it is water-soluble and Water-insoluble salt, the benzene sulfonate for being such as substituted or being unsubstituted, acetate, amsonate (4,4- diamino-stilbene -2,2- bis- Sulfonate), benzoate, bicarbonate, disulfate, biatrate, borate, bromide, butyrate, calcium, ethylenediamine Tetraacethyl calcium, camsilate, carbonate, chloride, citrate, Clavulanate, dihydrochloride, ethylenediamine tetra-acetic acid Salt, ethanedisulphonate, estolate, esilate, fumarate, gluceptate, gluconate, glutamate, acyl in second Amine phenyl-arsonate, hexafluorophosphate, hexyl resorcin hydrochlorate, hetramine, hydrobromate, hydrochloride, Hydroxynaphthoate, iodine Compound, isethionate, lactate, lactobionate, laruate, magnesium, malate, maleate, mandelate, methylsulphur Hydrochlorate, methyl bromide, methyl nitrate, Methylsulfate, galactosaccharic acid salt, naphthalene sulfonate, nitrate, N-METHYL-ALPHA-L-GLUCOSAMINE ammonium Salt, 3- hydroxy-2-naphthoic acids salt, oleate, oxalates, palmitate, embonate (1,1- methylene-bis- -2- hydroxyls - 3- naphthoates, embonate), it is pantothenate, phosphate/diphosphate, picrate, Polygalacturonate, propionate, right Toluene fulfonate, salicylate, stearate, basic acetate, succinate, sulfate, sulfosalicylate, Ursula acid Salt, tannate, tartrate, teoclate, toluene fulfonate, triethiodide and valerate.The particular instance of basic group Including tosilate, fluoroform sulphonate and mesylate.

Term " salt " refers to pharmaceutically acceptable salt

Term " pharmaceutically acceptable salt " also refers to this hair with acidic functionality (such as carboxylic acid functional) and alkali The salt of bright composition.

Term " treatment " about individual refers at least one symptom for the illness for improving individual.Treatment can be to cure, change It is apt to or at least partly mitigates illness.

" administration (administer) ", " administration (administering) " or " administration as that term is used in this disclosure (administration) " individual directly administration composition or the pharmaceutically acceptable salt or combination of compound are directed to Object, or to the prodrug derivant of individual administration composition or the pharmaceutically acceptable salt or composition of compound or similar Object can form the reactive compound of equivalent in individual body.

The measurable of pathogenicity rate that " effective quantity " effectively provides relevant disease when being used in combination with medical usage controls The amount treated, prevent or reduced.

The present invention relates to for tumour growth, invasion, interior ooze, spread, the treatment of metastasis of cancer and tumour immunity tolerance (blocking) or the method prevented.The method include to need the patient of the treatment to the prevention effect of these patient's condition or reduction throw The Formulas I composition described in the dosage regimen that TIE2 inhibits is being adjusted with a effective amount of herein.

The amount of composition needed for realization therapeutic effect as described herein can according to the conventional program for specific purposes with It is empirically determined.In general, for therapeutic purpose administration therapeutic agent, (such as Formulas I as described herein or II compositions are (and/or additional Medicament)), therapeutic agent is given with pharmacological effective dose." pharmaceutical effective amount ", " pharmacological effective dose ", " treatment is effective Amount " or " effective quantity " refer to being enough to generate the amount of required physiological action or capable of realizing the amount of required result, particularly with treatment For conditions or diseases.Effective quantity as used herein will be including being enough such as development of the symptom of delay conditions or diseases, changing Become the process (such as slowing down the progress of the symptom of disease) of the symptom of conditions or diseases, reduce or eliminate one kind of conditions or diseases Or the amount of a variety of symptoms or the symptom of performance and reverse conditions or diseases.For example, to suffering from the treatment of cancered patient's administration Agent is not only reported and the severity of the relevant symptom of disease or duration when eradicating or improving the potential patient's condition, but also in patient Treatment benefit is provided when reducing (such as tumor load is reduced, circulating tumor cell is reduced, progresson free survival rate improves).Treatment benefit Place further includes pause or slows down the progress of potential disease or illness, and whether realizes that improvement is unrelated.

In one embodiment of the invention, Formulas I composition is 1- (3- tertiary butyls -1- (quinoline -6- bases) -1H- of Formula II Pyrazoles -5- bases) -3- (the fluoro- 4- of 2- (2- (methylcarbamoyl) pyridin-4-yls oxygroup) phenyl) urea tosilate, be The potent inhibitor of TIE2 (receptor tyrosine kinase of angiogenin ligand).

Formulas I composition is used for cancer, and the TIE2 expression wherein in tumour cell or in tumor microenvironment is primary by mediating Property tumour growth, primary tumor invasion, be seeped into blood flow in tumour, tumour cell diffusion, neoplasm metastasis to distal end group It knits or the mechanism of tumour immunity tolerance causes tumour progression.Therefore, Formulas I composition to the inhibition of TIE2 kinases for passing through Inhibition includes primary tumor growth, primary tumor invasion, be seeped into blood flow in tumour, tumour cell is spread, tumour cancer The process of remote organization or tumour immunity tolerance is transferred to be used for treating cancer.

The treatment concentration of Formulas I composition block notified in tumor microenvironment cause tumour growth, invasion, it is interior ooze, spread, The cell of the immunological tolerance of metastasis of cancer or tumor inducing.The cell type in tumor microenvironment includes TIE2 expression monokaryons Cell, TIE2 expression macrophages and TIE2 express endothelial cell.

The tumour to react to angiogenin/TIE2 signal transductions includes but is not limited to breast cancer, oophoroma, liver cell Cancer, glioma, colorectal cancer and Hematological Malignancies.

In another embodiment, Formulas I composition is free alkali compound 1- (3- tertiary butyl -1- (quinoline in the absence of HX - 6- bases) -1H- pyrazoles -5- bases) -3- (the fluoro- 4- of 2- (2- (methylcarbamoyl) pyridin-4-yls oxygroup) phenyl) urea, there is knot Structure：

Formulas I composition can combine administration with single medicine type or with other therapeutic agents of known treatment cancer.It is described its Its therapeutic agent includes radiotherapy, antitublin, DNA alkylating agent, DNA synthetic inhibitors, DNA intercalators, anti-female swashs Plain agent, antiandrogen, steroids, anti-EGFR agent, kinase inhibitor, topoisomerase enzyme inhibitor, histone deacetylase (HDAC) inhibitor, DNA methylation inhibitor, anti-HER2 agent, anti-angiogenic agent, proteasome inhibitor, Distaval (thalidomide), lenalidomide (lenalidomide), antibody-drug conjugates (ADC), immunomodulator or cancer epidemic disease Seedling.

Effective quantity, toxicity and therapeutic effect can by the standard pharmaceutical procedures in cell culture or experimental animal, such as It is measured by measuring LD50 (about 50% dead dosage in group) and ED50 (the about 50% effective dosage for the treatment of in group). Dosage can change depending on used dosage form and the dosing way utilized.Dose ratio between toxicity and therapeutic effect is to control It treats index and it is represented by ratio LD50/ED50.In some embodiments, show the composition and method of larger therapeutic index It is preferred.Treatment effective dose can initially be estimated from analyzed in vitro, including such as cell culture assays.In addition, dosage can be Allotment is to realize circulating plasma concentration range in animal model comprising such as the institute in cell culture or in appropriate animal model The IC50 of measurement.The level of composition described in blood plasma can for example pass through high-efficient liquid phase color spectrometry.Any given dose Effect can be monitored by suitable bioanalysis.Dosage can be determined by doctor and be adjusted as needed to be suitble to that is observed to control Treatment acts on.

In certain embodiments, prevention effect will cause at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 70% or at least about 90% quantitatively variation.In some embodiments, the effect will cause about 10%, About 20%, about 30%, about 50%, about 70% or even about 90% or more quantify changes.Treatment benefit further includes pause Or slow down the progress of potential disease or illness, and whether realize that improvement is unrelated.

When the composition of Formulas I or II and other anticancer agents are applied in combination, other anticancer agents can be with Formulas I or the composition of II Administration time-histories be independently administered.Other anticancer agents can be with its previously determined therapeutic dose and the administration of administration time-histories or its agent It measures and administration time-histories can be altered to optimize effect, safety or tolerance in the combination of compositions use with Formulas I or II.

In addition, the composition (and/or additional agent) of any Formulas I as described herein or II can include that can pharmaceutically connect The chemical species administration individual of the composition of the supporting agent or mediator received.The composition is optionally including proper amount of medicine and pharmacology Upper acceptable excipient is in order to provide the form for appropriate administration.

Drug excipient can be liquid, Ru Shui and oil, including oil, animal, plant or synthesis source oil, such as peanut Oil, soybean oil, mineral oil, sesame oil etc..Drug excipient can be such as brine, Arabic gum, gelatin, gelatinized corn starch, talcum, angle Albumen, colloidal silicon dioxide, urea etc..In addition, auxiliary agent, stabilizer, thickener, lubricant and colorant can be used.At one In embodiment, pharmaceutically acceptable excipient is sterile when administration individual.When any medicament vein as described herein When interior administration, water is the excipient being applicable in.Saline solution and aqueous dextrose and glycerite can also be used as liquid Body excipient is especially used for Injectable solution.Suitable drug excipient further includes starch, glucose, lactose, sucrose, bright It is glue, malt, rice, powder, chalk, silica gel, odium stearate, glycerin monostearate, talcum, sodium chloride, anhydrous defatted milk, sweet Oil, propylene glycol, ethylene glycol, water, ethyl alcohol etc..If desired, any medicament as described herein can also include a small amount of wetting agent or Emulsifier or pH buffer.

Formulas I composition can be with other medicaments including chemotherapeutant, target therapeutic agent, biological agent or radiotherapy It is applied in combination.

Formulas I composition can be used with chemotherapeutic combination, and the chemotherapeutant includes but is not limited to anti-micro-pipe egg White agent (Paclitaxel (paclitaxel), Paclitaxel protein binding particle, Ai for injectable suspensions Bu Lin (eribulin), docetaxel (docetaxel), Ipsapirone (ixabepilone), vincristine (vincristine)), vinorelbine (vinorelbine), DNA alkylating agent (including cis-platinum (cisplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), cyclophosphamide (cyclophosphamide), ifosfamide (ifosfamide), Temozolomide (temozolomide)), DNA intercalators it is (including Doxorubicin (doxorubicin), poly- Glycation liposomal doxorubicin, daunomycin (daunorubicin), Ida mycin (idarubicin) and epirubicin (epirubicin)), 5 FU 5 fluorouracil, capecitabine (capecitabine), cytarabine (cytarabine), Decitabine (decitabine), 5-azacitidine, gemcitabine (gemcitabine) and methotrexate (MTX) (methotrexate).

Formulas I composition can be used with kinase inhibitor combination, and the kinase inhibitor includes but is not limited to Erlotinib (erlotinib), Gefitinib (gefitinib), Lapatinib (lapatanib), everolimus (everolimus), smooth sieve Department (temsirolimus), LY2835219, LEE011, PD 0332991, gram Zhuo are rich for Buddhist nun for Buddhist nun (crizotinib), card (cabozantinib), Sutent (sunitinib), pazopanib (pazopanib), Sorafenib (sorafenib), auspicious Ge Feini (regorafenib), Axitinib (axitinib), Dasatinib (dasatinib), Imatinib (imatinib), nilotinib (nilotinib), Wei Luofeini (vemurafenib), dabrafenib (dabrafenib), song U.S. is miscellaneous for Buddhist nun (quizartinib) for Buddhist nun (trametinib), Ai De former times cloth (idelalisib) and quinoline.

Formulas I composition can be applied in combination with antiestrogenic agent, and the antiestrogenic agent includes but is not limited to tamoxifen (tamoxifen), fulvestrant (fulvestrant), Anastrozole (anastrozole), Letrozole (letrozole) and according to Xi Meitan (exemestane).

Formulas I composition can be applied in combination with antiandrogenic agents, and the antiandrogenic agents include but is not limited to acetic acid Ah ratio Special dragon ester (abiraterone acetate), the miscellaneous Shandong amine (enzalutamide) of grace, Nilutamide (nilutamide), than card Shandong amine (bicalutamide), Flutamide (flutamide), Cyproterone Acetate (cyproterone acetate).

Formulas I composition can be applied in combination with steroid dose, and the steroid dose includes but is not limited to prednisone (prednisone) and dexamethasone (dexamethazone).

Formulas I composition can be applied in combination with topoisomerase I inhibitor, and the topoisomerase I inhibitor includes (but not It is limited to) Irinotecan (irinotecan), camptothecine (camptothecin) and topotecan (topotecan).

Formulas I composition can be applied in combination with Topoisomerase II inhibitors, the Topoisomerase II inhibitors include (but It is not limited to) Etoposide (etoposide), etoposide phosphate (etoposide phosphate) and mitoxantrone (mitoxantrone)。

Formulas I composition can be applied in combination with histone deacetylase (HDAC) inhibitor, the histone deacetylase Enzyme (HDAC) inhibitor includes but is not limited to Vorinostat (vorinostat), romidepsin (romidepsin), Pa Bisi He (panobinostat), valproic acid (valproic acid) and Belling promise he (belinostat).

Formulas I composition can be applied in combination with DNA methylation inhibitor, and the DNA methylation inhibitor includes (but unlimited In) DZNep and 5- azepine -2'- deoxycytidines.

Formulas I composition can be applied in combination with proteasome inhibitor, and the proteasome inhibitor includes but is not limited to Bortezomib (bortezomib) and the non-azoles rice (carfilzomib) of card.

Formulas I composition can be applied in combination with Distaval, lenalidomide and pomalidomide (pomalidomide).

Formulas I composition can be applied in combination with following：Biological agent, including but not limited to Herceptin (trastuzumab), Ah Duo-Herceptin (ado-trastuzumab), handkerchief trastuzumab (pertuzumab), western appropriate former times Monoclonal antibody (cetuximab), Victibix (panitumumab), Yi Paili monoclonal antibodies (ipilimumab)；Anti- PD-1 agent, including draw Vertical pearl monoclonal antibody (labrolizumab) and Buddhist nun irrigate monoclonal antibody (nivolumab)；Anti- Pd-L1 agent, including MPDL3280A；Anti-angiogenic life At agent, including bevacizumab (bevacizumab) and VEGF Trap (aflibercept)；With antibody-drug conjugates (ADC), Including the appropriate monoclonal antibody Wei Duoting in Belém (brentuximab vedotin) and Herceptin En Taxin (trastuzumab emtansine)。

Formulas I composition can be applied in combination with radiotherapy.

Formulas I composition can be applied in combination with therapeutic vaccine, and the therapeutic vaccine includes but is not limited to western general bright plug- T (sipuleucel-T)。

In some embodiments, the composition of Formulas I or Formula II can with it is one or more in other medicaments as described herein It is applied in combination.

The method for blocking primary mammary tumor growth and invasion：

The first aspect of the present invention be related to it is a kind of blocking primary mammary tumor growth and invasion method, it includes with It is enough to block the dosage regimen of the TIE2 kinases in tumor microenvironment to a effective amount of Formulas I composition of patient's administration in need.

In one embodiment in this aspect of the invention, the dosage regimen of Formulas I composition is daily administration administration.

In another embodiment in this aspect of the invention, the dosage regimen of Formulas I composition is daily administration administration. Intermittent non-daily administration scheme may include (but not limited to) be administered every other day, administration, administration twice weekly or every every three days All single administrations.

In another embodiment in this aspect of the invention, the suitable dosage regimen of Formulas I composition includes weekly Twice, once a week or every other week administration.

In another embodiment in this aspect of the invention, the dosage regimen of Formulas I composition is twice a week or often Zhou Yici.

In other embodiments in this aspect of the invention, the dosage regimen of Formulas I composition is administration twice a week.

The present invention still another embodiment in, block primary mammary tumor growth and invasion method include with Be enough to block the TIE2 kinases in tumor microenvironment dosage regimen administration Formulas I composition and it is one or more be obtained from it is following Medicament：Antitublin, DNA alkylating agent, DNA synthetic inhibitors, DNA intercalators, antiestrogenic agent, anti-HER2 agent, Kinase inhibitor or anti-angiogenic agent.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes administration Formulas I composition and Paclitaxel.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes administration Formulas I composition and the Paclitaxel protein binding particle for injectable suspensions.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes administration Formulas I composition and docetaxel.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes administration Formulas I composition and eribulin.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes administration Formulas I composition and Ipsapirone.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes administration Formulas I composition and vinorelbine.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes administration Formulas I composition and capecitabine.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes administration Formulas I composition and gemcitabine.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes administration Formulas I composition and 5 FU 5 fluorouracil.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes administration Formulas I composition and methotrexate (MTX).

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes administration Formulas I composition and cyclophosphamide.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes administration Formulas I composition and cis-platinum.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes administration Formulas I composition and carboplatin.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes administration Formulas I composition and Doxorubicin.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes administration Formulas I composition and pegylated liposomal Doxorubicin.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes administration Formulas I composition and epirubicin.

