DOSAGE FORMS OF TIE-2 ACTIVATORS

CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63/127,412, filed December 18, 2020, which is incorporated by reference herein in its entirety.

BACKGROUND

[0002] Tie-2 is a transmembrane tyrosine-protein kinase receptor expressed in the vascular endothelium that regulates vascular stability. Disease states associated with the deactivation of Tie-2 include vascular inflammation and leakage, pathologic neovascularization, and angiogenesis.

INCORPORATION BY REFERENCE

[0003] Each patent, publication, and non-patent literature cited in the application is hereby incorporated by reference in its entirety as if each was incorporated by reference individually.

SUMMARY OF THE INVENTION

[0004] In some embodiments, the invention provides a pharmaceutical composition comprising, in a unit dosage form: a) a Tie-2 modulator; and b) another compound, wherein the other compound comprises: 1) a hydrophobic chain; and 2) a remainder of the compound, wherein the remainder of the compound is attached to the hydrophobic chain, wherein the hydrophobic chain comprises: i) a point of attachment that attaches the hydrophobic chain to the remainder of the compound; ii) at least five consecutive carbon atoms; iii) a terminal methyl group; and iv) a substituted carbon atom between the terminal methyl group and the point of attachment, wherein the substituted carbon atom is within fifteen atoms of the terminal methyl group; and wherein the remainder of the compound comprises a repeat unit, wherein the repeat unit comprises an oxygen atom that is sp ³ .

[0005] In some embodiments, the invention provides a pharmaceutical composition comprising in a unit dosage form: a) a Tie-2 modulator; b) a surfactant at an amount of from about 0.05% (v/v) to about 20% (v/v) of the unit dosage form, wherein the surfactant comprises a hydrophilic region connected to a hydrophobic region, wherein the hydrophilic region contains a linear oligomeric moiety; and c) a fluid carrier, wherein the pharmaceutical composition exhibits no more than about 1% degradation of the Tie-2 modulator after storage at room temperature for about 5 weeks. [0006] In some embodiments, the invention provides a pharmaceutical composition comprising in unit dosage form: a) a Tie-2 modulator; and b) a surfactant at an amount of from about 0.05% (v/v) to about 20% (v/v) of the unit dosage form, wherein the surfactant comprises a hydrophilic region connected to a hydrophobic region, wherein the hydrophilic region contains a linear oligomeric moiety; and c) a fluid carrier, wherein the pharmaceutical composition remains clear for at least about 7 weeks while being stored at room temperature. [0007] In some embodiments, the invention provides a pharmaceutical composition comprising in a unit dosage form: a) a Tie-2 modulator; b) a surfactant; and c) a fluid carrier, wherein the pharmaceutical composition exhibits no more than about 1% degradation of the Tie-2 modulator after storage at room temperature for about 2 weeks, and wherein the pharmaceutical composition remains clear after storage at room temperature for about 2 weeks.

DETAILED DESCRIPTION

[0008] Described herein are pharmaceutical compositions for the treatment of vascular disease, including those associated with inflammation and leakage, pathologic neovascularization, and angiogenesis.

[0009] In some embodiments, the disclosure provides a pharmaceutical composition comprising an anti -angiogenic agent, vasculature stabilizing agent, an ocular drug, a visionimproving agent, an intraocular pressure modulating agent, or a glaucoma agent. In some embodiments, the pharmaceutical composition comprises a modulator of Tie-2. In some embodiments, a Tie-2 modulator of the disclosure can activate Tie-2 signaling by promoting protein phosphorylation, such as phosphorylation of the Tie-2 protein.

[0010] Tie-2 (tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2) is a membrane receptor tyrosine kinase expressed primarily in vascular endothelial cells and a subset of hematopoietic stem cells (HSCs) and macrophages. The principal regulators of Tie-2 phosphorylation are angiopoietin 1 (Ang-1) and angiopoietin 2 (Ang-2). Ang-1 is an agonist of Tie-2, and binding of Ang-1 to Tie-2 promotes receptor phosphorylation. Ang-2 is a Tie-2 ligand that acts in a context-dependent antagonistic or agonistic manner. Binding of Ang-1 to Tie-2 increases the level of endogenous Tie-2 receptor phosphorylation and initiates downstream AKT signaling. This binding initiates a signaling cascade that can induce distinctive vascular remodeling through highly organized angiogenesis and tightening of the endothelial cell junctions (endothelium cell proximity). Within the vascular endothelium, Ang-1 -Tie-2 signaling promotes endothelial cell proximity. In the HSC microenvironment, Ang-1 -Tie-2 signaling contributes in a paracrine manner to the long-term repopulation of HSCs.

[0011] Under physiological conditions, the duration of Tie-2 phosphorylation is regulated by the human protein tyrosine phosphatase beta (often abbreviated as HPTPp or HPTP beta), which removes the phosphate from the Tie-2 receptor. By inhibiting HPTPP, the level of Tie- 2 phosphorylation substantially increases, restoring proper cell proximity. HPTPP plays a functional role in endothelial cell proliferation, viability, differentiation, vasculogenesis, and angiogenesis. HPTPp and vascular endothelial protein tyrosine phosphatase (VE-PTP; the mouse orthologue of HPTPP) are expressed in vascular endothelial cells throughout development. A small molecule of the disclosure can activate Tie-2 downstream signaling by inhibiting HPTPp/VE-PTP.

[0012] Compounds that activate Tie-2 can treat disorders and injuries associated with vascular instability, which include, for example, nephropathy, acute kidney injury, cancer, systemic vascular leak syndromes including acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), hypertension including hypertensive crisis/urgency, pulmonary artery hypertension, hepatorenal syndrome, cerebrovascular leakage, and brain edema.

[0013] Compounds that activate Tie-2 can treat disorders of the vascular networks of the eye that include, for example, retinopathies, ocular edema, and ocular neovascularization. Nonlimiting examples of diseases or conditions that involve retinopathy, ocular edema, or neovascularization can include, for example, diabetic macular edema, age-related macular degeneration (wet form), choroidal neovascularization, diabetic retinopathy, retinal vein occlusion (central or branch), ocular trauma, surgery induced edema, surgery induced neovascularization, cystoid macular edema, ocular ischemia, and uveitis. These diseases or conditions are characterized by changes in the ocular vasculature whether progressive or nonprogressive, whether a result of an acute disease or condition, or a chronic disease or condition.

[0014] Compounds that activate Tie-2 can also treat disorders related to the impairment of aqueous humor outflow from the anterior chamber of the eye, which can include, for example, glaucoma, primary glaucoma, pseudoexfoliative glaucoma, pigmentary glaucoma, primary juvenile glaucoma, open angle glaucoma, wide-angle glaucoma, close-angle glaucoma, congenital glaucoma, acquired glaucoma, secondary glaucoma, inflammatory glaucoma, phacogenic glaucoma, or neovascular glaucoma. In some embodiments, a Tie-2 activator of the disclosure can stabilize vasculature associated with the trabecular meshwork, reducing intraocular pressure and treating ocular hypertension.

[0015] The disclosed compositions can comprise one or more pharmaceutically-acceptable agents, which alone or in combination can solubilize a compound herein or a pharmaceutically-acceptable salt thereof and can provide a formulation that has a higher amount of a Tie-2 modulator in solution relative to other formulations of Tie-2 modulators. The solubility of a therapeutic compound, or the ability of a compound to dissolve in a solvent to afford a homogeneous system, can be a principal factor in increasing the bioavailability of a compound due to the enhanced ability to be absorbed and dispersed to the target site of therapy. Additives that increase solubility can decrease the dosage required to achieve an efficacious outcome and reduce the amount of time required for a therapeutically- effective concentration of a compound to be reached at the target site of therapy in a subject. Such compositions can also offer greatly enhanced chemical and physical stability. The stability of a compound in solution, or the ability of the compound to maintain a homogenous state over time, can contribute to enhanced shelf life.

[0016] The pharmaceutical compositions of the present disclosure can include formulations of activators of Tie-2 that include surface active agents, or surfactants. Surfactants can reduce the interfacial tension between two substances, such as a liquid and a liquid or a solid and a liquid, and can enhance the miscibility of two liquids or the solubility of a solid in a liquid. Surfactants include compounds that possess both hydrophobic and hydrophilic moieties, meaning that an individual surfactant molecule possesses functionalities that strongly differ in the thermodynamic strength of interactions with polar substances. Surfactants can also include non-ionic surfactants, which contain hydrophilic moieties that include ethers, esters, and alcohols.

Activators of Tie-2.

[0017] Compounds disclosed herein can be effective as Tie-2 modulators. The compounds can affect Tie-2 activity, for example, by binding or inhibiting HPTP-p. Such compounds can bind HPTP-P, for example, by mimicking the binding mechanism of a native substrate, such as a phosphorylated compound. A compound can be a phosphate mimetic or bioisostere, for example, a sulfamic acid. The compound could also be derived from an amino acid building block or comprise an amino acid backbone for efficiency and economy of synthesis.

[0018] In some embodiments, a compound disclosed herein is a compound of the formula:

Aryl ¹ is an aryl group which is substituted or unsubstituted; Aryl ² is an aryl group which is substituted or unsubstituted; X is alkylene, alkenylene, alkynylene, an ether linkage, an amine linkage, an amide linkage, an ester linkage, a thioether linkage, a carbamate linkage, a carbonate linkage, a sulfone linkage, any of which is substituted or unsubstituted, or a chemical bond; and Y is H, aryl, heteroaryl, NH(aryl), NH(heteroaryl), NHSChR ⁸ , or NHCOR ^S , any of which is substituted or unsubstituted, or wherein:

L ² is alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted, or together with the nitrogen atom to which L ² is bound forms an amide linkage, a carbamate linkage, or a sulfonamide linkage, or a chemical bond, or together with any of R ^a , R ^b , R ^c , and R ^d forms a ring that is substituted or unsubstituted; R ^a is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or together with any of L ² , R ^b , R ^c , and R ^d forms a ring that is substituted or unsubstituted; R ^b is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or together with any of L ² , R ^a , R ^c , and R ^d forms a ring that is substituted or unsubstituted; R ^c is H or alkyl which is substituted or unsubstituted, or together with any of L ² , R ^a , R ^b , and R ^d forms a ring that is substituted or unsubstituted; R ^d is H or alkyl which is substituted or unsubstituted, or together with any of L ² , R ^a , R ^b , and R ^c forms a ring that is substituted or unsubstituted; and R ^s is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or a pharmaceutically-acceptable salt, tautomer, or zwitterion thereof.

[0019] In some embodiments, Aryl ¹ is substituted or unsubstituted phenyl, Aryl ² is substituted or unsubstituted heteroaryl, and X is alkylene. In some embodiments, Aryl ¹ is substituted phenyl, Aryl ² is substituted heteroaryl, and X is methylene.

[0020] In some embodiments, a compound is of the formula:

wherein Aryl ¹ is para-substituted phenyl, Aryl ² is substituted heteroaryl; X is methylene; L ² is alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted, or together with the nitrogen atom to which L ² is bound forms an amide linkage, a carbamate linkage, or a sulfonamide linkage, or a chemical bond; R ^a is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; R ^b is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; R ^c is H or alkyl which is substituted or unsubstituted; and R ^d is H or alkyl which is substituted or unsubstituted.

[0021] In some embodiments, Aryl ¹ is para-substituted phenyl; Aryl ² is a substituted thiazole moiety; X is methylene; L ² together with the nitrogen atom to which L ² is bound forms a carbamate linkage; R ^a is alkyl, which is substituted or unsubstituted; R ^b is arylalkyl, which is substituted or unsubstituted; R ^c is H; and R ^d is H.

[0022] In some embodiments, Aryl ² is: wherein R ^e is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; and R ^f is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted. [0023] In some embodiments, R ^e is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; and R ^f is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted. In some embodiments, R ^e is H, OH, F, Cl, Br, I, alkyl, or an alkoxy group, any of which is substituted or unsubstituted and R ^f is alkyl, aryl, heterocyclyl, or heteroaryl, any of which is substituted or unsubstituted. In some embodiments, Aryl ¹ is 4- phenylsulfamic acid; R ^a is alkyl, which is substituted or unsubstituted; R ^b is arylalkyl, which is substituted or unsubstituted; R ^e is H; and R ^f is heteroaryl. In some embodiments, Aryl ¹ is 4-phenylsulfamic acid; R ^a is alkyl; which is substituted or unsubstituted; R ^b is arylalkyl, which is substituted or unsubstituted; R ^e is H; and R ^f is alkyl.

[0024] In some embodiments, Aryl ² is: wherein R ^e is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, R ^f is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted. In some embodiments, R ^e is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; and R ^f is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted. In some embodiments, R ^e is H, OH, F, Cl, Br, I, alkyl, or an alkoxy group, any of which is substituted or unsubstituted; and R ^f is alkyl, aryl, heterocyclyl, or heteroaryl, any of which is substituted or unsubstituted. In some embodiments, Aryl ¹ is 4-phenylsulfamic acid; R ^a is alkyl, which is substituted or unsubstituted; R ^b is arylalkyl, which is substituted or unsubstituted; R ^e is H; and R ^f is heteroaryl.

[0025] In some embodiments, a substituted phenyl group is: each of R ^phl , R ^ph2 , R ^ph3 , R ^ph4 , and R ^ph5 is independently H, OH, F, Cl, Br, I, CN, sulfamic acid, tosylate, mesylate, triflate, besylate, alkyl, alkenyl, alkynyl, an alkoxy group, a sulfhydryl group, a nitro group, a nitroso group, an azido group, a sulfoxide group, a sulfone group, a sulfonamide group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

[0026] Illustrative compounds include the following:

Optional Substituents for Chemical Groups.

[0027] Non-limiting examples of optional substituents include hydroxyl groups, sulfhydryl groups, halogens, amino groups, nitro groups, nitroso groups, cyano groups, azido groups, sulfoxide groups, sulfone groups, sulfonamide groups, carboxyl groups, carboxaldehyde groups, imine groups, alkyl groups, halo-alkyl groups, alkenyl groups, halo-alkenyl groups, alkynyl groups, halo-alkynyl groups, alkoxy groups, aryl groups, aryloxy groups, aralkyl groups, arylalkoxy groups, heterocyclyl groups, acyl groups, acyloxy groups, carbamate groups, amide groups, and ester groups.

[0028] Non-limiting examples of alkyl and alkylene groups include straight, branched, and cyclic alkyl and alkylene groups. An alkyl group can be, for example, a Ci, C2, C3, C4, C5, Ce, C ₇ , C ₈ , C ₉ , C10, Cn, C12, C13, C14, Ci ₅ , Ci6, C17, Ci ₈ , C19, C20, C21, C22, C23, C ₂₄ , C ₂₅ , C ₂₆ , C27, C ₂₈ , C29, C30, C31, C32, C33, C34, C ₃₅ , C ₃ 6, C37, C ₃₈ , C39, C ₄₀ , C ₄ i, C ₄₂ , C43, C44, C ₄₅ , C ₄₆ , C47, C ₄₈ , C49, or C50 group that is substituted or unsubstituted.

[0029] Non-limiting examples of straight alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

[0030] Branched alkyl groups include any straight alkyl group substituted with any number of alkyl groups. Non-limiting examples of branched alkyl groups include isopropyl, isobutyl, sec-butyl, and t-butyl.

[0031] Non-limiting examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptlyl, and cyclooctyl groups. Cyclic alkyl groups also include fused-, bridged-, and spiro-bicycles and higher fused-, bridged-, and spiro-systems. A cyclic alkyl group can be substituted with any number of straight, branched, or cyclic alkyl groups.

[0032] Non-limiting examples of alkenyl and alkenylene groups include straight, branched, and cyclic alkenyl groups. The olefin or olefins of an alkenyl group can be, for example, E, Z. cis, trans, terminal, or exo-methylene. An alkenyl or alkenylene group can be, for example, a C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , Cio, Cu, C12, C13, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, c ₂₅ , C26, C27, C ₂₈ , C29, C30, C31, C32, C33, C34, c ₃₅ , C36, C37, C ₃₈ , C39, C40, C41, C42, C43, C44, C45, C46, C47, c ₄₈ , C49, or C50 group that is substituted or unsubstituted.

[0033] Non-limiting examples of alkynyl or alkynylene groups include straight, branched, and cyclic alkynyl groups. The triple bond of an alkynyl or alkynylene group can be internal or terminal. An alkynyl or alkynylene group can be, for example, a C ₂ , C3, C ₄ , C5, Ce, C ₇ , C ₈ , C ₉ , Cio, Cu, C12, C13, C14, C15, C16, C17, Cl ₈ , C19, C ₂ 0, C ₂ 1, C ₂ 2, C ₂ 3, C ₂ 4, C ₂₅ , C ₂ 6, C ₂ 7, C ₂₈ , C29, C30, C31, C32, C33, C34, c ₃₅ , C36, C37, c ₃₈ , C39, C40, C41, C42, C43, C44, c ₄₅ , C ₄₆ , C47, c ₄₈ , C49, or C50 group that is substituted or unsubstituted.

[0034] A halo-alkyl group can be any alkyl group substituted with any number of halogen atoms, for example, fluorine, chlorine, bromine, and iodine atoms. A halo-alkenyl group can be any alkenyl group substituted with any number of halogen atoms. A halo-alkynyl group can be any alkynyl group substituted with any number of halogen atoms.

[0035] An alkoxy group can be, for example, an oxygen atom substituted with any alkyl, alkenyl, or alkynyl group. An ether or an ether group comprises an alkoxy group. Nonlimiting examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and isobutoxy.

[0036] An aryl group can be heterocyclic or non-heterocyclic. An aryl group can be monocyclic or polycyclic. An aryl group can be substituted with any number of substituents described herein, for example, hydrocarbyl groups, alkyl groups, alkoxy groups, and halogen atoms. Non-limiting examples of aryl groups include phenyl, toluyl, naphthyl, pyrrolyl, pyridyl, imidazolyl, thiophenyl, and furyl.

[0037] An aryl oxy group can be, for example, an oxygen atom substituted with any aryl group, such as phenoxy.

[0038] An aralkyl group can be, for example, any alkyl group substituted with any aryl group, such as benzyl.

[0039] An arylalkoxy group can be, for example, an oxygen atom substituted with any aralkyl group, such as benzyloxy.

[0040] A heterocycle can be any ring containing a ring atom that is not carbon, for example, N, O, S, P, Si, B, or any other heteroatom. A heterocycle can be substituted with any number of substituents, for example, alkyl groups and halogen atoms. A heterocycle can be aromatic (heteroaryl) or non-aromatic. Non-limiting examples of heterocycles include pyrrole, pyrrolidine, pyridine, piperidine, succinimide, maleimide, morpholine, imidazole, thiophene, furan, tetrahydrofuran, pyran, and tetrahydropyran.

