KR20160070188A - Methods for inhibiting tie2 kinase useful in the treatment of cancer - Google Patents

Abstract

The present invention relates to a method of inhibiting TIE2 kinase useful for the treatment of tumor growth, invasion, intravascular invasion, propagation, metastasis, and immunosuppression. In particular, the present invention relates to a process for the preparation of 1- (3-tert-butyl-1- (quinolin-6-yl) -1H-pyrazol- Methylcarbamoyl) pyridin-4-yloxy) phenyl) urea and salts of formula (I).

Description

FIELD OF THE INVENTION [0001] The present invention relates to a method for inhibiting TIE2 kinase,

Description of the electronically submitted text file

The contents of an electronically submitted text file are incorporated herein by reference: a computer-readable formatted copy of the sequence listing (file name: DECP_066_00WO_SeqList_ST25.txt, date of data recording: November 7, 2013, file size 6 kilobytes) .

Field of invention

The present invention relates to a method of inhibiting TIE2 kinase useful in the treatment of tumor growth, tumor invasion, tumor vascular invasion, tumor spread, tumor metastasis, and tumor immunity tolerance. In particular, the present invention relates to a method of using the composition of formula I as described herein as a potent inhibitor of TIE2 for treating breast cancer growth, invasion, intravascular invasion propagation, metastasis, and immune tolerance.

Endothelial endothelial cell kinase-2 (TIE2) generally limits expression in the endothelial cells of the vasculature and in subpopulations of bone marrow-derived TIE2-expressing mononuclear cells (TEM). TIE2 is a receptor for angiopoietin 1 (ANG1), angiopoietin 2 (ANG2), and angiopoietin 4 (ANG4), and this signal transduction system is involved in angiogenesis (neovascular germination from existing blood vessels) And vasculogenesis ( de novo angiogenesis). TEM is a subset of circulating mononuclear and macrophage macrophages that have angiogenic and angiogenic promoting activity in tumor models (De Palma MD et al., Cancer Cell 2005; 8: 211-226). TIE2 inhibition reduces the ability of the TEM to relate to blood vessels (Mazzieri R, Cancer Cell 2011; 19: 512-526), and significantly reduces the angiogenic activity of the macrophage population (De Palma M, Clin Cancer Res 2011 ; 17 (16): 5226-5232).

Cytotoxic chemotherapy, radiation therapy, and anti-angiogenic treatment impair the tumor-associated vasculature and thus cause a hypoxic tumor environment. The hypoxic tumor environment causes rebound tumor vascularization by activating the ANG / TIE2 pathway from the vascular endothelial growth factor (VEGF) / VEGFR2 pathway in vascular endothelial cells. The influx of angiogenesis-promoting TEM from bone marrow to these hypoxic tumor sites promotes re-angiogenesis by the association of endothelial cells with TEM in the tumor microenvironment. TEM and TIE2-expressing endothelial cells are thus thought to play an important role in tumor re-angiogenesis following this treatment, which is caused by the growth of residual tumor cells (De Palma M, et al. Trends Immunol 2007; 28 : 519-524).

TIE2 is the mediator of osteoclast differentiation and TIE2 inhibition results in reduced osteolytic bone invasion and reduced tumor growth in the 4T1 mouse breast cancer model (Dales JP, et al. Int J Oncol 2003; 22: 391-397). After physiological expression of osteoclast cells in the tumor microenvironment, and TIE2 on endothelial mononuclear cells / macrophages, TIE2 has also been demonstrated to be present in breast cancer cells. The tumor cell expression of TIE2 is associated with an increased risk of metastatic disease and independent predictors of prediction of multivariate analysis (Min Y, et al. Cancer Res 2010; 70: 2918-2828).

Importantly, the subpopulation of TIE2-expressing tissue macrophages is located within a specialized vascular structure known as the tumor microenvironment (TMEM) for metastasis. Recent studies have linked TIE2-expressing macrophages in the TMEM structure to vascular circulation as an essential requirement for extravasation of breast cancer cells and subsequent propagation to the metastatic distal site (Condeelis J, Pollard JW. Cell 2006; 124 : 263-6; Ginter PS, et al. Cancer Res 2012; 72 (24 Suppl): Abstract # P6-02-04). Inhibition of TIE2 and macrophages in the TMEM structure can reduce new metastasis.

TIE2-expressing tissue macrophages (TEM) have recently been shown to play a role in breast cancer immune tolerance. TEM from breast tumors can inhibit tumor-specific immune responses. In detail, the inhibitory function of TEM is likewise induced by TIE2 and VEGFR kinase activity. The TEM isolated from breast cancer tissue can serve as an antigen-transferring cell that only induces weak proliferation of T cells. Inhibition of TIE2 and VEGFR kinase activity is induced to alter its phenotype in cells with characteristics of bone marrow dendritic cells with potent antigen-providing ability. The immunosuppressive activity of TEM is also associated with extensive involvement of T regulatory cells in mammary tumors and high CD86 surface expression. TIE2 and VEGFR kinase activity was required to maintain high CD86 surface expression levels and to convert T cells into immunosuppressive regulatory cells (Ibberson M, et al. Clin Cancer Res 2013; 19: 3439-3449).

The polyoma middle-T antigen (PyMT) syngeneic mouse breast cancer model of the polyoma mid-T antigen (PyMT) was used to express the mouse mammary tumor virus (MMTV) promoter, Lt; / RTI > promoter. In this model, PyMT breast cancer cells are implanted in the mouse mammary gland, and these cancers are metastasized, resulting in the death of mice. Unlike the xenotransplantation model, the PyMT model uses an immunological mouse as a whole. Transition in this model is known to be mediated by TIE2 expression macrophages in the TMEM vasculature. Thus, there is a need for novel treatments for diseases associated with TIE2.

SUMMARY OF THE INVENTION

The method of the present invention finds utility in TIE2 kinase inhibition. As a result of this inhibition, the present invention is useful in the treatment or prevention of tumor growth, invasion, intravascular invasion, spreading, metastasis, and tumor immunity tolerance. In particular, the invention relates to a method of using a composition of formula I as described below as a potent inhibitor of TIE2 for treating breast cancer growth, invasion, intravascular invasion, spreading, metastasis, and immunotolerance:

Wherein n is an integer from 0 to 7;

X is a basic radical of a pharmaceutically acceptable salt;

When n is 0, the composition of formula (I) is a parent free base. In some embodiments, when HX is absent, the structure of formula I is the parent free base.

The compositions of formula I are also found to be useful in other cancers, whereby expression of TIE2 in tumor cell or tumor microenvironment is associated with primary tumor growth, primary tumor invasion, tumor invasion into the bloodstream, tumor cell propagation, , Or tumor progression by a mechanism mediating tumor immunity tolerance. Thus, the inhibition of TIE2 kinase by the composition of formula I is effective to inhibit actions, including primary tumor growth, primary tumor invasion, intratumoral invasion of the blood stream, tumor cell spread, tumor metastasis to distal tissue, or tumor immunity tolerance In the treatment of cancer.

TIE2 kinase has been reported to be useful in the treatment of glioma (Liu et al., Oncotarget (2010) 1: 700-709; Brunckhorst et al., Cancer Research (2010) 70: 7283-7293), melanoma (Helfrich et al ., Clin Cancer Res (2009) 15: 1392), ovarian cancer (Karlan et al., J. Clinical Oncology (2012) 30: 362-370), colon cancer (Ahmad et al., Cancer (2001) 92: 1138-1143, Hashizume et al., Cancer Research Hepatology (2013) 57: 1416-1425; Mitsuhashi et al., Hepatology (2003) 37: 1105-1113; Tanaka et al., J. Clin Invest (1999) 103: 341-345) , And cancer in cancer of the blood (Muller et al., Leukemia Research (2002) 26: 163-168; Hou et al., Leukemia Research (2008) 32: 904-912).

Figure 1 shows inhibition of primary PyMT tumor growth using a composition of formula II, paclitaxel, or a combination thereof.
Figure 2 shows inhibition of PyMT tumor macrophage accumulation using a composition of formula II, paclitaxel, or a combination thereof.
Figure 3 shows the inhibition of PyMT tumor TIE2-expressing cell accumulation using a composition of formula II, paclitaxel, or a combination thereof.
Figure 4 shows the inhibition of lung metastasis in a PyMT breast cancer model using a composition of formula II, paclitaxel, or a combination thereof.
Figure 5 shows lung metastasis inhibition in a PyMT breast cancer model comparing the activity of a combination of paclitaxel and a compound of formula II with paclitaxel.
Figure 6 shows the inhibition of lung metastasis in a PyMT breast cancer model using eribulin as a single agent or in combination with a composition of formula II.
Figure 7 shows the enzymatic in vivo activity of eribulin as a single agent or in combination with a composition of formula II.

DETAILED DESCRIPTION OF THE INVENTION

Justice:

The term "basic radical of a pharmaceutically acceptable salt" in the composition of formula I includes, but is not limited to, water-soluble and water-insoluble salts such as substituted or unsubstituted benzenesulfonates, acetates, amsonates Diminostilbene-2,2-disulfonate), benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camylate, carbonate, chloride, citrate, But are not limited to, clavulanic acid, clavulariate, dihydrochloride, edetate, eddylate, esterolate, ethylate, fiunarate, glucosate, gluconate, glutamate, glycolylarsanylate, hexafluorophosphate, Hexylenesorbate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthenate, IaO But are not limited to, but are not limited to, aldehyde, isodonate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, ethylate, methyl bromide, methyl nitrate, methyl sulfate, , N-methylglucamine ammonium salt, 3-hydroxy-2-naphthenate, oleate, oxalate, palmitate, pamoate (1,1- , Ebonite), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, sebacate, succinate, Sulfates, sulfates, succinates, tartrates, theoclates, tosylates, triethiodides, and valerate salts. Specific examples of basic radicals include para-toluene sulfonate, triflate, and methanesulfonate.

The term "salt" relates to pharmaceutically acceptable salts.

The term " pharmaceutically acceptable salts "also relates to salts of the compositions of the present invention having an acidic functional group, such as a carboxylic acid functional group, and a base.

The term "treating" associated with an object relates to ameliorating at least one symptom of a disorder of the subject. Treatment may be to manage, improve, or at least partially alleviate the disorder.

The term " administering ", "administering ", or" administering ", as used in this disclosure, refers to administering a composition or a compound or a pharmaceutically acceptable salt of the composition directly to a subject, Or analogs or compounds or pharmaceutically acceptable salts of the compositions to a subject, which may form equivalent amounts of the active compound in the subject ' s body.

An "effective amount" in the context of a medical use is an amount effective to provide a measurable treatment, prevention, or reduction in the incidence of a disease of interest.

The present invention relates to methods of treating (blocking) or preventing tumor growth, invasion, intravascular invasion, spreading, metastasis, and tumor immunity tolerance. The method comprises administering to a patient in need of such treatment an effective amount of a composition of Formula I as herein described in a dosage regimen that modulates TIE2 inhibition, for the treatment, reduction, or prevention of such a disease.

The amount of composition described herein that is needed to achieve a therapeutic effect can be determined empirically according to conventional procedures for a particular purpose. Generally, to administer a therapeutic agent (e.g., a composition of Formula I or II described herein) and / or an additional agent) for therapeutic purposes, the therapeutic agent is given in a pharmaceutically effective dose. A "pharmaceutically effective amount "," pharmaceutically effective dose ", "therapeutically effective amount ", or" effective amount "means an amount sufficient to produce the desired physiological effect, . An effective amount as used herein is, for example, an amount sufficient to delay the development of the symptoms of a disorder or disease, to alter the course of a disorder or condition of the disease (e. G., Slow the progression of symptoms of the disease) Will reduce or eliminate one or more symptoms or indications, and will include an amount sufficient to reverse the symptoms of the disorder or disease. For example, the administration of a therapeutic agent to a patient suffering from cancer may be useful not only in the case where the underlying disease is eradicated or alleviated, but also in the severity or duration of the disease-related symptom in the patient, for example, , Reduction in purified tumor cells, and an increase in progression-free survival are reported. Therapeutic benefits also include stopping or slowing the progression of the underlying disease or disorder, regardless of whether the improvement is realized.

In one embodiment of the invention, the composition of formula I is a potent inhibitor of TIE2, 1- (3-tert-butyl-1- (quinolin-6-yl Pyrazol-5-yl) -3- (2-fluoro-4- (2- (methylcarbamoyl) pyridin-4-yloxy) phenyl) urea p-toluenesulfonate.

The composition of formula I is found to be useful in cancer, where expression of TIE2 in tumor cell or tumor microenvironment is associated with primary tumor growth, primary tumor invasion, intravascular tumor invasion into the bloodstream, tumor cell propagation, Tumor metastasis, or tumor-mediated tolerance mechanisms. Thus, inhibition of TIE2 kinase by the composition of formula I inhibits the action, including primary tumor growth, primary tumor invasion, intravascular tumor invasion into the bloodstream, tumor cell spread, tumor metastasis to the distal tissue, or tumor immunity tolerance In the treatment of cancer.

The therapeutic concentration of the composition of formula I blocks the cells in the tumor microenvironment known to cause tumor growth, invasion, intravascular invasion, propagation, metastasis, tumor-induced immune tolerance. Such cell types in the tumor microenvironment include TIE2-expressing monocytes, TIE2-expressing macrophages, and TIE2-expressing endothelial cells.

Tumors responsive to angiopoietin / TIE2 signaling include, but are not limited to, breast, ovarian, hepatocellular, glioma, colorectal, and hematologic malignancies.

In another embodiment, the composition of formula I where HX is absent comprises a free base compound 1- (3-tert-butyl-1- (quinolin-6-yl) Yl) -3- (2-fluoro-4- (2- (methylcarbamoyl) pyridin-4- yloxy) phenyl) urea:

The composition of formula I may be administered in combination with other therapeutic agents known to treat cancer or as a single agent. Such other therapeutic agents may be selected from the group consisting of radiotherapy, anti-tubulin agents, DNA alkylating agents, DNA synthesis inhibitors, DNA intervening drugs, anti-estrogen agents, anti- androgens, steroids, anti-EGFR agents, kinase inhibitors, topoisomerase inhibitors , Histone deacetylase (HDAC) inhibitors, DNA methylation inhibitors, anti-HER2 agents, anti-angiogenic agents, proteasome inhibitors, thalidomide, lenalidomide, antibody-drug-conjugate , Or a cancer vaccine.

Effective amounts, toxicity, and therapeutic efficacy may be determined, for example, in cell cultures to determine LD50 (lethal dose at about 50% of the population) and ED50 (therapeutically effective dose at about 50% of the population) Can be determined by standard pharmaceutical procedures in animals. The dosage may vary depending on the dosage form used and the route of administration utilized. The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the LD50 / ED50 ratio. In some embodiments, compositions and methods that exhibit a large therapeutic index are preferred. Therapeutically effective doses can be initially estimated from in vitro assays, including, for example, cell culture assays. In addition, the dose can be formulated in animal models to achieve circulating plasma concentration ranges, including IC50 as determined in cell culture, or in appropriate animal models. The level of the composition described in plasma can be measured, for example, by high performance liquid chromatography. The effect of any particular dose can be monitored by suitable biological assays. The dose is determined by the physician and can be adjusted for the appropriate observation effect of the treatment as required.

In certain embodiments, the prophylactic effect will result in a quantifiable change of 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%. In some embodiments, the effect will result in a quantifiable change of about 10%, about 20%, about 30%, about 50%, about 70%, or even about 90% or more. Therapeutic benefits also include stopping or slowing the progression of the underlying disease or disorder, regardless of whether the improvement is realized.

When the composition of formula I or II is used in combination with another anti-cancer agent, the other anti-cancer agent may be administered independently of the dosing schedule of the composition of formula I or II. Other anticancer agents may be administered with their previously established therapeutic doses and dosing regimens, or their dosing and dosing regimens may be used to optimize efficacy, safety, or tolerability when used in combination with a composition of formula I or II Can be modified.

In addition, any composition (s) (and / or additional agents) of Formula I or II described herein may be administered to a subject as a component of a composition comprising a pharmaceutically acceptable carrier or vehicle. Such compositions may optionally comprise a suitable amount of a pharmaceutically acceptable excipient to provide a suitable dosage form.

Pharmaceutical excipients may be oils including liquids such as water and oils, animal, vegetable, or synthetic ones such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. The pharmaceutical excipient may be, for example, saline, acacia gum, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. Adjuvants, stabilizers, thickeners, lubricants, and coloring agents may also be used. In one embodiment, the pharmaceutically acceptable excipient can be sterilized when administered to a subject. Water is a useful excipient when any of the formulations described herein are administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions may also be used, especially as liquid excipients for injection solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, powder, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk, glycerol, Ethanol and the like. Any of the formulations described herein may also contain small amounts of wetting or emulsifying agents, or pH buffering, if desired.

The composition of Formula I may be used in combination with other agents, including chemotherapeutic agents, targeted therapeutic agents, biological agents, or radiation therapy.

The compositions of formula I may be formulated with a variety of excipients including, but not limited to, antitubulin agents (paclitaxel, paclitaxel protein-bound particles for injection suspensions, eribulin, docetaxel, xavaveilon, vincristine), vinorelbine, DNA- alkylating agents (cisplatin, , Including DNA-mediated drugs (including doxorubicin, pegylated liposomes doxorubicin, daunorubicin, idarubicin, and epirubicin), 5-fluorouracil , Capecitabine, cytarabine, decitabine, 5-azacytidine, gemcitabine, and methotrexate.

The compositions of formula I include, but are not limited to, erlotinib, gefitinib, lapatanib, everolimus, temsirolimus, LY2835219, LEE011, PD 0332991, chrysotanib, carbosanthinib, In combination with kinase inhibitors, including, but not limited to, sorafenib, legorapenib, acacinib, dasatinib, imatinib, neilotinib, bemurafenib, dabrafenip, trametinib, Can be used.

The compositions of formula I may be used in combination with anti-estrogenic agents including, but not limited to, tamoxifen, fulvestrant, anastrozole, letrozole, and exemestane.

The composition of Formula I may be used in combination with an anti-androgen agent including, but not limited to, aviratorone acetate, ezalutamide, nilutamide, bicalutamide, flutamide, cyproterone acetate.