In still another embodiment in this aspect of the invention, primary mammary tumor growth and invasion are blocked Method includes administration Formulas I composition and tamoxifen.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes administration Formulas I composition and fulvestrant.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes administration Formulas I composition and Anastrozole.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes administration Formulas I composition and Letrozole.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes administration Formulas I composition and Exemestane.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes administration Formulas I composition and Herceptin.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes administration Formulas I composition and Ah Duo-Herceptin En Taxin.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes administration Formulas I composition and handkerchief trastuzumab.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes administration Formulas I composition and Lapatinib.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes administration Formulas I composition and everolimus.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes administration Formulas I composition and tamiros.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes administration Formulas I composition and CDK4/6 inhibitor LY2835219.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes administration Formulas I composition and CDK4/6 inhibitor LEE011.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes administration Formulas I composition and CDK4/6 inhibitor PD 0332991.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes administration Formulas I composition and bevacizumab.

Another aspect of the present invention is related to a kind of method of blocking primary mammary tumor growth and invasion, it includes To be enough to block the dosage administration Formulas I composition of the TIE2 kinases in tumor microenvironment, wherein the Formulas I composition is with intermittent Non- daily administration scheme administration.In some embodiments, intermittent non-daily administration scheme includes being administered, giving every three days every other day It medicine, administration twice weekly and is administered once a week.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes to be enough to block the dosage administration Formulas I composition of the TIE2 kinases in tumor microenvironment, wherein the Formulas I composition is every All administrations twice, once a week or every other week.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes to be enough to block the dosage administration Formulas I composition of the TIE2 kinases in tumor microenvironment, wherein the Formulas I composition is every Week twice or once a week administration.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method includes to be enough to block the dosage administration Formulas I composition of the TIE2 kinases in tumor microenvironment, wherein the Formulas I composition is every All administrations twice.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method include to be enough to block the dosage administration Formulas I composition of the TIE2 kinases in tumor microenvironment, wherein the Formulas I composition with It is one or more to be obtained from pharmaceutical agent combinations administration below：Antitublin, DNA alkylating agent, DNA synthetic inhibitors, DNA Intercalator, antiestrogenic agent, anti-HER2 agent, kinase inhibitor or anti-angiogenic agent.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method include to be enough to block the dosage administration Formulas I composition of the TIE2 kinases in tumor microenvironment TIE2 expression macrophage, with Lapatinib combines administration.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method include to be enough to block the dosage administration Formulas I composition of the TIE2 kinases in tumor microenvironment TIE2 expression macrophage, with Everolimus combines administration.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method include to be enough to block the dosage administration Formulas I composition of the TIE2 kinases in tumor microenvironment TIE2 expression macrophage, with Tamiros combines administration.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method include to be enough to block the dosage administration Formulas I composition of the TIE2 kinases in tumor microenvironment TIE2 expression macrophage, with CDK4/6 inhibitor LY2835219 combines administration.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method include to be enough to block the dosage administration Formulas I composition of the TIE2 kinases in tumor microenvironment TIE2 expression macrophage, with CDK4/6 inhibitor LEE011 combines administration.

In another embodiment in this aspect of the invention, the side of primary mammary tumor growth and invasion is blocked Method include to be enough to block the dosage administration Formulas I composition of the TIE2 kinases in tumor microenvironment TIE2 expression macrophage, with CDK4/6 inhibitor PD 0332991 combines administration.

It blocks and oozes, spreads and the method for metastasis of cancer in breast cancer：

In the yet other aspects of the present invention, provides and ooze, spread and the method for metastasis of cancer in a kind of blockings breast cancer, wrap Containing a effective amount of Formulas I composition for being enough to block the TIE2 kinases in tumor microenvironment to patient's administration in need.

In one embodiment in this aspect of the invention, blocks and ooze, spread and the method for metastasis of cancer includes in breast cancer To be enough to block the dosage regimen of the TIE2 kinases in tumor microenvironment to be combined to a effective amount of Formulas I of patient's administration in need Object.

In another embodiment in this aspect of the invention, it is sufficient to block in breast cancer ooze, spread and metastasis of cancer to Prescription case includes daily administration Formulas I composition.

In another embodiment in this aspect of the invention, the dosage regimen of Formulas I composition is with intermittent non-every Its administering mode administration, including be administered every other day, every three days administration, administration twice weekly or be administered once a week.

In another embodiment in this aspect of the invention, the dosage regimen of Formulas I composition is twice a week, on every Mondays Secondary or administration every other week.

In another embodiment in this aspect of the invention, the dosage regimen of Formulas I composition is twice a week or often Zhou Yici administrations.

In another embodiment in this aspect of the invention, the dosage regimen of Formulas I composition is administration twice a week.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer Containing to be enough to block the dosage regimen of the TIE2 kinases in tumor microenvironment to be combined to a effective amount of Formulas I of patient's administration in need Object and one or more it is obtained from medicament below：Antitublin, DNA alkylating agent, DNA synthetic inhibitors, DNA are embedding Enter agent, antiestrogenic agent, anti-HER2 agent, kinase inhibitor or anti-angiogenic agent.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and Paclitaxel.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and Paclitaxel protein binding particle for injectable suspensions.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and docetaxel.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and eribulin.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and Ipsapirone.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and vinorelbine.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and capecitabine.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and gemcitabine.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and 5 FU 5 fluorouracil.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and methotrexate (MTX).

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and cyclophosphamide.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and cis-platinum.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and carboplatin.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and Doxorubicin.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and epirubicin.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and tamoxifen.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and fulvestrant.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and Anastrozole.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and Letrozole.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and Exemestane.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and Herceptin.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and more than Ah-Herceptin En Taxin.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and handkerchief trastuzumab.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and Lapatinib.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and everolimus.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and tamiros.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and CDK4/6 inhibitor LY2835219.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and CDK4/6 inhibitor LEE011.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and CDK4/6 inhibitor PD 0332991.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and bevacizumab.

In another aspect of the present invention, block breast cancer in ooze, spread and the method for metastasis of cancer include to be enough to block The dosage administration Formulas I composition of TIE2 kinases in tumor microenvironment, the wherein dosage regimen of Formulas I composition are with intermittent non- Daily administration form administration.In some embodiments, administration every other day includes administration, administration twice weekly or on every Mondays every three days Secondary administration.

In one embodiment in this aspect of the invention, blocks and ooze, spread and the method for metastasis of cancer includes in breast cancer To be enough to block the dosage administration Formulas I composition of the TIE2 kinases in tumor microenvironment, the dosage regimen of wherein Formulas I composition to be Twice a week, once a week or every other week administration.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer Containing to be enough to block the dosage administration Formulas I composition of the TIE2 kinases in tumor microenvironment, the wherein dosage regimen of Formulas I composition For twice a week or once a week administration.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer Containing to be enough to block the dosage administration Formulas I composition of the TIE2 kinases in tumor microenvironment, the wherein dosage regimen of Formulas I composition For administration twice a week.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer Containing to be enough to block the dosage administration Formulas I composition of the TIE2 kinases in tumor microenvironment, with it is one or more be obtained from it is following Pharmaceutical agent combinations administration：Antitublin, DNA synthetic inhibitors, DNA intercalators, antiestrogenic agent, resists DNA alkylating agent HER2 agent, kinase inhibitor or anti-angiogenic agent.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer The composition of Formulas I containing administration and pegylated liposomal Doxorubicin.

In still another embodiment in this aspect of the invention, blocks and ooze, spread and the method for metastasis of cancer in breast cancer Including administration Formulas I composition and tamoxifen.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer Containing to be enough to block tumor microenvironment TIE2 to express the dosage administration Formulas I composition of the TIE2 kinases in macrophage, and pa is drawn Administration is combined for Buddhist nun.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer Containing to be enough to block tumor microenvironment TIE2 to express the dosage administration Formulas I composition of the TIE2 kinases in macrophage, and according to dimension Not department's combination administration.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer Containing to be enough to block tumor microenvironment TIE2 to express the dosage administration Formulas I composition of the TIE2 kinases in macrophage, with smooth sieve Not department's combination administration.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer Containing to be enough to block tumor microenvironment TIE2 to express the dosage administration Formulas I composition of the TIE2 kinases in macrophage, with CDK4/6 inhibitor LY2835219 combines administration.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer Containing to be enough to block tumor microenvironment TIE2 to express the dosage administration Formulas I composition of the TIE2 kinases in macrophage, with CDK4/6 inhibitor LEE011 combines administration.

In another embodiment in this aspect of the invention, blocks and ooze, spread and the method packet of metastasis of cancer in breast cancer Containing to be enough to block tumor microenvironment TIE2 to express the dosage administration Formulas I composition of the TIE2 kinases in macrophage, with CDK4/6 inhibitor PD 0332991 combines administration.

The method for blocking breast cancer immunological tolerance：

Another aspect of the present invention is related to a kind of method blocking breast cancer immunological tolerance.The method include to have need A effective amount of Formulas I composition of patient's administration wanted.In one embodiment, the dosage regimen of salt is enough that mediated immunity is blocked to be resistant to TIE2 kinases in the tumor microenvironment of property.

In one embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes to be enough to hinder The dosage regimen of TIE2 kinases in the tumor microenvironment of disconnected mediating immune tolerance is a effective amount of to patient's administration in need Formulas I composition.

In one embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes daily administration Formulas I composition.

In another embodiment in this aspect of the invention, Formulas I composition by it is intermittent it is non-it is daily in a manner of administration. In some embodiments, intermittent non-daily mode includes administration every other day, every three days administration, administration twice weekly or once a week Administration.

In another embodiment in this aspect of the invention, the administration of Formulas I composition is twice a week, once a week Or every other week.

In another embodiment in this aspect of the invention, Formulas I composition twice a week or once a week administration.

In another embodiment in this aspect of the invention, Formulas I composition administration twice a week.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes to be enough Block the dosage regimen of the TIE2 kinases in tumor microenvironment to a effective amount of Formulas I composition of patient's administration in need and one Kind or a variety of be obtained from medicament below：Antitublin, DNA synthetic inhibitors, DNA intercalators, resists DNA alkylating agent Estrogenic agents, anti-HER2 agent, kinase inhibitor, anti-angiogenic agent or immunomodulator.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula I compositions and Paclitaxel.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula I compositions and Paclitaxel protein binding particle for injectable suspensions.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula I compositions and docetaxel.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula I compositions and eribulin.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula I compositions and Ipsapirone.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula I compositions and vinorelbine.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula I compositions and capecitabine.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula I compositions and gemcitabine.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula I compositions and 5 FU 5 fluorouracil.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula I compositions and 5- methotrexate (MTX)s.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula I compositions and cyclophosphamide.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula I compositions and cis-platinum.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula I compositions and carboplatin.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula I compositions and Doxorubicin.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula I compositions and pegylated liposomal Doxorubicin.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula I compositions and epirubicin.

In still another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration Formulas I composition and tamoxifen.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula I compositions and fulvestrant.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula I compositions and Anastrozole.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula I compositions and Letrozole.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula I compositions and Exemestane.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula I compositions and Herceptin.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula I compositions and Ah Duo-Herceptin En Taxin.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula I compositions and handkerchief trastuzumab.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes to be enough The dosage administration Formulas I composition for blocking the TIE2 kinases in tumor microenvironment TIE2 expression macrophages, is combined with Lapatinib Administration.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes to be enough The dosage administration Formulas I composition for blocking the TIE2 kinases in tumor microenvironment TIE2 expression macrophages, is combined with everolimus Administration.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes to be enough The dosage administration Formulas I composition for blocking the TIE2 kinases in tumor microenvironment TIE2 expression macrophages, is combined with tamiros Administration.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes to be enough The dosage administration Formulas I composition for blocking the TIE2 kinases in tumor microenvironment TIE2 expression macrophages, with CDK4/6 inhibitor LY2835219 combines administration.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes to be enough The dosage administration Formulas I composition for blocking the TIE2 kinases in tumor microenvironment TIE2 expression macrophages, with CDK4/6 inhibitor LEE011 combines administration.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes to be enough The dosage administration Formulas I composition for blocking the TIE2 kinases in tumor microenvironment TIE2 expression macrophages, with CDK4/6 inhibitor PD 0332991 combines administration.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula I compositions and bevacizumab.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula I compositions and anti-CTLA-4 agent.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula I compositions and Yi Paili monoclonal antibodies.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula I compositions and anti-PD-1 agent.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula Pearl monoclonal antibody is found in I compositions and drawing.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula I compositions and anti-PD L-1 agent.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula I compositions and MPDL3280A.

The method for blocking breast cancer immunological tolerance：

In another aspect of the present invention, the method for blocking breast cancer immunological tolerance includes to be enough to block tumour micro-loop The dosage administration Formulas I composition of TIE2 kinases in border, wherein the dosage regimen of Formulas I composition is with intermittent non-daily administration side Formula administration, including be administered every other day, every three days administration, administration twice weekly or be administered once a week.

In one embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes to be enough to hinder The dosage administration Formulas I composition of TIE2 kinases in disconnected tumor microenvironment, wherein the Formulas I composition is twice a week, on every Mondays Secondary or administration every other week.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes to be enough The dosage administration Formulas I composition of the TIE2 kinases in tumor microenvironment is blocked, wherein the Formulas I composition is twice a week or weekly Administration.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes to be enough The dosage administration Formulas I composition of the TIE2 kinases in tumor microenvironment is blocked, wherein Formulas I composition administration twice a week.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes to be enough The dosage administration Formulas I composition for blocking the TIE2 kinases in tumor microenvironment, medicament group below is obtained from one or more Close administration：Antitublin, DNA alkylating agent, DNA synthetic inhibitors, DNA intercalators, antiestrogenic agent, anti-HER2 agent, Kinase inhibitor, anti-angiogenic agent or immunomodulator.

In another embodiment in this aspect of the invention, the method for blocking breast cancer immunological tolerance includes administration formula I compositions and methotrexate (MTX).

The method for improving the overall survival of patients with mastocarcinoma：

Another aspect of the present invention is related to a kind of method for the overall survival improving patients with mastocarcinoma, and it includes Xiang Youxu A effective amount of Formulas I composition of patient's administration wanted.In one embodiment, dosage regimen is enough to block in tumor microenvironment TIE2 kinases.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes The wherein dosage regimen of the daily administration of Formulas I composition.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes By it is intermittent it is non-it is daily in a manner of administration dosage regimen in Formulas I composition, including be administered every other day, every three days administration, weekly It is administered or is administered once a week twice.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Twice a week, the once a week or every other week Formulas I composition in the dosage regimen of administration.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma, Formulas I The dosage regimen of composition is twice a week or once a week administration.

In another embodiment in this aspect of the invention, the dosage regimen of Formulas I composition is only to throw twice a week With.

Another embodiment in terms of this of the present invention is related to the method for improving the overall survival of patients with mastocarcinoma, described Method includes to be enough to block the dosage regimen administration Formulas I composition of the TIE2 kinases in tumor microenvironment and one or more It is obtained from medicament below：Antitublin, DNA alkylating agent, DNA synthetic inhibitors, DNA intercalators, antiestrogenic agent, Anti- HER2 agent, kinase inhibitor, anti-angiogenic agent or immunomodulator.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Administration Formulas I composition and Paclitaxel.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Administration Formulas I composition and Paclitaxel protein binding particle for injectable suspensions.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Administration Formulas I composition and docetaxel.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Administration Formulas I composition and eribulin.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Administration Formulas I composition and Ipsapirone.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Administration Formulas I composition and vinorelbine.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Administration Formulas I composition and capecitabine.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Administration Formulas I composition and gemcitabine.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Administration Formulas I composition and 5 FU 5 fluorouracil.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Administration Formulas I composition and methotrexate (MTX).

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Administration Formulas I composition and cyclophosphamide.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Administration Formulas I composition and cis-platinum.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Administration Formulas I composition and carboplatin.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Administration Formulas I composition and Doxorubicin.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Administration Formulas I composition and pegylated liposomal Doxorubicin.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Administration Formulas I composition and epirubicin.

In still another embodiment in this aspect of the invention, the method packet of the overall survival of patients with mastocarcinoma is improved The composition of Formulas I containing administration and tamoxifen.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Administration Formulas I composition and fulvestrant.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Administration Formulas I composition and Anastrozole.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Administration Formulas I composition and Letrozole.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Administration Formulas I composition and Exemestane.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Administration Formulas I composition and Herceptin.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Administration Formulas I composition and Ah Duo-Herceptin En Taxin.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Administration Formulas I composition and handkerchief trastuzumab.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes To be enough the dosage administration Formulas I composition for blocking tumor microenvironment TIE2 to express the TIE2 kinases in macrophage, replaced with pa is drawn Buddhist nun combines administration.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes To be enough the dosage administration Formulas I composition for blocking tumor microenvironment TIE2 to express the TIE2 kinases in macrophage, with Yi Weimo Department's combination administration.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes To be enough the dosage administration Formulas I composition for blocking tumor microenvironment TIE2 to express the TIE2 kinases in macrophage, with Tan Luomo Department's combination administration.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes To be enough the dosage administration Formulas I composition for blocking tumor microenvironment TIE2 to express the TIE2 kinases in macrophage, with CDK4/6 Inhibitor LY2835219 combines administration.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes To be enough the dosage administration Formulas I composition for blocking tumor microenvironment TIE2 to express the TIE2 kinases in macrophage, with CDK4/6 Inhibitor LEE011 combines administration.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes To be enough the dosage administration Formulas I composition for blocking tumor microenvironment TIE2 to express the TIE2 kinases in macrophage, with CDK4/6 Inhibitor PD 0332991 combines administration.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Administration Formulas I composition and bevacizumab.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Administration Formulas I composition and anti-CTLA-4 agent.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Administration Formulas I composition and Yi Paili monoclonal antibodies.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Administration Formulas I composition and anti-PD-1 agent.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Pearl monoclonal antibody is found in administration Formulas I composition and drawing.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Administration Formulas I composition and anti-PD L-1 agent.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes Administration Formulas I composition and MPDL3280A.