[0041] An acyl group can be, for example, a carbonyl group substituted with hydrocarbyl, alkyl, hydrocarbyloxy, alkoxy, aryl, aryloxy, aralkyl, arylalkoxy, or a heterocycle. Nonlimiting examples of acyl include acetyl, benzoyl, benzyloxycarbonyl, phenoxycarbonyl, methoxy carbonyl, and ethoxy carbonyl.

[0042] An acyloxy group can be an oxygen atom substituted with an acyl group. An ester or an ester group comprises an acyloxy group. A non-limiting example of an acyloxy group, or an ester group, is acetate.

[0043] A carbamate group can be an oxygen atom substituted with a carbamoyl group, wherein the nitrogen atom of the carbamoyl group is unsubstituted, monosubstituted, or disubstituted with one or more of hydrocarbyl, alkyl, aryl, heterocyclyl, or aralkyl. When the nitrogen atom is di substituted, the two substituents together with the nitrogen atom can form a heterocycle.

Pharmaceutically-Acceptable Salts.

[0044] The present disclosure provides the use of pharmaceutically-acceptable salts of any compound described herein. Pharmaceutically-acceptable salts include, for example, acidaddition salts and base-addition salts. The acid that is added to the compound to form an acidaddition salt can be an organic acid or an inorganic acid. A base that is added to the compound to form a base-addition salt can be an organic base or an inorganic base. In some embodiments, a pharmaceutically-acceptable salt is a metal salt. In some embodiments, a pharmaceutically-acceptable salt is an ammonium salt.

[0045] Metal salts can arise from the addition of an inorganic base to a compound of the present disclosure. The inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate. The metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc. [0046] In some embodiments, a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt. [0047] Ammonium salts can arise from the addition of ammonia or an organic amine to a compound of the present disclosure. In some embodiments, the organic amine is trimethyl amine, triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine, morpholine, A-methylmorpholine, piperidine, A-methylpiperidine, A-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrazole, pyrazolidine, pyrazoline, pyridazine, pyrimidine, imidazole, or pyrazine.

[0048] In some embodiments, an ammonium salt is a triethyl amine salt, trimethyl amine salt, a diisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, a triethanol amine salt, a morpholine salt, an A-methylmorpholine salt, a piperidine salt, an A-methylpiperidine salt, an A-ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrazole salt, a pyridazine salt, a pyrimidine salt, an imidazole salt, or a pyrazine salt.

[0049] Acid addition salts can arise from the addition of an acid to a compound of the present disclosure. In some embodiments, the acid is organic. In some embodiments, the acid is inorganic. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisic acid, gluconic acid, glucuronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid.

[0050] In some embodiments, the salt is a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactate salt, a salicylate salt, a tartrate salt, an ascorbate salt, a gentisate salt, a gluconate salt, a glucuronate salt, a saccharate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a propionate salt, a butyrate salt, a fumarate salt, a succinate salt, a methanesulfonate salt, an ethanesulfonate salt, a benzenesulfonate salt, a p-toluenesulfonate salt, a citrate salt, an oxalate salt, or a maleate salt.

[0051] A compound herein can be a salt of an acidic group, for example:

[0052] A compound herein can be a salt of a basic group formed from a strong acid, for example:

[0053] A compound herein can also exist in a zwitterionic form, for example:

Pharmaceutical Compositions.

[0054] A pharmaceutical composition of the disclosure can provide a therapeutically- effective amount of an inhibitor of HPTPp. A pharmaceutical composition of the disclosure can provide a therapeutically-effective amount of a Tie-2 modulator.

[0055] A pharmaceutical composition of the disclosure can be a combination of any pharmaceutical compounds described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, solubilizing agents, or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can be administered in therapeutically-effective amounts as pharmaceutical compositions by various forms and routes including, for example, intravenous, intravitreal, subcutaneous, intramuscular, oral, rectal, aerosol, parenteral, ophthalmic, pulmonary, transdermal, vaginal, otic, nasal, and topical administration.

[0056] In some embodiments, Tie-2 modulator is present in a pharmaceutical composition in an amount of from about 0.1 mg/mL to about 300 mg/mL, from about 30 mg/mL to about 300 mg/mL, from about 10 mg/mL to about 120 mg/mL, from about 0.1 mg/mL to about 1 mg/mL, from about 0.1 mg/mL to about 5 mg/mL, , from about 5 mg/mL to about 10 mg/mL, from about 10 mg/mL to about 15 mg/mL, from about 10 mg/mL to about 120 mg/L, from about 15 mg/mL to about 20 mg/mL, from about 20 mg/mL to about 25 mg/mL, from about 25 mg/mL to about 30 mg/mL, from about 30 mg/mL to about 35 mg/mL, from about 35 mg/mL to about 40 mg/mL, from about 40 mg/mL to about 45 mg/mL, about 45 mg/mL to about 50 mg/mL, from about 50 mg/mL to about 55 mg/mL, from about 55 mg/mL to about 60 mg/mL, from about 60 mg/mL to about 65 mg/mL, from about 65 mg/mL to about 70 mg/mL, from about 70 mg/mL to about 75 mg/mL, about 75 mg/mL to about 80 mg/mL, from about 80 mg/mL to about 85 mg/mL, from about 85 mg/mL to about 90 mg/mL, from about 90 mg/mL to about 95 mg/mL, from about 95 mg/mL to about 100 mg/mL, from about 100 mg/mL to about 110 mg/mL, from about 110 mg/mL to about 120 mg/mL, from about 120 mg/mL to about 130 mg/mL, from about 130 mg/mL to about 140 mg/mL, from about 140 mg/mL to about 150 mg/mL, from about 150 mg/mL to about 160 mg/mL, from about 160 mg/mL to about 170 mg/mL, from about 170 mg/mL to about 180 mg/mL, from about 180 mg/mL to about 190 mg/mL, from about 190 mg/mL to about 200 mg/mL, from about 200 mg/mL to about 220 mg/mL, from about 220 mg/mL to about 240 mg/mL, from about 240 mg/mL to about 260 mg/mL, from about 260 mg/mL to about 280 mg/mL, or from about 280 mg/mL to about 300 mg/mL.

[0057] In some embodiments, Tie-2 modulator is present in a pharmaceutical composition in an amount of from about 0.1 mg/mL to about 100 mg/mL, from about 0.1 mg/mL to about 1 mg/mL, from about 0.1 mg/mL to about 5 mg/mL, from about 5 mg/mL to about 10 mg/mL, from about 10 mg/mL to about 15 mg/mL, from about 15 mg/mL to about 20 mg/mL, from about 20 mg/mL to about 25 mg/mL, from about 25 mg/mL to about 30 mg/mL, from about 30 mg/mL to about 35 mg/mL, from about 30 mg/mL to about 50 mg/mL, from about 35 mg/mL to about 40 mg/mL, from about 40 mg/mL to about 45 mg/mL, about 45 mg/mL to about 50 mg/mL, from about 50 mg/mL to about 55 mg/mL, from about 55 mg/mL to about 60 mg/mL, from about 60 mg/mL to about 65 mg/mL, from about 65 mg/mL to about 70 mg/mL, from about 70 mg/mL to about 75 mg/mL, about 75 mg/mL to about 80 mg/mL, from about 80 mg/mL to about 85 mg/mL, from about 85 mg/mL to about 90 mg/mL, from about 90 mg/mL to about 95 mg/mL, or from about 95 mg/mL to about 100 mg/mL. In some embodiments, a Tie-2 or pharmaceutically-acceptable salt thereof is present in a pharmaceutical composition in at a concentration of at least about 30 mg/mL.

[0058] In some embodiments, a Tie-2 modulator is present in a pharmaceutical composition in an amount of about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 11 mg/mL about 12 mg/mL, about 13 mg/mL, about 14 mg/mL, about 15 mg/mL, about 16 mg/mL, about 17 mg/mL, about 18 mg/mL, about 19 mg/mL, about 20 mg/mL, about 21 mg/mL about 22 mg/mL, about 23 mg/mL, about 24 mg/mL, about 25 mg/mL, about 26 mg/mL, about 27 mg/mL, about 28 mg/mL, about 29 mg/mL, about 30 mg/mL, about 31 mg/mL about 32 mg/mL, about 33 mg/mL, about 34 mg/mL, about 35 mg/mL, about 36 mg/mL, about 37 mg/mL, about 38 mg/mL, about 39 mg/mL, about 40 mg/mL, about 41 mg/mL about 42 mg/mL, about 43 mg/mL, about 44 mg/mL, about 45 mg/mL, about 46 mg/mL, about 47 mg/mL, about 48 mg/mL, about 49 mg/mL, about 50 mg/mL, about 51 mg/mL about 52 mg/mL, about 53 mg/mL, about 54 mg/mL, about 55 mg/mL, about 56 mg/mL, about 57 mg/mL, about 58 mg/mL, about 59 mg/mL, about 60 mg/mL, about 61 mg/mL about 62 mg/mL, about 63 mg/mL, about 64 mg/mL, about 65 mg/mL, about 66 mg/mL, about 67 mg/mL, about 68 mg/mL, about 69 mg/mL, about 70 mg/mL, about 71 mg/mL about 72 mg/mL, about 73 mg/mL, about 74 mg/mL, about 75 mg/mL, about 76 mg/mL, about 77 mg/mL, about 78 mg/mL, about 79 mg/mL, about 80 mg/mL, about 81 mg/mL about 82 mg/mL, about 83 mg/mL, about 84 mg/mL, about 85 mg/mL, about 86 mg/mL, about 87 mg/mL, about 88 mg/mL, about 89 mg/mL, about 90 mg/mL, about 91 mg/mL about 92 mg/mL, about 93 mg/mL, about 94 mg/mL, about 95 mg/mL, about 96 mg/mL, about 97 mg/mL, about 98 mg/mL, about 99 mg/mL, or about 100 mg/mL. [0059] In some embodiments, a Tie-2 modulator is present in a pharmaceutical composition, including those in unit dosage forms, in an amount of about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 35 mg, from about 30 mg to about 50 mg, from about 35 mg to about 40 mg, from about 40 mg to about 45 mg, from about 45 mg to about 50 mg, from about 50 mg to about 55 mg, from about 55 mg to about 60 mg, from about 60 mg to about 65 mg, from about 65 mg to about 70 mg, from about 70 mg to about 75 mg, from about 75 mg to about 80 mg, from about 80 mg to about 85 mg, from about 85 mg to about 90 mg, from about 90 mg to about 95 mg, from about 95 mg to about 100 mg, from about 100 mg to about 125 mg, from about 125 mg to about 150 mg, from about 150 mg to about 175 mg, from about 175 mg to about 200 mg, from about 200 mg to about 225 mg, from about 225 mg to about 250 mg, or from about 250 mg to about 300 mg.

[0060] In some embodiments, a Tie-2 modulator or pharmaceutically-acceptable salt thereof is present in a pharmaceutical composition, including those in unit dosage forms, in an amount of about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, or about 300 mg.

[0061] A pharmaceutical composition can be administered in a local or systemic manner, for example, via injection of the compound directly into an organ, optionally in a depot or sustained release formulation. Pharmaceutical compositions can be provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. A rapid release form can provide an immediate release. An extended release formulation can provide a controlled release or a sustained delayed release. [0062] Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Cores can be provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which can contain an excipient such as gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or to characterize different combinations of active compound doses.

[0063] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In some embodiments, the capsule comprises a hard gelatin capsule comprising one or more of pharmaceutical, bovine, and plant gelatins. A gelatin can be alkaline- processed. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, or lubricants such as talc or magnesium stearate and, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. Stabilizers can be added. All formulations for oral administration are provided in dosages suitable for such administration.

[0064] Depending on the intended mode of administration, the pharmaceutical compositions administered as part of the disclosed methods can be in the form of solid, semi-solid, or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, lotions, creams, gels, for example, in unit dosage form suitable for single administration of a precise dosage. The compositions can contain, as noted above, an effective amount of the Tie-2 activator or a pharmaceutically-acceptable salt thereof in combination with a pharmaceutically-acceptable carrier and, in addition, can include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, etc.

[0065] For oral administration, pharmaceutical compositions can be formulated readily by combining the active compounds with pharmaceutically-acceptable carriers or excipients. Such carriers can be used to formulate tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like, for oral ingestion by a subject. [0066] The disclosed methods include administration of an HPTPP inhibitor, or a pharmaceutically-acceptable salt thereof, in combination with a pharmaceutically-acceptable carrier. The carrier can be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject.

[0067] The disclosed methods include administration of a Tie-2 activator, or a pharmaceutically-acceptable salt thereof, in combination with a pharmaceutically-acceptable carrier. The carrier can be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject.

[0068] For solid compositions, nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, and magnesium carbonate. In one embodiment, a composition comprising the Tie-2 activator or a pharmaceutically-acceptable salt thereof in an amount of approximately 4 mg per 0.1 mL liquid is prepared. The liquid phase can comprise sterile water and an appropriate amount of a saccharide or polysaccharide.

[0069] For buccal or sublingual administration, the compositions can be tablets, lozenges, or gels.

[0070] Parenteral injections can be formulated for bolus injection or continuous infusion. The pharmaceutical compositions can be in a form suitable for parenteral injection as a sterile suspension, solution or emulsion in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Suspensions of the active compounds can be prepared as oily injection suspensions.

Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. The suspension can also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0071] The active compounds can be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, and ointments. Such pharmaceutical compositions can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives. [0072] Formulations suitable for transdermal administration of the active compounds can employ transdermal delivery devices and transdermal delivery patches, and can be lipophilic emulsions or buffered aqueous solutions, dissolved or dispersed in a polymer or an adhesive. Such patches can be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical compounds. Transdermal delivery can be accomplished by means of iontophoretic patches. Additionally, transdermal patches can provide controlled delivery. The rate of absorption can be slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. Conversely, absorption enhancers can be used to increase absorption. An absorption enhancer or carrier can include absorbable pharmaceutically-acceptable solvents to assist passage through the skin. For example, transdermal devices can be in the form of a bandage comprising a backing member, a reservoir containing compounds and carriers, a rate controlling barrier to deliver the compounds to the skin of the subject at a controlled and predetermined rate over a prolonged period of time, and adhesives to secure the device to the skin or the eye.

[0073] For administration by inhalation, the active compounds can be in a form as an aerosol, a mist, or a powder. Pharmaceutical compositions are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. The Tie-2 modulator or a pharmaceutically-acceptable salt thereof can also be present in liquids, emulsions, or suspensions for delivery of active therapeutic agents in aerosol form to cavities of the body such as the nose, throat, or bronchial passages. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compounds and a suitable powder base such as lactose or starch. The ratio of Tie-2 modulator or a pharmaceutically-acceptable salt thereof to the other compounding agents in these preparations can vary as the dosage form requires.

[0074] The compounds can also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone and PEG. In suppository forms of the compositions, a low-melting wax such as a mixture of fatty acid glycerides or cocoa butter can be used.

[0075] In practicing the methods of treatment or use provided herein, therapeutically- effective amounts of the compounds described herein are administered in pharmaceutical compositions to a subject having a disease or condition to be treated. In some embodiments, the subject is a mammal such as a human. A therapeutically-effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors. The compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.

[0076] Pharmaceutical compositions can be formulated using one or more physiologically- acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations that can be used pharmaceutically. Formulation can be modified depending upon the route of administration chosen. Pharmaceutical compositions comprising a compound described herein can be manufactured, for example, by mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compression processes.

[0077] The pharmaceutical compositions can include at least one pharmaceutically- acceptable carrier, diluent, or excipient and compounds described herein as free-base or pharmaceutically-acceptable salt form. The methods and pharmaceutical compositions described herein include the use of crystalline forms (also known as polymorphs), and active metabolites of these compounds having the same type of activity.

[0078] Methods for the preparation of compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically- acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions include, for example, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include, for example, solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, for example, gels, suspensions, and creams. The compositions can be in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions can also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives. [0079] Non-limiting examples of dosage forms suitable for use in the present disclosure include feed, food, pellet, lozenge, liquid, elixir, aerosol, inhalant, spray, powder, tablet, pill, capsule, gel, geltab, nanosuspension, nanoparticle, microgel, suppository troches, aqueous or oily suspensions, ointment, patch, lotion, dentifrice, emulsion, creams, drops, dispersible powders or granules, emulsion in hard or soft gel capsules, syrups, phytoceuticals, nutraceuticals, and any combination thereof.

[0080] The disclosure can be administered as an eye drop. The average volume of each drop administered to a subject can be about 5 pl, about 10 pl, about 15 pl, about 20 pl, about 30 pl, about 40 pl, about 50 pl, about 60 pl, about 70 pl, about 80 pl, about 90 pl, or about 100 pl. The eye drops can contain about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 10.5%, about 11%, about 11.5%, about 12%, about 12.5%, about 13%, about 13.5%, about 14%, about 14.5%, about 15%, about 15.5%, about 16%, about 16.5%, about 17%, about 17.5%, about 18%, about 18.5%, about 19%, about 19.5%, or about 20% of a compound of the disclosure by mass. The drops can contain about 1 mg/ml, about 5 mg/ml, about 10 mg/ml, about 15 mg/ml, about 20 mg/ml, about 25 mg/ml, about 30 mg/ml, about 35 mg/ml, about 40 mg/ml, about 45 mg/ml, about 50 mg/ml, about 60 mg/ml, about 70 mg/ml, about 80 mg/ml, about 90 mg/ml, about 100 mg/ml, about 120 mg/ml, about 140 mg/ml, about 160 mg/ml, about 180 mg/ml, or about 200 mg/ml of a compound of the disclosure. The individual dose administered to a subject can be about 0.5 pg, about 1 pg, about 2 pg, about 3 pg, about 4 pg, about 5 pg, about 6 pg, about 7 pg, about 8 pg, about 9 pg, about 10 pg, about 20 pg, about 30 pg, about 40 pg, about 50 pg, about 60 pg, about 70 pg, about 80 pg, about 90 pg, about 100 pg, about 150 pg, about 200 pg, about 250 pg, about 300 pg, about 350 pg, about 400 pg, about 450 pg, about 500 pg, about 550 pg, about 600 pg, about 650 pg, about 700 pg, about 750 pg, about 800 pg, about 850 pg, about 900 pg, about 950 pg, about 1 mg, about 1.1 mg, about 1.2 mg, 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, or about 5 mg of a compound of the disclosure. In some embodiments, more than one drop can be administered to an eye either at one time or at multiple times throughout the day.

[0081] Non-limiting examples of excipients suitable for use in a formulation described herein include cyclodextrin, a-cyclodextrin, P-cyclodextrin, 2-hydroxypropyl-P-cyclodextrin (HP-P- CD), random methyl-P-cyclodextrin (RM-P-CD), sulfobutyl ether P-cyclodextrin (SBE-P- CD), y-cyclodextrin, hydroxypropyl-y-cyclodextrin (HP-y-CD), hydroxyethyl-P-cyclodextrin (HE-P-CD), heptakis (2,6-di-O-methyl)-P-cyclodextrin (DMpCD), saline, sodium bisulfate, metabi sulfate, ascorbic acid, acetylcysteine, benzalkonium chloride, boric acid, hyaluronic acid, hypromellose, propylene glycol, potassium sorbate, sodium chloride, sodium acetate, di sodium edetate, sodium dihydrogen phosphate monohydrate, di sodium phosphate, sodium hydroxide, hydrochloric acid, glycerol, mannitol, trometamol, tyloxapol, non-ionic surfactants, and any combination thereof.

