WO2019173482A1

WO2019173482A1 - 4-aminoquinoline compounds for the treatment of angiogenesis

Info

Publication number: WO2019173482A1
Application number: PCT/US2019/020965
Authority: WO
Inventors: Layton Harris SMITH; Patrick Maloney; Danielle MCANALLY; Paul HERSHBERGER; Hampton Sessions; Satyamaheshwar Peddibhotla
Original assignee: Sanford Burnham Prebys Medical Discovery Institute
Priority date: 2018-03-06
Filing date: 2019-03-06
Publication date: 2019-09-12

Abstract

Described herein is the use of 4-aminoquinoline compounds as inhibitors of angiogenesis, such as retinal pathological angiogensis. Also described herein are compositions and formulations comprising such compounds for the use in treatment of pathological angiogenesis.

Description

4-AMINOQUINOLINE COMPOUNDS FOR THE TREATMENT OF ANGIOGENESIS

RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62/639,291 filed on March 6, 2018, which is herein incorporated by reference in its entirety.

STATEMENT OF GOVERNMENT-SPONSORED RESEARCH

[0002] This invention was made with United States government support under grant No.

R21NS059422 awarded by the National Institutes of Health. The United States government has certain rights in the invention.

FIELD OF THE INVENTION

[0003] This invention relates to small molecule antagonists of the apelin receptor (APJ) and, more specifically, to small molecule compounds for the treatment of apelin receptor-mediated diseases and disorders.

SUMMARY OF THE INVENTION

[0004] Described herein is the use of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for the treatment of pathological angiogenesis.

Formula (I);

wherein:

each R¹ is independently halogen, -CN, -OH, -OR^a, -SH, -SR^a, -NR^cR^d, -C(=0)R^a, -C(=0)OR^b, - C(=0)NR^cR^d, -NR^bC(=0)R^a, C,-C_f> alky l. C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,

heterocycloalkyl, aryl, or heteroaryl; wherein each each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R²⁰;

n is 0, 1, 2, or 3;

Z is -NR²R³, -OR⁴, -SR⁵, or -CR⁶R⁷R⁸;

R² and R³ are each independently hydrogen, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆ alkyl(heteroaryl), Ci-C₆

alkyl(cycloalkyl), Ci-C₆ alkyl(heterocycloalkyl), -S(=0)₂R^lla, -S(=0)₂NR^12aR^13a, or -C(=0)₂R^lla; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R^20a; or R² and R³ are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl that is unsubstituted or substituted with one, two, or three R^20b;

R⁴ is hydrogen, -C(=0)R^llb, -C(=0)0R^12b, -C(=0)NR^12bR^13b, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆

alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆ alkyl(heteroaryl), Ci-C₆ alkyl(cycloalkyl), Ci-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R^20c;

R⁵ is hydrogen, -C(=0)R^llc, -C(=0)0R^12c, -C(=0)NR^12cR^13c, C^Q, alkyl, C₂-C₆ alkenyl, C₂-C₆

alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆ alkyl(heteroaryl), Ci-C₆ alkyl(cycloalkyl), Ci-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R^20d;

R⁶, R⁷, and R⁸ are each independently hydrogen, halogen, -CN, -OH, -OR^lld, -SH, -SR^lld, - S(=0)R^lld, -N0₂, -NR^12dR^13d, -S(=0)₂R^lld, -NHS(=0)₂R^lld, -S(=0)₂NR^12dR^13d, -C(=0)R^lld, - 0C(=0)R^lld, -C(=0)0R^12d, -0C(=0)0R^12d, -C(=0)NR^12gR^13d, -0C(=0)NR^12dR^13d, - NR^12dC(=0)NR^12dR^13d, -NR^12gC(=0)R^llg, -NR^12gC(=0)0R^12g, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆ alkyl(heteroaryl), Ci-C₆ alkyl(cycloalkyl), or Ci-C₆ alkyl (heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R^20e;

R^lla, _R I iiy _R ^| iy _an(j _{R i} id _{are cac}|₁ i_nd_ep_end_ently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,

cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R^20f;

R^12a R^12b, R^12c, R^12d, R^13a, R^13b, R^13c, and R^13d are each independently hydrogen, C ,-C₍, alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one, two, or three R^20g;

or R^12a and R^13a or R^12b and R^13b or R^12c and R^13c or R^12d and R^13d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl;

each

NR^bC(=0)0R^b, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆ alkyl(heteroaryl), Ci-C₆ alkyl(cycloalkyl), or Ci-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R²¹; each R²¹ is independently halogen, -CN, -OH, -OR^a, -SH, -SR^a, -S(=0)R^a, -N0₂, -NR^cR^d, -S(=0)₂R^a, -NHS(=0)₂R^a, -S(=0)₂NR^cR^d, -C(=0)R^a, -0C(=0)R^a, -C(=0)0R^b, -0C(=0)0R^b, -C(=0)NR^cR^d, -0C(=0)NR^cR^d, -NR^bC(=0)NR^cR^d, -NR^bC(=0)R^a, -NR^bC(=0)0R^b, Ci-C₆ alkyl, Ci-C₆ haloalkyl, Ci-C₆hydroxyalkyl, Ci-C₆ heteroalkyl, or cycloalkyl that is unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl;

each R^a is independently Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci-C₆ haloalkyl;

each R^b is independently hydrogen, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci-C₆ haloalkyl; and

R^c and R^d are each independently hydrogen, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆

heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci-C₆ haloalkyl;

or R^c and R^d are taken together with the nitrogen atom to which they are attached to form a

heterocycloalkyl that is unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl.

[0005] In some aspects, the compound of Formula (I) is a compound of Formula (II):

Formula (II);

wherein:

each R¹ is independently halogen, -CN, -OH, -OR^a, -SH, -SR^a, -NR^cR^d, -C(=0)R^a, -C(=0)0R^b, - C(=0)NR^cR^d, -NR^bC(=0)R^a, Ci-C₆ alkyl, Ci-C₆ haloalkyl, Ci-C₆hydroxyalkyl, Ci-C₆ heteroalkyl, or cycloalkyl unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl;

R² is hydrogen, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆ heteroalkyl, cycloalkyl, or

heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, and

heterocycloalkyl is unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci-C₆ haloalkyl; and

m is 0, 1, 2, or 3. [0006] In some aspects, the compound of Formula (I) or Formula (II) is a compound of Formula (III):

Formula (III);

wherein:

R² is hydrogen, or Ci-C₆ alkyl;

each R^20a is independently halogen, -CN, -OH, -OR^a, -NR^cR^d, -S(=0)₂R^a, -NHS(=0)₂R^a, - S(=0)₂NR^cR^d, -C(=0)R^a, -OC(=0)R^a, -C(=0)OR^b, -OC(=0)OR^b, -C(=0)NR^cR^d, - OC(=0)NR^cR^d, -NR^bC(=0)NR^cR^d, -NR^bC(=0)R^a, -NR^bC(=0)OR^b, Ci-C₆ alkyl; cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆ alkyl(heteroaryl), Ci-C₆

alkyl(cycloalkyl), or Ci-C₆ alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl,

heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R²¹;

each R²¹ is independently halogen, -CN, -OH, -OR^a, -NR^cR^d, -S(=0)₂R^a, -NHS(=0)₂R^a, - S(=0)₂NR^cR^d, -C(=0)R^a, -OC(=0)R^a, -C(=0)OR^b, -OC(=0)OR^b, -C(=0)NR^cR^d, - OC(=0)NR^cR^d, -NR^bC(=0)NR^cR^d, -NR^bC(=0)R^a, -NR^bC(=0)OR^b, C C₆ alkyl, Cj-C ialoalkyl. Ci-C₆hydroxyalkyl, Ci-C₆ heteroalkyl, or cycloalkyl that is unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl.

[0007] Also described herein is the use of compounds of Formulas (I), (II), and (III) in combination therapies with VEGF or PDGFR inhibitors for the treatment of pathological angiogenesis.

[0008] Also described herein are compositions comprising compounds of Formulas (I), (II), and (III) which are suitable for the treatment of pathological angiogenesis.

BRIEF DESCRIPTION OF THE FIGURES

[0009] The invention has other advantages and features which will be more readily apparent from the following detailed description of the invention and the appended claims, when taken in conjunction with the accompanying drawings.

[0010] Figure 1. Data showing that amodiaquine (AQ) is a non-competitive antagonist of the apelin receptor. (A) Apl3 concentration response curves showing the effect of pre -incubation either in the absence (O) or with different concentrations of AQ for 0.5 h at 37 °C: 0.3 mM (X), 2.4 pM (D), 19.7 pM (▼), 157.4 pM (¨), after which increasing concentrations of Apl3 were added and the incubation continued for 0.5 h. AQ reduced the E_ma of Apl3 responses, reflecting insurmountable inhibition. Data are mean ± SEM (n = 3). Curves represent the best fit non-linear regression analysis calculated using a 4- paramter logistic with GraphPad Prism 7. (B) Radioligand binding inhibition curves showing percent bound [¹²⁵I]-Glp65, Nle75, Tyr77-Apl3 with different concentrations of cold, unlabeled Apl3 (A), and the competitive apelin receptor antagonist ML221 (·) and AQ (■). Data shown are the mean ± SEM of two independent experiments (n = 2) with each data point performed in duplicate.

[0011] Figure 2. Human retinal endothelial cells (HREC) express APJ. (A) APJ protein was detected and visualized in HRECs by immunocytochemistry using the anti -APJ antibody ab 140508, and Alexa488 conjugated secondary antibody. (B) A control experiment in which the primary anti -APJ antibody was omitted shows the specificity of ab 140508 for APJ. (C) Cytosolic (c), membrane (m) and nuclear (n) fractions of HREC cells were isolated and subjected to SDS-PAGE and Western blotting as described. APJ immunoreactivity was observed only in the membrane fraction, with a migration of < 49 kDa. The efficiency of the cellular fractionation was monitored by blotting for the membrane bound Na/KATPase (m) and nuclear laminin (n). St = molecular weight marker. (D, E) Incubation of HRECs with Apl3 (1 nM) led to the aggregation of APJ immunoreactivity into bright puncta after 60 min. Cell images are maximal intensity projections taken using a confocal microscope.

[0012] Figure 3. Effects of Apl3, ML221, and AQ on HREC proliferation, migration, and tube formation. (A) Proliferation: human retinal endothelial cells (HRECs) were exposed to vehicle (DMSO 1% v/v), VEGF (100 ng/mL), and Apl3 (10 nM) for 16 h. Proliferation was determined as described in Example III. (B) Migration. Data plotted is the mean percent (%) change ± SEM normalized to vehicle control. (C) Apl3 induces HREC tubular network formation in vitro. (D, E) The prototypical APJ antagonists ML221 and AQ block Ap 13 -induced HREC tube formation in a concentration dependent manner. (F) Both AQ (black bar) and ML221 (grey bar) block VEGF -induced HREC tube formation in a concentration dependent manner. Data plotted is the mean ± SEM length of endothelial tubes measured in micrometers (pm), normalized to vehicle control. Mean and SEM are calculated from an experiment that was performed twice with each treatment condition tested in triplicate ( n = 3). NS = not significant; ** = p<0.0l; *** = p<0.00l vs vehicle;† = p<0.000l vs Apl3 as determined by ANOVA with

Dunnett’s test for multiple comparisons.

[0013] Figure 4. In vivo efficacy of amodiaquine in mice with laser-induced choroidal neovascularization (CNV) as visualized by optical coherence tomography (OCT). (A-F)

Representative images of laser-induced CNV lesions (brackets), showing a significant reduction in size and/or in intensities (black holes) of injury after the treatment with AQ. Eyes had received intravitreal injection of (A) Saline, (B) vehicle (1% DMSO), or AQ (C-F) at the indicated doses at the time of receiving laser bums. (G) The extent of the lesions were quantified by confocal microscopy to measure the volume of the CNV lesions (mean ± SEM, n = 5).

[0014] Figure 5. In vivo efficacy of amodiaquine in mice with laser-induced choroidal neovascularization (CNV) as visualized by confocal miscroscopy. RPE choroidal flat mounts were stained with agglutinin-TRITC conjugate to visualize the CNV lesions by confocal microscopy. Eyes had received intravitreal injection of (A) Saline, (B) vehicle (1% DMSO), or AQ (C-F) at the indicated doses at the time of receiving laser bums. Reduction in lesion size and the spotted black replacement to the staining in eyes treated with AQ is indicative of angiogenesis subsiding which showed most effectively at the dose of 50 mg.

[0015] Figure 6. Metabolism of AQ in microsomes yields DEAQ. The conversion of AQ to the metabolite desethylaminoquinoline (DEAQ) was monitored in vitro using (A) mouse, (B) human and (C) rat hepatic microsomes. The consumption of AQ and a production of DEAQ was measured by quantitative LC-MS/MS using internal standards and a standard curve for both AQ and DEAQ. Data points represent the mean ± SEM ng/mL of each compound from an experiment performed in duplicate. Curves represent the best fit non-linear regression analysis for AQ and linear regression analysis for DEAQ.

DETAILED DESCRIPTION OF THE INVENTION

[0016] Both the human apelin receptor (APJ, gene symbol APLNR) and apelin have been implicated as the key mediators of physiological responses to multiple homeostatic perturbations, including cardiovascular control, water balance, hypothalamic-pituitary-adrenal (HP A) axis regulation, and metabolic homeostasis. Homeostatic stability is critical in mammalian organisms, and knowledge as to how this vital function is regulated and how this mechanism can go wrong in pathological conditions is still limited.

[0017] APJ was first identified as an orphan G-protein coupled receptor (GPCR), with closest identity to the angiotensin II (Ang II) receptor, type AT_ia. APJ remained an orphan receptor until 1998 when a 36-amino acid peptide termed apelin, for APJ endogenous ligand, was identified. In the ensuing years, the receptor was deorphanised when its cognate ligand, apelin, was isolated from bovine stomach extracts. Recently, the apelinergic system has been shown to be critically involved in multiple homeostatic processes.

[0018] Although APJ does not bind Ang II, apelin- 13 shares a limited homology (four amino acids) with the vasoconstrictive peptide. Moreover, Ang I-converting enzyme 2 (ACE2), which catalyzes the C- terminal dipeptide cleavage of Ang I to Ang II, or Ang II to Ang 1-7, also acts on apelin- 13 with a high catalytic efficiency, removing the C-terminal phenylalanine (Phe) residue. However, this cleavage may not inactivate the peptide, as the apelin isoform K16P, which lacks the terminal Phe, while ineffective at inducing receptor internalization or regulating blood pressure (BP) (effects associated with the full peptide), still binds to APJ and inhibits forskolin-stimulated cAMP production.

[0019] APJ binds numerous apelin isoforms and signals through various G proteins to a variety of signaling pathways to culminate in different patterns of activation and de sensitization that may be tissue- and cell type-specific. Recently, APJ has also been reported to heterodimerize with other GPCRs and to signal in the absence of an endogenous ligand.

[0020] Although progress has been made in recent years in clarifying the physiological significance of apelin/APJ, much remains to be discovered about the expression of the apelinergic system and precisely how it affects numerous physiological functions. Since the discovery of the apelin ligand, both apelin and APJ have been implicated as key regulators of central and peripheral responses to multiple homeostatic perturbations. These include playing pivotal roles in the regulation of cardiovascular function, angiogenesis, fluid homeostasis, and energy metabolism and acting as neuroendocrine modulators of the HPA axis responses to stress. It is becoming apparent that the apelinergic system may play a pathophysiological role within many of these regulatory systems.

[0021] Apelin is an angiogenic factor and a mitogen of endothelial cells. Significantly, apelin is required for the normal development of frog heart and formation of murine blood vessels. Additionally, the development of the retinal vasculature is stunted in apelin KO mice, and apelin is necessary for hypoxia-induced retinal angiogenesis, and is also involved in non-neovascular remodeling of the retina.

[0022] The apelinergic system has been implicated in tumor neoangiogenesis. In brain tumors, the expression of apelin and APJ is up-regulated in microvascular proliferations, while tumor cell lines overexpressing apelin show increased growth. The pathophysiological effects of apelin in angiogenesis have also been reported for the liver, where the apelinergic system is a factor in portosystemic collaterization and splanchnic neovascularization in portal hypotensive rats as well as in

neovascularization during liver cirrhosis. However, apelin may have therapeutic effects in ischemia recovery due to vessel regeneration and endothelial proliferation and blood vessel diameter regulation. These findings indicate that apelin is a crucial factor for angiogenesis and that there may be therapeutic potential in both the disruption of its signaling (e.g., tpMors) and the stimulation of APJ expression (e.g., ischemia recovery).

[0023] Amodiaquine is a 4-aminoquinoline antimalarial drug that is widely used for the treatment and prevention of infection by Plasmodium falciparum. It is no longer used in the United States because of rare but serious side effects, including agranulocytosis and hepatitis. This class of compounds is also associated with retinal toxicity if overdosed. Herein, amodiaquine and related compounds are shown to be antagonists of the apelin receptor which block both apelin and VEGF mediated angiogenesis. While there are several anti-VEGF therapies currently in clinical use, they are expensive and -30% of patients are non-responsive or refractory. Therefore, there is a need for therapies that do not target VEGF.

Definitions

[0024] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as,“comprises” and“comprising” are to be construed in an open, inclusive sense, that is, as“including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0025] Reference throughout this specification to“one embodiment” or“an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases“in one embodiment” or“in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms“a,”“an,” and“the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term“or” is generally employed in its sense including“and/or” unless the content clearly dictates otherwise.

