CN105873440A

CN105873440A - Methods for inhibiting tie2 kinase useful in the treatment of cancer

Info

Publication number: CN105873440A
Application number: CN201380081931.2A
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: 2016-08-17
Anticipated expiration: 2033-11-07
Also published as: CN105873440B; WO2015069266A1; CN108464981B; EP3065549A1; AU2021200113A1; JP2017500371A; JP6568093B2; CA2929715A1; EP3065549A4; AU2013404949B2; KR20210063475A; KR20160070188A; AU2013404949A1; CN108464981A; AU2019200261A1

Abstract

The present invention relates to methods of inhibiting TIE2 kinase useful in the treatment of tumor growth, invasiveness, intravasation, dissemination, metastasis, and immunosuppression. Specifically, the invention relates to methods of using 1-(3-tert-butyl-1-(quinolin-6-yl)-1Hpyrazol- 5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea and salts thereof of Formula I.

Description

Be applicable to treat cancer for suppressing the kinase whose method of TIE2

The description of the text electronically submitted to

The content of the text electronically submitted to is incorporated herein the most in entirety by reference: the meter of sequence table Calculation machine readable format copy (filename: DECP_066_00WO_SeqList_ST25.txt, record date: 2013 November 7, file size 6 kilobytes).

Technical field

The present invention relates to suppress the kinase whose method of TIE2, it is applicable to treat tumor growth, tumor invasiveness, intra-tumor Ooze, tumor diffusion, neoplasm metastasis and tumour immunity toleration.In particular it relates to use Formulas I compositions Method, described Formulas I compositions is described herein as the potent inhibitor of TIE2, is used for treating breast carcinoma growth, invades Attacking property, endosmosis diffusion, cancerometastasis and immunologic tolerance.

Background technology

Inner membrance endotheliocyte kinases-2 (TIE2) is basically limited in the endotheliocyte of blood vessel and at the TIE2 of bone marrow derived Express in the subset of mononuclear cell (TEM) and express.TIE2 is Ang-1 (ANG1), ANG2 (ANG2) With the receptor of angiogenin 4 (ANG4), and this signal transducting system at angiogenesis, (neovascularity is from existing blood vessel Sprout) and blood tubule generate (from the beginning neovascularity is formed) and both play an important role.TEM be circulating monocytic cell and The subset of tissue macrophages, it has Angiogensis in tumor model and promotees Angiogenic activity (De Palma MD Et al., " cancerous cell " (Cancer Cell) 2005；8:211-226).TIE2 suppression can reduce TEM and associate with blood vessel Ability (Mazzieri R, " cancerous cell " 2011；19:512-526) and be substantially reduced the rush of this macrophage subset Angiogenic activity (De Palma M, " Clinical Cancer Research " (Clin Cancer Res) 2011； 17 (16): 5226-5232).

Cytotoxic chemotherapy, X-ray therapy can damage, with antiangiogenesis therapy, the blood vessel that tumor is relevant, thus produce Hypoxic tumors environment.Hypoxic tumors environment passes through in activating vascular endothelial cell from VEGF (VEGF) The Tumor angiogenesis that/VEGFR2 path draws backlash to the angiogenic switch in ANG/TIE2 path.Promote blood vessel to send out Raw TEM raises these hypoxic tumors positions by by the TEM tumor microenvironment and endotheliocyte association from bone marrow Promote that this blood vessel is formed again.TEM and TIE2 expresses endotheliocyte and thereby is thought to after these are treated in tumor Blood vessel plays an important role in being formed again, causes progress (De Palma M et al. due to the growth of residual tumor cells Trends Immunol 2007；28:519-524).

TIE2 is also the amboceptor of differentiation of osteoclast, and TIE2 suppression causes bone resorption to attack in 4T1 mouse mammary cancer model Reduce and reduce tumor growth (Dales JP et al. Int J Oncol 2003；22:391-397).Except TIE2 is in tumor micro-loop Beyond physiology in the endotheliocyte in border, monocyte/macrophage and osteoclast is expressed, TIE2 also exhibits existence On breast cancer cell.The risk of the tumor cells expression of TIE2 and metastatic disease improves and to the prognosis of multivariate analysis Independentpredictor is associated (Min Y et al. " cancer research " (Cancer Res) 2010；70:2918-2828).

Noteworthy, the subset of TIE2 expression tissue macrophage is positioned at the tumor microenvironment being referred to as cancerometastasis (TMEM) in specific blood vessels structure.TIE2 in TMEM structure has been expressed huge biting carefully by recent observed result Born of the same parents' contact is for being seeped into outside breast cancer cell in vascular circulation and follow-up being diffused into necessary to far-end transitivity position (Condeelis J, Pollard JW. " cell " (Cell) 2006；124:263-6；Ginter PS et al. " cancer research " 2012；72 (24 supplementary issues): summary #P6-02-04).Therefore, to the TIE2 in TMEM structure and the suppression of macrophage New cancerometastasis may be caused to reduce.

TIE2 expression tissue macrophage (TEM) recently has shown that out and works in breast carcinoma immunologic tolerance.From breast The TEM of room tumor can suppress tumor-specific immunity to react.Specifically, the suppression function of TEM is similarly by TIE2 Drive with VEGFR kinase activity.The TEM separated from breast carcinoma tissue may act as antigen presenting cells, and it only causes T The faint propagation of cell.Block TIE2 and VEGFR kinase activity induction TEM its phenotype to be become there is myeloid dendritic Shape cell characteristic has the cell that firm antigen presents.The immunosuppressive activity of TEM also regulates with the T in mammary neoplasms The high CD86 surface expression of cell and wide participation are associated.TIE2 and VEGFR kinase activity is for maintaining high CD86 Surface expression levels and T cell is changed into inhibitive ability of immunity regulation cell required for (Ibberson M et al. " faces Bed cancer research " 2013；19:3439-3449).

In polyoma virus, T antigen (PyMT) homogenic type mouse mammary cancer model uses MMTV (MMTV) Promoter, specific breast promoter are to express PyMT in mouse mammary tissue.In this model, by PyMT Breast cancer cell implants mouse mammary fat pad, and these cancer metastasiss and cause dead mouse.It is different from heteroplastic transplantation model, PyMT model uses complete immunocompetent mice.Cancerometastasis in this model known is tied by TMEM blood vessel TIE2 in structure expresses macrophage and regulates.Accordingly, it would be desirable to the novel treatment of the disease relevant to TIE2.

Summary of the invention

The method of the present invention is used for suppressing TIE2 kinases.Due to this suppression, the present invention be suitable for tumor growth, Aggressive, endosmosis, diffusion, cancerometastasis and the treatment of tumour immunity toleration or prevention.In particular it relates to The method using Formulas I compositions, the described Formulas I compositions potent inhibitor for TIE2 as described below, it is used for treating breast carcinoma Growth, aggressive, endosmosis, diffusion, cancerometastasis and immunologic tolerance:

Wherein

N is the integer of 0 to 7；

X is the basic group of pharmaceutically acceptable salt；

Its restrictive condition is for when n is 0, and described Formulas I compositions is parent free alkali.In certain embodiments, HX Not existing, the structure of Formulas I is parent free alkali whereby.

Formulas I compositions is additionally operable to other cancer, and wherein the TIE2 in tumor cell or in tumor microenvironment expresses by being situated between Lead primary tumor growth, primary tumor aggressive, intra-tumor is seeped in blood flow, tumor cell spreads, tumor cancer turns The mechanism of remote organization or tumour immunity toleration that moves on to is to cause tumour progression.Therefore, TIE2 is swashed by Formulas I compositions The suppression of enzyme for by suppression include primary tumor growth, primary tumor aggressive, intra-tumor be seeped in blood flow, The process of tumor cell diffusion, neoplasm metastasis to remote organization or tumour immunity toleration is for treating cancer.

TIE2 kinases has shown that out the reason of the cancer progression that can become the following: glioma (Liu et al., Oncotarget (2010) 1:700-709；Brunckhorst et al., " cancer research " (2010) 70:7283-7293), Melanoma (Helfrich et al., " Clinical Cancer Research " (2009) 15:1384-1392), ovarian cancer (Karlan et al., " Journal of Clinical Oncology " (J.Clinical Oncology) (2012) 30:362-370), colorectal carcinoma (Ahmad Et al., " cancer " (Cancer) (2001) 92:1138-1143；Hashizume et al., " cancer research " (2010) 70:2213-2223), hepatocarcinoma (Matsubara et al., " hepatology " (Hepatology) (2013) 57: 1416-1425；Mitsuhashi et al., " hepatology " (2003) 37:1105-1113；Tanaka et al., " clinical Research magazine " (J.Clin Invest) (1999) 103:341-345) and hematologic cancers (Muller et al., " white blood Sick research " (Leukemia Research) (2002) 26:163-168；Hou et al., " leukemia research " (2008) 32: 904-912)。

Accompanying drawing explanation

Fig. 1 shows use Formula II compositions, Paclitaxel or a combination thereof suppression constitutional PyMT tumor growth.

Fig. 2 shows use Formula II compositions, Paclitaxel or a combination thereof suppression PyMT tumor macrophage and builds up.

Fig. 3 shows use Formula II compositions, Paclitaxel or a combination thereof suppression PyMT tumor TIE2 and expresses thin Born of the same parents build up.

Fig. 4 shows the pulmonary carcinoma used in Formula II compositions, Paclitaxel or a combination thereof suppression PyMT breast cancer model Transfer.

Fig. 5 shows the PyMT of the activity of the combination comparing Paclitaxel with Paclitaxel and Formula II compositions The suppression of the lung cancer metastasis in breast cancer model.

Fig. 6 show use eribulin as single medicament or with Formula II combination of compositions suppression PyMT breast cancer model in Lung cancer metastasis.

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

Detailed description of the invention

Definition:

Term " basic group of the pharmaceutically acceptable salt in Formulas I compositions " includes, but is not limited to water solublity And water-insoluble salt, such as the benzene sulfonate being substituted or being unsubstituted, acetate, amsonate (4,4-diamino-stilbene -2,2-disulfonate), benzoate, bicarbonate, disulfate, biatrate, borate, bromide, fourth Hydrochlorate, calcium, Ca-EDTA, camsilate, carbonate, chloride, citrate, Clavulanate, Dihydrochloride, edetate, ethanedisulphonate, estolate, esilate, fumarate, glucoheptonic acid Salt, gluconate, glutamate, Glu, beta-lactam phenyl-arsonate, hexafluorophosphate, hexyl resorcin hydrochlorate, Hai Zhuo Amine, hydrobromate, hydrochlorate, Hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, Laruate, magnesium, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, first Base sulfate, galactosaccharic acid salt, naphthalene sulfonate, nitrate, N-METHYL-ALPHA-L-GLUCOSAMINE ammonium salt, 3-hydroxy-2-naphthoic acid salt, Oleate, oxalates, palmitate, embonate (1,1-methylene-bis--2-hydroxyl-3-naphthoates, embonate), Pantothenate, phosphate/diphosphate, picrate, Polygalacturonate, propionate, tosilate, bigcatkin willow Hydrochlorate, stearate, basic acetate, succinate, sulfate, sulfosalicylate, Ursula hydrochlorate, tannic acid Salt, tartrate, teoclate, toluene fulfonate, triethiodide and valerate.The particular instance of basic group includes Tosilate, fluoroform sulphonate and mesylate.

Term " salt " refers to pharmaceutically acceptable salt

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

At least one symptom referring to improve individual disease " is treated " about individual term.Treatment can be healing, change It is apt to or at least partly alleviates disease.

" administration (administer) ", " administration (administering) " or " throwing as that term is used in this disclosure With (administration) " it is directed to individual directly administration compositions or the pharmaceutically acceptable salt of compound or group Compound, or to individual administration compositions or the pharmaceutically acceptable salt of compound or the prodrug derivant of compositions or class Like thing, it can form the reactive compound of equivalent in individual health.

" effective dose " is controlled for effective the measurable of pathogenicity rate providing relevant disease when being used in combination with medical usage The amount treat, prevented or reduce.

The present invention relates to for tumor growth, aggressive, endosmosis, diffusion, cancerometastasis and the treatment of tumour immunity toleration (blocking-up) or the method for prevention.Described method comprises to the treatment needing the preventive effect to these patient's condition or the trouble reduced Person's administration effective dose herein regulation TIE2 suppression dosage regimen described in Formulas I compositions.

The amount of the compositions realized needed for therapeutical effect as herein described can be according to the conventional program for specific purposes with warp Test and determine.Generally, for therapeutic purpose administration therapeutic agent (Formulas I the most as herein described or II compositions (and/or volume Outer medicament)), therapeutic agent gives with pharmacological effective dose." pharmaceutical effective amount ", " pharmacological effective dose ", " therapeutically effective amount " or " effective dose " refers to the amount that be enough to produce required physiological action or is capable of results needed Amount, for treatment disease or disease.Effective dose will include being enough to such as postpone disease or disease as used herein The process (progress of the symptom of the disease that such as slows down) of the symptom of the development of sick symptom, change disease or disease, minimizing Or eliminate the amount of the symptom of disease or one or more symptoms of disease or performance and reverse disease or disease.For example, To suffering from cancered patient's administration therapeutic agent not only when eradicating or improving the potential patient's condition, and in patient's report and disease phase (such as tumor load reduces, circulating tumor cell reduces, gets nowhere and deposit for the severity of the symptom closed or persistent period minimizing Motility rate improve) time provide treatment benefit.Treatment benefit also includes suspending or slow down the progress of potential disease or disease, and is No realization improves unrelated.

In one embodiment of the invention, Formulas I compositions is 1-(the 3-tert-butyl group-1-(quinoline-6-the base)-1H-pyrazoles of Formula II -5-base)-3-(the fluoro-4-of 2-(2-(methylcarbamoyl) pyridin-4-yl epoxide) phenyl) urea tosilate, it is TIE2 (blood Pipe generate element part receptor tyrosine kinase) potent inhibitor.

Formulas I compositions is used for cancer, and wherein the TIE2 in tumor cell or in tumor microenvironment expresses by mediation primary Property tumor growth, primary tumor aggressive, intra-tumor are seeped in blood flow, tumor cell diffusion, neoplasm metastasis is to far The mechanism of end tissue or tumour immunity toleration causes tumour progression.Therefore, Formulas I compositions presses down TIE2 is kinase whose System for by suppression include primary tumor growth, primary tumor aggressive, intra-tumor be seeped in blood flow, tumor thin The process of born of the same parents' diffusion, neoplasm metastasis to remote organization or tumour immunity toleration is for treating cancer.

The treatment concentration of Formulas I compositions block tumor microenvironment has been notified cause tumor growth, invasion and attack, endosmosis, diffusion, The cell of the immunologic tolerance of cancerometastasis or tumor inducing.Described cell type in tumor microenvironment includes that TIE2 expresses Mononuclear cell, TIE2 express macrophage and TIE2 expresses endotheliocyte.

It is thin that the tumor reacting the conduction of angiogenin/TIE2 signal includes, but is not limited to breast carcinoma, ovarian cancer, liver Born of the same parents' cancer, glioma, colorectal carcinoma and Hematological Malignancies.

In another embodiment, when HX not in the presence of Formulas I compositions be free alkali compound 1-(the 3-tert-butyl group-1-(quinoline -6-base)-1H-pyrazoles-5-base)-3-(the fluoro-4-of 2-(2-(methylcarbamoyl) pyridin-4-yl epoxide) phenyl) urea, there is structure:

Formulas I compositions can with single medicine type or with other therapeutic combination administration of known treatment cancer.Described other Therapeutic agent include X-ray therapy, antitublin, DNA alkylating agent, DNA synthetic inhibitor, DNA intercalator, Estrogen antagonist agent, androgen antagonist, steroid, anti-EGFR agent, inhibitors of kinases, topoisomerase enzyme inhibitor, group egg White deacetylase (HDAC) inhibitor, DNA methylation inhibitor, anti-HER2 agent, anti-angiogenic agent, egg White enzyme body inhibitor, thalidomide (thalidomide), lenalidomide (lenalidomide), antibody-drug conjugates (ADC), immunomodulator or cancer vaccine.