[0082] Non-limiting examples of classes of pharmaceutically-acceptable excipients suitable for use in the present disclosure include granulating agents, binding agents, lubricating agents, disintegrating agents, sweetening agents, glidants, anti-adherents, anti-static agents, surfactants, anti-oxidants, gums, coating agents, coloring agents, flavoring agents, coating agents, plasticizers, preservatives, suspending agents, emulsifying agents, anti-microbial agents, plant cellulosic material and spheronization agents, and any combination thereof. [0083] The individual dose administered to a subject can be about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg of a compound of the present disclosure. The individual dose administered to a subject can be from about 0.1 mg to about 25 mg, about 0.1 mg to about 50 mg, about 0.1 mg to about 75 mg, or about 0.1 mg to about 100 mg. The individual dose administered to a subject can be from about 0.5 mg to about 10 mg, about 0.5 mg to about 20 mg, or about 0.5 mg to about 30 mg. In some embodiments, the individual dose administered to a subject can be about 10 mg of a compound of the present disclosure. In some embodiments, the individual dose administered to a subject can be about 15 mg of a compound of the present disclosure. In some embodiments, the individual dose administered to a subject can be about 20 mg of a compound of the present disclosure. In some embodiments, the individual dose administered to a subject can be about 30 mg of a compound of the present disclosure. In some embodiments, the individual dose of a compound of the present disclosure administered to a subject can be about 15 mg twice per day or about 30 mg per day.

[0084] A composition of the present disclosure can be, for example, an immediate release form or a controlled release formulation. An immediate release formulation can be formulated to allow the compounds to act rapidly. Non-limiting examples of immediate release formulations include readily dissolvable formulations. A controlled release formulation can be a pharmaceutical formulation that has been adapted such that drug release rates and drug release profiles can be matched to physiological and chronotherapeutic requirements or, alternatively, has been formulated to effect release of a drug at a programmed rate. Non-limiting examples of controlled release formulations include granules, delayed release granules, hydrogels (e.g., of synthetic or natural origin), other gelling agents (e.g., gel-forming dietary fibers), matrix-based formulations (e.g., formulations comprising a polymeric material having at least one active ingredient dispersed through), granules within a matrix, polymeric mixtures, and granular masses.

[0085] In some embodiments, a controlled release formulation is a delayed release form. A delayed release form can be formulated to delay a compound’s action for an extended period of time. A delayed release form can be formulated to delay the release of an effective dose of one or more compounds, for example, for about 4, about 8, about 12, about 16, or about 24 hours.

[0086] A controlled release formulation can be a sustained release form. A sustained release form can be formulated to sustain, for example, the compound’s action over an extended period of time. A sustained release form can be formulated to provide an effective dose of any compound described herein (e.g., provide a physiologically-effective blood profile) over about 4, about 8, about 12, about 16, or about 24 hours.

[0087] Non-limiting examples of pharmaceutically-acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington ’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), each of which is incorporated by reference in its entirety.

[0088] The compound or a pharmaceutically-acceptable salt thereof herein can be conveniently formulated into pharmaceutical compositions composed of one or more pharmaceutically-acceptable carriers. See e.g., Remington ’s Pharmaceutical Sciences, latest edition, by E.W. Martin Mack Pub. Co., Easton, PA, which discloses typical carriers, including fluid carriers, and conventional methods of preparing pharmaceutical compositions that can be used in conjunction with the preparation of formulations of the compound described herein and which is incorporated by reference herein. Such pharmaceuticals can be standard carriers for administration of compositions to humans and non-humans, including solutions such as sterile water, saline, and buffered solutions at physiological pH. Other compositions can be administered according to standard procedures. For example, pharmaceutical compositions can also include one or more additional active ingredients such as antimicrobial agents, anti-inflammatory agents, and anesthetics.

[0089] Non-limiting examples of pharmaceutically-acceptable liquid carriers include water, saline solution, Ringer’s solution, glycerol, ethanol, and dextrose solution. The pH of the solution can be from about 5 to about 8, and can be from about 7 to about 7.5. Further carriers include sustained release preparations such as semipermeable matrices of solid hydrophobic polymers containing the compound or a pharmaceutically-acceptable salt thereof, where the matrices are in the form of shaped articles, such as films, liposomes, microparticles, and microcapsules.

[0090] The disclosed methods relate to administering the compound or a pharmaceutically- acceptable salt thereof as part of a pharmaceutical composition. The disclosed methods relate to administering the HPTPp inhibitor or a pharmaceutically-acceptable salt thereof as part of a pharmaceutical composition. In some embodiments, compositions of the present disclosure can comprise a liquid comprising an active agent in solution, in suspension, or both. Liquid compositions can include gels. In some embodiments, the liquid composition is aqueous. Alternatively, the composition can take form of an ointment. In some embodiments, the composition is an in situ gellable aqueous composition. In some embodiments, the composition is an in situ gellable aqueous solution.

[0091] Pharmaceutical formulations can include additional carriers, as well as thickeners, diluents, buffers, preservatives, and surface active agents in addition to the compounds disclosed herein. Pharmaceutical formulations can also include one or more additional active ingredients such as antimicrobial agents, anti-inflammatory agents, or anesthetics.

[0092] An excipient can fill a role as simple and direct as being an inert filler, or an excipient as used herein can be part of a pH stabilizing system or coating to ensure delivery of the ingredients safely to the stomach.

[0093] Pharmaceutical compositions containing the compounds described herein can be administered for prophylactic or therapeutic treatments. Compositions can contain any number of active agents. In therapeutic applications, the compositions can be administered to a subject already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition, or to cure, heal, improve, reduce, lessen, ameliorate, or reduce a likelihood the disease or condition. Compounds can also be administered to lessen or reduce a likelihood of developing, contracting, or worsening a condition. Amounts effective for this use can vary based on the severity and course of the disease or condition, previous therapy, the subject’s health status, weight, response to the drugs, and the judgment of the treating physician.

[0094] Multiple therapeutic agents can be administered in any order or simultaneously. If simultaneously, the multiple therapeutic agents can be provided in a single, unified form, or in multiple forms, for example, as multiple separate pills or injections. The compounds can be packed together or separately, in a single package or in a plurality of packages. One or all of the therapeutic agents can be given in multiple doses. If not simultaneous, then the timing between the multiple doses can vary.

[0095] Compounds and compositions described herein can be packaged as a kit. In some embodiments, the present disclosure provides a kit comprising a compound disclosed herein, or a pharmaceutically-acceptable salt thereof, and written instructions on use of the kit in the treatment of a condition described herein. In some embodiments, the present disclosure provides a kit comprising a compound disclosed herein, or a pharmaceutically-acceptable salt thereof, an antibody, and written instructions on use of the kit in the treatment of a condition described herein.

[0096] The compounds described herein can be administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound can vary. For example, the compounds can be used as a prophylactic and can be administered continuously to subjects with a propensity to conditions or diseases in order to lessen or reduce a likelihood of the occurrence of the disease or condition. The compounds and compositions can be administered to a subject during or as soon as possible after the onset of the symptoms. The administration of the compounds can be initiated within the first 48 hours of the onset of the symptoms, within the first 24 hours of the onset of the symptoms, within the first 6 hours of the onset of the symptoms, or within 3 hours of the onset of the symptoms. The initial administration can be via any route practical, such as by any route described herein using any formulation described herein. [0097] A compound can be administered as soon as is practical after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for example, from about 1 month to about 3 months. In some embodiments, the length of time a compound can be administered can be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 2 months, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 3 months, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 4 months, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 5 months, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months about 23 months, about 2 years, about 2.5 years, about 3 years, about 3.5 years, about 4 years, about 4.5 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, or about 10 years. The length of treatment can vary for each subject.

[0098] Pharmaceutical compositions of the invention can be used, stored, tested, analyzed or assayed at room temperature. The room temperature can be, for example, about 20.0 °C, about 20.1 °C, about 20.2 °C, about 20.3 °C, about 20.4 °C, about 20.5 °C, about 20.6 °C, about 20.7 °C, about 20.8 °C, about 20.9 °C, about 21.0 °C, about 21.1 °C, about 21.2 °C, about 21.3 °C, about 21.4 °C, about 21.5 °C, about 21.6 °C, about 21.7 °C, about 21.8 °C, about 21.9 °C, about 22.0 °C, about 22.1 °C, about 22.2 °C, about 22.3 °C, about 22.4 °C, about 22.5 °C, about 22.6 °C, about 22.7 °C, about 22.8 °C, about 22.9 °C, about 23.0 °C, about 23.1 °C, about 23.2 °C, about 23.3 °C, about 23.4 °C, about 23.5 °C, about 23.6 °C, about 23.7 °C, about 23.8 °C, about 23.9 °C, about 24.0 °C, about 24.1 °C, about 24.2 °C, about 24.3 °C, about 24.4 °C, about 24.5 °C, about 24.6 °C, about 24.7 °C, about 24.8 °C, about 24.9 °C, or about 25.0 °C.

[0099] Any compound herein can be purified. A compound herein, such as a Tie-2 modulator, can be least 1% pure, at least 2% pure, at least 3% pure, at least 4% pure, at least 5% pure, at least 6% pure, at least 7% pure, at least 8% pure, at least 9% pure, at least 10% pure, at least 11% pure, at least 12% pure, at least 13% pure, at least 14% pure, at least 15% pure, at least 16% pure, at least 17% pure, at least 18% pure, at least 19% pure, at least 20% pure, at least 21% pure, at least 22% pure, at least 23% pure, at least 24% pure, at least 25% pure, at least 26% pure, at least 27% pure, at least 28% pure, at least 29% pure, at least 30% pure, at least 31% pure, at least 32% pure, at least 33% pure, at least 34% pure, at least 35% pure, at least 36% pure, at least 37% pure, at least 38% pure, at least 39% pure, at least 40% pure, at least 41% pure, at least 42% pure, at least 43% pure, at least 44% pure, at least 45% pure, at least 46% pure, at least 47% pure, at least 48% pure, at least 49% pure, at least 50% pure, at least 51% pure, at least 52% pure, at least 53% pure, at least 54% pure, at least 55% pure, at least 56% pure, at least 57% pure, at least 58% pure, at least 59% pure, at least 60% pure, at least 61% pure, at least 62% pure, at least 63% pure, at least 64% pure, at least 65% pure, at least 66% pure, at least 67% pure, at least 68% pure, at least 69% pure, at least 70% pure, at least 71% pure, at least 72% pure, at least 73% pure, at least 74% pure, at least 75% pure, at least 76% pure, at least 77% pure, at least 78% pure, at least 79% pure, at least 80% pure, at least 81% pure, at least 82% pure, at least 83% pure, at least 84% pure, at least 85% pure, at least 86% pure, at least 87% pure, at least 88% pure, at least 89% pure, at least 90% pure, at least 91% pure, at least 92% pure, at least 93% pure, at least 94% pure, at least 95% pure, at least 96% pure, at least 97% pure, at least 98% pure, at least 99% pure, at least 99.1% pure, at least 99.2% pure, at least 99.3% pure, at least 99.4% pure, at least 99.5% pure, at least 99.6% pure, at least 99.7% pure, at least 99.8% pure, or at least 99.9% pure.

Solubilizing agents.

[0100] A Tie-2 modulator described herein can be present in a composition with one or more solubilizing and preservative agents. The concentration of a solubilizing agent or additive in a pharmaceutical composition of the disclosure, for example, a non-ionic surfactant, can be from about 0.1 mg/mL to about 300 mg/mL, from about 0.1 mg/mL to about 1 mg/mL, from about 0.1 mg/mL to about 5 mg/mL, from about 1 mg/mL to about 50 mg/mL, from about 5 mg/mL to about 10 mg/mL, from about 10 mg/mL to about 15 mg/mL, from about 15 mg/mL to about 20 mg/mL, from about 20 mg/mL to about 25 mg/mL, from about 25 mg/mL to about 30 mg/mL, from about 30 mg/mL to about 35 mg/mL, from about 35 mg/mL to about 40 mg/mL, from about 40 mg/mL to about 45 mg/mL, about 45 mg/mL to about 50 mg/mL, from about 50 mg/mL to about 55 mg/mL, from about 55 mg/mL to about 60 mg/mL, from about 60 mg/mL to about 65 mg/mL, from about 65 mg/mL to about 70 mg/mL, from about 70 mg/mL to about 75 mg/mL, about 75 mg/mL to about 80 mg/mL, from about 80 mg/mL to about 85 mg/mL, from about 85 mg/mL to about 90 mg/mL, from about 90 mg/mL to about 95 mg/mL, from about 95 mg/mL to about 100 mg/mL, from about 100 mg/mL to about 110 mg/mL, from about 110 mg/mL to about 120 mg/mL, from about 120 mg/mL to about 130 mg/mL, from about 130 mg/mL to about 140 mg/mL, from about 140 mg/mL to about 150 mg/mL, from about 150 mg/mL to about 160 mg/mL, from about 160 mg/mL to about 170 mg/mL, from about 170 mg/mL to about 180 mg/mL, from about 180 mg/mL to about 190 mg/mL, from about 190 mg/mL to about 200 mg/mL, from about 200 mg/mL to about 220 mg/mL, from about 220 mg/mL to about 240 mg/mL, from about 240 mg/mL to about 260 mg/mL, from about 260 mg/mL to about 280 mg/mL, or from about 280 mg/mL to about 300 mg/mL.

[0101] In some embodiments, a Tie-2 modulator of the disclosure has a solubility in a pharmaceutical composition of at least about 10 mg/mL, such as from about 10 mg/mL to about 120 mg/mL, from about 30 mg/mL to about 35 mg/mL, from about 30 mg/mL to about 200 mg/mL, from about 35 mg/mL to about 40 mg/mL, from about 40 mg/mL to about 45 mg/mL, about 45 mg/mL to about 50 mg/mL, from about 50 mg/mL to about 55 mg/mL, from about 55 mg/mL to about 60 mg/mL, from about 60 mg/mL to about 65 mg/mL, from about 65 mg/mL to about 70 mg/mL, from about 70 mg/mL to about 75 mg/mL, about 75 mg/mL to about 80 mg/mL, from about 80 mg/mL to about 85 mg/mL, from about 85 mg/mL to about 90 mg/mL, from about 90 mg/mL to about 95 mg/mL, from about 95 mg/mL to about 100 mg/mL, from about 100 mg/mL to about 110 mg/mL, from about 110 mg/mL to about 120 mg/mL, from about 120 mg/mL to about 130 mg/mL, from about 130 mg/mL to about 140 mg/mL, from about 140 mg/mL to about 150 mg/mL, from about 150 mg/mL to about 160 mg/mL, from about 160 mg/mL to about 170 mg/mL, from about 170 mg/mL to about 180 mg/mL, from about 180 mg/mL to about 190 mg/mL, from about 190 mg/mL to about 200 mg/mL, from about 200 mg/mL to about 220 mg/mL, from about 220 mg/mL to about 240 mg/mL, from about 240 mg/mL to about 260 mg/mL, from about 260 mg/mL to about 280 mg/mL, or from about 280 mg/mL to about 300 mg/mL.

[0102] In some embodiments, the disclosure provides a pharmaceutical composition comprising an aqueous solution of a compound of the disclosure, wherein the concentration of the compound in the solution phase is at least about 25 mg/mL, at least about 30 mg/mL, at least about 35 mg/mL, at least about 40 mg/mL, at least about 45 mg/mL, at least about 50 mg/mL, at least about 55 mg/mL, at least about 60 mg/mL, at least about 65 mg/mL, at least about 70 mg/mL, at least about 75 mg/mL, at least about 80 mg/mL, at least about 85 mg/mL, at least about 90 mg/mL, at least about 95 mg/mL, at least about 100 mg/mL, at least about 105 mg/mL, at least about 110 mg/mL, at least about 115 mg/mL, at least about 120 mg/mL, at least about 125 mg/mL, at least about 130 mg/mL, at least about 135 mg/mL, at least about 140 mg/mL, at least about 145 mg/mL, at least about 150 mg/mL, at least about 155 mg/mL, at least about 160 mg/mL, at least about 165 mg/mL, at least about 170 mg/mL, at least about 175 mg/mL, at least about 180 mg/mL, at least about 185 mg/mL, at least about 190 mg/mL, at least about 195 mg/mL, or at least about 200 mg/mL.

[0103] In some embodiments, the disclosure provides a pharmaceutical composition comprising an aqueous solution of Compound 1 or Compound 2 of TABLE 1, wherein the concentration of Compound 1 or Compound 2 of TABLE 1 in the solution phase is at least 25 mg/mL. In some embodiments, the concentration of Compound 1 or Compound 2 of TABLE 1 in the solution phase is at least 30 mg/mL. In some embodiments, the concentration of Compound 1 or Compound 2 of TABLE 1 in the solution phase is at least 40 mg/mL. In some embodiments, the composition of Compound 1 or Compound 2 of TABLE 1 in the solution phase is at least 50 mg/mL.

[0104] In some embodiments, a Tie-2 modulator of the disclosure has a solubility in a pharmaceutical composition of at least about 30 mg/mL, such as, for example, at least about 40 mg/mL, at least about 50 mg/mL, at least about 60 mg/mL, at least about 70 mg/mL, at least about 80 mg/mL, at least about 90 mg/mL, or at least about 100 mg/mL.

[0105] In some embodiments, the solubility of a compound of the disclosure is increased by addition of an additive or agent to a composition containing the compound. A solubilizing agent, for example, a non-ionic surfactant, can increase the solubility of a compound of the disclosure by about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% about 80%, about 85%, about 90%, about 95%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 225%, about 250%, about 275%, about 300%, about 325%, about 350%, about 375%, about 400%, about 450%, or about 500%.