In another aspect of the present invention, the method for improving the overall survival of patients with mastocarcinoma includes swollen to be enough to block The dosage administration Formulas I composition of TIE2 kinases in tumor microenvironment, the wherein dosage regimen of Formulas I composition are intermittent non-daily Administration is administered, including be administered every other day, every three days administration, administration twice weekly or be administered once a week.

In one embodiment in this aspect of the invention, improve the overall survival of patients with mastocarcinoma method include with It is enough to block the dosage administration Formulas I composition of the TIE2 kinases in tumor microenvironment, the dosage regimen of wherein Formulas I composition is every All administrations twice, once a week or every other week.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes To be enough to block the dosage administration Formulas I composition of the TIE2 kinases in tumor microenvironment, the dosage regimen of wherein Formulas I composition to be Twice a week or once a week administration.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes To be enough to block the dosage administration Formulas I composition of the TIE2 kinases in tumor microenvironment, the dosage regimen of wherein Formulas I composition to be Administration twice a week.

In another embodiment in this aspect of the invention, the method for improving the overall survival of patients with mastocarcinoma includes To be enough to block the dosage administration Formulas I composition of the TIE2 kinases in tumor microenvironment, with it is one or more be obtained from it is below Pharmaceutical agent combinations administration：Antitublin, DNA synthetic inhibitors, DNA intercalators, antiestrogenic agent, resists DNA alkylating agent HER2 agent, kinase inhibitor, anti-angiogenic agent or immunomodulator.

In another embodiment in this aspect of the invention, the method administration of the overall survival of patients with mastocarcinoma is improved Formulas I composition and Paclitaxel.

The method for treating the patients with mastocarcinoma before ocal resection in new aided case：

Another aspect of the present invention is related to a kind of breast treated before ocal resection in new aided case The method of cancer patient, it includes to patient's administration in need and a effective amount of Formulas I composition, the dosage regimen of Formulas I composition It is enough to block the TIE2 kinases in tumor microenvironment.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes to be enough to block the dosage regimen of the TIE2 kinases in tumor microenvironment in need A effective amount of Formulas I composition of patient's administration.

In another embodiment in this aspect of the invention, treatment is before operation is cut off in new aided case Patients with mastocarcinoma method include to be enough to block the dosage administration Formulas I composition of the TIE2 kinases in tumor microenvironment, wherein The dosage regimen of Formulas I composition is daily administration.

In another embodiment in this aspect of the invention, treatment is before operation is cut off in new aided case The method of patients with mastocarcinoma include to be enough to block the dosage regimen of the TIE2 kinases in tumor microenvironment to patient in need A effective amount of Formulas I composition of administration, the wherein dosage regimen of Formulas I composition by it is intermittent it is non-it is daily in a manner of administration, including every other day Administration, every three days administration, administration twice weekly are administered once a week.

In another embodiment in this aspect of the invention, treatment is before operation is cut off in new aided case The method of patients with mastocarcinoma include with the dosage regimen of administration twice a week, once a week or every other week to patient's administration in need A effective amount of Formulas I composition.

In another embodiment in this aspect of the invention, treatment is before operation is cut off in new aided case The method of patients with mastocarcinoma include with the twice a week or once a week dosage regimen administration Formulas I composition of administration.

In another embodiment in this aspect of the invention, treatment is before operation is cut off in new aided case Patients with mastocarcinoma method include with block tumor microenvironment TIE2 express macrophage in TIE2 kinases dosage regimen throw With Formulas I composition and one or more be obtained from medicament below：Antitublin, DNA alkylating agent, DNA synthesis suppressions Preparation, DNA intercalators, antiestrogenic agent, anti-HER2 agent, kinase inhibitor, anti-angiogenic agent or immunomodulator.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes administration Formulas I composition and Paclitaxel.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes administration Formulas I composition and the Paclitaxel albumen knot for injectable suspensions Close particle.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes administration Formulas I composition and docetaxel.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes administration Formulas I composition and eribulin.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes administration Formulas I composition and Ipsapirone.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes administration Formulas I composition and vinorelbine.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes administration Formulas I composition and capecitabine.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes administration Formulas I composition and gemcitabine.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes administration Formulas I composition and 5 FU 5 fluorouracil.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes administration Formulas I composition and methotrexate (MTX).

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes administration Formulas I composition and cyclophosphamide.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes administration Formulas I composition and cis-platinum.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes administration Formulas I composition and carboplatin.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes administration Formulas I composition and Doxorubicin.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes administration Formulas I composition and pegylated liposomal Doxorubicin.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes administration Formulas I composition and epirubicin.

In still another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary The method of patients with mastocarcinoma in situation includes administration Formulas I composition and tamoxifen.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes administration Formulas I composition and fulvestrant.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes administration Formulas I composition and Anastrozole.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes administration Formulas I composition and Letrozole.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes administration Formulas I composition and Exemestane.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes administration Formulas I composition and Herceptin.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes administration Formulas I composition and Ah Duo-Herceptin En Taxin.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes administration Formulas I composition and handkerchief trastuzumab.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes to be enough to block the agent of the TIE2 kinases in tumor microenvironment TIE2 expression macrophages Administration Formulas I composition is measured, administration is combined with Lapatinib.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes to be enough to block the agent of the TIE2 kinases in tumor microenvironment TIE2 expression macrophages Administration Formulas I composition is measured, administration is combined with everolimus.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes to be enough to block the agent of the TIE2 kinases in tumor microenvironment TIE2 expression macrophages Administration Formulas I composition is measured, administration is combined with tamiros.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes to be enough to block the agent of the TIE2 kinases in tumor microenvironment TIE2 expression macrophages Administration Formulas I composition is measured, administration is combined with CDK4/6 inhibitor LY2835219.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes to be enough to block the agent of the TIE2 kinases in tumor microenvironment TIE2 expression macrophages Administration Formulas I composition is measured, administration is combined with CDK4/6 inhibitor LEE011.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes to be enough to block the agent of the TIE2 kinases in tumor microenvironment TIE2 expression macrophages Administration Formulas I composition is measured, administration is combined with CDK4/6 inhibitor PD 0332991.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes administration Formulas I composition and bevacizumab.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes administration Formulas I composition and anti-CTLA-4 agent.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes administration Formulas I composition and Yi Paili monoclonal antibodies.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes administration Formulas I composition and anti-PD-1 agent.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes that pearl monoclonal antibody is found in administration Formulas I composition and drawing.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes administration Formulas I composition and anti-PD L-1 agent.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes administration Formulas I composition and MPDL3280A.

The method for treating the patients with mastocarcinoma before operation is cut off in new aided case：

In another aspect of the present invention, treatment is in the patients with mastocarcinoma in new aided case before operation is cut off Method includes to be enough to block the dosage administration Formulas I composition of the TIE2 kinases in tumor microenvironment, and wherein Formulas I composition is given Prescription case administration in the form of intermittent non-daily administration, including be administered every other day, administration, administration twice weekly or weekly every three days Single administration.

In one embodiment in this aspect of the invention, treatment is before operation is cut off in new aided case The method of patients with mastocarcinoma includes to be enough to block the dosage administration Formulas I composition of the TIE2 kinases in tumor microenvironment, wherein Formulas I The dosage regimen of composition administration twice a week, once a week or every other week.

In another embodiment in this aspect of the invention, treatment is before operation is cut off in new aided case Patients with mastocarcinoma method include to be enough to block the dosage administration Formulas I composition of the TIE2 kinases in tumor microenvironment, wherein The dosage regimen of Formulas I composition twice a week or once a week administration.

In another embodiment in this aspect of the invention, treatment is before operation is cut off in new aided case Patients with mastocarcinoma method include to be enough to block the dosage administration Formulas I composition of the TIE2 kinases in tumor microenvironment, wherein The dosage regimen of Formulas I composition administration twice a week.

In another embodiment in this aspect of the invention, treatment is before operation is cut off in new aided case Patients with mastocarcinoma method include to be enough to block the dosage administration Formulas I composition of the TIE2 kinases in tumor microenvironment, with one Kind or a variety of be obtained from pharmaceutical agent combinations administration below：Antitublin, DNA alkylating agent, DNA synthetic inhibitors, DNA are embedding Enter agent, antiestrogenic agent, anti-HER2 agent, kinase inhibitor, anti-angiogenic agent or immunomodulator.

In another embodiment in this aspect of the invention, treatment is before ocal resection in new auxiliary feelings The method of patients with mastocarcinoma in condition includes administration Formulas I composition and 5- methotrexate (MTX)s.

Another aspect of the present invention is related to a kind of method for treating oophoroma, because the conduction of TIE2 path signals has shown that Go out to promote ovarian cancer progress (Karlan et al.,《Journal of Clinical Oncology》(2012)30:362-370).The method includes To be enough to block the dosage regimen of the TIE2 kinases in tumor microenvironment to be combined to a effective amount of Formulas I of patient's administration in need Object.In one embodiment in this aspect of the invention, Formulas I composition is with single medicine type administration.

In another embodiment in this aspect of the invention, Formulas I composition and Paclitaxel+carboplatin, mostly west He combines administration at match+carboplatin, Paclitaxel+cis-platinum or other taxanes+platinum medicine scheme.

Another aspect of the present invention is related to a kind of method for treating hepatocellular carcinoma, because the conduction of TIE2 path signals has been opened up Show to promote hepatocellular carcinoma be in progress and as diagnostic marker (Matsubara et al.,《Hepatology》(2013)57: 1416-1425；Mitsuhashi et al.,《Hepatology》(2003)37:1105-1113；Tanaka et al.,《Clinical research is miscellaneous Will》(1999)103:341-345).The method includes to be enough to block the dosage regimen of the TIE2 kinases in tumor microenvironment To a effective amount of Formulas I composition of patient's administration in need.

In one embodiment in this aspect of the invention, Formulas I composition is with single medicine type administration.

In another embodiment in this aspect of the invention, Formulas I composition and kinase inhibitor combination administration are described Kinase inhibitor includes that Sorafenib, gram Zhuo are rich for Buddhist nun, Sutent, pazopanib, Sorafenib, Rui Gefeini for Buddhist nun, card Or Axitinib.

Another aspect of the present invention is related to a kind of method for treating glioma, because the conduction of TIE2 path signals is Gliomas cancer progress (Liu et al. people, Oncotarget (2010) 1 can be promoted by showing:700-709；Brunckhorst Et al.,《Cancer research》(2010)70:7283-7293).The method includes to be enough to block the TIE2 in tumor microenvironment The dosage regimen of kinases is to a effective amount of Formulas I composition of patient's administration in need.

In another embodiment in this aspect of the invention, Formulas I composition combines administration with radiotherapy.

In another embodiment in this aspect of the invention, Formulas I composition combines administration with Temozolomide therapy.

In another embodiment in this aspect of the invention, Formulas I composition is treated with radiotherapy and Temozolomide Method combines administration.

In another embodiment in this aspect of the invention, Formulas I composition combines administration with bevacizumab therapy.

In another embodiment in this aspect of the invention, Formulas I composition is treated with radiotherapy and bevacizumab Method combines administration.

In another embodiment in this aspect of the invention, Formulas I composition and Temozolomide therapy and bevacizumab Therapy combines administration.

Another aspect of the present invention is related to a kind of method for treating melanoma, because the conduction of TIE2 path signals has shown that Go out to promote melanoma progression (Helfrich et al.,《Clinical Cancer Research》(2009)15:1384-1392；Peinado etc. People,《Natural medicine》(Nature Medicine)(2012)18:883-891).The method includes to be enough to block tumour The dosage regimen of TIE2 kinases in microenvironment is to a effective amount of Formulas I composition of patient's administration in need.

In another embodiment in this aspect of the invention, Formulas I composition combines administration with Wei Luofeini.

In another embodiment in this aspect of the invention, Formulas I composition combines administration with dabrafenib.

In another embodiment in this aspect of the invention, Formulas I composition is combined with dabrafenib and Trimetinib Administration.

In another embodiment in this aspect of the invention, Formulas I composition combines administration with Temozolomide.

In another embodiment in this aspect of the invention, Formulas I composition combines administration with Dacarbazine.

In another embodiment in this aspect of the invention, Formulas I composition combines administration with Yi Paili monoclonal antibodies.

In another embodiment in this aspect of the invention, Formulas I composition irrigates monoclonal antibody group with vertical pearl monoclonal antibody or Buddhist nun is drawn Close administration.

In another embodiment in this aspect of the invention, Formulas I composition combines administration with MPDL3280A.

In another embodiment in this aspect of the invention, Formulas I composition combines administration with Imatinib.

Another aspect of the present invention is related to a kind of method for treating colorectal cancer, because the conduction of TIE2 path signals is Show can promote colorectal cancer progress (Ahmad et al.,《Cancer》(2001)92:1138-1143；Hashizume et al., 《Cancer research》(2010)70:2213-2223).The method includes to be enough to block the TIE2 kinases in tumor microenvironment Dosage regimen is to a effective amount of Formulas I composition of patient's administration in need.

In another embodiment in this aspect of the invention, Formulas I composition and mFOLFOX6 therapies (oxaliplatin+ Formyl tetrahydrofolic acid (leucovorin)+5 FU 5 fluorouracil) combination administration.

In another embodiment in this aspect of the invention, Formulas I composition and mFOLFOX6 therapies and bevacizumab Combine administration.

In another embodiment in this aspect of the invention, Formulas I composition and mFOLFOX6 therapies and Victibix Combine administration.

In another embodiment in this aspect of the invention, Formulas I composition and mFOLFOX6 therapies and western appropriate former times are single Anti- combination administration.

In another embodiment in this aspect of the invention, Formulas I composition combines administration with capecitabine.

In another embodiment in this aspect of the invention, Formulas I composition is combined with capecitabine and bevacizumab Administration.

In another embodiment in this aspect of the invention, Formulas I composition and FOLFIRI therapies (Irinotecan+first Acyl tetrahydrofolic acid+5 FU 5 fluorouracil) combination administration.

In another embodiment in this aspect of the invention, Formulas I composition and FOLFIRI therapies and bevacizumab group Close administration.

In another embodiment in this aspect of the invention, Formulas I composition and FOLFIRI therapies and VEGF Trap group Close administration.

In another embodiment in this aspect of the invention, Formulas I composition and FOLFIRI therapies and Cetuximab Combine administration.

In another embodiment in this aspect of the invention, Formulas I composition and FOLFIRI therapies and Victibix group Close administration.

In another embodiment in this aspect of the invention, Formulas I composition combines administration with Victibix.

In another embodiment in this aspect of the invention, Formulas I composition and Victibix and irinotecan combination Administration.

In another embodiment in this aspect of the invention, Formulas I composition combines administration with Cetuximab.

In another embodiment in this aspect of the invention, Formulas I composition and Cetuximab and Irinotecan group Close administration.

Another aspect of the present invention is related to a kind of method for treating acute myelogenous leukemia, because of TIE2 path signals Conduction have shown that out can promote acute myelogenous leukemia progress (Muller et al.,《Leukaemia research》(2002)26: 163- 168；Hou et al.,《Leukaemia research》(2008)32:904-912).The method includes to be enough to block in tumor microenvironment TIE2 kinases dosage regimen to a effective amount of Formulas I composition of patient's administration in need.

In another embodiment in this aspect of the invention, Formulas I composition is combined with daunomycin and cytarabine Administration.

In another embodiment in this aspect of the invention, Formulas I composition is combined with Ida mycin and cytarabine Administration.

In another embodiment in this aspect of the invention, Formulas I composition is combined with mitoxantrone and cytarabine Administration.

In another embodiment in this aspect of the invention, Formulas I composition combines administration with cytarabine.

In another embodiment in this aspect of the invention, Formulas I composition combines administration with 5-azacitidine.

In another embodiment in this aspect of the invention, Formulas I composition combines administration with Decitabine.

In another embodiment in this aspect of the invention, Formulas I composition with quinoline is miscellaneous combines administration for Buddhist nun.

Another aspect of the present invention is related to a kind of method for the treatment of cancer.The method includes to be thrown to patient in need With a effective amount of Formulas I composition.In one embodiment, patient over-expresses inner membrance endothelial cell kinases 2 (TIE2), and described Cancer be selected from breast cancer, colorectal cancer, hepatocellular carcinoma, head and neck cancer, carcinoma of urinary bladder, oophoroma, glioma, angiosarcoma, Melanoma or acute myelogenous leukemia.

In the certain embodiments of the present invention of therapeutic scheme, Formulas I composition is with daily frequency administration.

In other embodiments of the invention of therapeutic scheme, Formulas I composition is with non-intermittent frequency administration daily.