The composition of Formula I may be used in combination with steroid agents, including but not limited to prednisone and dexamethasone.

The composition of Formula I may be used in combination with a topoisomerase I inhibitor including, but not limited to, irinotecan, camptothecin, and topotecan.

The composition of Formula I may be used in combination with a topoisomerase II inhibitor including, but not limited to, etoposide, etoposide phosphate, and mitoxantrone.

The composition of Formula I may be used in combination with a histone deacetylase (HDAC) inhibitor, including, but not limited to, barrenostat, roximidethine, panovinostat, valproic acid, and valinostat.

The composition of Formula I may be used in combination with DNA methylation inhibitors that include, but are not limited to, DZNep and 5-aza-2'-deoxycytidine.

The composition of Formula I may be used in combination with proteasome inhibitors including, but not limited to, bortezomib and < RTI ID = 0.0 >

The compositions of formula I can be used in combination with, but not limited to, thalidomide, lenalidomide and fomalidomide.

Compositions of Formula I include, but are not limited to, anti-PD-1 formulations including, but not limited to, Trastuzumab, Ado-Trastuzumab, Pertuzumab, Cetuximab, Panifumeum, Eilemimab, Labrolizumab, An anti-angiogenic agent comprising MPDL3280A, an anti-PD-L1 formulation, bevacizumab and an anti-viral agent, and an antibody-drug conjugate comprising brenuxuxmabodotin and trastuzumam manganese RTI ID = 0.0 > (ADC). ≪ / RTI >

The compositions of formula I may be used in combination with radiation therapy.

The composition of Formula I may be used in combination with a therapeutic vaccine, including, but not limited to, Sipuylose-T.

In some embodiments, a composition of Formula I or Formula II may be used in combination with one or more of the other agents described herein.

Methods of blocking primary breast tumor growth and invasion:

A first aspect of the present invention relates to a method of blocking primary breast tumor growth and invasion comprising administering to a patient in need thereof an effective amount of a composition of formula I in a dosage regimen sufficient to block TIE2 kinase in a tumor microenvironment .

In one embodiment of this aspect of the invention, the regimen of administration of the composition of formula I is a daily dose regimen.

In another embodiment of this aspect of the invention, the regimen of administration of the composition of Formula I is a daily dose regimen. Non-daily, intermittent dosing regimens include, but are not limited to, all-dose regimen, once-every 3 days, twice-weekly, or once-weekly dosing.

In another embodiment of this aspect of the invention, a suitable regimen of the composition of Formula I comprises twice a week, once a week, or biweekly.

In another embodiment of this aspect of the invention, the dosage regimen of the composition of formula I is twice a week or once a week.

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

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

In another embodiment of the present invention, the method of blocking primary breast tumor growth and invasion comprises administering to the mammal a therapeutically effective amount of an anti-tuberculosis agent, a DNA alkylating agent, a DNA synthesis inhibitor, a DNA intervening drug, an anti- estrogen agent, Or an anti-angiogenesis agent in combination with one or more agents selected from the group consisting of anti-angiogenic agents, to block TIE2 kinase in the tumor microenvironment.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administering a composition of formula I in combination with paclitaxel.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administering a composition of formula I in combination with a paclitaxel protein-bound particle for a parenteral suspension.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administering a composition of formula I in combination with docetaxel.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with eribulin.

In another embodiment of this aspect of the present invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with an ixabepilone.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with vinorelbine.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with capecitabine.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with gemcitabine.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with 5-fluorouracil.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with methotrexate.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with a cyclophosphamide.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with cisplatin.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with carboplatin.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administering a composition of Formula I in combination with doxorubicin.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administering a composition of formula I in combination with a pegylated liposomal doxorubicin.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administering a composition of formula I in combination with epirubicin.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with tamoxifen.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with a full-vended rant.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with anastrozole.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with letrozole.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with an exemestane.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with trastuzumab.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with ado-trastuzumab manganese.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administering a composition of formula I in combination with pertuzumab.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administering a composition of formula I in combination with lapatinib.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with Everolimus.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises the administration of a composition of formula I in combination with temairolimus.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with a CDK4 / 6 inhibitor LY2835219.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with a CDK4 / 6 inhibitor LEE011.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with a CDK4 / 6 inhibitor PD 0332991.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with bevacizumab.

Another aspect of the present invention relates to a method of blocking primary breast tumor growth and invasion, comprising administering a composition of formula I in a volume sufficient to block TIE2 kinase in a tumor microenvironment, wherein the composition of formula I Is administered in an intermittent dosing regimen, not daily. In some embodiments, non-daily, intermittent dosing regimens include all-day regimens, once every 3 days, twice weekly, and once weekly.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in a sufficient amount to block TIE2 kinase in a tumor microenvironment, I is administered twice a week, once a week, or every other week.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in a sufficient amount to block TIE2 kinase in a tumor microenvironment, I is administered twice a week or once a week.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in a sufficient amount to block TIE2 kinase in a tumor microenvironment, The composition of I is administered twice a week.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in a sufficient amount to block TIE2 kinase in a tumor microenvironment, I is administered in combination with one or more agents from an anti-tubulin, a DNA alkylating agent, a DNA synthesis inhibitor, a DNA intervening drug, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor or an anti-angiogenesis agent .

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administering a composition of formula I in combination with paclitaxel.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administering a composition of formula I in combination with a paclitaxel protein-bound particle for a parenteral suspension.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administering a composition of formula I in combination with docetaxel.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with eribulin.

In another embodiment of this aspect of the present invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with an ixabepilone.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with vinorelbine.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with vinorelbine.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with capecitabine.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with gemcitabine.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with 5-fluorouracil.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with methotrexate.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with a cyclophosphamide.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with cisplatin.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with carboplatin.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administering a composition of Formula I in combination with doxorubicin.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administering a composition of formula I in combination with a pegylated liposomal doxorubicin.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administering a composition of formula I in combination with epirubicin.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with tamoxifen.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with a full-vended rant.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with anastrozole.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with letrozole.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with an exemestane.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with trastuzumab.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with ado-trastuzumab manganese.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administering a composition of formula I in combination with pertuzumab.

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administering a therapeutically effective amount of a compound of formula < RTI ID = 0.0 > I, < / RTI > ≪ / RTI >

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administering to the tumor microenvironment TIE2-expressing macrophages administered in combination with Everolimus in sufficient volume to block TIE2 kinase The administration of a composition of formula (I).

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administering to the tumor microenvironment TIE2-expressing macrophages administered in combination with Temicrylolimus at a dose sufficient to block TIE2 kinase The administration of a composition of formula (I).

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administering to the tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4 / 6 inhibitor LY2835219 a sufficient dose to block TIE2 kinase Lt; RTI ID = 0.0 > I < / RTI >

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administering to the tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4 / 6 inhibitor LEE011 a sufficient dose to block TIE2 kinase Lt; RTI ID = 0.0 > I < / RTI >

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion is sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4 / 6 inhibitor PD 0332991 Dose < / RTI > of the composition of formula (I).

In another embodiment of this aspect of the invention, the method of blocking primary breast tumor growth and invasion comprises administration of a composition of formula I in combination with bevacizumab.

Breast cancer Intravascular invasion , Methods of blocking propagation and transition:

In another aspect of the invention, there is provided a method of blocking intravascular invasion, spreading, and metastasis of breast cancer comprising administering to a patient in need of an effective amount of a composition of formula I sufficient to block TIE2 kinase in a tumor microenvironment / RTI >

In one embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering to a patient in need thereof an effective amount of a composition of formula I in a dosage regimen sufficient to block TIE2 kinase in a tumor microenvironment Lt; / RTI >

In another embodiment of this aspect of the invention, the dosage regimen sufficient to block intravascular invasion, spread and metastasis of the breast cancer comprises daily administration of a composition of formula (I).

In another embodiment of this aspect of the invention, the regimen of administration of the composition of Formula I is administered daily, but not daily, including once-daily dosing, once-daily dosing, twice weekly dosing, or once-weekly dosing Administration method.

In another embodiment of this aspect of the invention, the regimen of administration of the composition of formula I is administered twice a week, once a week, or biweekly.

In another embodiment of this aspect of the invention, the regimen of administration of the composition of formula I is administered twice a week or once a week.

In another embodiment of this aspect of the invention, the regimen of administration of the composition of formula I is administered twice a week.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering an anti-tubulin agent, a DNA alkylating agent, a DNA synthesis inhibitor, a DNA intervening drug, an anti- Administering to a patient in need thereof an effective amount of a composition of Formula I in a dosage regimen sufficient to block TIE2 kinase in a tumor microenvironment in combination with one or more agents selected from HER2 agents, kinase inhibitors or anti-angiogenic agents, .

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with paclitaxel.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with a paclitaxel protein-binding particle for a parenteral suspension.

In another embodiment of this aspect of the present invention, a method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of Formula I in combination with docetaxel.

In another embodiment of this aspect of the invention, a method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with eribulin.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, spreading and metastasis of breast cancer comprises administering a composition of formula I in combination with ixabepilone.

In another embodiment of this aspect of the present invention, a method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with vinorelbine.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with capecitabine.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with gemcitabine.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with 5-fluorouracil.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with methotrexate.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with a cyclophosphamide.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with cisplatin.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with carboplatin.

In another embodiment of this aspect of the invention, a method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with doxorubicin.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with epirubicin.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with tamoxifen.

In another embodiment of this aspect of the invention, a method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with a full-vortrant.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with anastrozole.

In another embodiment of this aspect of the present invention, a method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with letrozole.

In another embodiment of this aspect of the invention, a method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with an exemestane.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with trastuzumab.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, spreading and metastasis of breast cancer comprises administering a composition of formula I in combination with ado-trastuzumab manganese.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administration of a composition of formula I in combination with pertuzumab.

In another embodiment of this aspect of the invention, a method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with lapatinib.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with everolimus.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with Temicrylolimus.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with a CDK4 / 6 inhibitor LY2835219.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with a CDK4 / 6 inhibitor LEE011.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with a CDK4 / 6 inhibitor PD 0332991.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with bevacizumab.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administration of a composition of formula I in a sufficient amount to block TIE2 kinase in a tumor microenvironment, The dosage regimen of the composition of Formula I is administered as an intermittent dose, not daily. In some embodiments, full-day dosing includes once-daily dosing, twice-weekly dosing, or once-weekly dosing.

In one embodiment of this aspect of the present invention, a method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of Formula I in a sufficient amount to block TIE2 kinase in a tumor microenvironment, Of the composition is administered twice a week or every other week.

In one embodiment of this aspect of the present invention, a method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of Formula I in a sufficient amount to block TIE2 kinase in a tumor microenvironment, Of the composition is administered twice a week or once a week.

In another embodiment of this aspect of the invention, a method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administration of a composition of formula I in a sufficient amount to block TIE2 kinase in a tumor microenvironment, The dosage regimen of the composition of formula I is administered twice a week.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering an anti-tubulin agent, a DNA alkylating agent, a DNA synthesis inhibitor, a DNA intervening drug, an anti- Comprising administering a composition of Formula I in a sufficient amount to block TIE2 kinase in a tumor microenvironment, wherein the composition is administered in combination with one or more agents from a HER2 agent, a kinase inhibitor, or an anti-angiogenesis agent.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with paclitaxel.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with a paclitaxel protein-binding particle for a parenteral suspension.

In another embodiment of this aspect of the present invention, a method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of Formula I in combination with docetaxel.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administration of a composition of formula I in combination with eribulin.

In another embodiment of this aspect of the invention, a method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administration of a composition of formula I in combination with an ixabepilone.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administration of a composition of formula I in combination with vinorelbine.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administration of a composition of formula I in combination with capecitabine.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administration of a composition of formula I in combination with gemcitabine.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administration of a composition of formula I in combination with 5-fluorouracil.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administration of a composition of formula I in combination with methotrexate.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administration of a composition of formula I in combination with a cyclophosphamide.

In another embodiment of this aspect of the invention, a method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administration of a composition of formula I in combination with cisplatin.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administration of a composition of formula I in combination with carboplatin.

In another embodiment of this aspect of the invention, a method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with doxorubicin.

In another embodiment of this aspect of the invention, a method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with a pegylated liposomal doxorubicin.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with epirubicin.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administration of a composition of formula I in combination with tamoxifen.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administration of a composition of formula I in combination with a full-vintment.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administration of a composition of formula I in combination with anastrozole.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administration of a composition of formula I in combination with letrozole.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering a composition of formula I in combination with an exemestane.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administration of a composition of formula I in combination with trastuzumab.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administration of a composition of formula I in combination with ado-trastuzumab manganese.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administration of a composition of formula I in combination with pertuzumab.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, spreading and metastasis of breast cancer comprises administering to the tumor microenvironment TIE2-expressing macrophages administered in combination with lapatinib at a dose sufficient to block TIE2 kinase The administration of a composition of formula (I).

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering to the tumor microenvironment TIE2-expressing macrophages administered in combination with Everolimus a sufficient dose to block TIE2 kinase Lt; RTI ID = 0.0 > I < / RTI >

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administering to the tumor microenvironment TIE2-expressing macrophages administered in combination with Temicrylolimus a sufficient dose to block TIE2 kinase Lt; RTI ID = 0.0 > I < / RTI >

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer is to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4 / 6 inhibitor LY2835219 Administration of the composition of formula I in sufficient doses.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer is to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4 / 6 inhibitor LEE011 Administration of the composition of formula I in sufficient doses.

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises blocking TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with CDK4 / 6 inhibitor PD 0332991 RTI ID = 0.0 > I < / RTI >

In another embodiment of this aspect of the invention, the method of blocking intravascular invasion, propagation and metastasis of breast cancer comprises administration of a composition of formula I in combination with bevacizumab.

Blocking method for breast cancer immunity tolerance:

Another aspect of the invention relates to a method of screening for breast cancer immune tolerance. The method comprises administering an effective amount of a composition of formula I to a patient in need thereof. In one embodiment, the dosing regimen of the salt is sufficient to block TIE2 kinase in a tumor microenvironment that mediates immune tolerance.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulants comprises administering an effective amount of a composition of formula I in a dosage regimen sufficient to block TIE2 kinase in a tumor microenvironment that mediates immune tolerance, And administering to the patient.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immune tolerance comprises the administration of a composition of formula I daily.

In another embodiment of this aspect of the invention, the composition of formula I is administered in an intermittent manner rather than daily. In some embodiments, non-daily, intermittent dosing includes all-day dosing, every three days dosing, twice weekly dosing, or once-weekly dosing.

In another embodiment of this aspect of the invention, the administration of the composition of formula I is administered twice a week, once a week, or every other week.

In another embodiment of this aspect of the invention, the composition of formula I is administered twice a week or once a week.

In another embodiment of this aspect of the invention, the composition of formula I is administered twice weekly.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulants comprises administering an anti-tubulin agent, a DNA alkylating agent, a DNA synthesis inhibitor, a DNA intervening drug, an anti-estrogen agent, an anti-HER2 agent, Comprising administering to a patient in need thereof an effective amount of a composition of Formula I in a dosage regimen sufficient to block TIE2 kinase in a tumor microenvironment in combination with one or more agents from an anti-angiogenesis agent, or immunomodulator do.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immune tolerance comprises administering a composition of formula I in combination with paclitaxel.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostaining comprises administering a composition of formula I in combination with a paclitaxel protein-binding particle for a parenteral suspension.

In another embodiment of this aspect of the invention, the method of blocking breast cancer immunity comprises administering a composition of Formula I in combination with docetaxel.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immune tolerance comprises administration of a composition of formula I in combination with eribulin.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulation comprises the administration of a composition of formula I in combination with ixabepilone.

In another embodiment of this aspect of the invention, the method of screening for breast cancer immunity comprises administration of a composition of formula I in combination with vinorelbine.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulation comprises administration of a composition of formula I in combination with capecitabine.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immune tolerance comprises administration of a composition of formula I in combination with gemcitabine.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immune tolerance comprises the administration of a composition of formula I in combination with 5-fluorouracil.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulation comprises administration of a composition of formula I in combination with 5-methotrexate.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulation comprises administration of a composition of formula I in combination with a cyclophosphamide.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immune tolerance comprises the administration of a composition of formula I in combination with cisplatin.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulation comprises administration of a composition of formula I in combination with carboplatin.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulants comprises administering a composition of formula I in combination with doxorubicin.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostaining comprises administering a composition of formula I in combination with a pegylated liposomal doxorubicin.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immune tolerance comprises administering a composition of formula I in combination with epirubicin.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulants comprises the step of administering a composition of formula I in combination with tamoxifen.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulation comprises the administration of a composition of formula I in combination with a full bestort.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulation comprises administration of a composition of formula I in combination with anastrozole.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulation comprises administration of a composition of formula I in combination with letrozole.

In another embodiment of this aspect of the invention, the method of screening for breast cancer immunity comprises the administration of a composition of formula I in combination with an exemestane.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immune tolerance comprises administration of a composition of formula I in combination with trastuzumab.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immune tolerance comprises the administration of a composition of formula I in combination with ado-trastuzumab manganese.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immune tolerance comprises administration of a composition of formula I in combination with pertuzumab.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulants comprises administering to a mammal in need of such treatment a composition of Formula I in a sufficient amount to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with lapatinib ≪ / RTI >

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulants comprises administering a therapeutically effective amount of a compound of formula < RTI ID = 0.0 > (I) < / RTI > in sufficient amount to block TIE2 kinase in tumor microenvironment TIE2- expressing macrophages administered in combination with Everolimus. Administration of the composition.

In another embodiment of this aspect of the present invention, the blocking method for breast cancer immunostimulants comprises administering to a mammal in need of treatment a therapeutically effective amount of a compound of formula < RTI ID = 0.0 > I, < / RTI & Administration of the composition.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immune tolerance comprises administering to the mammal a therapeutically effective amount of a compound of formula < RTI ID = 0.0 > (I) < / RTI > in a sufficient amount to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with CDK4 / 6 inhibitor LY2835219 I < / RTI >

In another embodiment of this aspect of the invention, the blocking method for breast cancer immune tolerance comprises administering a therapeutically effective amount of a compound of formula < RTI ID = 0.0 > (I) < / RTI & I < / RTI >

In another embodiment of this aspect of the invention, the blocking method for breast cancer immune tolerance comprises administering to the tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4 / 6 inhibitor PD 0332991 at a dose sufficient to block TIE2 kinase The administration of a composition of formula (I).