[0106] In some embodiments, a composition disclosed herein can comprise a ratio of about 20 parts of a compound herein or a pharmaceutically-acceptable salt thereof to about 1 part solubilizing agent (about 20 : about 1), to about 1 part of the compound herein or a pharmaceutically-acceptable salt thereof to about 20 parts solubilizing system (about 1 : about 20). For example, a formulation containing about 100 mg of a compound herein or a pharmaceutically-acceptable salt thereof can contain from about 5 mg to about 2000 mg of a solubilizing agent, such as polyoxyl 35. In another embodiment, the ratio can be based on number, or moles, or compound compared to number, or moles, of the solubilizing system. [0107] The following are non-limiting examples of ratios of a compound herein and a solubilizing agent, such as a non-ionic surfactant. The following examples alternatively describe the mass ratio of a solubilizing agent, such as a non-ionic surfactant, and a compound herein. The ratio can be: about 20 : about 1; about 19.9 : about 1; about 19.8 : about 1; about 19.7 : about 1; about 19.6 : about 1; about 19.5 : about 1; about 19.4 : about 1; about 19.3 : about 1; about 19.2 : about 1; about 19.1 : about 1; about 19 : about 1; about 18.9 : about 1; about 18.8 : about 1; about 18.7 : about 1; about 18.6 : about 1; about 18.5 : about 1; about 18.4 : about 1; about 18.3 : about 1; about 18.2 : about 1; about 18.1 : about 1; about 18 : about 1; about 17.9 : about 1; about 17.8 : about 1; about 17.7 : about 1; about 17.6 : about 1; about 17.5 : about 1; about 17.4 : about 1; about 17.3 : about 1; about 17.2 : about 1; about 17.1 : about 1; about 17 : about 1; about 16.9 : about 1; about 16.8 : about 1; about 16.7 : about 1; about 16.6 : about 1; about 16.5 : about 1; about 16.4 : about 1; about 16.3 : about 1; about 16.2 : about 1; about 16.1 : about 1; about 16 : about 1; about 15.9 : about 1; about 15.8 : about 1; about 15.7 : about 1; about 15.6 : about 1; about 15.5 : about 1; about 15.4 : about 1; about 15.3 : about 1; about 15.2 : about 1; about 15.1 : about 1; about 15 : about 1; about 14.9 : about 1; about 14.8 : about 1; about 14.7 : about 1; about 14.6 : about 1; about

14.5 : about 1; about 14.4 : about 1; about 14.3 : about 1; about 14.2 : about 1; about 14.1 : about 1; about 14 : about 1; about 13.9 : about 1; about 13.8 : about 1; about 13.7 : about 1; about 13.6 : about 1; about 13.5 : about 1; about 13.4 : about 1; about 13.3 : about 1; about 13.2 : about 1; about 13.1 : about 1; about 13 : about 1; about 12.9 : about 1; about 12.8 : about 1; about 12.7 : about 1; about 12.6 : about 1; about 12.5 : about 1; about 12.4 : about 1; about 12.3 : about 1; about 12.2 : about 1; about 12.1 : about 1; about 12 : about 1; about 11.9 : about 1; about 11.8 : about 1; about 11.7 : about 1; about 11.6 : about 1; about 11.5 : about 1; about 11.4 : about 1; about 11.3 : about 1; about 11.2 : about 1; about 11.1 : about 1; about 11 : about 1; about 10.9 : about 1; about 10.8 : about 1; about 10.7 : about 1; about 10.6 : about 1; about 10.5 : about 1; about 10.4 : about 1; about 10.3 : about 1; about 10.2 : about 1; about 10.1 : about 1; about 10 : about 1; about 9.9 : about 1; about 9.8 : about 1; about 9.7 : about 1; about 9.6 : about 1; about 9.5 : about 1; about 9.4 : about 1; about 9.3 : about 1; about 9.2 : about 1; about 9.1 : about 1; about 9 : about 1; about 8.9 : about 1; about 8.8 : about 1; about 8.7 : about 1; about 8.6 : about 1; about 8.5 : about 1; about 8.4 : about 1; about 8.3 : about 1; about 8.2 : about 1; about 8.1 : about 1; about 8 : about 1; about 7.9 : about 1; about 7.8 : about 1; about 7.7 : about 1; about 7.6 : about 1; about 7.5 : about 1; about 7.4 : about 1; about 7.3 : about 1; about 7.2 : about 1; about 7.1 : about 1; about 7 : about 1; about 6.9 : about 1; about 6.8 : about 1; about 6.7 : about 1; about 6.6 : about 1; about 6.5 : about 1; about 6.4 : about 1; about 6.3 : about 1; about 6.2 : about 1; about 6.1 : about 1; about 6 : about 1; about 5.9 : about 1; about 5.8 : about 1; about 5.7 : about 1; about 5.6 : about 1; about 5.5 : about 1; about 5.4 : about 1; about 5.3 : about 1; about 5.2 : about 1; about 5.1 : about 1; about 5 : about 1; about 4.9 : about 1; about 4.8 : about 1; about 4.7 : about 1; about 4.6 : about 1; about 4.5 : about 1; about 4.4 : about 1; about 4.3 : about 1; about 4.2 : about 1; about 4.1 : about 1; about 4 : about 1; about 3.9 : about 1; about 3.8 : about 1; about 3.7 : about 1; about 3.6 : about 1; about 3.5 : about 1; about 3.4 : about 1; about 3.3 : about 1; about 3.2 : about 1; about 3.1 : about 1; about 3 : about 1; about 2.9 : about 1; about 2.8 : about 1; about 2.7 : about 1; about 2.6 : about 1; about 2.5 : about 1; about 2.4 : about 1; about 2.3 : about 1; about 2.2 : about 1; about 2.1 : about 1; about 2 : about 1; about 1.9 : about 1; about 1.8 : about 1; about 1.7 : about 1; about 1.6 : about 1; about 1.5 : about 1; about 1.4 : about 1; about 1.3 : about 1; about 1.2 : about 1; about 1.1 : about 1; or about 1 : about 1.

Cyclodextrins.

[0108] Non-limiting examples of cyclodextrins include P-cyclodextrin, methyl P- cyclodextrin, 2-hydroxypropyl-P-cyclodextrin (HPpCD), hydroxy ethyl -P-cyclodextrin (HE- P-CD), heptakis (2,6-di-O-methyl)-P-cyclodextrin (DMpCD), a-cyclodextrin, y-cyclodextrin, 2-hydroxypropyl-y-cyclodextrin (HPyCD), and sulfobutylether-P-cyclodextrin (SBECD) sodium salt. A cyclodextrin can possess a large cyclic structure with a channel passing through the center of the structure. The interior of the cyclodextrin can be hydrophobic, and interact favorably with hydrophobic molecules. The exterior of the cyclodextrin can be highly hydrophilic owing to the several hydroxyl groups exposed to bulk solvent. Capture of a hydrophobic molecule, such as a compound disclosed herein, in the channel of the cyclodextrin can result in the formation of a complex stabilized by non-covalent hydrophobic interactions. The complex can be soluble in water, and carry the captured hydrophobic molecule into the bulk solvent.

[0109] Compositions of the disclosure can comprise randomly methylated P-cyclodextrins (RAMEB or RMCD). The compositions of the disclosure can comprise RAMEB comprising at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 methyl groups.

[0110] The disclosed solubilizing systems comprise 2-hydroxypropyl-beta-cyclodextrin (HPpCD). 2-Hydroxypropyl-P-cyclodextrin [CAS No. 128446-35-5] is commercially available as Cavitron™. 2-Hydroxypropyl-P-cyclodextrin, also described known as hydroxypropyl-P-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin, hydroxypropyl-beta- cyclodextrin or HPpCD, can be represented by either of the following formulae:

[OHl] The average molecular weight of Cavitron™, is approximately 1396 Da, wherein the average degree of substitution is from about 0.5 to about 1.3 units of 2-hydroxypropyl per ring glucose unit.

Surfactants.

[0112] Solubilizing agents of the present disclosure can also comprise non-ionic surfactants, such as polyvinylpyrrolidones, polyalkyleneoxides and ethers thereof including sorbitan derivatives, polyalkylated fatty acid esters, alkoxylated alkylphenols, polypropylene glycols, and vitamin E derivatives.

[0113] In some embodiments, a pharmaceutical composition of the disclosure can comprise a Tie-2 modulator and a surfactant, wherein the surfactant has a concentration in the composition that is from about 0.05% (v/v) to about 20% (v/v), such as from about 0.05% to about 0.06%, from about 0.05% to about 0.07%, from about 0.05% to about 0.08%, from about 0.05% to about 0.09%, from about 0.05% to about 0.1%, from about 0.05% to about 0.2%, from about 0.05% to about 0.3%, from about 0.05% to about 0.4%, from about 0.05% to about 0.5%, from about 0.05% to about 1%, from about 0.05% to about 2%, from about 0.05% to about 3%, from about 0.05% to about 4%, from about 0.05% to about 5%, from about 0.05% to about 6%, from about 0.05% to about 7%, from about 0.05% to about 8%, from about 0.05% to about 9%, from about 0.05% to about 10%, from about 0.1% to about 0.5%, from about 0.5% to about 1%, from about 0.5% to about 2%, from about 1% to about 2%, from about 2% to about 3%, from about 2% to about 4%, from about 3% to about 4%, from about 3% to about 5%, from about 3% to about 6%, from about 3% to about 7%, from about 5% to about 10%, from about 5% to about 15%, and from about 5% to about 20% (v/v).

[0114] In some embodiments, a pharmaceutical composition of the disclosure can comprise a Tie-2 modulator and a surfactant, wherein the surfactant has a concentration in the composition that is at least about 0.05%, such as about 0.05% about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% (v/v).

[0115] In some embodiments, a pharmaceutical composition of the disclosure can comprise an aqueous solution of Compound 1 or Compound 2 of TABLE 1 with one or more nonionic surfactants and one or more preservatives. In some embodiments, the concentration of the nonionic surfactant in the composition is at least about 0.05%, such as about 0.05% about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% (v/v).

Polyvinylpyrrolidones. [0116] Another non-limiting example of a solubilizing agent is polyvinylpyrrolidone (PVP), having the formula: where the index n is from about 40 to about 200. PVPs can have an average molecular weight from about 5,500 to about 28,000 g/mol. One non-limiting example is PVP-10, having an average molecular weight of approximately 10,000 g/mol. Other non-limiting examples include povidone K12, povidone K25, povidone K27, povidone K29/32, povidone K30, and povidone K90. In some embodiments, the solubilizing agent can be a copolymer, such as a block copolymer comprising povidone and vinyl acetate monomers. One non-limiting example is copovidone K25-31, a copolymer of l-vinyl-2-pyrrolidone and vinyl acetate in the mass proportion of 3 :2 with an average molecular weight of 40,000.

Polyalkyleneoxides and Ethers Thereof.

[0117] Another non-limiting example of solubilizing agents and non-ionic surfactants includes polyalkyleneoxides, and polymers of alcohols or polyols. Polymers can be mixed, or contain a single monomeric repeat subunit.

Polyethylene Glycols.

[0118] A polyalkyleneoxide of the disclosure can be a polyethylene glycol of the following formula:

HO[CH ₂ CH ₂ O] _X H where x represents the average number of ethylene oxide units in the polymer.

[0119] For example, polyethylene glycols can have an average molecular weight of from about 200 to about 20,000, for example, PEG 200, PEG 400, PEG 600, PEG 1000, PEG 1450, PEG 1500, PEG 4000, PEG 4600, PEG 6000, and PEG 8000. In a same embodiment, a composition comprises one or more polyethylene glycols chosen from PEG 400, PEG 1000, PEG 1450, PEG 4600, and PEG 8000.

Sorbitan derivatives.

[0120] In some embodiments, the solubilizing agent can be a sorbitan derivative, such as a sorbitan ester or polysorbate. A sorbitan ester can be, for example, sorbitan monostearate, sorbitan tristearate, sorbitan monolaurate, sorbitan monooleate, and sorbitan monopalmitate. In some embodiments, the solubilizing agent is a polysorbate, which can include polyethoxylated derivates of sorbitan that are esterfied with fatty acids, such as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, and polysorbate 80, as well as PEG-20 sorbitan isostearate and PEG-40 sorbitan diisostearate. In some embodiments, the solubilizing agent comprises Polysorbate 80 (Tween™ 80), which is an oleate ester of sorbitol and anhydrides thereof copolymerized with approximately 20 moles of ethylene oxide for each mole of sorbitol and sorbitol anhydrides. Polysorbate 80 is made up of sorbitan mono-9- octadecanoate poly(oxy-l,2-ethandiyl) derivatives.

Polyalkoxylated fatty acid esters.

[0121] In some embodiments, the solubilizing agent can be a composition containing polyethoxyl fatty acid esters, such as a polyethoxylated castor oil, including compositions containing polyethylene glycol ethers, and the esters of ricinoleic acid and glycerol or polyethylene glycol. In some embodiments, the solubilizing agent can be polyoxyl-35 castor oil (polyoxyl 35) comprising ricinoleate esters having the formula: where the indices x, y, and x have average values that result from the reaction of 35 moles of ethylene oxide with one mole of glycerol ricinoleate.

[0122] In some embodiments, the solubilizing agent can be polyoxyl 40 hydrogenated castor oil. In some embodiments, the solubilizing agent can comprise polyethoxyl sterates, isostearates, hydroxystearates, or oleates, such as polyoxyl 40 stearate, polyoxyl 50 stearate, PEG-2 stearate, PEG-50 stearate, PEG-100 stearate, PEG-120 glyceryl stearate, polyoxyl glyceryl stearate, PEG- 15 hydroxy stearate, polyoxyl 20 cetostearyl ether, or polyoxyl 10 oleyl ether.

Alkoxylated alkylphenols.

[0123] In some embodiments, the solubilizing agent can be an alkoxylated or polyalkoxylated alkylphenol, such as an octoxynol. Octoxynols are octylphenoxypoly— (ethyleneoxy)ethanols with the structural formula: wherein the index x represents the average number of ethyleneoxy units in the polymer. Octoxynols can be characterized by an average number of ethyleneoxy units. For example, octoxynol-40 is formed by the condensation of octyl phenol with 40 moles of ethylene oxide. Other non-limiting examples of octoxynols include Octoxynol-1, Octoxynol-3, Octoxynol-5, Octoxynol-6, Octoxynol-7, Octoxynol-8, Octoxynol-9, Octoxynol-10, Octoxynol-11, Octoxynol-12, Octoxynol-13, Octoxynol-16, Octoxynol-20, Octoxynol-25, Octoxynol-30, Octoxynol-33, Octoxynol-40, or Octoxynol-70. In some embodiments, the solubilizing agent can be a nonoxynol, such as nonoxynol-9 or nonoxynol-10. In some embodiments, the solubilizing agent is a crosslinked polyethoxylated alkylphenol, such as tyloxapol.

Polypropylene glycols.

[0124] Other polyalkyleneoxides are polypropylene glycols having the formula: HO[CH(CH ₃ )CH ₂ O] _X H wherein the index x represents the average number of propyleneoxy units in the polymer. The index x can be represented by a whole number or a fraction. For example, a polypropylene glycol having an average molecular weight of 8,000 g/mole (PPG 8000) can be represented by the formulae:

HO[CH(CH ₃ )CH ₂ O]i ₃₈ H or HO[CH(CH ₃ )CH ₂ O]I _{37 6} H or the polypropylene glycol can be represented by the common shorthand notation: PPG 8000.

[0125] Another example of polypropylene glycols can have an average molecular weight from about 1,200 g/mol to about 20,000 g/mol, i.e., a polypropylene glycol having an average molecular weight of about 8,000 g/mol, for example, PPG 8000.

[0126] Solubilizing agents also include poloxamers having the formula: HO(CH ₂ CH ₂ ) _y i(CH ₂ CH ₂ CH ₂ O) _y2 (CH ₂ CH ₂ O) _y3 OH which are nonionic block copolymers composed of a polypropyleneoxy unit flanked by two polyethyleneoxy units. The indices y ¹ , y ² , and y ³ have values such that the poloxamer has an average molecular weight of from about 1,000 g/mol to about 20,000 g/mol. Such solubilizing agents can include, for example, poloxamer 124, poloxamer 182, poloxamer 188, poloxamer 331, or poloxamer 407, including those listed in the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration.

Vitamin E derivatives.

[0127] In some embodiments, the solubilizing agent can be a substance belonging to the Vitamin E group of compounds or a derivative thereof, such as a tocopherol or a tocotrienol. In some embodiments, the solubilizing agent can be a modified tocopheryl, such as a polyethoxylated tocopheryl, which can include succinyl derivatives of the following structural formula: where x is the average number of ethyleneoxy units in the polymer. One such tocopherol derivative can be d-a-Tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS). In another aspect of the disclosure, the compounds disclosed herein (e.g., Compound 1 and Compound 2 of TABLE 1) can be dissolved in a non-aqueous formulation, which can include formulations in which the total water content is below 5% of the total weight of the composition.

[0128] In some embodiments, a pharmaceutical composition of the disclosure can comprise a mixture of two or more surfactants, including, for example, a mixture of polyethylene glycol and a tocopherol, a sorbitan and an alkoxylated alkylphenol, a polyvinylpyrrolidone and a sorbitan, a poloxamer and a tocopherol, a polyethoxyl fatty acid ester and a tocopherol, a polyethoxyl fatty acid ester and a polyvinylpyrrolidone, a polyethoxyl fatty acid ester and a sorbitan, a polyethoxyl fatty acid ester and a polyethylene glycol, a polyethoxyl fatty acid ester and an alkoxylated alkylphenol, and a polyethoxyl fatty acid ester and a poloxamer. In some embodiments, a pharmaceutical composition of the disclosure can comprise a polyvinylpyrrolidone and another surfactant, such as an alkoxylated alkylphenol, a tocopherol, a polyethoxyl fatty acid ester, a sorbitan, or a poloxamer. In some embodiments, the polyvinylpyrrolidone is PVP K30.

[0129] Non-limiting examples of pharmaceutical compositions of the disclosure that comprise two or more surfactants include compositions that comprise PEG400 and vitamin E TPGS, octoxynol-40 and polysorbate 80, octoxynol-40 and polyoxyl 35, PVP K30 and polysorbate 80, and poloxamer 704 and vitamin E TPGS. [0130] In some embodiments, a compound disclosed herein can be dissolved in a mixture of Vitamin E TPGS and PEG 400. For example, a solubilizing agent of the disclosure can be a mixture of Vitamin E TPGS and PEG 400 in a mass to volume ratio equal to or no larger than 20: 1, such as about 20: 1, about 15: 1. about 10: 1, about 10:3, about 5: 1, about 5:2, about 4: 1, about 3: 1, about 2: 1, about 1 : 1, about 1 :2, about 1 :3, about 1 :4, about 1 :5, about 1 : 10, or about 1 :20. In some embodiments, a ratio of Vitamin E TPGS to PEG400 in a pharmaceutical composition of the disclosure is from about 5: 1 to about 1 : 1 by volume. In some embodiments, the weight to volume ratio of Vitamin E TPGS EG 400 is about 4: 1. In some embodiments, a ratio of Vitamin E TPGS to PEG 400 can be expressed as mass/volume.

[0131] In some embodiments, the pharmaceutical composition comprises no more than about 20% water by mass. In some embodiments, the pharmaceutical composition comprises no more than about 10% water by mass. In some embodiments, the pharmaceutical composition comprises no more than about 5% water by mass. In some embodiments, the pharmaceutical composition comprises no more than about 1% water by mass. In some embodiments, the pharmaceutical composition comprises no more than about 0.5% water by mass. In some embodiments, the pharmaceutical composition comprises no more than about 0.1% water by mass.