In other embodiments of the invention of therapeutic scheme, Formulas I composition is with frequency administration three-times-weekly.

In other embodiments of the invention of therapeutic scheme, Formulas I composition is with semiweekly frequency administration.

In other embodiments of the invention of therapeutic scheme, Formulas I composition is with frequency administration once a week.

In other embodiments of the invention of therapeutic scheme, Formulas I composition is with frequency administration once every two weeks.

In other embodiments, the cancer is metastatic, (estrogen receptor negative, PgR are cloudy for three negative breast cancers Property, HER2 it is negative).

In other embodiments, the cancer is estrogen positive (ER⁺) and HER2 receptor kinase feminine genders (HER2^-) breast cancer.

In other embodiments, the cancer is inflammatory breast cancer.

In another embodiment, the method includes to prevent or reduce primary tumor growth, tumor invasiveness, in cancer It oozes, one or more treatments in cancer diffusion, metastasis of cancer and tumour immunity tolerance.In some embodiments, the method Improve survival.

Composite, administration, administration and therapeutic scheme

The present invention is included in the salt (and/or additional agent) of described Formulas I and/or II in various composites.Herein Described any composition (and/or additional agent) can be in the form of the following：Solution, suspension, lotion, drops, tablet, pill, Spherolite, capsule, containing iquid capsule, powder, sustained release formulation, suppository, lotion, aerosol, spraying, suspension or it is any its Its applicable form.In one embodiment, composition is in capsule form (see, for example, U.S. Patent No. 5,698,155). Other examples of suitable drug excipient are described in Remington ' s Pharmaceutical Sciences 1447-1676 In (Alfonso R.Gennaro are compiled, the 19th edition .1995), it is incorporated herein by reference.

When necessary, salt described herein may also comprise solubilizer.In addition, medicament is available as known in fields Suitable mediator or transfer device transmit.Combination treatment outlined herein can altogether pass in single transmission mediator or transfer device It passs.Composition for administration optionally includes local anesthetic (such as lignocaine (lignocaine)) to mitigate injection part The pain of position.

In one embodiment, the salt (and/or additional agent) of Formulas I as described herein and/or II are according to conventional program tune With to be suitable for the composition of administration pattern.

In certain embodiments, administration approach includes for example：It is intradermal, intramuscular, peritonaeum is interior, intravenous, subcutaneous, intranasal, hard Film is outer, oral, sublingual, intranasal, intracerebral, intravaginal, percutaneous, per rectum, by sucking or part, especially arrive ear, nose, eye or Skin.In some embodiments, administration is oral or is realized by parenteral injection.Administration pattern can leave doctor's judgement for, and Depend in part on the position of medical condition.In most cases, administration causes any medicament as described herein to be discharged into blood flow In.

In a particular embodiment, can be desirably to the region part administration for needing to treat or block.

In one embodiment, salt (and/or additional agent) as described herein according to conventional program be allocated as being suitable for through The composition of the mouth administration mankind.The composition orally transmitted can for example in tablet, buccal tablet, aqueous or oily suspensions, particle, Powder, lotion, capsule, syrup or elixirs.The composition being administered orally may include one or more reagents, such as sweet taste Agent, such as fructose, Aspartame or saccharin；Flavoring agent, such as peppermint, wintergreen or cherry oil；Colorant；And preservative, To provide pharmaceutically agreeable to the taste preparation.In addition, when in tablet or pill, composition can be coated to postpone in stomach and intestine Disintegration in road and absorption, to provide the continuous action through extending the period.Encirclement osmotically active drive-type I as described herein Or the alternative permeable membrane of the salt (and/or additional agents) of II applies also for the composition being administered orally.In below these In platform, absorbed by driving composition from the fluid of environment for surrounding capsule, the driving composition expansion so that medicament or Medicament composition is shifted across opening.These transmission platforms can provide opposite with the needle pattern curve of composite is released immediately Substantially zero level transfer curve.Time delay material can also be used, such as glycerin monostearate or tristerin.Oral compositions Object may include standard excipients, such as mannitol, lactose, starch, magnesium stearate, saccharin sodium, cellulose and magnesium carbonate.One In a embodiment, the excipient is pharmaceutical grade.Other than active compound, suspension can contain suspending agent, such as ethoxy Base isooctadecanol, polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, inclined aluminium hydroxide, bentonite, fine jade Fat-agar, tragacanth etc. and its mixture.

Dosage form suitable for parenteral administration (such as in intravenous, intramuscular, peritonaeum, subcutaneous and intra-articular injection and perfusion) Including such as solution, suspension, dispersion liquid, lotion etc..It can be in the form of aseptic solid composite (such as freeze-dried composition) Manufacture can will dissolve or be suspended in sterile injectable medium before use.It can contain in such as fields The suspension known or dispersant.

The dosage and administration time-histories of the salt (and/or additional agents) of Formulas I described herein and/or II may depend on respectively Kind parameter, the judgement of the disease including but not limited to treated, the general health and administration doctor of individual.It is described herein Any medicament can before another therapeutic agent of administration (such as before 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 Hour, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks), simultaneously or after which (5 minutes after such as, 15 minutes, 30 minutes, 45 minutes, 1 hour, it is 2 small When, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 Week or 12 weeks) administration individual in need.In various embodiments, any medicament as described herein is separated by 1 minute, is separated by 10 points Clock, be separated by 30 minutes, be separated by less than 1 hour, be separated by 1 hour, be separated by 1 hour to 2 hours, be separated by 2 hours to 3 hours, be separated by 3 hours to 4 hours, be separated by 4 hours to 5 hours, be separated by 5 hours to 6 hours, being separated by 6 hours to 7 hours, being separated by 7 hours to 8 Hour is separated by 8 hours to 9 hours, is separated by 9 hours to 10 hours, being separated by 10 hours to 11 hours or be separated by 11 hours to 12 Hour administration.

The dosage of the salt (and/or additional agents) of Formulas I as described herein or II may depend on several factors, including the patient's condition Severity, the patient's condition are age, weight and the health status of individual being treated or be prevented and to be treated.In addition, closing In drug gene body (effect of the genotype to the pharmacokinetics for the treatment of, the pharmacodynamics or effect overview) letter of specific individual Breath can influence used dosage.In addition, the exact visual many factors of individual dose and adjust slightly, the factor includes institute The specific combination of the medicament of administration, the time of administration, the approach of administration, the property of composite, the rate of excretion, the tool treated The anatomical location of body disease, the severity of illness and illness.Some variations of expectable dosage.

In general, when being administered orally mammal, the agent of any Formulas I composition (and/or additional agent) as described herein Amount can be 0.001 mg/kg/day to 100 mg/kg/days, 0.01 mg/kg/day to 50 mg/kg/days or 0.1 mg/kg/day to 10 mg/kg/days.When being administered orally the mankind, the dosage of any medicament as described herein is usual For daily 0.001mg to 1500mg, daily 1mg to 600mg or daily 5mg to 30mg.In some embodiments, salt (or medicine Agent) dosage in daily 57mg to 1200mg ranges.In other embodiments, the dosage of medicament or salt is arrived in daily 100mg Within the scope of 200mg.

For Formulas I as described herein or II salt (and/or additional agent) by the administration of parenteral injection, dosage is usual For daily 0.1mg to 250mg, daily 1mg to 20mg or daily 3mg to 5mg.Injection can be given at most four times per day.In general, When oral or parenteral administration, the dosage of any medicament as described herein is usually daily 0.1mg to 1500mg or daily 0.5mg to 10mg or daily 0.5mg to 5mg.Daily can the most 3000mg of administration dosage.

The administration of salt (and/or additional agent) as described herein can independently be daily one to four times.Specifically, salt Administration can be with salt the dosage regimen of about 50mg to 1500mg once a day.Daily agent suitable for sought prophylactic action Amount is 57-1200 mg/days.If administration twice daily, suitable dosage is the salt of 100mg to 200mg.Salt can also between It has a rest non-daily administration.Specifically, can monthly one to four times or it is annual one to six times or every two years, 3 years, 4 years or 5 years The primary administration for carrying out salt.In certain embodiments, the administration of salt is carried out weekly or every two weeks.When weekly or every two weeks administration When, suitable salt dosage regimen is within the scope of 50-200mg/ is per administration.Certain weekly or every two weeks in administration, dosage is 200-400mg/ is per administration.Other patterns again of administration include 400-500 mg/ per administration, 500-600mg/ weekly or every two weeks Per administration, 600-700mg/ per administration, 700-800mg/ per administration, 800-900mg/ per administration, 900-1000mg/ per administration, 1000-1100mg/ is per administration or 1100-1200mg/ is per administration.The duration of administration can be one day or one month, two months, Three months, six months, 1 year, 2 years, 3 years, thereby increases and it is possible to or even continue the service life of individual.It will indicate in many cases chronic Long-term administration.Dosage with single dose form or can be divided into multiple dosage administrations.In general, required dosage should with setting when Between interval spans extended period administrations, typically at least through several weeks or several months, but the administration of several months or several years may be needed Longer period.

The invention further relates to following aspect：

A kind of 1. methods blocking primary mammary tumor growths and invasion, it includes to patient's administration in need A effective amount of Formulas I composition

Wherein

The integer that n is 0 to 7；

X is the basic group of pharmaceutically acceptable salt；

Its restrictive condition is when n is 0, and the Formulas I composition is parent free alkali；

By the dosage regimen for being enough to block the TIE2 kinases in tumor microenvironment.

Method of the item 2. according to item 1, wherein the daily administration of the dosage regimen.

Method of the item 3. according to item 1, wherein the dosage regimen is intermittent non-daily administration, is administered every other day, is every It is administered every administration in two days, administration twice weekly or once a week.

4. method according to item 1, wherein the dosage regimen is twice a week, once a week or by giving every other week Medicine.

Method of the item 5. according to any one of item 1 to 4, wherein the Formulas I composition is obtained from one or more Pharmaceutical agent combinations below use：Antitublin, DNA alkylating agent, DNA synthetic inhibitors, DNA intercalators, antiestrogenic Agent, anti-HER2 agent, kinase inhibitor or anti-angiogenic agent.

Method of the item 6. according to any one of item 1 to 4, wherein the Formulas I composition is combined with Paclitaxel It uses.

7. method according to any one of item 1 to 4, wherein the Formulas I composition be used for injectable suspensions Paclitaxel protein binding particle combinations use.

Method of the item 8. according to any one of item 1 to 4, wherein the compound of formula I is applied in combination with eribulin.

Method of the item 9. according to any one of item 1 to 4, wherein the Formulas I composition is applied in combination with Ipsapirone.

Method of the item 10. according to any one of item 1 to 4, makes wherein the Formulas I composition is combined with vinorelbine With.

Method of the item 11. according to any one of item 1 to 4, makes wherein the Formulas I composition is combined with capecitabine With.

Method of the item 12. according to any one of item 1 to 4, makes wherein the Formulas I composition is combined with gemcitabine With.

Method of the item 13. according to any one of item 1 to 4, makes wherein the Formulas I composition is combined with 5 FU 5 fluorouracil With.

Method of the item 14. according to any one of item 1 to 4, makes wherein the Formulas I composition is combined with methotrexate (MTX) With.

Method of the item 15. according to any one of item 1 to 4, makes wherein the Formulas I composition is combined with cyclophosphamide With.

Method of the item 16. according to any one of item 1 to 4, wherein the Formulas I composition is used with cisplatin combination.

Method of the item 17. according to any one of item 1 to 4, wherein the Formulas I composition is applied in combination with carboplatin.

Method of the item 18. according to any one of item 1 to 4, makes wherein the Formulas I composition is combined with Doxorubicin With.

Method of the item 19. according to any one of item 1 to 4, wherein the Formulas I composition and pegylated liposomal Doxorubicin is applied in combination.

Method of the item 20. according to any one of item 1 to 4, makes wherein the Formulas I composition is combined with epirubicin With.

Method of the item 21. according to any one of item 1 to 4, makes wherein the Formulas I composition is combined with tamoxifen With.

Method of the item 22. according to any one of item 1 to 4, makes wherein the Formulas I composition is combined with fulvestrant With.

Method of the item 23. according to any one of item 1 to 4, makes wherein the Formulas I composition is combined with Anastrozole With.

Method of the item 24. according to any one of item 1 to 4, wherein the Formulas I composition is applied in combination with Letrozole.

Method of the item 25. according to any one of item 1 to 4, makes wherein the Formulas I composition is combined with Exemestane With.

Method of the item 26. according to any one of item 1 to 4, makes wherein the Formulas I composition is combined with Herceptin With.

Method of the item 27. according to any one of item 1 to 4, wherein the Formulas I composition and Ah Duo-Herceptin His Combination nova of grace uses.

Method of the item 28. according to any one of item 1 to 4, makes wherein the Formulas I composition is combined with handkerchief trastuzumab With.

Method of the item 29. according to any one of item 1 to 4, makes wherein the Formulas I composition is combined with Lapatinib With.

Method of the item 30. according to any one of item 1 to 4, makes wherein the Formulas I composition is combined with everolimus With.

Method of the item 31. according to any one of item 1 to 4, makes wherein the Formulas I composition is combined with tamiros With.

Method of the item 32. according to any one of item 1 to 4, wherein the Formulas I composition and CDK4/6 inhibitor LY2835219 is applied in combination.

Method of the item 33. according to any one of item 1 to 4, wherein the Formulas I composition and CDK4/6 inhibitor LEE011 is applied in combination.

Method of the item 34. according to any one of item 1 to 4, wherein the Formulas I composition and CDK4/6 inhibitor PD 0332991 is applied in combination.

Method of the item 35. according to any one of item 1 to 4, makes wherein the Formulas I composition is combined with bevacizumab With.

Method of the item 36. according to any one of item 1 to 35, wherein the composition is Formula II composition.

Method of the item 37. according to any one of item 1 to 36, wherein the Formulas I or Formula II composition are arrived with such as item 6 One or more of other medicaments differentiated in 35 are applied in combination.

It oozes, spread and the method for metastasis of cancer in a kind of 38. blocking breast cancers, it includes effective to patient's administration in need The Formulas I composition of amount

Wherein

The integer that n is 0 to 7；

X is the basic group of pharmaceutically acceptable salt；

Its restrictive condition is when n is 0, and the Formulas I composition is parent free alkali,

By the dosage regimen for being enough that tumor microenvironment TIE2 is blocked to express the TIE2 kinases in macrophage.

Method of the item 39. according to item 38, wherein the daily administration of the dosage regimen.

40. method according to item 38, wherein the dosage regimen be intermittent non-daily administration, administration every other day, Every three days administration, administration twice weekly or be administered once a week.

41. method according to item 38, wherein the dosage regimen is twice a week, once a week or by giving every other week Medicine.

Method of the item 42. according to any one of item 38 to 41, wherein the Formulas I composition and one or more acquisitions It is used from pharmaceutical agent combinations below：Antitublin, DNA synthetic inhibitors, DNA intercalators, anti-female swashs at DNA alkylating agent Plain agent, anti-HER2 agent, kinase inhibitor or anti-angiogenic agent.

Method of the item 43. according to any one of item 38 to 41, wherein the Formulas I composition and Paclitaxel group It closes and uses.

Method of the item 44. according to any one of item 38 to 41, wherein the Formulas I composition suspends with for injectable The Paclitaxel protein binding particle combinations of liquid use.

Method of the item 45. according to any one of item 38 to 41, makes wherein the Formulas I composition is combined with eribulin With.

Method of the item 46. according to any one of item 38 to 41, makes wherein the Formulas I composition is combined with Ipsapirone With.

Method of the item 47. according to any one of item 38 to 41, makes wherein the Formulas I composition is combined with vinorelbine With.

Method of the item 48. according to any one of item 38 to 41, makes wherein the Formulas I composition is combined with capecitabine With.

Method of the item 49. according to any one of item 38 to 41, makes wherein the Formulas I composition is combined with gemcitabine With.

Method of the item 50. according to any one of item 38 to 41, wherein the Formulas I composition is combined with 5 FU 5 fluorouracil It uses.

Method of the item 51. according to any one of item 38 to 41, makes wherein the Formulas I composition is combined with methotrexate (MTX) With.

Method of the item 52. according to any one of item 38 to 41, makes wherein the Formulas I composition is combined with cyclophosphamide With.

Method of the item 53. according to any one of item 38 to 41, wherein the Formulas I composition is used with cisplatin combination.

Method of the item 54. according to any one of item 38 to 41, wherein the Formulas I composition is applied in combination with carboplatin.

Method of the item 55. according to any one of item 38 to 41, makes wherein the Formulas I composition is combined with Doxorubicin With.

Method of the item 56. according to any one of item 38 to 41, wherein the Formulas I composition and pegylated lipids Body Doxorubicin is applied in combination.

Method of the item 57. according to any one of item 38 to 41, makes wherein the Formulas I composition is combined with epirubicin With.

Method of the item 58. according to any one of item 38 to 41, makes wherein the Formulas I composition is combined with tamoxifen With.

Method of the item 59. according to any one of item 38 to 41, makes wherein the Formulas I composition is combined with fulvestrant With.

Method of the item 60. according to any one of item 38 to 41, makes wherein the Formulas I composition is combined with Anastrozole With.