[0026] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0027] “Alkyl” refers to an optionally substituted straight-chain, or optionally substituted branched- chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms, wherein an sp3 -hybridized carbon of the alkyl residue is attached to the rest of the molecule by a single bond. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl- 1 -propyl, 2-methyl -2 -propyl, 2-methyl- 1 -butyl, 3 -methyl- 1 -butyl, 2-methyl -3 -butyl, 2,2-dimethyl- 1 -propyl, 2-methyl-l -pentyl, 3 -methyl- 1 -pentyl, 4-methyl- 1 -pentyl, 2-methyl-2-pentyl, 3- methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l-butyl, 3,3-dimethyl-l-butyl, 2-ethyl- 1 -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as“Ci-C₆ alkyl” or “Ci-₆alkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term“alkyl” where no numerical range is designated. In some embodiments, the alkyl is a Ci-Cio alkyl. In some embodiments, the alkyl is a Ci-C₆ alkyl. In some embodiments, the alkyl is a Ci-C₅ alkyl. In some embodiments, the alkyl is a C₁-C₄ alkyl. In some embodiments, the alkyl is a C₁-C₃ alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -OH, -OMe, -NH₂, or -N0₂. In some embodiments, the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0028] “Alkenyl” refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms, wherein an sp2- hybridized carbon of the alkenyl residue is attached to the rest of the molecule by a single bond. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH₂), l-propenyl (-CH₂CH=CH₂), isopropenyl [-C(CH₃)=CH₂], butenyl, l,3-butadienyl and the like. Whenever it appears herein, a numerical range such as“C₂-C₆ alkenyl” or“C_2-6alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term“alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkenyl is optionally substituted with oxo, halogen, -CN, -OH, -OMe, -NH₂, or -N0₂. In some embodiments, the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0029] “Alkynyl” refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, l,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as“C₂-C₆ alkynyl” or“C_2-6alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term“alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl group may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, -CN, -OH, -OMe, -NH₂, or -N0₂. In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0030] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -OH, -OMe, -NH₂, or -N0₂. In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.

[0031] “Alkoxy” refers to a radical of the formula -OR_a where R_a is an alkyl, alkenyl, or alkynyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, -OMe, -NH₂, or -N0₂. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0032] “Aryl” refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to lO-membered aryl. In some embodiments, the aryl is a 6-membered aryl. Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as- indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted as described below, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF₃, -OH, - OMe, -NH₂, or -N0₂. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF₃, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

[0033] “Cycloalkyl” refers to a stable, fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C₃-Ci₅ cycloalkyl), from three to ten carbon atoms (C₃-Ci₀ cycloalkyl), from three to eight carbon atoms (C₃-C₈ cycloalkyl), from three to six carbon atoms (C₃-C₆ cycloalkyl), from three to five carbon atoms (C₃-C₅ cycloalkyl), or three to four carbon atoms (C₃-C₄ cycloalkyl). Monocyclic cycloalkyls or carbocycles include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbomyl, decalinyl, bicyclo[3.3.0]octane,

bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo[2.2.l]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and

7,7-dimethyl-bicyclo[2.2. l]heptanyl. Unless stated otherwise specifically in the specification, a cycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF₃, -OH, -OMe, -NH₂, or -N0₂. In some embodiments, the cycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF₃, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0034] “Halo” or“halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0035] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, l,2-difluoroethyl, 3-bromo-2-fluoropropyl, l,2-dibromoethyl, and the like.

[0036] “Heterocycloalkyl” refers to a stable 3- to 24-membered fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,

2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,

thiomorpholinyl, thiamorpholinyl, l-oxo-thiomorpholinyl, l,l-dioxo-thiomorpholinyl, 1,3- dihydroisobenzofuran-l-yl, 3-oxo-l,3-dihydroisobenzofuran-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2- oxo-l,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a

3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3 - to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5 - to 6-membered heterocycloalkyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF₃, -OH, -OMe, -NH₂, or -N0₂. In some embodiments, the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF₃, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0037] “Heteroaryl” refers to a 5 - to l4-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous and sulfur, and at least one aromatic ring. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. In some embodiments, the heteroaryl is a 5- to lO-membered heteroaryl. In some embodiments, the heteroaryl is a 5 - to 6-membered

heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, l,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl

(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, l-oxidopyridinyl, l-oxidopyrimidinyl, l-oxidopyrazinyl, l-oxidopyridazinyl, 1 -phenyl -lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl may be optionally substituted as described below, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl,

heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF₃, -OH, -OMe, -NH₂, or -N0₂. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF₃, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0038] The term“optional” or“optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example,“optionally substituted alkyl” means either“alkyl” or“substituted alkyl” as defined above. Further, an optionally substituted group may be un-substituted (e.g., -CH₂CH₃), fully substituted (e.g., -CF₂CF₃), mono-substituted (e.g., -CH₂CH₂F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH₂CHF₂, - CH₂CF₃, -CF₂CH₃, -CFHCHF₂, etc.). It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns (e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum) that are sterically impractical and/or synthetically non -feasible. Thus, any substituents described should generally be understood as having a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.

[0039] An“effective amount” or“therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.

[0040] The terms“inhibit,”“block,”“suppress,” and grammatical variants thereof are used interchangeably herein and refer to any statistically significant decrease in biological activity, including full blocking of the activity. In some embodiments,“inhibition” refers to a decrease of about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or about 100% in biological activity. Accordingly, when the terms“inhibition” or“suppression” are applied to describe, e.g., an effect of Apl3 on the activity of APJ, the term refers to the ability of a compound disclosed herein to statistically significantly decrease the activity of the Ap 13 -mediated inhbition in forskolin stimulated intracellular cAMP (a net increase in forskolin stimulated intracellular cAMP), relative to the activity in an untreated (control) cell. In some instances, the cell which expresses APJ is a naturally occurring cell or cell line (e.g., a cancer cell) or is recombinantly produced by introducing a nucleic acid encoding APJ into a host cell. In one aspect, the compound disclosed herein inhibits Ap 13 -mediated inhibition by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or about 100%, as determined, for example, by the methods described in the Examples and/or methods known in the art.

[0041] As used herein,“treatment” or“treating,” or“palliating” or“ameliorating” or“reducing” or “inhibiting progression” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By“therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.

[0042] ‘Administration of’ or“administering a” compound should be understood to mean providing a compound of the disclosure or a pharmaceutical composition to the subject in need of treatment.

[0043] ‘Patient” refers to a mammal (e.g., human, dog, rat) that is suffering from a disease. In some aspects, the disease is mediated by apelin or APJ.

[0044] The term“VEGF” as used herein refers to the signal protein vascular endothelial growth factor. VEGF is a subfamily of growth factors, the platelet-derived growth factor family of cystine -knot growth factors. They are important signaling proteins involved in both vasculogenesis (the c/e novo formation of the embryonic circulatory system) and angiogenesis. VEGF's normal function is to create new blood vessels during embryonic development, new blood vessels after injury, muscle following exercise, and new vessels (collateral circulation) to bypass blocked vessels. The VEGF family comprises five members in mammals, including VEGF-A, which is involved in angiogenesis.

[0045] The term“VEGF receptor” or“VEGFR” as used herein refers to a cellular receptor for VEGF^’, ordinarily a cell -surface receptor found on vascular endothelial cells, as well as variants thereof which retain the ability to bind VEGF. One example of a VEGF receptor is the fms-like tyrosine kinase (fit) (also known as VEGFR 1), a transmembrane receptor in the tyrosine kinase family. The fit receptor comprises an extracellular domain, a transmembrane domain, and an intracellular domain with tyrosine kinase activity. The extracellular domain is involved in the binding of VEGF, whereas the intracellular domain is involved in the signal transduction. Another example of a VEGF receptor is the flk-l receptor (also referred to as KDR or VEGFR2). VEGFR2 exhibits strong tyrosine kinase receptor activity and plays an important role in angiogenesis.

[0046] As used herein, the term“VEGF inhibitor” or“VEGFR inhibitor” refers to a molecule that blocks VEGF or VEGF function or VEGF binding to the VEGF receptor. A VEGF inhibitor can be an antibody, which binds to either VEGF or to the VEGF receptor. Examples of such antibodies include, but are not limited to, ranibizumab, bevacizumab, aflibercept, tanibirumab, vanucizumab, or combinations thereof. A VEGF inhibitor can also be a small molecule inhibitor that binds to either VEGF or to the VEGF receptor. If it binds to VEFGR, the VEGF inhibitor can, for example, block binding of VEGF or inhibit the enzymatic activity of VEGFR. Examples of small molecule inhibitors of VEGF include, but are not limited to, SU5416 (semaxinib), SU11248, SU6668 (TSU-68), PTK787/ZK222584, ZD6474 (AZD-6474), ZD2171, CEP-7055, CP-547,632, AG013736, GW786034, AEE788, or combinations thereof.

[0047] The term“PDGF” as used herein refers to platelet-derived growth factor. PDGF is a dimeric glycoprotein that can be composed of two A subunits (PDGF-AA), two B subunits (PDGF- BB), or one of each (PDGF-AB). PDGF is one of numerous growth factors that regulate cell growth and division. In particular, PDGF plays a significant role in angiogenesis, the growth of blood vessels from already-existing blood vessel tissue, mitogenesis, i.e. proliferation, of mesenchymal cells such as fibroblasts, osteoblasts, tenocytes, vascular smooth muscle cells and mesenchymal stem cells as well as chemotaxis, the directed migration, of mesenchymal ceils hr addition to driving mesenchymal proliferation, PDGFs have been shown to direct tire migration, differentiation and function of a variety of specialised mesenchymal and migratory ceil types, both during development and in the adult animal . Other growth factors in this family include vascular endothelial growth factors B and C (VEGF-B, VEGF-C) which are active in angiogenesis and endothelial cell growth, and placenta growth factor (P1GF) which is also active in angiogenesis.

[0048] The temr“PDGF receptor” or“PDGFR” as used herein refers to a cellular receptor for PDGF, ordinarily a cell-surface receptor found on vascular endothelial cells, as well as variants thereof which retain the ability to bind PDGF. There are two forms of the PDGFR, a and [3, each encoded by a different gene. Depending on which growth factor is bound, PDGFR homo- or heterodimenzes. Upon binding to PDGF, the PDGFR tyrosine activity is activated and signal transduction pathways are activated, including pathways that lead to a variety of intracellular processes such as proliferation, angiogenesis, and cell motility.

[0049] As used herein, the term“PDGF inhibitor” or“PDGFR inhibitor” refers to a molecule that blocks PDGF or PDGFR function or PDGF binding to the PDGF receptor. A PDGFR inhibitor can be an antibody, which binds to either PDGF or to the PDGF receptor. An example of such antibodies includes, but is not limited to, olaratumab. A PDGFR inhibitor can also be a small molecule inhibitor that binds to either PDGF or to the PDGF receptor. If it binds to PDFGR, the PDGFR inhibitor can, for example, block binding of PDGF or inhibit the enzymatic activity of PDGFR. Examples of small molecule inhibitors of PDGFR include, but are not limited to, imatinib, sunitinib, sorafenib, pazopanib, nilotinib, or combinations thereof.

Angiogenesis

[0050] As used herein, the term“angiogenesis” means the generation of new blood vessels into a tissue or organ. Under normal physiological conditions, or animals only undergo angiogenesis in very specific restricted situations. For example, angiogenesis is normally observed in wound healing, fetal and embryonal development and formation of the corpus luteum, endometrium and placenta. The control of angiogenesis is a highly regulated system of angiogenic stimulators and inhibitors. The control of angiogenesis has been found to be altered in certain disease states and, in many cases, the pathological damage associated with the disease is related to the uncontrolled angiogenesis.

[0051] “Physiological angiogenesis” is involved in normal physiological processes such as reproduction and wound healing. Physiological angiogenesis is an important step in ovulation and also in implantation of the blastula after fertilization. Prevention of angiogenesis could be used to induce amenorrhea, to block ovulation or to prevent implantation by the blastula.

[0052] In wound healing, excessive repair or fibroplasia can be a detrimental side effect of surgical procedures and may be caused or exacerbated by physiological angiogenesis. Adhesions are a frequent complication of surgery and lead to problems such as small bowel obstruction.

[0053] As used herein, the term“pathological angiogenesis” refers to angiogenesis associated with a cancer, tumor, or other disease or condition, such as a disease or condition associated with increased vasculature, and is distinct from physiological angiogenesis, such as occurs during growth, wound healing, and the formation of granulation tissue.

[0054] Pathological angiogenesis occurs in a multiplicity of disease states, tumor metastasis and abnormal growth by endothelial cells and supports the pathological damage seen in these conditions. The diverse pathological states created due to unregulated angiogenesis have been grouped together as angiogenic dependent or angiogenic associated diseases. Such diseases include, but are not limited to, neoplasia, peripheral vascular disease, hypertension, preeclampsia syndrome, abnormal angiogenesis, diabetes, fibrosis such as idiopathic pulmonary fibrosis, wound healing, chronic obstructive pulmonary disease, cardiovascular disease, avascular or ischemic insult, myocardial infarction, stroke, vasculitis, systemic or vascular sclerosis, gangrene, congelation, alopecia, eczema, ulcers, lymphedema, vascular hyperplasia, hemangioma, psoriasis, endometriosis, inflammatory disease such as arthritis and inflammatory bowel disease, and retinal disease such as ocular degeneration, diabetic retinopathy, or macular degeneration.

[0055] One disease class in which pathological angiogenesis is believed to be involved is inflammatory disease, such as rheumatoid arthritis. In rheumatoid arthritis, the blood vessels in the synovial lining of the joints undergo angiogenesis. In addition to forming new vascular networks, the endothelial cells release factors and reactive oxygen species that lead to pannus growth and cartilage destruction. The factors involved in angiogenesis may actively contribute to, and help maintain, the chronically inflamed state of rheatoid arthritis.

[0056] Chronic inflammation may also involve pathological angiogenesis. Such disease states as ulcerative colitis and Crohn's disease show histological changes with the ingrowth of new blood vessels into the inflamed tissues. Bartonellosis, a bacterial infection found in South America, can result in a chronic stage that is characterized by proliferation of vascular endothelial cells. Another pathological role associated with angiogenesis is found in atherosclerosis. The plaques formed within the lumen of blood vessels have been shown to have angiogenic stimulatory activity.

[0057] Factors associated with angiogenesis may also have a role in osteoarthritis. The activation of the chondrocytes by angiogenic-related factors contributes to the destruction of the joint. At a later stage, the angiogenic factors would promote new bone formation. Therapeutic intervention that prevents the bone destruction could halt the progress of the disease and provide relief for persons suffering with arthritis.

[0058] One of the most frequent angiogenic diseases of childhood is the hemangioma. In most cases, the tumors are benign and regress without intervention. In more severe cases, the tumors progress to large cavernous and infiltrative forms and create clinical complications. Systemic forms of hemangiomas, the hemangiomatoses, have a high mortality rate. Therapy-resistant hemangiomas exist that cannot be treated with therapeutics currently in use.

[0059] Pathological angiogenesis has also been implicated in many forms of fibrosis. Hepatic angiogenesis takes place in chronic liver diseases that are characterized by inflammation and progressive fibrosis. Additionally, idiopathic pulmonary fibrosis is a chronic, progressive, and usually fatal disease where a balance of angiogenic and angiostatic factors regulate vessel homeostasis in the normal physiological conditions of the lung.

[0060] Pathological angiogenesis is also responsible for damage found in hereditary diseases such as Osler-Weber-Rendu disease, or hereditary hemorrhagic telangiectasia. This is an inherited disease characterized by multiple small angiomas, tumors of blood or lymph vessels. The angiomas are found in the skin and mucous membranes, often accompanied by epistaxis (nosebleeds) or gastrointestinal bleeding and sometimes with pulmonary or hepatic arteriovenous fistula.

[0061] Pathological angiogenesis is prominent in solid tumor formation and metastasis. Angiogenic factors have been found associated with several solid tumors such as rhabdomyosarcomas,

retinoblastoma, Ewing sarcoma, neuroblastoma, and osteosarcoma. A tumor cannot expand without a blood supply to provide nutrients and remove cellular wastes. Tumors in which angiogenesis is important include solid tumors, and benign tumors such as acoustic neuroma, neurofibroma, trachoma and pyogenic granulomas. Prevention of angiogenesis could halt the growth of these tumors and the resultant damage to the animal due to the presence of the tumor.

[0062] In some instances, angiogenesis is associated with blood-bom tumors such as leukemias, any of various acute or chronic neoplastic diseases of the bone marrow in which unrestrained proliferation of white blood cells occurs, usually accompanied by anemia, impaired blood clotting, and enlargement of the lymph nodes, liver, and spleen. It is believed that angiogenesis plays a role in the abnormalities in the bone marrow that give rise to leukemia-like tumors.

[0063] Pathological angiogenesis is important in two stages of tumor metastasis. The first stage where angiogenesis stimulation is important is in the vascularization of the tumor which allows minor cells to enter the blood stream and to circulate throughout the body. After the tumor cells have left the primary site, and have settled into the secondary, metastasis site, angiogenesis must occur before the new tumor can grow and expand. Therefore, prevention of angiogenesis could lead to the prevention of metastasis of tumors and possibly contain the neoplastic growth at the primary site.

[0064] Knowledge of the role of angiogenesis in the maintenance and metastasis of tumors has led to a prognostic indicator for breast cancer. The amount of neovascularization found in the primary tumor was determined by counting the microvessel density in the area of the most intense neovascularization in invasive breast carcinoma. A high level of microvessel density was found to correlate with tumor recurrence. Control of angiogenesis by therapeutic means could possibly lead to cessation of the recurrence of the tumors.

[0065] A further example of a disease mediated by pathological angiogenesis is ocular neovascular disease, or retinal pathological angiogenesis. This disease is characterized by invasion of new blood vessels into the structures of the eye such as the retina or cornea. It is the most common cause of blindness and is involved in approximately twenty eye diseases. In age-related macular degeneration, the associated visual problems are caused by an ingrowth of chorioidal capillaries through defects in Bruch's membrane with proliferation of fibrovascular tissue beneath the retinal pigment epithelium. Angiogenic damage is also associated with diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma and retrolental fibroplasia. Other diseases associated with corneal

neovascularization include, but are not limited to, epidemic keratoconjunctivitis, Vitamin A deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, sjogrens, acne rosacea, phylectenulosis, syphilis, Mycobacteria infections, lipid degeneration, chemical bums, bacterial ulcers, fungal ulcers, Herpes simplex infections, Herpes zoster infections, protozoan infections, Kaposi sarcoma, Mooren ulcer, Terrien's marginal degeneration, mariginal keratolysis, rheumatoid arthritis, systemic lupus, polyarteritis, trauma, Wegener’s sarcoidosis, Scleritis, Stevens Johnson disease, periphigoid radial keratotomy, and comeal graph rejection.