Organic solvents.

[0132] A non-limiting example of a solubilizing agent includes an organic solvent. Nonlimiting examples of organic solvents include alcohols, for example, C1-C4 linear alkyl, C3-C4 branched alkyl, ethanol, ethylene glycol, glycerin, 2-hydroxypropanol, propylene glycol, maltitol, sorbitol, xylitol; substituted or unsubstituted aryl, benzyl alcohol, and 2- phenyl ethanol.

Preservatives and tonicity agents.

[0133] In some embodiments, the solubilizing agent is co-formulated with a preservative, where the concentration of the preservative. In some embodiments, the preservative is an alcohol. In some embodiments, the preservative is 2-phenylethanol. In some embodiments, the 2-phenylethanol is present in the composition at a concentration from about 0.01% to about 2%, such as about 0.01%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2% (v/v).

[0134] In some embodiments, the solubilizing agent is co-formulated with a tonicity agent. In some embodiments, the tonicity agent is mannitol. In some embodiments, the mannitol is present in the composition at a concentration from about 0.01% to about 5%, such as about 0.01%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 3%, about 4%, or about 5% (m/v). In some embodiments, the mannitol is present in the composition at a concentration from about 0.8% (m/v) to about 2.2% (m/v).

[0135] In some embodiments, the tonicity agent is glycerol. In some embodiments, the glycerol is present in the composition at a concentration from about 0.05% (v/v) to about 5% (v/v). In some embodiments, the glycerol is present in the composition at a concentration from about 0.4% (v/v) to about 1.2% (v/v), such as about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, or about 1.2% (v/v).

[0136] In some embodiments, the tonicity agent is dextrose. In some embodiments, the dextrose is present in the composition at a concentration from about 0.05% (v/v) to about 5% (v/v). In some embodiments, the dextrose is present in the composition at a concentration from about 0.4% (v/v) to about 1.2% (v/v), such as about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, or about 1.2% (v/v).

[0137] In some embodiments, the pharmaceutical composition comprises about 5% polyoxyl 35, about 0.4% 2 -phenyl ethanol, and a tonicity agent. In some embodiments, the tonicity agent is glycerol at a concentration of about 0.5% to about 1%. In some embodiments, the tonicity agent is mannitol at a concentration of about 1% to about 2%. In some embodiments, the tonicity agent is glycerol at a concentration of about 0.92% or about 0.65%. In some embodiments, the tonicity agent is mannitol at a concentration of about 1.2% or about 1.8%. [0138] In some embodiments, the solubility of Compound 1 or Compound 2 of TABLE 1 in the pharmaceutical composition is at least 25 mg/mL. In some embodiments, the solubility of Compound 1 or Compound 2 of TABLE 1 in the pharmaceutical composition is at least 30 mg/mL. In some embodiments, the solubility of Compound 1 or Compound 2 of TABLE 1 in the pharmaceutical composition is at least 40 mg/mL. In some embodiments, the solubility of Compound 1 or Compound 2 of TABLE 1 in the pharmaceutical composition is at least 50 mg/mL. Stability and Storage.

[0139] In some embodiments, a pharmaceutical composition of the disclosure remains chemically stable for at least about 1 week when stored at room temperature, including, for example, for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, or at least about 10 weeks when stored at room temperature.

[0140] In some embodiments, the pharmaceutical composition exhibits no more than about 10%, about 9%, about 8%, about 7%, about 6%, about 5%, about 4.9%, about 4.8%, about 4.7%, about 4.6%, about 4.5%, about 4.4%, about 4.3%, about 4.2%, about 4.1%, about 4%, about 3.9%, about 3.8%, about 3.7%, about 3.6%, about 3.5%, about 3.4%, about 3.3%, about 3.2%, about 3.1%, about 3%, about 2.9%, about 2.8%, about 2.7%, about 2.6%, about 2.5%, about 2.4%, about 2.3%, about 2.2%, about 2.1%, about 2%, about 1.9%, about 1.8%, about 1.7%, about 1.6%, about 1.5%, about 1.4%, about 1.3%, about 1.2%, about 1.1%, about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, or about 0.05% degradation of the Tie-2 modulator after storage at room temperature.

[0141] A composition disclosed herein can be stable for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 15 days, about 20 days, about 25 days, about 30 days, about 35 days, about 40 days, about 45 days, about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about one year. A formulation disclosed herein can be stable, for example, at about 0 °C, about 5 °C, about 10 °C, about 15 °C, about 20 °C, about 25 °C, about 30 °C, about 35 °C, about 40 °C, about 45 °C, about 50 °C, about 60 °C, about 70 °C, or about 80 °C.

[0142] In some embodiments, the pharmaceutical composition exhibits no more than about 2% degradation of the Tie-2 modulator after storage at room temperature for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, or at least about 10 weeks when stored at room temperature.

[0143] In some embodiments, the pharmaceutical composition exhibits no more than about 1% degradation of the Tie-2 modulator after storage at room temperature for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, or at least about 10 weeks when stored at room temperature.

[0144] In some embodiments, the pharmaceutical composition exhibits no more than about 2%, no more than about 1.9%, no more than about 1.8%, no more than about 1.7%, no more than about 1.6%, no more than about 1.5%, no more than about 1.4%, no more than about 1.3%, no more than about 1.2%, no more than about 1.1%, no more than about 1%, no more than about 0.9%, no more than about 0.8%, no more than about 0.7%, no more than about 0.6%, no more than about 0.5%, no more than about 0.4%, no more than about 0.3%, no more than about 0.2%, no more than about 0.1%, no more than about 0.09%, no more than about 0.08%, no more than about 0.07%, no more than about 0.06%, or no more than about 0.05% degradation of the Tie-2 modulator after storage at room temperature.

[0145] In some embodiments, the pharmaceutical composition remains physically stable for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, or at least about 10 weeks.

[0146] In some embodiments, a concentration of the Tie-2 modulator in the pharmaceutical composition decreases by no more than about 2%, no more than about 1.9%, no more than about 1.8%, no more than about 1.7%, no more than about 1.6%, no more than about 1.5%, no more than about 1.4%, no more than about 1.3%, no more than about 1.2%, no more than about 1.1%, no more than about 1%, no more than about 0.9%, no more than about 0.8%, no more than about 0.7%, no more than about 0.6%, or no more than about 0.5% after storage at any temperature disclosed herein for any time disclosed herein.

[0147] In some embodiments, a viscosity of a pharmaceutical composition disclosed herein is measured in Pascal-seconds (Pa s) can increase by no more than a factor of about 10 ⁴ , no more than a factor of about 10 ³ , no more than a factor of about 10 ² , or no more than a factor of about 10. In some embodiments, a viscosity of a pharmaceutical composition disclosed herein is measured in centipoise (mPa s; cP).

[0148] In some embodiments, a viscosity of the pharmaceutical composition increases by no more than a factor of 10 after storage at room temperature for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, or about 10 weeks.

[0149] In some embodiments, a viscosity of the pharmaceutical composition increases by no more than a factor of 10 ⁴ after storage at room temperature for about 5 weeks, including, for example, no more than a factor of about 10 ³ , about 10 ² , or about 10 after storage at room temperature for about 5 weeks.

[0150] In some embodiments, a viscosity of the pharmaceutical composition at 1 atmosphere and 25 °C increases by no more than a factor of 10 ⁴ after storage at room temperature for about 5 weeks, including, for example, no more than a factor of about 10 ³ , about 10 ² , or about 10 after storage at room temperature for about 5 weeks.

[0151] In some embodiments, the pharmaceutical composition remains clear for at least about 2 weeks while being stored at room temperature. In some embodiments, the pharmaceutical composition remains clear for at least about 3 weeks while being stored at room temperature. In some embodiments, the pharmaceutical composition remains clear for at least about 5 weeks while being stored at room temperature. In some embodiments, the pharmaceutical composition remains clear for at least about 7 weeks while being stored at room temperature.

Additional agents.

[0152] A pharmaceutical composition disclosed herein can be formulated with another compound, such as a compound that can enhance the solubility of an agent that treats vascular disease. The other compound can be a surfactant, which can comprise a hydrophilic region connected to a hydrophobic region. The hydrophilic region can comprise a linear oligomeric moiety, which can be, for example, a substituted or unsubstituted aliphatic chain, such as an alkyl, alkenyl, or alkynyl group.

[0153] In some embodiments, the other compound comprises a hydrophobic chain and a remainder of the compound, wherein the remainder of the compound is attached to the hydrophobic chain.

[0154] In some embodiments, the hydrophobic chain comprises a point of attachment that attaches the hydrophobic chain to the remainder of the compound, and at least five consecutive carbon atoms. In some embodiments, the hydrophobic chain comprises at least six, at least seven, at least eight, at least nine, or at least ten carbon atoms.

[0155] In some embodiments, the hydrophobic chain further comprises a terminal methyl group and a substituted carbon atom between the terminal methyl group and the point of attachment that attaches the hydrophobic chain to the remainder of the compound. In some embodiments, the substituted carbon atom is within about 20 atoms, about 19 atoms, about 18 atoms, about 17 atoms, about 16 atoms, about 15 atoms, about 14 atoms, about 13 atoms, about 12 atoms, about 11 atoms, about 10 atoms, about 9 atoms, about 8 atoms, about 7 atoms, about 6 atoms, or about 5 atoms of the terminal methyl group. In some embodiments, the substituted carbon atom is substituted with methyl, ethyl, hydroxyl, or methoxy.

[0156] In some embodiments, the remainder of the compound comprises a repeat unit. In some embodiments, the repeat unit comprises an oxygen atom that is sp ³ . In some embodiments, the repeat unit is part of the hydrophilic moiety. In some embodiments, the repeat unit is the repeating unit of a polyethylene glycol chain. In some embodiments, the repeat unit is the repeating unit of a polypropylene glycol chain. In some embodiments, the repeat unit is -CH2CH2O-.

[0157] In some embodiments, the repeat unit is present in the hydrophilic moiety at a number from 2 to about 1600, including, for example, from about 700 to about 1300, from about 800 to about 1200, from about 900 to about 1100, from 2 to about 1500, from 2 to about 6000, from 2 to about 200, from 2 to about 160, from 2 to about 80, from 2 to about 20, from 2 to about 15, from 3 to about 1600, from 3 to about 1200, from 3 to about 800, from 3 to about 600, from 3 to about 400, from 3 to about 300, from 3 to about 200, and from 3 to about 120.

[0158] In some embodiments, the other compound is of the formula: wherein

R ¹ is alkyl substituted with methyl, ethyl, hydroxyl, or methoxy;

G is -CH2CH2O-;

L is -C(=O)(CH ₂ ) _m C(=O)-, wherein m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each R ^a , R ^b , and R ^c is independently hydrogen, methyl, ethyl, hydroxyl, or -OMe; and n is from 2 to about 6000.

[0159] In some embodiments, the other compound is of the formula: wherein n is from about 900 to about 1100.

[0160] In some embodiments, the other compound is Vitamin E TPGS. In some embodiments, the Vitamin E TPGS is present in the composition at a concentration from about 1 mg/mL to about 300 mg/mL. In some embodiments, the Vitamin E TPGS is present in the composition at a concentration from about 5 mg/mL to about 200 mg/mL. In some embodiments, the Vitamin E TPGS is present in the composition at a concentration of about 5 mg/mL, about 10 mg/mL, about 15 mg/mL, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL, about 60 mg/mL, about 70 mg/mL, about 80 mg/mL, about 90 mg/mL, about 100 mg/mL, about 110 mg/mL, about 120 mg/mL, about 130 mg/mL, about 140 mg/mL, about 150 mg/mL, about 160 mg/mL, about 170 mg/mL, about 180 mg/mL, about 190 mg/mL, about 200 mg/mL, about 250 mg/mL, or about 300 mg/mL.

[0161] In some embodiments, the other compound is of the formula: wherein

G is -CH2CH2O-; one of R ¹ , R ² , R ³ , R ⁴ , and R ⁵ is alkyl substituted with methyl, ethyl, hydroxyl, or methoxy, and each R ¹ , R ² , R ³ , R ⁴ , and R ⁵ that is not alkyl is H; and n is from 2 to about 200.

[0162] In some embodiments, the other compound is of the formula: wherein n is from 2 to about 80.

[0163] In some embodiments, the other compound is octoxynol-40. In some embodiments, the octoxynol-40 is present in the composition at a concentration from about 0.1 mg/mL to about 20 mg/mL, from about 0.1 mg/mL to about 10 mg/mL, from about 0.1 mg/mL to about 5 mg/mL, or from about 0.01 mg/mL to about 2 mg/mL. In some embodiments, the octoxynol-40 is present in the composition at a concentration of about 2 mg/mL, about 1.9 mg/mL, about 1.8 mg/mL, about 1.7 mg/mL, about 1.6 mg/mL, about 1.5 mg/mL, about 1.4 mg/mL, about 1.3 mg/mL, about 1.2 mg/mL, about 1.1 mg/mL, about 1 mg/mL, about 0.9 mg/mL, about 0.8 mg/mL, about 0.7 mg/mL, about 0.6 mg/mL, about 0.5 mg/mL, about 0.4 mg/mL, about 0.3 mg/mL, about 0.2 mg/mL, about 0.1 mg/mL, about 0.09 mg/mL, about 0.08 mg/mL, about 0.07 mg/mL, about 0.06 mg/mL, about 0.05 mg/mL, about 0.04 mg/mL, about 0.03 mg/mL. about 0.03 mg/mL, about 0.02 mg/mL, or about 0.01 mg/mL.

[0164] In some embodiments, the other compound is of the formula: wherein each G is -CH2CH2O-; each of R ¹ and R ² is independently hydrogen or methyl; each instance of any one of R ^a , R ^b , and R ^c is alkyl substituted with methyl, ethyl, hydroxyl, or methoxy, and each R ^a , R ^b , and R ^c that is not alkyl is H; each n is independently 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; and z is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0165] In some embodiments, the other compound is of the formula: wherein n is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; and z is 1, 2, 3, 4, 5, 6, 7, 8, or 9.

[0166] In some embodiments, the other compound is tyloxapol. In some embodiments, the tyloxapol is present in the composition at a concentration from about 0.1 mg/mL to about 20 mg/mL, from about 0.1 mg/mL to about 10 mg/mL, from about 0.1 mg/mL to about 5 mg/mL, or from about 0.01 mg/mL to about 2 mg/mL. In some embodiments, the tyloxapol is present in the composition at a concentration of about 2 mg/mL, about 1.9 mg/mL, about 1.8 mg/mL, about 1.7 mg/mL, about 1.6 mg/mL, about 1.5 mg/mL, about 1.4 mg/mL, about 1.3 mg/mL, about 1.2 mg/mL, about 1.1 mg/mL, about 1 mg/mL, about 0.9 mg/mL, about 0.8 mg/mL, about 0.7 mg/mL, about 0.6 mg/mL, about 0.5 mg/mL, about 0.4 mg/mL, about 0.3 mg/mL, about 0.2 mg/mL, about 0.1 mg/mL, about 0.09 mg/mL, about 0.08 mg/mL, about 0.07 mg/mL, about 0.06 mg/mL, about 0.05 mg/mL, about 0.04 mg/mL, about 0.03 mg/mL. about 0.03 mg/mL, about 0.02 mg/mL, or about 0.01 mg/mL.

[0167] In some embodiments, the other compound is of the formula: wherein each of R ¹ , R ² , and R ³ is independently alkyl or alkenyl, wherein each alkyl or alkenyl is independently substituted with methyl, ethyl, hydroxyl, or methoxy; each of G ¹ , G ² , and G ³ is -CH2CH2O-; and each of x, y, and z is independently from 1 to about 400.

[0168] In some embodiments, the other compound is of the formula: wherein x+y+z has a sum that is from 3 to about 120.

[0169] In some embodiments, the other compound is polyoxyl 35 castor oil. In some embodiments, the polyoxyl 35 castor oil is present in the composition at a concentration from about 1 mg/mL to about 50 mg/mL. In some embodiments, the polyoxyl 35 castor oil is present in the composition at a concentration from about 1 mg/mL to about 10 mg/mL. In some embodiments, the polyoxyl 35 castor oil is present in the composition at a concentration of about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, or about 10 mg/mL.

Treatment of Subjects with a Tie-2 activator.

[0170] The present disclosure provides methods for treating a subject having a vascular disorder with an activator of Tie-2 or an inhibitor of HPTPp. The subject can be a human. Treatment can include treating a human in a clinical trial. A treatment can comprise administering to a subject a pharmaceutical composition comprising one or more of the activators of Tie-2 described throughout the disclosure. A treatment can comprise administrating to a subject a therapy that promotes the phosphorylation of a Tie-2 molecule. [0171] The present disclosure provides methods for treating a subject having a vascular disorder with a therapeutically-effective amount of an activator of Tie-2 or an inhibitor of HPTPp. The subject can be a human. Treatment can include treating a human in a clinical trial. A treatment can comprise administering to a subject a pharmaceutical composition comprising one or more of the activators of Tie-2 described throughout the disclosure. A treatment can comprise administering to a subject a therapy that promotes the phosphorylation of a Tie-2 molecule. A therapeutically-effective amount can be from about 0.1 mg to about 100 mg or from about 0.5 mg to about 30 mg.

[0172] Non-limiting examples of possible subjects for administration include the following. Subjects can be humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; and laboratory animals including rats, mice, and guinea pigs. A subject can be of any age. Subjects can be, for example, elderly adults, adults, adolescents, pre-adolescents, children, toddlers, and infants.

[0173] A subject described herein can express Ang-1. A subject described herein can express Ang2. A subject described herein can express both Ang-1 and Ang-2.

[0174] Some conditions can lead to an increase in the levels of Ang-2, altering the ratio of Ang-l/Ang-2 in circulation. In some embodiments, a therapy can improve the outcome of a disease state by altering the ratio of Ang-l/Ang-2 in circulation. A therapy can provide an Ang-l/Ang-2 ratio or an Ang-2/ Ang-1 ratio of about 1 : about 1, about 2 : about 1, about 3 : about 1, about 4 : about 1, about 5 : about 1, about 6 : about 1, about 7 : about 1, about 8 : about 1, about 9 : about 1, or about 10 : about 1.

EXAMPLES

[0175] Non-limiting examples of compounds disclosed herein are listed in TABLE 1.

TABLE 1

EXAMPLE 1: Determination of Solubility, Physical Stability, and Chemical Stability of Compounds 1 and 2 in Formulations Containing Surfactants.

[0176] Z>-a-Tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) (10 mg) was added to water (2 mL), and the resulting mixture was stirred at room temperature for 20 min. Compound 1 was then added, and the resulting suspension was stirred at room temperature for 30 min, whereupon complete dissolution was observed. Additional aliquots of Compound 1 were added portionwise in approximately 20 mg increments until dissolution was no longer observed and a suspension remained in the mixture. The suspension was stirred at room temperature for 4-6 hours and was left to stand overnight. The resulting gel-like suspension was filtered through a 0.22 pm inline syringe filter. Formulations containing other surfactants were prepared in an analogous manner except for Compound 1 in 4: 1 PEG 400:vitamin E TPGS, which became too viscous to stir and required heating at 40-45 °C to facilitate further dissolution of Compound 1.