Method of the item 61. according to any one of item 38 to 41, makes wherein the Formulas I composition is combined with Letrozole With.

Method of the item 62. according to any one of item 38 to 41, makes wherein the Formulas I composition is combined with Exemestane With.

Method of the item 63. according to any one of item 38 to 41, wherein the Formulas I composition is combined with Herceptin It uses.

Method of the item 64. according to any one of item 38 to 41, wherein the Formulas I composition and Ah Duo-toltrazuril list His Combination nova of anti-grace uses.

Method of the item 65. according to any one of item 38 to 41, wherein the Formulas I composition is combined with handkerchief trastuzumab It uses.

Method of the item 66. according to any one of item 38 to 41, makes wherein the Formulas I composition is combined with Lapatinib With.

Method of the item 67. according to any one of item 38 to 41, makes wherein the Formulas I composition is combined with everolimus With.

Method of the item 68. according to any one of item 38 to 41, makes wherein the Formulas I composition is combined with tamiros With.

Method of the item 69. according to any one of item 38 to 41, wherein the Formulas I composition and CDK4/6 inhibitor LY2835219 is applied in combination.

Method of the item 70. according to any one of item 38 to 41, wherein the Formulas I composition and CDK4/6 inhibitor LEE011 is applied in combination.

Method of the item 71. according to any one of item 38 to 41, wherein the Formulas I composition and CDK4/6 inhibitor PD 0332991 is applied in combination.

Method of the item 72. according to any one of item 38 to 41, makes wherein the Formulas I composition is combined with bevacizumab With.

Method of the item 73. according to any one of item 38 to 72, wherein the composition is Formula II composition.

Method of the item 74. according to any one of item 38 to 73, wherein the Formulas I or Formula II composition and such as item 43 It is applied in combination to one or more of the other medicaments differentiated in 72.

A kind of 75. methods blocking breast cancer immunological tolerance, it includes to a effective amount of Formulas I of patient's administration in need Composition

Wherein

The integer that n is 0 to 7；

X is the basic group of pharmaceutically acceptable salt；

By the TIE2 kinases in the tumor microenvironment TIE2 expression macrophages for being enough to block mediating immune tolerance to Prescription case.

Method of the item 76. according to item 75, wherein the daily administration of the dosage regimen.

77. method according to item 75, wherein the dosage regimen be intermittent non-daily administration, administration every other day, Every three days administration, administration twice weekly or be administered once a week.

Method of the item 78. according to item 75, wherein the dosage regimen is twice a week, once a week or by side every other week Case.

Method of the item 79. according to any one of item 75 to 78, wherein the Formulas I composition and one or more acquisitions It is used from pharmaceutical agent combinations below：Antitublin, DNA synthetic inhibitors, DNA intercalators, anti-female swashs at DNA alkylating agent Plain agent, anti-HER2 agent, kinase inhibitor, anti-angiogenic agent or immunomodulator.

Method of the item 80. according to any one of item 75 to 78, wherein the Formulas I composition and Paclitaxel group It closes and uses.

Method of the item 81. according to any one of item 75 to 78, wherein the Formulas I composition suspends with for injectable The Paclitaxel protein binding particle combinations of liquid use.

Method of the item 82. according to any one of item 75 to 78, makes wherein the Formulas I composition is combined with eribulin With.

Method of the item 83. according to any one of item 75 to 78, makes wherein the Formulas I composition is combined with Ipsapirone With.

Method of the item 84. according to any one of item 75 to 78, makes wherein the Formulas I composition is combined with vinorelbine With.

Method of the item 85. according to any one of item 75 to 78, makes wherein the Formulas I composition is combined with capecitabine With.

Method of the item 86. according to any one of item 75 to 78, makes wherein the Formulas I composition is combined with gemcitabine With.

Method of the item 87. according to any one of item 75 to 78, wherein the Formulas I composition is combined with 5 FU 5 fluorouracil It uses.

Method of the item 88. according to any one of item 75 to 78, makes wherein the Formulas I composition is combined with methotrexate (MTX) With.

Method of the item 89. according to any one of item 75 to 78, makes wherein the Formulas I composition is combined with cyclophosphamide With.

Method of the item 90. according to any one of item 75 to 78, wherein the Formulas I composition is used with cisplatin combination.

Method of the item 91. according to any one of item 75 to 78, wherein the Formulas I composition is applied in combination with carboplatin.

Method of the item 92. according to any one of item 75 to 78, makes wherein the Formulas I composition is combined with Doxorubicin With.

Method of the item 93. according to any one of item 75 to 78, wherein the Formulas I composition and pegylated lipids Body Doxorubicin is applied in combination.

Method of the item 94. according to any one of item 75 to 78, makes wherein the Formulas I composition is combined with epirubicin With.

Method of the item 95. according to any one of item 75 to 78, makes wherein the Formulas I composition is combined with tamoxifen With.

Method of the item 96. according to any one of item 75 to 78, makes wherein the Formulas I composition is combined with fulvestrant With.

Method of the item 97. according to any one of item 75 to 78, makes wherein the Formulas I composition is combined with Anastrozole With.

Method of the item 98. according to any one of item 75 to 78, makes wherein the Formulas I composition is combined with Letrozole With.

Method of the item 99. according to any one of item 75 to 78, makes wherein the Formulas I composition is combined with Exemestane With.

Method of the item 100. according to any one of item 75 to 78, wherein the Formulas I composition and Herceptin group It closes and uses.

Method of the item 101. according to any one of item 75 to 78, wherein the Formulas I composition and Ah Duo-toltrazuril list His Combination nova of anti-grace uses.

Method of the item 102. according to any one of item 75 to 78, wherein the Formulas I composition and handkerchief trastuzumab group It closes and uses.

Method of the item 103. according to any one of item 75 to 78, wherein the Formulas I composition is combined with Lapatinib It uses.

Method of the item 104. according to any one of item 75 to 78, wherein the Formulas I composition is combined with everolimus It uses.

Method of the item 105. according to any one of item 75 to 78, wherein the Formulas I composition is combined with tamiros It uses.

Method of the item 106. according to any one of item 75 to 78, wherein the Formulas I composition and CDK4/6 inhibitor LY2835219 is applied in combination.

Method of the item 107. according to any one of item 75 to 78, wherein the Formulas I composition and CDK4/6 inhibitor LEE011 is applied in combination.

Method of the item 108. according to any one of item 75 to 78, wherein the Formulas I composition and CDK4/6 inhibitor PD 0332991 is applied in combination.

Method of the item 109. according to any one of item 75 to 78, wherein the Formulas I composition is combined with bevacizumab It uses.

Method of the item 110. according to any one of item 75 to 78, wherein the Formulas I composition and anti-CTLA-4 agent group It closes and uses.

Method of the item 111. according to any one of item 75 to 78, wherein the Formulas I composition and Yi Paili monoclonal antibody groups It closes and uses.

Method of the item 112. according to any one of item 75 to 78, wherein the Formulas I composition is combined with anti-PD-1 agent It uses.

Method of the item 113. according to any one of item 75 to 78, wherein the Formulas I composition founds pearl monoclonal antibody group with drawing It closes and uses.

Method of the item 114. according to any one of item 75 to 78, wherein the Formulas I composition and anti-PD L-1 agent groups It closes and uses.

Method of the item 115. according to any one of item 75 to 78, wherein the Formulas I composition and MPDL3280A groups It closes and uses.

Method of the item 116. according to any one of item 75 to 115, wherein the composition is Formula II composition.

Method of the item 117. according to any one of item 75 to 116, wherein the Formulas I or Formula II composition and such as item One or more of other medicaments differentiated in 80 to 115 are applied in combination.

A kind of methods for the whole survival period extending patients with mastocarcinoma of item 118., it includes effective to patient's administration in need The Formulas I composition of amount

Wherein

The integer that n is 0 to 7；

X is the basic group of pharmaceutically acceptable salt；

Method of the item 119. according to item 118, wherein the daily administration of the dosage regimen.

Method of the item 120. according to item 118, wherein the dosage regimen is intermittent non-daily administration, gives every other day Medicine, every three days administration, administration twice weekly are administered once a week.

Method of the item 121. according to item 118, wherein the dosage regimen is twice a week, once a week or by every other week Scheme.

122. method according to item 118 to 121, wherein the Formulas I composition with it is one or more be obtained from Under pharmaceutical agent combinations use：Antitublin, DNA alkylating agent, DNA synthetic inhibitors, DNA intercalators, antiestrogenic agent, Anti- HER2 agent, kinase inhibitor, anti-angiogenic agent or immunomodulator.

Method of the item 123. according to any one of item 118 to 121, wherein the Formulas I composition and Pacific yew Alcohol is applied in combination.

124. method according to any one of item 118 to 121, wherein the Formulas I composition be used for injectable The Paclitaxel protein binding particle combinations of suspension use.

Method of the item 125. according to any one of item 118 to 121, wherein the Formulas I composition and eribulin group It closes and uses.

Method of the item 126. according to any one of item 118 to 121, wherein the Formulas I composition and Ipsapirone group It closes and uses.

Method of the item 127. according to any one of item 118 to 121, wherein the Formulas I composition and vinorelbine group It closes and uses.

Method of the item 128. according to any one of item 118 to 121, wherein the Formulas I composition and capecitabine group It closes and uses.

Method of the item 129. according to any one of item 118 to 121, wherein the Formulas I composition and gemcitabine group It closes and uses.

Method of the item 130. according to any one of item 118 to 121, wherein the Formulas I composition and 5 FU 5 fluorouracil It is applied in combination.

Method of the item 131. according to any one of item 118 to 121, wherein the Formulas I composition and methotrexate (MTX) group It closes and uses.

Method of the item 132. according to any one of item 118 to 121, wherein the Formulas I composition and cyclophosphamide group It closes and uses.

Method of the item 133. according to any one of item 118 to 121, wherein the Formulas I composition makes with cisplatin combination With.

Method of the item 134. according to any one of item 118 to 121, makes wherein the Formulas I composition is combined with carboplatin With.

Method of the item 135. according to any one of item 118 to 121, wherein the Formulas I composition and Doxorubicin group It closes and uses.

Method of the item 136. according to any one of item 118 to 121, wherein the Formulas I composition and Pegylation Liposomal doxorubicin is applied in combination.

Method of the item 137. according to any one of item 118 to 121, wherein the Formulas I composition and epirubicin group It closes and uses.

Method of the item 138. according to any one of item 118 to 121, wherein the Formulas I composition and tamoxifen group It closes and uses.

Method of the item 139. according to any one of item 118 to 121, wherein the Formulas I composition and fulvestrant group It closes and uses.

Method of the item 140. according to any one of item 118 to 121, wherein the Formulas I composition and Anastrozole group It closes and uses.

Method of the item 141. according to any one of item 118 to 121, wherein the Formulas I composition is combined with Letrozole It uses.

Method of the item 142. according to any one of item 118 to 121, wherein the Formulas I composition and Exemestane group It closes and uses.

Method of the item 143. according to any one of item 118 to 121, wherein the Formulas I composition and Herceptin It is applied in combination.

Method of the item 144. according to any one of item 118 to 121, wherein the Formulas I composition and Ah Duo-toltrazuril His Combination nova of monoclonal antibody grace uses.

Method of the item 145. according to any one of item 118 to 121, wherein the Formulas I composition and handkerchief trastuzumab It is applied in combination.

Method of the item 146. according to any one of item 118 to 121, wherein the Formulas I composition and Lapatinib group It closes and uses.

Method of the item 147. according to any one of item 118 to 121, wherein the Formulas I composition and everolimus group It closes and uses.

Method of the item 148. according to any one of item 118 to 121, wherein the Formulas I composition and tamiros group It closes and uses.

Method of the item 149. according to any one of item 118 to 121, wherein the Formulas I composition inhibits with CDK4/6 Agent LY2835219 is applied in combination.

Method of the item 150. according to any one of item 118 to 121, wherein the Formulas I composition inhibits with CDK4/6 Agent LEE011 is applied in combination.

Method of the item 151. according to any one of item 118 to 121, wherein the Formulas I composition inhibits with CDK4/6 Agent PD 0332991 is applied in combination.

Method of the item 152. according to any one of item 118 to 121, wherein the Formulas I composition and bevacizumab group It closes and uses.

Method of the item 153. according to any one of item 118 to 121, wherein the Formulas I composition and anti-CTLA-4 agent It is applied in combination.

Method of the item 154. according to any one of item 118 to 121, wherein the Formulas I composition and Yi Paili monoclonal antibodies It is applied in combination.

Method of the item 155. according to any one of item 118 to 121, wherein the Formulas I composition and anti-PD-1 agent group It closes and uses.

Method of the item 156. according to any one of item 118 to 121, wherein the Formulas I composition founds pearl monoclonal antibody with drawing It is applied in combination.

Method of the item 157. according to any one of item 118 to 121, wherein the Formulas I composition and anti-PD L-1 agent It is applied in combination.

Method of the item 158. according to any one of item 118 to 121, wherein the Formulas I composition and MPDL3280A It is applied in combination.

Method of the item 159. according to any one of item 118 to 158, wherein the composition is Formula II composition.

Method of the item 160. according to any one of item 118 to 159, wherein the Formulas I or Formula II composition and such as item One or more of other medicaments differentiated in 123 to 158 are applied in combination.

A kind of methods of patients with mastocarcinoma of 161. treatments in new aided case, it includes ocal resection it A effective amount of Formulas I composition of forward direction patient's administration in need.

Method of the item 162. according to item 161, wherein the daily administration of the dosage regimen.

Method of the item 163. according to item 161, wherein the dosage regimen is intermittent non-daily administration, gives every other day Medicine, every three days administration, administration twice weekly are administered once a week.

A kind of methods of patients with mastocarcinoma of 164. treatment of item before ocal resection in new aided case, packet Containing to be enough to block the dosage regimen of the TIE2 kinases in tumor microenvironment to be combined to a effective amount of Formulas I of patient's administration in need Object, twice a week, once a week or by Formulas I composition described in scheme administration every other week dosage.

165. method according to any one of item 161 to 164, wherein the Formulas I composition with it is one or more Pharmaceutical agent combinations below are obtained to use：Antitublin, DNA synthetic inhibitors, DNA intercalators, resists DNA alkylating agent Estrogenic agents, anti-HER2 agent, kinase inhibitor, anti-angiogenic agent or immunomodulator.

Method of the item 166. according to any one of item 161 to 164, wherein the Formulas I composition and Pacific yew Alcohol is applied in combination.

167. method according to any one of item 161 to 164, wherein the Formulas I composition be used for injectable The Paclitaxel protein binding particle combinations of suspension use.

Method of the item 168. according to any one of item 161 to 164, wherein the Formulas I composition and eribulin group It closes and uses.

Method of the item 169. according to any one of item 161 to 164, wherein the Formulas I composition and Ipsapirone group It closes and uses.

Method of the item 170. according to any one of item 161 to 164, wherein the Formulas I composition and vinorelbine group It closes and uses.

Method of the item 171. according to any one of item 161 to 164, wherein the Formulas I composition and capecitabine group It closes and uses.

Method of the item 172. according to any one of item 161 to 164, wherein the Formulas I composition and gemcitabine group It closes and uses.

Method of the item 173. according to any one of item 161 to 164, wherein the Formulas I composition and 5 FU 5 fluorouracil It is applied in combination.

Method of the item 174. according to any one of item 161 to 164, wherein the Formulas I composition and methotrexate (MTX) group It closes and uses.

Method of the item 175. according to any one of item 161 to 164, wherein the Formulas I composition and cyclophosphamide group It closes and uses.

Method of the item 176. according to any one of item 161 to 164, wherein the Formulas I composition makes with cisplatin combination With.

Method of the item 177. according to any one of item 161 to 164, makes wherein the Formulas I composition is combined with carboplatin With.

Method of the item 178. according to any one of item 161 to 164, wherein the Formulas I composition and Doxorubicin group It closes and uses.

Method of the item 179. according to any one of item 161 to 164, wherein the Formulas I composition and Pegylation Liposomal doxorubicin is applied in combination.

Method of the item 180. according to any one of item 161 to 164, wherein the Formulas I composition and epirubicin group It closes and uses.

Method of the item 181. according to any one of item 161 to 164, wherein the Formulas I composition and tamoxifen group It closes and uses.

Method of the item 182. according to any one of item 161 to 164, wherein the Formulas I composition and fulvestrant group It closes and uses.

Method of the item 183. according to any one of item 161 to 164, wherein the Formulas I composition and Anastrozole group It closes and uses.

Method of the item 184. according to any one of item 161 to 164, wherein the Formulas I composition is combined with Letrozole It uses.

Method of the item 185. according to any one of item 161 to 164, wherein the Formulas I composition and Exemestane group It closes and uses.

Method of the item 186. according to any one of item 161 to 164, wherein the Formulas I composition and Herceptin It is applied in combination.

Method of the item 187. according to any one of item 161 to 164, wherein the Formulas I composition and Ah Duo-toltrazuril His Combination nova of monoclonal antibody grace uses.

Method of the item 188. according to any one of item 161 to 164, wherein the Formulas I composition and handkerchief trastuzumab It is applied in combination.

Method of the item 189. according to any one of item 161 to 164, wherein the Formulas I composition and Lapatinib group It closes and uses.