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulation comprises administration of a composition of formula I in combination with bevacizumab.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostaining comprises administering a composition of formula I in combination with a anti-CTLA-4 agent.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulants comprises administering a composition of formula I in combination with eicilimumab.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immune tolerance comprises administering a composition of formula I in combination with an anti-PD-1 agent.

In another embodiment of this aspect of the invention, the method of screening for breast cancer immunity comprises administering a composition of formula I in combination with < RTI ID = 0.0 > Rambrolizumab. ≪ / RTI >

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulants comprises administering a composition of formula I in combination with an anti-PD L-1 agent.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulants comprises administering a composition of formula I in combination with MPDL3280A.

Blocking method for breast cancer immunity tolerance:

In another embodiment of the invention, the method of blocking breast cancer immunity comprises administering a composition of Formula I in a sufficient amount to block TIE2 kinase in a tumor microenvironment, wherein the regimen of the composition of Formula I Daily dosing, every other day, once every three days, twice a week, or once a week.

In another embodiment of this aspect of the invention, the method of screening for breast cancer immunity comprises administering a composition of formula I in a sufficient amount to block TIE2 kinase in a tumor microenvironment, wherein the composition of formula I Is administered twice a week, once a week, or every other week.

In another embodiment of this aspect of the invention, the method of screening for breast cancer immunity comprises administering a composition of formula I in a sufficient amount to block TIE2 kinase in a tumor microenvironment, wherein the composition of formula I Is administered twice a week or once a week.

In another embodiment of this aspect of the invention, the method of screening for breast cancer immunity comprises administering a composition of formula I in a sufficient amount to block TIE2 kinase in a tumor microenvironment, wherein the composition of formula I Is administered twice a week.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulants comprises administering an anti-tubulin agent, a DNA alkylating agent, a DNA synthesis inhibitor, a DNA intervening drug, an anti-estrogen agent, an anti-HER2 agent, , An anti-angiogenesis agent, or an immunomodulator in a tumor microenvironment in a mammalian subject in need thereof.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immune tolerance comprises administering a composition of formula I in combination with paclitaxel.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostaining comprises administering a composition of formula I in combination with a paclitaxel protein-binding particle for a parenteral suspension.

In another embodiment of this aspect of the invention, the method of blocking breast cancer immunity comprises administering a composition of Formula I in combination with docetaxel.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immune tolerance comprises administration of a composition of formula I in combination with eribulin.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulation comprises the administration of a composition of formula I in combination with ixabepilone.

In another embodiment of this aspect of the invention, the method of screening for breast cancer immunity comprises administration of a composition of formula I in combination with vinorelbine.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulation comprises administration of a composition of formula I in combination with capecitabine.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immune tolerance comprises administration of a composition of formula I in combination with gemcitabine.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immune tolerance comprises the administration of a composition of formula I in combination with 5-fluorouracil.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulation comprises administration of a composition of formula I in combination with methotrexate.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulation comprises administration of a composition of formula I in combination with a cyclophosphamide.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immune tolerance comprises the administration of a composition of formula I in combination with cisplatin.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulation comprises administration of a composition of formula I in combination with carboplatin.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulants comprises administering a composition of formula I in combination with doxorubicin.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostaining comprises administering a composition of formula I in combination with a pegylated liposomal doxorubicin.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immune tolerance comprises administering a composition of formula I in combination with epirubicin.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulants comprises the step of administering a composition of formula I in combination with tamoxifen.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulation comprises the administration of a composition of formula I in combination with a full bestort.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulation comprises administration of a composition of formula I in combination with anastrozole.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulation comprises administration of a composition of formula I in combination with letrozole.

In another embodiment of this aspect of the invention, the method of screening for breast cancer immunity comprises the administration of a composition of formula I in combination with an exemestane.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immune tolerance comprises administration of a composition of formula I in combination with trastuzumab.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immune tolerance comprises the administration of a composition of formula I in combination with ado-trastuzumab manganese.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immune tolerance comprises administration of a composition of formula I in combination with pertuzumab.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulants comprises administering to a mammal in need of such treatment a composition of Formula I in a sufficient amount to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with lapatinib ≪ / RTI >

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulants comprises administering a therapeutically effective amount of a compound of formula < RTI ID = 0.0 > (I) < / RTI > in sufficient amount to block TIE2 kinase in tumor microenvironment TIE2- expressing macrophages administered in combination with Everolimus. Administration of the composition.

In another embodiment of this aspect of the present invention, the blocking method for breast cancer immunostimulants comprises administering to a mammal in need of treatment a therapeutically effective amount of a compound of formula < RTI ID = 0.0 > I, < / RTI & Administration of the composition.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immune tolerance comprises administering to the mammal a therapeutically effective amount of a compound of formula < RTI ID = 0.0 > (I) < / RTI > in a sufficient amount to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with CDK4 / 6 inhibitor LY2835219 I < / RTI >

In another embodiment of this aspect of the invention, the blocking method for breast cancer immune tolerance comprises administering a therapeutically effective amount of a compound of formula < RTI ID = 0.0 > (I) < / RTI & I < / RTI >

In another embodiment of this aspect of the invention, the blocking method for breast cancer immune tolerance comprises administering to the tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4 / 6 inhibitor PD 0332991 at a dose sufficient to block TIE2 kinase The administration of a composition of formula (I).

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulation comprises administration of a composition of formula I in combination with bevacizumab.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostaining comprises administering a composition of formula I in combination with a anti-CTLA-4 agent.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulants comprises administering a composition of formula I in combination with eicilimumab.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immune tolerance comprises administering a composition of formula I in combination with an anti-PD-1 agent.

In another embodiment of this aspect of the invention, the method of screening for breast cancer immunity comprises administering a composition of formula I in combination with < RTI ID = 0.0 > Rambrolizumab. ≪ / RTI >

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulants comprises administering a composition of formula I in combination with an anti-PD L-1 agent.

In another embodiment of this aspect of the invention, the blocking method for breast cancer immunostimulants comprises administering a composition of formula I in combination with MPDL3280A.

Breast cancer In patients  How to increase overall survival rate

Another aspect of the present invention relates to a method for increasing overall survival in a breast cancer patient, comprising administering an effective amount of a composition of formula I to a patient in need thereof. In one embodiment, the dosing regimen is sufficient to block TIE2 kinase in the tumor microenvironment.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises an administration regimen wherein the composition of formula I is administered daily.

In another embodiment of this aspect of the invention, the method of increasing the overall survival rate in a breast cancer patient is a non-daily intermittent method comprising daily dosing, every 3 days dosing, twice weekly dosing, or once weekly dosing 0.0 > (I) < / RTI >

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises the composition of formula I in a dosage regimen administered twice a week, once a week, or biweekly.

In another embodiment of this aspect of the invention, the method of administration of the composition of formula I in a method of increasing overall survival in a breast cancer patient is administered twice a week or once a week.

In another embodiment of this aspect of the invention, the dosage regimen of the composition of formula I is administered only two times per week.

Another embodiment of this aspect of the invention is a method for the treatment or prevention of an autoimmune disorder selected from the group consisting of an anti-tubulin, a DNA alkylating agent, a DNA synthesis inhibitor, a DNA intervening drug, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor or anti- Comprising administering a composition of formula I in a dosage regimen sufficient to block TIE2 kinase in a tumor microenvironment in combination with one or more agents selected from immunomodulators.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with paclitaxel.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with a paclitaxel protein-binding particle for a parenteral suspension.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with docetaxel.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administration of a composition of formula I in combination with eribulin.

In another embodiment of this aspect of the invention, a method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with an ixabepilone.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with vinorelbine.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administration of a composition of Formula I in combination with capecitabine.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with gemcitabine.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with 5-fluorouracil.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with methotrexate.

In another embodiment of this aspect of the invention, a method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with a cyclophosphamide.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administration of a composition of formula I in combination with cisplatin.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with carboplatin.

In another embodiment of this aspect of the invention, a method of increasing overall survival in a breast cancer patient comprises administering a composition of Formula I in combination with doxorubicin.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with a pegylated liposomal doxorubicin.

In another embodiment of this aspect of the invention, a method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with epirubicin.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of Formula I in combination with tamoxifen.

In another embodiment of this aspect of the invention, a method of increasing overall survival in a breast cancer patient comprises administering a composition of Formula I in combination with a full-vast rant.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administration of a composition of formula I in combination with anastrozole.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administration of a composition of formula I in combination with letrozole.

In another embodiment of this aspect of the invention, a method for increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with an exemestane.

In another embodiment of this aspect of the invention, a method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with trastuzumab.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with ado-trastuzumem manganese.

In another embodiment of this aspect of the invention, a method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with pertuzumab.

In another embodiment of this aspect of the invention, the method of increasing the overall survival rate in a breast cancer patient comprises administering to the mammal a therapeutically effective amount of a compound of formula < RTI ID = 0.0 > I, < / RTI & Administration of the composition.

In another embodiment of this aspect of the invention, the method of increasing the overall survival rate in a breast cancer patient comprises administering to the tumor microenvironment TIE2-expressing macrophages administered in combination with < RTI ID = 0.0 > Everolimus < I < / RTI >

In another embodiment of this aspect of the invention, the method of increasing overall survival in a patient with breast cancer comprises administering to the mammal a therapeutically effective amount of a compound of formula < RTI ID = 0.0 > I < / RTI >

In another embodiment of this aspect of the invention, the method of increasing overall survival in a patient with breast cancer comprises administering to the tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4 / 6 inhibitor LY2835219 a sufficient dose to block TIE2 kinase RTI ID = 0.0 > I < / RTI >

In another embodiment of this aspect of the invention, the method of increasing the overall survival rate in a breast cancer patient comprises administering to the tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4 / 6 inhibitor LEE011 a sufficient dose to block TIE2 kinase RTI ID = 0.0 > I < / RTI >

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient is sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4 / 6 inhibitor PD 0332991 0.0 > (I) < / RTI >

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with bevacizumab.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with a anti-CTLA-4 agent.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with eicilimumim.

In another embodiment of this aspect of the invention, a method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with an anti-PD-1 agent.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a patient with breast cancer comprises administering a composition of formula I in combination with < RTI ID = 0.0 > Rambrolizumab. ≪ / RTI >

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with an anti-PD L-1 agent.

In another embodiment of this aspect of the invention, a method for increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with MPDL3280A.

Breast cancer In patients  Methods of increasing overall survival:

In another aspect of the invention, a method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in a sufficient amount to block TIE2 kinase in a tumor microenvironment, wherein administration of the composition of formula I The regimen is non-daily, intermittent administration, including all-day, every 3 days, twice weekly, or once-weekly.

In one embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in a sufficient amount to block TIE2 kinase in a tumor microenvironment, wherein the composition of formula I Is administered twice a week, once a week, or every other week.

In another embodiment of this aspect of the invention, a method of increasing overall survival in a breast cancer patient comprises administering a composition of Formula I in a sufficient amount to block TIE2 kinase in a tumor microenvironment, Of the composition is administered twice a week or once a week.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in a sufficient amount to block TIE2 kinase in a tumor microenvironment, The administration regimen of the composition of I is twice a week.

In another embodiment of this aspect of the invention, the method of increasing the overall survival rate in a breast cancer patient comprises administering an anti-tubulin agent, a DNA alkylating agent, a DNA synthesis inhibitor, a DNA intervening drug, an anti- estrogen agent, Comprising administering an effective amount of a composition of Formula I in a sufficient amount to block TIE2 kinase in a tumor microenvironment that is administered in combination with one or more agents selected from the group consisting of a kinase inhibitor, an anti-angiogenic agent, or an immunomodulator.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with paclitaxel.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with a paclitaxel protein-binding particle for a parenteral suspension.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with docetaxel.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administration of a composition of formula I in combination with eribulin.

In another embodiment of this aspect of the invention, a method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with an ixabepilone.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with vinorelbine.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administration of a composition of Formula I in combination with capecitabine.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with gemcitabine.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with 5-fluorouracil.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with methotrexate.

In another embodiment of this aspect of the invention, a method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with a cyclophosphamide.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administration of a composition of formula I in combination with cisplatin.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with carboplatin.

In another embodiment of this aspect of the invention, a method of increasing overall survival in a breast cancer patient comprises administering a composition of Formula I in combination with doxorubicin.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with a pegylated liposomal doxorubicin.

In another embodiment of this aspect of the invention, a method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with epirubicin.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of Formula I in combination with tamoxifen.

In another embodiment of this aspect of the invention, a method of increasing overall survival in a breast cancer patient comprises administering a composition of Formula I in combination with a full-vast rant.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administration of a composition of formula I in combination with anastrozole.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administration of a composition of formula I in combination with letrozole.

In another embodiment of this aspect of the invention, a method for increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with an exemestane.

In another embodiment of this aspect of the invention, a method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with trastuzumab.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with ado-trastuzumem manganese.

In another embodiment of this aspect of the invention, a method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with pertuzumab.

In another embodiment of this aspect of the invention, a method of increasing overall survival in a breast cancer patient is provided by administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula < RTI ID = 0.0 > I, < / RTI & ≪ / RTI >

In another embodiment of this aspect of the invention, the method of increasing overall survival in a patient with breast cancer comprises administering to the tumor microenvironment TIE2-expressing macrophages administered in combination with < RTI ID = 0.0 > Everolimus < The administration of a composition of formula (I).

In another embodiment of this aspect of the invention, the method of increasing the overall survival rate in a patient with breast cancer comprises administering to the tumor microenvironment TIE2-expressing macrophages administered in combination with Temicrylolimus at a dose sufficient to block TIE2 kinase The administration of a composition of formula (I).

In another embodiment of this aspect of the invention, the method of increasing overall survival in a patient with breast cancer comprises administering to the tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4 / 6 inhibitor LY2835219 a sufficient dose to block TIE2 kinase Lt; RTI ID = 0.0 > I < / RTI >

In another embodiment of this aspect of the invention, the method of increasing the overall survival rate in a breast cancer patient comprises administering to the tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4 / 6 inhibitor LEE011 a sufficient dose to block TIE2 kinase Lt; RTI ID = 0.0 > I < / RTI >

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient is sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with CDK4 / 6 inhibitor PD 0332991 Dose < / RTI > of the composition of formula (I).

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with bevacizumab.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with a anti-CTLA-4 agent.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with eicilimumim.

In another embodiment of this aspect of the invention, a method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with an anti-PD-1 agent.

In another embodiment of this aspect of the invention, the method of increasing overall survival in a patient with breast cancer comprises administering a composition of formula I in combination with < RTI ID = 0.0 > Rambrolizumab. ≪ / RTI >

In another embodiment of this aspect of the invention, the method of increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with an anti-PD L-1 agent.

In another embodiment of this aspect of the invention, a method for increasing overall survival in a breast cancer patient comprises administering a composition of formula I in combination with MPDL3280A.

Prior to surgical resection of the tumor Neoadjuvant therapy  Treatment of Breast Cancer Patients in Settings:

Another aspect of the present invention relates to a method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of a tumor, comprising administering to a patient in need thereof an effective amount of a composition of formula (I) The dosing regimen of the composition is sufficient to block TIE2 kinase in the tumor microenvironment.

In another embodiment of this aspect of the invention, a method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering an effective amount of a compound of formula < RTI ID = 0.0 > And administering the composition to a patient in need thereof.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of Formula I in a dosage amount sufficient to block TIE2 kinase in a tumor microenvironment And the regimen of administration of the composition of Formula I is administered daily.

In another embodiment of this aspect of the invention, a method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering an effective amount of a compound of formula < RTI ID = 0.0 > The dosage regimen of the composition of Formula I, which comprises administering the composition to a patient in need thereof, wherein the composition of Formula I is administered in an intermittent manner rather than daily, may be administered every other day, every 3 days, twice a week, .

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of a tumor comprises administering an effective amount of a compound of formula < RTI ID = 0.0 > I < / RTI > to a patient in need thereof.

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection comprises administering an effective amount of a compound of formula < RTI ID = 0.0 > To a patient in need thereof.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical ablation comprises administering the composition of formula I in a dosage regimen administered twice weekly or weekly, do.

In another embodiment of this aspect of the invention, the regimen of administration of the composition of formula I is administered twice a week.

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection comprises administering an anti-tubulin agent, a DNA alkylating agent, a DNA synthesis inhibitor, a DNA- Administration of a composition of Formula I in a dosage regimen sufficient to block TIE2 kinase in a tumor microenvironment in combination with one or more agents selected from a prodrug, an anti-HER2 agent, a kinase inhibitor, an anti-angiogenesis agent, .

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering the composition of formula I in combination with paclitaxel.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of formula I in combination with a paclitaxel protein-binding particle for injectable suspension .

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of Formula I in combination with docetaxel.

In another embodiment of this aspect of the invention, a method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of a tumor comprises administering a composition of Formula I in combination with eribulin.

In another embodiment of this aspect of the invention, a method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of Formula I in combination with an ixabepilone.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of Formula I in combination with vinorelbine.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of a tumor comprises administration of a composition of Formula I in combination with capecitabine.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of Formula I in combination with gemcitabine.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of formula I in combination with 5-fluorouracil.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of Formula I in combination with methotrexate.

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection of the tumor comprises administration of a composition of formula I in combination with a cyclophosphamide.

In another embodiment of this aspect of the invention, a method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of Formula I in combination with cisplatin.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administration of a composition of Formula I in combination with carboplatin.

In another embodiment of this aspect of the invention, a method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of Formula I in combination with doxorubicin.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administration of a composition of Formula I in combination with a pegylated liposomal doxorubicin.

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection of the tumor comprises administration of a composition of formula I in combination with epirubicin.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administration of a composition of Formula I in combination with tamoxifen.

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection of the tumor comprises administration of a composition of formula I in combination with a fulvestrant.

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection of the tumor comprises administration of a composition of formula I in combination with anastrozole.