[0066] Diseases associated with retinal/choroidal neovascularization include, but are not limited to, diabetic retinopathy, macular degeneration, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum, Paget’s disease, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis/vitritis, mycobacterial infections, Lyme disease, systemic lupus erythematosis, retinopathy of prematurity, Eale’s disease, Bechet’s disease, infections causing a retinitis or choroiditis, presumed ocular histoplasmosis, Best’s disease, myopia, optic pits, Stargart’s disease, pars planitis, chronic retinal detachment, hyperviscosity syndromes, toxoplasmosis, trauma and post-laser complications. Other diseases include, but are not limited to, diseases associated with rubeosis (neovasculariation of the angle) and diseases caused by the abnormal proliferation of fibrovascular or fibrous tissue including all forms of proliferative vitreoretinopathy.

[0067] In many forms of retinal pathological angiogenesis, the disease has an etiology of inflammation. Such diseases include, but are not limited to, diabetic retinopathy, dry age-related macular degeneration, exudative (or wet) age-related macular degeneration, diabetic macular endema, retinal detatchment, posterior uveitis, comeal neovascularization, iris neovascularization, and combinations thereof.

[0068] To date, various agents that inhibit angiogenesis (e.g., endostatin, angiostatin, and thrombospondin) have been described. However, angiogenesis is important to physiological processes, such as growth and development or wound healing. Current anti-angiogenesis therapies that do not discriminate between physiological versus pathological angiogenesis, such as anti-VEGF monoclonal antibodies and receptor tyrosine kinase inhibitors, suppress beneficial as well as pathological

angiogenesis, by inducing systemic depression of cell signaling. For example, considering the vast biological role of VEGF in thyroid function, bone marrow function, immunomodulation, kidney function, vascular homeostasis, coagulation initiation, and physiological angiogenesis, the systematic suppression of VEGF can interfere will all of these essential functions.

[0069] Additionally, for retinal pathological angiogenesis, while there are several anti-VEGF therapies currently in clinical use, they are expensive and -30% of patients are non -responsive or refractory. Therefore, there is a need for therapies that do not target VEGF, and for therapies that discriminate between physiological versus pathological angiogenesis. One way to discriminate between physiological versus pathological angiogenesis might be through topical rather than systemic delivery of the therapy.

Compounds

[0070] Described herein are compounds of Formula (I), Formula (II), Formula (III), or a

pharmaceutically acceptable salt, solvate, or stereoisomer thereof useful in the treatment of pathological angiogenesis. In some embodiments, the pathological angiogenesis is retinal pathological angiogenesis.

[0071] In some embodiments provided herein is a compound having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

Formula (I);

wherein:

each R¹ is independently halogen, -CN, -OH, -OR^a, -SH, -SR^a, -NR^cR^d, -C(=0)R^a, -C(=0)OR^b, - C(=0)NR^cR^d, -NR^bC(=0)R^a, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,

n is 0, 1, 2, or 3;

Z is -NR²R³, -OR⁴, -SR⁵, or -CR⁶R⁷R⁸;

alkyl(cycloalkyl), C,-C₍ alkyl(heterocycloalkyl), -S(=0)₂R^lla, -S(=0)₂NR^12aR^13a, or -C(=0)₂R^lla; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R^20a;

or R² and R³ are taken together with the nitrogen atom to which they are attached to form a

heterocycloalkyl that is unsubstituted or substituted with one, two, or three R^20b; R⁴ is hydrogen, -C(=0)R^llb, -C(=0)0R^12b, -C(=0)NR^12bR^13b, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆ alkyl(heteroaryl), Ci-C₆ alkyl(cycloalkyl), Ci-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R^20c;

each R²⁰, R^20a, R^20b, R^20c, R^20d, R^20e, R^20f, and R^20g is independently halogen, -CN, -OH, -OR^a, -SH, - SR^a, -S(=0)R^a, -N0₂, -NR^cR^d, -S(=0)₂R^a, -NHS(=0)₂R^a, -S(=0)₂NR^cR^d, -C(=0)R^a, -0C(=0)R^a, -C(=0)0R^b, -0C(=0)0R^b, -C(=0)NR^cR^d, -0C(=0)NR^cR^d, -NR^bC(=0)NR^cR^d, -NR^bC(=0)R^a, - NR^bC(=0)0R^b, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆ alkyl(heteroaryl), Ci-C₆ alkyl(cycloalkyl), or Ci-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R²¹;

each R²¹ is independently halogen, -CN, -OH, -OR^a, -SH, -SR^a, -S(=0)R^a, -N0₂, -NR^cR^d, -S(=0)₂R^a, -NHS(=0)₂R^a, -S(=0)₂NR^cR^d, -C(=0)R^a, -0C(=0)R^a, -C(=0)0R^b, -0C(=0)0R^b, -C(=0)NR^cR^d, -0C(=0)NR^cR^d, -NR^bC(=0)NR^cR^d, -NR^bC(=0)R^a, -NR^bC(=0)0R^b, Ci-C₆ alkyl, Ci-C₆ haloalkyl, Ci-C₆ hydroxyalkyl, Ci-C₆ heteroalkyl, or cycloalkyl that is unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl;

heterocycloalkyl that is unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl;

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0072] For any and all of the embodiments of Formula (I), substituents are selected from among a subset of the listed alternatives.

[0073] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is -NR²R³ or -OR⁴. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, Z is -NR²R³.

[0074] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R² and R³ are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl that is unsubstituted or substituted with one, two, or three R^20b. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R^20b is independently halogen, -CN, -OH, -OR^a, -NR^cR^d, -C(=0)R^a, - OC(=0)R^a, -C(=0)OR^b, -C(=0)NR^cR^d, -NR^bC(=0)R^a, C ,-C_f> alky l or cycloalkyl; wherein each alkyl and cycloalkyl is independently unsubstituted or substituted with one, two, or three halogen, -OH, -OR^a, Ci- C₆ alkyl, or Ci-C₆ haloalkyl. In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R^20b is independently -OH or -OR^a.

[0075] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R³ is Ci-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), C C₆ alkyl(heteroaryl), -S(=0)₂R^lla, -S(=0)₂NR^12aR^13a, or -C(=0)₂R^lla; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R^20a. [0076] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R³ is aryl which is substituted with one, two, or three R^20a.

[0077] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R¹ is independently halogen, -CN, -OH, -OR^a, -SH, -SR^a, -NR^cR^d, -

C(=0)R^a, -C(=0)OR^b, -C(=0)NR^cR^d, -NR^bC(=0)R^a, C,-C_f> alky l. CrQ, haloalkyl, CrCJiydroxyalkyl.

Ci-C₆ heteroalkyl, or cycloalkyl unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl.

[0078] In some embodiments of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R² is hydrogen, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆ heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci-C₆ haloalkyl.

[0079] In some embodiments of a compound of Formula (I), the compound has the structure of Formula (II):

Formula (II);

wherein:

each R¹ is independently halogen, -CN, -OH, -OR^a, -SH, -SR^a, -NR^cR^d, -C(=0)R^a, -C(=0)OR^b, -

C(=0)NR^cR^d, -NR^bC(=0)R^a, C C₆ alkyl, CrQ, haloalkyl, CrCJiydroxyalkyl. CrC₆ heteroalkyl, or cycloalkyl unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl;

m is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0080] In some embodiments of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R¹ is independently halogen, -CN, -OH, -OR^a, -NR^cR^d, -

C(=0)R^a, -C(=0)OR^b, -C(=0)NR^cR^d, -NR^bC(=0)R^a, C,-C_f> alky l. C,-C₍, haloalkyl. CrCJiydroxyalkyl.

Ci-C₆ heteroalkyl, or cycloalkyl that is unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl. In some embodiments of a compound of Formula (I) or (II), or a

pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R¹ is each R¹ is independently halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl; and n is 0, 1, or 2. [0081] In some embodiments of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R² is hydrogen, or Ci-C₆ alkyl.

[0082] In some embodiments of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R^20a is independently halogen, -CN, -OH, -OR^a, -NR^cR^d, - R^b, -

alkyl;

cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆ alkyl(heteroaryl), Ci-C₆ alkyl(cycloalkyl), or Ci-C₆ alkyl(heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R²¹; and each

R²¹ is independently halogen, -CN, -OH, -OR^a, -NR^cR^d, -S(=0)₂R^a, -NHS(=0)₂R^a, -S(=0)₂NR^cR^d, - C(=0)R^a, -0C(=0)R^a, -C(=0)0R^b, -0C(=0)0R^b, -C(=0)NR^cR^d, -0C(=0)NR^cR^d, -NR^b C(=0)NR^cR^d, -

NR^bC(=0)R^a, -NR^bC(=0)0R^b, C^Q, alkyl, C haloalkyl, C Cehydroxyalkyl, C^Q, heteroalkyl, or cycloalkyl that is unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl.

[0083] In some embodiments of a compound of Formula (I) or (II), the compound has the structure of Formula (III):

Formula (III);

wherein:

R² is hydrogen, or Ci-C₆ alkyl;

each ^a, -

ycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆ alkyl(heteroaryl), Ci-C₆

heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R²¹; and

each R²¹ is independently halogen, -CN, -OH, -OR^a, -NR^cR^d, -S(=0)₂R^a, -NHS(=0)₂R^a, - S(=0)₂NR^cR^d, -C(=0)R^a, -0C(=0)R^a, -C(=0)0R^b, -0C(=0)0R^b, -C(=0)NR^cR^d, - 0C(=0)NR^cR^d, -NR^bC(=0)NR^cR^d, -NR^bC(=0)R^a, -NR^bC(=0)0R^b, Ci-C₆ alkyl, Ci-C₆ haloalkyl, Ci-C₆hydroxyalkyl, Ci-C₆ heteroalkyl, or cycloalkyl that is unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl;

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [0084] In some embodiments of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R² is Ci-C₆ alkyl. In some embodiments of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R² is methyl or ethyl. In some embodiments of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R² is methyl. In some embodiments of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R² is hydrogen.

[0085] In some embodiments of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R^20a is independently halogen, -CN, -OH, -OR^a, - N0₂, -NR^cR^d, -NHS(=0)₂R^a, -S(=0)₂NR^cR^d, -C(=0)R^a, -OC(=0)R^a, -C(=0)OR^b, -C(=0)NR^cR^d, - NR^bC(=0)R^a, Ci-C₆ alkyl, Ci-C₆ haloalkyl, Ci-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci-C₆ haloalkyl.

[0086] In some embodiments of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R^20a is independently halogen, -CN, -OH, -OR^a, - C(=0)R^a, -C(=0)OR^b, -C(=0)NR^cR^d, Ci-C₆ alkyl, Ci-C₆ haloalkyl, or Ci-C₆ heteroalkyl.

[0087] In some embodiments of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R^a is independently Ci-C₆ alkyl, Ci-C₆ heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci-C₆ haloalkyl. In some embodiments of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R^a is independently Ci-C₆ alkyl, or Ci-C₆ haloalkyl.

[0088] In some embodiments of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R^b is independently hydrogen, Ci-C₆ alkyl, Ci-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci-C₆ haloalkyl. In some embodiments of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, each R^b is independently hydrogen, or Ci-C₆ alkyl which is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci-C₆ haloalkyl.

[0089] In some embodiments of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R^c and R^d are each independently hydrogen, Ci-C₆ alkyl, Ci-C₆ heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci- C₆ alkyl, or Ci-C₆ haloalkyl. In some embodiments of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R^c and R^d are each independently hydrogen, Ci-C₆ alkyl, Ci-C₆ heteroalkyl, or heterocycloalkyl which is unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci-C₆ haloalkyl.

[0090] In some embodiments of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R^c and R^d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl that is unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl. In some embodiments of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R^c and R^d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl.

[0091] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

[0092] Described herein is a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from a compound in Table 1.

Table 1. Exemplary compounds.

Further Forms of Compounds Disclosed Herein

Isomers/Stereoisomers

[0093] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.

Labeled compounds

[0094] In some embodiments, the compounds described herein exist in their isotopically -labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as ¾, ¾, ¹³C, ¹⁴C, ¹⁵N, ¹⁸0, ¹⁷0, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Compounds described herein, and the metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvate, hydrates or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ¾ and carbon-l4, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., ²H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compounds, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof is prepared by any suitable method. [0095] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Pharmaceutically acceptable salts

[0096] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0097] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0098] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fiimarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-l,6-dioate, hydroxybenzoate, g-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, l-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate,

tosylateundeconate and xylene sulfonate.

[0099] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, f imaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, l,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 2 -naphthalene sulfonic acid, 4-methylbicyclo- [2.2.2]oct-2-ene-l -carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-l - carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid.

In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.

[00100] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N⁺(C_I-4 alkyl)₄, and the like.

[00101] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quatemization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quatemization.

Solvates

[00102] In some embodiments, the compounds described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates. The invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.

[00103] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

Tautomers

[00104] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.

Pharmaceutical Compositions

[00105] In certain embodiments, the compound disclosed herein is administered as a pure chemical. In some embodiments, the compound disclosed herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 2 I^st Ed. Mack Pub. Co., Easton, PA (2005)).

[00106] Accordingly, provided herein is a pharmaceutical composition comprising at least one compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the composition.

[00107] Some embodiments provide a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[00108] In certain embodiments, the compound disclosed herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[00109] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[00110] In some embodiments, the pharmaceutical compositions are provided in a dosage form for oral administration, which comprise a compound disclosed herein, and one or more pharmaceutically acceptable excipients or carriers. The pharmaceutical compositions provided herein that are formulated for oral administration may be in tablet, capsule, powder, or liquid form. A tablet may comprise a solid carrier or an adjuvant. Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil, or synthetic oil. Physiological saline solution, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol, or polyethylene glycol may be included. A capsule may comprise a solid carrier such as gelatin.

[00111] In some embodiments, the pharmaceutical compositions are provided in a dosage form for parenteral administration, which comprise a compound provided herein, and one or more

pharmaceutically acceptable excipients or carriers. Where pharmaceutical compositions may be formulated for intraveneous, cutaneous, subcutaneous, or intravitreal injection, the active ingredient will be in the form of the parentreally acceptable aqueous solution, which has a suitable pH, isotonicity, and stability. Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles, such as Sodium Chloride injection Ringer’s injection, or Lactated Ringer’s injection. Preservatives, stabilizers, buffers, antioxidants, and/or other additives may be included as required.

[00112] In some embodiments, the pharmaceutical compositions are provided in a dosage form suitable for topical administration, which comprise a compound provided herein, and one or more pharmaceutically acceptable excipients or carriers.

[00113] The pharmaceutical compositions can also be formulated as modified release dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted- , and programmed-release, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art.

[00114] The pharmaceutical compositions provided herein can be provided in a unit-dosage form or multiple-dosage form. A unit-dosage form, as used herein, refers to a physically discrete unit suitable for administration to a human and/or animal subject, and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of at least one active ingredient sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients.

Examples of a unit-dosage form include and ampoule, a syringe, an individually packaged tablet or a capsule. A unit-dosage form may be administered in fractions or multiples thereof. A multiple -dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dosage form. Examples of a multiple-dosage form include a vial, bottle of tablets or capsules, or bottle of liquid formulation.

[00115] The pharmaceutical compositions provided herein can be administered at once or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro tests or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgement of the person administering or supervising the administration of the formulations.

[00116] In some embodiments, the pharmaceutical compositions are suitable for administering to an ocular environment. In some embodiments, the pharmaceutical compositions are solutions, suspensions, or ointments. In some embodiments, the pharmaceutical compositions are suitable for intravitreal, posterior juxtascleral, or periocular injection. In some embodiments, the pharmaceutical compositions are suitable for intravitreal injection. In some embodiments, the pharmaceutical compositions are suitable for topical administration to the ocular environment.

[00117] In some embodiments, the pharmaceutical composition which is suitable for topical administration, which comprises a compound disclosed herein, and one or more pharmaceutically acceptable excipients or carriers is a solution. In some embodiments, the pharmaceutical composition which is suitable for topical administration, which comprises a compound disclosed herein, and one or more pharmaceutically acceptable excipients or carriers is a solution suitable for topical administration as eye drops. In some embodiments, the pharmaceutical composition which is suitable for topical administration, which comprises a compound disclosed herein, and one or more pharmaceutically acceptable excipients or carriers is a gel, ointment, ocular insert, spray, or other topical ocular delivery method. In some embodiments, the pharmaceutical composition which is suitable for topical administration, which comprises a compound disclosed herein, and one or more pharmaceutically acceptable excipients or carriers is a solution suitable for topical administration is a semi-solid. In some embodiments, the pharmaceutical composition which is suitable for topical administration, which comprises a compound disclosed herein, and one or more pharmaceutically acceptable excipients or carriers is homogenous. In some embodiments, the pharmaceutical composition which is suitable for topical administration, which comprises a compound disclosed herein, and one or more pharmaceutically acceptable excipients or carriers is a dispersion. In some embodiments, the pharmaceutical composition which is suitable for topical administration, which comprises a compound disclosed herein, and one or more pharmaceutically acceptable excipients or carriers is hydrophilic. In some embodiments, the pharmaceutical composition which is suitable for topical administration, which comprises a compound disclosed herein, and one or more pharmaceutically acceptable excipients or carriers has an oleaginous base. In some embodiments, the pharmaceutical composition which is suitable for topical administration, which comprises a compound disclosed herein, and one or more pharmaceutically acceptable excipients or carriers has at least one ophthalmically-acceptable excipient.