[0177] The solubility and purity of the clear filtrates was determined by HPLC analysis immediately after filtration and again after storage at room temperature for 2 weeks. The physical appearance of each formulation was evaluated immediately after filtration, and after 1 and 2 weeks standing at room temperature. The results are summarized in TABLE 2 and TABLE 3 for Compound 1 and Compound 2 formulations, respectively.

TABLE 2

¹ N.D. = not determined; C = clear; P = precipitate; G = gel; ² After the 2nd filtration; ^J Before the 2nd filtration.

TABLE 3

¹ N.D. = not determined; C = clear; P = precipitate; G = gel; ² After the 2nd filtration; Before the 2nd filtration. ⁴ Many other impurities with longer retention time were present.

[0178] As shown in TABLE 2, all nonionic surfactant-containing formulations except the 0.5% vitamin E TPGS formulation increased the initial solubility of Compound 1 relative to to its solubility in pure water (~15 mg/mL). Where tested, the increased solubility persisted for at least 2 weeks. All Compound 1 formulations containing at least 2% (v/v) vitamin E TPGS remained clear solutions, while the remaining formulations formed a precipitate or gelled. All formulations of Compound 1 were chemically stable over the two-week period. [0179] As shown in TABLE 3, all nonionic surfactant-containing formulations of Compound 2 except for those containing 0.1% Tyloxapol and 0.05% octoxynol-40 increased the initial solubility of Compound 2 compared to its solubility in pure water (~48 mg/mL). All Compound 2 formulations were chemically stable except for the non-aqueous 4: 1 PEG 400: vitamin E TPGS formulation. Where tested, the increased solubility persisted for at least 2 weeks.

EXAMPLE 2: Determination of Solubility, Physical Stability, and Chemical Stability of Compounds 1 and 2 in Binary Surfactant Formulations.

[0180] Octoxynol (1 mg) and polysorbate 80 (80 pL) were added to water (2 mL). The resulting mixture was stirred at room temperature for 20 min, and Compound 1 (60 mg) was then added. The suspension was stirred at room temperature for 30 min, whereupon complete dissolution was observed. Additional Compound 1 was added portionwise in approximately 20 mg increments until some solid remained undissolved. The suspension was stirred at room temperature for 4-6 hours and was left standing on a bench top at ambient temperature overnight. The resulting gel-like suspension was filtered through a 0.22 pm inline syringe filter. A similar procedure was used to prepare the remaining Compound 1 and Compound 2 formulations. The solubility of the clear filtrates was determined by HPLC analysis immediately after the initial filtration (T = 0) and after 2 weeks (T = 2 weeks). The results are summarized in TABLE 4.

TABLE 4 the 2nd filtration.

[0181] For Compound 1, all nonionic surfactant-containing formulations increased the initial solubility of Compound 1 relative to its solubility in pure water (~15 mg/mL). All formulations were chemically stable. The polysorbate 80 and polyoxyl 35 formulations provided the largest increases in solubility. In all formulations, increased solubility persisted over two weeks, although all formulations formed a precipitate or gelled.

[0182] All nonionic surfactant-containing formulations of Compound 2 increased the initial solubility of Compound 2 relative to its solubility in pure water (~48 mg/mL), and all the formulations were chemically stable. The increase in solubility persisted over two weeks, and all the formulations formed a precipitate or gelled.

EXAMPLE 3: Physical and Chemical Stability of Fixed Concentrations of Compounds 1 and 2 in Non-Ionic Surfactant-Containing Formulations.

[0183] Polyoxyl 35 (100 pL) was added to water (1.6 mL), and the mixture was stirred at room temperature for 20 min, whereupon complete dissolution was observed. Compound 1 (65.2 mg, equivalent to 60 mg of the corresponding pure sulfamic acid) was added. The suspension was stirred at room temperature for 60 min to yield a clear solution. Additional water was added until the total volume of the solution was 2 mL. The solution was stirred for an additional 5 min and then filtered through a 0.45 pm inline syringe filter to produce a formulation of 30 mg/mL Compound 1 in 5% polyoxyl 35. A similar procedure was used to prepare the remaining formulations of Compounds 1 and 2. The composition of each formulation prepared is shown in TABLE 5. Because the aqueous solubility of Compound 2 is greater than that of Compound 1 (48 mg/mL versus 15 mg/mL), lower concentrations of the nonionic surfactants were used for formulations of Compound 2. The formulations were stored at room temperature for 4 weeks.

[0184] The physical appearance of the formulations was examined from T = 0 to 35 days as shown in TABLE 6. Formulations A-l-A, A-l-B, A-2-A, and A-2-B remained clear throughout the 35-day period. Gelation was observed in formulations A-3-A, A-3-B, A-4-A, and A-4-B after Day 3. Slight precipitation was also observed in Compound 2 formulations B-l-B, B-l-C, B-2-B, and B-2-C by Day 14.

TABLE 5

TABLE 6

^X C= Clear; G = gel; SP = slight precipitate

[0185] The formulations were also analyzed for concentration and purity determination. The results are summarized in TABLE 7.

TABLE 7

*API = Compound 1 or Compound 2

[0186] As shown in TABLE 7, polyoxyl-35-containing formulations of Compound 1 remained clear and chemically stable over 5 weeks. Polysorbate 80-containing formulations formed gels after 3 days and showed some chemical instability.

[0187] For Compound 2, all formulations were chemically stable but formed a slight precipitate after 14 days.

EXAMPLE 4: Physical and Chemical Stability of Fixed Concentrations of Compounds 1 and 2 in Non-Ionic Surfactant-Containing Formulations.

[0188] Polyoxyl 35 (100 pL) was added to water (1.5 mL), and the resulting suspension was stirred at room temperature for 20 min, whereupon complete dissolution was observed. 2- phenylethanol (2-PhEtOH) (8 pL) was then added and the solution was stirred at room temperature for 10 min. Glycerol (18.4 pL) was added, and the solution was stirred at room temperature for 10 min. Compound 1 (65.2 mg, equivalent to 60 mg of the corresponding free sulfamic acid) was added. The suspension was stirred at room temperature for 60 min to yield a clear solution. Additional water was added to adjust the total volume to 2 mL, and the solution was stirred for an additional 5 min. The solution was filtered through a 0.22 pm inline syringe filter to produce a formulation of 30 mg/mL Compound 1 in 5% polyoxyl 35 + 0.4% PhEtOH + 0.92% glycerol. A similar procedure was used to prepare the remaining nonionic formulations of Compounds 1 and 2 described in TABLE 8. All formulations were stored on a bench top at room temperature. The physical appearance of the formulations was examined weekly for 5 weeks and the chemical stability was assessed at T = 0, 2, and 5 weeks. The results are summarized in TABLE 9 and TABLE 10.

TABLE 8

[0189] Formulations A-l through A-6 examined the effect of various tonicity agents on the chemical and physical stability of 5% polyoxyl 35 + 0.4% 2-phenylethanol formulations of Compound 1. All of the formulations were clear solutions and were chemically stable except for those containing PEG 400 (Formulas A- 5 and A-6), which exhibited gel formation at Week 1 and beyond (TABLE 9) and showed chemical degradation after two weeks (TABLE 10).

[0190] Formulations B-l through B-6 and C-l through C-5 examined the effects of varying concentrations of polyoxyl 35 on the chemical and physical stability of Compounds 1 and 2, respectively, in the absence of tonicity agents. These formulations remained clear and were chemically stable.

TABLE 9

^X C= Clear; G = gel.

TABLE 10

HPLC Method used in EXAMPLES 1-4

[0191] All HPLC analyses conducted in EXAMPLES 1-4 used the parameters described in TABLE 11 and the gradient described in TABLE 12.

TABLE 11

TABLE 12

EMBODIMENTS

[0192] The following non-limiting embodiments provide illustrative examples of the invention, but do not limit the scope of the invention.

[0193] Embodiment 1. A pharmaceutical composition comprising, in a unit dosage form: a) a Tie-2 modulator; and b) another compound, wherein the other compound comprises: 1) a hydrophobic chain; and 2) a remainder of the compound, wherein the remainder of the compound is attached to the hydrophobic chain, wherein the hydrophobic chain comprises: i) a point of attachment that attaches the hydrophobic chain to the remainder of the compound; ii) at least five consecutive carbon atoms; iii) a terminal methyl group; and iv) a substituted carbon atom between the terminal methyl group and the point of attachment, wherein the substituted carbon atom is within fifteen atoms of the terminal methyl group; and wherein the remainder of the compound comprises a repeat unit, wherein the repeat unit comprises an oxygen atom that is sp ³ .

[0194] Embodiment 2. The pharmaceutical composition of embodiment 1, wherein the other compound is a solubilizing agent.

[0195] Embodiment 3. The pharmaceutical composition of any one of embodiments 1-2, wherein the other compound is a surfactant.

[0196] Embodiment 4. The pharmaceutical composition of any one of embodiments 1-3, wherein the other compound is a non-ionic surfactant.

[0197] Embodiment 5. The pharmaceutical composition of any one of embodiments 1-4, wherein the substituted carbon atom is substituted with methyl, ethyl, hydroxyl, or methoxy. [0198] Embodiment 6. The pharmaceutical composition of any one of embodiments 1-5, wherein the pharmaceutical composition remains chemically stable for at least about 5 weeks when stored at room temperature.

[0199] Embodiment 7. The pharmaceutical composition of any one of embodiments 1-6, wherein the pharmaceutical composition exhibits no more than about 1% degradation of the Tie-2 modulator after storage at room temperature for about 5 weeks.

[0200] Embodiment 8. The pharmaceutical composition of any one of embodiments 1-7, wherein the pharmaceutical composition remains physically stable for at least about 5 weeks when stored at room temperature.

[0201] Embodiment 9. The pharmaceutical composition of any one of embodiments 1-8, wherein a concentration of the Tie-2 modulator in the pharmaceutical composition decreases by no more than 2% after storage at room temperature for about 5 weeks.

[0202] Embodiment 10. The pharmaceutical composition of any one of embodiments 1-9, wherein a viscosity of the pharmaceutical composition at 1 atmosphere and 25 °C increases by no more than a factor of 10 after storage at room temperature for about 5 weeks.

[0203] Embodiment 11. The pharmaceutical composition of any one of embodiments 1-10, wherein the remainder of the other compound comprises a hydrophilic moiety.

[0204] Embodiment 12. The pharmaceutical composition of any one of embodiments 1-11, wherein the repeat unit is part of the hydrophilic moiety.

[0205] Embodiment 13. The pharmaceutical composition of any one of embodiments 1-12, wherein the repeat unit is -CH2CH2O-.

[0206] Embodiment 14. The pharmaceutical composition of any one of embodiments 1-13, wherein the repeat unit is present in the hydrophilic moiety at a number from 2 to 1500.

[0207] Embodiment 15. The pharmaceutical composition of any one of embodiments 1-14, wherein the substituted carbon atom is within six atoms of the terminal methyl group.

[0208] Embodiment 16. The pharmaceutical composition of any one of embodiments 1-15, wherein the other compound is of the formula: wherein R ¹ is alkyl substituted with methyl, ethyl, hydroxyl, or methoxy; G is -CH2CH2O-; L is -C(=O)(CH ₂ ) _m C(=O)-, wherein m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each R ^a , R ^b , and R ^c is independently hydrogen, methyl, ethyl, hydroxyl, or -OMe; and n is from 2 to about 6000. [0209] Embodiment 17. The pharmaceutical composition of any one of embodiments 1-16, wherein the other compound is of the formula: , wherein n is from about 900 to about

1100.

[0210] Embodiment 18. The pharmaceutical composition of embodiment 1, wherein the other compound is Vitamin E TPGS.

[0211] Embodiment 19. The pharmaceutical composition of embodiment 18, wherein the Vitamin E TPGS is present in the composition at a concentration from about 5 mg/mL to about 200 mg/mL.

[0212] Embodiment 20. The pharmaceutical composition of any one of embodiments 18-19, further comprising PEG400.

[0213] Embodiment 21. The pharmaceutical composition of any one of embodiments 18-20, comprising no more than about 5% water by mass.

[0214] Embodiment 22. The pharmaceutical composition of any one of embodiments 18-21, wherein a ratio of Vitamin E TPGS to PEG400 in the composition is from about 5: 1 to about 1 : 1 by mass/volume.

[0215] Embodiment 23. The pharmaceutical composition of embodiment 1, wherein the other compound is of the formula: wherein G is -CH2CH2O-; one of R ¹ , R ² , R ³ , R ⁴ , and R ⁵ is alkyl substituted with methyl, ethyl, hydroxyl, or methoxy, and each R ¹ , R ² , R ³ , R ⁴ , and R ⁵ that is not alkyl is H; and n is from 2 to about 200.

[0216] Embodiment 24. The pharmaceutical composition of embodiment 1, wherein the other compound is of the formula: wherein n is from 2 to about 80. [0217] Embodiment 25. The pharmaceutical composition of embodiment 1, wherein the other compound is octoxynol-40.

[0218] Embodiment 26. The pharmaceutical composition of embodiment 25, wherein the octoxynol-40 is present in the composition at a concentration from about 0.01 mg/mL to about 2 mg/mL.

[0219] Embodiment 27. The pharmaceutical composition of embodiment 1, wherein the other compound is of the formula: wherein each G is -CH2CH2O-; each of R ¹ and R ² is independently hydrogen or methyl; each instance of any one of R ^a , R ^b , and R ^c is alkyl substituted with methyl, ethyl, hydroxyl, or methoxy, and each R ^a , R ^b , and R ^c that is not alkyl is H; each n is independently 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; and z is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0220] Embodiment 28. The pharmaceutical composition of embodiment 1, wherein the other compound is of the formula: wherein n is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; and z is

1, 2, 3, 4, 5, 6, 7, 8, or 9.

[0221] Embodiment 29. The pharmaceutical composition of embodiment 1, wherein the other compound is tyloxapol.

[0222] Embodiment 30. The pharmaceutical composition of embodiment 29, wherein the tyloxapol is present in the composition at a concentration from about 0.01 mg/mL to about 2 mg/mL.

[0223] Embodiment 31. The pharmaceutical composition of embodiment 1, wherein the other compound is of the formula: wherein each of R ¹ , R ² , and R ³ is independently alkyl or alkenyl, wherein each alkyl or alkenyl is independently substituted with methyl, ethyl, hydroxyl, or methoxy; each of G ¹ , G ² , and G ³ is -CH2CH2O-; and each of x, y, and z is independently from 1 to about 400.

[0224] Embodiment 32. The pharmaceutical composition of embodiment 1, wherein the other compound is of the formula: sum that is from 3 to about 120.

[0225] Embodiment 33. The pharmaceutical composition of embodiment 1, wherein the other compound is polyoxyl 35 castor oil.

[0226] Embodiment 34. The pharmaceutical composition of embodiment 33, wherein the polyoxyl 35 castor oil is present in the composition at a concentration from about 1 mg/mL to about 50 mg/mL.

[0227] Embodiment 35. The pharmaceutical composition of any one of embodiments 33-34, wherein the polyoxyl 35 castor oil is present in the composition at a concentration from about 1 mg/mL to about 10 mg/mL.

[0228] Embodiment 36. The pharmaceutical composition of any one of embodiments 1-35, wherein the Tie-2 modulator is present in the composition at a concentration of at least about 30 mg/mL.

[0229] Embodiment 37. The pharmaceutical composition of any one of embodiments 1-36, wherein the Tie-2 modulator is present in the composition at a concentration from about 30 mg/mL to about 300 mg/mL.

[0230] Embodiment 38. The pharmaceutical composition of any one of embodiments 1-37, wherein the Tie-2 modulator is present in the composition at a concentration of about 30 mg/mL. [0231] Embodiment 39. The pharmaceutical composition of any one of embodiments 1-37, wherein the Tie-2 modulator is present in the composition at a concentration of about 40 mg/mL.

[0232] Embodiment 40. The pharmaceutical composition of any one of embodiments 1-37, wherein the Tie-2 modulator is present in the composition at a concentration of about 50 mg/mL.

[0233] Embodiment 41. The pharmaceutical composition of any one of embodiments 1-40, further comprising a preservative.

[0234] Embodiment 42. The pharmaceutical composition of embodiment 41, wherein the preservative is an alcohol.

[0235] Embodiment 43. The pharmaceutical composition of any of embodiments 41-42, wherein the preservative is 2-phenylethanol.

[0236] Embodiment 44. The pharmaceutical composition of embodiment 43, wherein the 2- phenylethanol is present in the composition at a concentration from about 0.05% (v/v) to about 4% (v/v).

[0237] Embodiment 45. The pharmaceutical composition of any one of embodiments 43-44, wherein the 2-phenylethanol is present in the composition at a concentration of about 0.4% (v/v).

[0238] Embodiment 46. The pharmaceutical composition of any one of embodiments 1-45, further comprising a tonicity agent.

[0239] Embodiment 47. The pharmaceutical composition of embodiment 46, wherein the tonicity agent is mannitol.

[0240] Embodiment 48. The pharmaceutical composition of embodiment 47, wherein the mannitol is present in the composition at a concentration from about 0.05% (v/v) to about 5% (v/v).

[0241] Embodiment 49. The pharmaceutical composition of any one of embodiments 47-48, wherein the mannitol is present in the composition at a concentration from about 0.8% (v/v) to about 2.5% (v/v).

[0242] Embodiment 50. The pharmaceutical composition of embodiment 46, wherein the tonicity agent is glycerol.

[0243] Embodiment 51. The pharmaceutical composition of embodiment 50, wherein the glycerol is present in the composition at a concentration from about 0.05% (v/v) to about 5% (v/v). [0244] Embodiment 52. The pharmaceutical composition of any one of embodiments 50-51, wherein the glycerol is present in the composition at a concentration from about 0.4% (v/v) to about 1.2% (v/v).

[0245] Embodiment 53. The pharmaceutical composition of any one of embodiments 1-52, wherein the Tie-2 modulator is a Tie-2 activator.