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection of the tumor comprises administration of a composition of formula I in combination with letrozole.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of formula I in combination with an exemestane.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administration of a composition of Formula I in combination with trastuzumab.

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection of the tumor comprises administration of a composition of formula I in combination with ado-trastuzumab manganese .

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of Formula I in combination with pertuzumab.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering TTA2 kinase in a tumor microenvironment TIE2-expressing macrophage administered in combination with lapatinib Comprising administering the composition of formula I in a sufficient amount as follows.

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection of the tumor comprises administering to the tumor microenvironment TIE2-expressing macrophages in combination with Everolimus a TIE2 kinase Lt; RTI ID = 0.0 > I < / RTI >

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection of the tumor comprises administering to the tumor microenvironment TIE2-expressing macrophages in combination with Temsirolimus TIE2 kinase Lt; RTI ID = 0.0 > I < / RTI >

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection of the tumor comprises administering to the tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4 / 6 inhibitor LY2835219 Lt; RTI ID = 0.0 > (I) < / RTI > with sufficient capacity to block TIE2 kinase.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering to the tumor microenvironment TIE2-expressing macrophages in combination with the CDK4 / 6 inhibitor LEE011 Lt; RTI ID = 0.0 > (I) < / RTI > with sufficient capacity to block TIE2 kinase.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering to the tumor microenvironment TIE2-expressing macrophages < RTI ID = 0.0 >Lt; RTI ID = 0.0 > of TIE2 < / RTI > kinase.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of Formula I in combination with bevacizumab.

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of formula I in combination with a anti-CTLA-4 agent do.

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of formula I in combination with eicilimumim.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of formula I in combination with an anti-PD-1 agent .

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of formula I in combination with rhamblorilimum.

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection of the tumor comprises administering the composition of formula I in combination with an anti-PD L-1 agent do.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of a tumor comprises administering a composition of Formula I in combination with MPDL3280A.

Preoperative Neoadjuvant therapy  Treatment of Breast Cancer Patients in Settings:

In another aspect of the invention, a method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection comprises administering a composition of Formula I in a volume sufficient to block TIE2 kinase in a tumor microenvironment, Dosage regimens of the compositions of formula I administered in an intermittent manner, rather than daily, include all-day, every 3 days, twice weekly, or once-weekly dosing.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection comprises administration of a composition of Formula I administered twice, weekly, or biweekly Of a composition of Formula I in a sufficient amount to block TIE2 kinase in a tumor microenvironment.

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection comprises administering to the mammal a therapeutically effective amount of the tumor micro- Lt; RTI ID = 0.0 > I < / RTI >

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection comprises administering to a patient in need of such treatment a therapeutically effective amount of a TIE2 kinase Lt; RTI ID = 0.0 > I < / RTI >

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection comprises administering an anti-tubulin agent, a DNA alkylating agent, a DNA synthesis inhibitor, a DNA- An effective amount of a composition of Formula I in a sufficient amount to block TIE2 kinase in a tumor microenvironment, in combination with one or more agents selected from an anti-HER2 agent, a kinase inhibitor, an anti-angiogenesis agent, ≪ / RTI >

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering the composition of formula I in combination with paclitaxel.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of formula I in combination with a paclitaxel protein-binding particle for injectable suspension .

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of Formula I in combination with docetaxel.

In another embodiment of this aspect of the invention, a method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of a tumor comprises administering a composition of Formula I in combination with eribulin.

In another embodiment of this aspect of the invention, a method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of Formula I in combination with an ixabepilone.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of Formula I in combination with vinorelbine.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of a tumor comprises administration of a composition of Formula I in combination with capecitabine.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of Formula I in combination with gemcitabine.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of formula I in combination with 5-fluorouracil.

In another embodiment of this aspect of the invention, a method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of Formula I in combination with 5-methotrexate.

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection of the tumor comprises administration of a composition of formula I in combination with a cyclophosphamide.

In another embodiment of this aspect of the invention, a method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of Formula I in combination with cisplatin.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administration of a composition of Formula I in combination with carboplatin.

In another embodiment of this aspect of the invention, a method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of Formula I in combination with doxorubicin.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administration of a composition of Formula I in combination with a pegylated liposomal doxorubicin.

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of formula I in combination with epirubicin.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administration of a composition of Formula I in combination with tamoxifen.

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection of the tumor comprises administration of a composition of formula I in combination with a fulvestrant.

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection of the tumor comprises administration of a composition of formula I in combination with anastrozole.

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection of the tumor comprises administration of a composition of formula I in combination with letrozole.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of formula I in combination with an exemestane.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administration of a composition of Formula I in combination with trastuzumab.

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection of the tumor comprises administration of a composition of formula I in combination with ado-trastuzumab manganese .

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of Formula I in combination with pertuzumab.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering TTA2 kinase in a tumor microenvironment TIE2-expressing macrophage administered in combination with lapatinib Comprising administering the composition of formula I in a sufficient amount as follows.

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection of the tumor comprises administering to the tumor microenvironment TIE2-expressing macrophages in combination with Everolimus a TIE2 kinase Lt; RTI ID = 0.0 > I < / RTI >

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection of the tumor comprises administering to the tumor microenvironment TIE2-expressing macrophages in combination with Temsirolimus TIE2 kinase Lt; RTI ID = 0.0 > I < / RTI >

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection of the tumor comprises administering to the tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4 / 6 inhibitor LY2835219 Lt; RTI ID = 0.0 > (I) < / RTI > with sufficient capacity to block TIE2 kinase.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering to the tumor microenvironment TIE2-expressing macrophages in combination with the CDK4 / 6 inhibitor LEE011 Lt; RTI ID = 0.0 > (I) < / RTI > with sufficient capacity to block TIE2 kinase.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering to the tumor microenvironment TIE2-expressing macrophages < RTI ID = 0.0 >Lt; RTI ID = 0.0 > of TIE2 < / RTI > kinase.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of Formula I in combination with bevacizumab.

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of formula I in combination with a anti-CTLA-4 agent do.

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of formula I in combination with eicilimumim.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of formula I in combination with an anti-PD-1 agent .

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection of the tumor comprises administering a composition of formula I in combination with rhamblorilimum.

In another embodiment of this aspect of the invention, the method of treating a patient with breast cancer in a neoadjuvant setting prior to surgical resection of the tumor comprises administering the composition of formula I in combination with an anti-PD L-1 agent do.

In another embodiment of this aspect of the invention, the method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of a tumor comprises administering a composition of Formula I in combination with MPDL3280A.

Another aspect of the invention relates to a method of treating ovarian cancer, since TIE2 pathway signaling has been shown to contribute to ovarian cancer progression (Karlan et al., J. Clinical Oncology (2012) 30: 362-370). The method comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosage regimen sufficient to block TIE2 kinase in a tumor microenvironment. In one embodiment of this aspect of the invention, the composition of formula I is administered as a single formulation.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with paclitaxel + carboplatin, poisoned cell + carboplatin, paclitaxel + cisplatin, or other taxane + platinum drug therapy.

Another aspect of the invention relates to a method of treating hepatocellular carcinoma, as TIE2 pathway signaling has been shown to contribute to the progression of hepatocellular carcinoma and as a diagnostic marker (Matsubara et al., Hepatology (2013) 57: 1416-1425 ; Mitsuhashi et al., Hepatology (2003) 37: 1105-1113; Tanaka et al., J. Clin Invest (1999) 103: 341-345). The method comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosage regimen sufficient to block TIE2 kinase in a tumor microenvironment.

In one embodiment of this aspect of the invention, the composition of formula I is administered as a single formulation.

In another embodiment of this aspect of the invention, the composition of formula I comprises sorapenib, clozotanib, carbozanthinib, suinitinib, parsofanib, sorapenib, legorapenib, or acitiniumib Lt; RTI ID = 0.0 > inhibitor < / RTI >

Another aspect of the present invention relates to a method of treating glioma glioma because TIE2 pathway signaling has been shown to contribute to glioma cancer progression (Liu et al., Oncotarget (2010) 1: 700-709; Brunckhorst et al. , Cancer Research (2010) 70: 7283-7293). The method comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosage regimen sufficient to block TIE2 kinase in a tumor microenvironment.

In one embodiment of this aspect of the invention, the composition of formula I is administered as a single formulation.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with radiation therapy.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with temozolomide therapy.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with radiation therapy and temozolomide therapy.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with bevacizumab.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with radiotherapy and bevacizumab.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with temozolomide therapy and bevacizumab.

Another aspect of the invention relates to a method of treating melanoma, as TIE2 pathway signaling has been shown to contribute to melanoma progression (Helfrich et al ., Clin Cancer Res (2009) 15: 1384-1392; Peinado Nature Medicine (2012) 18: 883-891). The method comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosage regimen sufficient to block TIE2 kinase in a tumor microenvironment.

In one embodiment of this aspect of the invention, the composition of formula I is administered as a single formulation.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with bemurafenid.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with dabbelipib.

In another embodiment of this aspect of the invention, the composition of formula (I) is administered in combination with dabrenepib and trametinib.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with temozolomide.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with Dakar Vazine.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with eicilimumab.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with labrolizumab or nobilisuip.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with MPDL3280A.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with imatinib.

Another embodiment of the present invention relates to a method of treating colon cancer, as TIE2 pathway signaling has been shown to contribute to colorectal cancer progression (Ahmad et al., Cancer (2001) 92: 1138-1143; Hashizume et al. Cancer Research (2010) 70: 2213-2223). The method comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosage regimen sufficient to block TIE2 kinase in a tumor microenvironment.

In one embodiment of this aspect of the invention, the composition of formula I is administered as a single formulation.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with mFOLFOX6 therapy (oxaplatin + leucovorin + 5-fluorouracil).

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with mFOLFOX6 therapy and bevacizumab.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with mFOLFOX6 therapy and panitumumum.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with mFOLFOX6 therapy and cetuximab.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with capecitabine.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with capecitabine and bevacizumab.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with FOLFIRI regimen (irinotecan + leucovorin + 5-fluorouracil).

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with FOLFIRI regimen and bevacizumab.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with FOLFIRI regimen and affluxcept.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with FOLFIRI therapy and cetuximab.

In another embodiment of this aspect of the present invention, the composition of formula I is administered in combination with FOLFIRI regimen and panituumatum.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with panituum atab.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with panitumum and irinotecan.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with cetuximab.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with cetuximab and irinotecan.

Another aspect of the invention relates to a method of treating acute myelogenous leukemia, as TIE2 pathway signaling has been shown to contribute to the progression of acute myelogenous leukemia (Muller et al., Leukemia Research (2002) 26: 163-168; Hou et al., Leukemia Research (2008) 32: 904-912). The method comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosage regimen sufficient to block TIE2 kinase in a tumor microenvironment.

In one embodiment of this aspect of the invention, the composition of formula I is administered as a single formulation.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with daunorubicin and cytarabine.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with idarubicin and cytarabine.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with mitoxantrone and cytarabine.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with cytarabine.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with 5-azacytabine.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with decitabine.

In another embodiment of this aspect of the invention, the composition of formula I is administered in combination with quizarthinib.

Another aspect of the invention relates to a method of treating cancer. The method comprises administering an effective amount of a composition of formula I to a patient in need thereof. In one embodiment, the patient is overexpressed with endothelial endothelial cell kinase-2 (TIE2) and the cancer is selected from the group consisting of breast cancer, colorectal cancer, hepatocellular carcinoma, head and neck cancer, bladder cancer, ovarian cancer, glioma, Leukemia.

In certain embodiments of the invention of therapeutic regimens, the composition of formula I is administered at a daily frequency.

In another embodiment of the invention of therapeutic regimens, the composition of formula I is administered at an intermittent frequency, rather than daily.

In another embodiment of the invention of therapy, the composition of formula I is administered at a frequency of three times per week.

In another embodiment of the invention of therapeutic regimen, the composition of formula I is administered at a frequency of twice a week.

In another embodiment of the invention of therapy, the composition of formula I is administered once a week once a week.

In another embodiment of the invention of therapy, the composition of formula I is administered once every two weeks once a week.

In another embodiment, the cancer is metastatic, triple negative breast cancer (estrogen receptor negative, progesterone receptor negative, HER2 negative).

In another embodiment, the cancer is estrogen-positive (ER ⁺⁾ and negative HER2 receptor kinase (HER2 ^-) is a breast cancer.

In another embodiment, the cancer is an inflammatory breast cancer.

In another embodiment, the method comprises treatment to prevent or reduce one or more of primary tumor growth, tumor invasion, cancer intravascular invasion, cancer propagation, metastasis, and tumor immunity tolerance.

Formulation, administration, administration, and therapy

The present invention includes the described salts of compounds of formula I and / or II (and / or additional agents) in various formulations. (And / or additional agents) described herein may be formulated as solutions, suspensions, emulsions, droplets, tablets, pellets, pellets, capsules, liquid containing capsules, powders, sustained release formulations, suppositories, emulsions, aerosols, , Or any other form suitable for use. In one embodiment, the composition is in the form of a capsule (see, for example, U.S. Patent No. 5,698,155). Other examples of suitable pharmaceutical excipients are described in Remington ' s Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19th ed. 1995), which is incorporated herein by reference.

If desired, the salts described herein may also comprise solubilizing agents. In addition, the agent may be delivered to a suitable vehicle or delivery device as is known in the art. Combination therapies outlined herein may be co-delivered with a single delivery vehicle or delivery device. The composition for administration may optionally include a local anesthetic such as, for example, lignocaine to reduce pain at the injection site.

In one embodiment, the salts of Formulas I and / or II described herein (and / or additional agents) are formulated according to the general procedure as a composition applied to the mode of administration.

In certain embodiments, the route of administration includes, for example, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, vaginal, transdermal, rectal Inhalation, or topical application, especially to the ear, nose, eyes, or skin. In some embodiments, the administration is effected by oral or parenteral injection. The mode of administration is left to the discretion of the physician and may depend in part on the disease site. In most instances, administration leads to the release of any of the agents described herein in the blood stream.

In certain embodiments, it may be desirable to administer topically to the site in need of treatment or interception.

In one embodiment, the salts (and / or additional agents) described herein are formulated in accordance with routine procedures as a composition to be applied for oral administration to humans. Compositions for oral delivery may be in the form of, for example, tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs. Orally administered compositions may contain one or more agents, for example, sweeteners such as fructose, aspartame or saccharin to provide pharmaceutically suitable agents; Flavors such as peppermint, oil of wintergreen, or cherry; coloring agent; And preservatives. Also, in the case of tablets or pills, the composition may be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained action over a prolonged period of time. Selective permeable membranes that induce osmotic activity around the salts (and / or additional agents) of formula I or II described herein are suitable for compositions for oral administration. In these latter platforms, fluid from the environment surrounding the capsule is imbibed by the inductive composition, which swells to discharge the formulation or formulation composition through the orifice. This delivery platform can essentially provide a zero order delivery profile that is opposite to the spiked profile of the immediate release formulation. Time-delaying substances such as glycerol monostearate or glycerol stearate may also be useful. Oral compositions may include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment, the excipient is a drug grade. Suspensions other than the active composition may also contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, And mixtures thereof.

Suitable dosage forms for parenteral (e.g. intravenous, intramuscular, intraperitoneal, subcutaneous and intraarticular injection and infusion) include, for example, solutions, suspensions, dispersions, emulsions and the like. It may also be prepared in the form of a sterile solid composition (e. G., A lyophilized composition), which may be dissolved or suspended in the sterile injectable medium immediately prior to use. It may contain, for example, suspending or dispersing agents known in the art.

The dosage and dosage regimen of salts (and / or additional agents) of formula I and / or II described herein may depend on a variety of parameters including, without limitation, the disease being treated, the general health of the subject and the discretion of the primary care physician have. Any of the formulations described herein may be administered to a subject in need thereof prior to administration of the additional therapeutic agent (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 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) 5 minutes, 15 minutes, 30 minutes, 45 minutes, 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 after 12 weeks). In various embodiments, the formulations described herein can be administered at intervals of 1 minute, 10 minutes, 30 minutes, less than 1 hour, 1 hour, 1 hour to 2 hours, 2 hours to 3 hours, 3 hours to 4 hours Interval of 4 hours to 5 hours, interval of 5 hours to 6 hours, interval of 6 hours to 7 hours, interval of 7 hours to 8 hours, interval of 8 hours to 9 hours, interval of 9 hours to 10 hours, interval of 10 hours to 11 hours , Or 11 hours to 12 hours apart.

The dosage of the salt (and / or additional agent) of formula I or II described herein may depend on a number of factors, including the severity of the disease to be treated or prevented, and the age, weight, and health of the subject being treated . In addition, pharmacogenomic information (effect of the genotype on the pharmacodynamic, pharmacokinetic or efficacy profile of the therapeutic agent) for a particular subject can affect the dose used. Also, the exact individual dosage will depend upon a variety of factors including the particular combination of agent being administered, the time of administration, the route of administration, the nature of the formulation, the rate of excretion, the particular disease being treated, the severity of the disorder, Can be adjusted. Some changes in dosage can be expected.

Generally, when administered orally to a mammal, the dosage of any of the compositions of Formula I (and / or additional agents) described herein is from 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. When administered orally to humans, the dosage of any of the formulations described herein is generally from 0.001 mg to 1500 mg per day, from 1 mg to 600 mg per day, or from 5 mg to 30 mg per day. In some embodiments, the dose of salt (or agent) ranges from 57 mg to 1200 mg per day. In other embodiments, the dosage of the agent or salt ranges from 100 mg to 200 mg per day.

For administration of the salts (and / or additional agents) of Formula I or II described herein by parenteral injection, the dosage will generally be from 0.1 mg to 250 mg per day, from 1 mg to 20 mg per day, 3 mg to 5 mg. Injection can be given up to four times a day. In general, when administered orally or parenterally, the dosage of any of the formulations described herein is generally from 0.1 mg to 1500 mg per day, or from 0.5 mg to 10 mg per day, or from 0.5 mg to 5 mg per day. A dose of up to 3000 mg per day may be administered.