Effective dose, toxicity and therapeutic effect can be cultivated by cell or standard pharmaceutical procedures in laboratory animal, the most logical Cross mensuration LD50 (dosage of about 50% death in colony) and ED50 (in colony, about 50% treats effective dosage) comes Measure.Dosage can change depending on the dosage form used and the dosing way utilized.Agent between toxicity and therapeutical effect Amount than for therapeutic index and its be represented by ratio LD50/ED50.In certain embodiments, bigger therapeutic index is represented Compositions and method are preferred.Treatment effective dose can initially be estimated from analyzed in vitro, including such as cell culture assays. Additionally, dosage can be allocated to realize circulating plasma concentration range in animal model, it include as cell cultivate in or The IC50 suitably measured in animal model.Described in blood plasma, the level of compositions can such as be surveyed by high performance liquid chromatography Amount.The effect of any given dose can be monitored by suitable bioanalysis.Dosage can be determined by doctor and as required Adjust to be suitable for the therapeutical effect observed.

In certain embodiments, preventive 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% can quantitatively change.In certain embodiments, described effect will cause about 10%, about 20%, about 30%, about 50%, about 70% or the most about 90% or more can quantitatively change.Treatment benefit Whether place also includes suspending or slow down the progress of potential disease or disease, unrelated with realizing improving.

When the compositions of Formulas I or II is applied in combination with other anticarcinogen, other anticarcinogen can be with Formulas I or the compositions of II Administration time-histories be independently administered.Other anticarcinogen can be administered with its previously determined therapeutic dose and administration time-histories, or its Dosage and administration time-histories can be altered to optimize effect, safety or tolerance when using with the combination of compositions of Formulas I or II Property.

Pharmaceutically can connect it addition, the compositions (and/or additional agent) of any Formulas I as herein described or II can comprise The supporting agent being subject to or the chemical species administration of the compositions of mediator are individual.Described compositions optionally comprises proper amount of medicine Acceptable excipient on is to provide the form for suitable administration.

Drug excipient can be liquid, Ru Shui and oil, including oil, animal, plant or the oil in synthesis source, such as Semen arachidis hypogaeae Oil, soybean oil, mineral oil, Oleum sesami etc..Drug excipient can be such as saline, arabic gum, gelatin, gelatinized corn starch, Talcum, keratin, colloidal silica, carbamide etc..It addition, used additives, stabilizer, thickening agent, lubricant can be made And coloring agent.In one embodiment, pharmaceutically acceptable excipient is aseptic when administration individuality.When herein During described any medicament intravenous administration, water is applicable excipient.Saline solution and dextrose can also be used water-soluble Liquid and glycerite are as liquid excipient, especially for Injectable solution.Suitably drug excipient also includes forming sediment Powder, glucose, lactose, sucrose, gelatin, Fructus Hordei Germinatus, rice, powder, Chalk, silica gel, sodium stearate, single tristearin Acid glyceride, Talcum, sodium chloride, anhydrous defatted milk, glycerol, propylene glycol, ethylene glycol, water, ethanol etc..If needed , any medicament as herein described can also comprise a small amount of wetting agent or emulsifying agent or pH buffer agent.

Formulas I compositions can be with other medicament including chemotherapeutant, target therapeutic agent, biological preparation or actinotherapy It is applied in combination.

Formulas I compositions can use with chemotherapeutic combination, and described chemotherapeutant includes, but is not limited to anti-micro-pipe egg White agent (Paclitaxel (paclitaxel), for injectable suspensions Paclitaxel protein binding particle, Eribulin (eribulin), docetaxel (docetaxel), ipsapirone (ixabepilone), vincristine (vincristine)), vinorelbine (vinorelbine), DNA alkylating agent (include cisplatin (cisplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), cyclophosphamide (cyclophosphamide), ifosfamide (ifosfamide), temozolomide (temozolomide)), DNA intercalator (include doxorubicin (doxorubicin), Pegylated liposomal doxorubicin, daunomycin (daunorubicin), Ida mycin (idarubicin) and table are soft Than star (epirubicin)), 5-fluorouracil, capecitabine (capecitabine), cytosine arabinoside (cytarabine), His shore (decitabine), west, 5-azacytidine, gemcitabine (gemcitabine) and methotrexate (methotrexate).

Formulas I compositions can use with kinase inhibitor combination, and described inhibitors of kinases includes, but is not limited to erlotinib (erlotinib), gefitinib (gefitinib), Lapatinib (lapatanib), everolimus (everolimus), smooth Luo Mosi (temsirolimus), LY2835219, LEE011, PD 0332991, gram Zhuo are for Buddhist nun (crizotinib), card Rich for Buddhist nun (cabozantinib), Sutent (sunitinib), pazopanib (pazopanib), Sorafenib (sorafenib), Rui Gefeini (regorafenib), Axitinib (axitinib), Dasatinib (dasatinib), imatinib (imatinib), Nilotinib (nilotinib), Wei Luofeini (vemurafenib), dabrafenib (dabrafenib), Sibutramine Hydrochloride replace Buddhist nun (trametinib), Ai De former times cloth (idelalisib) and quinoline are miscellaneous for Buddhist nun (quizartinib).

Formulas I compositions can be applied in combination with estrogen antagonist agent, and described estrogen antagonist agent includes, but is not limited to tamoxifen (tamoxifen), fulvestrant (fulvestrant), Anastrozole (anastrozole), letrozole (letrozole) and Exemestane (exemestane).

Formulas I compositions can be applied in combination with antiandrogenic agents, and described antiandrogenic agents includes, but is not limited to acetic acid Ah ratio Special dragon ester (abiraterone acetate), grace miscellaneous Shandong amine (enzalutamide), nilutamide (nilutamide), ratio block Shandong amine (bicalutamide), flutamide (flutamide), CPA (cyproterone acetate).

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

Formulas I compositions can be applied in combination with topoisomerase I inhibitor, described topoisomerase I inhibitor include (but Be not limited to) irinotecan (irinotecan), camptothecine (camptothecin) and topotecan (topotecan).

Formulas I compositions can be applied in combination with Topoisomerase II inhibitors, described Topoisomerase II inhibitors include (but Be not limited to) etoposide (etoposide), etoposide phosphate (etoposide phosphate) and mitoxantrone (mitoxantrone)。

Formulas I compositions can be applied in combination with histone deacetylase (HDAC) inhibitor, described histone deacetylase Base enzyme (HDAC) inhibitor include, but is not limited to Vorinostat (vorinostat), romidepsin (romidepsin), LBH589 (panobinostat), valproic acid (valproic acid) and Belling promise he (belinostat).

Formulas I compositions can be applied in combination with DNA methylation inhibitor, and described DNA methylation inhibitor includes (but not It is limited to) DZNep and DAC.

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

Formulas I compositions can be applied in combination with thalidomide, lenalidomide and pomalidomide (pomalidomide).

Formulas I compositions can be applied in combination with following: biological preparation, includes, but is not limited to Herceptin (trastuzumab), Ah many-Herceptin (ado-trastuzumab), handkerchief trastuzumab (pertuzumab), western appropriate Former times monoclonal antibody (cetuximab), Victibix (panitumumab), Yi Paili monoclonal antibody (ipilimumab)；Anti-PD-1 Agent, irrigates monoclonal antibody (nivolumab) including drawing vertical pearl monoclonal antibody (labrolizumab) and Buddhist nun；Anti-Pd-L1 agent, including MPDL3280A；Anti-angiogenic agent, including bevacizumab (bevacizumab) and VEGF Trap (aflibercept)； With antibody-drug conjugates (ADC), including Belém appropriate monoclonal antibody Wei Duoting (brentuximab vedotin) and toltrazuril list Anti-En Taxin (trastuzumab emtansine).

Formulas I compositions can be applied in combination with actinotherapy.

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

In certain embodiments, the compositions of Formulas I or Formula II can be with one or more groups in other medicament as herein described Close and use.

Blocking-up constitutional mammary tumor growth and invasive method:

A first aspect of the present invention relates to a kind of blocking-up constitutional mammary tumor growth and invasive method, and it comprises with foot To block the kinase whose dosage regimen of TIE2 in tumor microenvironment to the Formulas I compositions of patient's administration effective dose in need.

In an embodiment in this aspect of the invention, the dosage regimen of Formulas I compositions is to be administered administration every day.

In another embodiment in this aspect of the invention, the dosage regimen of Formulas I compositions is to be administered administration every day. The dosage regimen non-every day being interrupted can include, but is not limited to be administered every other day, is administered every three days, be administered twice a week Or be administered once in a week.

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

In another embodiment in this aspect of the invention, the dosage regimen of Formulas I compositions is twice a week or weekly Once.

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

In the still another embodiment of the present invention, block constitutional mammary tumor growth and invasive method comprises with foot With block the TIE2 kinase whose dosage regimen administration Formulas I compositions in tumor microenvironment and one or more be obtained from Under medicament: antitublin, DNA alkylating agent, DNA synthetic inhibitor, DNA intercalator, estrogen antagonist Agent, anti-HER2 agent, inhibitors of kinases or anti-angiogenic agent.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise administration Formulas I compositions and Paclitaxel.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise administration Formulas I compositions and the Paclitaxel protein binding particle for injectable suspensions.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise administration Formulas I compositions and docetaxel.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise administration Formulas I compositions and eribulin.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise administration Formulas I compositions and ipsapirone.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise administration Formulas I compositions and vinorelbine.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise administration Formulas I compositions and capecitabine.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise administration Formulas I compositions and gemcitabine.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise administration Formulas I compositions and 5-fluorouracil.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise administration Formulas I compositions and methotrexate.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise administration Formulas I compositions and cyclophosphamide.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise administration Formulas I compositions and cisplatin.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise administration Formulas I compositions and carboplatin.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise administration Formulas I compositions and doxorubicin.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise administration Formulas I compositions and pegylated liposomal doxorubicin.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise administration Formulas I compositions and epirubicin.

In still another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive side Method comprises administration Formulas I compositions and tamoxifen.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise administration Formulas I compositions and fulvestrant.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise administration Formulas I compositions and Anastrozole.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise administration Formulas I compositions and letrozole.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise administration Formulas I compositions and exemestane.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise administration Formulas I compositions and Herceptin.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise administration Formulas I compositions and Ah many-Herceptin En Taxin.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise administration Formulas I compositions and handkerchief trastuzumab.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise administration Formulas I compositions and Lapatinib.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise administration Formulas I compositions and everolimus.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise administration Formulas I compositions and CCI-779.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise administration Formulas I compositions and CDK4/6 inhibitor LY2835219.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise administration Formulas I compositions and CDK4/6 inhibitor LEE011.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise administration Formulas I compositions and CDK4/6 inhibitor PD 0332991.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise administration Formulas I compositions and bevacizumab.

Another aspect of the present invention relates to a kind of blocking constitutional mammary tumor growth and invasive method, its comprise with Be enough to the TIE2 kinase whose dosage administration Formulas I compositions blocking in tumor microenvironment, wherein said Formulas I compositions is to be interrupted Dosage regimen administration non-every day.In certain embodiments, the dosage regimen non-every day of interruption include being administered every other day, every Within two days, it is administered, is administered twice a week and is administered once in a week.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise the TIE2 kinase whose dosage administration Formulas I compositions that be enough to block in tumor microenvironment, wherein said Formulas I compositions Twice a week, once in a week or every other week administration.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise the TIE2 kinase whose dosage administration Formulas I compositions that be enough to block in tumor microenvironment, wherein said Formulas I compositions Twice a week or weekly administration.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise the TIE2 kinase whose dosage administration Formulas I compositions that be enough to block in tumor microenvironment, wherein said Formulas I compositions Administration twice a week.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise the TIE2 kinase whose dosage administration Formulas I compositions that be enough to block in tumor microenvironment, wherein said Formulas I compositions It is obtained from following pharmaceutical agent combinations administration: antitublin, DNA alkylating agent, DNA synthesize with one or more Inhibitor, DNA intercalator, estrogen antagonist agent, anti-HER2 agent, inhibitors of kinases or anti-angiogenic agent.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise to be enough to block tumor microenvironment TIE2 and express the TIE2 kinase whose dosage administration Formulas I compositions in macrophage, Administration is combined with Lapatinib.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise to be enough to block tumor microenvironment TIE2 and express the TIE2 kinase whose dosage administration Formulas I compositions in macrophage, Administration is combined with everolimus.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise to be enough to block tumor microenvironment TIE2 and express the TIE2 kinase whose dosage administration Formulas I compositions in macrophage, Administration is combined with CCI-779.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise to be enough to block tumor microenvironment TIE2 and express the TIE2 kinase whose dosage administration Formulas I compositions in macrophage, Administration is combined with CDK4/6 inhibitor LY2835219.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise to be enough to block tumor microenvironment TIE2 and express the TIE2 kinase whose dosage administration Formulas I compositions in macrophage, Administration is combined with CDK4/6 inhibitor LEE011.

In another embodiment in this aspect of the invention, block constitutional mammary tumor growth and invasive method Comprise to be enough to block tumor microenvironment TIE2 and express the TIE2 kinase whose dosage administration Formulas I compositions in macrophage, Administration is combined with CDK4/6 inhibitor PD 0332991.

Block breast carcinoma endosmosis, diffusion and the method for cancerometastasis:

In the yet other aspects of the present invention, it is provided that a kind of block breast carcinoma endosmosis, diffusion and the method for cancerometastasis, its bag Containing the Formulas I compositions that be enough to the kinase whose effective dose of TIE2 blocking in tumor microenvironment to patient's administration in need.

In an embodiment in this aspect of the invention, block that breast carcinoma is endosmosis, diffusion and the method for cancerometastasis comprise with The kinase whose dosage regimen of TIE2 that be enough to block in tumor microenvironment combines to the Formulas I of patient's administration effective dose in need Thing.

In another embodiment in this aspect of the invention, it is sufficient to block breast carcinoma endosmosis, diffusion and the administration of cancerometastasis Scheme comprises administration Formulas I compositions every day.

In another embodiment in this aspect of the invention, the dosage regimen of Formulas I compositions is the non-every day to be interrupted Administering mode administration, including being administered every other day, be administered every three days, being administered twice a week or be administered once in a week.

In another embodiment in this aspect of the invention, the dosage regimen of Formulas I compositions 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 compositions is twice a week or weekly Administration.

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

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises With the kinase whose dosage regimen of TIE2 that be enough to block in tumor microenvironment to the Formulas I group of patient's administration effective dose in need Compound and one or more be obtained from following medicament: antitublin, DNA alkylating agent, DNA synthesis presses down Preparation, DNA intercalator, estrogen antagonist agent, anti-HER2 agent, inhibitors of kinases or anti-angiogenic agent.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and Paclitaxel.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and the Paclitaxel protein binding particle for injectable suspensions.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and docetaxel.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and eribulin.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and ipsapirone.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and vinorelbine.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and capecitabine.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and gemcitabine.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and 5-fluorouracil.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and methotrexate.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and cyclophosphamide.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and cisplatin.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and carboplatin.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and doxorubicin.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and epirubicin.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and tamoxifen.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and fulvestrant.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and Anastrozole.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and letrozole.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and exemestane.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and Herceptin.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and Ah many-Herceptin En Taxin.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and handkerchief trastuzumab.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and Lapatinib.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and everolimus.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and CCI-779.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and CDK4/6 inhibitor LY2835219.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and CDK4/6 inhibitor LEE011.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and CDK4/6 inhibitor PD 0332991.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and bevacizumab.

In another aspect of the present invention, block that breast carcinoma is endosmosis, diffusion and the method for cancerometastasis comprise to be enough to block swollen TIE2 kinase whose dosage administration Formulas I compositions in tumor microenvironment, wherein the dosage regimen of Formulas I compositions is to be interrupted Non-every day form of medication administration.In certain embodiments, be administered every other day include being administered every three days, be administered twice a week or Weekly administration.

In an embodiment in this aspect of the invention, block that breast carcinoma is endosmosis, diffusion and the method for cancerometastasis comprise with Be enough to the TIE2 kinase whose dosage administration Formulas I compositions blocking in tumor microenvironment, the wherein dosage regimen of Formulas I compositions For twice a week, once in a week or every other week administration.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Be enough to the TIE2 kinase whose dosage administration Formulas I compositions blocking in tumor microenvironment, wherein Formulas I compositions to prescription Case is twice a week or weekly administration.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Be enough to the TIE2 kinase whose dosage administration Formulas I compositions blocking in tumor microenvironment, wherein Formulas I compositions to prescription Case is administration twice a week.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Be enough to the TIE2 kinase whose dosage administration Formulas I compositions blocking in tumor microenvironment, with one or more be obtained from Under pharmaceutical agent combinations administration: antitublin, DNA alkylating agent, DNA synthetic inhibitor, DNA intercalator, Estrogen antagonist agent, anti-HER2 agent, inhibitors of kinases or anti-angiogenic agent.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Administration Formulas I compositions and pegylated liposomal doxorubicin.