Method of the item 190. according to any one of item 161 to 164, wherein the Formulas I composition and everolimus group It closes and uses.

Method of the item 191. according to any one of item 161 to 164, wherein the Formulas I composition and tamiros group It closes and uses.

Method of the item 192. according to any one of item 161 to 164, wherein the Formulas I composition inhibits with CDK4/6 Agent LY2835219 is applied in combination.

Method of the item 193. according to any one of item 161 to 164, wherein the Formulas I composition inhibits with CDK4/6 Agent LEE011 is applied in combination.

Method of the item 194. according to any one of item 161 to 164, wherein the Formulas I composition inhibits with CDK4/6 Agent PD 0332991 is applied in combination.

Method of the item 195. according to any one of item 161 to 164, wherein the Formulas I composition and bevacizumab group It closes and uses.

Method of the item 196. according to any one of item 161 to 164, wherein the Formulas I composition and anti-CTLA-4 agent It is applied in combination.

Method of the item 197. according to any one of item 161 to 164, wherein the Formulas I composition and Yi Paili monoclonal antibodies It is applied in combination.

Method of the item 198. according to any one of item 161 to 164, wherein the Formulas I composition and anti-PD-1 agent group It closes and uses.

Method of the item 199. according to any one of item 161 to 164, wherein the Formulas I composition founds pearl monoclonal antibody with drawing It is applied in combination.

Method of the item 200. according to any one of item 161 to 164, wherein the Formulas I composition and anti-PD L-1 agent It is applied in combination.

Method of the item 201. according to any one of item 161 to 164, wherein the Formulas I composition and MPDL3280A It is applied in combination.

Method of the item 202. according to any one of item 161 to 201, wherein the composition is Formula II composition.

Method of the item 203. according to any one of item 161 to 202, wherein the Formulas I or Formula II composition and such as item One or more of other medicaments differentiated in 166 to 201 are applied in combination.

A kind of 204. methods for the treatment of cancer, it includes by a effective amount of Formulas I composition：

Wherein

The integer that n is 0 to 7；

X is the basic group of pharmaceutically acceptable salt；

Administration patient in need,

The wherein described patient over-expresses tyrosine kinase and inner membrance endothelial cell kinases -2 (TIE2), and the cancer is Selected from breast cancer, colorectal cancer, hepatocellular carcinoma, head and neck cancer, carcinoma of urinary bladder, oophoroma, glioma, angiosarcoma, melanoma Or acute myelogenous leukemia.

Method of the item 205. according to item 204, wherein the Formulas I composition is thrown with one or more other pharmaceutical agent combinations With.

Method of the item 206. according to item 204 or 205, wherein the daily administration of Formulas I composition.

Method of the item 207. according to item 204 or 205, wherein the intermittent non-daily administration of the Formulas I composition.

208. method according to item 204 or 205, wherein Formulas I composition administration three-times-weekly.

209. method according to item 204 or 205, wherein Formulas I composition administration twice a week.

210. method according to item 204 or 205, wherein Formulas I composition administration once a week.

211. method according to item 204 or 205, wherein Formulas I composition administration once every two weeks.

Method of the item 212. according to item 1,38,75,118,161,204 or 205, wherein the cancer is three negative breasts Cancer.

Method of the item 213. according to item 1,38,75,118,161,204 and 205, wherein the cancer is estrogen sun Property (ER⁺) and HER2 receptor kinase feminine genders (HER2^-) breast cancer.

Method of the item 214. according to item 1,38,75,118,161,204 or 205, wherein the cancer is inflammatory breast Cancer.

Method of the item 215. according to item 1,38,75,118,161,204 or 205, wherein the breast cancer is metastatic 's.

Method of the item 216. according to item 204 or 205, wherein the treatment is given birth to comprising prevention or reduction primary tumor Length tumor invasiveness, oozes in cancer, is in cancer diffusion, metastasis of cancer and tumour immunity tolerance one or more.

Method of the item 217. according to item 204 or 205, wherein the treatment includes raising patient survival.

218. method according to item 205, wherein other medicaments be it is following in it is one or more：The Pacific Ocean Taxol, the Paclitaxel protein binding particle for injectable suspensions, eribulin, docetaxel, Ipsapirone, Vincristine, cis-platinum, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, Temozolomide, Doxorubicin, gathers vinorelbine Glycation liposomal doxorubicin, daunomycin, Ida mycin and epirubicin, 5 FU 5 fluorouracil, capecitabine, arabinose Cytidine, Decitabine, 5-azacitidine, gemcitabine, methotrexate (MTX), Erlotinib, Gefitinib, Lapatinib, Yi Weimo Department, tamiros, LY2835219, LEE011, PD 0332991, gram Zhuo for Buddhist nun, card it is rich for Buddhist nun, Sutent, pazopanib, Sorafenib, Rui Gefeini, Axitinib, Dasatinib, Imatinib, nilotinib, Wei Luofeini, dabrafenib, Sibutramine Hydrochloride It is miscellaneous for Buddhist nun, tamoxifen, fulvestrant, Anastrozole, Letrozole, Exemestane, acetic acid Ah's bit for Buddhist nun, Ai De former times cloth, quinoline The miscellaneous Shandong amine of imperial ester, grace, Nilutamide, Bicalutamide, Flutamide, Cyproterone Acetate, prednisone, dexamethasone, Irinotecan, Camptothecine, topotecan, Etoposide, etoposide phosphate, mitoxantrone, Vorinostat, romidepsin, pabishta, third Valeric acid, Belling promise he, DZNep 5- azepine -2'- deoxycytidines, bortezomib, the non-azoles rice of card, Distaval, lenalidomide, pool Horse degree amine, handkerchief trastuzumab, Cetuximab, Victibix, Yi Paili monoclonal antibodies, draws and founds pearl monoclonal antibody, the fertile list of Buddhist nun Herceptin Anti-, MPDL3280A, bevacizumab, VEGF Trap, the appropriate monoclonal antibody Wei Duoting in Belém, Ah Duo-Herceptin En Taxin, radioactive ray Therapy and the bright plug-T of Xi Pu.

Method of the item 219. according to item 205, wherein the Formulas I composition administration adjuvant or neoadjuvant.

Example

Example 1.1- (3- tertiary butyls -1- (quinoline -6- bases) -1H- pyrazoles -5- bases) -3- (the fluoro- 4- of 2- (2- (methyl ammonia first Acyl group) pyridin-4-yl oxygroup) phenyl) biochemistry inhibition of the urea to unphosphorylated TIE2 (uTIE2)

The biochemical analysis of uTIE2 (sequence ID number 1)

The activity of uTIE2 kinases is by tracking from the kinases via the coupling with pyruvate kinase/lactate dehydrogenase system The ADP that generates is reacted to measure (such as Schindler et al.《Science》(Science)(2000)289:1938-1942).At this In one analysis, the oxidation of NADH is continuously monitored with spectrophotometry (thus in A_340nmUnder reduction).Reaction mixture (100 μ L) contain TIE2 (SignalChem) (5.6nM), BSA (0.004% (w/v)), polyEY (1.5mg/ml), MgCl₂ (15mM), DTT (0.5mM), pyruvate kinase (4 units), lactic dehydrogenase (7 units), phosphoenolpyruvate (1mM) With NADH (0.28mm) and ATP (1.5mM) in the 90mM Tris buffer solutions containing 0.2% octyl-glucoside and 1% DMSO In (pH 7.5).Reaction is inhibited to start by the way that the test composition of serial dilution is mixed with the above reaction mixture. The absorption continuously monitored at 30 DEG C on plate reader (BioTek) at 340nm continues 6 hours.Reaction rate uses 5 It is calculated to 6 hours time ranges.Suppression percentage is by by reaction rate and compareing the reaction rate of (that is, without test composition) Compare to obtain.IC₅₀Value is by using the software routines such as implemented in GraphPad Prism software packages in a series of inhibitor A series of suppression percentage values measured under concentration calculate.Composition 1- (3- tertiary butyls -1- (quinoline -6- bases) -1H- pyrazoles -5- Base) -3- (the fluoro- 4- of 2- (2- (methylcarbamoyl) pyridin-4-yls oxygroup) phenyl) urea tosilate is (as described in Figure Compound 1) show the IC of 3.5nM₅₀Value.

UTIE2 protein sequences (sequence ID number 1) for screening

Example 2.1- (3- tertiary butyls -1- (quinoline -6- bases) -1H- pyrazoles -5- bases) -3- (the fluoro- 4- of 2- (2- (methyl ammonia first Acyl group) pyridin-4-yl oxygroup) phenyl) biochemistry inhibition of the urea to phosphorylation TIE2 (pTIE2)

The biochemical analysis (sequence ID number 2) of pTIE2

The activity of pTIE2 kinases is by tracking from the kinases via the coupling with pyruvate kinase/lactate dehydrogenase system The ADP that generates is reacted to measure (such as Schindler et al.《Science》(2000)289:1938-1942).In this analysis, The oxidation of NADH is continuously monitored with spectrophotometry (thus in A_340nmUnder reduction).Reaction mixture (100 μ L) contains TIE2 (Life Technologies) (6nM), BSA (0.004% (w/v)), polyEY (1.5mg/ml), MgCl₂(15 mM)、 DTT (0.5mM), pyruvate kinase (4 units), lactic dehydrogenase (7 units), phosphoenolpyruvate (1mM) and NADH (0.28mm) and ATP (1.5mM) are in the 90 mM Tris buffer solutions (pH 7.5) containing 0.2% octyl-glucoside and 1%DMSO In.Reaction is inhibited to start by the way that the test composition of serial dilution is mixed with the above reaction mixture.It is read in plate The absorption continuously monitored at 30 DEG C on device (BioTek) at 340nm continues 6 hours.Reaction rate uses 2 to 3 hours Time range calculates.Suppression percentage by by reaction rate with compare the reaction rate of (that is, without test composition) relatively come It obtains.IC₅₀Value is by using the software routines such as implemented in GraphPad Prism software packages under a series of inhibitor concentrations A series of suppression percentage values measured calculate.When tested, composition 1- (3- tertiary butyls -1- (quinoline -6- bases) -1H- pyrroles Azoles -5- bases) -3- (the fluoro- 4- of 2- (2- (methylcarbamoyl) pyridin-4-yls oxygroup) phenyl) urea tosilate and 1- (3- Tertiary butyl -1- (quinoline -6- bases) -1H- pyrazoles -5- bases) -3- (the fluoro- 4- of 2- (2- (methylcarbamoyl) pyridin-4-yls oxygroup) Phenyl) urea dihydrochloride exists<Show under 0.1 μM of concentration>The inhibition of 50%pTIE2 kinases.1- (3- tertiary butyls -1- (quinoline -6- Base) -1H- pyrazoles -5- bases) -3- (the fluoro- 4- of 2- (2- (methylcarbamoyl) pyridin-4-yls oxygroup) phenyl) urea p-methyl benzenesulfonic acid Salt shows the IC of 4.2nM₅₀Value.1- (3- tertiary butyls -1- (quinoline -6- bases) -1H- pyrazoles -5- bases) -3- (2- fluoro- 4- (2- (first Base carbamyl) pyridin-4-yl oxygroup) phenyl) urea dihydrochloride shows the IC of 2.2nM₅₀Value.

PTIE2 protein sequences (sequence ID number 2) for screening

Example 3.1- (3- tertiary butyls -1- (quinoline -6- bases) -1H- pyrazoles -5- bases) -3- (the fluoro- 4- of 2- (2- (methyl ammonia first Acyl group) pyridin-4-yl oxygroup) phenyl) cell inhibition of the urea to the TIE2 in Chinese hamster ovary celI

CHO-K1 cell culture

CHO-K1 cells (catalog number (Cat.No.) CCL-61) are from American type culture collection (American Type Culture collection, ATCC, Virginia Manassas (Manassas, VA)) it obtains.In simple terms, cell exists 37 DEG C, 5%CO₂With grown in F12K culture mediums under 95% humidity, the F12K culture mediums are supplemented with 10% characterization tire ox Serum (the hero company (Invitrogen, Carlsbad, CA) of Carlsbad, CA), 100 units/mL are green Mycin G, 100 μ g/ml streptomysins and 0.29mg/mL L-Glutamines (the hero company of Carlsbad, CA). So that cell is expanded, converge until reaching 70%-95%, at this time by its secondary culture or collection for analyzing purposes.

The CHO K1 phosphorylation TIE2 western blot analysis (Western Blot Assay) of TIE2 transfections

By CHO K1 cells (1 × 10⁵A cells/well) it is added to being supplemented in the plate of 24 hole tissue culture processing 10% characterizes 1mL RPMI1640 culture mediums (this bar of California karr of fetal calf serum and 1 × nonessential amino acid The hero company of moral) in.Cell is then in 37 DEG C, 5%CO₂It is cultivated overnight under 95% humidity.Aspirate culture media, and will 0.5mL culture mediums are added in each hole.Grade Plasmid DNA will be transfected, and (TIE2 genes Gateway is cloned into pcDNA3.2^TM/V5- In DEST expression vectors, the hero company of Carlsbad, CA) in the room temperature of serum-freeI is trained It supports in base (the hero company of Carlsbad, CA) and is diluted to 5 μ g/mL.Every 0.5 μ g Plasmid DNA adds 2 μ L fat Contaminate amine (Lipofectamine) LTX reagents (the hero company of Carlsbad, CA).Test tube is lightly mixed, And 25 minutes are cultivated at room temperature to allow DNA- fat dye amine LTX compounds to be formed.100 μ L DNA- fat are contaminated into amine LTX compounds It is directly appended in each hole containing cell and lightly mixes.Twenty four hours after transfection, suction are multiple containing DNA- fat dye amine Close object culture medium, cells rinsed with PBS, and addition be supplemented with 10% characterization fetal calf serum (California karr this The hero company of Ahmedabad) and 1 × nonessential amino acid (the hero company of Carlsbad, CA) RPMI1640 Culture medium.Composition (1- (3- tertiary butyls -1- (quinoline -6- bases) -1H- pyrazoles -5- bases) -3- (2- fluoro- 4- (2- (first will be tested Base carbamyl) pyridin-4-yl oxygroup) phenyl) urea tosilate) or DMSO be added in each hole that (0.5% is final DMSO concentration).Plate is then in 37 DEG C, 5%CO₂It is cultivated 4 hours under 95% humidity.After cultivation, Aspirate culture media, and it is thin Born of the same parents are washed with PBS.Cell, which uses at 4 DEG C under oscillation, contains Halt phosphatases and protease inhibitors (Pierce, Illinois Her state Rockford (Rockford, IL)) and (Sigma Corporation of St. Louis of inhibitors of phosphatases mixed liquor 2 (Sigma, St.Louis, MO)) MPER dissolving buffer solution (Pierce, Illinois Rockford) dissolve 10 minutes.It is clear Clear dissolved matter is by SDS-PAGE in 4-12% Novex NuPage Bis-Tris gel (this bars of California karr The hero company of moral) on detach, and be then transferred to PVDF (the hero company of Carlsbad, CA).It is shifting Later, pvdf membrane BSA (Santa Cruz biotech company (the Santa Cruz of California Santa Cruz Biotechnology, Santa Cruz, CA)) block, and then use phosphorylation TIE2 antibody (Massachusetts Bei Fuli's Menaphtame leads to technology company (Cell Signaling Technology, Beverly, MA)) detection.It is incorporated into horseradish peroxidase The two level anti-rabbit antibody Menaphtame of Massachusetts Bei Fuli (lead to technology company) for detecting phosphorylation TIE2.Add ECL Plus (General Electric's Medical Group (GE Healthcare, Piscataway, NJ) of New Jersey Piscataway), it is a kind of Substrate for the horseradish peroxidase for generating fluorescence-causing substance.Fluorescence using 840 phosphorescence imaging instruments of Storm (New Jersey skin this General Electric's Medical Group of Ka Tawei) it is detected with fluorescence mode.160kDa phosphorylation TIE2 bands are soft using ImageQuant Part (General Electric's Medical Group of New Jersey Piscataway) is quantitative.Data use Prism softwares (GraphPad Software, San Diego, CA (San Diego, CA)) it analyzes to calculate IC₅₀Value.Composition 1- (the tertiary fourths of 3- Base -1- (quinoline -6- bases) -1H- pyrazoles -5- bases) -3- (the fluoro- 4- of 2- (2- (methylcarbamoyl) pyridin-4-yls oxygroup) benzene Base) urea tosilate shows the IC of 2.0nM₅₀Value.

Example 4.1- (3- tertiary butyls -1- (quinoline -6- bases) -1H- pyrazoles -5- bases) -3- (the fluoro- 4- of 2- (2- (methyl ammonia first Acyl group) pyridin-4-yl oxygroup) phenyl) cell inhibition of the urea to the TIE2 in the Chinese hamster ovary celI after being removed in inhibitor

CHO-K1 cell culture

CHO-K1 cells (catalog number (Cat.No.) CCL-61) are from American type culture collection (ATCC, Virginia Ma Na Sa Si) obtain.In simple terms, cell is in 37 DEG C, 5%CO₂With grown in F12K culture mediums under 95% humidity, F12K training Foster base is supplemented with 10% characterization fetal calf serum (the hero company of Carlsbad, CA), 100 unit/mL (hero of Carlsbad, CA is public for benzyl penicillin, 100 μ g/ml streptomysins and 0.29mg/mL L-Glutamines Department).So that cell is expanded, converge until reaching 70%-95%, at this time by its secondary culture or collection for analyzing purposes.