Administration of the salts (and / or additional agents) described herein may be independently from 1 to 4 times daily. In particular, the administration of the salt may be once a day and is about 50 mg to 1500 mg in the salt administration regimen. A suitable daily dosage for purposes of preventive efficacy is 57-1200 mg / day. When administered twice a day, a suitable dose is 100 mg to 200 mg of salt. Administration of the salt may also be intermittent, not daily. In particular, administration of the salt may be carried out once to four times per month or once to six times per year, or once every two, three, four or five years. In certain embodiments, administration of the salt may be weekly or biweekly. When administered weekly or biweekly, suitable salt dosing regimens range from 50-200 mg per dose. In certain cases, administered weekly or biweekly, the dosage ranges from 200-400 mg per dose. However, other, weekly or biweekly doses range from 400-500 mg per dose, 500-600 mg per dose, 600-700 mg per dose, 700-800 mg per dose, 800-900 mg per dose, 900-1000 mg per dose , 1000-1100 mg per administration, or 1100-1200 mg per administration. The administration can be for a period of 1 day or 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years, or even for a lifetime of the subject. Chronic, long-term administration will occur in many cases. Dosages may be divided into single doses or multi-dose doses. In general, the desired dosage can be administered over a prolonged period of time, usually over a period of at least weeks or months, while requiring a longer administration period of several months or years or more.

Example

Example  1. 1- (3- tert Butyl-1- (quinolin-6-yl) -lH- Pyrazole -5-yl) -3- (2- Fluoro -4- (2- (methylcarbamoyl) pyridin-4-yloxy) phenyl) urea Non-phosphorylated TIE2  ( uTIE2 ) Biochemical inhibition

uTIE2  (SEQ ID NO: 1) Biochemical assay

The activity of uTIE2 kinase was determined after the generation of ADP from the kinase reaction via conjugation with a pyruvate kinase / lactate dehydrogenase system (see, for example, Schindler et al . Science (2000) 289: 1938-1942). In this assay, the oxidation of NADH (and hence the reduction at A _{340 nm} ) was continuously monitored by spectrophotometry. The reaction mixture (100 μL) contained TIE2 (SignalChem) (5.6 nM), BSA (0.004% (w / v)), polyEY (1.5%) in 90 mM Tris buffer at pH 7.5 containing 0.2% octyl-glucoside and 1% MgCl ₂ (15 mM), DTT (0.5 mM), pyruvate kinase (4 units), lactate dehydrogenase (7 units), phosphoenolpyruvate (1 mM), and NADH mM) and ATP (1.5 mM). The inhibitory reaction was initiated by mixing the serially diluted test composition with the reaction mixture. Absorption at 340 nm was monitored continuously on a plate reader (BioTek) at 30 C for 6 hours. The reaction rate was calculated using a 5- to 6-hour time frame. Percent inhibition was obtained by comparing the rate of reaction with that of the control (i. E. No test composition). The IC ₅₀ value from a series of percent inhibition values determined from the inhibitor concentration range using software routines as is performed in GraphPad Prism software package was calculated. Preparation of 1- (3-tert-butyl-1- (quinolin-6-yl) -1H-pyrazol- 4-yloxy) phenyl) urea para-toluenesulfonate (Compound 1 as described in FIG. 1) exhibited an IC ₅₀ value of 3.5 nM.

Used for screening uTIE2  Protein sequence (SEQ ID NO: 1)

Example  2. 1- (3- tert Butyl-1- (quinolin-6-yl) -lH- Pyrazole -5-yl) -3- (2- Fluoro -4 - (2- (methylcarbamoyl) pyridin-4-yloxy) phenyl) urea TIE2  ( pTIE2 ) Biochemical inhibition

pTIE2  (SEQ ID NO: 2) Biochemical assay

The activity of pTIE2 kinase was determined after the generation of ADP from the kinase reaction via conjugation with a pyruvate kinase / lactate dehydrogenase system (see, for example, Schindler et al . Science (2000) 289: 1938-1942). In the present assay, oxidation of NADH (and thus reduction at A _{340 nm} ) was continuously monitored by spectrophotometry. The reaction mixture (100 [mu] L) was dialyzed against TIE2 (Life Technologies) (6 nM), BSA (0.004% (w / v)), polyEY 1.5 mM MgCl ₂ , 15 mM DTT 0.5 mM pyruvate kinase 4 units lactate dehydrogenase 7 units phosphoenolpyruvate 1 mM NADH 0.28 mM) and ATP (1.5 mM). The inhibitory reaction was initiated by mixing the serially diluted test composition with the reaction mixture. Absorption at 340 nm was monitored continuously on a plate reader (BioTek) at 30 C for 6 hours. The reaction rate was calculated using a 2 to 3 h time frame. Percent inhibition was obtained by comparing the rate of reaction with that of the control (i. E. No test composition). The IC ₅₀ value from a series of percent inhibition values determined from the inhibitor concentration range using software routines as is performed in GraphPad Prism software package was calculated. (3-tert-butyl-1- (quinolin-6-yl) -1H-pyrazol-5-yl) -3- Phenyl) urea p-toluenesulfonate and 1- (3-tert-butyl-1- (quinolin-6-yl) 2-fluoro-4- (2- (methylcarbamoyl) pyridin-4-yloxy) phenyl) urea bis-hydrochloride exhibited more than 50% inhibition of pTIE2 at concentrations below 0.1 μM. 3- (2-fluoro-4- (2- (methylcarbamoyl) pyridin-4-ylmethyl) -1H-pyrazol- - yloxy) phenyl) urea para-toluenesulfonate exhibited an IC ₅₀ value of 4.2 nM. 3- (2-fluoro-4- (2- (methylcarbamoyl) pyridin-4-ylmethyl) -1H-pyrazol- - yloxy) phenyl) urea bis-hydrochloride salt exhibited an IC ₅₀ value of 2.2 nM.

Used for screening pTIE2  Protein sequence (SEQ ID NO: 2)

Example  3. 1- (3- tert Butyl-1- (quinolin-6-yl) -lH- Pyrazole -5-yl) -3- (2- Fluoro -4- (2- (methylcarbamoyl) pyridin-4-yloxy) phenyl) urea CHO  In the cell Of TIE2  Cell inhibition

CHO - K1  Cell culture

CHO-K1 cells (catalog # CCL-61) were obtained from the American Type Culture Collection (ATCC, Manassas, Va.). Briefly, 37 degrees C, 5% CO _2, and 95% to 10% characterized in humidity fetal calf serum (Invitrogen, Carlsbad, CA), 100 unit / mL penicillin G, 100 μg / ml streptomycin, and 0.29 mg / mL Cells were grown in F12K medium supplemented with L-glutamine (Invitrogen, Carlsbad, Calif.). Cells were expanded until they reached 70-95% density when subcultured or harvested for assay use.

TIE2 - Transfected CHO K1 Force - TIE2 Western Blat  black

CHO K1 cells (1 x 10 ⁵ cells / well) were seeded in 24-well tissue-culture treated plates (10 μL) in 1 mL of RPMI 1640 medium supplemented with 10% characteristic abstinent serum and 1 × non-essential amino acid (Invitrogen, Carlsbad, Calif. Lt; / RTI > The cells were then incubated overnight at 37 ° C, 5% CO ₂ , and 95% humidity. The medium was inhaled and 0.5 mL of medium was added to each well. Transformation-grade plasmid DNA (TIE2 gene Gateway, Invitrogen, Carlsbad, Calif.) Replicated in pcDNA3.2 ™ / V5-DEST expression vector was diluted in Opti-MEM® I medium without serum (Invitrogen, Carlsbad, CA) 5 < / RTI > g / mL. 2 μL of lipofectamine LTX reagent (Invitrogen, Carlsbad, Calif.) Was added to 0.5 μg of plasmid DNA. The tubes were mixed vigorously and incubated at room temperature for 25 minutes to allow formation of the DNA-lipofectamine LTX complex. 100 [mu] L of DNA-lipofectamine LTX complex was added directly to each well containing cells and mixed vigorously. At 24 hours after transfection, the DNA-lipofectamine complex containing medium was inhaled, the cells were washed with PBS and resuspended in 10% specificiferal serum (Invitrogen, Carlsbad, Calif.) And 1X non-essential amino acids (Invitrogen, Carlsbad , CA) supplemented with RPMI1640 medium. (2-fluoro-4- (2- (methylcarbamoyl) -1H-pyrazol-5-yl) Pyridin-4-yloxy) phenyl) urea para-toluenesulfonate) or DMSO was added to the wells (0.5% final DMSO concentration). After the plates at 37 degrees C, 5% CO _2, and 95% humidity and incubated for 4 hours. After incubation, the medium was inhaled and the cells were washed with PBS. (Pierce, Rockford, Ill.) Containing Halt phosphatase and protease inhibitor (Pierce, Rockford, IL) and phosphatase inhibitor cocktail 2 (Sigma, St. Louis, Mo.) And the cells were lysed. The clear lysates were separated by SDS-PAGE on 4-12% Novex NuPage Bis-Tris gel (Invitrogen, Carlsbad, Calif.) And then transferred to PVDF (Invitrogen, Carlsbad, Calif.). After transfer, the PVDF membrane was blocked with BSA (Santa Cruz Biotechnology, Santa Cruz, Calif.) And then probed with the antibody against Cell Signaling Technology, Beverly, Mass. A secondary anti-rabbit antibody conjugated with horseradish peroxidase (Cell Signaling Technology, Beverly, Mass.) Was used to detect phospho-TEE2. ECL Plus (GE Healthcare, Piscataway, NJ), a substrate for holdish peroxidase generating a fluorescent product was added. Fluorescence was detected in the fluorescence mode using a Storm 840 fluorescence observer (GE Healthcare, Piscataway, NJ). The 160 kDa phospho-TTI2 band was quantified using ImageQuant software (GE Healthcare, Piscataway, NJ). Data were analyzed using Prism software (GraphPad Software, San Diego, Calif.) To calculate IC ₅₀ values. Preparation of 1- (3-tert-butyl-1- (quinolin-6-yl) -1H-pyrazol- 4-yloxy) phenyl) urea p-toluenesulfonate showed an IC ₅₀ value of 2.0 nM.

Example  4. 1- (3- tert Butyl-1- (quinolin-6-yl) -lH- Pyrazole -5-yl) -3- (2- Fluoro (2- (methylcarbamoyl) pyridin-4-yloxy) phenyl) urea CHO  Cell inhibition of TIE2 in cells

CHO - K1  Cell culture

CHO-K1 cells (catalog # CCL-61) were obtained from the American Type Culture Collection (ATCC, Manassas, Va.). Briefly, 37 degrees C, 5% CO _2, and 95% to 10% characterized in humidity fetal calf serum (Invitrogen, Carlsbad, CA), 100 unit / mL penicillin G, 100 μg / ml streptomycin, and 0.29 mg / mL Cells were grown in F12K medium supplemented with L-glutamine (Invitrogen, Carlsbad, Calif.). Cells were expanded until they reached 70-95% density when subcultured or harvested for assay use.

TIE2 - Transfected CHO K1 Force - TIE2 Western Blat  Composition cleaning

CHO K1 cells (1 x 10 ⁵ cells / well) were seeded in 24-well tissue-culture treated plates (10 μL) in 1 mL of RPMI 1640 medium supplemented with 10% characteristic abstinent serum and 1 × non-essential amino acid (Invitrogen, Carlsbad, Calif. Lt; / RTI > The cells were then incubated overnight at 37 ° C, 5% CO ₂ , and 95% humidity. The medium was inhaled and 0.5 mL of medium was added to each well. Transformation-grade plasmid DNA (TIE2 gene Gateway, Invitrogen, Carlsbad, Calif.) Replicated in pcDNA3.2 ™ / V5-DEST expression vector was diluted in Opti-MEM® I medium without serum (Invitrogen, Carlsbad, CA) 5 < / RTI > g / mL. 2 μL of lipofectamine LTX reagent (Invitrogen, Carlsbad, Calif.) Was added to 0.5 μg of plasmid DNA. The tubes were mixed vigorously and incubated at room temperature for 25 minutes to allow formation of the DNA-lipofectamine LTX complex. 100 [mu] L of DNA-lipofectamine LTX complex was added directly to each well containing cells and mixed vigorously. At approximately 18-24 hours after transfection, the DNA-lipofectamine complex containing medium is inhaled, the cells are washed with PBS and resuspended in 10% specificiferal serum (Invitrogen, Carlsbad, Calif.) And 1X non- Invitrogen, Carlsbad, CA) supplemented with RPMI 1640 medium. (2-fluoro-4- (2- (methylcarbamoyl) -1H-pyrazol-5-yl) Pyridin-4-yloxy) phenyl) urea para-toluenesulfonate) or DMSO was added to the wells (0.5% final DMSO concentration). The plate was incubated for 2 hours at 37 degrees C after, 5% CO _2, and 95% humidity. After the culture, the culture medium was aspirated, and the cells were rinsed three times with 1 mL of medium to wash the glass composition. Next, 1 mL of fresh medium was added and the cells were incubated for a certain time ( i.e. , 0, 1, 2, 4, 6, and 24 hours) before cell lysis. (Pierce, Rockford, Ill.) Containing Halt phosphatase and protease inhibitor (Pierce, Rockford, IL) and phosphatase inhibitor cocktail 2 (Sigma, St. Louis, Mo.) And the cells were lysed. The clear lysates were separated by SDS-PAGE on 4-12% Novex NuPage Bis-Tris gel (Invitrogen, Carlsbad, Calif.) And then transferred to PVDF (Invitrogen, Carlsbad, CA). After transfection, the PVDF membrane was blocked with BSA (Santa Cruz Biotechnology, Santa Cruz, Calif.) And then challenged with the Cell Signaling Technology, Beverly, MA. A secondary anti-rabbit antibody conjugated with horseradish peroxidase (Cell Signaling Technology, Beverly, Mass.) Was used to detect phospho-TEE2. ECL Plus (GE Healthcare, Piscataway, NJ), a substrate for holdish peroxidase generating a fluorescent product was added. Fluorescence was detected in the fluorescence mode using a Storm 840 fluorescence observer (GE Healthcare, Piscataway, NJ). The PVDF membrane was stripped and then re-probed with the entire TIE2 antibody (Santa Cruz Biotechnology, Inc., Dallas, Tex.) As above. The 160 kDa phospho-TTI2 and total TIE2 bands were quantified using ImageQuant software (GE Healthcare, Piscataway, NJ). The phospho-TEE2 level was normalized to the total TIE2 level and the data was graphed using Prism software (GraphPad Software, San Diego, Calif.). When cultured in TIE2-transfected CHO K1 cells for 2 hours at 0.1 μM - 1 μM prior to washing, the composition 1- (3-tert-butyl-1- (quinolin- Yl) -3- (2-fluoro-4- (2- (methylcarbamoyl) pyridin-4-yloxy) phenyl) urea pa- toluenesulfonate salt was used as the phospho- Gt; 50% < / RTI > inhibition of the TIE2 level.

Example  5. 1- (3- tert Butyl-1- (quinolin-6-yl) -lH- Pyrazole -5-yl) -3- (2- Fluoro -4- (2- (methylcarbamoyl) pyridin-4-yloxy) phenyl) urea HUVEC  In the cell TIE2 Cell inhibition

HUVEC  Cell culture

HUVEC (Human Umbilical Vein Endothelial Cell; Catalog # CRL-1730) cells were obtained from the American Type Culture Collection (ATCC, Manassas, Va.). Briefly, were grown at 37 degrees C, EGM-2 cells (Lonza, Walkersville, MD) in 5% CO _2, and 95% humidity. Cells were expanded until they reached 90-95% density at the time of subculture or collection for assay use.

HUVEC Force - TIE2 Western Blat  black

Was added to the culture plate treated - HUVEC cells (2.5 x 10 ⁵ cells / well) to 24-well tissue in 1 mL EGM-2 culture medium (Lonza, Walkersville, MD). The cells were then incubated overnight at 37 ° C, 5% CO ₂ , and 95% humidity. The medium was inhaled and 1 mL EBM-2 basal medium (Lonza, Walkersville, MD) supplemented with 2% FBS (Invitrogen, Carlsbad, Calif.) Was added. Test composition or DMSO was added to each well (0.5% final DMSO concentration). After the plates at 37 degrees C, 5% CO _2, and 95% humidity and incubated for 4 hours. In culture, histidine-tagged angiopoietin 1 (ANG1) growth factor (R & D System, Minneapolis, Minn.) Was added to the anti-polyhistidine antibody (R & D system, Minneapolis, MN) To produce a multimer. After 4 hours of incubation of the composition, cells were stimulated with a mixture of 800 ng / mL ANG1 / anti-polyhistidine antibody complex for 15 minutes. The medium was aspirated and the cells were washed with PBS. (Pierce, Rockford, Ill.) Containing Halt phosphatase and protease inhibitor (Pierce, Rockford, IL) and phosphatase inhibitor cocktail 2 (Sigma, St. Louis, Mo.) And the cells were lysed. The clear lysates were separated by SDS-PAGE on 4-12% Novex NuPage Bis-Tris gel (Invitrogen, Carlsbad, Calif.) And then transferred to PVDF (Invitrogen, Carlsbad, Calif.). After transfer, the PVDF membrane was blocked with BSA (Santa Cruz Biotechnology, Santa Cruz, Calif.) And then probed with the antibody against Cell Signaling Technology, Beverly, Mass. A secondary anti-rabbit antibody conjugated with horseradish peroxidase (Cell Signaling Technology, Beverly, Mass.) Was used to detect phospho-TEE2. ECL Plus (GE Healthcare, Piscataway, NJ), a substrate for holdish peroxidase generating a fluorescent product was added. Fluorescence was detected in the fluorescence mode using a Storm 840 fluorescence observer (GE Healthcare, Piscataway, NJ). The 160 kDa phospho-TTI2 band was quantified using ImageQuant software (GE Healthcare, Piscataway, NJ). Data were analyzed using Prism software (GraphPad Software, San Diego, Calif.) To calculate IC ₅₀ values. 3- (2-fluoro-4- (2- (methylcarbamoyl) -lH-pyrazol-5-yl) ) Pyridin-4-yloxy) phenyl) urea p-toluenesulfonate showed an IC ₅₀ value of 0.018 nM.