In still another embodiment in this aspect of the invention, block breast carcinoma endosmosis, diffusion and the method bag of cancerometastasis Containing administration Formulas I compositions and tamoxifen.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Express the TIE2 kinase whose dosage administration Formulas I compositions in macrophage being enough to block tumor microenvironment TIE2, and draw Handkerchief combines administration for Buddhist nun.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Express the TIE2 kinase whose dosage administration Formulas I compositions in macrophage being enough to block tumor microenvironment TIE2, and depend on Wei Mosi combines administration.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Be enough to block the TIE2 kinase whose dosage administration Formulas I compositions in tumor microenvironment TIE2 expression macrophage, with smooth Luo Mosi combines administration.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Be enough to block the TIE2 kinase whose dosage administration Formulas I compositions in tumor microenvironment TIE2 expression macrophage, with CDK4/6 inhibitor LY2835219 combines administration.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Be enough to block the TIE2 kinase whose dosage administration Formulas I compositions in tumor microenvironment TIE2 expression macrophage, with CDK4/6 inhibitor LEE011 combines administration.

In another embodiment in this aspect of the invention, blocking-up breast carcinoma is endosmosis, spread and the method for cancerometastasis comprises Be enough to block the TIE2 kinase whose dosage administration Formulas I compositions in tumor microenvironment TIE2 expression macrophage, with CDK4/6 inhibitor PD 0332991 combines administration.

The method blocking breast carcinoma immunologic tolerance:

Another aspect of the present invention relates to a kind of method blocking breast carcinoma immunologic tolerance.Described method comprises to there is a need to The Formulas I compositions of patient's administration effective dose.In one embodiment, to be enough to block mediated immunity resistance to for the dosage regimen of salt By the TIE2 kinases in the tumor microenvironment of property.

In an embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises to be enough to block The kinase whose dosage regimen of TIE2 in the tumor microenvironment of mediating immune tolerance is to patient's administration effective dose in need Formulas I compositions.

In an embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration formula every day I compositions.

In another embodiment in this aspect of the invention, Formulas I compositions is with the mode administration non-every day being interrupted.? In some embodiments, the mode non-every day of interruption includes being administered every other day, be administered every three days, be administered twice a week or weekly Single administration.

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

In another embodiment in this aspect of the invention, Formulas I compositions is twice a week or weekly administration.

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

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises to be enough to hinder Formulas I compositions from the kinase whose dosage regimen of TIE2 in disconnected tumor microenvironment to patient's administration effective dose in need and One or more are obtained from following medicament: antitublin, DNA alkylating agent, DNA synthetic inhibitor, DNA Intercalator, estrogen antagonist agent, anti-HER2 agent, inhibitors of kinases, anti-angiogenic agent or immunomodulator.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and Paclitaxel.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and the Paclitaxel protein binding particle for injectable suspensions.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and docetaxel.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and eribulin.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and ipsapirone.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and vinorelbine.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and capecitabine.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and gemcitabine.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and 5-fluorouracil.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and 5-methotrexate.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and cyclophosphamide.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and cisplatin.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and carboplatin.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and doxorubicin.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and pegylated liposomal doxorubicin.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and epirubicin.

In still another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration formula I compositions and tamoxifen.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and fulvestrant.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and Anastrozole.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and letrozole.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and exemestane.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and Herceptin.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and Ah many-Herceptin En Taxin.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and handkerchief trastuzumab.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises to be enough to hinder Disconnected tumor microenvironment TIE2 expresses the TIE2 kinase whose dosage administration Formulas I compositions in macrophage, with Lapatinib group Close administration.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises to be enough to hinder Disconnected tumor microenvironment TIE2 expresses the TIE2 kinase whose dosage administration Formulas I compositions in macrophage, with everolimus group Close administration.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises to be enough to hinder Disconnected tumor microenvironment TIE2 expresses the TIE2 kinase whose dosage administration Formulas I compositions in macrophage, with CCI-779 group Close administration.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises to be enough to hinder Disconnected tumor microenvironment TIE2 expresses the TIE2 kinase whose dosage administration Formulas I compositions in macrophage, presses down with CDK4/6 Preparation LY2835219 combines administration.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises to be enough to hinder Disconnected tumor microenvironment TIE2 expresses the TIE2 kinase whose dosage administration Formulas I compositions in macrophage, presses down with CDK4/6 Preparation LEE011 combines administration.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises to be enough to hinder Disconnected tumor microenvironment TIE2 expresses the TIE2 kinase whose dosage administration Formulas I compositions in macrophage, presses down with CDK4/6 Preparation PD 0332991 combines administration.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and bevacizumab.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and anti-CTLA-4 agent.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and Yi Paili monoclonal antibody.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and anti-PD-1 agent.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and draw vertical pearl monoclonal antibody.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and anti-PD L-1 agent.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and MPDL3280A.

The method blocking breast carcinoma immunologic tolerance:

In another aspect of the present invention, the method blocking breast carcinoma immunologic tolerance comprises to be enough to block tumor microenvironment In TIE2 kinase whose dosage administration Formulas I compositions, wherein the dosage regimen of Formulas I compositions be interrupted non-every day be administered Mode administration, including being administered every other day, be administered every three days, being administered twice a week or be administered once in a week.

In an embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises to be enough to block TIE2 kinase whose dosage administration Formulas I compositions in tumor microenvironment, wherein said Formulas I compositions is twice a week, weekly Once or every other week administration.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises to be enough to hinder TIE2 kinase whose dosage administration Formulas I compositions in disconnected tumor microenvironment, wherein said Formulas I compositions is twice a week or often Zhou Yici administration.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises to be enough to hinder TIE2 kinase whose dosage administration Formulas I compositions in disconnected tumor microenvironment, wherein said Formulas I compositions administration twice a week.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises to be enough to hinder TIE2 kinase whose dosage administration Formulas I compositions in disconnected tumor microenvironment, is obtained from following medicament with one or more Combination administration: antitublin, DNA alkylating agent, DNA synthetic inhibitor, DNA intercalator, estrogen antagonist Agent, anti-HER2 agent, inhibitors of kinases, anti-angiogenic agent or immunomodulator.

In another embodiment in this aspect of the invention, the method blocking breast carcinoma immunologic tolerance comprises administration Formulas I Compositions and methotrexate.

The method improving the overall survival of patients with mastocarcinoma:

Another aspect of the present invention relates to a kind of method of overall survival improving patients with mastocarcinoma, and it comprises to there is a need to The Formulas I compositions of patient's administration effective dose.In one embodiment, dosage regimen be enough to block in tumor microenvironment TIE2 kinases.

In another embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises it The dosage regimen of middle Formulas I compositions administration every day.

In another embodiment in this aspect of the invention, improve the method for overall survival of patients with mastocarcinoma comprise with Be interrupted non-every day mode administration dosage regimen in Formulas I compositions, including being administered every other day, be administered every three days, every Week twice administration or be administered once in a week.

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

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

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

Another embodiment in terms of this of the present invention relates to the method improving the overall survival of patients with mastocarcinoma, described side Method comprises TIE2 kinase whose dosage regimen administration Formulas I compositions and the one or many that be enough to block in tumor microenvironment Kind be obtained from following medicament: antitublin, DNA alkylating agent, DNA synthetic inhibitor, DNA intercalator, Estrogen antagonist agent, anti-HER2 agent, inhibitors of kinases, anti-angiogenic agent or immunomodulator.

In another embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises throwing With Formulas I compositions and Paclitaxel.

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

In another embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises throwing With Formulas I compositions and docetaxel.

In another embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises throwing With Formulas I compositions and eribulin.

In another embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises throwing With Formulas I compositions and ipsapirone.

In another embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises throwing With Formulas I compositions and vinorelbine.

In another embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises throwing With Formulas I compositions and capecitabine.

In another embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises throwing With Formulas I compositions and gemcitabine.

In another embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises throwing With Formulas I compositions and 5-fluorouracil.

In another embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises throwing With Formulas I compositions and methotrexate.

In another embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises throwing With Formulas I compositions and cyclophosphamide.

In another embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises throwing With Formulas I compositions and cisplatin.

In another embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises throwing With Formulas I compositions and carboplatin.

In another embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises throwing With Formulas I compositions and doxorubicin.

In another embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises throwing With Formulas I compositions and pegylated liposomal doxorubicin.

In another embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises throwing With Formulas I compositions and epirubicin.

In still another embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises Administration Formulas I compositions and tamoxifen.

In another embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises throwing With Formulas I compositions and fulvestrant.

In another embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises throwing With Formulas I compositions and Anastrozole.

In another embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises throwing With Formulas I compositions and letrozole.

In another embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises throwing With Formulas I compositions and exemestane.

In another embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises throwing With Formulas I compositions and Herceptin.

In another embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises throwing With Formulas I compositions and Ah many-Herceptin En Taxin.

In another embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises throwing With Formulas I compositions and handkerchief trastuzumab.

In another embodiment in this aspect of the invention, improve the method for overall survival of patients with mastocarcinoma comprise with Be enough to block tumor microenvironment TIE2 and express the TIE2 kinase whose dosage administration Formulas I compositions in macrophage, and draw handkerchief Administration is combined for Buddhist nun.

In another embodiment in this aspect of the invention, improve the method for overall survival of patients with mastocarcinoma comprise with Be enough to block tumor microenvironment TIE2 and express the TIE2 kinase whose dosage administration Formulas I compositions in macrophage, tie up with depending on Not department's combination administration.

In another embodiment in this aspect of the invention, improve the method for overall survival of patients with mastocarcinoma comprise with Be enough to block tumor microenvironment TIE2 and express the TIE2 kinase whose dosage administration Formulas I compositions in macrophage, with smooth sieve Not department's combination administration.

In another embodiment in this aspect of the invention, improve the method for overall survival of patients with mastocarcinoma comprise with Be enough to block tumor microenvironment TIE2 and express the TIE2 kinase whose dosage administration Formulas I compositions in macrophage, with CDK4/6 inhibitor LY2835219 combines administration.

In another embodiment in this aspect of the invention, improve the method for overall survival of patients with mastocarcinoma comprise with Be enough to block tumor microenvironment TIE2 and express the TIE2 kinase whose dosage administration Formulas I compositions in macrophage, with CDK4/6 inhibitor LEE011 combines administration.

In another embodiment in this aspect of the invention, improve the method for overall survival of patients with mastocarcinoma comprise with Be enough to block tumor microenvironment TIE2 and express the TIE2 kinase whose dosage administration Formulas I compositions in macrophage, with CDK4/6 inhibitor PD 0332991 combines administration.

In another embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises throwing With Formulas I compositions and bevacizumab.

In another embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises throwing With Formulas I compositions and anti-CTLA-4 agent.

In another embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises throwing With Formulas I compositions and Yi Paili monoclonal antibody.

In another embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises throwing With Formulas I compositions and anti-PD-1 agent.

In another embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises throwing With Formulas I compositions and draw vertical pearl monoclonal antibody.

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

In another embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises throwing With Formulas I compositions and MPDL3280A.

The method improving the overall survival of patients with mastocarcinoma:

In another aspect of the present invention, the method for the overall survival improving patients with mastocarcinoma comprises to be enough to block tumor TIE2 kinase whose dosage administration Formulas I compositions in microenvironment, wherein the dosage regimen of Formulas I compositions be interrupted non-often It is administered administration, including being administered every other day, be administered every three days, being administered twice a week or be administered once in a week.

In an embodiment in this aspect of the invention, the method for the overall survival improving patients with mastocarcinoma comprises with foot To block the TIE2 kinase whose dosage administration Formulas I compositions in tumor microenvironment, wherein the dosage regimen of Formulas I compositions is Twice a week, once in a week or every other week administration.

In another embodiment in this aspect of the invention, improve the method for overall survival of patients with mastocarcinoma comprise with Be enough to the TIE2 kinase whose dosage administration Formulas I compositions blocking in tumor microenvironment, the wherein dosage regimen of Formulas I compositions For twice a week or weekly administration.

In another embodiment in this aspect of the invention, improve the method for overall survival of patients with mastocarcinoma comprise with Be enough to the TIE2 kinase whose dosage administration Formulas I compositions blocking in tumor microenvironment, the wherein dosage regimen of Formulas I compositions For administration twice a week.

In another embodiment in this aspect of the invention, improve the method for overall survival of patients with mastocarcinoma comprise with Be enough to the TIE2 kinase whose dosage administration Formulas I compositions blocking in tumor microenvironment, be obtained from following with one or more Pharmaceutical agent combinations administration: antitublin, DNA alkylating agent, DNA synthetic inhibitor, DNA intercalator, anti- Estrogenic agents, anti-HER2 agent, inhibitors of kinases, anti-angiogenic agent or immunomodulator.

In another embodiment in this aspect of the invention, improve the method administration formula of the overall survival of patients with mastocarcinoma I compositions and Paclitaxel.

The method of the patients with mastocarcinoma that treatment was in new aided case before ocal resection:

Another aspect of the present invention relates to the breast carcinoma that a kind for the treatment of was in new aided case before ocal resection The method of patient, it comprises the Formulas I compositions to patient's administration in need and effective dose, Formulas I compositions to prescription Case be enough to the TIE2 kinases blocking in tumor microenvironment.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for the patients with mastocarcinoma kinase whose dosage regimen of TIE2 that comprises to be enough to block in tumor microenvironment in need The Formulas I compositions of patient's administration effective dose.

In another embodiment in this aspect of the invention, treatment was in new aided case before excision The method of patients with mastocarcinoma comprises the TIE2 kinase whose dosage administration Formulas I compositions that be enough to block in tumor microenvironment, its The dosage regimen of middle Formulas I compositions is administration every day.

In another embodiment in this aspect of the invention, treatment was in new aided case before excision The kinase whose dosage regimen of TIE2 that the method for patients with mastocarcinoma comprises to be enough to block in tumor microenvironment is to patient in need The Formulas I compositions of administration effective dose, wherein the dosage regimen of Formulas I compositions is with the mode administration non-every day being interrupted, including It is administered every other day, is administered every three days, is administered twice a week or is administered once in a week.

In another embodiment in this aspect of the invention, treatment was in new aided case before excision The method of patients with mastocarcinoma comprises with twice a week, the dosage regimen of once in a week or every other week administration is to patient's administration in need The Formulas I compositions of effective dose.

In another embodiment in this aspect of the invention, treatment was in new aided case before excision The method of patients with mastocarcinoma comprises with twice a week or the dosage regimen administration Formulas I compositions of weekly administration.

In another embodiment in this aspect of the invention, treatment was in new aided case before excision The method of patients with mastocarcinoma comprises to block the TIE2 kinase whose dosage regimen throwing that tumor microenvironment TIE2 expresses in macrophage With Formulas I compositions and one or more be obtained from following medicament: antitublin, DNA alkylating agent, DNA Synthetic inhibitor, DNA intercalator, estrogen antagonist agent, anti-HER2 agent, inhibitors of kinases, anti-angiogenic agent or exempt from Epidemic disease regulator.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and Paclitaxel.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and the Paclitaxel albumen for injectable suspensions is tied Close particle.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and docetaxel.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and eribulin.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and ipsapirone.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and vinorelbine.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and capecitabine.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and gemcitabine.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and 5-fluorouracil.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and methotrexate.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and cyclophosphamide.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and cisplatin.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and carboplatin.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and doxorubicin.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and pegylated liposomal doxorubicin.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and epirubicin.

In still another embodiment in this aspect of the invention, treatment was in before ocal resection and newly assists feelings The method of the patients with mastocarcinoma in condition comprises administration Formulas I compositions and tamoxifen.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and fulvestrant.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and Anastrozole.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and letrozole.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and exemestane.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and Herceptin.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and Ah many-Herceptin En Taxin.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and handkerchief trastuzumab.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise to be enough to block tumor microenvironment TIE2 and express kinase whose dose of TIE2 in macrophage Amount administration Formulas I compositions, combines administration with Lapatinib.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise to be enough to block tumor microenvironment TIE2 and express kinase whose dose of TIE2 in macrophage Amount administration Formulas I compositions, combines administration with everolimus.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise to be enough to block tumor microenvironment TIE2 and express kinase whose dose of TIE2 in macrophage Amount administration Formulas I compositions, combines administration with CCI-779.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise to be enough to block tumor microenvironment TIE2 and express kinase whose dose of TIE2 in macrophage Amount administration Formulas I compositions, combines administration with CDK4/6 inhibitor LY2835219.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise to be enough to block tumor microenvironment TIE2 and express kinase whose dose of TIE2 in macrophage Amount administration Formulas I compositions, combines administration with CDK4/6 inhibitor LEE011.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise to be enough to block tumor microenvironment TIE2 and express kinase whose dose of TIE2 in macrophage Amount administration Formulas I compositions, combines administration with CDK4/6 inhibitor PD 0332991.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and bevacizumab.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and anti-CTLA-4 agent.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and Yi Paili monoclonal antibody.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and anti-PD-1 agent.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and draw vertical pearl monoclonal antibody.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and anti-PD L-1 agent.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and MPDL3280A.

The method of the patients with mastocarcinoma that treatment was in new aided case before excision:

In another aspect of the present invention, the side of the patients with mastocarcinoma that treatment was in new aided case before excision Method comprises the TIE2 kinase whose dosage administration Formulas I compositions that be enough to block in tumor microenvironment, wherein Formulas I compositions Dosage regimen is with the form of medication administration non-every day being interrupted, including being administered every other day, be administered every three days, being administered twice a week Or be administered once in a week.

In an embodiment in this aspect of the invention, treatment was in the breast in new aided case before excision The method of cancer patient comprises the TIE2 kinase whose dosage administration Formulas I compositions that be enough to block in tumor microenvironment, wherein The dosage regimen of Formulas I compositions administration twice a week, once in a week or every other week.

In another embodiment in this aspect of the invention, treatment was in new aided case before excision The method of patients with mastocarcinoma comprises the TIE2 kinase whose dosage administration Formulas I compositions that be enough to block in tumor microenvironment, its The dosage regimen of middle Formulas I compositions is twice a week or weekly administration.

In another embodiment in this aspect of the invention, treatment was in new aided case before excision The method of patients with mastocarcinoma comprises the TIE2 kinase whose dosage administration Formulas I compositions that be enough to block in tumor microenvironment, its The dosage regimen administration twice a week of middle Formulas I compositions.

In another embodiment in this aspect of the invention, treatment was in new aided case before excision The method of patients with mastocarcinoma comprises the TIE2 kinase whose dosage administration Formulas I compositions that be enough to block in tumor microenvironment, with One or more are obtained from following pharmaceutical agent combinations administration: antitublin, DNA alkylating agent, DNA synthesis presses down Preparation, DNA intercalator, estrogen antagonist agent, anti-HER2 agent, inhibitors of kinases, anti-angiogenic agent or immunomodulating Agent.

In another embodiment in this aspect of the invention, treatment was in new aided case before ocal resection In the method for patients with mastocarcinoma comprise administration Formulas I compositions and 5-methotrexate.

Another aspect of the present invention relates to a kind of method treating ovarian cancer, because the conduction of TIE2 path signal has shown that Go out to promote ovarian cancer progress (Karlan et al., " Journal of Clinical Oncology " (2012) 30:362-370).Described side The kinase whose dosage regimen of TIE2 that method comprises to be enough to block in tumor microenvironment is to patient's administration effective dose in need Formulas I compositions.In an embodiment in this aspect of the invention, Formulas I compositions is with single medicine type administration.

In another embodiment in this aspect of the invention, Formulas I compositions and Paclitaxel+carboplatin, Duo Xi His match+carboplatin, Paclitaxel+cisplatin or other taxane+platinum pharmaceutical admixtures combination administration.

Another aspect of the present invention relates to a kind of method treating hepatocarcinoma, because the conduction of TIE2 path signal is opened up Illustrate can promote hepatocellular carcinoma 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 magazine " (1999) 103:341-345).Described method comprises the TIE2 kinases that be enough to block in tumor microenvironment Dosage regimen to the Formulas I compositions of patient's administration effective dose in need.

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

In another embodiment in this aspect of the invention, Formulas I compositions and kinase inhibitor combination administration, described Inhibitors of kinases include Sorafenib, gram Zhuo for Buddhist nun, card rich for Buddhist nun, Sutent, pazopanib, Sorafenib, auspicious Ge Feini or Axitinib.

Another aspect of the present invention relates to one and treats gliomatous method, because TIE2 path signal has conducted Show and can promote gliomas cancer progress (Liu et al., Oncotarget (2010) 1:700-709；Brunckhorst Et al., " cancer research " (2010) 70:7283-7293).Described method comprises to be enough to block in tumor microenvironment The kinase whose dosage regimen of TIE2 is to the Formulas I compositions of patient's administration effective dose in need.

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

In another embodiment in this aspect of the invention, Formulas I compositions combines administration with temozolomide's therapy.

In another embodiment in this aspect of the invention, Formulas I compositions and actinotherapy and temozolomide's therapy Combination administration.

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

In another embodiment in this aspect of the invention, Formulas I compositions and actinotherapy and bevacizumab therapy Combination administration.

In another embodiment in this aspect of the invention, Formulas I compositions is treated with temozolomide's therapy and bevacizumab Method combination administration.

Another aspect of the present invention relates to one and treats melanomatous method, because the conduction of TIE2 path signal has shown that Go out to promote melanoma progression (Helfrich et al., " Clinical Cancer Research " (2009) 15:1384-1392；Peinado Et al., " Natural medicine " (Nature Medicine) (2012) 18:883-891).Described method comprises to be enough to block The kinase whose dosage regimen of TIE2 in tumor microenvironment is to the Formulas I compositions of patient's administration effective dose in need.

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

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

In another embodiment in this aspect of the invention, Formulas I compositions combines throwing with dabrafenib and Sibutramine Hydrochloride for Buddhist nun With.

In another embodiment in this aspect of the invention, Formulas I compositions and temozolomide combine administration.

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

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

In another embodiment in this aspect of the invention, Formulas I compositions irrigates monoclonal antibody combination with drawing vertical pearl monoclonal antibody or Buddhist nun Administration.

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

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

Another aspect of the present invention relates to a kind of method treating colorectal carcinoma, because TIE2 path signal has conducted Show and can promote colorectal carcinoma progress (Ahmad et al., " cancer " (2001) 92:1138-1143；Hashizume Et al., " cancer research " (2010) 70:2213-2223).Described method comprises to be enough to block in tumor microenvironment The kinase whose dosage regimen of TIE2 is to the Formulas I compositions of patient's administration effective dose in need.

In another embodiment in this aspect of the invention, Formulas I compositions and mFOLFOX6 therapy (Ao Shali Platinum+formyl tetrahydrofolic acid (leucovorin)+5-fluorouracil) combination administration.

In another embodiment in this aspect of the invention, Formulas I compositions cuts down list with mFOLFOX6 therapy and shellfish Anti-combination administration.

In another embodiment in this aspect of the invention, Formulas I compositions is mono-with mFOLFOX6 therapy and Pa Ni Anti-combination administration.

In another embodiment in this aspect of the invention, Formulas I compositions and mFOLFOX6 therapy and western appropriate former times Monoclonal antibody combination administration.

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

In another embodiment in this aspect of the invention, Formulas I compositions is thrown with capecitabine and bevacizumab combination With.

In another embodiment in this aspect of the invention, Formulas I compositions and FOLFIRI therapy (irinotecan+ Formyl tetrahydrofolic acid+5-fluorouracil) combination administration.

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

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

In another embodiment in this aspect of the invention, Formulas I compositions and FOLFIRI therapy and Cetuximab Combination administration.

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

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

In another embodiment in this aspect of the invention, Formulas I compositions is thrown with Victibix and irinotecan combination With.

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

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

Another aspect of the present invention relates to a kind of method treating acute myelogenous leukemia, because TIE2 path signal Conduction have shown that out can promote acute myelogenous leukemia progress (Muller et al., " leukemia research " (2002) 26: 163-168；Hou et al., " leukemia research " (2008) 32:904-912).Described method comprises to be enough to block swollen The kinase whose dosage regimen of TIE2 in tumor microenvironment is to the Formulas I compositions of patient's administration effective dose in need.

In another embodiment in this aspect of the invention, Formulas I compositions is thrown with daunomycin and cytosine arabinoside combination With.

In another embodiment in this aspect of the invention, Formulas I compositions is thrown with Ida mycin and cytosine arabinoside combination With.

In another embodiment in this aspect of the invention, Formulas I compositions is thrown with mitoxantrone and cytosine arabinoside combination With.

In another embodiment in this aspect of the invention, Formulas I compositions combines administration with cytosine arabinoside.

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

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

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

Another aspect of the present invention relates to a kind of method treating cancer.Described method comprises to patient's administration in need The Formulas I compositions of effective dose.In one embodiment, patient's overexpression inner membrance endotheliocyte kinases 2 (TIE2), and Described cancer be selected from breast carcinoma, colorectal carcinoma, hepatocarcinoma, head and neck cancer, bladder cancer, ovarian cancer, glioma, Angiosarcoma, melanoma or acute myelogenous leukemia.

In the certain embodiments of the present invention of therapeutic scheme, Formulas I compositions is with the frequency administration of every day.

In other embodiments of the invention of therapeutic scheme, Formulas I compositions is with the frequency administration being interrupted non-every day.

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

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

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

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

In other embodiments, described cancer is transitivity, (estrogen receptor negative, progesterone receptor are cloudy for three negative breast carcinomas Property, HER2 negative).

In other embodiments, described cancer is estrogen positive (ER⁺) and HER2 receptor kinase feminine gender (HER2-) Breast carcinoma.

In other embodiments, described cancer is inflammatory breast carcinoma.

In another embodiment, described method comprises prevention or reduces in primary tumor growth, tumor invasiveness, cancer Ooze, cancer diffusion, the treatment of one or more in cancerometastasis and tumour immunity toleration.In some embodiment, described Method improves survival.

Composite, administration, administration and therapeutic scheme

Present invention resides in the salt (and/or additional agent) of the described Formulas I in various composite and/or II.Institute herein Any compositions (and/or additional agent) stated can be in the form of: solution, suspension, emulsion, drop, tablet, Pill, spherolite, capsule, containing liquid capsule, powder, sustained release formulation, suppository, emulsion, aerosol, spraying, Suspension or other form being suitable for any.In one embodiment, compositions is that capsule form (see for example the U.S. special Profit the 5,698,155th).Suitably other example of drug excipient is described in Remington ' s Pharmaceutical In Sciences 1447-1676 (Alfonso R.Gennaro compiles, the 19th edition .1995), it is herein incorporated by reference this Wen Zhong.

If desired, salt described herein may also comprise solubilizing agent.Additionally, medicament can be with as known in art Suitably mediator or transfer device transmission.Combination treatment outlined herein can be total in single transmission mediator or transfer device Transmission.Compositions for administration optionally includes that local anesthetic (such as lignocaine (lignocaine)) is to alleviate The pain of injection site.

In one embodiment, the salt (and/or additional agent) of Formulas I as herein described and/or II is adjusted according to conventional program Join the compositions for being suitable for administration pattern.

In certain embodiments, administration approach includes such as: Intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, In epidural, oral, Sublingual, intranasal, brain, intravaginal, percutaneous, per rectum, by sucking or local, especially To ear, nose, eye or skin.In certain embodiments, administration is per os or is realized by parenteral injection.Administration pattern Doctor can be left for judge, and depend in part on the position of medical condition.In most of the cases, administration causes described herein Any medicament be discharged in blood flow.

In a particular embodiment, can be desirably to needing treatment or local, the region administration blocked.

In one embodiment, salt as herein described (and/or additional agent) is allocated as being suitable for per os according to conventional program The compositions of the administration mankind.The compositions of per os transmission can such as in tablet, buccal tablet, aqueous or oily suspensions, Grain, powder, emulsion, capsule, syrup or elixirs.Oral administration and compositions can comprise one or more reagent, Such as sweeting agent, such as fructose, aspartame or saccharin；Flavoring agent, such as Mentha arvensis L. syn.M.haplocalyxBrig, wintergreen oil or Fructus Pruni pseudocerasi oil；Coloring Agent；And preservative, with the preparation that offer is the most agreeable to the taste.Additionally, when in tablet or during pill, compositions Can be coated to postpone disintegrate in the gastrointestinal tract and absorption, thus the continuous action through extending the time period is provided.Institute herein The alternative permeable membrane of the salt (and/or additional agents) of encirclement osmotically active drive-type I or II stated applies also for per os The compositions of administration.In these platforms below, from surrounding the fluid of environment of capsule by driving compositions to absorb, Described driving compositions expands so that medicament or medicament composition shift through opening.These transmission platforms can provide with vertical I.e. discharge the substantially zero level transfer curve that the needle pattern curve of composite is relative.Time delay material can also be used, as single hard Glycerol or tristerin.Orally administered composition can include standard excipients, such as mannitol, lactose, shallow lake Powder, magnesium stearate, saccharin sodium, cellulose and magnesium carbonate.In one embodiment, described excipient is pharmaceutical grade. In addition to active compound, suspension can contain suspending agent, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol With sorbitan ester, microcrystalline Cellulose, inclined aluminium hydroxide, bentonite, aga agar, tragacanth etc. and its mix Compound.

It is applicable to the agent of parenteral administration (such as intravenous, intramuscular, intraperitoneal, subcutaneous and intra-articular injection and perfusion) Type includes such as solution, suspension, dispersion liquid, emulsion etc..It can be with aseptic solid composite (such as lyophilizing combination Thing) form manufacture, it can will dissolve before using or be suspended in sterile injectable medium.It can contain such as institute Known suspension or dispersant in genus field.

Dosage and the administration time-histories of the salt (and/or additional agents) of Formulas I described herein and/or II can be depending on respectively Plant parameter, include, but is not limited to treated disease, individual general health and the judgement of administration doctor.This Any medicament described in literary composition can before another therapeutic agent of administration (such as before 5 minutes, 15 minutes, 30 minutes, 45 Minute, 1 hour, 2 hours, 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 (after such as 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 little Time, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks) Administration individuality in need.In various embodiments, any medicament as herein described be separated by 1 minute, be separated by 10 minutes, It is separated by 30 minutes, is separated by less than 1 hour, is separated by 1 hour, is separated by 1 hour to 2 hours, is separated by 2 hours to 3 Hour, be separated by 3 hours to 4 hours, be separated by 4 hours to 5 hours, be separated by 5 hours to 6 hours, be separated by 6 hours To 7 hours, be separated by 7 hours to 8 hours, be separated by 8 hours to 9 hours, be separated by 9 hours to 10 hours, be separated by 10 hours to 11 hours or be separated by 11 hours to 12 hours administrations.

The dosage of the salt (and/or additional agents) of Formulas I as herein described or II can be depending on several factor, including the patient's condition Severity, the patient's condition are that be treated or be prevented and to be treated individual age, body weight and health status.This Outward, about concrete individual drug gene body (genotype pharmacokinetics, pharmacodynamics or effect overview to treating Effect) information can affect used dosage.Additionally, the visual many factors of definite individual dose and adjust slightly, institute The factor of stating includes the particular combination of medicament of institute's administration, the time of administration, the approach of administration, the character of composite, excretion Speed, the disease specific treated, the severity of disease and the anatomical location of disease.Can some of projected dose Change.

Generally, when oral administration and mammal, the agent of any Formulas I compositions (and/or additional agent) as herein described Amount can be 0.001 mg/kg/day to 100 mg/kg/day, 0.01 mg/kg/day to 50 mg/kg/day, Or 0.1 mg/kg/day to 10 mg/kg/day.As oral administration and the mankind, the agent of any medicament as herein described Amount usually 0.001mg to 1500mg every day, 1mg to 600mg every day or 5mg to 30mg every day.One In a little embodiments, the dosage of salt (or medicament) is in the range of every day 57mg to 1200mg.In other embodiments, The dosage of medicament or salt is in the range of every day 100mg to 200mg.

For the salt (and/or additional agent) of Formulas I as herein described or the II administration by parenteral injection, dosage is usual For 0.1mg to 250mg every day, 1mg to 20mg every day or 3mg to 5mg every day.Injection can give at most Four times per day.Generally, when oral or parenteral administration, the dosage of any medicament as herein described is usually 0.1mg every day To 1500mg or 0.5mg to 10mg every day or 0.5mg to 5mg every day.Every day can the most 3000mg of administration Dosage.

The administration of salt as herein described (and/or additional agent) can independently be every day one to four times.Specifically, salt Administration can be about the dosage regimen of 50mg to 1500mg once a day with salt.It is applicable to sought prophylactic action Every day, dosage was 57-1200 mg/day.If administration twice daily, then suitably dosage is 100mg to 200mg Salt.Salt also can the most non-every day administration.Specifically, can monthly one to four times or annual one to six times or every two years, 3 years, 4 years or twice-a-decade carry out the administration of salt.In certain embodiments, the administration of salt weekly or is carried out every two weeks. When weekly or during administration every two weeks, suitable salt dosage regimen is in the range of the every administration of 50-200mg/.Some weekly or Every two weeks in administration, dosage is the every administration of 200-400mg/.Weekly or every two weeks other pattern again of administration includes 400-500 The every administration of mg/, the every administration of 500-600mg/, the every administration of 600-700mg/, the every administration of 700-800mg/, 800-900mg/ Every administration, the every administration of 900-1000mg/, the every administration of 1000-1100mg/ or the every administration of 1100-1200mg/.Holding of administration The continuous time 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 even Continue the individual life-span.Chronic long administration will be indicated in many cases.Dosage can be with single dose form or be divided into many Individual dosage administration.In general, required dosage should cover an extended administration at set time intervals, typically at least Through several weeks or several months, but the longer period of the administration of several months or several years may be needed.

Example

Example 1. 1-(the 3-tert-butyl group-1-(quinoline-6-base)-1H-pyrazoles-5-base)-3-(the fluoro-4-of 2-(2-(methylcarbamoyl) pyridine -4-base epoxide) phenyl) urea biochemistry suppression to unphosphorylated TIE2 (uTIE2)

The biochemical analysis of uTIE2 (serial ID number 1)

The kinase whose activity of uTIE2 is by following the trail of from via anti-with the kinases of the coupling of pyruvate kinase/lactate dehydrogenase system The ADP that should produce measures (such as Schindler et al. " science " (Science) (2000) 289:1938-1942). In this analysis, monitor the oxidation of NADH continuously with spectrophotography (thus at A_340nmUnder minimizing).Instead Answer mixture (100 μ L) containing TIE2 (SignalChem) (5.6nM), BSA (0.004% (w/v)), polyEY (1.5mg/ml)、MgCl₂(15mM), DTT (0.5mM), pyruvate kinase (4 units), lactic acid dehydrogenase (7 units), phosphoenolpyruvate (1mM) and NADH (0.28mm) and ATP (1.5mM) are in containing In the 90mM Tris buffer (pH 7.5) of 0.2% octyl group-glucoside and 1%DMSO.Suppression reaction is by by continuously The test compositions of dilution is mixed with above reactant mixture and starts.At 30 DEG C on plate reader (BioTek) Under monitor continuously the absorption under 340nm continue 6 hours.Reaction rate uses 5 to 6 hours range computation. Suppression percentage ratio is by relatively obtaining reaction rate with the reaction rate compareing (that is, without test compositions).IC₅₀ It is worth by use the software routines such as implemented in GraphPad Prism software kit to measure under a series of inhibitor concentration one Series suppression percent value calculates.Compositions 1-(the 3-tert-butyl group-1-(quinoline-6-base)-1H-pyrazoles-5-base)-3-(2-fluorine -4-(2-(methylcarbamoyl) pyridin-4-yl epoxide) phenyl) urea tosilate (compound 1 as described in Figure) exhibition The IC of existing 3.5nM₅₀Value.

UTIE2 protein sequence (serial ID number 1) for screening

QLKRANVQRRMAQAFQNVREEPAVQFNSGTLALNRKVKNNPDPTIYPVLDWNDIKFQ DVIGEGNFGQVLKARIKKDGLRMDAAIKRMKEYASKDDHRDFAGELEVLCKLGHHPNI INLLGACEHRGYLYLAIEYAPHGNLLDFLRKSRVLETDPAFAIANSTASTLSSQQLLHFA ADVARGMDYLSQKQFIHRDLAARNILVGENYVAKIADFGLSRGQEVYVKKTMGRLPV RWMAIESLNYSVYTTNSDVWSYGVLLWEIVSLGGTPYCGMTCAELYEKLPQGYRLEKP LNCDDEVYDLMRQCWREKPYERPSFAQILVSLNRMLEERKTYVNTTLYEKFTYAGIDC SAEEAA

Example 2. 1-(the 3-tert-butyl group-1-(quinoline-6-base)-1H-pyrazoles-5-base)-3-(the fluoro-4-of 2-(2-(methylcarbamoyl) pyridine -4-base epoxide) phenyl) urea biochemistry suppression to phosphorylation TIE2 (pTIE2)

The biochemical analysis (serial ID number 2) of pTIE2

The kinase whose activity of pTIE2 is by following the trail of from via anti-with the kinases of the coupling of pyruvate kinase/lactate dehydrogenase system The ADP that should produce measures (such as Schindler et al. " science " (2000) 289:1938-1942).At this In analysis, monitor the oxidation of NADH continuously with spectrophotography (thus at A_340nmUnder minimizing).Reaction mixing Thing (100 μ L) contains TIE2 (Life Technologies) (6nM), BSA (0.004% (w/v)), polyEY (1.5 mg/ml)、MgCl₂(15mM), DTT (0.5mM), pyruvate kinase (4 units), lactic acid dehydrogenase (7 Individual unit), phosphoenolpyruvate (1mM) and NADH (0.28mm) and ATP (1.5mM) be in containing 0.2% In the 90mM Tris buffer (pH 7.5) of octyl group-glucoside and 1%DMSO.Suppression reaction is by by serial dilution Test compositions be mixed with above reactant mixture and start.Plate reader (BioTek) connects at 30 DEG C Monitor the absorption under 340nm continuously and continue 6 hours.Reaction rate uses 2 to 3 hours range computation.Press down Percentage ratio processed is by relatively obtaining reaction rate with the reaction rate compareing (that is, without test compositions).IC₅₀Value By using such as the software routines of enforcement measures under a series of inhibitor concentration in GraphPad Prism software kit one it is Row suppression percent value calculates.When tested, compositions 1-(the 3-tert-butyl group-1-(quinoline-6-base)-1H-pyrazoles-5-base)-3-(2- Fluoro-4-(2-(methylcarbamoyl) pyridin-4-yl epoxide) phenyl) urea tosilate and 1-(the 3-tert-butyl group-1-(quinoline-6- Base)-1H-pyrazoles-5-base)-3-(the fluoro-4-of 2-(2-(methylcarbamoyl) pyridin-4-yl epoxide) phenyl) urea dihydrochloride is at ＜ 0.1 The kinase whose suppression of ＞ 50%pTIE2 is represented under μM concentration.1-(the 3-tert-butyl group-1-(quinoline-6-base)-1H-pyrazoles-5-base)-3-(2- Fluoro-4-(2-(methylcarbamoyl) pyridin-4-yl epoxide) phenyl) urea tosilate represents the IC of 4.2nM₅₀Value.1-(3- The tert-butyl group-1-(quinoline-6-base)-1H-pyrazoles-5-base)-3-(the fluoro-4-of 2-(2-(methylcarbamoyl) pyridin-4-yl epoxide) phenyl) urea Dihydrochloride represents the IC of 2.2nM₅₀Value.

PTIE2 protein sequence (serial ID number 2) for screening

PVLDWNDIKFQDVIGEGNFGQVLKARIKKDGLRMDAAIKRMKEYASKDDHRDFAGELE VLCKLGHHPNIINLLGACEHRGYLYLAIEYAPHGNLLDFLRKSRVLETDPAFAIANSTAS TLSSQQLLHFAADVARGMDYLSQKQFIHRDLAARNILVGENYVAKIADFGLSRGQEVY VKKTMGRLPVRWMAIESLNYSVYTTNSDVWSYGVLLWEIVSLGGTPYCGMTCAELYE KLPQGYRLEKPLNCDDEVYDLMRQCWREKPYERPSFAQILVSLNRMLEERKT

Example 3. 1-(the 3-tert-butyl group-1-(quinoline-6-base)-1H-pyrazoles-5-base)-3-(the fluoro-4-of 2-(2-(methylcarbamoyl) pyridine -4-base epoxide) phenyl) urea Carbazole alkaloid to the TIE2 in Chinese hamster ovary celI

CHO-K1 cell is cultivated

CHO-K1 cell (catalog number (Cat.No.) CCL-61) is from American type culture collection (American Type Culture Collection, ATCC, Manassas, Virginia (Manassas, VA)) obtain.In simple terms, cell 37 DEG C, 5%CO₂Growing in F12K culture medium with under 95% humidity, described F12K culture media supplemented has 10% characterization tire cattle Serum (the hero company (Invitrogen, Carlsbad, CA) of Carlsbad, CA), 100 unit/mL Benzylpenicillin, 100 μ g/ml streptomycins and the 0.29mg/mL L-glutaminate (English of Carlsbad, CA Outstanding company).Make cell amplification, converging until reaching 70%-95%, now being used for analyzing use by its Secondary Culture or collection On the way.

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

By CHO K1 cell (1 × 10⁵Individual cells/well) add being supplemented with in the plate that 24 hole tissue cultures process to 1mL RPMI1640 culture medium (the California karr of 10% characterization hyclone and 1 × non essential amino acid The hero company of this Ahmedabad) in.Cell is then at 37 DEG C, 5%CO₂Cultivate overnight with under 95% humidity.Suction is cultivated Base, and 0.5mL culture medium is added in each hole.(TIE2 gene Gateway is cloned into will to transfect level plasmid DNA pcDNA3.2^TMIn/V5-DEST expression vector, the hero company of Carlsbad, CA) at serum-free Room temperatureI culture medium (the hero company of Carlsbad, CA) is diluted to 5 μ g/mL. Every 0.5 μ g plasmid DNA add 2 μ L fat dye amine (Lipofectamine) LTX reagent (California karr this The hero company of Ahmedabad).Mix test tube lightly, and at room temperature cultivate 25 minutes to allow DNA-fat dye amine LTX Complex is formed.100 μ L DNA-fat dye amine LTX complex are directly appended in each hole containing cell and lightly Mixing.Twenty four hours after transfection, the suction culture medium containing DNA-fat dye amine compound, cells rinsed with PBS, And add and be supplemented with 10% characterization hyclone (the hero company of Carlsbad, CA) and 1 × nonessential The RPMI1640 culture medium of aminoacid (the hero company of Carlsbad, CA).Will test compositions (1-(3- The tert-butyl group-1-(quinoline-6-base)-1H-pyrazoles-5-base)-3-(the fluoro-4-of 2-(2-(methylcarbamoyl) pyridin-4-yl epoxide) phenyl) urea Tosilate) or DMSO add (0.5% final DMSO concentration) in each hole to.Plate is then at 37 DEG C, 5%CO₂ Cultivate 4 hours with under 95% humidity.After cultivating, Aspirate culture media, and cells rinsed with PBS.Cell is at 4 DEG C Under use containing Halt phosphatase and protease inhibitor (Pierce, Illinois Rockford under vibration (Rockford, IL)) and inhibitors of phosphatases mixed liquor 2 (Sigma (Sigma, the St. of St. Louis Louis, MO)) MPER dissolve buffer (Pierce, Illinois Rockford) dissolve 10 minutes.Clarification Solute by SDS-PAGE at 4-12%Novex NuPage Bis-Tris gel (this bar of California karr The hero company of moral) upper separation, and it is then transferred to PVDF (the hero company of Carlsbad, CA). After the transfer, the pvdf membrane BSA (Santa Cruz biotech company (Santa of California Santa Cruz Cruz Biotechnology, Santa Cruz, CA)) block, and then with the antibody (Massachusetts of phosphorylation TIE2 The Menaphtame of Bei Fuli leads to technology company (Cell Signaling Technology, Beverly, MA)) detection.It is incorporated into Radix Cochleariae officinalis Two grades of anti-rabbit antibody (Menaphtame of Massachusetts Bei Fuli leads to technology company) of peroxidase are used for detecting phosphorylation TIE2. Add ECL Plus (General Electric's Medical Group of New Jersey Piscataway (GE Healthcare, Piscataway, NJ)), the substrate of a kind of horseradish peroxidase for producing fluorescence-causing substance.Fluorescence uses Storm 840 Phosphorescence imaging instrument (General Electric's Medical Group of New Jersey Piscataway) detects with fluorescence mode.160kDa phosphorylation TIE2 bar Band uses ImageQuant software (General Electric's Medical Group of New Jersey Piscataway) quantitative.Data use Prism software (GraphPad Software, San Diego, CA (San Diego, CA)) is analyzed to calculate IC₅₀Value.Compositions 1-(the 3-tert-butyl group-1-(quinoline-6-base)-1H-pyrazoles-5-base)-3-(the fluoro-4-of 2-(2-(methylcarbamoyl) pyrrole Pyridine-4-base epoxide) phenyl) urea tosilate represents the IC of 2.0nM₅₀Value.

Example 4. 1-(the 3-tert-butyl group-1-(quinoline-6-base)-1H-pyrazoles-5-base)-3-(the fluoro-4-of 2-(2-(methylcarbamoyl) pyridine -4-base epoxide) phenyl) urea Carbazole alkaloid to the TIE2 in the Chinese hamster ovary celI after removing at inhibitor

CHO-K1 cell is cultivated

CHO-K1 cell (catalog number (Cat.No.) CCL-61) is from American type culture collection (ATCC, Virginia Manassas) obtain.In simple terms, cell is at 37 DEG C, 5%CO₂With life in F12K culture medium under 95% humidity Long, described F12K culture media supplemented has 10% characterization hyclone, and (hero of Carlsbad, CA is public Department), 100 unit/mL benzylpenicillins, 100 μ g/ml streptomycins and 0.29mg/mL L-glutaminate (Jia Lifuni The hero company of Ya Zhou Carlsbad).Make cell amplification, converging until reaching 70%-95%, now being passed on training Support or collect and be used for analyzing purposes.

The CHO K1 phosphorylation TIE2 Western blotting composition removing of TIE2 transfection is analyzed

By CHO K1 cell (1 × 10⁵Individual cells/well) add being supplemented with in the plate that 24 hole tissue cultures process to 1mL RPMI1640 culture medium (the California karr of 10% characterization hyclone and 1 × non essential amino acid The hero company of this Ahmedabad) in.Cell is then at 37 DEG C, 5%CO₂Cultivate overnight with under 95% humidity.Suction is cultivated Base, and 0.5mL culture medium is added in each hole.(TIE2 gene Gateway is cloned into will to transfect level plasmid DNA pcDNA3.2^TMIn/V5-DEST expression vector, the hero company of Carlsbad, CA) at serum-free Room temperatureI culture medium (the hero company of Carlsbad, CA) is diluted to 5 μ g/mL. Every 0.5 μ g plasmid DNA adds 2 μ L fat dye amine LTX reagent (the hero company of Carlsbad, CA). Mix test tube lightly, and at room temperature cultivate 25 minutes to allow DNA-fat dye amine LTX complex to be formed.By 100 μ L DNA-fat dye amine LTX complex is directly appended in each hole containing cell and mixes lightly.About 18-24 after transfection Hour, the suction culture medium containing DNA-fat dye amine compound, cells rinsed with PBS is, and add that to be supplemented with 10% special Levying hyclone (the hero company of Carlsbad, CA) and 1 × non essential amino acid (California The hero company of Carlsbad, state) RPMI1640 culture medium.Will test compositions (1-(the 3-tert-butyl group-1-(quinoline-6- Base)-1H-pyrazoles-5-base)-3-(the fluoro-4-of 2-(2-(methylcarbamoyl) pyridin-4-yl epoxide) phenyl) urea tosilate) or DMSO adds (0.5% final DMSO concentration) in each hole to.Plate is then at 37 DEG C, 5%CO₂With under 95% humidity Cultivate 2 hours.After cultivating, Aspirate culture media, and cell 1mL culture medium washs three times to remove free group Compound.It follows that add 1mL fresh culture, and by cell dissolve before cultivate concrete time point (that is, 0, 1,2,4,6 and 24 hours).Cell uses containing Halt phosphatase and protease inhibitor at 4 DEG C under vibration (Pierce, Illinois Rockford) and the inhibitors of phosphatases mixed liquor 2 (Sigma of St. Louis Company) MPER dissolve buffer (Pierce, Illinois Rockford) dissolve 10 minutes.The dissolving of clarification Thing passes through SDS-PAGE at the 4-12%Novex NuPage Bis-Tris gel (English of Carlsbad, CA Outstanding company) upper separation, and it is then transferred to PVDF (the hero company of Carlsbad, CA).In transfer Afterwards, pvdf membrane BSA (the Santa Cruz biotech company of California Santa Cruz) blocks, and connects The antibody by phosphorylation TIE2 (Menaphtame of Massachusetts Bei Fuli leads to technology company) detection.It is incorporated into Radix Cochleariae officinalis mistake Oxidasic two grades of anti-rabbit antibody (Menaphtame of Massachusetts Bei Fuli leads to technology company) are used for detecting phosphorylation TIE2. Add ECL Plus (General Electric's Medical Group of New Jersey Piscataway), a kind of for producing fluorescence-causing substance The substrate of horseradish peroxidase.Fluorescence uses Storm 840 Phosphorescence imaging instrument (the general electricity of New Jersey Piscataway Gas Medical Group) detect with fluorescence mode.Peel off pvdf membrane, and then (Texas reaches with total TIE2 antibody The Santa Cruz biotech company of Lars (Dallas, TX)) detect the most again.160kDa phosphorylation TIE2 is with total TIE2 band uses ImageQuant software (General Electric's Medical Group of New Jersey Piscataway) quantitative.Phosphorus Acidifying TIE2 level according to total TIE2 level standard, and data use Prism software (GraphPad Software, San Diego, CA) draw.When training together with the CHO K1 cell of TIE2 transfection with 0.1 μM-1 μM Educate 2 hours when removing subsequently, composition disclosed herein 1-(the 3-tert-butyl group-1-(quinoline-6-base)-1H-pyrazoles-5-base)-3-(2- Fluoro-4-(2-(methylcarbamoyl) pyridin-4-yl epoxide) phenyl) urea tosilate represents phosphorylation TIE2 level ＞ 50% suppression continues ＞ 24 hours.

Example 5. 1-(the 3-tert-butyl group-1-(quinoline-6-base)-1H-pyrazoles-5-base)-3-(the fluoro-4-of 2-(2-(methylcarbamoyl) pyridine -4-base epoxide) phenyl) urea Carbazole alkaloid to the TIE2 in HUVEC cell

HUVEC cell is cultivated

HUVEC (human umbilical vein endothelial cell；Catalog number (Cat.No.) CRL-1730) cell is from American Type Tissue Culture The heart (ATCC, Manassas, Virginia) obtains.In simple terms, cell is in EGM-2 (Walker's, the Maryland State The Long Sha company (Lonza, Walkersville, MD) of Wei Er) at 37 DEG C, 5%CO₂Grow with under 95% humidity. Make cell amplification, until it is saturated to reach 90%-95%, now be used for analyzing purposes by its Secondary Culture or collection.

HUVEC phosphorylation TIE2 western blot analysis

By HUVEC cell (2.5 × 10⁵Individual cells/well) add the 1mL in the plate that 24 hole tissue cultures process to In EGM-2 culture medium (the Long Sha company of Walker's, Maryland State Wei Er).Cell is then at 37 DEG C, 5%CO₂With 95% Cultivate overnight under humidity.Then Aspirate culture media, and add be supplemented with 2%FBS (Carlsbad, CA Hero company) 1mL EBM-2 basal medium (the Long Sha company of Walker's, Maryland State Wei Er).Group will be tested Compound or DMSO add (0.5% final DMSO concentration) in each hole to.Plate is then at 37 DEG C, 5%CO₂With 95% Cultivate 4 hours under humidity.In the nurturing period, by Ang-1 (ANG1) somatomedin (R&D of histidine mark Systems, Minneapolis, Minnesota (Minneapolis, MN)) at room temperature add anti-polyhistidine to and resist Body (R&D Systems, Minneapolis, Minnesota) continues 30 minutes with the polymer producing ANG1. After four hours cultivate compositions, cell 800ng/mLANG1/ anti-polyhistidine antibody compound mixture stimulates 15 Minute.Aspirate culture media, and cells rinsed with PBS.Cell use under vibration at 4 DEG C containing Halt phosphatase and Protease inhibitor (Pierce, Illinois Rockford) and inhibitors of phosphatases mixed liquor 2 (Missouri State Sheng Lu The Sigma of Yi Si) MPER dissolve buffer (Pierce, Illinois Rockford) dissolve 10 minutes. The solute of clarification passes through SDS-PAGE in 4-12%Novex NuPage Bis-Tris gel (California karr The hero company of this Ahmedabad) upper separation, and (hero of Carlsbad, CA is public to be then transferred to PVDF Department).After the transfer, pvdf membrane is with BSA (the Santa Cruz biotech company of California Santa Cruz) Block, and then detect with the antibody (Menaphtame of Massachusetts Bei Fuli leads to technology company) of phosphorylation TIE2.Knot Two grades of anti-rabbit antibody (Menaphtame of Massachusetts Bei Fuli leads to technology company) together in horseradish peroxidase are used for detecting phosphorus Acidifying TIE2.Adding ECL Plus (General Electric's Medical Group of New Jersey Piscataway), one is used for producing The substrate of the horseradish peroxidase of fluorescence-causing substance.Fluorescence uses Storm 840 Phosphorescence imaging instrument (New Jersey skin SIKA tower General Electric's Medical Group of Wei) detect with fluorescence mode.160kDa phosphorylation TIE2 band uses ImageQuant Software (General Electric's Medical Group of New Jersey Piscataway) is quantitative.Data use Prism software (GraphPad Software, San Diego, CA) analyze to calculate IC₅₀Value.Composition disclosed herein 1-(the 3-tert-butyl group -1-(quinoline-6-base)-1H-pyrazoles-5-base)-3-(the fluoro-4-of 2-(2-(methylcarbamoyl) pyridin-4-yl epoxide) phenyl) urea is to toluene Sulfonate represents the IC of 0.018nM₅₀Value.

Example 6. 1-(the 3-tert-butyl group-1-(quinoline-6-base)-1H-pyrazoles-5-base)-3-(the fluoro-4-of 2-(2-(methylcarbamoyl) pyridine -4-base epoxide) phenyl) the urea capillary that stimulates Ang-1 (ANG1) or ANG2 (ANG2) is tubular The suppression become

HMVEC cell is cultivated

HMVEC (human microvascular endothelial cell；Catalog number (Cat.No.) PCS-110-010) cell is from American Type Tissue Culture Center (ATCC, Manassas, Virginia) obtains.In simple terms, cell is in the EGM-2MV (Maryland State The Long Sha company of Walker's Wei Er) at 37 DEG C, 5%CO₂Grow with under 95% humidity.Make cell amplification, until reaching Saturated to 90%-95%, now it is used for analyzing purposes by its Secondary Culture or collection.

HMVEC capillary tube is formed to be analyzed

HMVEC cell (1.5 × 10⁴Individual cells/well) compare be mixed together with test compositions or DMSO, and will be suitable When 96 hole tissues of the matrigel coating reduced with somatomedin are added in somatomedin (ANG1 or ANG2) or comparison to In 0.1mL EBM-2 basal medium (the Long Sha company of Walker's, Maryland State Wei Er) in the plate that culture processes. Cell is then at 37 DEG C, 5%CO₂Cultivate 18 hours with under 95% humidity.Aspirate culture media the most lightly, and each hole Wash lightly with 0.1mL EBM-2 basal medium.Same Aspirate culture media, and 1 μM of Calcein-Safranine T will be contained The basal medium of solution (the hero company of Carlsbad, CA) adds in each hole lives with fluorescent labeling Cell.Cell is then at 37 DEG C, 5%CO₂Cultivate 30 minutes with under 95% humidity.Aspirate culture media, and each hole phosphorus Hydrochlorate buffer saline washes twice lightly.The image fluorescence microscope in each hole obtains, and uses ImagePro to analyze Instrument (Media Cybernetics, Inc., Rockville, MD (Rockville, MD)) uses measures total long capillary tube The auto macro of degree processes.Data use Prism software (GraphPad Software, San Diego, CA) Analyze to calculate IC₅₀Value.Composition disclosed herein 1-(the 3-tert-butyl group-1-(quinoline-6-base)-1H-pyrazoles-5-base)-3-(2- Fluoro-4-(2-(methylcarbamoyl) pyridin-4-yl epoxide) phenyl) urea tosilate HMVEC that ANG1 is stimulated The suppression that capillary tube is formed represents the IC of 6.9nM₅₀Value.Formulas I compositions disclosed herein stimulates for ANG2 The suppression that HMVEC capillary tube is formed represents the IC of 34nM₅₀Value.

Example 7. 1-(the 3-tert-butyl group-1-(quinoline-6-base)-1H-pyrazoles-5-base)-3-(the fluoro-4-of 2-(2-(methylcarbamoyl) pyridine -4-base epoxide) phenyl) urea as single medicament and with Paclitaxel combine to the body in muroid PyMT breast cancer model Interior primary tumor growth and invasive suppression

PyMT homogenic type breast cancer model primary tumor growth

PyMT homogenic type breast carcinoma implants mouse model for assessing the activity in vivo of compound 1.In simple terms, will be total The 1 × 10 of volume 0.1mL⁶Individual cell (dissociating from PyMT tumor fragment) be implanted to female mice (FVB/NJ, JAXWEST:RB05 mice, from Jackson Labs) left side on the 4th mammary fat pad in.Each group is implanted 10 mices altogether.The animal care of Molecular Imaging, Inc. and use committee (Animal Care and Use Committee) ratify all experimental programs and according to NIH (National Institutes of Health, NIH) all laws, regulation and guide are tested.Treatment starts in the following manner: when tumor size reaches about During 850mg, according to indivedual body weight on treatment same day with every 20g 0.2mL oral administration and (tube feed) compound 1 every day Twice or mediator (0.4% hydroxypropyl methyl cellulose is in water) and/or intravenous administration (IV) Paclitaxel are every Five days once or mediator (10% ethanol, 10%Cremophor EL and 80% saline).Animal is administered and continues 21 days.Often Wednesday time records body weight and measurement of tumor value.Tumor load (mg) by caliber gauge measurement method by for prolate ellipsoid volume Formula is estimated, it is assumed that unit intensity is: tumor load (mg)=(L × W²)/2, wherein L and W is the orthogonal swollen of correspondence Tumor length and width measured value (mm).In PyMT model, compound 1 and Paclitaxel group all prove tumor Growth inhibited.Additive activity (Fig. 1) is shown in the combination of compound 1 and Paclitaxel.These data prove compound The activity in vivo of 1, and show and enzymatic and the dependency of cell data.

Example 8. 1-(the 3-tert-butyl group-1-(quinoline-6-base)-1H-pyrazoles-5-base)-3-(the fluoro-4-of 2-(2-(methylcarbamoyl) pyridine -4-base epoxide) phenyl) urea as single medicament and with Paclitaxel combination in muroid PyMT breast cancer model The suppression that internal primary tumor macrophage is built up

PyMT homogenic type breast cancer model primary tumor macrophage is built up

PyMT homogenic type breast carcinoma implants mouse model for assessing the activity in vivo of compound 1.In simple terms, will be total The 1 × 10 of volume 0.1mL⁶Individual cell (dissociating from PyMT tumor fragment) be implanted to female mice (FVB/NJ, JAXWEST:RB05 mice, from Jackson Labs) left side on the 4th mammary fat pad in.Each group is implanted 10 mices altogether.The animal care of Molecular Imaging, Inc. and use committee ratify all experimental programs and press All laws, regulation and guide according to NIH (NIH) are tested.Treatment is in the following manner Start: when tumor size reaches about 850mg, according to treating indivedual body weight on the same day with every 20g 0.2mL oral administration With (tube feed) compound 1 twice daily or mediator (0.4% hydroxypropyl methyl cellulose is in water) and/or intravenous administration (IV) every five days of Paclitaxel is once or mediator (10% ethanol, 10%Cremophor EL and 80% saline).Dynamic Thing is administered and continues 21 days.Record body weight and measurement of tumor value three-times-weekly.

At the end of research, by tumor resection and put in formalin (formalin).Then, formalin is solid Fixed tumor sample is put in paraffin mass.The paraffin-embedded tissue slice dimethylbenzene deparaffnize that formalin is fixing, and It is hydrated in distilled water via the alcohol flushing liquor of a series of classifications.Antigen retrieval uses the PT Link module of Dako to use Tris/EDTA buffering target is repaired solution and is carried out at 95 DEG C 20 minutes.Once cut into slices cooling, be loaded into Dako At room temperature enter with F4/80 and the CD31 antibody of dyeing macrophage and endotheliocyte respectively on AutostainerPlusLink Row immunohistochemical staining.Intrinsic oversxidase and alkaline phosphatase activities in tissue block with dual endogenous enzyme Solution (Dako, S2003) cancellation 5 minutes.Nonspecific proteins combines and blocks (serum free for serum-free albumen Protein Block) (Dako, X0909) block 5 minutes.Rat anti-mouse CD31 primary antibody is then at experimental group Knit and cultivate 30 minutes under the immunogenicity concentration of 1: 100 in section.Primary antibody then with rabbit anti-rat Ig Secondary antibody (Dako, E0468) combines.Secondary antibody then with the polymer of goat antirabbit peroxidase labelling (Dako, K4003) amplify 30 minutes.Enzymatic dyeing substrate-chromogen DAB+ (Dako, K3468) develops 5 minutes.Cross Amount rat IgG component additionally with rodent block rat (Rodent Block Rat) (Biocare Medical, RBR962H) block 5 minutes.Rat anti-mouse F4/80 primary antibody is cultivated 30 minutes on experiment tissue slice. F4/80 then combines with rabbit anti-rat Ig secondary antibody (Dako, E0468).Secondary antibody then uses goat The polymer (Biocare RALP525) of anti-rabbit alkali phosphatase enzyme mark amplifies 30 minutes.Substrate chromogen is used in enzymatic dyeing Body WARP Red (Biocare WR806) develops.Counterstaining automatization's hematoxylin (hematoxylin) is carried out 10 minutes.Tissue slice then air-dries and with dimethylbenzene clarification so that glass cover-plate slides.Section use following scale for F4/80 dyes scoring: 0, without visible stain；1, weak dyeing；2, appropriateness dyeing；The last 3 is dyeed.At PyMT model In, compound 1 proves that the macrophage at primary tumor is built up to be reduced, and Paclitaxel does not reduce macrophage Build up.Compound 1 shows the similar activity of pharmaceutical treatment single with compound 1 (figure with the combination of Paclitaxel 2).These data prove the activity in vivo of compound 1, and show and enzymatic and the dependency of cell data.

Example 9. 1-(the 3-tert-butyl group-1-(quinoline-6-base)-1H-pyrazoles-5-base)-3-(the fluoro-4-of 2-(2-(methylcarbamoyl) pyridine -4-base epoxide) phenyl) urea as single medicament and with Paclitaxel combination in muroid PyMT breast cancer model The suppression of internal primary tumor TIE2 cell accumulation

PyMT homogenic type breast cancer model primary tumor macrophage is built up

At the end of research, by tumor resection and put in formalin.Then, tumor sample formalin fixed Put in paraffin mass.The paraffin-embedded tissue slice dimethylbenzene deparaffnize that experiment formalin is fixing, and via one be The alcohol flushing liquor of row classification is hydrated in distilled water.Antigen retrieval uses the PT Link module citrate pH of Dako 6 buffering targets are repaired solution and are carried out at 95 DEG C 20 minutes.Once cut into slices cooling, be loaded into Dako At room temperature immunohistochemical staining is carried out with TIE2 and CD31 antibody on AutostainerPlusLink.Tissue In intrinsic oversxidase and alkaline phosphatase activities dual endogenous enzyme blocking solution (Dako, S2003) cancellation 5 minutes.Nonspecific proteins combines and blocks 5 minutes for serum-free albumen blocking-up (Dako, X0909).Big mouse-anti Mice CD31 primary antibody is then cultivated 30 minutes on experiment tissue slice under the immunogenicity concentration of 1: 100.Just Level antibody then combines with rabbit anti-rat Ig secondary antibody (Dako, E0468).Secondary antibody then uses mountain The polymer (Dako, K4003) of goat-anti rabbit peroxidase labelling amplifies 30 minutes.Enzymatic dyeing substrate-chromogen DAB+ (Dako, K3468) develops 5 minutes.Excess protein component additionally with albumen block (Protein Block) (Dako, X0909) block 5 minutes.Rabbit anti-TIE2 primary antibody is cultivated 30 minutes on experiment tissue slice.TIE2 antibody connects The goat antirabbit polymer with alkali phosphatase enzyme mark and be combined 30 minutes.Enzymatic dyeing substrate chromogen WARP Red (Biocare WR806) develops.Counterstaining automatization's hematoxylin carries out 10 minutes.Tissue slice then air-dry and With dimethylbenzene clarification so that glass cover-plate slides.Section uses following scale for TIE2 dyeing scoring: 0, without visible dye Color；1, weak dyeing；2, appropriateness dyeing；The last 3 is dyeed.In PyMT model, compound 1 proves primary tumor The TIE2 express cell at place is built up and is reduced, and Paclitaxel does not reduce TIE2 express cell and builds up.Compound 1 with Increased activity (Fig. 3) compared with the combination displaying pharmaceutical treatment single with compound 1 of Paclitaxel.These data prove The activity in vivo of compound 1, and show and enzymatic and the dependency of cell data.

Example 10. 1-(the 3-tert-butyl group-1-(quinoline-6-base)-1H-pyrazoles-5-base)-3-(the fluoro-4-of 2-(2-(methylcarbamoyl) pyridine -4-base epoxide) phenyl) urea as single medicament and with Paclitaxel combine to the body in muroid PyMT breast cancer model The suppression of interior lung cancer metastasis

PyMT homogenic type breast cancer model lung cancer metastasis is assessed

At the end of research, lung tissue is excised and puts in formalin.Then, lung sample formalin fixed Put in paraffin mass.Each lung block has three sections, the most often two aspects of section cutting, and uses h and E (Eosin) dyeing.Transitivity Lung neoplasm is via microscopic counting.In PyMT model, compound 1 and the Pacific Ocean are purple China fir alcohol all proves the similar minimizing of lung cancer metastasis.Compound 1 is controlled with single medicament with the combination of Paclitaxel displaying Treat and compare cumulative activity (Fig. 4).These data prove the activity in vivo of compound 1, and show and enzymatic and cell The dependency of data.

1-(the 3-tert-butyl group-1-(quinoline-the 6-that the interval (non-every day) that example 11. combines with Paclitaxel is administered Base)-1H-pyrazoles-5-base)-3-(the fluoro-4-of 2-(2-(methylcarbamoyl) pyridin-4-yl epoxide) phenyl) urea to muroid PyMT breast The suppression of the internal lung cancer metastasis in cancer model

PyMT homogenic type breast cancer model lung cancer metastasis is assessed

PyMT homogenic type breast carcinoma implants mouse model for assessing the activity in vivo of compound 1.In simple terms, will be total The 1 × 10 of volume 0.1mL⁶Individual cell (dissociate from PyMT tumor fragment and stored frozen in cell freezing media) It is implanted to the 4th on the left side of female mice (FVB/NJ, JAXWEST:RB05 mice, from Jackson Labs) In mammary fat pad.Each group is implanted three mices altogether.The animal care of Molecular Imaging, Inc. and use committee Member can ratify all experimental programs and enter according to all laws, regulation and the guide of NIH (NIH) Row experiment.Treatment starts in the following manner: when tumor size reaches about 600mg, according to treating the indivedual of the same day Body weight with every 20g 0.2mL oral administration and (tube feed) compound 1 twice a week or mediator (0.4% hydroxypropyl methyl is fine Dimension element is in water) and/or every five days of intravenous administration (IV) Paclitaxel once or mediator (10% ethanol, 10% Cremophor EL and 80% saline).Animal is administered and continues 12 days.Record body weight and measurement of tumor value three-times-weekly.

At the end of research, lung tissue is excised and puts in formalin.Then, lung sample formalin fixed Put in paraffin mass.Each lung block has three sections, the most often two aspects of section cutting, and contaminates with h and E Color.Transitivity Lung neoplasm is via microscopic counting.In PyMT model, Paclitaxel proves subtracting of lung cancer metastasis Few.Compound 1 shows activity (Fig. 5) cumulative compared with single pharmaceutical treatment with the combination of Paclitaxel.These Data prove the activity in vivo of compound 1, and show and enzymatic and the dependency of cell data.

1-(the 3-tert-butyl group-1-(quinoline-6-the base)-1H-that the interval (non-every day) that example 12. combines with eribulin is administered Pyrazoles-5-base)-3-(the fluoro-4-of 2-(2-(methylcarbamoyl) pyridin-4-yl epoxide) phenyl) urea is in muroid PyMT breast cancer model The suppression of internal lung cancer metastasis

PyMT homogenic type breast cancer model lung cancer metastasis is assessed

PyMT homogenic type breast carcinoma implants mouse model for assessing the activity in vivo of compound 1.In simple terms, will be total The 1 × 10 of volume 0.1mL⁶Individual cell (dissociate from PyMT tumor fragment and stored frozen in cell freezing media) It is implanted to the 4th on the left side of female mice (FVB/NJ, JAXWEST:RB05 mice, from Jackson Labs) In mammary fat pad.Each group is implanted three mices altogether.The animal care of Molecular Imaging, Inc. and use committee Member can ratify all experimental programs and enter according to all laws, regulation and the guide of NIH (NIH) Row experiment.Treatment starts in the following manner: when tumor size reaches about 600mg, according to treating the indivedual of the same day Body weight with every 20g 0.2mL oral administration and (tube feed) compound 1 twice a week or mediator (0.4% hydroxypropyl methyl is fine Dimension element is in water) and/or intravenous administration (IV) eribulin is three-times-weekly or mediator (80% saline).Animal is administered Continue 12 days.Record body weight and measurement of tumor value three-times-weekly.

At the end of research, lung tissue is excised and puts in formalin.Then, lung sample formalin fixed Put in paraffin mass.Each lung block has three sections, the most often two aspects of section cutting, and contaminates with h and E Color.Transitivity Lung neoplasm is via microscopic counting.In PyMT model, eribulin prove lung cancer metastasis minimizing (or Increase under low dosage).Compound 1 shows activity (figure cumulative compared with single pharmaceutical treatment with the combination of eribulin 6).These data prove the activity in vivo of compound 1, and show and enzymatic and the dependency of cell data.

1-(the 3-tert-butyl group-1-(quinoline-6-the base)-1H-that the interval (non-every day) that example 13. combines with eribulin is administered Pyrazoles-5-base)-3-(the fluoro-4-of 2-(2-(methylcarbamoyl) pyridin-4-yl epoxide) phenyl) urea is in muroid PyMT breast cancer model The raising of overall survival

PyMT homogenic type breast cancer model survival rate is assessed

PyMT homogenic type breast carcinoma implants mouse model for assessing the activity in vivo of compound 1.In simple terms, will be total The 1 × 10 of volume 0.1mL⁶Individual cell (dissociate from PyMT tumor fragment and stored frozen in cell freezing media) It is implanted to the 4th on the left side of female mice (FVB/NJ, JAXWEST:RB05 mice, from Jackson Labs) In mammary fat pad.Each group is implanted ten mices altogether.The animal care of Molecular Imaging, Inc. and use committee Member can ratify all experimental programs and enter according to all laws, regulation and the guide of NIH (NIH) Row experiment.Treatment starts in the following manner: when tumor size reaches about 850mg, according to treating the indivedual of the same day Body weight is or twice or mediator (0.4% hydroxypropyl weekly with (tube feed) compound 1 with every 20g 0.2mL oral administration Methylcellulose is in water) and/or intravenous administration (IV) eribulin is three-times-weekly or mediator (80% saline).Swollen Tumor the most after treatment begins three days through excision.Animal is then administered the persistent period of continued survival rate experiment.On every Wendesdays Secondary record body weight and measurement of tumor value.In PyMT model, the eribulin of 0.1mg/kg proves that survival rate is without improving. Compound 1 significantly improves (Fig. 7) with the combination displaying survival rate of eribulin.These data prove the internal of compound 1 Activity, and show and enzymatic and the dependency of cell data.

Specific embodiment disclosed in the scope of the present invention example by the explanation that is intended as the several aspect of the present invention Limit, and functionally equivalent any embodiment is within the scope of the present invention.It practice, except illustrated and described herein with Outward, the various amendments of the present invention are by and the model of to be belonged to appended claims apparent for those skilled in the art In enclosing.

Equivalent

Those skilled in the art will use normal experiment to be it can be appreciated that or can determine institute the most in this article at most Many equivalents of the specific embodiment stated.Described equivalent intends to contain within the scope of the appended claims.

Claims

1. blocking constitutional mammary tumor growth and an invasive method, it comprises to patient's administration in need effective The Formulas I compositions of amount

Wherein

N is the integer of 0 to 7；

X is the basic group of pharmaceutically acceptable salt；

Its restrictive condition is for when n is 0, and described Formulas I compositions is parent free alkali；

By being enough to the kinase whose dosage regimen of TIE2 that blocks in tumor microenvironment.

Method the most according to claim 1, wherein said dosage regimen administration every day.

Method the most according to claim 1, wherein said dosage regimen be interrupted non-every day be administered, every other day be administered, It is administered every three days, is administered twice a week or is administered once in a week.

Method the most according to claim 1, wherein said dosage regimen be twice a week, weekly or by every other week It is administered.

5., according to the method according to any one of claim 1 to 4, wherein said Formulas I compositions obtains with one or more Take from following pharmaceutical agent combinations to use: antitublin, DNA alkylating agent, DNA synthetic inhibitor, DNA are embedding Enter agent, estrogen antagonist agent, anti-HER2 agent, inhibitors of kinases or anti-angiogenic agent.

6. according to the method according to any one of claim 1 to 4, wherein said Formulas I compositions and Paclitaxel It is applied in combination.

7., according to the method according to any one of claim 1 to 4, wherein said Formulas I compositions is hanged with for injectable The Paclitaxel protein binding particle combinations of supernatant liquid uses.

8., according to the method according to any one of claim 1 to 4, wherein said compound of formula I combines with eribulin Use.

9., according to the method according to any one of claim 1 to 4, wherein said Formulas I compositions combines with ipsapirone Use.

10., according to the method according to any one of claim 1 to 4, wherein said Formulas I compositions combines with vinorelbine Use.

11. combine with capecitabine according to the method according to any one of claim 1 to 4, wherein said Formulas I compositions Use.

12. combine with gemcitabine according to the method according to any one of claim 1 to 4, wherein said Formulas I compositions Use.

13. according to the method according to any one of claim 1 to 4, wherein said Formulas I compositions and 5-fluorouracil group Close and use.

14. combine with methotrexate according to the method according to any one of claim 1 to 4, wherein said Formulas I compositions Use.

15. combine with cyclophosphamide according to the method according to any one of claim 1 to 4, wherein said Formulas I compositions Use.

16. use with cisplatin combination according to the method according to any one of claim 1 to 4, wherein said Formulas I compositions.

17. are applied in combination with carboplatin according to the method according to any one of claim 1 to 4, wherein said Formulas I compositions.

18. combine with doxorubicin according to the method according to any one of claim 1 to 4, wherein said Formulas I compositions Use.

19. according to the method according to any one of claim 1 to 4, wherein said Formulas I compositions and Pegylation fat Liposomal doxorubicin is applied in combination.

20. combine with epirubicin according to the method according to any one of claim 1 to 4, wherein said Formulas I compositions Use.

21. combine with tamoxifen according to the method according to any one of claim 1 to 4, wherein said Formulas I compositions Use.

22. combine with fulvestrant according to the method according to any one of claim 1 to 4, wherein said Formulas I compositions Use.

23. combine with Anastrozole according to the method according to any one of claim 1 to 4, wherein said Formulas I compositions Use.

24. make with letrozole combination according to the method according to any one of claim 1 to 4, wherein said Formulas I compositions With.

25. combine with exemestane according to the method according to any one of claim 1 to 4, wherein said Formulas I compositions Use.

26. according to the method according to any one of claim 1 to 4, wherein said Formulas I compositions and Herceptin group Close and use.

27. according to the method according to any one of claim 1 to 4, wherein said Formulas I compositions and Ah many-toltrazuril His Combination nova of monoclonal antibody grace uses.

28. according to the method according to any one of claim 1 to 4, wherein said Formulas I compositions and handkerchief trastuzumab group Close and use.

29. combine with Lapatinib according to the method according to any one of claim 1 to 4, wherein said Formulas I compositions Use.

30. combine with everolimus according to the method according to any one of claim 1 to 4, wherein said Formulas I compositions Use.

31. combine with CCI-779 according to the method according to any one of claim 1 to 4, wherein said Formulas I compositions Use.

32. suppress with CDK4/6 according to the method according to any one of claim 1 to 4, wherein said Formulas I compositions Agent LY2835219 is applied in combination.

33. suppress with CDK4/6 according to the method according to any one of claim 1 to 4, wherein said Formulas I compositions Agent LEE011 is applied in combination.

34. suppress with CDK4/6 according to the method according to any one of claim 1 to 4, wherein said Formulas I compositions Agent PD 0332991 is applied in combination.

35. combine with bevacizumab according to the method according to any one of claim 1 to 4, wherein said Formulas I compositions Use.

36. according to the method according to any one of Claim 1-3 5, and wherein said compositions is Formula II compositions.

37. according to the method according to any one of Claim 1-3 6, wherein said Formulas I or Formula II compositions and such as power Profit require in 6 to 35 differentiate other medicament in more than one be applied in combination.

38. 1 kinds block breast carcinoma endosmosis, diffusion and the method for cancerometastasis, it comprises to patient's administration effective dose in need Formulas I compositions

Wherein

N is the integer of 0 to 7；

X is the basic group of pharmaceutically acceptable salt；

Its restrictive condition is for when n is 0, and described Formulas I compositions is parent free alkali,

The kinase whose dosage regimen of TIE2 in macrophage is expressed by being enough to block tumor microenvironment TIE2.

39. according to the method described in claim 38, wherein said dosage regimen administration every day.

40. according to the method described in claim 38, and wherein said dosage regimen is the administration non-every day of interruption, gives every other day Medicine, every three days be administered, twice a week be administered or be administered once in a week.

41. according to the method described in claim 38, wherein said dosage regimen be twice a week, weekly or by every Week is administered.

42. according to the method according to any one of claim 38 to 41, wherein said Formulas I compositions and one or more It is obtained from following pharmaceutical agent combinations to use: antitublin, DNA alkylating agent, DNA synthetic inhibitor, DNA Intercalator, estrogen antagonist agent, anti-HER2 agent, inhibitors of kinases or anti-angiogenic agent.

43. according to the method according to any one of claim 38 to 41, wherein said Formulas I compositions and Pacific yew Alcohol is applied in combination.

44. according to the method according to any one of claim 38 to 41, wherein said Formulas I compositions with for injectable The Paclitaxel protein binding particle combinations of suspension uses.

45. according to the method according to any one of claim 38 to 41, wherein said Formulas I compositions and eribulin group Close and use.

46. according to the method according to any one of claim 38 to 41, wherein said Formulas I compositions and ipsapirone group Close and use.

47. according to the method according to any one of claim 38 to 41, wherein said Formulas I compositions and vinorelbine group Close and use.

48. according to the method according to any one of claim 38 to 41, wherein said Formulas I compositions and capecitabine group Close and use.

49. according to the method according to any one of claim 38 to 41, wherein said Formulas I compositions and gemcitabine group Close and use.

50. according to the method according to any one of claim 38 to 41, wherein said Formulas I compositions and 5-fluorouracil It is applied in combination.

51. according to the method according to any one of claim 38 to 41, wherein said Formulas I compositions and methotrexate group Close and use.

52. according to the method according to any one of claim 38 to 41, wherein said Formulas I compositions and cyclophosphamide group Close and use.

53. make with cisplatin combination according to the method according to any one of claim 38 to 41, wherein said Formulas I compositions With.

54. make with carboplatin combination according to the method according to any one of claim 38 to 41, wherein said Formulas I compositions With.

55. according to the method according to any one of claim 38 to 41, wherein said Formulas I compositions and doxorubicin group Close and use.

56. according to the method according to any one of claim 38 to 41, wherein said Formulas I compositions and Pegylation Liposomal doxorubicin is applied in combination.

57. according to the method according to any one of claim 38 to 41, wherein said Formulas I compositions and epirubicin group Close and use.

58. according to the method according to any one of claim 38 to 41, wherein said Formulas I compositions and tamoxifen group Close and use.

59. according to the method according to any one of claim 38 to 41, wherein said Formulas I compositions and fulvestrant group Close and use.

60. according to the method according to any one of claim 38 to 41, wherein said Formulas I compositions and Anastrozole group Close and use.

61. combine with letrozole according to the method according to any one of claim 38 to 41, wherein said Formulas I compositions Use.

62. according to the method according to any one of claim 38 to 41, wherein said Formulas I compositions and exemestane group Close and use.

63. according to the method according to any one of claim 38 to 41, wherein said Formulas I compositions and Herceptin It is applied in combination.

64. according to the method according to any one of claim 38 to 41, and wherein said Formulas I compositions is appropriate with Ah many-song His Combination nova of pearl monoclonal antibody grace uses.

65. according to the method according to any one of claim 38 to 41, wherein said Formulas I compositions and handkerchief trastuzumab It is applied in combination.

66. according to the method according to any one of claim 38 to 41, wherein said Formulas I compositions and Lapatinib group Close and use.

67. according to the method according to any one of claim 38 to 41, wherein said Formulas I compositions and everolimus group Close and use.

68. according to the method according to any one of claim 38 to 41, wherein said Formulas I compositions and CCI-779 group Close and use.

69. press down with CDK4/6 according to the method according to any one of claim 38 to 41, wherein said Formulas I compositions Preparation LY2835219 is applied in combination.

70. press down with CDK4/6 according to the method according to any one of claim 38 to 41, wherein said Formulas I compositions Preparation LEE011 is applied in combination.

71. press down with CDK4/6 according to the method according to any one of claim 38 to 41, wherein said Formulas I compositions Preparation PD 0332991 is applied in combination.

72. according to the method according to any one of claim 38 to 41, wherein said Formulas I compositions and bevacizumab group Close and use.

73. according to the method according to any one of claim 38 to 72, and wherein said compositions is Formula II compositions.

74. according to the method according to any one of claim 38 to 73, wherein said Formulas I or Formula II compositions with such as More than one in other medicament differentiated in claim 43 to 72 are applied in combination.

75. 1 kinds of methods blocking breast carcinoma immunologic tolerance, it comprises the Formulas I combination to patient's administration effective dose in need Thing

Wherein

N is the integer of 0 to 7；

X is the basic group of pharmaceutically acceptable salt；

Kinase whose by the TIE2 that be enough to block in the tumor microenvironment TIE2 expression macrophage of mediating immune tolerance Dosage regimen.

76. according to the method described in claim 75, wherein said dosage regimen administration every day.

77. according to the method described in claim 75, and wherein said dosage regimen is the administration non-every day of interruption, gives every other day Medicine, every three days be administered, twice a week be administered or be administered once in a week.

78. according to the method described in claim 75, wherein said dosage regimen be twice a week, weekly or by every All schemes.

79. according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions and one or more It is obtained from following pharmaceutical agent combinations to use: antitublin, DNA alkylating agent, DNA synthetic inhibitor, DNA Intercalator, estrogen antagonist agent, anti-HER2 agent, inhibitors of kinases, anti-angiogenic agent or immunomodulator.

80. according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions and Pacific yew Alcohol is applied in combination.

81. according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions with for injectable The Paclitaxel protein binding particle combinations of suspension uses.

82. according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions and eribulin group Close and use.

83. according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions and ipsapirone group Close and use.

84. according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions and vinorelbine group Close and use.

85. according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions and capecitabine group Close and use.

86. according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions and gemcitabine group Close and use.

87. according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions and 5-fluorouracil It is applied in combination.

88. according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions and methotrexate group Close and use.

89. according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions and cyclophosphamide group Close and use.

90. make with cisplatin combination according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions With.

91. make with carboplatin combination according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions With.

92. according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions and doxorubicin group Close and use.

93. according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions and Pegylation Liposomal doxorubicin is applied in combination.

94. according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions and epirubicin group Close and use.

95. according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions and tamoxifen group Close and use.

96. according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions and fulvestrant group Close and use.

97. according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions and Anastrozole group Close and use.

98. combine with letrozole according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions Use.

99. according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions and exemestane group Close and use.

100. according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions and toltrazuril list Resist and be applied in combination.

101. according to the method according to any one of claim 75 to 78, and wherein said Formulas I compositions is appropriate with Ah many-song His Combination nova of pearl monoclonal antibody grace uses.

102. according to the method according to any one of claim 75 to 78, and wherein said Formulas I compositions is single with the appropriate pearl of handkerchief Resist and be applied in combination.

103. according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions and Lapatinib It is applied in combination.

104. according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions and everolimus It is applied in combination.

105. according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions and CCI-779 It is applied in combination.

106. according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions and CDK4/6 Inhibitor LY2835219 is applied in combination.

107. according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions and CDK4/6 Inhibitor LEE011 is applied in combination.

108. according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions and CDK4/6 Inhibitor PD 0332991 is applied in combination.

109. according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions and bevacizumab It is applied in combination.

110. according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions and anti-CTLA-4 Agent is applied in combination.

111. according to the method according to any one of claim 75 to 78, and wherein said Formulas I compositions is mono-with Yi Paili Resist and be applied in combination.

112. according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions and anti-PD-1 agent It is applied in combination.

113. according to the method according to any one of claim 75 to 78, and wherein said Formulas I compositions is with to draw vertical pearl single Resist and be applied in combination.

114. according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions and anti-PD L-1 Agent is applied in combination.

115. according to the method according to any one of claim 75 to 78, wherein said Formulas I compositions with MPDL3280A is applied in combination.

116. according to the method according to any one of claim 75 to 115, and wherein said compositions is Formula II compositions.

117. according to the method according to any one of claim 75 to 116, wherein said Formulas I or Formula II compositions with such as More than one in other medicament differentiated in claim 80 to 115 are applied in combination.

The method of 118. 1 kinds of overall survival periods extending patients with mastocarcinoma, it comprises to patient's administration effective dose in need Formulas I compositions

Wherein

N is the integer of 0 to 7；

X is the basic group of pharmaceutically acceptable salt；

119. according to the method described in claim 118, wherein said dosage regimen administration every day.

120. according to the method described in claim 118, and wherein said dosage regimen is to be administered, every other day the non-every day being interrupted It is administered, is administered every three days, is administered twice a week or is administered once in a week.

121. according to the method described in claim 118, wherein said dosage regimen for twice a week, weekly or press Scheme every other week.

122. obtain with one or more according to the method described in claim 118 to 121, wherein said Formulas I compositions Use from following pharmaceutical agent combinations: antitublin, DNA alkylating agent, DNA synthetic inhibitor, DNA embed Agent, estrogen antagonist agent, anti-HER2 agent, inhibitors of kinases, anti-angiogenic agent or immunomodulator.

123. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions and the Pacific Ocean Paclitaxel combinations uses.

124. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions with for can The Paclitaxel protein binding particle combinations of injectable suspensions uses.

125. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions and Ai Bu Woods is applied in combination.

126. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions and Yi Sha Grand it is applied in combination.

127. according to the method according to any one of claim 118 to 121, and wherein said Formulas I compositions is auspicious with Changchun Shore is applied in combination.

128. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions and Ka Peita Shore is applied in combination.

129. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions and Ji Xita Shore is applied in combination.

130. urinate with 5-fluorine according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions Pyrimidine is applied in combination.

131. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions and first ammonia butterfly Purine is applied in combination.

132. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions and ring phosphinylidyne Amine is applied in combination.

133. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions and cisplatin group Close and use.

134. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions and carboplatin group Close and use.

135. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions and how soft ratio Star is applied in combination.

136. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions and poly-second two Alcoholization liposomal doxorubicin is applied in combination.

137. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions ratio soft with table Star is applied in combination.

138. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions and tamoxifen Sweet smell is applied in combination.

139. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions and fluorine dimension department Group is applied in combination.

140. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions and Ah Nagqu Azoles is applied in combination.

141. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions and letrozole It is applied in combination.

142. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions and Yi Ximei Smooth it is applied in combination.

143. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions and toltrazuril Monoclonal antibody is applied in combination.

144. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions and Ah many-song His Combination nova of trastuzumab grace uses.

145. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions and the appropriate pearl of handkerchief Monoclonal antibody is applied in combination.

146. replace with drawing handkerchief according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions Buddhist nun is applied in combination.

147. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions and Yi Weimo Department is applied in combination.

148. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions and Tan Luomo Department is applied in combination.

149. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions and CDK4/6 Inhibitor LY2835219 is applied in combination.

150. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions and CDK4/6 Inhibitor LEE011 is applied in combination.

151. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions and CDK4/6 Inhibitor PD 0332991 is applied in combination.

152. cut down list according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions and shellfish Resist and be applied in combination.

153. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions and anti-CTLA-4 Agent is applied in combination.

154. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions and Yi Paili Monoclonal antibody is applied in combination.

155. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions and anti-PD-1 Agent is applied in combination.

156. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions with draw vertical pearl Monoclonal antibody is applied in combination.

157. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions and anti-PD L-1 Agent is applied in combination.

158. according to the method according to any one of claim 118 to 121, wherein said Formulas I compositions with MPDL3280A is applied in combination.

159. according to the method according to any one of claim 118 to 158, and wherein said compositions is Formula II compositions.

160. according to the method according to any one of claim 118 to 159, wherein said Formulas I or Formula II compositions with As more than one in other medicament of discriminating in claim 123 to 158 are applied in combination.

The method that 161. 1 kinds of treatments are in the patients with mastocarcinoma in new aided case, it is included in the forward direction of ocal resection The Formulas I compositions of patient's administration effective dose in need.

162. according to the method described in claim 161, wherein said dosage regimen administration every day.

163. according to the method described in claim 161, and wherein said dosage regimen is to be administered, every other day the non-every day being interrupted It is administered, is administered every three days, is administered twice a week or is administered once in a week.

The methods of patients with mastocarcinoma that 164. 1 kinds of treatments were in new aided case before ocal resection, its comprise with The kinase whose dosage regimen of TIE2 that be enough to block in tumor microenvironment combines to the Formulas I of patient's administration effective dose in need Thing, twice a week, once in a week or as described in scheme administration every other week the dosage of Formulas I compositions.

165. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions with a kind of or Multiple be obtained from following pharmaceutical agent combinations and use: antitublin, DNA alkylating agent, DNA synthetic inhibitor, DNA intercalator, estrogen antagonist agent, anti-HER2 agent, inhibitors of kinases, anti-angiogenic agent or immunomodulator.

166. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions and the Pacific Ocean Paclitaxel combinations uses.

167. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions with for can The Paclitaxel protein binding particle combinations of injectable suspensions uses.

168. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions and Ai Bu Woods is applied in combination.

169. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions and Yi Sha Grand it is applied in combination.

170. according to the method according to any one of claim 161 to 164, and wherein said Formulas I compositions is auspicious with Changchun Shore is applied in combination.

171. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions and Ka Peita Shore is applied in combination.

172. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions and Ji Xita Shore is applied in combination.

173. urinate with 5-fluorine according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions Pyrimidine is applied in combination.

174. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions and first ammonia butterfly Purine is applied in combination.

175. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions and ring phosphinylidyne Amine is applied in combination.

176. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions and cisplatin group Close and use.

177. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions and carboplatin group Close and use.

178. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions and how soft ratio Star is applied in combination.

179. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions and poly-second two Alcoholization liposomal doxorubicin is applied in combination.

180. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions ratio soft with table Star is applied in combination.

181. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions and tamoxifen Sweet smell is applied in combination.

182. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions and fluorine dimension department Group is applied in combination.

183. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions and Ah Nagqu Azoles is applied in combination.

184. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions and letrozole It is applied in combination.

185. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions and Yi Ximei Smooth it is applied in combination.

186. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions and toltrazuril Monoclonal antibody is applied in combination.

187. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions and Ah many-song His Combination nova of trastuzumab grace uses.

188. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions and the appropriate pearl of handkerchief Monoclonal antibody is applied in combination.

189. replace with drawing handkerchief according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions Buddhist nun is applied in combination.

190. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions and Yi Weimo Department is applied in combination.

191. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions and Tan Luomo Department is applied in combination.

192. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions and CDK4/6 Inhibitor LY2835219 is applied in combination.

193. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions and CDK4/6 Inhibitor LEE011 is applied in combination.

194. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions and CDK4/6 Inhibitor PD 0332991 is applied in combination.

195. cut down list according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions and shellfish Resist and be applied in combination.

196. according to the method according to any one of claim 161 to 164, and wherein said Formulas I compositions is with anti- CTLA-4 agent is applied in combination.

197. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions and Yi Paili Monoclonal antibody is applied in combination.

198. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions and anti-PD-1 Agent is applied in combination.

199. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions with draw vertical pearl Monoclonal antibody is applied in combination.

200. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions and anti-PD L-1 Agent is applied in combination.

201. according to the method according to any one of claim 161 to 164, wherein said Formulas I compositions with MPDL3280A is applied in combination.

202. according to the method according to any one of claim 161 to 201, and wherein said compositions is Formula II compositions.

203. according to the method according to any one of claim 161 to 202, wherein said Formulas I or Formula II compositions with As more than one in other medicament of discriminating in claim 166 to 201 are applied in combination.

204. 1 kinds of methods treating cancer, it comprises the Formulas I compositions of effective dose:

Wherein

N is the integer of 0 to 7；

X is the basic group of pharmaceutically acceptable salt；

Administration patient in need,

Wherein said patient's overexpression tyrosine kinase and inner membrance endotheliocyte kinases-2 (TIE2), and described cancer It is selected from breast carcinoma, colorectal carcinoma, hepatocarcinoma, head and neck cancer, bladder cancer, ovarian cancer, glioma, blood vessel Sarcoma, melanoma or acute myelogenous leukemia.

205. according to the method described in claim 204, wherein said Formulas I compositions and one or more other medicament groups Close administration.

206. according to the method described in claim 204 or 205, wherein said Formulas I compositions administration every day.

207. according to the method described in claim 204 or 205, the administration non-every day that wherein said Formulas I compositions is interrupted.

208. according to the method described in claim 204 or 205, wherein said Formulas I compositions administration three-times-weekly.

209. according to the method described in claim 204 or 205, wherein said Formulas I compositions administration twice a week.

210. according to the method described in claim 204 or 205, the wherein said weekly administration of Formulas I compositions.

211. according to the method described in claim 204 or 205, wherein said Formulas I compositions administration once every two weeks.

212. according to the method described in claim 1,38,75,118,161,204 or 205, and wherein said cancer is Three negative breast carcinomas.

213. according to the method described in claim 1,38,75,118,161,204 and 205, and wherein said cancer is Estrogen positive (ER⁺) and the negative (HER2 of HER2 receptor kinase^-) breast carcinoma.

214. according to the method described in claim 1,38,75,118,161,204 or 205, and wherein said cancer is Inflammatory breast carcinoma.

215. according to the method described in claim 1,38,75,118,161,204 or 205, and wherein said breast carcinoma is Metastatic.

216. according to the method described in claim 204 or 205, and wherein said treatment comprises prevention or minimizing constitutional swells Tumor growth, tumor invasiveness, cancer are endosmosis, cancer diffusion, one or more in cancerometastasis and tumour immunity toleration.

217. according to the method described in claim 204 or 205, and wherein said treatment comprises raising patient survival.

218. according to the method described in claim 205, other medicament wherein said be following in one or more: too Flat ocean paclitaxel, Paclitaxel protein binding particle for injectable suspensions, eribulin, docetaxel, Ipsapirone, vincristine, vinorelbine, cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, replace Muzolimine, doxorubicin, pegylated liposomal doxorubicin, daunomycin, Ida mycin and epirubicin, 5-fluorouracil, capecitabine, cytosine arabinoside, decitabine, 5-azacytidine, gemcitabine, methotrexate, angstrom Sieve for Buddhist nun, gefitinib, Lapatinib, everolimus, CCI-779, LY2835219, LEE011, PD 0332991, Ke Zhuo for Buddhist nun, card rich for Buddhist nun, Sutent, pazopanib, Sorafenib, Rui Gefeini, Axitinib, reach sand and replace Buddhist nun, imatinib, nilotinib, Wei Luofeini, dabrafenib, Sibutramine Hydrochloride for Buddhist nun, Ai De former times cloth, quinoline miscellaneous for Buddhist nun, he Not former times sweet smell, fulvestrant, Anastrozole, letrozole, exemestane, abiraterone acetate ester, grace miscellaneous Shandong amine, Ni Lu Meter Te, bicalutamide, flutamide, CPA, prednisone, dexamethasone, irinotecan, camptothecine, open up Flutter for health, etoposide, etoposide phosphate, mitoxantrone, Vorinostat, romidepsin, LBH589, the third penta Acid, Belling promise he, DZNep DAC, bortezomib, card non-azoles rice, thalidomide, come that degree Amine, pomalidomide, Herceptin, handkerchief trastuzumab, Cetuximab, Victibix, Yi Paili monoclonal antibody, draw vertical Pearl monoclonal antibody, Buddhist nun irrigate monoclonal antibody, MPDL3280A, bevacizumab, VEGF Trap, Belém appropriate monoclonal antibody Wei Duoting, Ah many-song Trastuzumab En Taxin, actinotherapy and Xi Pu bright plug-T.

219. according to the method described in claim 205, wherein said Formulas I compositions administration adjuvant or neoadjuvant.