[00118] In some embodiments, the pharmaceutical compositions which are suitable for intravitreal administration, which comprise a compound disclosed herein, and one or more pharmaceutically acceptable excipients or carriers is a solution. In some embodiments, the pharmaceutical compositions which are suitable for intravitreal administration, which comprise a compound disclosed herein, and one or more pharmaceutically acceptable excipients or carriers is a solution which comprises a buffer and/or an inorganic salt and/or a surfactant and/or a saccharide. In some enbodiments, the pharmaceutical compositions which are suitable for intravitreal administration, which comprise a compound disclosed herein, and one or more pharmaceutically acceptable excipients or carriers is a solution with properties such that upon injection, the formulation will precipitate for sustained delivery.

[00119] In some embodiments, the pharmaceutical compositions which are suitable for intravitreal administration, which comprise a compound disclosed herein, and one or more pharmaceutically acceptable excipients or carriers comprises an ophthalmic device. In some embodiments, the

pharmaceutical compositions which are suitable for intravitreal administration, which comprise a compound disclosed herein, and one or more pharmaceutically acceptable excipients or carriers comprises an ophthalmic device and the device is implanted in the posterior segment of the affected eye.

[00120] In one aspect described herein is a composition for treating, reducing, ameliorating, or inhibiting progression of retinal pathological angiogenesis in a subject suitable for intravitreal injection, the composition comprising:

(a) a compound having formula (I);

Formula (I);

wherein:

each R¹ is independently halogen, -CN, -OH, -OR^a, -SH, -SR^a, -NR^cR^d, -C(=0)R^a, -C(=0)0R^b, - C(=0)NR^cR^d, -NR^bC(=0)R^a, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R²⁰;

n is 0, 1, 2, or 3;

Z is -NR²R³, -OR⁴, -SR⁵, or -CR⁶R⁷R⁸;

R² and R³ are each independently hydrogen, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,

cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆ alkyl(heteroaryl), Ci- C₆ alkyl(cycloalkyl), C C₆ alkyl(heterocycloalkyl), -S(=0)₂R^lla, -S(=0)₂NR^12aR^13a, or - C(=0)₂R^lla; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R^20a;

heterocycloalkyl that is unsubstituted or substituted with one, two, or three R^20b;

R⁴ is hydrogen, -C(=0)R^llb, -C(=0)OR^12b, -C(=0)NR^12bR^13b, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆ alkyl(heteroaryl), Ci-C₆ alkyl(cycloalkyl), Ci-C₆ alkyl (heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R^20c;

R⁵ is hydrogen, -C(=0)R^llc, -C(=0)OR^12c, -C(=0)NR^12cR^13c, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆ alkyl(heteroaryl), Ci-C₆ alkyl(cycloalkyl), Ci-C₆ alkyl (heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R^20d;

R⁶, R⁷, and R⁸ are each independently hydrogen, halogen, -CN, -OH, -OR^lld, -SH, -SR^lld, - S(=0)R^lld, -N0₂, -NR^12dR^13d, -S(=0)₂R^lld, -NHS(=0)₂R^lld, -S(=0)₂NR^12dR^13d, -C(=0)R^lld, - 0C(=0)R^lld, -C(=0)0R^12d, -0C(=0)0R^12d, -C(=0)NR^12gR^13d, -0C(=0)NR^12dR^13d, - NR^12dC(=0)NR^12dR^13d, -NR^12gC(=0)R^llg, -NR^12gC(=0)0R^12g, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂- C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆ alkyl(heteroaryl), Ci-C₆ alkyl(cycloalkyl), or Ci-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R^20e;

R^lla, _R I iiy _R ^| iy _{R i} id _{are cac}|₁ i_nd_ep_end_ently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,

R^12a R^12b, R^12c, R^12d, R^13a, R^13b, R^13c, and R^13d are each independently hydrogen, C ,-C₍, alkyl, C₂- C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one, two, or three R^20g;

each

, - NR^bC(=0)R^a, -NR^bC(=0)0R^b, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆ alkyl(heteroaryl), Ci-C₆ alkyl(cycloalkyl), or Ci-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R²¹;

each R²¹ is independently halogen, -CN, -OH, -OR^a, -SH, -SR^a, -S(=0)R^a, -N0₂, -NR^cR^d, - S(=0)₂R^a, -NHS(=0)₂R^a, -S(=0)₂NR^cR^d, -C(=0)R^a, -0C(=0)R^a, -C(=0)0R^b, -0C(=0)0R^b, -C(=0)NR^cR^d, -0C(=0)NR^cR^d, -NR^bC(=0)NR^cR^d, -NR^bC(=0)R^a, -NR^bC(=0)0R^b, C ,-C₍, alkyl, Ci-C₆ haloalkyl, Ci-C₆ hydroxyalkyl, Ci-C₆ heteroalkyl, or cycloalkyl that is unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl; each R^a is independently Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆ heteroalkyl,

cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci-C₆ haloalkyl;

each R^b is independently hydrogen, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci-C₆ haloalkyl; R^c and R^d are each independently hydrogen, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci-C₆ haloalkyl;

or R^c and R^d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl that is unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl;

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof;

(b) water; and

(c) a buffer capable of achieving and maintaining the pH of the composition at about pH 4.5 to about pH 8.0.

[00121] In some embodiments, the buffer is a Tris buffer, a phosphate buffer, a histidine buffer, a citrate buffer, or an acetate buffer. In some embodiments, the buffer is a Tris buffer. In some embodiments, the buffer is a phosphate buffer. In some embodiments, the buffer is a histidine buffer. In some embodiments, the buffer is a citrate buffer. In some embodiments, the buffer is an acetate buffer.

[00122] In some embodiments, the concentration of the buffer is about 1 mM to about 100 mM. In some embodiments, the concentration of the buffer is about 1 mM to about 20 mM. In some

embodiments, the concentration of the buffer is about 5 mM to about 20 mM. In some embodiments, the concentration of the buffer is about 1 mM to about 10 mM. In some embodiments, the concentration of the buffer is about 5 mM to about 10 mM. In some embodiments, the concentration of the buffer is about 10 mM to about 20 mM.

[00123] In some embodiments, the buffer has a pH of about 5.0 to about 6.5. In some embodiments, the buffer has a pH of about 5.5 to about 6.2. In some embodiments, the buffer has a pH of about 5.5 to about 7.5.

[00124] In some embodiments, the composition further comprises (d) an inorganic salt. In some embodiments, the concentration of inorganic salt is about 10 mM to about 200 mM. In some embodiments, the concentration of inorganic salt is about 10 mM to about 100 mM. In some embodiments, the concentration of inorganic salt is about 10 mM to about 50 mM. In some

embodiments, the inorganic salt is NaCl.

[00125] In some embodiments, the composition further comprises (e) a surfactant. In some embodiments, the surfactant is non-ionic. In some embodiments, the surfactant is a polysorbate. In some embodiments, the surfactant is polysorbate 20 or polysorbate 80. In some embodiments, the surfactant is polysorbate 20. In some embodiments, the surfactant is polysorbate 80. In some embodiments, the concentration of the surfactant is from about 0.001% to about 0.5%.

[00126] In some embodiments, the composition further comprises (f) a saccharide. In some embodiments, the saccharide is a,a-trehalose, sucrose, glucose, mannitol, or sorbitol. In some embodiments, the saccharide is a,a-trehalose. In some embodiments, the saccharide is sucrose. In some embodiments, the saccharide is glucose. In some embodiments, the saccharide is mannitol. In some embodiments, the saccharide is sorbitol. In some embodiments, the concentration of the saccharide is about 5% to 20%. In some embodiments, the concentration of the saccharide is about 5%. In some embodiments, the concentration of the saccharide is about 10%.

[00127] In some embodiments, the composition further comprises (g) a thickening or emulsifying agent. In some embodiments, the thickening or emulsifying agent is a polyethylene glycol (PEG), polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), polyacrylic acid (PAA), polyacrylamide, polyphosphate, xanthan gum, pectin, chitosan, dextran, carrageenan, guar gum, or cellulose ether. In some embodiments, the thickening or emulsifying agent is a polyethylene glycol. In some embodiments, the average molecular weight of the polyethylene glycol is within the range of 90 to 2200. In some embodiments, the polyethylene glycol is selected from the group consisting of PEG400, PEG600, PEG800, and PEG1000. In some embodiments, the concentration of the thickening or emulsifying agent is from l% to 20%.

[00128] In some embodiments, the composition further comprises a VEGF inhibitor.

[00129] In some embodiments, the composition further comprises a PDGFR inhibitor.

[00130] In some embodiments, the composition further comprises an anti-inflammatory agent.

Combination Therapy

[00131] In certain instances, the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in combination with a second therapeutic agent.

[00132] In some embodiments, the benefit experienced by a patient is increased by administering one of the compounds described herein with a second therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.

[00133] In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is co-administered with a second therapeutic agent, wherein the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.

[00134] In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient is simply additive of the two therapeutic agents or the patient experiences a synergistic benefit.

[00135] In certain embodiments, different therapeutically-effective dosages of the compounds disclosed herein will be utilized in formulating a pharmaceutical composition and/or in treatment regimens when the compounds disclosed herein are administered in combination with a second therapeutic agent. Therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens are optionally determined by means similar to those set forth hereinabove for the actives themselves. Furthermore, the methods of prevention/treatment described herein encompasses the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects. In some embodiments, a combination treatment regimen encompasses treatment regimens in which administration of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is initiated prior to, during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which a compound disclosed herein, or a

pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and the second agent being used in combination are administered simultaneously or at different times and/or at decreasing or increasing intervals during the treatment period. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.

[00136] It is understood that the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought, is modified in accordance with a variety of factors (e.g., the disease, disorder or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject). Thus, in some instances, the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.

[00137] For combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated, and so forth. In additional embodiments, when co-administered with a second therapeutic agent, the compound provided herein is administered either simultaneously with the second therapeutic agent, or sequentially.

[00138] In combination therapies, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single injection or as two separate injections).

[00139] The compounds disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, as well as combination therapies, are administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies. Thus, in one embodiment, the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms. In specific embodiments, a compound described herein is administered as soon as is practicable 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. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject. For example, in specific embodiments, a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years.

[00140] In certain embodiments, the second therapeutic agent is an adjuvant. In certain embodiments, the second therapeutic agent is a VEGF inhibitor. In certain embodiments, the second therapeutic agent is a PDGFR inhibitor. In certain embodiments, the second therapeutic agent is an anti-inflammatory agent. In certain embodiments, there is a third, fourth, or fifth therapeutic agent, or so on, as described in this paragraph.

[00141] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in combination with an adjuvant. In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).

[00142] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in combination with a VEGF inhibitor. In certain embodiments, the VEGF inhibitor is a small molecule inhibitor, such as SU5416 (semaxinib), SU11248, SU6668 (TSU-68), PTK787/ZK222584, ZD6474 (AZD-6474), ZD2171, CEP-7055, CP-547,632, AG013736, GW786034, AEE788, or a combination thereof. In other embodiments, the VEGF inhibitor is an anti-VEGF antibody, such as ranibizumab, bevacizumab, aflibercept, tanibirumab, vanucizumab, or a combination thereof.

[00143] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in combination with a PDGFR inhibitor. In certain embodiments, the PDGFR inhibitor is a small molecule inhibitor, such as imatinib, sunitinib, sorafenib, pazopanib, nilotinib, or a combination thereof. In other embodiments, the PDGFR inhibitor is an anti- PDGFR antibody, such as olaratumab.

[00144] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is administered in combination with an anti-inflammatory agent. In some embodiments the anti-inflammatory agent is a non-steroidal anti-inflammatory drug (NS AID) or peroxisome proliferator-activated receptors (PPAR) ligand. NSAIDs include, but are not limited to: aspirin, salicylic acid, gentisic acid, choline magnesium salicylate, choline salicylate, choline magnesium salicylate, choline salicylate, magnesium salicylate, sodium salicylate, diflunisal, carprofen, fenoprofen, fenoprofen calcium, fluorobiprofen, ibuprofen, ketoprofen, nabutone, ketolorac, ketorolac tromethamine, naproxen, oxaprozin, diclofenac, etodolac, indomethacin, sulindac, tolmetin, meclofenamate, meclofenamate sodium, mefenamic acid, piroxicam, meloxicam, COX-2 specific inhibitors (such as, but not limited to, celecoxib, rofecoxib, valdecoxib, parecoxib, etoricoxib, lumiracoxib, CS-502, JTE-522, F- 745 337, and NS398).

[00145] In one aspect, disclosed herein is a composition comprising:

(a) a compound having formula (I);

Formula (I);

wherein: each R¹ is independently halogen, -CN, -OH, -OR^a, -SH, -SR^a, -NR^cR^d, -C(=0)R^a, -C(=0)0R^b, - C(=0)NR^cR^d, -NR^bC(=0)R^a, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R²⁰;

n is 0, 1, 2, or 3;

Z is -NR²R³, -OR⁴, -SR⁵, or -CR⁶R⁷R⁸;

R⁴ is hydrogen, -C(=0)R^llb, -C(=0)0R^12b, -C(=0)NR^12bR^13b, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆

alkyl(heteroaryl), Ci-C₆ alkyl(cycloalkyl), Ci-C₆ alkyl (heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R^20c;

R⁵ is hydrogen, -C(=0)R^llc, -C(=0)0R^12c, -C(=0)NR^12cR^13c, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆

alkyl(heteroaryl), Ci-C₆ alkyl(cycloalkyl), Ci-C₆ alkyl (heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R^20d;

R⁶, R⁷, and R⁸ are each independently hydrogen, halogen, -CN, -OH, -OR^lld, -SH, -SR^lld, - S(=0)R^lld, -N0₂, -NR^12dR^13d, -S(=0)₂R^lld, -NHS(=0)₂R^lld, -S(=0)₂NR^12dR^13d, -C(=0)R^lld, - 0C(=0)R^lld, -C(=0)0R^12d, -0C(=0)0R^12d, -C(=0)NR^12gR^13d, -0C(=0)NR^12dR^13d, - NR^12dC(=0)NR^12dR^13d, -NR^12gC(=0)R^llg, -NR^12gC(=0)0R^12g, C ,-C_f> alky l. C₂-C₆ alkenyl, C₂- C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆ alkyl(heteroaryl), Ci-C₆ alkyl(cycloalkyl), or Ci-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R^20e;

R^lla, _R I iiy _R ^| iy _an(j _{R i} id _{are cac|1} i_nd_ep_end_ently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,

each

, - NR^bC(=0)R^a, -NR^bC(=0)0R^b, -Ce alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆ alkyl(heteroaryl), Ci-C₆ alkyl(cycloalkyl), or Ci-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R²¹;

each R²¹ is independently halogen, -CN, -OH, -OR^a, -SH, -SR^a, -S(=0)R^a, -N0₂, -NR^cR^d, - S(=0)₂R^a, -NHS(=0)₂R^a, -S(=0)₂NR^cR^d, -C(=0)R^a, -0C(=0)R^a, -C(=0)0R^b, -0C(=0)0R^b, -C(=0)NR^cR^d, -0C(=0)NR^cR^d, -NR^bC(=0)NR^cR^d, -NR^bC(=0)R^a, -NR^bC(=0)0R^b, Ci-C₆ alkyl, Ci-C₆ haloalkyl, Ci-C₆hydroxyalkyl, Ci-C₆ heteroalkyl, or cycloalkyl that is unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl; each R^a is independently Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆ heteroalkyl,

each R^b is independently hydrogen, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci-C₆ haloalkyl;

R^c and R^d are each independently hydrogen, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci-C₆ haloalkyl;

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and

(b) a VEGF inhibitor.

[00146] In some embodiments, the VEGF inhibitor comprises a small molecule inhibitor. In some embodiments, the VEGF inhibitor comprises SU5416 (semaxinib), SU11248, SU6668 (TSU-68), PTK787/ZK222584, ZD6474 (AZD-6474), ZD2171, CEP-7055, CP-547,632, AG013736, GW786034, AEE788, or a combination thereof.

[00147] In some embodiments, the VEGF inhibitor comprises an anti-VEGF antibody. In some embodiments, the VEGF inhibitor comprises ranibizumab, bevacizumab, aflibercept, tanibirumab, vanucizumab, or a combination thereof.

[00148] In some embodiments, the composition further comprises an anti-inflammatory agent.

[00149] In some embodiments, an anti-inflammatory agent is a compound selected from the group consisting of NSAIDs and PPAR ligands. In some embodiments, the anti-inflammatory agent is selected from the group consisting of: aspirin, celecoxib, diclofenac, diflunisal, etodolac, ibuprofen,

indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, and tolmetin, or a combination thereof.

[00150] In some embodiments, the composition further comprises a PDGFR inhibitor. In some embodiments, the PDGFR inhibitor comprises a small molecule inhibitor. In some embodiments, the PDGFR inhibitor comprises imatinib, sunitinib, sorafenib, pazopanib, nilotinib, or a combination thereof. In some embodiments, the PDGFR inhibitor comprises an anti-PDGFR antibody. In some embodiments, the PDGFR inhibitor comprises olaratumab.

[00151] In another aspect, disclosed herein is a composition comprising:

(a) a compound having formula (I);

Formula (I);

wherein:

each R¹ is independently halogen, -CN, -OH, -OR^a, -SH, -SR^a, -NR^cR^d, -C(=0)R^a, -C(=0)OR^b, - C(=0)NR^cR^d, -NR^bC(=0)R^a, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R²⁰;

n is 0, 1, 2, or 3;

Z is -NR²R³, -OR⁴, -SR⁵, or -CR⁶R⁷R⁸;

heterocycloalkyl that is unsubstituted or substituted with one, two, or three R^20b; R⁴ is hydrogen, -C(=0)R^llb, -C(=0)0R^12b, -C(=0)NR^12bR^13b, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆

R⁵ is hydrogen, -C(=0)R^llc, -C(=0)0R^12c, -C(=0)NR^12cR^13c, C^Q, alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆

each R²⁰, R^20a, R^20b, R^20c, R^20d, R^20e, R^20f, and R^20g is independently halogen, -CN, -OH, -OR^a, - SH, -SR^a, -S(=0)R^a, -N0₂, -NR^cR^d, -S(=0)₂R^a, -NHS(=0)₂R^a, -S(=0)₂NR^cR^d, -C(=0)R^a, - 0C(=0)R^a, -C(=0)0R^b, -0C(=0)0R^b, -C(=0)NR^cR^d, -0C(=0)NR^cR^d, -NR^bC(=0)NR^cR^d, - NR^bC(=0)R^a, -NR^bC(=0)0R^b, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆ alkyl(heteroaryl), Ci-C₆ alkyl(cycloalkyl), or Ci-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R²¹; each R²¹ is independently halogen, -CN, -OH, -OR^a, -SH, -SR^a, -S(=0)R^a, -N0₂, -NR^cR^d, - S(=0)₂R^a, -NHS(=0)₂R^a, -S(=0)₂NR^cR^d, -C(=0)R^a, -0C(=0)R^a, -C(=0)0R^b, -0C(=0)0R^b, -C(=0)NR^cR^d, -0C(=0)NR^cR^d, -NR^bC(=0)NR^cR^d, -NR^bC(=0)R^a, -NR^bC(=0)0R^b, Ci-C₆ alkyl, Ci-C₆ haloalkyl, Ci-C₆hydroxyalkyl, Ci-C₆ heteroalkyl, or cycloalkyl that is unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl; each R^a is independently Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆ heteroalkyl,

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and

(b) a PDGFR inhibitor.

[00152] In some embodiments, the PDGFR inhibitor comprises a small molecule inhibitor. In some embodiments, the PDGFR inhibitor comprises imatinib, sunitinib, sorafenib, pazopanib, nilotinib, or a combination thereof.

[00153] In some embodiments, the PDGFR inhibitor comprises an anti-PDGFR antibody. In some embodiments, the PDGFR inhibitor comprises olaratumab.

[00154] In some embodiments, the composition further comprises an anti-inflammatory agent. In some embodiments, the anti-inflammatory agent is a compound selected from the group consisting of NSAIDs and PPAR ligands. In some embodiments, wherein the anti-inflammatory agent is selected from the group consisting of: aspirin, celecoxib, diclofenac, diflunisal, etodolac, ibuprofen, indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, and tolmetin, or a combination thereof.

Methods

[00155] In one aspect, provided herein is a method for treating, reducing, ameliorating, or inhibiting progression of pathological angiogenesis in a subject, the method comprising administering to the subject in need thereof a pharmaceutical composition comprising a compound of Formula (I):

each R¹ is independently halogen, -CN, -OH, -OR^a, -SH, -SR^a, -NR^cR^d, -C(=0)R^a, -C(=0)0R^b, - C(=0)NR^cR^d, -NR^bC(=0)R^a, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl,

n is 0, 1, 2, or 3;

Z is -NR²R³, -OR⁴, -SR⁵, or -CR⁶R⁷R⁸;

alkyl(cycloalkyl), C ,-C₍, alkyl(heterocycloalkyl), -S(=0)₂R^lla, -S(=0)₂NR^12aR^13a, or -C(=0)₂R^lla; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R^20a;

R⁴ is hydrogen, -C(=0)R^llb, -C(=0)0R^12b, -C(=0)NR^12bR^13b, C,-C₍, alkyl, C₂-C₆ alkenyl, C₂-C₆

R⁵ is hydrogen, -C(=0)R^llc, -C(=0)0R^12c, -C(=0)NR^12cR^13c, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆

R⁶, R⁷, and R⁸ are each independently hydrogen, halogen, -CN, -OH, -OR^lld, -SH, -SR^lld, - S(=0)R^lld, -N0₂, -NR^12dR^13d, -S(=0)₂R^lld, -NHS(=0)₂R^lld, -S(=0)₂NR^12dR^13d, -C(=0)R^lld, - 0C(=0)R^lld, -C(=0)0R^12d, -0C(=0)0R^12d, -C(=0)NR^12gR^13d, -0C(=0)NR^12dR^13d, - NR^12dC(=0)NR^12dR^13d, -NR^12gC(=0)R^llg, -NR^12gC(=0)0R^12g, C ,-C_f> alky l. C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆ alkyl(heteroaryl), Ci-C₆ alkyl(cycloalkyl), or Ci-C₆ alkyl (heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R^20e; Rii^a, _R I ⁱⁱy _R I ⁱy _ancj Riid _{arc cac}]₁ independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R^20f;

heterocycloalkyl that is unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[00156] For any and all of the embodiments, substituents of Formula (I) are selected from among a subset of the listed alternatives.

[00157] In some embodiments, Z is -NR²R³ or -OR⁴. In some embodiments, Z is -NR²R³.

[00158] In some embodiments, R² and R³ are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl that is unsubstituted or substituted with one, two, or three R^20b. In some embodiments, each R^20b is independently halogen, -CN, -OH, -OR^a, -NR^cR^d, -C(=0)R^a, - 0C(=0)R^a, -C(=0)0R^b, -C(=0)NR^cR^d, -NR^bC(=0)R^a, C ,-C_f> alky l or cycloalkyl; wherein each alkyl and cycloalkyl is independently unsubstituted or substituted with one, two, or three halogen, -OH, -OR^a, Ci- C₆ alkyl, or Ci-C₆ haloalkyl. In some embodiments, each R^20b is independently -OH or -OR^a.

[00159] In some embodiments, R³ is Ci-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), C C₆ alkyl(heteroaryl), -S(=0)₂R^lla, -S(=0)₂NR^12aR^13a, or -C(=0)₂R^lla; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R^20a.

[00160] In some embodiments, R³ is aryl which is substituted with one, two, or three R^20a.

[00161] In some embodiments, each R¹ is independently halogen, -CN, -OH, -OR^a, -SH, -SR^a, -

NR^cR^d, -C(=0)R^a, -C(=0)0R^b, -C(=0)NR^cR^d, -NR^bC(=0)R^a, Ci-C₆ alkyl, Ci-C₆ haloalkyl, Ci-C_« hydroxyalkyl, Ci-C₆ heteroalkyl, or cycloalkyl unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl.

[00162] In some embodiments, R² is hydrogen, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆ heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci-C₆ haloalkyl.

[00163] In some embodiments of the method, the compound of Formula (I) has the structure of Formula (II):

Formula (II);

wherein:

C(=0)NR^cR^d, -NR^bC(=0)R^a, C ,-C_f> alky l. C ,-C₍, haloalkyl. C_rC_f hydroxyalkyh -Ce heteroalkyl, or cycloalkyl unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl;

heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci-C₆ haloalkyl; and

m is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[00164] In some embodiments, each R¹ is independently halogen, -CN, -OH, -OR^a, -NR^cR^d, -

C(=0)R^a, -C(=0)OR^b, -C(=0)NR^cR^d, -NR^bC(=0)R^a, C ,-C_f> alky l. C^Q, haloalkyl, -Ce hydroxyalkyl,

Ci-C₆ heteroalkyl, or cycloalkyl that is unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl. In some embodiments, each R¹ is each R¹ is independently halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl; and n is 0, 1, or 2.

[00165] In some embodiments, R² is hydrogen, or Ci-C₆ alkyl.

[00166] In some embodiments, each R^20a is independently halogen, -CN, -OH, -OR^a, -NR^cR^d, - S(=0)₂R^a, -NHS(=0)₂R^a, -S(=0)₂NR^cR^d, -C(=0)R^a, -OC(=0)R^a, -C(=0)OR^b, -OC(=0)OR^b, - C(=0)NR^cR^d, -OC(=0)NR^cR^d, -NR^bC(=0)NR^cR^d, -NR^bC(=0)R^a, -NR^bC(=0)OR^b, Ci-C₆ alkyl;

R²¹ is independently halogen, -CN, -OH, -OR^a, -NR^cR^d, -S(=0)₂R^a, -NHS(=0)₂R^a, -S(=0)₂NR^cR^d, - C(=0)R^a, -OC(=0)R^a, -C(=0)OR^b, -OC(=0)OR^b, -C(=0)NR^cR^d, -OC(=0)NR^cR^d, -NR^b C(=0)NR^cR^d, -

NR^bC(=0)R^a, -NR^bC(=0)OR^b, Ci-C₆ alkyl, Ci-C₆ haloalkyl, Ci-C₆ hydroxyalkyl, Ci-C₆ heteroalkyl, or cycloalkyl that is unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl.

[00167] In some embodiments of the method, the compound of Formula (I) or (II) has the structure of Formula (III):

Formula (III);

wherein:

R² is hydrogen, or Ci-C₆ alkyl;

heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R²¹; and each R²¹ is independently halogen, -CN, -OH, -OR^a, -NR^cR^d, -S(=0)₂R^a, -NHS(=0)₂R^a, - S(=0)₂NR^cR^d, -C(=0)R^a, -0C(=0)R^a, -C(=0)0R^b, -0C(=0)0R^b, -C(=0)NR^cR^d, - 0C(=0)NR^cR^d, -NR^bC(=0)NR^cR^d, -NR^bC(=0)R^a, -NR^bC(=0)0R^b, Ci-C₆ alkyl, Ci-C₆haloalkyl, Ci-C₆hydroxyalkyl, Ci-C₆ heteroalkyl, or cycloalkyl that is unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl;

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[00168] In some embodiments, R² is Ci-C₆ alkyl. In some embodiments of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, R² is methyl or ethyl. In some embodiments, R² is methyl. In some embodiments, R² is hydrogen.

[00169] In some embodiments, each R^20a is independently halogen, -CN, -OH, -OR^a, -N0₂, -NR^cR^d, - NHS(=0)₂R^a, -S(=0)₂NR^cR^d, -C(=0)R^a, -OC(=0)R^a, -C(=0)OR^b, -C(=0)NR^cR^d, -NR^bC(=0)R^a, C,-C₍, alkyl, Ci-C₆ haloalkyl, Ci-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci-C₆ haloalkyl.

[00170] In some embodiments, each R^20a is independently halogen, -CN, -OH, -OR^a, -C(=0)R^a, - C(=0)OR^b, -C(=0)NR^cR^d, Ci-C₆ alkyl, Ci-C₆ haloalkyl, or Ci-C₆ heteroalkyl.

[00171] In some embodiments, each R^a is independently Ci-C₆ alkyl, Ci-C₆ heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci-C₆ haloalkyl. In some embodiments, each R^a is independently Ci-C₆ alkyl, or Ci-C₆ haloalkyl.

[00172] In some embodiments, each R^b is independently hydrogen, Ci-C₆ alkyl, Ci-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci-C₆ haloalkyl. In some embodiments, each R^b is independently hydrogen, or Ci-C₆ alkyl which is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci-C₆ haloalkyl.

[00173] In some embodiments, R^c and R^d are each independently hydrogen, Ci-C₆ alkyl, Ci-C₆ heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl, and

heterocycloalkyl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci- C₆ alkyl, or Ci-C₆ haloalkyl. In some embodiments, R^c and R^d are each independently hydrogen, Ci-C₆ alkyl, Ci-C₆ heteroalkyl, or heterocycloalkyl which is unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci-C₆ haloalkyl.

[00174] In some embodiments, R^c and R^d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl that is unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl. In some embodiments, R^c and R^d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl. [00175] In some embodiments the compound used

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[00176] In some embodiments the compound used

, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[00177] In some embodiments the compound used

pharmaceutically acceptable salt, solvate, or stereoisomer thereof. [00178] In some embodiments the compound used

pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[00179] In some embodiments, the pathological angiogenesis comprises a disease selected from the group consisting of neoplasia, peripheral vascular disease, hypertension, preeclampsia syndrome, abnormal angiogenesis, diabetes, fibrosis such as idiopathic pulmonary fibrosis, wound healing, chronic obstructive pulmonary disease, cardiovascular disease, avascular or ischemic insult, myocardial infarction, stroke, vasculitis, systemic or vascular sclerosis, gangrene, congelation, alopecia, eczema, ulcers, lymphedema, vascular hyperplasia, hemangioma, psoriasis, endometriosis, inflammatory disease such as arthritis and inflammatory bowel disease, or retinal disease such as ocular degeneration, diabetic retinopathy, or macular degeneration.

[00180] In some embodiments, the pathological angiogenesis comprises fibrosis. In other embodiments, the pathological angiogenesis comprises cardiovascular disease. In other embodiments, the pathological angiogenesis comprises a tumor.

[00181] In some embodiments, wherein the pathological angiogenesis comprises retinal pathological angiogenesis. In some embodiments, the retinal pathological angiogenesis has an etiology in

inflammation. In some embodiments, the retinal pathological angiogenesis is selected from the group consisting of diabetic retinopathy (“DR”), dry age-related macular degeneration (“AMD”), exudative AMD, diabetic macular edema (“DME”), retinal detachment, posterior uveitis, comeal

neovascularization, iris neovascularization, and combinations thereof. In some embodiments, the retinal pathological angiogenesis is exudative AMD. In some embodiments, the retinal pathological angiogenesis is diabetic retinopathy.

[00182] In some embodiments, the compound of Formula (I), (II), or (III) is present in the composition in an amount sufficient to be effective for said treating, reducing, ameliorating, alleviating, or inhibiting progression of, said pathological angiogenesis.

[00183] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutically acceptable excipient is acceptable for administering to an ocular environment.

[00184] In some embodiments, wherein the composition comprises liquid medium. In some embodiments, the composition is a solution. In some embodiments, the solution is isotonic. [00185] In some embodiments, the composition is a suspension.

[00186] In some embodiments, the composition is an ointment.

[00187] In some embodiments, the method further comprises administering the compound to the ocular environment of an affected eye of the subject in need thereof. In some embodiments, the composition is injected into the vitreous of the affected eye. In some embodiments, the composition is administered topically to the ocular environment.

[00188] In some embodiments, the composition comprises an ophthalmic device. In some

embodiments, the composition is formed into an ophthalmic device and the device is implanted in the posterior segment of the affected eye.

[00189] In some embodiments, the method further comprises administering a VEGF inhibitor. In some embodiments, the VEGF inhibitor comprises a small molecule inhibitor. In some embodiments, the VEGF inhibitor comprises SU5416 (semaxinib), SU11248, SU6668 (TSU-68), PTK787/ZK222584, ZD6474 (AZD-6474), ZD2171, CEP-7055, CP-547,632, AG013736, GW786034, AEE788, or a combination thereof. In some embodiments, the VEGF inhibitor comprises an anti-VEGF antibody.

[00190] In some embodiments, the VEGF inhibitor comprises ranibizumab, bevacizumab, aflibercept, tanibirumab, vanucizumab, or a combination thereof. In some embodiments, the compound of Formula

(I), (II), or (III) and the VEGF inhibitor are administered within 24 hours of each other. In some embodiments, the compound of Formula (I), (II), or (III) and the VEGF inhibitor are administered within 60 minutes of each other. In some embodiments, the compound of Formula (I), (II), or (III) and the VEGF inhibitor are administered concurrently. In some embodiments, the compound of Formula (I), (II), or (III) and the VEGF inhibitor are present in the same composition.

[00191] In some embodiments, the method further comprises administering a PDGFR inhibitor. In some embodiments, the PDGFR inhibitor comprises a small molecule inhibitor. In some embodiments, the PDGFR inhibitor comprises imatinib, sunitinib, sorafenib, pazopanib, nilotinib, or a combination thereof. In some embodiments, the PDGFR inhibitor comprises an anti-PDGFR antibody. In some embodiments, the PDGFR inhibitor comprises olaratumab. In some embodiments, the compound of Formula (I), (II), or (III) and the PDGFR inhibitor are administered within 24 hours of each other. In some embodiments, the compound of Formula (I), (II), or (III) and the PDGFR inhibitor are administered within 60 minutes of each other. In some embodiments, the compound of Formula (I), (II), or (III) and the PDGFR inhibitor are administered concurrently. In some embodiments, the compound of Formula (I),

(II), or (III) and the PDGFR inhibitor are present in the same composition.

[00192] In some embodiments, the composition further comprises an anti-inflammatory agent. In some embodiments, the anti-inflammatory agent is a material selected from the group consisting of NSAIDs and PPAR ligands. In some embodiments, the anti-inflammatory agent is selected from the group consisting of: aspirin, celecoxib, diclofenac, difhmisal, etodolac, ibuprofen, indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, and tolmetin, or a combination thereof. [00193] In another aspect provided herein is a method for treating, reducing, ameliorating, or inhibiting progression of pathological angiogenesis in a subject, the method comprising administering to an ocular environment of an affected eye of a subject who has received anti-VEGF therapy, a pharmaceutical composition that comprises a compound of Formula (I):

Formula (I);

wherein:

n is 0, 1, 2, or 3;

Z is -NR²R³, -OR⁴, -SR⁵, or -CR⁶R⁷R⁸;

alkyl(cycloalkyl), Cj-C₍, alkyl(heterocycloalkyl), -S(=0)₂R^lla, -S(=0)₂NR^12aR^13a, or -C(=0)₂R^lla; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R^20a;

R^{l l a}. R^llb, R^llc, and R^lld are each independently Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,

each

NR^bC(=0)0R^b, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆ alkyl(heteroaryl), Ci-C₆ alkyl(cycloalkyl), or Ci-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R²¹;

each R²¹ is independently halogen, -CN, -OH, -OR^a, -SH, -SR^a, -S(=0)R^a, -N0₂, -NR^cR^d, -S(=0)₂R^a, -NHS(=0)₂R^a, -S(=0)₂NR^cR^d, -C(=0)R^a, -0C(=0)R^a, -C(=0)0R^b, -0C(=0)0R^b, -C(=0)NR^cR^d, -0C(=0)NR^cR^d, -NR^bC(=0)NR^cR^d, -NR^bC(=0)R^a, -NR^bC(=0)0R^b, C,-C_f< alkyl. C haloalkyl, Ci-C₆ hydroxyalkyl, Ci-C₆ heteroalkyl, or cycloalkyl that is unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl;

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[00194] In some embodiments, the anti-VEGF therapy thereof did not fully treat, reduce, ameliorate, or inhibit progression of retinal pathological angiogenesis in the subject thereof.