Example  6. 1- (3- tert Butyl-1- (quinolin-6-yl) -lH- Pyrazole -5-yl) -3- (2- Fluoro -4- (2- (methylcarbamoyl) pyridin-4-yloxy) phenyl) urea Anjiopoietin  One ( ANG1 ) Or angiopoietin 2 (ANG2) inhibition of stimulating capillary tube formation

HMVEC  Cell culture

HMVEC (Human Microvascular Endothelial Cell; Catalog # PCS-110-010) cells were obtained from the American Type Culture Collection (ATCC, Manassas, Va.). Briefly, cells were grown in EGM-2 MV (Lonza, Walkersville, MD) at 37 degrees C, 5% CO ₂ , and 95% humidity. Cells were expanded until they reached 90-95% density at the time of subculture or collection for assay use.

HMVEC  Capillary tube formation test

HMVEC cells (1.5 x 10 ⁴ cells / well) mixed with a test composition or a DMSO control and appropriate growth factors (ANG1 or ANG2) or a control were added to 0.1 ml EBM-2 based medium (Lonza, Walkersville, MD) Was added to the 96-well tissue-culture treated plates coated with the reduced matrigel. The cells after 37 degrees C, in 5% CO _2, and 95% humidity and cultured for 18 hours. The medium was then inhaled mildly and the wells were lightly washed with 0.1 mL EBM-2 basal medium. The medium was again inhaled and 1 μM Calcein AM solution (Invitrogen, Carlsbad, Calif.) In the basal medium was added to each well to label the biomolecules with fluorescence. After cells were incubated at 37 degrees C, 5% CO _2, and 95% humidity for 30 minutes. The medium was aspirated and the wells washed briefly twice with phosphate-buffered saline. Images of each well were obtained by fluorescence microscopy and processed using an ImagePro analyzer (Media Cybernetics, Inc., Rockville, Md.) Using automated macros measuring total capillary tube length. Data were analyzed using Prism software (GraphPad Software, San Diego, Calif.) To calculate IC ₅₀ values. 3- (2-fluoro-4- (2- (methylcarbamoyl) -lH-pyrazol-5-yl) ) Pyridin-4-yloxy) phenyl) urea para-toluenesulfonate showed an IC ₅₀ value of 6.9 nM for inhibition of ANG1-stimulated HMVEC capillary tube formation. The compositions of formula I disclosed herein exhibited an IC ₅₀ value of 34 nM for inhibition of ANG2-stimulated HMVEC capillary tube formation.

Example  7. As a single agent and Paclitaxel  Pyrazol-5-yl) -3- (2-fluoro-4- (2- (methylcarbamoyl) pyridine -4-yloxy) phenyl) urea PyMT  In the breast cancer model In vivo  Inhibition of primary tumor growth and invasion

PyMT  Breast cancer model of winterized primary tumor growth

Using a PyMT winter breast cancer transplant mouse model, the in vivo Activity. Briefly, 1 x 10 ⁶ cells (isolated from PyMT tumor fragments) in a total volume of 0.1 mL were transplanted onto the fourth mammary gland on the left side of female mice (FVB / NJ from Jackson Lab, JAXWEST: RB05 mice). A total of 10 mice were injected into each group. Molecular Imaging, Inc.'s Animal Care and Use Committee approved all experimental protocols and conducted tests that comply with all NIH laws, rules and guidelines. Oral administration of Compound 1 or vehicle (0.4% hydroxypropylmethylcellulose in water) twice daily (depending on the individual body weight at the treatment date) to 0.2 mL / 20 g when the tumor size reaches approximately 850 mg ) And / or intravenous administration (IV) of every 5 days of paclitaxel or vehicle (10% ethanol, 10% cremophor EL and 80% saline). Animals were administered for 21 days. Body weight and tumor measurements were recorded three times per week. Tumor load (mg) was estimated from caliper measurements by the formula for the volume of elongated ellipsoid assumed unit density as follows: Tumor load (mg) = (L x W ² ) / 2 where L and W Are the vertical tumor length and width measurements (mm), respectively. In the PyMT model, both compound 1 and paclitaxel groups have been shown to inhibit tumor growth. Compound 1 in combination with paclitaxel proved additive activity (Figure 1). These data demonstrate in vivo activity by Compound 1 and show the correlation to enzyme and cellular data.

Example  8. As a single agent and Paclitaxel  Pyrazol-5-yl) -3- (2-fluoro-4- (2- (methylcarbamoyl) pyridine -4-yloxy) phenyl) urea PyMT  In the breast cancer model In vivo  Inhibition of primary tumor macrophage accumulation

PyMT  Breast cancer model of winter, primary tumor macrophage accumulation

Using a PyMT winter breast cancer transplant mouse model, the in vivo Activity. Briefly, 1 x 10 ⁶ cells (isolated from PyMT tumor fragments) in a total volume of 0.1 mL were transplanted onto the fourth mammary gland on the left side of female mice (FVB / NJ from Jackson Lab, JAXWEST: RB05 mice). A total of 10 mice were transplanted into each group. Molecular Imaging, Inc.'s Animal Care and Use Committee approved all experimental protocols and conducted tests that comply with all NIH laws, rules and guidelines. Oral administration of Compound 1 or vehicle (0.4% hydroxypropylmethylcellulose in water) twice daily (depending on the individual body weight at the treatment date) to 0.2 mL / 20 g when the tumor size reaches approximately 850 mg ) And / or intravenous administration (IV) of every 5 days of paclitaxel or vehicle (10% ethanol, 10% cremophor EL and 80% saline). Animals were administered for 21 days. Body weight and tumor measurements were recorded three times per week.

At the end of the study, the tumors were resected and placed in formalin. The formalin-fixed tumor sample was then placed in a paraffin block. Formalin fixed-paraffin embedded tissue slides were deparaffinized with xylene and hydrated to distilled water through a graded series of alcohol rinses. Antigen collection was performed using Dako's PT Link module as a Tris / EDTA buffer target recovery solution at 95 ° C for 20 minutes. When the slides were cooled, they were mounted on Dako AutostainerPlusLink for immunohistochemical staining with F4 / 80 and CD31 antibodies at room temperature and stained for macrophages and endothelial cells, respectively. The endogenous peroxidase and alkaline phosphatase activity in the tissue was quenched for 5 minutes with a double endogenous enzyme block solution (Dako, S2003). Non-specific protein binding was blocked with serum-free protein blocks (Dako, X0909) for 5 minutes. The rat anti-mouse CD31 primary antibody was then incubated on experimental tissue sections at an immunogen concentration of 1: 100 for 30 minutes. The primary antibody was then conjugated with rabbit anti-rat immunoglobulin secondary antibody (Dako, E0468). The secondary antibody was then amplified with a chlorinated anti-rabbit peroxidase labeled polymer (Dako, K4003) for 30 minutes. Enzyme staining was carried out for 5 minutes with substrate-colored DAB + (Dako, K3468). Excess rat IgG components were further blocked with rodent block rats (Biocare Medical, RBR962H) for 5 minutes. The rat anti-mouse F4 / 80 primary antibody was incubated for 30 minutes on experimental tissue sections. F4 / 80 was then conjugated with rabbit anti-rat immunoglobulin secondary antibody (Dako, E0468). The secondary antibody was then amplified with a goat anti-rabbit alkaline phosphatase-labeled polymer (Biocare RALP525) for 30 minutes. Enzymatic staining was carried out with the substrate, WARP Red (Biocare WR806). Counter staining was performed with automated hematoxylin for 10 minutes. The tissue slides were then air dried and rinsed with xylene for glass cover slips. Slides were 0 for F4 / 80 staining, no visible staining; 1, weak staining; 2, medium staining; 3 Scored using a size of strong staining. In the PyMT model, Compound 1 demonstrated a decrease in macrophage accumulation in primary tumors, whereas paclitaxel did not decrease macrophage accumulation. Compound 1 in combination with paclitaxel demonstrated similar activity to the Compound 1 single-agent treatment (Figure 2). These data demonstrate in vivo activity by Compound 1 and show the correlation to enzyme and cellular data.

Example  9. As a single preparation and Paclitaxel  Pyrazol-5-yl) -3- (2-fluoro-4- (2- (methylcarbamoyl) pyridine -4-yloxy) phenyl) urea PyMT  In the breast cancer model In vivo  Primary tumor TIE2  Inhibition of cell accumulation

PyMT  Breast cancer model of winter, primary tumor macrophage accumulation

Using a PyMT winter breast cancer transplant mouse model, the in vivo Activity. Briefly, 1 x 10 ⁶ cells (isolated from PyMT tumor fragments) in a total volume of 0.1 mL were transplanted onto the fourth mammary gland on the left side of female mice (FVB / NJ from Jackson Lab, JAXWEST: RB05 mice). A total of 10 mice were transplanted into each group. Molecular Imaging, Inc.'s Animal Care and Use Committee approved all experimental protocols and conducted tests that comply with all NIH laws, rules and guidelines. Oral administration of Compound 1 or vehicle (0.4% hydroxypropylmethylcellulose in water) twice daily (depending on the individual body weight at the treatment date) to 0.2 mL / 20 g when the tumor size reaches approximately 850 mg ) And / or intravenous administration (IV) of every 5 days of paclitaxel or vehicle (10% ethanol, 10% cremophor EL and 80% saline). Animals were administered for 21 days. Body weight and tumor measurements were recorded three times per week.

At the end of the study, the tumors were resected and placed in formalin. The formalin-fixed tumor sample was then placed in a paraffin block. Formalin fixed-paraffin embedded tissue slides were deparaffinized with xylene and hydrated to distilled water through a graded series of alcohol rinses. Antigen collection was performed using Dako's PT Link module as a citrate pH 6 buffer target recovery solution at 95 占 폚 for 20 minutes. When the slides were cooled, they were mounted on a Dako AutostainerPlusLink for immunohistochemical staining with both TIE2 and CD31 antibodies at room temperature. The endogenous peroxidase and alkaline phosphatase activity in the tissue was quenched for 5 minutes with a double endogenous enzyme block solution (Dako, S2003). Non-specific protein binding was blocked with serum-free protein blocks (Dako, X0909) for 5 minutes. The rat anti-mouse CD31 primary antibody was then incubated on experimental tissue sections at an immunogen concentration of 1: 100 for 30 minutes. The primary antibody was then conjugated with rabbit anti-rat immunoglobulin secondary antibody (Dako, E0468). The secondary antibody was then amplified with a chlorinated anti-rabbit peroxidase labeled polymer (Dako, K4003) for 30 minutes. Enzyme staining was carried out for 5 minutes with substrate-colored DAB + (Dako, K3468). Excess protein components were further blocked with protein block (Dako, X0909) for 5 minutes. Rabbit anti-TIE2 primary antibodies were incubated on experimental tissue sections for 30 minutes. The TIE2 antibody was then conjugated with an alkaline phosphatase labeled goat anti-rabbit polymer for 30 minutes. Enzymatic staining was carried out with the substrate, WARP Red (Biocare WR806). Control staining was performed with automated hematoxylin for 10 minutes. The tissue slides were then air dried and rinsed with xylene for glass cover slips. Slides were 0 for TIE2 staining, no visible staining; 1, weak staining; 2, medium staining; 3 Scored using a size of strong staining. In the PyMT model, Compound 1 demonstrated a decrease in TIE2-expressing cell accumulation in primary tumors, whereas paclitaxel did not decrease TIE2-expressing cell accumulation. Compound 1 in combination with paclitaxel demonstrated improved activity compared to Compound 1 single-agent treatment (Figure 3). These data demonstrate in vivo activity by Compound 1 and show the correlation to enzyme and cellular data.

Example  10. As a single agent and Paclitaxel  Pyrazol-5-yl) -3- (2-fluoro-4- (2- (methylcarbamoyl) pyridine -4-yloxy) phenyl) urea and PyMT Breast Cancer Model In vivo Inhibition of lung metastasis

PyMT  Breast cancer model lung metastasis in winter

Using a PyMT winter breast cancer transplant mouse model, the in vivo Activity. Briefly, 1 x 10 ⁶ cells (isolated from PyMT tumor fragments) in a total volume of 0.1 mL were transplanted onto the fourth mammary gland on the left side of female mice (FVB / NJ from Jackson Lab, JAXWEST: RB05 mice). A total of 10 mice were injected into each group. Molecular Imaging, Inc.'s Animal Care and Use Committee approved all experimental protocols and conducted tests that comply with all NIH laws, rules and guidelines. Oral administration of Compound 1 or vehicle (0.4% hydroxypropylmethylcellulose in water) twice daily (depending on the individual body weight at the treatment date) to 0.2 mL / 20 g when the tumor size reaches approximately 850 mg ) And / or intravenous administration (IV) of every 5 days of paclitaxel or vehicle (10% ethanol, 10% cremophor EL and 80% saline). Animals were administered for 21 days. Body weight and tumor measurements were recorded three times per week.

At the end of the study, lung tissue was resected and placed in formalin. Formalin-fixed lung samples were then placed in paraffin blocks. Each closed block had three slides with two levels per slice and stained with hematoxylin and eosin. Metastatic pulmonary nodules were counted by microscopic examination. In the PyMT model, both compound 1 and paclitaxel demonstrated a similar decrease in lung metastasis. Compound 1 in combination with paclitaxel demonstrated additive activity as compared to single-agent treatment (Figure 4). These data demonstrate in vivo activity by Compound 1 and show the correlation to enzyme and cellular data.

Example  11. Paclitaxel  By combining ( Every day  Yl) -3- (2-fluoro-4- (2- (methyl) -1,2,3,4-tetrahydronaphthalene- Carbamoyl) pyridin-4-yloxy) phenyl) urea PyMT  In the breast cancer model In vivo  Inhibition of lung metastasis

PyMT  Breast cancer model lung metastasis in winter

Using a PyMT winter breast cancer transplant mouse model, the in vivo Activity. Briefly, 1 x 10 ⁶ cells (isolated from PyMT tumor fragments) in a total volume of 0.1 mL were transplanted onto the fourth mammary gland on the left side of female mice (FVB / NJ from Jackson Lab, JAXWEST: RB05 mice). A total of three mice were injected into each group. Molecular Imaging, Inc.'s Animal Care and Use Committee approved all experimental protocols and conducted tests that comply with all NIH laws, rules and guidelines. Oral administration (gavage) of compound 1 or vehicle (0.4% hydroxypropylmethylcellulose in water) twice a week according to the individual body weight at the treatment date of 0.2 mL per 20 g when the tumor size reaches approximately 600 mg. And / or intravenous administration (IV) of 5 days of paclitaxel or vehicle (10% ethanol, 10% crmorphol EL and 80% saline). Animals were administered for 12 days. Body weight and tumor measurements were recorded three times per week.

At the end of the study, lung tissue was resected and placed in formalin. Formalin-fixed lung samples were then placed in paraffin blocks. Each closed block had three slides with two levels per slice and stained with hematoxylin and eosin. Metastatic pulmonary nodules were counted by microscopic examination. In the PyMT model, paclitaxel demonstrated a reduction in lung metastasis. Compound 1 in combination with paclitaxel demonstrated additive activity as compared to single-agent treatment (Figure 5). These data demonstrate in vivo activity by Compound 1 and show the correlation to enzyme and cellular data.

Example  12. Eribulin and  By combining ( Every day  Yl) -3- (2-fluoro-4- (2- (methyl) -1,2,3,4-tetrahydronaphthalene- Carbamoyl) pyridin-4-yloxy) phenyl) urea PyMT  In the breast cancer model In vivo  Inhibition of lung metastasis

PyMT  Breast cancer model lung metastasis in winter

Using a PyMT winter breast cancer transplant mouse model, the in vivo Activity. Briefly, 1 x 10 ⁶ cells (isolated from PyMT tumor fragments) in a total volume of 0.1 mL were transplanted onto the fourth mammary gland on the left side of female mice (FVB / NJ from Jackson Lab, JAXWEST: RB05 mice). A total of three mice were injected into each group. Molecular Imaging, Inc.'s Animal Care and Use Committee approved all experimental protocols and conducted tests that comply with all NIH laws, rules and guidelines. Oral administration (gavage) of compound 1 or vehicle (0.4% hydroxypropylmethylcellulose in water) twice a week according to the individual body weight at the treatment date of 0.2 mL per 20 g when the tumor size reaches approximately 600 mg. And / or intravenous administration (IV) of eribulin or vehicle (80% saline) three times per week. Animals were administered for 12 days. Body weight and tumor measurements were recorded three times per week.

At the end of the study, lung tissue was resected and placed in formalin. Formalin-fixed lung samples were then placed in paraffin blocks. Each closed block had three slides with two levels per slice and stained with hematoxylin and eosin. Metastatic pulmonary nodules were counted by microscopic examination. In the PyMT model, eribulin demonstrated a decrease in lung metastasis (or an increase in low dose). Compound 1 in combination with eribulin demonstrated additive activity as compared to single-agent treatment (Figure 6). These data demonstrate in vivo activity by Compound 1 and show the correlation to enzyme and cellular data.

Example  13. Eribulin and  By combining ( Every day  Yl) -3- (2-fluoro-4- (2- (methyl) -1,2,3,4-tetrahydronaphthalene- Carbamoyl) pyridin-4-yloxy) phenyl) urea PyMT  The increase in overall survival in the breast cancer model

PyMT  Assessment of Breast Cancer Model Survival in Winter

Using a PyMT winter breast cancer transplant mouse model, the in vivo Activity. Briefly, 1 x 10 ⁶ cells in a total volume of 0.1 mL (isolated from PyMT tumor fragments and stored frozen in cell freezing medium) were seeded onto the left side of female mice (FVB / NJ from Jackson Lab, JAXWEST: RB05 mice) And were transplanted into the fourth wired region. A total of 10 mice were injected into each group. Molecular Imaging, Inc.'s Animal Care and Use Committee approved all experimental protocols and conducted tests that comply with all NIH laws, rules and guidelines. Oral administration of Compound 1 or vehicle (0.4% hydroxypropyl methylcellulose in water) once or twice a week, depending on the individual body weight at the treatment day, at a dose of 0.2 mL per 20 g when the tumor size reaches approximately 850 mg Treatment was initiated by intravenous (IV) administration of eribulin or vehicle (80% saline) three times weekly and / or gavage. Tumors were resected three days after starting treatment. Animals were administered during the duration of the survival experiment. Body weight and tumor measurements were recorded three times per week. In the PyMT model, eribulence at 0.1 mg / kg was demonstrated to have no increase in survival rate. Compound 1 in combination with eribulin demonstrated a significant increase in survival (Figure 7). These data demonstrate the in vivo activity of the compound 1, and shows a correlation between the enzyme and the cell data.