The CHO K1 phosphorylation TIE2 Western blotting composition removings analysis of TIE2 transfections

By CHO K1 cells (1 × 10⁵A cells/well) it is added to being supplemented in the plate of 24 hole tissue culture processing 10% characterizes 1mL RPMI1640 culture mediums (this bar of California karr of fetal calf serum and 1 × nonessential amino acid The hero company of moral) in.Cell is then in 37 DEG C, 5%CO₂It is cultivated overnight under 95% humidity.Aspirate culture media, and will 0.5mL culture mediums are added in each hole.Grade Plasmid DNA will be transfected, and (TIE2 genes Gateway is cloned into pcDNA3.2^TM/V5- In DEST expression vectors, the hero company of Carlsbad, CA) in the room temperature of serum-freeI is trained It supports in base (the hero company of Carlsbad, CA) and is diluted to 5 μ g/mL.Every 0.5 μ g Plasmid DNA adds 2 μ L fat Contaminate amine LTX reagents (the hero company of Carlsbad, CA).Test tube is lightly mixed, and cultivates 25 at room temperature Minute is to allow DNA- fat dye amine LTX compounds to be formed.By 100 μ L DNA- fat dye amine LTX compounds be directly appended to containing It mixes in each hole of cell and lightly.About 18-24 hours after transfection, the culture medium that amine compound is contaminated containing DNA- fat is aspirated, Cells rinsed with PBS, and addition is supplemented with 10% characterization fetal calf serum (hero's public affairs of Carlsbad, CA Department) and 1 × nonessential amino acid (the hero company of Carlsbad, CA) RPMI1640 culture mediums.It will test Composition (1- (3- tertiary butyls -1- (quinoline -6- bases) -1H- pyrazoles -5- bases) -3- (the fluoro- 4- of 2- (2- (methylcarbamoyl) pyrroles Pyridine -4- bases oxygroup) phenyl) urea tosilate) or DMSO be added in each hole (0.5% final DMSO concentration).Plate is then In 37 DEG C, 5%CO₂It is cultivated 2 hours under 95% humidity.After cultivation, Aspirate culture media, and cell is washed with 1mL culture mediums It washs three times to remove the composition that dissociates.Next, addition 1mL fresh cultures, and when cell is cultivated specific before dissolving Between point (that is, 0,1,2,4,6 and 24 hour).Cell inhibits under oscillation using containing Halt phosphatases and protease at 4 DEG C (Sigma of St. Louis is public for agent (Pierce, Illinois Rockford) and inhibitors of phosphatases mixed liquor 2 Department) MPER dissolving buffer solution (Pierce, Illinois Rockford) dissolve 10 minutes.Clear dissolved matter passes through SDS- PAGE divides on 4-12% Novex NuPage Bis-Tris gels (the hero company of Carlsbad, CA) From, and it is then transferred to PVDF (the hero company of Carlsbad, CA).After the transfer, pvdf membrane BSA (the Santa Cruz biotech company of California Santa Cruz) blocks, and then uses the antibody (horse of phosphorylation TIE2 The Menaphtame of the states Sa Zhusai Bei Fuli leads to technology company) detection.It is incorporated into the two level anti-rabbit antibody (Massachusetts of horseradish peroxidase The Menaphtame of state Bei Fuli leads to technology company) for detecting phosphorylation TIE2.Addition ECL Plus be (New Jersey Piscataway General Electric's Medical Group), a kind of substrate for generating the horseradish peroxidase of fluorescence-causing substance.Fluorescence uses Storm 840 Phosphorescence imaging instrument (General Electric's Medical Group of New Jersey Piscataway) is detected with fluorescence mode.Pvdf membrane is removed, and Then it is as above visited again with total TIE2 antibody (the Santa Cruz biotech company of Dallas, Texas (Dallas, TX)) It surveys.160kDa phosphorylations TIE2 and total TIE2 bands use ImageQuant softwares (the general electricity of New Jersey Piscataway Gas Medical Group) it is quantitative.Phosphorylation TIE2 levels are according to total TIE2 level standards, and data use Prism softwares (GraphPad Software, San Diego, CA) is drawn.As the CHO K1 with 0.1 μM -1 μM with TIE2 transfections When cell cultivates subsequent removing in 2 hours together, composition disclosed herein 1- (3- tertiary butyls -1- (quinoline -6- bases) -1H- pyrroles Azoles -5- bases) -3- (the fluoro- 4- of 2- (2- (methylcarbamoyl) pyridin-4-yls oxygroup) phenyl) urea tosilate shows phosphoric acid Change TIE2 levels>50% inhibits to continue>24 hours.

Example 5.1- (3- tertiary butyls -1- (quinoline -6- bases) -1H- pyrazoles -5- bases) -3- (the fluoro- 4- of 2- (2- (methyl ammonia first Acyl group) pyridin-4-yl oxygroup) phenyl) cell inhibition of the urea to the TIE2 in HUVEC cells

HUVEC cell culture

HUVEC (human umbilical vein endothelial cells；Catalog number (Cat.No.) CRL-1730) cell is from American type culture collection (ATCC, Virginia Manassas) obtains.In simple terms, (dragon of Maryland State Walker's Wei Er is husky public in EGM-2 for cell Take charge of (Lonza, Walkersville, MD)) in 37 DEG C, 5%CO₂It is grown under 95% humidity.Cell is set to expand, until reaching 90%-95% is saturated, at this time by its secondary culture or collection for analyzing purposes.

HUVEC phosphorylation TIE2 western blot analysis

By HUVEC cells (2.5 × 10⁵A cells/well) it is added to the 1mL in the plate of 24 hole tissue culture processing In EGM-2 culture mediums (the Long Sha companies of Maryland State Walker's Wei Er).Cell is then in 37 DEG C, 5%CO₂Under 95% humidity It cultivates overnight.Then Aspirate culture media, and addition is supplemented with 2%FBS (the hero company of Carlsbad, CA) 1mL EBM-2 basal mediums (the Long Sha companies of Maryland State Walker's Wei Er).Test composition or DMSO are added to In each hole (0.5% final DMSO concentration).Plate is then in 37 DEG C, 5%CO₂It is cultivated 4 hours under 95% humidity.In the nurturing period Between, by Ang-1 (ANG1) growth factor (R＆D Systems, Minneapolis, Minnesota of histidine mark (Minneapolis, MN)) it is added to anti-polyhistidine antibody (R＆D Systems, Minnesota State Ming Niabo at room temperature Continue 30 minutes in Li Si) to generate the polymer of ANG1.After composition being cultivated at four hours, cell 800ng/mL The anti-polyhistidine antibody compound mixtures of ANG1/ stimulate 15 minutes.Aspirate culture media, and cells rinsed with PBS.Cell is at 4 DEG C Under under oscillation using containing Halt phosphatases and protease inhibitors (Pierce, Illinois Rockford) and phosphatase MPER dissolving buffer solutions (Pierce, the Illinois of inhibitor mixed liquid 2 (Sigma Corporation of St. Louis) Rockford) it dissolves 10 minutes.Clear dissolved matter is solidifying in 4-12%Novex NuPage Bis-Tris by SDS-PAGE It is detached on glue (the hero company of Carlsbad, CA), and is then transferred to PVDF (California karrs The hero company of this Ahmedabad).After the transfer, PVDF films BSA (the Santa Cruz biologies of California Santa Cruz Technology company) it blocks, and the antibody (Menaphtame of Massachusetts Bei Fuli leads to technology company) of phosphorylation TIE2 is then used to visit It surveys.The two level anti-rabbit antibody (Menaphtame of Massachusetts Bei Fuli leads to technology company) of horseradish peroxidase is incorporated into for detecting Phosphorylation TIE2.ECL Plus (General Electric's Medical Group of New Jersey Piscataway) are added, one kind is glimmering for generating The substrate of the horseradish peroxidase of photoproduct.Fluorescence using 840 phosphorescence imaging instruments of Storm (New Jersey Piscataway it is logical With electrical Medical Group) it is detected with fluorescence mode.160kDa phosphorylation TIE2 bands use ImageQuant softwares (New Jersey General Electric's Medical Group of Piscataway) it is quantitative.Data use Prism softwares (GraphPad Software, Jia Lifu The Santiago Buddhist nun Ya Zhou) it analyzes to calculate IC₅₀Value.Composition disclosed herein 1- (3- tertiary butyls -1- (quinoline -6- bases) -1H- Pyrazoles -5- bases) -3- (the fluoro- 4- of 2- (2- (methylcarbamoyl) pyridin-4-yls oxygroup) phenyl) urea tosilate shows The IC of 0.018nM₅₀Value.

Example 6.1- (3- tertiary butyls -1- (quinoline -6- bases) -1H- pyrazoles -5- bases) -3- (the fluoro- 4- of 2- (2- (methyl ammonia first Acyl group) pyridin-4-yl oxygroup) phenyl) urea capillary that Ang-1 (ANG1) or angiopoietin 2 (ANG2) are stimulated The inhibition of formation

HMVEC cell culture

HMVEC (human microvascular endothelial cells；Catalog number (Cat.No.) PCS-110-010) cell is from American Type Tissue Culture The heart (ATCC, Virginia Manassas) obtains.In simple terms, cell is in the EGM-2MV (dragons of Maryland State Walker's Wei Er Sha companies) in 37 DEG C, 5%CO₂It is grown under 95% humidity.Cell is set to expand, until reaching 90%-95% saturations, at this time By its secondary culture or collect for analyzing purposes.

HMVEC capillaries form analysis

HMVEC cells (1.5 × 10⁴A cells/well) it compares and is mixed together with test composition or DMSO, and will suitably give birth to The long factor (ANG1 or ANG2) or control are added to 96 hole tissue culture processing being coated with the matrigel of growth factor reduction Plate in 0.1mL EBM-2 basal mediums (the Long Sha companies of Maryland State Walker's Wei Er) in.Cell then 37 DEG C, 5%CO₂It is cultivated 18 hours under 95% humidity.Then lightly Aspirate culture media, and each hole bases 0.1mL EBM-2 culture Base lightly washs.Same Aspirate culture media, and will contain 1 μM of Calcein-Safranine T solution (Carlsbad, CA Hero company) basal medium be added in each hole with fluorescent marker living cells.Cell is then in 37 DEG C, 5%CO₂With 95% It is cultivated 30 minutes under humidity.Aspirate culture media, and each hole is lightly washed twice with phosphate buffered saline (PBS).The image in each hole is used Fluorescence microscope obtains, and uses ImagePro analyzers (Media Cybernetics, Inc., Rockville, MD (Rockville, MD)) it is handled using the auto macro for measuring total capillary pipe length.Data use Prism softwares (GraphPad Software, San Diego, CA) it analyzes to calculate IC₅₀Value.Composition disclosed herein 1- (3- tertiary butyls -1- (quinoline -6- bases) -1H- pyrazoles -5- bases) -3- (the fluoro- 4- of 2- (2- (methylcarbamoyl) pyridin-4-yls oxygroup) phenyl) urea pair The inhibition that toluene fulfonate forms the HMVEC capillaries that ANG1 is stimulated shows the IC of 6.9nM₅₀Value.Formulas I group disclosed herein Close the IC that the inhibition that object forms the HMVEC capillaries that ANG2 is stimulated shows 34nM₅₀Value.

Example 7.1- (3- tertiary butyls -1- (quinoline -6- bases) -1H- pyrazoles -5- bases) -3- (the fluoro- 4- of 2- (2- (methyl ammonia first Acyl group) pyridin-4-yl oxygroup) phenyl) urea combines as single medicament and with Paclitaxel to muroid PyMT breast cancer models In internal primary tumor growth and invasion inhibition

PyMT homogenic type breast cancer model primary tumor growths

PyMT homogenic type breast cancers implantation mouse model is used to assess the activity in vivo of compound 1.It in simple terms, will be overall The 1 × 10 of product 0.1mL⁶A cell (dissociating from PyMT tumor fragments) is implanted to female mice (FVB/NJ, JAXWEST:RB05 is small Mouse, come from Jackson Labs) left side on the 4th mammary fat pad in.10 mouse in total are implanted into each group. The animal care of Molecular Imaging, Inc. and the use committee (Animal Care and Use Committee) batch Accurate all experimental programs and according to National Institutes of Health (National Institutes of Health, NIH) All laws, regulation and guide are tested.Treatment starts in the following manner：When tumor size reaches about 850 mg, root (tube feed) compound 1 is administered orally twice daily or mediator (0.4% hydroxyl with every 20g 0.2mL according to individual weight on the treatment same day Propyl methocel is in water) and/or intravenous administration (IV) Paclitaxel is once every five days or mediator (10% second Alcohol, 10%Cremophor EL and 80% brine).Animal administration continues 21 days.Weight and measurement of tumor value are recorded three-times-weekly. Tumor load (mg) is passed through by caliber gauge mensuration to be estimated for the formula of prolate ellipsoid volume, it is assumed that unit intensity is：Tumour is negative Lotus (mg)=(L × W²)/2, wherein L and W are corresponding orthogonal length of tumor and width measurement (mm).In PyMT models, Compound 1 and Paclitaxel group prove Tumor growth inhibition.Compound 1 and the combination displaying of Paclitaxel are tired Add active (Fig. 1).These data prove the activity in vivo of compound 1, and show the correlation with enzymatic and cell data.

Example 8.1- (3- tertiary butyls -1- (quinoline -6- bases) -1H- pyrazoles -5- bases) -3- (the fluoro- 4- of 2- (2- (methyl ammonia first Acyl group) pyridin-4-yl oxygroup) phenyl) combination of the urea as single medicament and with Paclitaxel be to muroid PyMT breast cancer moulds The inhibition that internal primary tumor macrophage in type is built up

PyMT homogenic type breast cancer model primary tumor macrophages are built up

PyMT homogenic type breast cancers implantation mouse model is used to assess the activity in vivo of compound 1.It in simple terms, will be overall The 1 × 10 of product 0.1mL⁶A cell (dissociating from PyMT tumor fragments) is implanted to female mice (FVB/NJ, JAXWEST:RB05 Mouse, come from Jackson Labs) left side on the 4th mammary fat pad in.10 mouse in total are implanted into each group. The animal care of Molecular Imaging, Inc. and ratifies all experimental programs using the committee and defended according to American National All laws, regulation and the guide of raw research institute (NIH) are tested.Treatment starts in the following manner：When tumor size reaches When to about 850mg, (tube feed) compound 1 is administered orally twice daily with every 20g 0.2mL according to individual weight on the treatment same day Or mediator (0.4% hydroxypropyl methyl cellulose is in water) and/or intravenous administration (IV) Paclitaxel are once every five days Or mediator (10% ethyl alcohol, 10%Cremophor EL and 80% brine).Animal administration continues 21 days.Body is recorded three-times-weekly Weight and measurement of tumor value.

At the end of the study, it by tumor resection and is put into formalin (formalin).Then, formalin is fixed Tumor sample be put into paraffin mass.The histotomy of the fixed paraffin embedding of formalin with dimethylbenzene deparaffnize, and via In a series of alcohol flushing liquor hydration to distilled water of classifications.Antigen retrieval using Dako PT Link modules Tris/EDTA Buffering target is repaired solution and is carried out 20 minutes at 95 DEG C.Once slice cooling, is loaded into Dako On AutostainerPlusLink at room temperature with dye respectively F4/80 the and CD31 antibody of macrophage and endothelial cell into Row immunohistochemical staining.Intrinsic oversxidase and alkaline phosphatase activities in tissue are blocked molten with dual endogenous enzyme Liquid (Dako, S2003) is quenched 5 minutes.Nonspecific proteins are combined blocks (serum free Protein for serum-free albumen Block) (Dako, X0909) is blocked 5 minutes.Rat anti-mouse CD31 primary antibodies are then 1 on experiment histotomy:100 Immunogenicity concentration under cultivate 30 minutes.Primary antibody then with rabbit-anti rat immunoglobulin secondary antibody (Dako, E0468 it) combines.The polymer (Dako, K4003) that secondary antibody then uses goat antirabbit peroxidase to mark amplifies 30 minutes. Enzymatic dyeing is developed 5 minutes with substrate-chromogen DAB+ (Dako, K3468).In addition excessive rat IgG components use rodent Rat (Rodent Block Rat) (Biocare Medical, RBR962H) is blocked to block 5 minutes.Rat anti-mouse F4/80 Primary antibody is cultivated 30 minutes on experiment histotomy.F4/80 then with rabbit-anti rat immunoglobulin secondary antibody (Dako, E0468) is combined.Secondary antibody then uses the polymer (Biocare of goat antirabbit alkali phosphatase enzyme mark RALP525) amplify 30 minutes.Enzymatic dyeing is developed with substrate chromogen WARP Red (Biocare WR806).Counterstain is used Hematoxylin (hematoxylin) is automated to carry out 10 minutes.Histotomy is then air-dried and is clarified so as to glass cover with dimethylbenzene Plate slides.Slice is using following scale for F4/80 dyeing scorings：0, no visible stain；1, weak dyeing；2, appropriateness dyes；The last 3 Dyeing.In PyMT models, compound 1 proves that the macrophage at primary tumor is built up and reduces, and Paclitaxel is not Macrophage is reduced to build up.Compound 1 shows similar with 1 single pharmaceutical treatment of compound with the combination of Paclitaxel Active (Fig. 2).These data prove the activity in vivo of compound 1, and show the correlation with enzymatic and cell data.

Example 9.1- (3- tertiary butyls -1- (quinoline -6- bases) -1H- pyrazoles -5- bases) -3- (the fluoro- 4- of 2- (2- (methyl ammonia first Acyl group) pyridin-4-yl oxygroup) phenyl) combination of the urea as single medicament and with Paclitaxel be to muroid PyMT breast cancer moulds The inhibition of internal primary tumor TIE2 cell accumulations in type

PyMT homogenic type breast cancer model primary tumor macrophages are built up

At the end of the study, it by tumor resection and is put into formalin.Then, by the fixed tumor sample of formalin It is put into paraffin mass.The histotomy of the fixed paraffin embedding of formalin is tested with dimethylbenzene deparaffnize, and via a series of In the alcohol flushing liquor hydration to distilled water of classification.Antigen retrieval is buffered using the PT Link modules citrate pH 6 of Dako Target is repaired solution and is carried out 20 minutes at 95 DEG C.Once slice cooling, is loaded into Dako On AutostainerPlusLink immunohistochemical staining is carried out with both TIE2 and CD31 antibody at room temperature.In tissue Intrinsic oversxidase and alkaline phosphatase activities be quenched 5 minutes with dual endogenous enzyme blocking solution (Dako, S2003). Nonspecific proteins are combined blocks (Dako, X0909) to block 5 minutes for serum-free albumen.Rat anti-mouse CD31 primary is anti- Body is then 1 on experiment histotomy:It is cultivated 30 minutes under 100 immunogenicity concentration.Primary antibody is then big with rabbit-anti Rat immune globulin secondary antibody (Dako, E0468) combines.Secondary antibody then uses the polymerization that goat antirabbit peroxidase marks Object (Dako, K4003) amplifies 30 minutes.Enzymatic dyeing is developed 5 minutes with substrate-chromogen DAB+ (Dako, K3468).It is excessive In addition protein component blocks (Protein Block) (Dako, X0909) to block 5 minutes with albumen.Rabbit-anti TIE2 primary antibodies It is cultivated 30 minutes on experiment histotomy.TIE2 antibody is then combined 30 with the goat antirabbit polymer of alkali phosphatase enzyme mark Minute.Enzymatic dyeing is developed with substrate chromogen WARP Red (Biocare WR806).Counterstain is progressed greatly with automation bush Row 10 minutes.Histotomy is then air-dried and is clarified with dimethylbenzene so that glass cover-plate slides.Slice is directed to using following scale TIE2 dyeing scorings：0, no visible stain；1, weak dyeing；2, appropriateness dyes；The last 3 is dyed.In PyMT models, compound 1 is demonstrate,proved TIE2 expression cells at bright primary tumor, which are built up, to be reduced, and Paclitaxel does not reduce the accumulation of TIE2 expression cells.Change Conjunction object 1 increased activity (Fig. 3) compared with 1 single pharmaceutical treatment of compound with the combination displaying of Paclitaxel.These data It proves the activity in vivo of compound 1, and shows the correlation with enzymatic and cell data.

Example 10.1- (3- tertiary butyls -1- (quinoline -6- bases) -1H- pyrazoles -5- bases) -3- (the fluoro- 4- of 2- (2- (methyl ammonia first Acyl group) pyridin-4-yl oxygroup) phenyl) urea combines as single medicament and with Paclitaxel to muroid PyMT breast cancer models In internal lung cancer metastasis inhibition

PyMT homogenic type breast cancer model lung cancer metastasis is assessed

At the end of the study, lung tissue is cut off and is put into formalin.Then, by the fixed lung sample of formalin It is put into paraffin mass.There are three slices for each lung block, wherein two levels of often slice cutting, and use h and E (Eosin) it dyes.Metastatic Lung neoplasm is via microscopic counting.In PyMT models, compound 1 and Paclitaxel are demonstrate,proved The similar reduction of bright lung cancer metastasis.Compound 1 shows with the combination of Paclitaxel and adds up compared with single pharmaceutical treatment Activity (Fig. 4).These data prove the activity in vivo of compound 1, and show the correlation with enzymatic and cell data.

1- (3- tertiary butyls -1- (quinoline-the 6- of interval (non-daily) administration that example 11. is combined with Paclitaxel Base) -1H- pyrazoles -5- bases) -3- (the fluoro- 4- of 2- (2- (methylcarbamoyl) pyridin-4-yls oxygroup) phenyl) urea is to muroid PyMT The inhibition of internal lung cancer metastasis in breast cancer model

PyMT homogenic type breast cancer model lung cancer metastasis is assessed

PyMT homogenic type breast cancers implantation mouse model is used to assess the activity in vivo of compound 1.It in simple terms, will be overall The 1 × 10 of product 0.1mL⁶A cell (dissociation is from PyMT tumor fragments and stored frozen is in cell freezing media) is implanted to female Property mouse (FVB/NJ, JAXWEST:RB05 mouse, come from Jackson Labs) left side on the 4th mammary fat pad in.Respectively Three mouse in total are implanted into group.The animal care of Molecular Imaging, Inc. and ratify all experiments using the committee It scheme and is tested according to all laws, regulation and the guide of National Institutes of Health (NIH).Treatment is by with lower section Formula starts：When tumor size reaches about 600mg, it is administered orally with every 20g 0.2mL according to individual weight on the treatment same day (tube feed) compound 1 is twice a week or mediator (0.4% hydroxypropyl methyl cellulose is in water) and/or intravenous administration (IV) Paclitaxel is once every five days or mediator (10% ethyl alcohol, 10%Cremophor EL and 80% brine).Animal administration is held It is 12 days continuous.Weight and measurement of tumor value are recorded three-times-weekly.

At the end of the study, lung tissue is cut off and is put into formalin.Then, by the fixed lung sample of formalin It is put into paraffin mass.There are three slices for each lung block, wherein two levels of often slice cutting, and dyed with h and E. Metastatic Lung neoplasm is via microscopic counting.In PyMT models, Paclitaxel proves the reduction of lung cancer metastasis.Compound 1 activity (Fig. 5) to add up compared with single pharmaceutical treatment with the combination displaying of Paclitaxel.These data prove compound 1 activity in vivo, and show the correlation with enzymatic and cell data.

1- (3- tertiary butyls-the 1- (quinoline -6- bases)-of interval (non-daily) administration that example 12. is combined with eribulin 1H- pyrazoles -5- bases) -3- (the fluoro- 4- of 2- (2- (methylcarbamoyl) pyridin-4-yls oxygroup) phenyl) urea is to muroid PyMT breast cancers The inhibition of internal lung cancer metastasis in model

PyMT homogenic type breast cancer model lung cancer metastasis is assessed

PyMT homogenic type breast cancers implantation mouse model is used to assess the activity in vivo of compound 1.It in simple terms, will be overall The 1 × 10 of product 0.1mL⁶A cell (dissociation is from PyMT tumor fragments and stored frozen is in cell freezing media) is implanted to female Property mouse (FVB/NJ, JAXWEST:RB05 mouse, come from Jackson Labs) left side on the 4th mammary fat pad in.Respectively Three mouse in total are implanted into group.The animal care of Molecular Imaging, Inc. and ratify all experiments using the committee It scheme and is tested according to all laws, regulation and the guide of National Institutes of Health (NIH).Treatment is by with lower section Formula starts：When tumor size reaches about 600mg, it is administered orally with every 20g 0.2mL according to individual weight on the treatment same day (tube feed) compound 1 is twice a week or mediator (0.4% hydroxypropyl methyl cellulose is in water) and/or intravenous administration (IV) Eribulin is three-times-weekly or mediator (80% brine).Animal administration continues 12 days.Weight and measurement of tumor are recorded three-times-weekly Value.

At the end of the study, lung tissue is cut off and is put into formalin.Then, by the fixed lung sample of formalin It is put into paraffin mass.There are three slices for each lung block, wherein two levels of often slice cutting, and dyed with h and E. Metastatic Lung neoplasm is via microscopic counting.In PyMT models, eribulin proves the reduction of lung cancer metastasis (or in low dosage Lower increase).The activity (Fig. 6) that compound 1 adds up with the combination displaying of eribulin compared with single pharmaceutical treatment.These numbers It is demonstrated that the activity in vivo of compound 1, and show the correlation with enzymatic and cell data.

1- (3- tertiary butyls-the 1- (quinoline -6- bases)-of interval (non-daily) administration that example 13. is combined with eribulin 1H- pyrazoles -5- bases) -3- (the fluoro- 4- of 2- (2- (methylcarbamoyl) pyridin-4-yls oxygroup) phenyl) urea is to muroid PyMT breast cancers The raising of overall survival in model

PyMT homogenic type breast cancer model survival rates are assessed

PyMT homogenic type breast cancers implantation mouse model is used to assess the activity in vivo of compound 1.It in simple terms, will be overall The 1 × 10 of product 0.1mL⁶A cell (dissociation is from PyMT tumor fragments and stored frozen is in cell freezing media) is implanted to female Property mouse (FVB/NJ, JAXWEST:RB05 mouse, come from Jackson Labs) left side on the 4th mammary fat pad in.Respectively Ten mouse in total are implanted into group.The animal care of Molecular Imaging, Inc. and ratify all experiments using the committee It scheme and is tested according to all laws, regulation and the guide of National Institutes of Health (NIH).Treatment is by with lower section Formula starts：When tumor size reaches about 850mg, it is administered orally with every 20g 0.2mL according to individual weight on the treatment same day (tube feed) compound 1 is once a week or twice or mediator (0.4% hydroxypropyl methyl cellulose is in water) and/or intravenous administration (IV) eribulin is three-times-weekly or mediator (80% brine).Tumour then after treatment begins three days through excision.Animal connects The duration of administration continued survival rate experiment.Weight and measurement of tumor value are recorded three-times-weekly.In PyMT models, The eribulin of 0.1mg/kg proves survival rate without raising.Compound 1 and the combination displaying survival rate of eribulin significantly improve (Fig. 7).These data prove the activity in vivo of compound 1, and show the correlation with enzymatic and cell data.

The scope of the present invention not particular implementation disclosed in the example by the explanation for being intended as the several aspects of the present invention Example limitation, and functionally equivalent any embodiment is within the scope of the present invention.In fact, except it is illustrated and described herein with Outside, various modifications of the invention will be that those skilled in the art is apparent and the scope of the appended claims to be belonged to It is interior.

Equivalent

Those skilled in the art will be at most using routine experiment i.e. it can be appreciated that or can determine especially herein Many equivalents of the specific embodiment.The equivalent plan is covered within the scope of the appended claims.

Sequence table

<110>De Xifeila Pharmaceutical Co (Deciphera Pharmaceuticals, LLC)

DL not woods (Flynn, Daniel)

MD Kaufmans (Kaufman, Michael)

B Smiths (Smith, Brian)

MS Lu Daozi (Rudoltz, Marc)

<120>Method (the METHODS FOR INHIBITING TIE2 for inhibiting TIE2 kinases suitable for treating cancer KINASE USEFUL IN THE TREATMENT OF CANCER)

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Claims

1. Formulas I composition is being prepared for blocking mammary tumor growth, invasion, diffusion, metastasis of cancer or improving patients with mastocarcinoma The tumor microenvironment expression TIE2 of purposes in the drug of survival, the patient expresses the TIE2 kinases in macrophage

Wherein

The integer that n is 0 to 7；

X is the basic group of pharmaceutically acceptable salt；

The wherein described drug is enough the TIE2 kinases for blocking tumor microenvironment TIE2 to express in macrophage.

2. purposes according to claim 1, wherein the drug is suitable for daily administration or non-is given daily suitable for intermittent Medicine, every other day administration, every three days administration, administration twice weekly are administered once a week.

3. purposes according to any one of claim 1 or 2, wherein the Formulas I composition is obtained from one or more Pharmaceutical agent combinations below use：Antitublin, immunomodulator, Paclitaxel, for injectable suspensions too Flat ocean taxol protein binding particle or eribulin.

4. Formulas I composition is being prepared for blocking the purposes in patient in the drug of breast cancer immunological tolerance, the patient's is swollen Tumor microenvironment expresses the TIE2 kinases in TIE2 expression macrophages

Wherein

The integer that n is 0 to 7；

X is the basic group of pharmaceutically acceptable salt；

The wherein described drug is enough to block the TIE2 in the tumor microenvironment TIE2 expression macrophages of mediating immune tolerance to swash Enzyme.

5. purposes according to claim 4, wherein the drug is suitable for daily administration or non-is given daily suitable for intermittent Medicine, every other day administration, every three days administration, administration twice weekly are administered once a week.

6. purposes according to any one of claim 4 or 5, wherein the Formulas I composition is obtained from one or more Pharmaceutical agent combinations below use：Antitublin, immunomodulator, Paclitaxel, for injectable suspensions too Flat ocean taxol protein binding particle, anti-CTLA-4 agent, Yi Paili monoclonal antibodies, anti-PD-1 agent, draws and founds pearl monoclonal antibody, resists eribulin PD L-1 agent or MPDL3280A.

7. Formulas I composition is being prepared for treating the breast cancer in patient in new aided case before ocal resection The tumor microenvironment expression TIE2 of purposes in drug, the patient expresses the TIE2 kinases in macrophage

Wherein

The integer that n is 0 to 7；

X is the basic group of pharmaceutically acceptable salt；

TIE2 wherein in ocal resection foregoing description drug is enough that tumor microenvironment TIE2 is blocked to express macrophage Kinases.

8. purposes according to claim 7, wherein the drug is suitable for daily administration or non-is given daily suitable for intermittent Medicine, every other day administration, every three days administration, administration twice weekly are administered once a week.

9. according to the purposes described in any one of claim 7 or 8, wherein the Formulas I composition and Paclitaxel, being used for Paclitaxel protein binding particle, eribulin, anti-CTLA-4 agent, Yi Paili monoclonal antibodies, the anti-PD-1 of injectable suspensions Agent draws vertical pearl monoclonal antibody, anti-PD L-1 agent or MPDL3280A to be applied in combination.

10. purposes of the Formulas I composition in preparing drug for treating the cancer in patient, in the tumour expression of the patient Film endothelial cell kinases -2 (TIE2 kinases)：

Wherein

The integer that n is 0 to 7；

X is the basic group of pharmaceutically acceptable salt；

The wherein described patient expresses inner membrance endothelial cell kinases -2 (TIE2 kinases).

11. purposes according to claim 10, wherein the Formulas I composition makes with one or more other pharmaceutical agent combinations With, wherein other medicaments be it is following in it is one or more：Paclitaxel, the Pacific Ocean for injectable suspensions Taxol protein binding particle, eribulin, docetaxel, Ipsapirone, vincristine, vinorelbine, cis-platinum, carboplatin, Austria Husky profit platinum, cyclophosphamide, ifosfamide, Temozolomide, Doxorubicin, pegylated liposomal Doxorubicin, road promise are mould Element, Ida mycin and epirubicin, 5 FU 5 fluorouracil, capecitabine, cytarabine, Decitabine, 5-azacitidine, Ji Xi His shore, methotrexate (MTX), Erlotinib, Gefitinib, Lapatinib, everolimus, tamiros, LY2835219, LEE011, PD 0332991, gram Zhuo are won for Buddhist nun for Buddhist nun, card, Sutent, pazopanib, Sorafenib, Rui Gefeini, Axitinib, are reached Sand is miscellaneous for Buddhist nun, tamoxifen for Buddhist nun, Imatinib, nilotinib, Wei Luofeini, dabrafenib, Trimetinib, Ai De former times cloth, quinoline The miscellaneous Shandong amine of sweet smell, fulvestrant, Anastrozole, Letrozole, Exemestane, abiraterone acetate ester, grace, Nilutamide, than card Shandong Amine, Flutamide, Cyproterone Acetate, prednisone, dexamethasone, Irinotecan, camptothecine, topotecan, Etoposide, phosphoric acid Etoposide, mitoxantrone, Vorinostat, romidepsin, pabishta, valproic acid, Belling promise he, DZNep 5- azepines -2'- Deoxycytidine, bortezomib, the non-azoles rice of card, Distaval, lenalidomide, pomalidomide, Herceptin, handkerchief trastuzumab, Cetuximab, Yi Paili monoclonal antibodies, draws and founds pearl monoclonal antibody, the fertile monoclonal antibody of Buddhist nun, MPDL3280A, bevacizumab, A Baixi Victibix General, the appropriate monoclonal antibody Wei Duoting in Belém, Ah Duo-Herceptin En Taxin, radiotherapy and the bright plug-T of Xi Pu.

12. the purposes according to claim 10 or 11, wherein the drug is suitable for daily administration or suitable for intermittent non-every Its administration.

13. the purposes according to claim 10 or 11, wherein the drug reduces primary tumor growth, tumor invasion Property, ooze in cancer, be in cancer diffusion, metastasis of cancer and tumour immunity tolerance one or more.