[0246] Embodiment 54. The pharmaceutical composition of any one of embodiments 1-53, wherein the Tie-2 modulator is a compound of the formula: , wherein:

Aryl ¹ is an aryl group which is substituted or unsubstituted; Aryl ² is an aryl group which is substituted or unsubstituted; X is alkylene, alkenylene, alkynylene, an ether linkage, an amine linkage, an amide linkage, an ester linkage, a thioether linkage, a carbamate linkage, a carbonate linkage, a ureido linkage, a sulfone linkage, any of which is substituted or unsubstituted, or a chemical bond; and Y is H, aryl, heteroaryl, NH(aryl), NH(heteroaryl), NHSCbR ⁸ , orNHCOR ^s , any of which is substituted or unsubstituted, or , wherein:

L ² is alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted, or together with the nitrogen atom to which L ² is bound forms an amide linkage, a carbamate linkage, a ureido linkage, or a sulfonamide linkage, or a chemical bond, or together with any of R ^a , R ^b , R ^c , and R ^d forms a ring that is substituted or unsubstituted;

R ^a is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or together with any of L ² , R ^b , R ^c , and R ^d forms a ring that is substituted or unsubstituted;

R ^b is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or together with any of L ² , R ^a , R ^c , and R ^d forms a ring that is substituted or unsubstituted;

R ^c is H or alkyl which is substituted or unsubstituted, or together with any of L ² , R ^a , R ^b , and R ^d forms a ring that is substituted or unsubstituted;

R ^d is H or alkyl which is substituted or unsubstituted, or together with any of L ² , R ^a , R ^b , and R ^c forms a ring that is substituted or unsubstituted; and

R ^s is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or a pharmaceutically-acceptable salt, tautomer, or zwitterion thereof.

[0247] Embodiment 55. The pharmaceutical composition of embodiment 54, wherein: -

Aryl ¹ is substituted or unsubstituted phenyl; - Aryl ² is substituted or unsubstituted heteroaryl; and - X is alkylene.

[0248] Embodiment 56. The pharmaceutical composition of any one of embodiments 54-55, wherein: - Aryl ¹ is substituted phenyl; -Aryl ² is substituted heteroaryl; and - X is methylene. [0249] Embodiment 57. The pharmaceutical composition of any one of embodiments 54-56, wherein the Tie-2 modulator is a compound of the formula: , wherein

Aryl ¹ is para-substituted phenyl;

Aryl ² is substituted heteroaryl;

L ² is alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted, or together with the nitrogen atom to which L ² is bound forms an amide linkage, a carbamate linkage, a ureido linkage, or a sulfonamide linkage, or a chemical bond;

R ^a is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted;

R ^b is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; R ^c is H or alkyl which is substituted or unsubstituted; and

R ^d is H or alkyl which is substituted or unsubstituted.

[0250] Embodiment 58. The pharmaceutical composition of embodiment 57, wherein: -

Aryl ¹ is para-substituted phenyl; - Aryl ² is a substituted thiazole moiety; - X is methylene; - L ² together with the nitrogen atom to which L ² is bound forms a carbamate linkage; - R ^a is alkyl, which is substituted or unsubstituted; - R ^b is arylalkyl, which is substituted or unsubstituted; - R ^c is H; and - R ^d is H.

[0251] Embodiment 59. The pharmaceutical composition of any one of embodiments 54-58, wherein Aryl ² is: , wherein:

R ^e is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a ureido group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; and

R ^f is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a ureido group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted.

[0252] Embodiment 60. The pharmaceutical composition of embodiment 59, wherein: - R ^e is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; and - R ^f is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted.

[0253] Embodiment 61. The pharmaceutical composition of any one of embodiments 59-60, wherein: - R ^e is H, OH, F, Cl, Br, I, alkyl, or an alkoxy group, any of which is substituted or unsubstituted; and - R ^f is alkyl, aryl, heterocyclyl, or heteroaryl, any of which is substituted or unsubstituted. [0254] Embodiment 62. The pharmaceutical composition of any one of embodiments 59-61, wherein: - Aryl ¹ is 4-phenylsulfamic acid; - R ^a is alkyl, which is substituted or unsubstituted; -R ^b is arylalkyl, which is substituted or unsubstituted; - R ^e is H; and - R ^f is heteroaryl.

[0255] Embodiment 63. The pharmaceutical composition of any one of embodiments 1-62, wherein the Tie-2 modulator is: pharmaceutically acceptable salt thereof.

[0256] Embodiment 64. The pharmaceutical any one of embodiments 1-63, wherein the Tie-2 modulator is: pharmaceutically acceptable salt thereof.

[0257] Embodiment 65. The pharmaceutical composition of any one of embodiments 54-58, wherein Aryl ² is: wherein:

R ^e is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a ureido group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; and

R ^f is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a ureido group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted.

[0258] Embodiment 66. The pharmaceutical composition of embodiment 65, wherein: - R ^e is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; and - R ^f is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted.

[0259] Embodiment 67. The pharmaceutical composition of any one of embodiments 65-66, wherein: - R ^e is H, OH, F, Cl, Br, I, alkyl, or an alkoxy group, any of which is substituted or unsubstituted; and - R ^f is alkyl, aryl, heterocyclyl, or heteroaryl, any of which is substituted or unsubstituted.

[0260] Embodiment 68. The pharmaceutical composition of any one of embodiments 65-67, wherein: - Aryl ¹ is 4-phenylsulfamic acid; - R ^a is alkyl, which is substituted or unsubstituted; - R ^b is arylalkyl, which is substituted or unsubstituted; - R ^e is H; and -R ^f is alkyl.

[0261] Embodiment 69. The pharmaceutical composition of any one of embodiments 1-58 and 65-68, wherein the Tie-2 modulator is: , or a pharmaceutically acceptable salt thereof.

[0262] Embodiment 70. The pharmaceutical composition of any one of embodiments 1-58 and 65-69, wherein the Tie-2 modulator is: , or a pharmaceutically acceptable salt thereof.

[0263] Embodiment 71. The pharmaceutical composition of embodiment 65, wherein: -

Aryl ¹ is 4-phenylsulfamic acid; - R ^a is alkyl, which is substituted or unsubstituted; - R ^b is arylalkyl, which is substituted or unsubstituted; - R ^e is H; and - R ^f is heteroaryl. [0264] Embodiment 72. The pharmaceutical composition of any one of embodiments 1-54, 65, and 71, wherein the Tie-2 modulator is: pharmaceutically acceptable salt thereof.

[0265] Embodiment 73. The pharmaceutical composition of any one of embodiments 1-54, 65, and 71-72, wherein the Tie-2 modulator is: pharmaceutically acceptable salt thereof.

[0266] Embodiment 74. The pharmaceutical composition of any one of embodiments 1-54, 65, and 71-72, wherein the Tie-2 modulator is a compound of the formula:

[0267] Embodiment 75. The pharmaceutical composition of any one of embodiments 1-54, 65, and 71-72, wherein the Tie-2 modulator is a compound of the formula:

[0268] Embodiment 76. The pharmaceutical composition of embodiment 73, wherein the pharmaceutical composition comprises no more than 0.1% area percent of a compound of the formula: determined by HPLC.

[0269] Embodiment 77. The pharmaceutical composition of embodiment 73, wherein the Tie-2 modulator is present in the unit dosage form in an amount that is from about 1 mg to about 50 mg.

[0270] Embodiment 78. The pharmaceutical composition of embodiment 73, wherein the Tie-2 modulator has a solubility in the composition of at least about 30 mg/mL.

[0271] Embodiment 79. The pharmaceutical composition of embodiment 73, wherein the Tie-2 modulator has a solubility in the composition that is from about 30 mg/mL to about 200 mg/mL.

[0272] Embodiment 80. A pharmaceutical composition comprising in a unit dosage form: a) a Tie-2 modulator; b) a surfactant at an amount of from about 0.05% (v/v) to about 20% (v/v) of the unit dosage form, wherein the surfactant comprises a hydrophilic region connected to a hydrophobic region, wherein the hydrophilic region contains a linear oligomeric moiety; and c) a fluid carrier, wherein the pharmaceutical composition exhibits no more than about 1% degradation of the Tie-2 modulator after storage at room temperature for about 5 weeks. [0273] Embodiment 81. The pharmaceutical composition of embodiment 80, wherein solubility of the Tie-2 modulator is from about 10 mg/mL to about 120 mg/mL in the pharmaceutical composition.

[0274] Embodiment 82. The pharmaceutical composition of any one of embodiments 80-81, wherein the pharmaceutical composition is a clear solution after the storage at room temperature for about 5 weeks.

[0275] Embodiment 83. The pharmaceutical composition of any one of embodiments 80-82, wherein the Tie-2 modulator is a pharmaceutically-acceptable salt, and the pharmaceutically- acceptable salt is a sodium salt.

[0276] Embodiment 84. The pharmaceutical composition of any one of embodiments 80-82, wherein the Tie-2 modulator is a pharmaceutically-acceptable salt, and the pharmaceutically- acceptable salt is a lithium salt.

[0277] Embodiment 85. The pharmaceutical composition of any one of embodiments 80-84, wherein the surfactant is a non-ionic surfactant.

[0278] Embodiment 86. The pharmaceutical composition of any one of embodiments 80-85, wherein the surfactant is a tocopherol.

[0279] Embodiment 87. The pharmaceutical composition of any one of embodiments 80-86, wherein the surfactant is vitamin E TPGS.

[0280] Embodiment 88. The pharmaceutical composition of embodiment 80, wherein the surfactant is a polyalkoxylated alkylphenol.

[0281] Embodiment 89. The pharmaceutical composition of embodiment 88, wherein the polyalkoxylated alkylphenol is an octoxynol.

[0282] Embodiment 90. The pharmaceutical composition of embodiment 89, wherein the octoxynol is octoxynol-40.

[0283] Embodiment 91. The pharmaceutical composition of embodiment 88, wherein the polyalkoxylated alkylphenol is tyloxapol.

[0284] Embodiment 92. The pharmaceutical composition of embodiment 80, wherein the surfactant is a polyethoxyl fatty acid ester.

[0285] Embodiment 93. The pharmaceutical composition of embodiment 92, wherein the polyethoxyl fatty acid ester is polyoxyl 35.

[0286] Embodiment 94. The pharmaceutical composition of embodiment 80, wherein the surfactant is a sorbitan derivative. [0287] Embodiment 95. The pharmaceutical composition of embodiment 94, wherein the sorbitan derivative is polysorbate 80.

[0288] Embodiment 96. The pharmaceutical composition of any one of embodiments 80-95, wherein the pharmaceutical composition comprises an additional surfactant.

[0289] Embodiment 97. The pharmaceutical composition of embodiment 96, wherein the additional surfactant is polyvinylpyrrolidone.

[0290] Embodiment 98. The pharmaceutical composition of any one of embodiments 80-97, further comprising a polyethylene glycol.

[0291] Embodiment 99. The pharmaceutical composition of any one of embodiments 80-98, wherein the Tie-2 modulator is a Tie-2 activator.

[0292] Embodiment 100. The pharmaceutical composition of any one of embodiments 80-99, wherein the Tie-2 modulator is a compound of the formula: , wherein:

Aryl ¹ is an aryl group which is substituted or unsubstituted; Aryl ² is an aryl group which is substituted or unsubstituted; X is alkylene, alkenylene, alkynylene, an ether linkage, an amine linkage, an amide linkage, an ester linkage, a thioether linkage, a carbamate linkage, a carbonate linkage, a ureido linkage, a sulfone linkage, any of which is substituted or unsubstituted, or a chemical bond; and Y is H, aryl, heteroaryl, NH(aryl), NH(heteroaryl), f which is substituted or unsubstituted, or , wherein:

L ² is alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted, or together with the nitrogen atom to which L ² is bound forms an amide linkage, a carbamate linkage, a ureido linkage, or a sulfonamide linkage, or a chemical bond, or together with any of R ^a , R ^b , R ^c , and R ^d forms a ring that is substituted or unsubstituted;

R ^a is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or together with any of L ² , R ^b , R ^c , and R ^d forms a ring that is substituted or unsubstituted;

R ^b is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or together with any of L ² , R ^a , R ^c , and R ^d forms a ring that is substituted or unsubstituted;

R ^c is H or alkyl which is substituted or unsubstituted, or together with any of L ² , R ^a , R ^b , and R ^d forms a ring that is substituted or unsubstituted;

R ^d is H or alkyl which is substituted or unsubstituted, or together with any of L ² , R ^a , R ^b , and R ^c forms a ring that is substituted or unsubstituted; and

R ^s is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or a pharmaceutically-acceptable salt, tautomer, or zwitterion thereof.

[0293] Embodiment 101. The pharmaceutical composition of embodiment 100, wherein: -

Aryl ¹ is substituted or unsubstituted phenyl; - Aryl ² is substituted or unsubstituted heteroaryl; and - X is alkylene.

[0294] Embodiment 102. The pharmaceutical composition of any one of embodiments 100-

101, wherein: - Aryl ¹ is substituted phenyl; - Aryl ² is substituted heteroaryl; and - X is methylene.

[0295] Embodiment 103. The pharmaceutical composition of any one of embodiments 80-

102, wherein the Tie-2 modulator is a compound of the formula: , wherein

Aryl ¹ is para-substituted phenyl;

Aryl ² is substituted heteroaryl;

L ² is alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted, or together with the nitrogen atom to which L ² is bound forms an amide linkage, a carbamate linkage, a ureido linkage, or a sulfonamide linkage, or a chemical bond;

R ^a is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted;

R ^b is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted;

R ^c is H or alkyl which is substituted or unsubstituted; and

R ^d is H or alkyl which is substituted or unsubstituted.

[0296] Embodiment 104. The pharmaceutical composition of any one of embodiments 100-

103, wherein: - Aryl ¹ is para-substituted phenyl; - Aryl ² is a substituted thiazole moiety; - X is methylene; - L ² together with the nitrogen atom to which L ² is bound forms a carbamate linkage; - R ^a is alkyl, which is substituted or unsubstituted; - R ^b is arylalkyl, which is substituted or unsubstituted; - R ^c is H; and - R ^d is H.

[0297] Embodiment 105. The pharmaceutical composition of any one of embodiments 100-

104, wherein Aryl ² is: , wherein:

R ^e is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a ureido group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; and

R ^f is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a ureido group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted.

[0298] Embodiment 106. The pharmaceutical composition of embodiment 105, wherein:- R ^e is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; and - R ^f is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted.

[0299] Embodiment 107. The pharmaceutical composition of any one of embodiments 105- 106, wherein: - R ^e is H, OH, F, Cl, Br, I, alkyl, or an alkoxy group, any of which is substituted or unsubstituted; and - R ^f is alkyl, aryl, heterocyclyl, or heteroaryl, any of which is substituted or unsubstituted.

[0300] Embodiment 108. The pharmaceutical composition of any one of embodiments 105- 107, wherein: - Aryl ¹ is 4-phenylsulfamic acid; - R ^a is alkyl, which is substituted or unsubstituted; - R ^b is arylalkyl, which is substituted or unsubstituted; - R ^e is H; and - R ^f is heteroaryl.

[0301] Embodiment 109. The pharmaceutical composition of any one of embodiments 80-

108, wherein the Tie-2 modulator is: pharmaceutically acceptable salt thereof.

[0302] Embodiment 110. The pharmaceutical composition of any one of embodiments 80-

109, wherein the Tie-2 modulator is: pharmaceutically acceptable salt thereof.

[0303] Embodiment 111. The pharmaceutical composition of any one of embodiments 100- 104, wherein Aryl ² is: wherein:

R ^e is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a ureido group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; and

R ^f is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a ureido group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted.

[0304] Embodiment 112. The pharmaceutical composition of embodiment 111, wherein: - R ^e is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; and - R ^f is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted.

[0305] Embodiment 113. The pharmaceutical composition of any one of embodiments 111-

112, wherein: - R ^e is H, OH, F, Cl, Br, I, alkyl, or an alkoxy group, any of which is substituted or unsubstituted; and - R ^f is alkyl, aryl, heterocyclyl, or heteroaryl, any of which is substituted or unsubstituted.

[0306] Embodiment 114. The pharmaceutical composition of any one of embodiments 111-

113, wherein: - Aryl ¹ is 4-phenylsulfamic acid; - R ^a is alkyl, which is substituted or unsubstituted; - R ^b is arylalkyl, which is substituted or unsubstituted; - R ^e is H; and - R ^f is alkyl.

[0307] Embodiment 115. The pharmaceutical composition of any one of embodiments 80- 100 and 111-114, wherein the Tie-2 modulator is: , or a pharmaceutically acceptable salt thereof.

[0308] Embodiment 116. The pharmaceutical composition of any one of embodiments 80- 100 and 111-115, wherein the Tie-2 modulator is: pharmaceutically acceptable salt thereof.

[0309] Embodiment 117. The pharmaceutical composition of embodiment 111, wherein: - Aryl ¹ is 4-phenylsulfamic acid; - R ^a is alkyl, which is substituted or unsubstituted; - R ^b is arylalkyl, which is substituted or unsubstituted; - R ^e is H; and - R ^f is heteroaryl.

[0310] Embodiment 118. The pharmaceutical composition of any one of embodiments 80- 100, 111, and 117, wherein the Tie-2 modulator is: pharmaceutically acceptable salt thereof.

[0311] Embodiment 119. The pharmaceutical composition of any one of embodiments 80- 100, 111, and 117-118, wherein the Tie-2 modulator is: pharmaceutically acceptable salt thereof.

[0312] Embodiment 120. The pharmaceutical composition of any one of embodiments 80- 100, 111, and 117-118, wherein the Tie-2 modulator is a compound of the formula:

[0313] Embodiment 121. The pharmaceutical composition of any one of embodiments 80- 100, 111, and 117-118, wherein the Tie-2 modulator is a compound of the formula:

[0314] Embodiment 122. A pharmaceutical composition comprising in unit dosage form: a) a Tie-2 modulator; and b) a surfactant at an amount of from about 0.05% (v/v) to about 20% (v/v) of the unit dosage form, wherein the surfactant comprises a hydrophilic region connected to a hydrophobic region, wherein the hydrophilic region contains a linear oligomeric moiety; and c) a fluid carrier, wherein the pharmaceutical composition remains clear for at least about 7 weeks while being stored at room temperature.

[0315] Embodiment 123. The pharmaceutical composition of embodiment 122, wherein the Tie-2 modulator is present in the pharmaceutical composition at an amount from about 30 mg/mL to about 50 mg/mL.

[0316] Embodiment 124. The pharmaceutical composition of embodiment 122, wherein solubility of the Tie-2 modulator is from about 10 mg/mL to about 120 mg/mL in the pharmaceutical composition.

[0317] Embodiment 125. The pharmaceutical composition of any one of embodiments 122- 124, wherein the Tie-2 modulator is a pharmaceutically-acceptable salt, and the pharmaceutically-acceptable salt is a sodium salt. [0318] Embodiment 126. The pharmaceutical composition of any one of embodiments 122- 124, wherein the Tie-2 modulator is a pharmaceutically-acceptable salt, and the pharmaceutically-acceptable salt is a lithium salt.

[0319] Embodiment 127. The pharmaceutical composition of any one of embodiments 122- 126, wherein the surfactant is a non-ionic surfactant.

[0320] Embodiment 128. The pharmaceutical composition of any one of embodiments 122- 126, wherein the surfactant is a tocopherol.