The invention is not to be limited in scope by the specific embodiments described in the intended embodiments as examples of the many aspects of the invention and any embodiments which are functionally equivalent within the scope of the invention. Indeed, various modifications of the invention in addition to those described and illustrated herein will be readily apparent to those skilled in the art and are intended to be included within the scope of the appended claims.

Equivalent

Those skilled in the art will recognize, and be able to ascertain using no more than routine experimentation, numerous equivalents to the specific embodiments detailed in this disclosure. Such equivalents are intended to be encompassed within the scope of the following claims.

                         SEQUENCE LISTING <110> DECIPHERA PHARMACEUTICALS, LLC   <120> METHODS FOR INHIBITING TIE2 KINASE USEFUL IN THE TREATMENT OF        CANCER &Lt; 130 > DECP-066 / 00WO 313114-2322 <160> 2 <170> Kopatentin 1.71 <210> 1 <211> 354 <212> PRT <213> Homo sapiens <400> 1 Gln Leu Lys Arg Ala Asn Val Gln Arg Arg Met Ala Gln Ala Phe Gln 1 5 10 15 Asn Val Arg Glu Glu Pro Ala Val Gln Phe Asn Ser Gly Thr Leu Ala             20 25 30 Leu Asn Arg Lys Val Lys Asn Asn Pro Asp Pro Thr Ile Tyr Pro Val         35 40 45 Leu Asp Trp Asn Asp Ile Lys Phe Gln Asp Val Ile Gly Glu Gly Asn     50 55 60 Phe Gly Gln Val Leu Lys Ala Arg Ile Lys Lys Asp Gly Leu Arg Met 65 70 75 80 Asp Ala Ala Ile Lys Arg Met Lys Glu Tyr Ala Ser Lys Asp Asp His                 85 90 95 Arg Asp Phe Ala Gly Glu Leu Glu Val Leu Cys Lys Leu Gly His His             100 105 110 Pro Asn Ile Ile Asn Leu Leu Gly Ala Cys Glu His Arg Gly Tyr Leu         115 120 125 Tyr Leu Ala Ile Glu Tyr Ala Pro His Gly Asn Leu Leu Asp Phe Leu     130 135 140 Arg Lys Ser Arg Val Leu Glu Thr Asp Pro Ala Phe Ala Ile Ala Asn 145 150 155 160 Ser Thr Ala Ser Thr Leu Ser Ser Gln Gln Leu Leu His Phe Ala Ala                 165 170 175 Asp Val Ala Arg Gly Met Asp Tyr Leu Ser Gln Lys Gln Phe Ile His             180 185 190 Arg Asp Leu Ala Ala Arg Asn Ile Leu Val Gly Glu Asn Tyr Val Ala         195 200 205 Lys Ile Ala Asp Phe Gly Leu Ser Arg Gly Gln Glu Val Tyr Val Lys     210 215 220 Lys Thr Met Gly Arg Leu Pro Val Arg Trp Met Ala Ile Glu Ser Leu 225 230 235 240 Asn Tyr Ser Val Tyr Thr Thr Asn Ser Asp Val Trp Ser Tyr Gly Val                 245 250 255 Leu Leu Trp Glu Ile Val Ser Leu Gly Gly Thr Pro Tyr Cys Gly Met             260 265 270 Thr Cys Ala Glu Leu Tyr Glu Lys Leu Pro Gln Gly Tyr Arg Leu Glu         275 280 285 Lys Pro Leu Asn Cys Asp Asp Glu Val Tyr Asp Leu Met Arg Gln Cys     290 295 300 Trp Arg Glu Lys Pro Tyr Glu Arg Pro Ser Phe Ala Gln Ile Leu Val 305 310 315 320 Ser Leu Asn Arg Met Leu Glu Glu Arg Lys Thr Tyr Val Asn Thr Thr                 325 330 335 Leu Tyr Glu Lys Phe Thr Tyr Ala Gly Ile Asp Cys Ser Ala Glu Glu             340 345 350 Ala Ala          <210> 2 <211> 285 <212> PRT <213> Homo sapiens <400> 2 Pro Val Leu Asp Trp Asn Asp Ile Lys Phe Gln Asp Val Ile Gly Glu 1 5 10 15 Gly Asn Phe Gly Gln Val Leu Lys Ala Arg Ile Lys Lys Asp Gly Leu             20 25 30 Arg Met Asp Ala Ale Ile Lys Arg Met Lys Glu Tyr Ala Ser Lys Asp         35 40 45 Asp His Arg Asp Phe Ala Gly Glu Leu Glu Val Leu Cys Lys Leu Gly     50 55 60 His His Pro Asn Ile Ile Asn Leu Leu Gly Ala Cys Glu His Arg Gly 65 70 75 80 Tyr Leu Tyr Leu Ala Ile Glu Tyr Ala Pro His Gly Asn Leu Leu Asp                 85 90 95 Phe Leu Arg Lys Ser Arg Val Leu Glu Thr Asp Pro Ala Phe Ala Ile             100 105 110 Ala Asn Ser Thr Ala Ser Thr Leu Ser Ser Gln Gln Leu Leu His Phe         115 120 125 Ala Ala Asp Val Ala Arg Gly Met Asp Tyr Leu Ser Gln Lys Gln Phe     130 135 140 Ile His Arg Asp Leu Ala Ala Arg Asn Ile Leu Val Gly Glu Asn Tyr 145 150 155 160 Val Ala Lys Ile Ala Asp Phe Gly Leu Ser Arg Gly Gln Glu Val Tyr                 165 170 175 Val Lys Lys Thr Met Gly Arg Leu Pro Val Arg Trp Met Ala Ile Glu             180 185 190 Ser Leu Asn Tyr Ser Val Tyr Thr Thr Asn Ser Asp Val Trp Ser Tyr         195 200 205 Gly Val Leu Leu Trp Glu Ile Val Ser Leu Gly Gly Thr Pro Tyr Cys     210 215 220 Gly Met Thr Cys Ala Glu Leu Tyr Glu Lys Leu Pro Gln Gly Tyr Arg 225 230 235 240 Leu Glu Lys Pro Leu Asn Cys Asp Asp Glu Val Tyr Asp Leu Met Arg                 245 250 255 Gln Cys Trp Arg Glu Lys Pro Tyr Glu Arg Pro Ser Phe Ala Gln Ile             260 265 270 Leu Val Ser Leu Asn Arg Met Leu Glu Glu Arg Lys Thr         275 280 285

Claims (219)

Comprising administering to a patient in need of such treatment an effective amount of a composition of Formula I &lt; RTI ID = 0.0 &gt; I, &lt; / RTI &gt; to a patient in need of interrupting primary breast tumor growth and invasion in a dosage regimen sufficient to block TIE2 kinase in a tumor microenvironment. How to block:

Wherein n is an integer from 0 to 7;
X is a basic radical of a pharmaceutically acceptable salt;
When n is 0, the composition of formula (I) is the parent free base. 2. The method of claim 1, wherein said dosing regimen is administered daily. 7. The method of claim 1, wherein said dose regimen is intermittent, every other day, every 3 days, twice a week, or once a week, rather than daily. 2. The method of claim 1, wherein said regimen is administered twice a week, once a week, or biweekly. The composition of claim 1, wherein the composition of formula (I) is selected from the group consisting of an anti-tubulin, a DNA alkylating agent, a DNA synthesis inhibitor, a DNA intervening drug, an anti- estrogen agent, an anti- , Or an anti-angiogenic agent. &Lt; Desc / Clms Page number 13 &gt; 5. The method according to any one of claims 1 to 4, wherein the composition of formula (I) is used in combination with paclitaxel. 5. The method according to any one of claims 1 to 4, wherein the composition of formula (I) is used in combination with paclitaxel protein-binding particles for injection suspensions. 5. The method according to any one of claims 1 to 4, wherein the compound of formula (I) is used in combination with eribulin. 5. The method according to any one of claims 1 to 4, wherein the composition of formula (I) is used in combination with xyvesperon. 5. The method according to any one of claims 1 to 4, wherein the composition of formula (I) is used in combination with vinorelbine. 5. The method according to any one of claims 1 to 4, wherein the composition of formula (I) is used in combination with capecitabine. 5. The method according to any one of claims 1 to 4, wherein the composition of formula (I) is used in combination with gemcitabine. 5. The method of any one of claims 1 to 4, wherein the composition of formula (I) is used in combination with 5-fluorouracil. 5. The method according to any one of claims 1 to 4, wherein the composition of formula (I) is used in combination with methotrexate. 5. The method according to any one of claims 1 to 4, wherein the composition of formula (I) is used in combination with cyclophosphamide. 5. The method according to any one of claims 1 to 4, wherein the composition of formula (I) is used in combination with cisplatin. 5. The method according to any one of claims 1 to 4, wherein the composition of formula (I) is used in combination with carboplatin. 5. The method according to any one of claims 1 to 4, wherein the composition of formula (I) is used in combination with doxorubicin. 5. The method according to any one of claims 1 to 4, wherein the composition of formula (I) is used in combination with a pegylated liposomal doxorubicin. 5. The method according to any one of claims 1 to 4, wherein the composition of formula (I) is used in combination with epirubicin. 5. The method according to any one of claims 1 to 4, wherein the composition of formula (I) is used in combination with tamoxifen. 5. The method according to any one of claims 1 to 4, wherein the composition of formula (I) is used in combination with a full-vast rant. 5. The method according to any one of claims 1 to 4, wherein the composition of formula (I) is used in combination with anastrozole. 5. The method according to any one of claims 1 to 4, wherein the composition of formula (I) is used in combination with letrozole. 5. The method according to any one of claims 1 to 4, wherein the composition of formula (I) is used in combination with an exemestane. 5. The method according to any one of claims 1 to 4, wherein the composition of formula (I) is used in combination with trastuzumab. 5. The method according to any one of claims 1 to 4, wherein the composition of formula (I) is used in combination with ado-trastuzumab manganese. 5. The method according to any one of claims 1 to 4, wherein the composition of formula (I) is used in combination with pertuzumab. 5. The method according to any one of claims 1 to 4, wherein the composition of formula (I) is used in combination with lapatinib. 5. The method according to any one of claims 1 to 4, wherein the composition of formula (I) is used in combination with everolimus. 5. The method according to any one of claims 1 to 4, wherein the composition of formula (I) is used in combination with temicrylrimus. 5. The method of any one of claims 1 to 4 wherein the composition of formula I is used in combination with the CDK4 / 6 inhibitor LY2835219. 5. The method of any one of claims 1 to 4 wherein the composition of formula I is used in combination with the CDK4 / 6 inhibitor LEE011. 5. The method according to any one of claims 1 to 4, wherein the composition of formula (I) is used in combination with a CDK4 / 6 inhibitor PD 0332991 for the prevention of primary breast tumor growth and invasion. 5. The method of any one of claims 1 to 4, wherein the composition of formula (I) is used in combination with bevacizumab. 37. The method of any one of claims 1 to 35, wherein said composition is a composition of formula II. 37. The use according to any one of claims 1 to 36, wherein the composition of formula (I) or (II) is used in combination with at least one of the other agents of claims 6 to 35, And methods of blocking invasion. Tumor microenvironment TIE2-expressing macrophage, comprising administering to a patient in need of such treatment an effective amount of a composition of formula I below, wherein said composition is administered to a patient in need of intervention of intravascular invasion, propagation and metastasis of breast cancer: Methods for blocking intravascular invasion, spread, and metastasis in breast cancer:

Wherein n is an integer from 0 to 7;
X is a basic radical of a pharmaceutically acceptable salt;
When n is 0, the composition of formula (I) is the parent free base. 39. The method of claim 38, wherein said dosing regimen is administered daily. 39. The method of claim 38, wherein said dose regimen is intermittent, every other day, every 3 days, twice a week, or once a week administration, rather than daily. 39. The method of claim 38, wherein said regimen is twice weekly, once every week, or biweekly. 42. A composition according to any one of claims 38 to 41, wherein the composition of formula I is selected from the group consisting of an anti-tubulin, a DNA alkylating agent, a DNA synthesis inhibitor, a DNA intervening drug, an anti- estrogen agent, an anti- , Or an anti-angiogenic agent, in a mammalian blood vessel. 42. The method according to any one of claims 38 to 41, wherein the composition of formula (I) is used in combination with paclitaxel in blocking intravascular invasion, propagation and metastasis of breast cancer. 42. The method according to any one of claims 38 to 41, wherein the composition of formula I is used in combination with a paclitaxel protein-binding particle for a parenteral suspension, for blocking invasion, propagation and metastasis of breast cancer. 42. The method according to any one of claims 38 to 41, wherein the composition of formula (I) is used in combination with eribulin. 42. The method according to any one of claims 38 to 41, wherein the composition of formula (I) is used in combination with ixabe pilone to block intravascular invasion, propagation and metastasis of breast cancer. 42. The method according to any one of claims 38 to 41, wherein the composition of formula (I) is used in combination with vinorelbine to block intravascular invasion, propagation and metastasis of breast cancer. 42. The method according to any one of claims 38 to 41, wherein the composition of formula (I) is used in combination with capecitabine. 42. A method according to any one of claims 38 to 41, wherein the composition of formula (I) is used in combination with gemcitabine. 42. A method according to any one of claims 38 to 41, wherein the composition of formula (I) is used in combination with 5-fluorouracil to block intravascular invasion, propagation and metastasis of breast cancer. 42. The method according to any one of claims 38 to 41, wherein the composition of formula (I) is used in combination with methotrexate. 42. The method according to any one of claims 38 to 41, wherein the composition of formula (I) is used in combination with cyclophosphamide. 42. A method according to any one of claims 38 to 41, wherein the composition of formula (I) is used in combination with cisplatin to block intravascular invasion, propagation and metastasis of breast cancer. 42. The method according to any one of claims 38 to 41, wherein the composition of formula (I) is used in combination with carboplatin. 42. The method according to any one of claims 38 to 41, wherein the composition of formula (I) is used in combination with doxorubicin. 42. A method according to any one of claims 38 to 41 wherein the composition of formula I is used in combination with a pegylated liposomal doxorubicin. 42. The method according to any one of claims 38 to 41, wherein the composition of formula (I) is used in combination with epirubicin. 42. The method according to any one of claims 38 to 41, wherein the composition of formula I is used in combination with tamoxifen. 42. The method according to any one of claims 38 to 41, wherein the composition of formula (I) is used in combination with full-vestanto. 42. The method according to any one of claims 38 to 41, wherein the composition of formula I is used in combination with anastrozole. 42. A method according to any one of claims 38 to 41, wherein the composition of formula (I) is used in combination with letrozole to block invasion, propagation and metastasis of breast cancer. 42. The method according to any one of claims 38 to 41, wherein the composition of formula (I) is used in combination with an exemestane. 42. A method according to any one of claims 38 to 41, wherein the composition of formula (I) is used in combination with trastuzumab in blocking intravascular invasion, spreading and metastasis. 42. The method according to any one of claims 38 to 41, wherein the composition of formula (I) is used in combination with ado-trastuzumab manganicin to block intravascular invasion, propagation and metastasis of breast cancer. 42. A method according to any one of claims 38 to 41, wherein the composition of formula (I) is used in combination with pertuzumab in blocking intravascular invasion, spreading and metastasis. 42. The method according to any one of claims 38 to 41, wherein the composition of formula (I) is used in combination with lapatinib to block intravascular invasion, propagation and metastasis of breast cancer. 42. The method according to any one of claims 38 to 41, wherein the composition of formula (I) is used in combination with everolimus. 42. A method according to any one of claims 38 to 41, wherein the composition of formula I is used in combination with Temicrylolimus. 42. A method according to any one of claims 38 to 41, wherein the composition of formula I is used in combination with the CDK4 / 6 inhibitor LY2835219. 42. The method according to any one of claims 38 to 41, wherein the composition of formula I is used in combination with the CDK4 / 6 inhibitor LEE011. 42. The method according to any one of claims 38 to 41, wherein the composition of formula I is used in combination with a CDK4 / 6 inhibitor PD 0332991. 42. A method according to any one of claims 38 to 41, wherein the composition of formula (I) is used in combination with bevacizumab in blocking intravascular invasion, propagation and metastasis of breast cancer. 72. The method according to any one of claims 38 to 72, wherein said composition is a composition of formula II, for blocking invasion, propagation and metastasis of breast cancer. 73. The use according to any one of claims 38 to 73, wherein the composition of formula (I) or (II) is used in combination with at least one of the other agents of claims 43 to 72, , A method of blocking propagation and transition. Comprising administering to a patient in need thereof an effective amount of a composition of formula (I): &lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &gt; Blocking method for breast cancer immunity tolerance:

Wherein n is an integer from 0 to 7;
X is a basic radical of a pharmaceutically acceptable salt;
When n is 0, the composition of formula (I) is the parent free base. 77. The method of claim 75, wherein said regimen is administered daily. 77. The method of claim 75, wherein said regimen is intermittent, daily, every 3 days, twice a week, or once a week, rather than daily. 77. The method of claim 75, wherein said dose regimen is twice weekly, once weekly, or biweekly. 78. The method of any one of claims 75-78, wherein the composition of formula (I) is selected from the group consisting of an anti-tubulin, a DNA alkylating agent, a DNA synthesis inhibitor, a DNA intervening drug, an anti- estrogen agent, , An anti-angiogenesis agent or an immunomodulator. &Lt; RTI ID = 0.0 &gt; 25. &lt; / RTI &gt; 78. The method of any one of claims 75-78, wherein the composition of formula (I) is used in combination with paclitaxel. 78. The method of any one of claims 75-78, wherein the composition of formula I is used in combination with a paclitaxel protein-binding particle for a parenteral suspension. 78. The method according to any one of claims 75 to 78, wherein the composition of formula (I) is used in combination with eribulin. 78. The method according to any one of claims 75 to 78, wherein the composition of formula (I) is used in combination with xrexepilone. 78. The method of any one of claims 75-78, wherein the composition of formula (I) is used in combination with vinorelbine. 78. The method according to any one of claims 75 to 78, wherein the composition of formula (I) is used in combination with capecitabine. 78. The method according to any one of claims 75 to 78, wherein the composition of formula (I) is used in combination with gemcitabine. 79. The method of any one of claims 75-78, wherein the composition of formula (I) is used in combination with 5-fluorouracil. 78. The method of any one of claims 75-78, wherein the composition of formula (I) is used in combination with methotrexate. 78. The method of any one of claims 75-78, wherein the composition of formula (I) is used in combination with a cyclophosphamide. 78. The method of any one of claims 75-78, wherein the composition of formula (I) is used in combination with cisplatin. 78. The method of any one of claims 75-78, wherein the composition of formula (I) is used in combination with carboplatin. 78. The method of any one of claims 75-78, wherein the composition of formula (I) is used in combination with doxorubicin. 78. The method of any one of claims 75-78, wherein the composition of formula (I) is used in combination with a pegylated liposomal doxorubicin. 78. The method of any one of claims 75-78, wherein the composition of formula (I) is used in combination with epirubicin. 78. The method of any one of claims 75-78, wherein the composition of formula (I) is used in combination with tamoxifen. 78. The method of any one of claims 75-78, wherein the composition of formula (I) is used in combination with full-vestanto. 78. The method of any one of claims 75-78, wherein the composition of formula (I) is used in combination with anastrozole. 78. The method of any one of claims 75-78, wherein the composition of formula (I) is used in combination with letrozole. 78. The method of any one of claims 75-78, wherein the composition of formula (I) is used in combination with an exemestane. 78. The method of any one of claims 75-78, wherein the composition of formula (I) is used in combination with trastuzumab. 78. The method according to any one of claims 75 to 78, wherein the composition of formula (I) is used in combination with ado-trastuzumab manganese. 78. The method of any one of claims 75-78, wherein the composition of formula (I) is used in combination with pertuzumab. 78. The method of any one of claims 75-78, wherein the composition of formula (I) is used in combination with lapatinib. 79. The method according to any one of claims 75 to 78, wherein the composition of formula (I) is used in combination with everolimus. 78. The method of any one of claims 75-78, wherein the composition of formula (I) is used in combination with a temicirolimus. 78. The method of any one of claims 75 to 78 wherein the composition of formula I is used in combination with the CDK4 / 6 inhibitor LY2835219. 78. The method of any one of claims 75-78, wherein the composition of formula I is used in combination with the CDK4 / 6 inhibitor LEE011. 78. The method of any one of claims 75-78, wherein the composition of Formula I is used in combination with a CDK4 / 6 inhibitor PD 0332991. 78. The method of any one of claims 75-78, wherein the composition of formula (I) is used in combination with bevacizumab. 78. The method according to any one of claims 75 to 78, wherein the composition of formula (I) is used in combination with a anti-CTLA-4 agent. 78. The method of any one of claims 75-78, wherein the composition of formula (I) is used in combination with eicilimumab. 78. The method of any one of claims 75-78, wherein the composition of formula (I) is used in combination with an anti-PD-1 agent. 78. The method of any one of claims 75-78, wherein the composition of formula (I) is used in combination with &lt; RTI ID = 0.0 &gt; Rambrolizumab. &Lt; / RTI &gt; 78. The method of any one of claims 75-78, wherein the composition of formula I is used in combination with an anti-PD L-1 agent. 78. The method of any one of claims 75-78, wherein the composition of formula I is used in combination with MPDL3280A. 114. The method of any one of claims 75 to 115, wherein said composition is a composition of formula II. 114. The use according to any one of claims 75 to 116, wherein the composition of formula (I) or formula (II) is used in combination with one or more of the other agents of claims 80 to 115. How to block. Comprising administering to a patient in need thereof an effective amount of a composition of formula I below, in a patient in need of an increase in overall survival in a breast cancer patient, in a dosage regimen sufficient to block TIE2 kinase in a tumor microenvironment. How to increase:

Wherein n is an integer from 0 to 7;
X is a basic radical of a pharmaceutically acceptable salt;
When n is 0, the composition of formula (I) is the parent free base. 119. The method of claim 118, wherein said regimen is administered daily. 119. The method of claim 118, wherein the dosage regimen is intermittent, every other day, every 3 days, twice a week, or once a week, rather than daily. 119. The method of claim 118, wherein said regimen is twice a week, once a week, or every other week. A composition according to any one of claims 118 to 121, wherein the composition of formula (I) is selected from the group consisting of an anti-tubulin, a DNA alkylating agent, a DNA synthesis inhibitor, a DNA intervening drug, an anti- estrogen agent, , An anti-angiogenesis agent or an immunomodulator, in a mammalian patient. 121. The method according to any one of claims 118 to 121, wherein the composition of formula (I) is used in combination with paclitaxel. 121. The method according to any one of claims 118 to 121, wherein the composition of Formula I is used in combination with a paclitaxel protein-binding particle for a parenteral suspension. 121. The method according to any one of claims 118 to 121, wherein the composition of Formula I is used in combination with eribulin. 121. The method according to any one of claims 118 to 121, wherein the composition of Formula I is used in combination with ixabe pilone. 121. The method according to any one of claims 118 to 121, wherein the composition of Formula I is used in combination with vinorelbine. 121. The method according to any one of claims 118 to 121, wherein the composition of Formula I is used in combination with capecitabine. 121. The method according to any one of claims 118 to 121, wherein the composition of Formula I is used in combination with gemcitabine. 121. The method according to any one of claims 118 to 121, wherein the composition of Formula I is used in combination with 5-fluorouracil. 121. The method according to any one of claims 118 to 121, wherein the composition of Formula I is used in combination with methotrexate. 121. The method according to any one of claims 118 to 121, wherein the composition of formula (I) is used in combination with a cyclophosphamide. 121. The method according to any one of claims 118 to 121, wherein the composition of Formula I is used in combination with cisplatin. 121. The method according to any one of claims 118 to 121, wherein the composition of Formula I is used in combination with carboplatin. 121. The method according to any one of claims 118 to 121, wherein the composition of Formula I is used in combination with doxorubicin. 121. The method of any one of claims 118 to 121 wherein the composition of Formula I is used in combination with a pegylated liposomal doxorubicin. 121. The method according to any one of claims 118 to 121, wherein the composition of formula I is used in combination with epirubicin. 121. The method according to any one of claims 118 to 121, wherein the composition of Formula I is used in combination with tamoxifen. 121. The method according to any one of claims 118 to 121, wherein the composition of formula (I) is used in combination with a full-vintment. 121. The method according to any one of claims 118 to 121, wherein the composition of Formula I is used in combination with anastrozole. 121. The method according to any one of claims 118 to 121, wherein the composition of formula I is used in combination with letrozole. 121. The method according to any one of claims 118 to 121, wherein the composition of formula I is used in combination with an exemestane. 121. The method according to any one of claims 118 to 121, wherein the composition of formula (I) is used in combination with trastuzumab. 121. The method according to any one of claims 118 to 121, wherein the composition of Formula I is used in combination with ado-trastuzumab manganicin. 121. The method according to any one of claims 118 to 121, wherein the composition of Formula I is used in combination with pertuzumab. 121. The method according to any one of claims 118 to 121, wherein the composition of formula I is used in combination with lapatinib. 121. The method according to any one of claims 118 to 121, wherein the composition of formula (I) is used in combination with everolimus. 121. The method according to any one of claims 118 to 121, wherein the composition of formula I is used in combination with a temsirolimus. 121. The method according to any one of claims 118 to 121, wherein the composition of Formula I is used in combination with the CDK4 / 6 inhibitor LY2835219. 121. The method according to any one of claims 118 to 121, wherein the composition of Formula I is used in combination with the CDK4 / 6 inhibitor LEE011. 121. The method according to any one of claims 118 to 121, wherein the composition of Formula I is used in combination with a CDK4 / 6 inhibitor PD 0332991. 121. The method according to any one of claims 118 to 121, wherein the composition of formula (I) is used in combination with bevacizumab. 121. The method according to any one of claims 118 to 121, wherein the composition of Formula I is used in combination with a anti-CTLA-4 agent. 121. The method according to any one of claims 118 to 121, wherein the composition of Formula I is used in combination with eicilimumab. 121. The method according to any one of claims 118 to 121, wherein the composition of formula I is used in combination with an anti-PD-1 agent. 121. The method according to any one of claims 118 to 121, wherein the composition of formula (I) is used in combination with &lt; RTI ID = 0.0 &gt; Rambrolizumab. &Lt; / RTI &gt; 121. The method according to any one of claims 118 to 121, wherein the composition of formula (I) is used in combination with an anti-PD L-1 agent. 121. The method according to any one of claims 118 to 121, wherein the composition of Formula I is used in combination with MPDL3280A. 143. The method according to any one of claims 118 to 158, wherein the composition is a composition of formula II. Use according to any one of claims 118 to 159, wherein the composition of formula (I) or (II) is used in combination with one or more of the other agents of claims 123 to 158. Increasing the overall survival rate. Comprising administering an effective amount of a composition of formula I to a patient in need of treatment of breast cancer in a neoadjuvant setting prior to surgical resection of the tumor. 160. The method of claim 161, wherein the dosage regimen is daily administered. 160. The method of claim 161, wherein the dosage regimen is intermittent, daily, every 3 days, twice weekly, or once weekly, rather than daily. A method of treating a breast cancer patient in a neoadjuvant setting prior to surgical resection of the tumor, comprising administering a dose of the composition of formula I in a bi-weekly, once-weekly, or bi-weekly manner to block the TIE2 kinase in a tumor microenvironment Comprising administering to a patient in need of such treatment an effective amount of a composition of formula I in a dosage regimen sufficient for the treatment of breast cancer. Wherein the composition of formula I is selected from the group consisting of an anti-tubulin, a DNA alkylating agent, a DNA synthesis inhibitor, a DNA intervening drug, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor , An anti-angiogenesis agent, or an immunomodulator. &Lt; / RTI &gt; 164. The method according to any one of claims 161 to 164, wherein the composition of formula (I) is used in combination with paclitaxel. 164. The method according to any one of claims 161 to 164, wherein the composition of formula (I) is used in combination with paclitaxel protein-binding particles for injection suspensions. 164. The method according to any one of claims 161 to 164, wherein the composition of formula (I) is used in combination with eribulin. 164. The method according to any one of claims 161 to 164, wherein the composition of formula (I) is used in combination with ixabepilone. 164. The method according to any one of claims 161 to 164, wherein the composition of Formula I is used in combination with vinorelbine. 164. The method according to any one of claims 161 to 164, wherein the composition of formula I is used in combination with capecitabine. 164. The method according to any one of claims 161 to 164, wherein the composition of formula (I) is used in combination with gemcitabine. 164. The method according to any one of claims 161 to 164, wherein the composition of Formula I is used in combination with 5-fluorouracil in a neoadjuvant setting. 164. The method according to any one of claims 161 to 164, wherein the composition of formula (I) is used in combination with methotrexate. 164. The method according to any one of claims 161 to 164, wherein the composition of formula (I) is used in combination with cyclophosphamide. 164. The method according to any one of claims 161 to 164, wherein the composition of formula (I) is used in combination with cisplatin. 164. The method according to any one of claims 161 to 164, wherein the composition of formula (I) is used in combination with carboplatin. 164. The method according to any one of claims 161 to 164, wherein the composition of formula (I) is used in combination with doxorubicin. 164. The method according to any one of claims 161 to 164, wherein the composition of Formula I is used in combination with a pegylated liposomal doxorubicin. 164. The method according to any one of claims 161 to 164, wherein the composition of formula (I) is used in combination with epirubicin. 164. The method according to any one of claims 161 to 164, wherein the composition of formula I is used in combination with tamoxifen. 164. The method according to any one of claims 161 to 164, wherein the composition of formula (I) is used in combination with a full vest. 164. The method according to any one of claims 161 to 164, wherein the composition of formula (I) is used in combination with anastrozole. 164. The method according to any one of claims 161 to 164, wherein the composition of formula (I) is used in combination with letrozole. 164. The method according to any one of claims 161 to 164, wherein the composition of Formula I is used in combination with an exemestane. 164. The method according to any one of claims 161 to 164, wherein the composition of formula (I) is used in combination with trastuzumab. 164. The method according to any one of claims 161 to 164, wherein the composition of formula (I) is used in combination with ado-trastuzumab manganicin. 164. The method according to any one of claims 161 to 164, wherein the composition of formula (I) is used in combination with pertuzumab in a neoadjuvant setting. 164. The method according to any one of claims 161 to 164, wherein the composition of formula I is used in combination with lapatinib. 164. The method according to any one of claims 161 to 164, wherein the composition of formula (I) is used in combination with everolimus. 164. The method according to any one of claims 161 to 164, wherein the composition of formula (I) is used in combination with Temsirolimus. 164. The method according to any one of claims 161 to 164, wherein the composition of Formula I is used in combination with the CDK4 / 6 inhibitor LY2835219. 164. The method according to any one of claims 161 to 164, wherein the composition of formula I is used in combination with the CDK4 / 6 inhibitor LEE011 in a neoadjuvant setting. 164. The method according to any one of claims 161 to 164, wherein the composition of Formula I is used in combination with the CDK4 / 6 inhibitor PD 0332991, in a neoadjuvant setting. 164. The method according to any one of claims 161 to 164, wherein the composition of Formula I is used in combination with bevacizumab in a neoadjuvant setting. 164. The method according to any one of claims 161 to 164, wherein the composition of formula (I) is used in combination with a anti-CTLA-4 agent. 164. The method according to any one of claims 161 to 164, wherein the composition of formula (I) is used in combination with eicilimumab. 164. The method according to any one of claims 161 to 164, wherein the composition of formula I is used in combination with an anti-PD-1 agent. 164. The method according to any one of claims 161 to 164, wherein the composition of formula (I) is used in combination with &lt; RTI ID = 0.0 &gt; Rambrolizumab &lt; / RTI &gt; 164. The method according to any one of claims 161 to 164, wherein the composition of formula I is used in combination with an anti-PD L-1 agent. 164. The method according to any one of claims 161 to 164, wherein the composition of formula I is used in combination with MPDL3280A. 201. The method according to any one of claims 161 to 201, wherein the composition is a composition of formula II. 203. The use according to any one of claims 161 to 202 wherein the composition of formula I or II is used in combination with one or more of the other agents identified in claims 166 to 201, A method of treating a patient with breast cancer in a setting. As a method of treating cancer,
Comprising administering to a patient in need thereof an effective amount of a composition of Formula I:
Wherein said patient is overexpressed with a tyrosine kinase together with endothelial endothelial cell kinase-2 (TIE2), said cancer being selected from the group consisting of breast cancer, colorectal cancer, hepatocellular carcinoma, head and neck cancer, bladder cancer, ovarian cancer, glioma, Method of treatment of cancer, selected from myeloid leukemia:

Wherein n is an integer from 0 to 7;
X is a basic radical of a pharmaceutically acceptable salt;
When n is 0, the composition of formula (I) is the parent free base. 204. The method of claim 204, wherein the composition of formula (I) is administered in combination with one or more other agents. 204. The method of claim 204 or 205 wherein the composition of formula (I) is administered daily. 204. The method of claim 204 or 205, wherein said composition is administered intermittently, but not daily. 204. The method of claim 204 or 205 wherein the composition of formula (I) is administered three times a week. 204. The method of claim 204 or 205 wherein the composition of formula (I) is administered twice a week. 204. The method of claim 204 or 205 wherein the composition of formula (I) is administered once a week. 204. The method of claim 204 or 205 wherein the composition of formula (I) is administered once every two weeks. The method according to any one of claims 1, 38, 75, 118, 161, 204, and 205, wherein the cancer is a triple negative breast cancer. Wherein said cancer is selected from the group consisting of estrogen-positive (ER ⁺ ) and HER2 receptor kinase negative (&lt; RTI ID = 0.0 & HER2 ^- ) breast cancer. 36. The method of any one of claims 1, 38, 75, 118, 161, 204, and 205 wherein the cancer is an inflammatory breast cancer. The method of any one of claims 1, 38, 75, 118, 161, 204, and 205, wherein said breast cancer is metastatic. 204. The method of claim 204 or 205 wherein the treatment is to prevent or reduce one or more of primary tumor growth, tumor invasion, cancer intravascular invasion, cancer propagation, metastasis, and tumor immunity tolerance. Way. 204. The method of claim 204 or 205, wherein said treatment comprises increasing patient survival. Wherein said other agent is selected from the group consisting of paclitaxel, paclitaxel protein-bound particles for injection suspensions, eribulin, docetaxel, xyvesperone, vincristine, vinorelbine, cisplatin, carboplatin, oxaliplatin, cyclophosphamide Idurubicin, epirubicin, 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-fluorouracil, 5-fluorouracil, decahydrate, doxorubicin, pegylated liposomal doxorubicin, But are not limited to, azathiotin, azacytidine, gemcitabine, methotrexate, erlotinib, gefitinib, lapatinib, everolimus, temsirolimus, LY2835219, LEE011, PD 0332991, chrysotript, carbothanib, Such as lycopene, sorafenib, legorapenib, acacitinib, dasatinib, imatinib, neilotinib, bemurafenip, dabrafenip, trametinib, edelalisis, quizarthinib, tamoxifen, Sol, But are not limited to, thiazolidinediones such as thiazolidinediones, thiazoles, thiazoles, thiols, exesestans, aviratorone acetates, enalutamide, nilutamide, bicalutamide, flutamide, cyproterone acetate, prednisone, dexamethasone, irinotecan, camptothecin, , Etoposide phosphate, mitoxantrone, borinostat, romidopsin, panovinostat, valproic acid, valinostat, DZNep 5-aza-2'-deoxycytidine, bortezomib, carfilzomip, thalidomide , Lenalidomide, fomalidomide, trastuzumab, pertuzumab, cetuximab, panituumatum, eicilimumab, lavulliumum, navelum, MPDL3280A, bevacizumab, affluxcept, Wherein the cancer is at least one of mabdotin, ado-trastuzumab manganic acid, radiotherapy, and sipurosel-T. 203. The method of claim 205, wherein the composition of formula I is administered in an adjunct or neoadjuvant therapy.

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