[00195] In some embodiments, the anti-VEGF therapy was administered as a plurality of doses of an anti-VEGF agent.

EXAMPLES

Preparation of Compounds

Abbreviations

DMSO: Dimethyl sulfoxide

EtOAc: Ethyl acetate

ESI-MS: Electrospray ionisation mass spectrometry

'H NMR: Proton nuclear magnetic resonance

HATU : 1 -[Bis(dimethylamino)methylene] - 1H- 1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid

hexafluorophosphate

HPLC: High-performance liquid chromatography

hr(s): Hour(s)

min: Minute

rt: Room temperature

THF: Tetrahydrofuran

EXAMPLE 1: 4-((7-Chloroquinolin-4-yl)amino)benzamide, Compound 12

[00196] Step 1) 4,7-Dichloroquinoline (101 mg, 0.51 mmol) and ethyl 4-aminobenzoate (87 mg, 0.53 mmol) were heated in ethanol at 80 °C for 45 minutes, then stirred at room temperature. The solids were filtered to provide ethyl 4-((7-chloroquinolin-4-yl)amino)benzoate hydrochloride (147 mg, 79%).

[00197] Step 2) The intermediate ester (143 mg, 0.39 mmol) was hydrolyzed with lithium hydroxide (32 mg, 1.34 mmol) in water (1 mL) and THF (4 mL) at room temperature. The mixture was partitioned with ethyl acetate and water. The aqueous phase was acidified with cone. HC1 to precipitate 4-((7- chloroquinolin-4-yl)amino)benzoic acid hydrochloride (131 mg, 99%).

[00198] Step 3) The intermediate acid (20 mg, 0.06 mmol) was activated with HATU (30 mg, 0.08 mmol) and triethylamine (0.045 mL, 0.32 mmol) in THF for 30 minutes prior to the introduction of excess ammonia (0.24 mL, 0.5 M in THF, 0.12 mmol). After stirring overnight the mixture was diluted with water, treated with sodium bicarbonate, and the product was extracted with ethyl acetate. The crude material was purified by reverse phase HPLC to provide 4-((7-chloroquinolin-4-yl)amino)benzamide (16 mg, 90%).‘HNMR (500 MHz, DMSO-ri₆) d 9.28 (s, 1H), 8.56 (d, J= 5.2 Hz, 1H), 8.41 (d, J= 9.0 Hz, 1H), 7.95 - 7.88 (m, 3H), 7.61 (dd, J= 9.0, 2.2 Hz, 1H), 7.41 (d, J= 8.6 Hz, 2H), 7.26 (s, 1H), 7.15 (d, J = 5.3 Hz, 1H). ESI-MS: Calculated for C₁₆H₁₂ClN₃0, [M+H] = 298.07, observed [M+H] = 298.21.

EXAMPLE 2: 7-Chloro-N-(4-methoxyphenyl)quinolin-4-amine, Compound 13

[00199] 7-Chloro-N-(4-methoxyphenyl)quinolin-4-amine was synthesized by analogous procedures used in Example 1. 4-Methoxyaniline was used in the first step to yield the desired product. 'H NMR (500 MHz, DMSO-ri₆) d 8.96 (s, 1H), 8.42 (d, J= 9.1 Hz, 1H), 8.39 (d, J= 5.4 Hz, 1H), 7.86 (d, J= 2.2 Hz, 1H), 7.54 (dd, J= 9.0, 2.3 Hz, 1H), 7.28 (d, J= 8.8 Hz, 2H), 7.02 (d, J= 8.8 Hz, 2H), 6.62 (d, J= 5.4 Hz, 1H), 3.79 (s, 3H). ESI-MS: Calculated for Ci₆H₁₃ClN₂0, [M+H] = 285.08, observed [M+H] =

285.22.

EXAMPLE 3: 2-((7-Chloroquinolin-4-yl)amino)benzoic acid, Compound 32

[00200] 2-((7-Chloroquinolin-4-yl)amino)benzoic acid was synthesized by analogous procedures used in Example 1. Ethyl 2-aminobenzoate was used in the first step and the desired product was isolated after step 2. ‘H NMR (500 MHz, DMSO-ri₆) d 8.63 (d, J= 9.1 Hz, 1H), 8.53 (d, J= 6.7 Hz, 1H), 8.10 (d, J = 8.4 Hz, 2H), 7.88 (d, J= 8.9 Hz, 1H), 7.78 (t, J= 7.6 Hz, 1H), 7.64 (d, J= 7.9 Hz, 1H), 7.52 (t, J= 7.6 Hz, 1H), 6.72 (d, J= 6.6 Hz, 1H). ESI-MS: Calculated for C₁₆H_nClN₂0₂, [M+H] = 299.06, observed [M+H] = 299.19. EXAMPLE 4: (2-((7-Chloroquinolin-4-yl)amino)phenyl)(morpholino)methanone, Compound 34

[00201] (2-((7-Chloroquinolin-4-yl)amino)phenyl)(morpholino)methanone was synthesized by analogous procedures used in Example 1. The product from Example 3 was treated with morpholine as in Step 3 of Example 1 to yield the desired product. *HNMR (500 MHz, Chloroform -ri) d 8.54 (d../ = 5.3 Hz, 1H), 7.96 (d, J= 2.1 Hz, 1H), 7.85 (d, J= 9.0 Hz, 1H), 7.62 (dd, J= 8.2, 1.2 Hz, 1H), 7.42 (dd, J = 8.9, 2.2 Hz, 1H), 7.38 (ddd, J= 8.4, 7.4, 1.6 Hz, 1H), 7.26 (dd, J= 7.7, 1.6 Hz, 1H), 7.10 (d, J= 5.3 Hz, 1H), 7.06 (td, J = 7.6, 1.1 Hz, 1H), 3.58 (s, 8H). ESI-MS: Calculated for C₂oH₁₈ClN₃0₂, [M+H] = 368.12, observed [M+H] = 368.32.

Biological Examples

EXAMPLE I: Identification of Aminoquinolines as APJ Antagonists

[00202] To identify small-molecule antagonists of the apelin receptor (APJ) we interrogated a compound library of -425,000 compounds using CHO-kl-AGTRLl cells overexpressing human APJ and a competitive immunoassay of intracellular cAMP. Active compounds were those that inhibited Apl3 (1.0 nM)-mediated decrease in forskolin stimulated intracellular cAMP by > 50%. Included in this hit set was a series of aminoquinolines, exemplified by amodiaquine (AQ). When tested in the primary APJ cAMP assay, aminoquinolines were found to be potent APJ antagonists (Tables 2-3). When tested in cells lacking the receptor (parental CHO-K1) or in those expressing the closely related angiotensin II type 1 (AT1), six compounds demonstrated selectivity for APJ (Table 2). None of the tested compounds exhibited cytotoxicity when tested on Fa2-N4 hepatocytes at concentrations up to 50 mM.

H YS, cAMP Assay

[00203] All reagents unless otherwise specified are components of the cAMP HitHunter (DiscoveRx) kit. Ligand Buffer + 60 mM Forskolin (Cayman Chemical, Ann Arbor, MI) was made fresh on the day of the experiment and used for the dilution of positive and negative controls as well as all peptides. CHO- Kl-APJ cells were dispensed into a 384-well tissue culture microplate (Coming, Coming, NY) using a Multidrop at a seeding density of 10,000 cells/well and returned to the incubator. The next day, the cell culture media was removed and replaced with 15 pL/well of assay buffer (IX HBSS, 10 mM HEPES) containing anti-cAMP antibody (DiscoveRx). Using the Janus Automated Workstation (Perkin Elmer), 5 pL of AP-13, ligand buffer (vehicle), or peptide (lO-point concentrations) were added to all wells, and subsequently incubated at 37 °C for 30 min. A working solution of ED/Lysis/CL substrate (20 pL/well) was added to all wells and incubated for 1 h at room temperature in the dark prior to a final addition of EA Reagent (20 mE/well). Plates were incubated at room temperature in the dark for 3 hrs prior to chemiluminescence detection on an EnVision (Perkin Elmer) using a counting time of 1 s/well.

APJ and ATI b-arrestin Recruitment Assay

[00204] CHO-K1 cells engineered to over-express APJ or AT1, and b-arrestin were removed from flasks using TrypLE Select (IX), no phenol red (Life Technologies, Grand Island, NY), centrifuged, and resuspended in CP2 Reagent (DiscoveRx, Fremont, CA). Cells were counted using a Countess

Automated Cell Counter (Invitrogen, Carlsbad, CA) and 5,000 cells/well were plated in a 384-well tissue culture treated microplate (Coming, Coming, NY). All plates were incubated overnight at 37 °C, 5% C0₂ in a final volume of 25 pL/well. Following incubation, 5 pL of peptides (10-point concentrations) and controls prepared in ligand buffer (IX HBSS, 10 mM HEPES, 0.1% BSA) were added to cells and incubated at 37 °C for 1.5 h. Using a Multidrop Combi Reagent Dispenser (Thermo Scientific), 12 pL of Detection Reagent (DiscoveRx) comprised of substrate and co-factors was added to all wells and incubated at room temperature in the dark for 1 h. Chemiluminescent signal was detected on an EnVision Multi -label plate reader (Perkin Elmer) using a counting time of 1 s/well.

[00205] Table 2 shows the IC₅₀s of representative 4-aminoquinolines in the primary APJ assay (cAMP), secondary assay (APJ b-arrestin recmitment), and counterassays (AT1 b-arrestin recmitment, and parental cells (cells lacking APJ) cAMP). General cytotoxicity was assessed using ATP-lite assay and HEK293t cells.

Table 2."

“All IC50 data are reported in mM. A < 1 mM < B < 10 mM < C

b ND = not determined.

[00206] Table 3 shows the activity of the compounds described herein in the primary APJ assay.

Table 3.

" A < 1 mM < B < 10 mM < C

EXAMPLE II: Validation of Aminoquinolines as APJ Antagonists

[00207] To better characterize the mechanism by which AQ antagonizes APJ, and determine the potency of the antagonism, we next tested the ability of AQ to increase the EC₅₀ of Apl3. AQ failed to produce parallel shifts in the concentration response curves for Apl3. At concentrations above 2.4 mM, AQ shifted the EC₅₀ of Apl3 and reduced E_ma correspondingly (Fig. 1A). At higher concentrations, AQ virtually eliminated all response to Apl3. Consistent with these functional results, AQ did not displace [¹²⁵I]-Glp65, Nle75, Tyr7-Apl3 binding to membranes containing APJ when tested as high as 100 mM. In contrast, unlabeled Apl3 and the prototypical APJ antagonist ML221 (4-oxo-6-((pyrimidin-2- ylthio)methyl)-4H-pyran-3-yl 4-nitrobenzoate) effectively displaced [¹²⁵I]-Glp65, Nle75, Tyr7-Apl3 with Ti = 0.18 nM and 1.33 mM, respectively (Fig. 1B). Taken together, these data indicate that AQ is a non competitive APJ antagonist.

Radioligand Binding

[00208] Prior to the initiation of the assay, soaking buffer (50 mM Tris-HCl pH 7.5, 0.5%

polyethyleneimine), assay buffer (25 mM HEPES pH 7.5, 10 mM MgCl₂, 1 mM CaCl₂, 0.5% BSA, protease inhibitor), and wash buffer (50 mM Tris-HCl pH 7.5, 0.5% BSA) were prepared. Soaking buffer (300 pL/well) was added to a 96-well GF/C filter plate (MultiScreen Harvest plate, Millipore) and left to equilibrate at room temperature for 3 h. Briefly, 25 pL peptide (8-point concentrations), 25 pL of 0.2 nM [¹²⁵I] Glp65, Nle75, Tyr77-Apl3 (Perkin Elmer), and 150 pL APJ membrane (Perkin Elmer) diluted 1: 150 in assay buffer, were added to a 96-well HB OptiPlate (Perkin Elmer) and incubated at room temperature for 45 min. Following incubation, contents were transferred from the OptiPlate to the pre- wet GF/C filter plate, and immediately underwent vacuum filtration. The filter plate was washed five times with 200 pL ice cold wash buffer and left at room temperature overnight to equilibrate. The next day, 20 pL scintillation liquid (Microscint 20, Perkin Elmer) was added and radioactivity quantified using a TopCount NXT (Perkin Elmer) microplate scintillation and luminescence counter.

[00209] Competition binding analysis was performed for the agonist [¹²⁵I]-Glp65, Nle75, Tyr7-Apl3 by AQ in the absence and presence of Ap 13 (100 nM).

EXAMPLE III: Anti-angiogenesis Activities of APJ Antagonists

[00210] The effect of AQ on the proliferation and migration of human retinal endothelial cells (HRECs) was determined. We applied immunohistologic and western blotting approaches to confirm endogenous expression of APJ in these cells. A polyclonal antibody targeting the intracellular C-terminal tail of human APJ and a fluorescently conjugated secondary detection antibody, identified APJ immunoreactivity throughout the cell in a generally diffuse speckled pattern. APJ immunoreactivity was not evenly distributed; it appeared to be enriched around the nucleus. This is likely reflective of the morphology of the HREC where the nucleus constitutes the thickest part of the cell. This staining pattern is consistent with that previously reported for APJ in HUVECs, rhesus choroid endothelial cells and retinal pericytes, as well as other GPCRs. (Fig. 2A). APJ immunoreactivity in HRECs was specific (Fig. 2B), and was confirmed using two additional APJ antibodies targeting other epitopes within the protein. The cytosolic, nuclear and membrane fractions of HRECs were subjected to western blotting using the same antibody. APJ immunoreactivity was highly enriched in the membrane fraction, but not the cytosolic or nuclear fractions. A single band consistent with a predicted APJ molecular weight of ~43kD was observed. The efficiency of the cellular fractionation method was monitored by blotting for the membrane bound Na/K ATPase and nuclear laminin (Fig. 2C). When HRECS were incubated with Apl3 (lnM) for 60min, the pattern of APJ immunoreactivity shifted from a diffuse speckled pattern to one characterized by aggregated bright puncta, indicating that the addition of ligand coalesced APJ immunoreactivity into pits characteristic of activated GPCRs (Fig. 2D,E).

[00211] Having confirmed that HREC cells express APJ, we next evaluated the effect of Apl3 and its inhibitors on HREC proliferation, migration and tube formation. The proangiogenic VEGF (0.25 nM) stimulated HREC proliferation and migration (Fig. 3A,B). Apl3 had no significant effect on either proliferation or migration of HRECs (Fig. 3A,B). Both VEGF and Apl3 stimulated the formation of endothelial tubes. When tested at multiple concentrations, Apl3 increased overall tube length in a concentration-dependent manner that was equivalent or greater than VEGF (Fig 3C). The combination of Apl3 with VEGF did not significantly increase the extent of tube formation formed when either factor was added alone, indicating that Apl3 and VEGF do not act synergistically.

[00212] Both AQ and the prototypical APJ antagonist ML221 blocked Ap 13 -dependent increases in tube formation. For both compounds this effect was concentration-dependent (Fig. 3D,E). Of critical importance, AQ and MF221 blocked both VEGF-induced tube formation as well (Fig 3F). This effect was sufficiently pronounced that it decreased the overall tube length compared to vehicle. We performed a cell viability assay on HRECs to ensure that this observation was not reflective of cytotoxicity. Neither MF221 nor AQ were significantly toxic to HRECs (Fig. 3F) when tested up to 100 mM.

HRECAPJ Receptor Immunofluorescence Labeling

[00213] HREC cells were seeded on four chamber Fab-Tek Chambered Coverglass (Thermo

Scientific; 1500 cells/chamber) for cell imaging in EGM-2 medium (Fonza) in a 5% C0₂ atmosphere at 37 °C for 1 day. Chambers were washed with ice-cold PBS and fixed for 10 min with paraformaldehyde (4%) on ice then washed in PBS containing Triton X-100 (0.2% v/v) for 2 x 20 min to permeabilize the cells. To block nonspecific protein-protein interactions, cells were washed with Odyssey Blocking Buffer and PBS (1: 1 v/v) containing 5% BS A for 1 hr at room temperature then incubated with rabbit anti -APJ antibodies (Abeam; ab662l8, ab84296, abl40508; 1:500 dilution, 2 pg/mF) overnight at +4 °C. Goat anti -rabbit Alexa Fluor 594 secondary IgG (H+F; Invitrogen, 1:500 dilution, 4 pg/mF) and DAPI Fluoromount-G (SouthemBiotech) were used for anti-APJ receptor antibodies labeling and cell nuclei staining for confocal fluorescence microscopy detection.

HREC APJ Receptor Aggregation

[00214] 1 x 10⁶ HREC cells were labeled with 0.5 pM carboxyfluorescein suecimmidyi ester (CFSE) at

37 °C for 15 min in EBM-2 media. After incubation cells were centrifuged and resuspended in EGM-2 media then 1700 cells were transferred to a well of Fab-Tek Chambered Coverglass and incubated in a 5% C0₂ atmosphere at 37 °C overnight. To induce APJ receptor internalization, apelin-l3 agonist (100 pM) was applied for 1.5, 3, 6, 12, 30, 60 and 240 min in separate chambers. After incubation the cells were washed, fixed, permeabilized, blocked and labeled with anti-APJ receptor antibody (ab 140508, 1:500 dilution, 2 pg/mF) and secondary Alexa Fluor 594 labeled antibody and DAPI as stated above. Confocal Fluorescence Microscopy

[00215] Immunofluorescent images (TIFF; 16 bit) were acquired by laser-scanning confocal microscopy with an A1R confocal microscope (Nikon Instruments) in single channel operation mode. Excitation lasers and emission filters were selected based on staining fluorochromes. Images were obtained with a Plan Apo 60x/l.40 oil objective (Nikon) as optical section Z-stacks. Identical acquisition settings were used for imaging for all time points using the NIS Elements AR software (Nikon). Specific fluorophore stainings were quantified on the Sum Slices Z-projection of the optical sections using Image J software (NIH). Area of nucleus of each cell from all time points were selected as region of interest (ROI) based on their DAPI staining. APJ receptor immunoreactivity was quantified as mean values of intensity in each ROI and normalized with the CFSE staining ROI mean intensity. The CFSE normalized APJ receptor intensity ratios are presented as the mean ratios ± SEM. Cell Culture

[00216] PathHunter™ GPCR Arrestin and cAMP Hunter™ cell lines (DiscoveRx Corp., Fremont, CA) were used to assay G-protein-dependent signaling and b-arrestin recruitment to APJ. CHO-K1 cells stably expressing APJ (CHO-K1-APJ) or AT1 (CHO-K1-AT1) with p-arrestin/p-galactosidase enzyme fragment complementation constructs were cultured in HAM's F-12 medium (Hyclone, Logan, UT) supplemented with 10% FBS, IX Penicillin-Streptomycin-Glutamine (Invitrogen; Carlsbad, CA), 300 pg/mL hygromycin (EMD Biosciences, San Diego, CA), and 800 pg/mL Geneticin (Cellgro, Manassas, VA). Primary Human Retinal Microvascular Endothelial Cells (HRECs) were purchased from Cell Systems (Kirkland, WA).

[00217] All cells were incubated at 37 °C (5% C0₂, 95% relative humidity) and maintained at less than 70% to 80% confluence (approximately 75,000 cells/cm²).

Proliferation Assay

[00218] The proliferation of HRECs was monitored by an a!amarBlue fluorescence assay. Briefly, 2,500 ceils in 100 pL Endothelial Basal Medium (EBM) (Lonza) in the presence of 50 ng/mL recombinant human VEGF165 (Biolegend, San Diego, CA, U SA), were incubated in 96 -well clear bottom black plates for 24 hrs followed by 48 hrs incubation with either 0.5 pM SH-11037, different concentration of aflibercept (Eylea, Regeneron) (50, 200, 400, 800 pg/mL), or combination treatment. At the end of the incubation, 11.1 pL of alamarBlue reagent was added and 4 hrs after, fluorescent readings were taken on a Synergy Hi plate reader (Biotek, Winooski, VT, USA) with excitation and emission wavelengths of 560 nm and 590 nm respectively. Data were analyzed using GraphPad Prism software (v 6.0).

in vitro Tube Formation Assay

[00219] Near confluent microvascular endothelial cells were pretreated with VEGF (lOOng/mL) for 2 hrs and then either a) treated for 24 hrs with test compounds at serial concentrations, as indicated, or VEGF 165 neutralizing antibody or b) washed and maintained in basal medium for 24 hrs to establish the intracrine VEGF signaling pathway prior to treatment with test compounds or VEGF 165 neutralizing antibody. Cells without VEGF treatment or with VEGF only were used as control. In addition, siRNA treated cells with or without VEGF were also assessed. The cells were then detached and plated sparsely (2.5 x l0⁴/well) on 24-well plates coated with 12.5% (v/v) Matrigei (BD, Franklin Lakes, NJ) and left overnight. Tire medium was then aspirated and 250pl/well of 12.5% Matrigei was overlaid on the cells for 2hr to allow the polymerization of Matrigei, followed by addition of 500pl/well of basal medium MCD131 with 10% fetal calf serum (FCS) for 24 hrs. The following day, the culture plates were observed under a phase contrast microscope and photographed at random in five fields (x 10). The tubule length (mm/mm²) per microscope field was quantified.

EXAMPLE IV: In vitro ADME of Amodiaquine (AQ)

[00220] The ADME (absorption, distribution, metabolism, excretion, and toxicity) and

pharmacokinetic properties of AQ were evaluated in a detailed in vitro pharmacology panel (Table 4). Table 4.

a AQ exhibited a two-phase exponential decay with a terminal half-life of 17.0 min.

[00221] AQ was moderately soluble in aqueous media and exhibited moderate permeability in the PAMPA assay. Plasma protein binding and stability were within the acceptable range. AQ was rapidly metabolized by human, mouse and rat liver microsomes. The primary metabolite of AQ is a desethyl form resulting from CYP450 metabolism. The metabolism of AQ coincided with the appearance of the desethylamodiaquine (DEAQ, 46) in both human and mouse, but not in rat microsomes (Fig. 6A-C). When tested on hepatocytes, AQ showed no signs of cytotoxicity at up to 50 mM. Similarly, AQ was not cytotoxic to HRECs at up to 100 pM. Additionally, DEAQ retained activity in the primary APJ cAMP assay, with a potency between 1 and 10 pM (see Table 3).

Animal Studies

[00222] All mice were housed under specific -pathogen-free conditions and handled in accordance with the ARVO statement for Use of Animals in Ophthalmic and Vision Research and the guidelines of the Institutional Animal Care and Use Committee at Indiana University, and Sanford Burnham Prebys Medical Discovery Institute.

EXAMPLE V: Laser-induced choroidal neovascularization (CNV) model

[00223] 8-week-old female C57BL-6 mice were anesthetized with a mixture of ketamine (80 mg/kg) and xylazine (10 mg/kg) and their pupils dilated with tropicamide (0.5%) and phenylephrine (2.5%). Under the fundus microscope an argon green ophthalmic laser, coupled to a slit lamp set to deliver a 50 ms pulse at 200 mW with a 50 pM spot size, was used to rupture Bruch’s membrane in three quadrants of the right eye located approximately 50 mm from the optic disc at relative positions of 9, 12 and 3 o’clock. The left eye served as an untreated control.

[00224] One day after laser injury, AQ was administered via intravitreal injection at 5.0, 10.0, 25.0, and 50.0 pg. A second injection at the same dose followed six days later (seven days post injury).

Fourteen days after injury, the mice were euthanized and the eyes collected to measure the extent of injury. The CNV lesion volumes in the AQ treated eyes were significantly lower than those in vehicle treated eyes in a dose-dependent manner at 14 days post-laser, as monitored in vivo by optical coherence tomography (OCT, Fig. 4A-4F). Additionally, fluorescein angiography revealed reduced leakiness of CNV lesions from known anti -angiogenic SH-l 1037 and anti-VEGFl64 treated eyes relative to the vehicle treatment. Although there was no statistically significant reduction in the CNV lesion volume compared to the vehicle control in eyes treated with AQ at 5.0 and 10.0 pg, there was a significant decrease in CNV lesion volume at 25 pg and an even greater decrease at 50.0 pg compared to the control eyes (Fig. 4G).

[00225] Additionally, confocal images of agglutinin-stained choroidal flatmounts revealed a reduction in CNV lesion size at 10 pg AQ and higher (Fig. 5). Mice were euthanized 14 days after laser injury. The eyes were enucleated and the RPE/choroid/sclera prepared. For measuring lesion volume we used a vascular specific dye (Ricinus Communis Agglutinin I; Vector Laboratories, Inc.) conjugated to rhodamine, to label whole flat mounts of RPE/choroid/sclera which were incubated for 30 minutes at room temperature in 1 :400 of 10 mM HEPES, 150 mM NaCl and 0.1% Tween 20. The tissues were covered in aqueous mounting medium (VectaShield; Vector Laboratories, Inc.) for observation on a confocal microscope (Olympus DSU-Olympus 1X81; Olympus America, Inc., Center Valley, PA).

Digital images were captured by using imaging software (SlideBook 4.2; Intelligent Imaging

Innovations, Inc., Denver, CO) in a three-dimensional stacked manner to facilitate volumetric analysis from experimental and control samples with identical photomultiplier tube gain settings. The confocal images were then processed identically in experimental and control eyes and measured using ImageJ software. In all CNV studies, animals were randomized and treatments blinded until all analysis is complete. All determinations were performed in at least 10 animals per group. In addition, gross retinal/choroidal structure, and vascular patterns were examined for possible adverse effects of the test compound or vehicle.

Treatment Regime

[00226] Mice received intravitreal injection (1.0 pL/eye/injection) into the right eye while the left eye acted as the uninjected control. Animals were randomly assigned to one of three treatment groups each consisting of n = 12 mice: vehicle (DMSO), or compounds (0-50 pg). On the day of injection the compounds were formulated in 100% DMSO and administered to mice via intravitreal injection immediately after laser injury and again 7 days after laser injury.

Optical Coherence Tomography (OCT) and Fluorescein Angiography

[00227] OCT was performed at the indicated times using the Micron III intraocular imaging system (Phoenix Research Labs, Pleasanton, CA, USA). Before the procedure, eyes were dilated with 1% tropicamide solution (Aicon, Fort Worth, TX, USA) and lubricated with hypromellose ophthalmic demulcent solution (Gonak) (Akora, Lake Forest, IL, USA). Mice were then placed on a custom heated stage that moves freely to position the mouse eye for imaging. Several horizontal and vertical images were taken per lesion to allow calculation of CNV lesion volume. Three -dimensional quantification of CNV lesion volumes was performed using an ellipsoid quantification method as previously described. Fluorescein angiography was performed 14 days post laser by intraperitoneal injection of 50 pL of 25% fluorescein sodium (Fisher Scientific, Pittsburgh, PA, USA). Fundus images were taken using the Micron III system and Streampix software.

Immunohistochemistry

[00228] Mice were euthanized by anesthetizing with isoflurane followed by cervical dislocation. The eyes were enucleated and fixed in 4% paraformaldehyde/PBS overnight. The anterior segment, lens, and vitreous were removed and the posterior eye cups were prepared for cryostat sections, paraffin sections, or retinal flat mounts The sections or flat mounts were washed with PBS then permeabilized with 0.2% Triton X-100 and nonspecific binding blocked by 10% normal goat serum in PBS. Samples then received primary antibody for 16 h at 4°C. The primary antibodies were polyclonal anti-APJ (1:2000), rat anti-HA (1 :500), rabbit anti-VEGF (1 :300), rabbit anti-angiogenin 1 (1 :500), anti-NFicB (1 :500), mouse anti- F4/80 (1 :500), or rabbit anti-Ibal (1 :200). After primary incubation, tissues were washed and incubated for 1.5 h at room temperature with the appropriate secondary antibody at 4°C with 0.2% Triton X-100. The secondary antibody was Cy3 conjugated goat anti -rabbit or mouse IgG (1 :250). After washing, specimens were mounted in aqueous mounting medium (VectaShield; Vector Laboratories, Inc.) and coverslipped for observation by microscopy.

EXAMPLE VI: Tissue Distribution of AQ

[00229] The distribution of AQ in the mouse eye was evaluated after a single intravitreal dose of 50 mg. Table 5 shows that after 24h AQ is found in the target tissue, the RPE/choroid/sclera section of mouse eyes receiving compound at levels that exceed the cellular EC₅₀ by ~20 fold. The retina contained a modest amount of compound, while the vitreous contained less than was accurately quantifiable via LC/MS. The compound was persistent showing sustained levels in the target tissues 7 d later.

Table 5.

a

BLOQ = below the lower imit of quantification.

b ND = not determined.

Tissue Distribution Study

[00230] Mice were assigned to groups (n = 6/group) that received either 50 pg compound, or vehicle via intravitreal injection (1 pL volume). One day after injection, ½ of the mice (n = 3/group) mice were euthanized. The eyes were enucleated and the vitreous humor, retina, and RPE/Choroid/sclera were isolated and snap frozen in liquid N₂. The remaining mice in each treatment group (n=3/group) were euthanized and the same tissues collected. The quantity of compound in the tissues (n= 6 eyes/ treatment group) was measured using LC-MS-MS. EXAMPLE VII: Pharmaceutical Compositions

[00231] The following examples disclose various possible compositions and methods of preparation for various formulations of AQ.

General Ocular Formulation

[00232] This example illustrates the composition and method of preparation of a selected formulation vehicle for intravitreal, posterior juxtascleral, or periocular injection, or for topical ocular administration.

[00233] In a 250 mL glass container was added 3.60 g sterile 10% dibasic sodium phosphate, dodecahydrate solution. To it was added 10 g sterile 10% polysorbate 80 solution, 50 g of a sterile 20% stock sucrose solution, and 7.2 g of sterile 5% sodium phosphate, dodecahydrate, 25 g 20% sucrose stock solution, and 3.6 g of sterile 5% sodium chloride solution were added sequentially. Sufficient amount of sterile water for injection was added to get 95% of batch size and was stirred at rt tor 30 min. The pH was adjusted to 6.5 and sterile water for injection was added to get to 100% of batch size (100 g).

[00234] All of the compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of selected or preferred embodiments, it will be apparent to those of skill the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and structurally related may be substituted for the agents described herein to achieve similar results. All such substitutions and modifications apparent to those skilled in the art are deemed to he within the spirit, scope and concept of the invention as defined by the appended claims.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A method for treating, reducing, ameliorating, or inhibiting progression of pathological

angiogenesis in a subject, the method comprising administering to the subject in need thereof a pharmaceutical composition comprising a compound of Formula (I):

Formula (I);

wherein:

each R¹ is independently halogen, -CN, -OH, -OR^a, -SH, -SR^a, -NR^cR^d, -C(=0)R^a, -C(=0)0R^b, - C(=0)NR^cR^d, -NR^bC(=0)R^a, Cj-C₍, alkyl. C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R²⁰;

n is 0, 1, 2, or 3;

Z is -NR²R³, -OR⁴, -SR⁵, or -CR⁶R⁷R⁸;

R² and R³ are each independently hydrogen, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆ alkyl(heteroaryl), Ci-C₆ alkyl(cycloalkyl), Ci-C₆ alkyl(heterocycloalkyl), -S(=0)₂R^lla, -S(=0)₂NR^12aR^13a, or - C(=0)₂R^lla; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R^20a;

or R² and R³ are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl that is unsubstituted or substituted with one, two, or three R^20b;

alkyl(heteroaryl), Ci-C₆ alkyl(cycloalkyl), Ci-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R^20c;

alkyl(heteroaryl), Ci-C₆ alkyl(cycloalkyl), Ci-C₆ alkyl(heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R^20d;

R⁶, R⁷, and R⁸ are each independently hydrogen, halogen, -CN, -OH, -OR^lld, -SH, -SR^lld, - S(=0)R^lld, -N0₂, -NR^12dR^13d, -S(=0)₂R^lld, -NHS(=0)₂R^lld, -S(=0)₂NR^12dR^13d, -C(=0)R^lld, - 0C(=0)R^lld, -C(=0)0R^12d, -0C(=0)0R^12d, -C(=0)NR^12gR^13d, -0C(=0)NR^12dR^13d, - NR^12dC(=0)NR^12dR^13d, -NR^12gC(=0)R^llg, -NR^12gC(=0)0R^12g, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆

alkyl(heteroaryl), Ci-C₆ alkyl(cycloalkyl), or Ci-C₆ alkyl (heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R^20e;

R^lla, _R I iiy _R ^| iy _an(j _{R i} id _{are cac}|₁ i_nd_ep_end_ently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R^20f;

ea , -

, - NR^bC(=0)R^a, -NR^bC(=0)0R^b, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆ alkyl(heteroaryl), Ci-C₆ alkyl(cycloalkyl), or Ci-C₆ alkyl (heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R²¹;

ea

l,

Ci-C₆ haloalkyl, Ci-C₆ hydroxyalkyl, Ci-C₆ heteroalkyl, or cycloalkyl that is unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl;

each R^a is independently Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆ heteroalkyl,

each R^b is independently hydrogen, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci-C₆ haloalkyl; and R^c and R^d are each independently hydrogen, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci-C₆ haloalkyl;

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

2. The method of claim 1, wherein:

Z is -NR²R³ or -OR⁴.

3. The method of claim 1 or 2, wherein:

Z is -NR²R³.

4. The method of any one of claims 1-3, wherein:

R² and R³ are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl that is unsubstituted or substituted with one, two, or three R^20b.

5. The method of any one of claims 1-3, wherein:

R³ is Ci-C₆ alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆ alkyl(heteroaryl), -S(=0)₂R^lla, -S(=0)₂NR^12aR^13a, or -C(=0)₂R^lla; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R^20a.

6. The method of any one of claims 1-3 or 5, wherein:

R³ is aryl which is substituted with one, two, or three R^20a.

7. The method of any one of claims 1-3 or 5-6, wherein the compound of Formula (I) is a

compound of Formula (II);

Formula (II);

wherein:

each R¹ is independently halogen, -CN, -OH, -OR^a, -SH, -SR^a, -NR^cR^d, -C(=0)R^a, -C(=0)0R^b, - C(=0)NR^cR^d, -NR^bC(=0)R^a, C^Q, alkyl, C.-Q, haloalkyl. C Ce hydroxyalkyl, C ,-C₍, heteroalkyl, or cycloalkyl unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl;

R² is hydrogen, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆ heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci-C₆ haloalkyl; and

m is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

8. The method of any one of the preceding claims, wherein:

each R¹ is independently halogen, -CN, -OH, -OR^a, -NR^cR^d, -C(=0)R^a, -C(=0)0R^b, - C(=0)NR^cR^d, -NR^bC(=0)R^a, C^Q, alkyl, C,-C₍, haloalkyl. C rC iydroxyalkyl. C ,-C₍, heteroalkyl, or cycloalkyl that is unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl.

9. The method of any one of the preceding claims, wherein:

each R¹ is independently halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl; and

n is 0, 1, or 2.

10. The method of any one of claims 1-3 or 5-9, wherein the compound of Formula (I) or Formula (II) is a compound of Formula (III):

Formula (III);

wherein:

R² is hydrogen, or Ci-C₆ alkyl;

each R^20a is independently halogen, -CN, -OH, -OR^a, -NR^cR^d, -S(=0)₂R^a, -NHS(=0)₂R^a, - S(=0)₂NR^cR^d, -C(=0)R^a, -0C(=0)R^a, -C(=0)0R^b, -0C(=0)0R^b, -C(=0)NR^cR^d, - 0C(=0)NR^cR^d, -NR^b C(=0)NR^cR^d, -NR^bC(=0)R^a, -NR^bC(=0)0R^b, Ci-C₆ alkyl; cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆ alkyl(heteroaryl), Ci-C₆ alkyl(cycloalkyl), or Ci-C₆ alkyl (heterocycloalkyl); wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R²¹;

each R²¹ is independently halogen, -CN, -OH, -OR^a, -NR^cR^d, -S(=0)₂R^a, -NHS(=0)₂R^a, - S(=0)₂NR^cR^d, -C(=0)R^a, -0C(=0)R^a, -C(=0)0R^b, -0C(=0)0R^b, -C(=0)NR^cR^d, - 0C(=0)NR^cR^d, -NR^b C(=0)NR^cR^d, -NR^bC(=0)R^a, -NR^bC(=0)0R^b, Ci-C₆ alkyl, Ci-C₆ haloalkyl, Ci-C₆ hydroxyalkyl, Ci-C₆ heteroalkyl, or cycloalkyl that is unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl;

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

11. The method of any one of the preceding claims, wherein:

R² is hydrogen.

12. The method of any one of claims 1-11, wherein: each R^20a is independently halogen, -CN, -OH, -OR^a, -N0₂, -NR^cR^d, -NHS(=0)₂R^a, - S(=0)₂NR^cR^d, -C(=0)R^a, -0C(=0)R^a, -C(=0)0R^b, -C(=0)NR^cR^d, -NR^bC(=0)R^a, Ci-C₆ alkyl, Ci-C₆ haloalkyl, Ci-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci-C₆ haloalkyl.

13. The method of any one of claims 1-12, wherein:

each R^20a is independently halogen, -CN, -OH, -OR^a, -C(=0)R^a, -C(=0)0R^b, -C(=0)NR^cR^d, C,- C₆ alkyl, Ci-C₆ haloalkyl, or Ci-C₆ heteroalkyl.

14. The method of any one of claims 1-13, wherein:

each R^a is independently Ci-C₆ alkyl, Ci-C₆ heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci-C₆ haloalkyl;

each R^b is independently hydrogen, Ci-C₆ alkyl, Ci-C₆ heteroalkyl, cycloalkyl, heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci-C₆ haloalkyl; and

R^c and R^d are each independently hydrogen, Ci-C₆ alkyl, Ci-C₆ heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein the alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci-C₆ haloalkyl;

or R^c and R^d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl that is unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl.

15. The method of any one of claims 1-14, wherein:

each R^a is independently Ci-C₆ alkyl, or Ci-C₆ haloalkyl;

each R^b is independently hydrogen, or Ci-C₆ alkyl which is independently unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci-C₆ haloalkyl; and

R^c and R^d are each independently hydrogen, Ci-C₆ alkyl, Ci-C₆ heteroalkyl, or heterocycloalkyl which is unsubstituted or substituted with one, two, or three halogen, -OH, Ci-C₆ alkyl, or Ci- C₆ haloalkyl;

or R^c and R^d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl.

16. The method of any one of claims 1-15, wherein the compound has one of the following

structures:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

17. The method of any one of claims 1-15, wherein the compound has one of the following structures:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

18. The method of any one of claims 1-15, wherein the compound has one of the following structures:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

19. The method of any one of claims 1-15, wherein the compound has one of the following

structures:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

20. The method of any one of claims 1-19, wherein the pathological angiogenesis comprises a

disease selected from the group consisting of neoplasia, peripheral vascular disease,

hypertension, preeclampsia syndrome, abnormal angiogenesis, diabetes, fibrosis such as idiopathic pulmonary fibrosis, wound healing, chronic obstructive pulmonary disease, cardiovascular disease, avascular or ischemic insult, myocardial infarction, stroke, vasculitis, systemic or vascular sclerosis, gangrene, congelation, alopecia, eczema, ulcers, lymphedema, vascular hyperplasia, hemangioma, psoriasis, endometriosis, inflammatory disease such as arthritis and inflammatory bowel disease, or retinal disease such as ocular degeneration, diabetic retinopathy, or macular degeneration.

21. The method of any one of claims 1-19, wherein the pathological angiogenesis comprises fibrosis.

22. The method of any one of claims 1-19, wherein the pathological angiogenesis comprises

cardiovascular disease.

23. The method of any one of claims 1-19, wherein the pathological angiogenesis comprises a tumor.

24. The method of any one of claims 1-19, wherein the pathological angiogenesis comprises retinal pathological angiogenesis.

25. The method of claim 24, wherein the retinal pathological angiogenesis has an etiology in

inflammation.

26. The method of claim 24 or 25, wherein the retinal pathological angiogenesis is selected from the group consisting of diabetic retinopathy (“DR”), dry age-related macular degeneration (“AMD”), exudative AMD, diabetic macular edema (“DME”), retinal detachment, posterior uveitis, comeal neovascularization, iris neovascularization, and combinations thereof.

27. The method of any one of claims 24-26, wherein the retinal pathological angiogenesis is

exudative AMD.

28. The method of any one of claims 24-26, wherein the retinal pathological angiogenesis is diabetic retinopathy.

29. The method of any of claims 1-28, wherein the compound of Formula (I), (II), or (III), or a

pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is present in the composition in an amount sufficient to be effective for said treating, reducing, ameliorating, alleviating, or inhibiting progression of, said pathological angiogenesis.

30. The method of any one of claims 1-29, wherein the pharmaceutical composition further

comprises a pharmaceutically acceptable excipient.

31. The method of claim 30, wherein the pharmaceutically acceptable excipient is acceptable for administering to an ocular environment.

32. The method of any of the preceding claims, wherein the composition comprises liquid medium.

33. The method of claim 32, wherein the composition is a solution.

34. The method of claim 33, wherein the solution is isotonic.

35. The method of claim 32, wherein the composition is a suspension.

36. The method of claim 32, wherein the composition is an ointment.

37. The method of any of the preceding claims, wherein the method further comprises administering the compound to the ocular environment of an affected eye of the subject in need thereof.

38. The method of claim 37, wherein the composition is injected into the vitreous of the affected eye.

39. The method of claim 37, wherein the composition is administered topically to the ocular

environment.

40. The method of claim 30, wherein the composition comprises an ophthalmic device.

41. The method of claim 40, wherein the composition is formed into an ophthalmic device and the device is implanted in the posterior segment of the affected eye.

42. The method of any one of the preceding claims, wherein the method further comprises

administering a VEGF inhibitor.

43. The method of claim 42, wherein the VEGF inhibitor comprises a small molecule inhibitor.

44. The method of claim 42 or 43, wherein the VEGF inhibitor comprises SU5416 (semaxinib),

SU11248, SU6668 (TSU-68), PTK787/ZK222584, ZD6474 (AZD-6474), ZD2171, CEP-7055, CP-547,632, AG013736, GW786034, AEE788, or a combination thereof.

45. The method of claim 42, wherein VEGF inhibitor comprises an anti -VEGF antibody.

46. The method of claim 42 or 45, wherein the VEGF inhibitor comprises ranibizumab,

bevacizumab, aflibercept, tanibirumab, vanucizumab, or a combination thereof.

47. The method of any one of claims 42-46, wherein the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and the VEGF inhibitor are administered within 24 hours of each other.

48. The method of any one of claims 42-47, wherein the compound of Formula (I), (II), or (III) , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and the VEGF inhibitor are administered within 60 minutes of each other.

49. The method of any one of claims 42-48, wherein the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and the VEGF inhibitor are administered concurrently.

50. The method of any one of claims 42-49, wherein the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and the VEGF inhibitor are present in the same composition.

51. The method of any one of claims 1-50, wherein the method further comprises administering a PDGFR inhibitor.

52. The method of claim 51, wherein the PDGFR inhibitor comprises a small molecule inhibitor.

53. The method of claim 51 or 52, wherein the PDGFR inhibitor comprises imatinib, sunitinib, sorafenib, pazopanib, nilotinib, or a combination thereof.

54. The method of claim 51, wherein the PDGFR inhibitor comprises an anti-PDGFR antibody.

55. The method of claim 51 or 54, wherein the PDGFR inhibitor comprises olaratumab.

56. The method of any one of claims 51-55, wherein the compound of Formula (I), (II), or (III) , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and the PDGFR inhibitor are administered within 24 hours of each other.

57. The method of any one of claims 51-56, wherein the compound of Formula (I), (II), or (III) , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and the PDGFR inhibitor are administered within 60 minutes of each other.

58. The method of any one of claims 51-57, wherein the compound of Formula (I), (II), or (III) , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and the PDGFR inhibitor are administered concurrently.

59. The method of any one of claims 51-58, wherein the compound of Formula (I), (II), or (III) , or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and the PDGFR inhibitor are present in the same composition.

60. The method of any of the preceding claims, wherein the composition further comprises an anti inflammatory agent.

61. The method of claim 60, wherein the anti-inflammatory agent is a material selected from the group consisting of NSAIDs and PPAR ligands.

62. The method of claim 60 or 61, wherein the anti-inflammatory agent is selected from the group consisting of: aspirin, celecoxib, diclofenac, difhmisal, etodolac, ibuprofen, indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, and tolmetin, or a combination thereof.

63. A method for treating, reducing, ameliorating, or inhibiting progression of retinal pathological angiogenesis in a subject, the method comprising administering to an ocular environment of an affected eye of a subject who has received anti-VEGF therapy, a pharmaceutical composition that comprises a compound of Formula (I):

Formula (I);

wherein:

n is 0, 1, 2, or 3;

Z is -NR²R³, -OR⁴, -SR⁵, or -CR⁶R⁷R⁸;

R² and R³ are each independently hydrogen, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆ alkyl(heteroaryl), Ci-C₆ alkyl(cycloalkyl), C C₆ alkyl(heterocycloalkyl), -S(=0)₂R^lla, -S(=0)₂NR^12aR^13a, or - C(=0)₂R^lla; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R^20a;

ea , -

ea

l,

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

64. The method of claim 63, wherein the anti-VEGF therapy thereof did not fully treat, reduce, ameliorate, or inhibit progression of retinal pathological angiogenesis in the subject thereof.

65. The method of claim 63 or 64, wherein the anti-VEGF therapy was administered as a plurality of doses of an anti-VEGF agent.

66. A composition comprising:

(a) a compound having formula (I);

Formula (I);

wherein:

n is 0, 1, 2, or 3;

Z is -NR²R³, -OR⁴, -SR⁵, or -CR⁶R⁷R⁸;

cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆ alkyl(heteroaryl), Ci-C₆ alkyl(cycloalkyl), Ci-C₆ alkyl(heterocycloalkyl), -S(=0)₂R^lla, -S(=0)₂NR^12aR^13a, or - C(=0)₂R^lla; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R^20a;

R⁴ is hydrogen, -C(=0)R^llb, -C(=0)0R^12b, -C(=0)NR^12bR^13b, Cj-C₍, alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆

R⁶, R⁷, and R⁸ are each independently hydrogen, halogen, -CN, -OH, -OR^lld, -SH, -SR^lld, -

NR^12dC(=0)NR^12dR^13d, -NR^12gC(=0)R^llg, -NR^12gC(=0)0R^12g, -Ce alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆

R^12a R^12b, R^12c, R^12d, R^13a, R^13b, R^13c, and R^13d are each independently hydrogen, Ci-C₆ alkyl, C₂- C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl is independently unsubstituted or substituted with one, two, or three R^20g;

ea , -

, - NR^bC(=0)R^a, -NR^bC(=0)0R^b, C ,-C_f> alky l. C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆ alkyl(heteroaryl), Ci-C₆ alkyl(cycloalkyl), or Ci-C₆ alkyl (heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R²¹;

ea

l, Ci-C₆ haloalkyl, Ci-C₆hydroxyalkyl, Ci-C₆ heteroalkyl, or cycloalkyl that is unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl;

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and

(b) a VEGF inhibitor.

67. The composition of claim 66, wherein the VEGF inhibitor comprises a small molecule inhibitor.

68. The composition of claim 66 or 67, wherein the VEGF inhibitor comprises SU5416 (semaxinib),

69. The composition of claim 66, wherein the VEGF inhibitor comprises an anti-VEGF antibody.

70. The composition of claim 66 or 69, wherein the VEGF inhibitor comprises ranibizumab,

bevacizumab, aflibercept, tanibirumab, vanucizumab, or a combination thereof.

71. The composition of any one of claims 66-70, wherein the composition further comprises an anti inflammatory agent.

72. The composition of claim 71, wherein the anti-inflammatory agent a compound selected from the group consisting of NSAIDs and PPAR ligands.

73. The composition of claim 71-72, wherein the anti-inflammatory agent is selected from the group consisting of: aspirin, celecoxib, diclofenac, diflunisal, etodolac, ibuprofen, indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, and tolmetin, or a combination thereof.

74. The composition of any one of claims 66-73, wherein the composition further comprises a

PDGFR inhibitor.

75 The composition claim 74, wherein the PDGFR inhibitor comprises a small molecule inhibitor.

76. The composition of claim 74 or 75, wherein the PDGFR inhibitor comprises imatinib, sunitinib, sorafenib, pazopanib, nilotinib, or a combination thereof.

77. The composition of claim 74, wherein the PDGFR inhibitor comprises an anti-PDGFR antibody.

78. The composition of claim 74 or 77, wherein the PDGFR inhibitor comprises olaratumab.

79. A composition comprising:

(a) a compound having formula (I);

Formula (I);

wherein:

n is 0, 1, 2, or 3;

Z is -NR²R³, -OR⁴, -SR⁵, or -CR⁶R⁷R⁸;

cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆ alkyl(heteroaryl), Ci-C₆ alkyl(cycloalkyl), C C₆ alkyl(heterocycloalkyl), -S(=0)₂R^lla, -S(=0)₂NR^12aR^13a, or - C(=0)₂R^lla; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R^20a;

ea , -

ea

l,

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; and

(b) a PDGFR inhibitor.

80. The composition claim 79, wherein the PDGFR inhibitor comprises a small molecule inhibitor.

81. The composition of claim 79 or 80, wherein the PDGFR inhibitor comprises imatinib, sunitinib, sorafenib, pazopanib, nilotinib, or a combination thereof.

82. The composition of claim 79, wherein the PDGFR inhibitor comprises an anti-PDGFR antibody.

83. The composition of claim 79 or 82, wherein the PDGFR inhibitor comprises olaratumab.

84. The composition of any one of claims 79-83, wherein the composition further comprises an anti inflammatory agent.

85. The composition claim 84, wherein the anti-inflammatory agent is a compound selected from the group consisting of NSAIDs and PPAR ligands.

86. The composition of claim 84 or 85, wherein the anti-inflammatory agent is selected from the group consisting of: aspirin, celecoxib, diclofenac, difhmisal, etodolac, ibuprofen, indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, and tolmetin, or a combination thereof.

87. A composition for treating, reducing, ameliorating, or inhibiting progression of pathological angiogenesis in a subject, the composition comprising:

(a) a compound having formula (I);

Formula (I);

wherein:

n is 0, 1, 2, or 3; Z is -NR²R³, -OR⁴, -SR⁵, or -CR⁶R⁷R⁸;

R⁴ is hydrogen, -C(=0)R^llb, -C(=0)0R^12b, -C(=0)NR^12bR^13b, C,-C₍, alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆

R⁶, R⁷, and R⁸ are each independently hydrogen, halogen, -CN, -OH, -OR^lld, -SH, -SR^lld, - S(=0)R^lld, -N0₂, -NR^12dR^13d, -S(=0)₂R^lld, -NHS(=0)₂R^lld, -S(=0)₂NR^12dR^13d, -C(=0)R^lld, - 0C(=0)R^lld, -C(=0)0R^12d, -0C(=0)0R^12d, -C(=0)NR^12gR^13d, -0C(=0)NR^12dR^13d, - NR^12dC(=0)NR^12dR^13d, -NR^12gC(=0)R^llg, -NR^12gC(=0)0R^12g, C,-C_f> alky l. C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆

or R^12a and R^13a or R^12b and R^13b or R^12c and R^13c or R^12d and R^13d are taken together with the nitrogen atom to which they are attached to form a heterocycloalkyl unsubstituted or substituted with one, two, or three halogen, Ci-C₆ alkyl, or Ci-C₆ haloalkyl; ea , -

, - NR^bC(=0)R^a, -NR^bC(=0)0R^b, C,-C_f> alky l. C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci-C₆ alkyl(aryl), Ci-C₆ alkyl(heteroaryl), Ci-C₆ alkyl(cycloalkyl), or Ci-C₆ alkyl (heterocycloalkyl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently unsubstituted or substituted with one, two, or three R²¹;

ea

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof;

(b) water; and

88. The composition of claim 87, wherein the buffer is a Tris buffer, a phosphate buffer, a histidine buffer, a citrate buffer, or an acetate buffer.

89. The composition of claim 87 or 88, wherein concentration of the buffer is about 1 mM to about 100 mM.

90. The composition of any one of claims 87-89, wherein the buffer has a pH of about 5.0 to about 6.5.

91. The composition of any one of claims 87-90, further comprising: (d) an inorganic salt.

92. The composition of claim 91, wherein the inorganic salt is NaCl.

93. The composition of claim 91 or 92, wherein the concentration of inorganic salt is about 10 mM to about 200 mM.

94. The composition of any one of claims 87-93, further comprising: (e) a surfactant.

95. The composition of claim 94, wherein the surfactant is non-ionic.

96. The composition of claim 94 or 95, wherein the surfactant is a polysorbate.

97. The composition of any one of claims 94-96, wherein the surfactant is polysorbate 20 or

polysorbate 80.

98. The composition of any one of claims 94-97, wherein the surfactant is present in concentrations from about 0.001% to about 0.5%.

99. The composition of any one of claims 87-98, further comprising: (f) a saccharide.

100. The composition of claim 99, wherein the saccharide is a,a-trehalose, sucrose, glucose, mannitol, or sorbitol.

101. The composition of claim 99 or 100, wherein the concentration of the saccharide is about 5% to 20%.

102. The composition of any one of claims 87-101, further comprising a VEGF inhibitor.

103. The composition of any one of claims 87-102, further comprising a PDGFR inhibitor.

104. The composition of any one of claims 87-103, further comprising an anti-inflammatory agent.