[0321] Embodiment 129. The pharmaceutical composition of embodiment 128, wherein the surfactant is vitamin E TPGS.

[0322] Embodiment 130. The pharmaceutical composition of any one of embodiments 122- 126, wherein the surfactant is a polyalkoxylated alkylphenol.

[0323] Embodiment 131. The pharmaceutical composition of embodiment 130, wherein the polyalkoxylated alkylphenol is an octoxynol.

[0324] Embodiment 132. The pharmaceutical composition of embodiment 131, wherein the octoxynol is octoxynol-40.

[0325] Embodiment 133. The pharmaceutical composition of embodiment 130, wherein the polyalkoxylated alkylphenol is tyloxapol.

[0326] Embodiment 134. The pharmaceutical composition of any one of embodiments 122- 126, wherein the surfactant is a polyethoxyl fatty acid ester.

[0327] Embodiment 135. The pharmaceutical composition of embodiment 134, wherein the polyethoxyl fatty acid ester is polyoxyl 35.

[0328] Embodiment 136. The pharmaceutical composition of any one of embodiments 122- 126, wherein the surfactant is a sorbitan derivative.

[0329] Embodiment 137. The pharmaceutical composition of embodiment 136, wherein the sorbitan derivative is polysorbate 80.

[0330] Embodiment 138. The pharmaceutical composition of any one of embodiments 122- 137, wherein the pharmaceutical composition comprises an additional surfactant.

[0331] Embodiment 139. The pharmaceutical composition of embodiment 138, wherein the additional surfactant is polyvinylpyrrolidone.

[0332] Embodiment 140. The pharmaceutical composition of any one of embodiments 122-

139, further comprising a polyethylene glycol.

[0333] Embodiment 141. The pharmaceutical composition of any one of embodiments 122-

140, wherein the Tie-2 modulator is a Tie-2 activator. [0334] Embodiment 142. The pharmaceutical composition of any one of embodiments 122- 141, wherein the Tie-2 modulator is a compound of the formula: Aryl i ¹ , wherein:

Aryl ¹ is an aryl group which is substituted or unsubstituted; Aryl ² is an aryl group which is substituted or unsubstituted; X is alkylene, alkenylene, alkynylene, an ether linkage, an amine linkage, an amide linkage, an ester linkage, a thioether linkage, a carbamate linkage, a carbonate linkage, a ureido linkage, a sulfone linkage, any of which is substituted or unsubstituted, or a chemical bond; and Y is H, aryl, heteroaryl, NH(aryl), NH(heteroaryl), NHSO2R ⁸ , or NHCOR ^S , any of which is substituted or unsubstituted, or , wherein:

L ² is alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted, or together with the nitrogen atom to which L ² is bound forms an amide linkage, a carbamate linkage, a ureido linkage, or a sulfonamide linkage, or a chemical bond, or together with any of R ^a , R ^b , R ^c , and R ^d forms a ring that is substituted or unsubstituted;

R ^a is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or together with any of L ² , R ^b , R ^c , and R ^d forms a ring that is substituted or unsubstituted; R ^b is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or together with any of L ² , R ^a , R ^c , and R ^d forms a ring that is substituted or unsubstituted; R ^c is H or alkyl which is substituted or unsubstituted, or together with any of L ² , R ^a , R ^b , and R ^d forms a ring that is substituted or unsubstituted; R ^d is H or alkyl which is substituted or unsubstituted, or together with any of L ² , R ^a , R ^b , and R ^c forms a ring that is substituted or unsubstituted; and

R ^s is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or a pharmaceutically-acceptable salt, tautomer, or zwitterion thereof.

[0335] Embodiment 143. The pharmaceutical composition of embodiment 142, wherein: - Aryl ¹ is substituted or unsubstituted phenyl; - Aryl ² is substituted or unsubstituted heteroaryl; and - X is alkylene.

[0336] Embodiment 144. The pharmaceutical composition of any one of embodiments 142-

143, wherein: - Aryl ¹ is substituted phenyl; - Aryl ² is substituted heteroaryl; and - X is methylene.

[0337] Embodiment 145. The pharmaceutical composition of any one of embodiments 142-

144, wherein the Tie-2 modulator is a compound of the formula: , wherein

Aryl ¹ is para-substituted phenyl;

Aryl ² is substituted heteroaryl;

L ² is alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted, or together with the nitrogen atom to which L ² is bound forms an amide linkage, a carbamate linkage, a ureido linkage, or a sulfonamide linkage, or a chemical bond;

R ^a is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted;

R ^b is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted;

R ^c is H or alkyl which is substituted or unsubstituted; and R ^d is H or alkyl which is substituted or unsubstituted. [0338] Embodiment 146. The pharmaceutical composition of embodiment 145, wherein: - Aryl ¹ is para-substituted phenyl; - Aryl ² is a substituted thiazole moiety; - X is methylene; - L ² together with the nitrogen atom to which L ² is bound forms a carbamate linkage; - R ^a is alkyl, which is substituted or unsubstituted; - R ^b is arylalkyl, which is substituted or unsubstituted; - R ^c is H; and - R ^d is H.

[0339] Embodiment 147. The pharmaceutical composition of any one of embodiments 142- 146, wherein Aryl ² is: wherein:

R ^e is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a ureido group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; and

R ^f is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a ureido group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted.

[0340] Embodiment 148. The pharmaceutical composition of embodiment 147, wherein: - R ^e is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; and - R ^f is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted.

[0341] Embodiment 149. The pharmaceutical composition of any one of embodiments 147-

148, wherein: - R ^e is H, OH, F, Cl, Br, I, alkyl, or an alkoxy group, any of which is substituted or unsubstituted; and - R ^f is alkyl, aryl, heterocyclyl, or heteroaryl, any of which is substituted or unsubstituted.

[0342] Embodiment 150. The pharmaceutical composition of any one of embodiments 147-

149, wherein: - Aryl ¹ is 4-phenylsulfamic acid; - R ^a is alkyl, which is substituted or unsubstituted; - R ^b is arylalkyl, which is substituted or unsubstituted; - R ^e is H; and - R ^f is heteroaryl.

[0343] Embodiment 151. The pharmaceutical composition of any one of embodiments 122- 150, wherein the Tie-2 modulator is: pharmaceutically acceptable salt thereof.

[0344] Embodiment 152. The pharmaceutical composition of any one of embodiments 122- 151, wherein the Tie-2 modulator is: pharmaceutically acceptable salt thereof.

[0345] Embodiment 153. The pharmaceutical composition of embodiment 146, wherein Aryl ² is: , wherein:

R ^e is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a ureido group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; and

R ^f is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a ureido group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted.

[0346] Embodiment 154. The pharmaceutical composition of embodiment 153, wherein: - R ^e is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; and - R ^f is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted.

[0347] Embodiment 155. The pharmaceutical composition of any one of embodiments 153- 154, wherein: - R ^e is H, OH, F, Cl, Br, I, alkyl, or an alkoxy group, any of which is substituted or unsubstituted; and - R ^f is alkyl, aryl, heterocyclyl, or heteroaryl, any of which is substituted or unsubstituted.

[0348] Embodiment 156. The pharmaceutical composition of any one of embodiments 153- 155, wherein: - Aryl ¹ is 4-phenylsulfamic acid; - R ^a is alkyl, which is substituted or unsubstituted; - R ^b is arylalkyl, which is substituted or unsubstituted; - R ^e is H; and - R ^f is alkyl.

[0349] Embodiment 157. The pharmaceutical composition of any one of embodiments 122- 142 and 153-156, wherein the Tie-2 modulator is: or a pharmaceutically acceptable salt thereof.

[0350] Embodiment 158. The pharmaceutical composition of any one of embodiments 122-

142 and 153-157, wherein the Tie-2 modulator is: pharmaceutically acceptable salt thereof.

[0351] Embodiment 159. The pharmaceutical composition of embodiment 153, wherein: - Aryl ¹ is 4-phenylsulfamic acid; - R ^a is alkyl, which is substituted or unsubstituted; - R ^b is arylalkyl, which is substituted or unsubstituted; - R ^e is H; and - R ^f is heteroaryl. [0352] Embodiment 160. The pharmaceutical composition of any one of embodiments 122- 142 and 159, wherein the Tie-2 modulator is: pharmaceutically acceptable salt thereof.

[0353] Embodiment 161. The pharmaceutical composition of any one of embodiments 122- 142 and 159-160, wherein the Tie-2 modulator is: pharmaceutically acceptable salt thereof.

[0354] Embodiment 162. The pharmaceutical composition of any one of embodiments 122- 142 and 159-160, wherein the Tie-2 modulator is a compound of the formula:

[0355] Embodiment 163. The pharmaceutical composition of any one of embodiments 122- 142 and 159-160, wherein the Tie-2 modulator is a compound of the formula:

[0356] Embodiment 164. A pharmaceutical composition comprising in a unit dosage form: a) a Tie-2 modulator; b) a surfactant; and c) a fluid carrier, wherein the pharmaceutical composition exhibits no more than about 1% degradation of the Tie-2 modulator after storage at room temperature for about 2 weeks, and wherein the pharmaceutical composition remains clear after storage at room temperature for about 2 weeks.

[0357] Embodiment 165. The pharmaceutical composition of embodiment 164, wherein the Tie-2 modulator is present in the pharmaceutical composition at an amount from about 30 mg/mL to about 50 mg/mL.

[0358] Embodiment 166. The pharmaceutical composition of embodiment 164, wherein solubility of the Tie-2 modulator is from about 10 mg/mL to about 120 mg/mL in the pharmaceutical composition.

[0359] Embodiment 167. The pharmaceutical composition of any one of embodiments 164- 166, wherein the Tie-2 modulator is a pharmaceutically-acceptable salt, and the pharmaceutically-acceptable salt is a sodium salt.

[0360] Embodiment 168. The pharmaceutical composition of any one of embodiments 164- 166, wherein the Tie-2 modulator is a pharmaceutically-acceptable salt, and the pharmaceutically-acceptable salt is a lithium salt.

[0361] Embodiment 169. The pharmaceutical composition of any one of embodiments 164- 168, wherein the surfactant is a non-ionic surfactant.

[0362] Embodiment 170. The pharmaceutical composition of any one of embodiments 164- 168, wherein the surfactant is a tocopherol.

[0363] Embodiment 171. The pharmaceutical composition of embodiment 170, wherein the surfactant is vitamin E TPGS.

[0364] Embodiment 172. The pharmaceutical composition of any one of embodiments 164- 168, wherein the surfactant is a polyalkoxylated alkylphenol.

[0365] Embodiment 173. The pharmaceutical composition of embodiment 172, wherein the polyalkoxylated alkylphenol is an octoxynol. [0366] Embodiment 174. The pharmaceutical composition of embodiment 173, wherein the octoxynol is octoxynol-40.

[0367] Embodiment 175. The pharmaceutical composition of embodiment 172, wherein the polyalkoxylated alkylphenol is tyloxapol.

[0368] Embodiment 176. The pharmaceutical composition of any one of embodiments 164- 168, wherein the surfactant is a polyethoxyl fatty acid ester.

[0369] Embodiment 177. The pharmaceutical composition of embodiment 176, wherein the polyethoxyl fatty acid ester is polyoxyl 35.

[0370] Embodiment 178. The pharmaceutical composition of any one of embodiments 164- 168, wherein the surfactant is a sorbitan derivative.

[0371] Embodiment 179. The pharmaceutical composition of embodiment 178, wherein the sorbitan derivative is polysorbate 80.

[0372] Embodiment 180. The pharmaceutical composition of any one of embodiments 164- 179, wherein the pharmaceutical composition comprises an additional surfactant.

[0373] Embodiment 181. The pharmaceutical composition of embodiment 180, wherein the additional surfactant is polyvinylpyrrolidone.

[0374] Embodiment 182. The pharmaceutical composition of any one of embodiments 164-

181, further comprising a polyethylene glycol.

[0375] Embodiment 183. The pharmaceutical composition of any one of embodiments 164-

182, wherein the Tie-2 modulator is a Tie-2 activator.

[0376] Embodiment 184. The pharmaceutical composition of any one of embodiments 164-

183, wherein the Tie-2 modulator is a compound of the formula: , wherein:

Aryl ¹ is an aryl group which is substituted or unsubstituted; Aryl ² is an aryl group which is substituted or unsubstituted; X is alkylene, alkenylene, alkynylene, an ether linkage, an amine linkage, an amide linkage, an ester linkage, a thioether linkage, a carbamate linkage, a carbonate linkage, a ureido linkage, a sulfone linkage, any of which is substituted or unsubstituted, or a chemical bond; and Y is H, aryl, heteroaryl, NH(aryl), NH(heteroaryl), NHSCbR ⁸ , or NHCOR ^S , any of which is substituted or unsubstituted, or , wherein:

L ² is alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted, or together with the nitrogen atom to which L ² is bound forms an amide linkage, a carbamate linkage, a ureido linkage, or a sulfonamide linkage, or a chemical bond, or together with any of R ^a , R ^b , R ^c , and R ^d forms a ring that is substituted or unsubstituted;

R ^a is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or together with any of L ² , R ^b , R ^c , and R ^d forms a ring that is substituted or unsubstituted;

R ^b is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or together with any of L ² , R ^a , R ^c , and R ^d forms a ring that is substituted or unsubstituted;

R ^c is H or alkyl which is substituted or unsubstituted, or together with any of L ² , R ^a , R ^b , and R ^d forms a ring that is substituted or unsubstituted;

R ^d is H or alkyl which is substituted or unsubstituted, or together with any of L ² , R ^a , R ^b , and R ^c forms a ring that is substituted or unsubstituted; and

R ^s is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or a pharmaceutically-acceptable salt, tautomer, or zwitterion thereof.

[0377] Embodiment 185. The pharmaceutical composition of embodiment 184, wherein: - Aryl ¹ is substituted or unsubstituted phenyl; - Aryl ² is substituted or unsubstituted heteroaryl; and - X is alkylene. [0378] Embodiment 186. The pharmaceutical composition of any one of embodiments 184-

185, wherein: - Aryl ¹ is substituted phenyl; - Aryl ² is substituted heteroaryl; and - X is methylene.

[0379] Embodiment 187. The pharmaceutical composition of any one of embodiments 184-

186, wherein the Tie-2 modulator is a compound of the formula: , wherein

Aryl ¹ is para-substituted phenyl;

Aryl ² is substituted heteroaryl;

L ² is alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted, or together with the nitrogen atom to which L ² is bound forms an amide linkage, a carbamate linkage, a ureido linkage, or a sulfonamide linkage, or a chemical bond;

R ^a is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted;

R ^b is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted;

R ^c is H or alkyl which is substituted or unsubstituted; and

R ^d is H or alkyl which is substituted or unsubstituted.

[0380] Embodiment 188. The pharmaceutical composition of embodiment 187, wherein:

Aryl ¹ is para-substituted phenyl;

Aryl ² is a substituted thiazole moiety;

X is methylene;

L ² together with the nitrogen atom to which L ² is bound forms a carbamate linkage;

R ^a is alkyl, which is substituted or unsubstituted;

R ^b is arylalkyl, which is substituted or unsubstituted;

R ^c is H; and

R ^d is H. [0381] Embodiment 189. The pharmaceutical composition of any one of embodiments 187- 188, wherein Aryl ² is:

, ,S- ^R ' -K jf

^N R ^f , wherein:

R ^e is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a ureido group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; and

R ^f is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a ureido group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted.

[0382] Embodiment 190. The pharmaceutical composition of embodiment 189, wherein: - R ^e is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; and - R ^f is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted.

[0383] Embodiment 191. The pharmaceutical composition of any one of embodiments 189-

190, wherein: - R ^e is H, OH, F, Cl, Br, I, alkyl, or an alkoxy group, any of which is substituted or unsubstituted; and - R ^f is alkyl, aryl, heterocyclyl, or heteroaryl, any of which is substituted or unsubstituted.

[0384] Embodiment 192. The pharmaceutical composition of any one of embodiments 189-

191, wherein: - Aryl ¹ is 4-phenylsulfamic acid; - R ^a is alkyl, which is substituted or unsubstituted; - R ^b is arylalkyl, which is substituted or unsubstituted; - R ^e is H; and - R ^f is heteroaryl.

[0385] Embodiment 193. The pharmaceutical composition of any one of embodiments 164-

192, wherein the Tie-2 modulator is: pharmaceutically acceptable salt thereof.

[0386] Embodiment 194. The pharmaceutical composition of any one of embodiments 164- 193, wherein the Tie-2 modulator is: pharmaceutically acceptable salt thereof.

[0387] Embodiment 195. The pharmaceutical composition of embodiment 188, wherein Aryl ² is: wherein:

R ^e is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a ureido group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; and

R ^f is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a ureido group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted.

[0388] Embodiment 196. The pharmaceutical composition of embodiment 195, wherein: - R ^e is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; and - R ^f is H, OH, F, Cl, Br, I, alkyl, an alkoxy group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted.

[0389] Embodiment 197. The pharmaceutical composition of any one of embodiments 195- 196, wherein: - R ^e is H, OH, F, Cl, Br, I, alkyl, or an alkoxy group, any of which is substituted or unsubstituted; and - R ^f is alkyl, aryl, heterocyclyl, or heteroaryl, any of which is substituted or unsubstituted.

[0390] Embodiment 198. The pharmaceutical composition of any one of embodiments 195-

197, wherein: - Aryl ¹ is 4-phenylsulfamic acid; - R ^a is alkyl, which is substituted or unsubstituted; - R ^b is arylalkyl, which is substituted or unsubstituted; - R ^e is H; and - R ^f is alkyl.

[0391] Embodiment 199. The pharmaceutical composition of any one of embodiments 164-

198, wherein the Tie-2 modulator is: or a pharmaceutically acceptable salt thereof.

[0392] Embodiment 200. The pharmaceutical composition of any one of embodiments 164-

199, wherein the Tie-2 modulator is: pharmaceutically acceptable salt thereof.

[0393] Embodiment 201. The pharmaceutical composition of embodiment 195, wherein: - Aryl ¹ is 4-phenylsulfamic acid; - R ^a is alkyl, which is substituted or unsubstituted; - R ^b is arylalkyl, which is substituted or unsubstituted; - R ^e is H; and - R ^f is heteroaryl.

[0394] Embodiment 202. The pharmaceutical composition of any one of embodiments 164- 184 and 201, wherein the Tie-2 modulator is: pharmaceutically acceptable salt thereof.

[0395] Embodiment 203. The pharmaceutical composition of any one of embodiments 164-

184 and 201-202, wherein the Tie-2 modulator is: pharmaceutically acceptable salt thereof.

[0396] Embodiment 204. The pharmaceutical composition of any one of embodiments 164-

184 and 201-202, wherein the Tie-2 modulator is a compound of the formula:

[0397] Embodiment 205. The pharmaceutical composition of any one of embodiments 164- 184 and 201-202, wherein the Tie-2 modulator is a compound of the formula: