Methods and compositions for treatment of geographic atrophy

Abstract

The invention provides methods, compositions, and kits containing a substituted 2,3-dimethoxyquinone of Formula I for treating patients suffering from geographic atrophy.

Description

METHODS AND COMPOSITIONS FOR TREATMENT OF GEOGRAPHIC ATROPHYCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to United States Provisional Patent Application serial number 63 / 541,631, filed September 29, 2023; the contents of which are hereby incorporated by reference in their entirety.FIELD OF THE INVENTION

[0002] The invention provides methods, compositions, and kits containing a substituted 2,3- dimethoxy quinone of Formula I for treating patients suffering from geographic atrophy.BACKGROUND

[0003] Geographic atrophy is an eye condition that can cause substantial and progressive visual impairment. The incidence of geographic atrophy is higher in patients presenting with preexisting clinical signs of age-related macular degeneration. Geographic atrophy often features confluent areas of apoptosis at the level of photoreceptors and retinal pigment epitheliumatrophy, which may occur in both of the patient’s eyes. The severity of geographic atrophy may progress over time, wherein the fovea may be more frequently impacted in the later stages of disease progression. The atrophy can be unifocal (one atrophic spot) or multifocal (multiple spots). New medical therapies are needed to treat geographic atrophy.

[0004] Various substituted dioxo-l,4-dihydronaphthalen-2-yl)acrylamide compounds that inhibit reduction-oxidation factor 1-apurunic / apyrimidinic endonuclease (Ref-l / APEl) are described in, for example, international patent application publication WO 2019 / 157163, which describes using such compounds to treat various ocular disorders. Additional description of Ref- l / APEl inhibitor compounds and medical uses are described in, for example, international patent application publication nos. WO 2012 / 162589, WO 2009 / 042544, WO 2009 / 042542, WO 2012 / 167122, WO 2018 / 175429, WO 2018 / 194976, and WO 2022 / 232597. New medical uses for Ref-l / APEl inhibitor compounds having superior properties for treating geographic atrophy are needed and would benefit patients.

[0005] The present invention addresses this need and provides other related advantages.SUMMARY

[0006] The invention provides methods, compositions, and kits containing a substituted 2,3- dimethoxyquinone of Formula I for treating patients suffering from geographic atrophy. The methods generally comprise administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, which is represented by:(I). or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the detailed description. Additional exemplary aspects and embodiments of the invention are described below.

[0007] Accordingly, one aspect of the invention provides a method of treating geographic atrophy, wherein the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, in order to treat the geographic atrophy, wherein Formula I is represented by:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the detailed description. Exemplary compounds of Formula I are also provided in the detailed description. The compound of Formula I may be formulated in a pharmaceutical composition. In certain embodiments, the compound may be administered orally to the patient. Additional features of the method are described in the detailed description.

[0008] Another aspect of the invention provides a method of inhibiting the progression of geographic atrophy in a patient, wherein the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, in order to inhibit the progression of geographic atrophy, wherein Formula is represented by:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the detailed description. Exemplary compounds of Formula I are also provided in the detailed description. The compound of Formula I may be formulated in a pharmaceutical composition. In certain embodiments, the compound may be administered orally to the patient. Additional features of the method are described in the detailed description.

[0009] Another aspect of the invention provides a method of reducing the size of a geographic atrophy lesion in a patient, wherein the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, in order to reduce the size of the geographic atrophy lesion, wherein Formula is represented by:or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the detailed description. Exemplary compounds of Formula I are also provided in the detailed description. The compound of Formula I may be formulated in a pharmaceutical composition. In certain embodiments, the compound may be administered orally to the patient. Additional features of the method are described in the detailed description.BRIEF DESCRIPTION OF FIGURES

[0010] Fig. 1 shows results for inhibition, by compounds of Formula I, of TNFa-induced activation of the NF -KB pathway in an NF-KB reporter cell line, as described in Example 1.

[0011] Fig. 2 shows reduction, by compounds of Formula I, of NalCh-induced cytotoxicity in induced-pluripotent stem cell retinal pigment epithelium (iPSC-RPE) cells, as described in Example 2.

[0012] Fig. 3 shows retinal function as measured by scotopic electroradiography (ERG), as described in Example 3.

[0013] Fig. 4 shows results for retinal function as measured by photopic ERG, as described in Example 3.

[0014] Fig. 5 shows results for retinal thickness as measured by optical coherence tomography (OCT), as described in Example 3.DETAILED DESCRIPTION OF THE INVENTION

[0015] The invention provides methods, compositions, and kits containing a substituted 2,3- dimethoxyquinone of Formula I for treating patients suffering from geographic atrophy. The methods generally comprise administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I. Various aspects of the invention are set forth below in sections; however, aspects of the invention described in one particular section are not to be limited to any particular section.Definitions

[0016] To facilitate an understanding of the present invention, a number of terms and phrases are defined below.

[0017] The terms “a,” “an” and “the” as used herein mean “one or more” and include the plural unless the context is inappropriate.

[0001] The term “about” means within 10% of the stated value. In certain embodiments, the value may be within 8%, 6%, 5%, 4%, 2%, or 1% of the stated value.

[0018] As used herein, the term “patient” refers to organisms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g.,murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans.

[0019] As used herein, the term “effective amount” refers to the amount of a compound sufficient to effect beneficial or desired results. Unless specified otherwise, an effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.

[0020] As used herein, the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for therapeutic use in vivo or ex vivo.

[0021] As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil / water or water / oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see Martin in Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] ,

[0022] As used herein, the term “pharmaceutically acceptable salt” refers to any pharmaceutically acceptable salt (e.g, acid or base) of a compound of the present invention which, upon administration to a subject, is capable of providing a compound of this invention. As is known to those of skill in the art, “salts” of the compounds of the present invention may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic acid, and the like. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.

[0023] Examples of bases include, but are not limited to, alkali metals e.g., sodium) hydroxides, alkaline earth metals (e.g., magnesium), hydroxides, ammonia, and compounds of formula NW3, wherein W is C1.4 alkyl, and the like.

[0024] Examples of salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate (mesylate), 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions of the compounds of the present invention compounded with a suitable cation such as Na+, NEU+, and NW4+(wherein W is a C1-4 alkyl group), and the like.

[0025] For therapeutic use, salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0026] The term "alkyl" is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In certain embodiments, a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), and alternatively, about 20 or fewer. Likewise, cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and alternatively about 5, 6 or 7 carbons in the ring structure.

[0027] Throughout the description, where compositions and kits are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.

[0028] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.I. Therapeutic Methods

[0029] The methods generally provide therapy for a patient suffering from geographic atrophy or at risk of developing geographic atrophy. The methods generally comprise administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. Various aspects and embodiments of the therapeutic methods are described in the sections below. The sections are arranged for convenience and information in one section is not to be limited to that section, but may be applied to methods in other sections.A. First Method

[0030] One aspect of the invention provides a method of treating geographic atrophy. The method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, in order to treat the geographic atrophy, wherein Formula I is represented by:or a pharmaceutically acceptable salt thereof, wherein:R1represents independently for each occurrence Ci-4 alkyl;R2is Ci-4 alkyl;R3is Ci-6 alkyl;R4is Ci-6 alkyl or hydrogen;R3is Ci-6 alkyl or Ci-4alkoxyl; and n is 0, 1, or 3.

[0031] The method may be further characterized by additional features, such as the identity of the compound of Formula I. In certain embodiments, the patient has been diagnosed with geographic atrophy. The invention embraces all permutations and combinations of these features.B. Second Method

[0032] Another aspect of the invention provides a method of reducing the size of a geographic atrophy lesion in a patient. The method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, in order to reduce the size of the geographic atrophy lesion, wherein Formula I is represented by:or a pharmaceutically acceptable salt thereof, wherein:R1represents independently for each occurrence C1-4 alkyl;R2is Ci-4 alkyl;R3is Ci-6 alkyl;R4is Ci-6 alkyl or hydrogen;R3is Ci-6 alkyl or C1-4 alkoxyl; and n is 0, 1, or 3.

[0033] The method may be further characterized by additional features, such as the identity of the compound of Formula I. In certain embodiments, the patient has been diagnosed with geographic atrophy. The invention embraces all permutations and combinations of these features.C. Third Method

[0034] Another aspect of the invention provides a method of preventing or slowing the increase in the size of a geographic atrophy lesion in a patient that presents with at least one geographic atrophy lesion. The method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, in order to prevent or slow the increase in the size of a geographic atrophy lesion, wherein Formula I is represented by:or a pharmaceutically acceptable salt thereof, wherein:R1represents independently for each occurrence C1-4 alkyl;R2is Ci-4 alkyl;R3is Ci-6 alkyl;R4is Ci-6 alkyl or hydrogen;R3is Ci-6 alkyl or Ci-4alkoxyl; and n is 0, 1, or 3.

[0035] The method may be further characterized by additional features, such as the identity of the compound of Formula I. In certain embodiments, the patient has been diagnosed with geographic atrophy. The invention embraces all permutations and combinations of these features.D. Fourth Method

[0036] Another aspect of the invention provides a method of preventing or reducing the risk of developing geographic atrophy. The method comprises administering to a patient in needthereof a therapeutically effective amount of a compound of Formula I, in order to prevent or reduce the risk of developing geographic atrophy, wherein Formula I is represented by:or a pharmaceutically acceptable salt thereof, wherein:R1represents independently for each occurrence C1-4 alkyl;R2is Ci-4 alkyl;R3is Ci-6 alkyl;R4is Ci-6 alkyl or hydrogen;R5is Ci-6 alkyl or C1-4 alkoxyl; and n is 0, 1, or 3.

[0037] The method may be further characterized by additional features, such as the identity of the compound of Formula I. The invention embraces all permutations and combinations of these features.

[0038] In certain embodiments, the method is to preventing geographic atrophy. In certain embodiments, the method is to reducing the risk of developing geographic atrophy.E. Fifth Method

[0039] Another aspect of the invention provides a method of inhibiting the progression of geographic atrophy in a patient. The method comprises administering to a patient in need thereofa therapeutically effective amount of a compound of Formula I, in order to inhibit the progression of geographic atrophy, wherein Formula I is represented by:or a pharmaceutically acceptable salt thereof, wherein:R1represents independently for each occurrence C1-4 alkyl;R2is Ci-4 alkyl;R3is Ci-6 alkyl;R4is Ci-6 alkyl or hydrogen;R5is Ci-6 alkyl or C1-4 alkoxyl; and n is 0, 1, or 3.

[0040] The method may be further characterized by additional features, such as the identity of the compound of Formula I. The invention embraces all permutations and combinations of these features.F. General Considerations for Therapeutic Methods

[0041] General considerations that may be applied to methods described herein (e.g., the methods described in Parts A to E above) are provided below and include, for example, the identity of compound of Formula I, the identity of the patient, the frequency of administration and duration of administration of the compound of Formula I, and combination therapy involving administering one or more additional therapeutic agents. A more thorough description of such features is provided below. The invention embraces all permutations and combinations of these features.Identity o f Compound of Formula I

[0042] In certain embodiments, the compound is a compound of Formula I in free base form.

[0043] In certain embodiments, R1is methyl.

[0044] In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2.

[0045] In certain embodiments, R2is methyl. In certain embodiments, R3is C3 alkyl. In certain embodiments, R3is -CH2CH2CH3.

[0046] In certain embodiments, R4is C1-6 alkyl. In certain embodiments, R4is ethyl. In certain embodiments, R4is hydrogen.

[0047] In certain embodiments, R?is C1-6 alkyl. In certain embodiments, R5is ethyl. In certain embodiments, R5is Ci-4 alkoxyl. In certain embodiments, R5is methoxy.

[0048] In certain embodiments, the compoundpharmaceutically acceptable salt thereof. In certain embodiments, the compound is

[0049] In certain embodiments, the compound ipharmaceutically acceptable salt thereof. In certain embodiments, the compound isRoute of Administration and Timing

[0050] In certain embodiments, the compound is administered orally to the patient.

[0051] In certain embodiments, the compound is administered locally to the eye. In certain embodiments, the compound is administered by injection into an eye of the patient. In certain embodiments, the compound is administered by intravitreal injection into an eye of the patient.

[0052] Local administration to the front of the eye can be done by subconjunctival injection. A subconjunctival injection can be used to inject a compound to either the subconjunctival space or the sub-Tenon's space. Local administration to the anterior and posterior segments of the eye can also be achieved by intraocular injection, e.g., an intracameral or intravitreal injection. An intracameral injection is an injection that is generally delivered into a chamber in the anterior of the eye (e.g., in front of the lens). An intravitreal injection is an injection delivered into the vitreous chamber in the posterior of the eye (e.g., behind the lens). In some cases, an intracameral injection can provide administration without an increase in intraocular pressure that is associated with an intravitreal injection.

[0053] In certain embodiments, the compound is administered to the suprachrodial region of the patient’s eye. In certain embodiments, the compound is administered by suprachrodial injection.

[0054] In certain embodiments, the compound is administered to the subretinal region of the patient’s eye. In certain embodiments, the compound is administered by subretinal injection.

[0055] In certain embodiments, the compound is administered topically to the patient’s eye (e.g., using a gel, ointment, eye drop, insert, contact lens, punctal plug, microemulsion, or suspension). In certain embodiments, the compound is administered by intravitreal injection, an intravitreal implant, a subconjuctival injection, a sub-tenon injection, a retrobulbar injection, orsuprachoroidal injection. In certain embodiments, the compound is administered to the sub- retinal space or intra-retinal space. In certain embodiments, the compound is administered using a wafer, microspheres, port delivery system, or by intracameral injection.

[0056] In certain embodiments, the compound is administered to the patient in the morning. In certain embodiments, the compound is administered to the patient in the patient in the evening.Frequency of Administration of Compound of Formula I

[0057] The methods may be further characterized according to the frequency of administration of the compound of Formula I. For example, in certain embodiments, the compound of Formula I is administered daily. In certain embodiments, the compound of Formula I is administered once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. In certain embodiments, the compound of Formula I is administered once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In certain embodiments, the compound of Formula I is administered once every 1, 2, 3, 4, 5, or 6 months.Duration of Administration of Compound of Formula I

[0058] The methods may be further characterized according to the duration of administration of compound of Formula I. For example, in certain embodiments, an amount of compound of Formula I is administered to the patient daily for at least 1 week. In certain embodiments, an amount of compound of Formula I is administered to the patient daily for at least 2 weeks. In certain embodiments, an amount of compound of Formula I is administered to the patient daily for at least 4 weeks. In certain embodiments, an amount of Compound of Formula I is administered to the patient daily for at least 6 weeks. In certain embodiments, an amount of compound of Formula I is administered to the patient daily for at least 8 weeks. In certain embodiments, an amount of compound of Formula I is administered to the patient daily for at least 10 weeks. In certain embodiments, an amount of compound of Formula I is administered to the patient daily for at least 12 weeks. In certain embodiments, an amount of compound of Formula I is administered to the patient daily for at least 24 weeks. In certain embodiments, an amount of compound of Formula I is administered to the patient daily for at least 30, 32, 34, 36, 38 40, 42, 44, 46, 48, 50, or 52 weeks.

[0059] In certain embodiments, an amount of compound of Formula I is administered to the patient at a specified frequency for at least 1 week. In certain embodiments, an amount of compound of Formula I is administered to the patient at a specified frequency for at least 2 weeks. In certain embodiments, an amount of compound of Formula I is administered to the patient at a specified frequency for at least 4 weeks. In certain embodiments, an amount of Compound of Formula I is administered to the patient at a specified frequency for at least 6 weeks. In certain embodiments, an amount of compound of Formula I is administered to the patient at a specified frequency for at least 8 weeks. In certain embodiments, an amount of compound of Formula I is administered to the patient at a specified frequency for at least 10 weeks. In certain embodiments, an amount of compound of Formula I is administered to the patient at a specified frequency for at least 12 weeks. In certain embodiments, an amount of compound of Formula I is administered to the patient at a specified frequency for at least 24 weeks. In certain embodiments, an amount of compound of Formula I is administered to the patient at a specified frequency for at least 30, 32, 34, 36, 38 40, 42, 44, 46, 48, 50, or 52 weeks.Characteristics of the Geographic Atrophy

[0060] The methods may be further characterized according to characteristics of the geographic atrophy. For example, in certain embodiments, the geographic atrophy may be characterized according to the size of a geographic atrophy lesion.

[0061] In certain embodiments, any geographic atrophy lesions in the patient have a size of less than 1 mm2. In certain embodiments, any geographic atrophy lesions in the patient have a size of less than 2 mm2. In certain embodiments, any geographic atrophy lesions in the patient have a size of less than 3 mm2. In certain embodiments, any geographic atrophy lesions in the patient have a size of less than 4 mm2. In certain embodiments, any geographic atrophy lesions in the patient have a size of less than 5 mm2. In certain embodiments, any geographic atrophy lesions in the patient have a size of less than 6 mm2. In certain embodiments, any geographic atrophy lesions in the patient have a size of less than 7 mm2. In certain embodiments, any geographic atrophy lesions in the patient have a size of less than 10 mm2. In certain embodiments, any geographic atrophy lesions in the patient have a size of less than 15 mm2. In certain embodiments, any geographic atrophy lesions in the patient have a size of less than 20 mm 2.

[0062] In certain embodiments, at least one geographic atrophy lesion in the patient has a size of greater than 0.5 mm2. In certain embodiments, at least one geographic atrophy lesion in the patient has a size of greater than 1 mm2. In certain embodiments, at least one geographic atrophy lesion in the patient has a size of greater than 2 mm2. In certain embodiments, at least one geographic atrophy lesion in the patient has a size of greater than 3 mm2. In certain embodiments, at least one geographic atrophy lesion in the patient has a size of greater than 4 mm2. In certain embodiments, at least one geographic atrophy lesion in the patient has a size of greater than 5 mm2. In certain embodiments, at least one geographic atrophy lesion in the patient has a size of greater than 6 mm2. In certain embodiments, at least one geographic atrophy lesion in the patient has a size of greater than 7 mm2. In certain embodiments, at least one geographic atrophy lesion in the patient has a size of greater than 8 mm2. In certain embodiments, at least one geographic atrophy lesion in the patient has a size of greater than 10 mm2. In certain embodiments, at least one geographic atrophy lesion in the patient has a size of greater than 15 mm2. In certain embodiments, at least one geographic atrophy lesion in the patient has a size of greater than 20 mm2.

[0063] In certain embodiments, the patient has at least one geographic atrophy lesion at a size in the range of from about 0.5 mm2to about 3 mm2. In certain embodiments, the patient has at least one geographic atrophy lesion at a size in the range of from about 2 mm2to about 5 mm2. In certain embodiments, the patient has at least one geographic atrophy lesion at a size in the range of from about 3 mm2to about 6 mm2. In certain embodiments, the patient has at least one geographic atrophy lesion at a size in the range of from about 4 mm2to about 7 mm2. In certain embodiments, the patient has at least one geographic atrophy lesion at a size in the range of from about 5 mm2to about 8 mm2. In certain embodiments, the patient has at least one geographic atrophy lesion at a size in the range of from about 5 mm2to about 10mm2. In certain embodiments, the patient has at least one geographic atrophy lesion at a size in the range of from about 7 mm2to about 10 mm2. In certain embodiments, the patient has at least one geographic atrophy lesion at a size in the range of from about 8 mm2to about 11 mm2. In certain embodiments, the patient has at least one geographic atrophy lesion at a size in the range of from about 10 mm2to about 13 mm2. In certain embodiments, the patient has at least one geographic atrophy lesion at a size in the range of from about 10 mm2to about 15 mm2. In certain embodiments, the patient has at least one geographic atrophy lesion at a size in the range of fromabout 12 mm2to about 15 mm2. In certain embodiments, the patient has at least one geographic atrophy lesion at a size in the range of from about 15 mm2to about 20 mm2.

[0064] In certain embodiments, a majority of geographic atrophy lesions in the patient have a size in the range of from about 0.5 mm2to about 3 mm2. In certain embodiments, a majority of geographic atrophy lesions in the patient have a size in the range of from about 2 mm2to about 5 mm2. In certain embodiments, a majority of geographic atrophy lesions in the patient have a size in the range of from about 3 mm2to about 6 mm2. In certain embodiments, a majority of geographic atrophy lesions in the patient have a size in the range of from about 4 mm2to about 7 mm2. In certain embodiments, a majority of geographic atrophy lesions in the patient have a size in the range of from about 5 mm2to about 8 mm2. In certain embodiments, a majority of geographic atrophy lesions in the patient have a size in the range of from about 5 mm2to about 10mm2. In certain embodiments, a majority of geographic atrophy lesions in the patient have a size in the range of from about 7 mm2to about 10 mm2. In certain embodiments, a majority of geographic atrophy lesions in the patient have a size in the range of from about 11 mm2. In certain embodiments, a majority of geographic atrophy lesions in the patient have a size in the range of from about 10 mm2to about 13 mm2. In certain embodiments, a majority of geographic atrophy lesions in the patient have a size in the range of from about 10 mm2to about 15 mm2. In certain embodiments, a majority of geographic atrophy lesions in the patient have a size in the range of from about 12 mm2to about 15 mm2. In certain embodiments, a majority of geographic atrophy lesions in the patient have a size in the range of from about 15 mm2to about 20 mm2.

[0065] In certain embodiments, the patient has at least one geographic atrophy lesion that prior to receiving a compound of Formula I is increasing in size at a rate of at least 1 mm2per year. In certain embodiments, the patient has at least one geographic atrophy lesion that prior to receiving a compound of Formula I is increasing in size at a rate of at least 2 mm2per year. In certain embodiments, the patient has at least one geographic atrophy lesion that prior to receiving a compound of Formula I is increasing in size at a rate of at least 3 mm2per year. In certain embodiments, the patient has at least one geographic atrophy lesion that prior to receiving a compound of Formula I is increasing in size at a rate of at least 4 mm2per year. In certain embodiments, the patient has at least one geographic atrophy lesion that prior to receiving acompound of Formula I is increasing in size at a rate of at least 5 mm2per year. In certain embodiments, the patient has at least one geographic atrophy lesion that prior to receiving a compound of Formula I is increasing in size at a rate of at least 6 mm2per year. In certain embodiments, the patient has at least one geographic atrophy lesion that prior to receiving a compound of Formula I is increasing in size at a rate of at least 7 mm2per year. In certain embodiments, the patient has at least one geographic atrophy lesion that prior to receiving a compound of Formula I is increasing in size at a rate of at least 8 mm2per year. In certain embodiments, the patient has at least one geographic atrophy lesion that prior to receiving a compound of Formula I is increasing in size at a rate of at least 9 mm2per year. In certain embodiments, the patient has at least one geographic atrophy lesion that prior to receiving a compound of Formula I is increasing in size at a rate of at least 10 mm2per year.Identity o f the Patient

[0066] In certain embodiments, the patient is a human. In certain embodiments, the patient is an adult human. In certain embodiments, the patient is a geriatric human patient.

[0067] In certain embodiments, the patient has more than one geographic atrophy lesion. In certain embodiments, the patient has at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 geographic atrophy lesions. In certain embodiments, the patient has a geographic atrophy lesion in the foveal region of the retina. In certain embodiments, the patient does not have a geographic atrophy lesion in the foveal region of the retina.

[0068] In certain embodiments, the patient for treatment is defined according to the size of one or more geographic atrophy lesions in the patient.

[0069] In certain embodiments, the patient has neovascular age-related macular degeneration. In certain embodiments, the patient has neovascular age-related macular degeneration in an eye other than the eye with geographic atrophy.

[0070] In certain embodiments, the patient does not have neovascular age-related macular degeneration.Impact of the Method

[0071] The methods may be further characterized according to the impact of the method. This includes, for example, reduction in the rate of geographic atrophy lesion growth, or improvement in patient’s vision.Reduction in the Rate of Geographic Atrophy Lesion Growth

[0072] The methods may be further characterized according to a reduction in the rate at which the size of a geographic atrophy lesion increases over time, due to the patient receiving a compound of Formula I. For example, in certain embodiments, the patient experiences at least a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% reduction in the rate at which the size of a geographic atrophy lesion grows over time, due to the patient receiving a compound of Formula I.

[0073] To illustrate: a patient may be characterized prior to treatment according to the rate at which a geographic atrophy lesion increases over time. For example, examination of the patient’s medical history may reveal that the size of a patient’s geographic atrophy lesion has been increasing at rate of 2 mm2per year for the last 1 year. Medical benefit to the patient is achieved if administering a compound of Formula I reduces the rate at which the size of the geographic atrophy lesion increases. For example, reducing the rate at which the size of a patient’s geographic atrophy lesion has been increasing from a rate of 2 mm2to a rate of 1 mm2per year would provide medical benefit to the patient.

[0074] In certain embodiments, the patient experiences at least a 5% reduction in the rate at which the size of a geographic atrophy lesion grows over time, due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 10% reduction in the rate at which the size of a geographic atrophy lesion grows over time, due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 15% reduction in the rate at which the size of a geographic atrophy lesion grows over time, due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 20% reduction in the rate at which the size of a geographic atrophy lesion grows over time, due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 25% reduction in the rate at which the size of a geographicatrophy lesion grows over time, due to the patient receiving a compound of Formula T. In certain embodiments, the patient experiences at least a 30% reduction in the rate at which the size of a geographic atrophy lesion grows over time, due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 35% reduction in the rate at which the size of a geographic atrophy lesion grows over time, due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 40% reduction in the rate at which the size of a geographic atrophy lesion grows over time, due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 45% reduction in the rate at which the size of a geographic atrophy lesion grows over time, due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 50% reduction in the rate at which the size of a geographic atrophy lesion grows over time, due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 55% reduction in the rate at which the size of a geographic atrophy lesion grows over time, due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 60% reduction in the rate at which the size of a geographic atrophy lesion grows over time, due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 65% reduction in the rate at which the size of a geographic atrophy lesion grows over time, due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 70% reduction in the rate at which the size of a geographic atrophy lesion grows over time, due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 75% reduction in the rate at which the size of a geographic atrophy lesion grows over time, due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 80% reduction in the rate at which the size of a geographic atrophy lesion grows over time, due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 85% reduction in the rate at which the size of a geographic atrophy lesion grows over time, due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 90% reduction in the rate at which the size of a geographic atrophy lesion grows over time, due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 90% reduction in the rate at which the size of a geographic atrophy lesion grows over time, due to the patient receiving a compound of Formula I.

[0075] In certain embodiments, the patient experiences at least a 10% reduction in rate at which the size of a geographic atrophy lesion has increased over the prior 1 year, due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 10% reduction in rate at which the size of a geographic atrophy lesion has increased over the prior 1 year, due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 20% reduction in rate at which the size of a geographic atrophy lesion has increased over the prior 1 year, due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 35% reduction in rate at which the size of a geographic atrophy lesion has increased over the prior 1 year, due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 50% reduction in rate at which the size of a geographic atrophy lesion has increased over the prior 1 year, due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 60% reduction in rate at which the size of a geographic atrophy lesion has increased over the prior 1 year, due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 70% reduction in rate at which the size of a geographic atrophy lesion has increased over the prior 1 year, due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least an 80% reduction in rate at which the size of a geographic atrophy lesion has increased over the prior 1 year, due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 90% reduction in rate at which the size of a geographic atrophy lesion has increased over the prior 1 year, due to the patient receiving a compound of Formula I.

[0076] In certain embodiments, the reduction is measured at a time that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction is measured at a time that is 1 month after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction is measured at a time that is 2 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction is measured at a time that is 3 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction is measured at a time that is 4 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction is measured at a time that is 5 months after the patient receives a first dose of a compound ofFormula I. In certain embodiments, the reduction is measured at a time that is 6 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction is measured at a time that is 7 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction is measured at a time that is 8 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction is measured at a time that is 9 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction is measured at a time that is 10 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction is measured at a time that is 11 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction is measured at a time that is 12 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction is measured at a time that is 13 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction is measured at a time that is 14 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction is measured at a time that is 15 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction is measured at a time that is 16 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction is measured at a time that is 17 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction is measured at a time that is 18 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction is measured at a time that is 19 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction is measured at a time that is 21 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction is measured at a time that is 22 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction is measured at a time that is 23 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction is measured at a time that is 24 months after the patient receives a first dose of a compound of Formula I.

[0077] In certain embodiments, the administering a compound of Formula I prevents the increase in size of a geographic atrophy lesion in a patient.Impact on Conversion from iRORA to cRORA

[0078] In certain embodiments, the method is further characterized by inhibiting the conversion from incomplete retinal pigment epithelial and outer retinal atrophy (iRORA) to complete retinal pigment epithelial and outer retinal atrophy (cRORA).

[0079] In certain embodiments, the method is further characterized by preventing the conversion from incomplete retinal pigment epithelial and outer retinal atrophy (iRORA) to complete retinal pigment epithelial and outer retinal atrophy (cRORA).

[0080] In certain embodiments, the method is further characterized by slowing the conversion from incomplete retinal pigment epithelial and outer retinal atrophy (iRORA) to complete retinal pigment epithelial and outer retinal atrophy (cRORA). For example, in certain embodiments, the patient experiences at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or greater reduction the rate of conversion from incomplete retinal pigment epithelial and outer retinal atrophy (iRORA) to complete retinal pigment epithelial and outer retinal atrophy (cRORA) due to the method.Decrease in Size of Geographic Atrophy Lesion

[0081] The methods may be further characterized according to a decrease in size of a geographic atrophy lesion due to the patient receiving a compound of Formula I. For example, in certain embodiments, the patient experiences at least a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% reduction in size of a geographic atrophy lesion due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 5% reduction in size of a geographic atrophy lesion due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 10% reduction in size of a geographic atrophy lesion due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 15% reduction in size of a geographic atrophy lesion due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 20% reduction in size of a geographic atrophy lesion due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 25% reduction in size of a geographic atrophy lesion due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 30% reduction in size of a geographic atrophy lesion due to the patientreceiving a compound of Formula I. In certain embodiments, the patient experiences at least a 40% reduction in size of a geographic atrophy lesion due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 50% reduction in size of a geographic atrophy lesion due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 60% reduction in size of a geographic atrophy lesion due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 70% reduction in size of a geographic atrophy lesion due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 80% reduction in size of a geographic atrophy lesion due to the patient receiving a compound of Formula I. In certain embodiments, the patient experiences at least a 90% reduction in size of a geographic atrophy lesion due to the patient receiving a compound of Formula I.

[0082] In certain embodiments, the reduction in size of the geographic atrophy lesion is measured at a time that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction in size of the geographic atrophy lesion is measured at a time that is1 month after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction in size of the geographic atrophy lesion is measured at a time that is2 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction in size of the geographic atrophy lesion is measured at a time that is3 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction in size of the geographic atrophy lesion is measured at a time that is4 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction in size of the geographic atrophy lesion is measured at a time that is5 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction in size of the geographic atrophy lesion is measured at a time that is6 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction in size of the geographic atrophy lesion is measured at a time that is7 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction in size of the geographic atrophy lesion is measured at a time that is8 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction in size of the geographic atrophy lesion is measured at a time that is9 months after the patient receives a first dose of a compound of Formula T. In certain embodiments, the reduction in size of the geographic atrophy lesion is measured at a time that is10 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction in size of the geographic atrophy lesion is measured at a time that is11 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction in size of the geographic atrophy lesion is measured at a time that is12 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction in size of the geographic atrophy lesion is measured at a time that is13 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction in size of the geographic atrophy lesion is measured at a time that is14 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction in size of the geographic atrophy lesion is measured at a time that is15 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction in size of the geographic atrophy lesion is measured at a time that is16 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction in size of the geographic atrophy lesion is measured at a time that is17 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction in size of the geographic atrophy lesion is measured at a time that is18 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction in size of the geographic atrophy lesion is measured at a time that is19 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction in size of the geographic atrophy lesion is measured at a time that is21 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction in size of the geographic atrophy lesion is measured at a time that is22 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction in size of the geographic atrophy lesion is measured at a time that is23 months after the patient receives a first dose of a compound of Formula I. In certain embodiments, the reduction in size of the geographic atrophy lesion is measured at a time that is24 months after the patient receives a first dose of a compound of Formula I.Improvement in Patient 's Vision

[0083] The methods may be further characterized according to the improvement in the patient’s vision. For example, in certain embodiments, the method provides an improvement in visual acuity characterized by at least a one-line improvement in the patient’s vision measured using a vision chart. In certain embodiments, the method results in an improvement in visual acuity characterized by at least a two-line improvement in the patient’s vision measured using a vision chart. In certain embodiments, the method results in an improvement in visual acuity characterized by at least a three-line improvement in the patient’s vision measured using a vision chart. In certain embodiments, the method results in an improvement in visual acuity characterized by an improvement in the patient’s vision of four or more lines measured using a vision chart. In certain embodiments, the vision chart is a Snellen chart. In certain other embodiments, the vision chart is a Iaeger chart. In certain other embodiments, the vision chart is a Rosenbaum chart or an ETDRS chart. In certain embodiments, the improvement in visual acuity is measured at a distance of about 4 meters. In certain embodiments, the improvement in visual acuity is measured under photopic conditions. In certain embodiments, the improvement in visual acuity is measured under mesopic conditions.Incidence of Adverse Side Effects

[0084] The methods may be further characterized according to the incidence of any adverse side effect. For example, in certain embodiments, the method is further characterized by the feature that the incidence of any eye disorder due to the compound of Formula I occurs no more frequently than one patient for every ten patients subjected to the same treatment. In certain embodiments, the method is further characterized by the feature that the incidence of any eye disorder due to the compound of Formula I occurs no more frequently than one patient for every 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, or 40 patients subjected to the same treatment.

[0085] In certain embodiments, the method is further characterized by the feature that the incidence of any eye disorder due to the compound of Formula I occurs no more frequently than one patient for every twenty patients subjected to the same treatment. In certain embodiments, the method is further characterized by the feature that the incidence of any eye disorder due tothe compound of Formula T occurs no more frequently than one patient for every 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, or 40 patients subjected to the same treatment.

[0086] In certain embodiments, the method is further characterized by the feature that the incidence of any gastrointestinal disorder due to the compound of Formula I occurs no more frequently than one patient for every ten patients subjected to the same treatment. In certain embodiments, the method is further characterized by the feature that the incidence of any gastrointestinal disorder to the compound of Formula I occurs no more frequently than one patient for every 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, or 40 patients subjected to the same treatment.

[0087] In certain embodiments, the method is further characterized by the feature that the incidence of any nervous system disorder due to the compound of Formula I occurs no more frequently than one patient for every twenty patients subjected to the same treatment. In certain embodiments, the method is further characterized by the feature that the incidence of any nervous system disorder due to the compound of Formula I occurs no more frequently than one patient for every 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, or 40 patients subjected to the same treatment.Impact on Neovascular Age-related Macular Degeneration

[0088] The method may be further characterized according to impact on neovascular age- related macular degeneration. In certain embodiments, the method is further characterized according to the feature that the administering reduces the progression of neovascular age-related macular degeneration in the subject. In certain embodiments, the method is further characterized according to the feature that the administering reduces the onset of neovascular age-related macular degeneration in the subject.Combination Therapy

[0089] Another aspect of the invention provides for combination therapy. Compounds described herein (e.g., a compound of Formula I) may be used in combination with additional therapeutic agents to treat diseases or conditions described herein.

[0090] Accordingly, in some embodiments, the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method includes co-administering one additional therapeutic agent. In some embodiments, the method includes co-administering two additional therapeutic agents.

[0091] One or more other therapeutic agents may be administered separately from a compound or composition of the invention, as part of a multiple dosage regimen. Alternatively, one or more other therapeutic agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as a multiple dosage regime, one or more other therapeutic agent and a compound or composition of the invention may be administered simultaneously, sequentially or within a period of time from one another.

[0092] In certain embodiments, the compounds of the disclosure can be administered with one or more of a second therapeutic agent, sequentially or concurrently, either by the same route or by different routes of administration. When administered sequentially, the time between administrations is selected to benefit, among others, the therapeutic efficacy and / or safety of the combination treatment. In certain embodiments, the compound of the disclosure can be administered first followed by a second therapeutic agent, or alternatively, the second therapeutic agent administered first followed by the compound of the disclosure. In certain embodiments, the compound of the disclosure can be administered for the same duration as the second therapeutic agent, or alternatively, for a longer or shorter duration as the second therapeutic compound.

[0093] When administered concurrently, the compounds of the disclosure can be administered separately at the same time as the second therapeutic agent, by the same or different routes, or administered in a single composition by the same route. In certain embodiments, the compound of the disclosure is prepared as a first pharmaceutical composition, and the second therapeutic agent prepared as a second pharmaceutical composition, where the first pharmaceutical composition and the second pharmaceutical composition are administered simultaneously, sequentially, or separately. In certain embodiments, the amount and frequencyof administration of the second therapeutic agent can used standard dosages and standard administration frequencies used for the particular therapeutic agent. See, e.g., Physicians ’ Desk Reference, 70th Ed., PDR Network, 2015; incorporated herein by reference.

[0094] In certain embodiments, the additional therapeutic agent is an inhibitor of Vascular endothelial growth factor (VEGF). Exemplary VEGF inhibitors include pazopanib, sunitinib, bevacizumab, sorafenib, regorafenib, cabozantinib, lenvatinib, ponatinib, cabozantinib, ziv- aflibercept, axitinib, bevacizumab, tivozanib, ramucirumab, vandetanib, bevacizumab, or a pharmaceutically acceptable salt thereof.

[0095] In certain embodiments, the compound of Formula I and additional therapeutic agent (e.g., a VEGF inhibitor) are present in an extended release pharmaceutical composition.

[0096] In certain embodiments, the additional therapeutic agent is an VEGF-Ang-2 bispecific antibody. An exemplary VEGF-Ang-2 bispecific antibody is that described in Proc. Natl. Acad. Sci. USA. 2016 Apr 19; 113(16): 4476-4481, which is hereby incorporated by reference.Medical Uses

[0097] Another aspect of the invention provides for the use of a compound described herein (e.g., a compound of Formula I) in the manufacture of a medicament. In certain embodiments, the medicament is for geographic atrophy.

[0098] Another aspect of the invention provides for the use of a compound described herein (e.g., a compound of Formula I), such as for treating a medical disorder, such as geographic atrophy.II. Preparation of Compounds

[0099] Procedures for preparing substituted 2,3 -dimethoxy quinone compounds are provided in, for example, WO 2019 / 157163, which includes procedures for preparing the following compounds:III. Pharmaceutical Compositions

[0100] As indicated above, the invention provides pharmaceutical compositions, which comprise a therapeutically effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and / or diluents. The pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue. The pharmaceutical compositions may be specially formulated for administration to the eye, such as a formulation for injection into the eye, or a gel or paste for topical application to the eye. In certain embodiments, the invention provides a pharmaceutical compositions, comprising a compound described herein (e.g., a compound of Formula I) and a pharmaceutically acceptable carrier.

[0101] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0102] Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate,butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0103] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety -nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

[0104] In certain embodiments, a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention. In certain embodiments, an aforementioned formulation renders orally bioavailable a compound of the present invention.

[0105] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0106] Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste.

[0107] In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, trouches and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fdlers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0108] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0109] The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices,liposomes and / or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0110] Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0111] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0112] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0113] Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0114] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions.

[0115] In certain embodiments, the pharmaceutical composition may be in the form of a cream, colloidal, suspension, spray, gel, lotion, ointment, foam, or solution. In certain embodiments, the pharmaceutical composition may be in the form of a solution for injection. In certain embodiments, the pharmaceutical composition may be in the form of a solution for subcutaneous injection.

[0116] In certain embodiments, the pharmaceutical compositions are specially formulated for administration to the eye, such as a pharmaceutical composition for injection into the eye. Exemplary excipients that may be used in pharmaceutical composition for intravitreal injection include excipients or carriers that cause little to no ocular irritation, provide suitable preservation if needed, and deliver one or more agents in a suitable volume. Examples of a base or carrier include water for injection and physiological saline.

[0117] The pharmaceutical composition may be presented in the form an aqueous, sterile ophthalmic suspension, solution, or viscous or semi-viscous gels or other types of solid or semisolid composition such as an ointment. Such compositions may be used for topical administration to the eye.

[0118] The pharmaceutical composition may also be in the form of an implantable ocular device, placed in the eye, for example, by corneal incision. Ocular devices include stents (e.g., trabecular stent), organo-gel implant, and those compositions and devices described in U.S. Patent Nos. 5,501,856, 5,869,079, 5,824,072, 4,997,652, 5,164,188, 5,443,505, and 5,766,242.

[0119] The pharmaceutical composition may be in the form of an extended release formulation. For example, U.S. Patent No. 5,501,856 discloses controlled-release pharmaceutical preparations for intraocular implants to be applied to the interior of the eye after a surgical operation for disorders in retina / vitreous body or for glaucoma. U.S. Patent No.5,869,079 discloses combinations of hydrophilic and hydrophobic entities in a biodegradable sustained release implant, and describes a polylactic acid polyglycolic acid (PLGA) copolymer implant comprising dexamethasone. U.S. Patent No. 5,824,072 discloses implants for introduction into a suprachoroidal space or an avascular region of the eye, and describes a methylcellulose implant comprising dexamethasone. U.S. Patent Nos. 4,997,652 and 5,164,188 disclose biodegradable ocular implants comprising microencapsulated drugs, and describes implanting microcapsules comprising hydrocortisone succinate into the posterior segment of the eye. U.S. Patent No. 5,164,188 discloses encapsulated agents for introduction into the suprachoroid of the eye. U.S. Patent Nos. 5,443,505 and 5,766,242 disclose implants comprising active agents for introduction into a suprachoroidal space or an avascular region of the eye. In certain embodiments, the controlled release pharmaceutical composition contains a biodegradable polymer.

[0120] Exemplary extended release technologies that may be used in an injectable formulation include hydrogels, microspheres and nanospheres, polymers and polymeric implants (biodegradable and non-biodegradable including dendrimers), microparticles and nanoparticles, liposomes, nanofibers. Exemplary polymers that may be used in such formulations include (poly(ethylene glycol) (PEG), poly(vinyl alcohol) (PVA), poly(glycolic acid) (PGA), poly(lactic- co-glycolic acid) (PLGA), poly[2-(dimethylamino)ethyl methacrylate] (DMAEM), poly(caprolactone) (PCL), poly(acrylic acid) (PAA), and poly(amidoamine) (PAMAM).

[0121] Exemplary extended release technologies that may be used in a topical formulation include nanoparticles of a polysaccharide such as pectin, hyaluronic acid, gum cordia, carboxymethyl tamarind kernel polysaccharide, galactomannan polysaccharide, nanomicelles, silica, dendrimers, and semifluorinated alkanes.

[0122] To provide a delayed release drug delivery implant or depot, an injectable formulation including the subject active agent can be injected into a subject, which results in the in situ formation of an organogel implant. Upon contact with bodily fluid, crosslinking agents begin to crosslink the organogel to form a more stable matrix that modulates the escape of the active agent to the eye of the subject. In some instances, this method of administration can provide a prolonged release period of the active agent. In some cases, an in vivo biodegradable crosslinked matrix is formed that includes a non-aqueous aprotic biocompatible solvent systemthat is non-miscible with water (Zhou, T, et al.," Journal of Controlled Release 55: 281-295, 1998).

[0123] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0124] The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0125] In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. When the compounds described herein are co-administered with another agent (e. ., as sensitizing agents), the effective amount may be less than when the agent is used alone.

[0126] If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.

[0127] The invention further provides a unit dosage form (such as a tablet or capsule) comprising a compound described herein in a therapeutically effective amount for the treatment of a medical disorder described herein.IV. Medical Kits

[0128] Another aspect of the invention provides a medical kit comprising, for example, (i) a compound described herein, and (ii) instructions for a use described herein, such as a method of treating geographic atrophy according to methods described herein.V. EXAMPLES

[0129] The invention now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustrating certain aspects and embodiments of the present invention, and are not intended to limit the invention.EXAMPLE 1 - Inhibition of TN Fa-induced Activation of NF-KB Pathway Using Exemplary Compounds in an NF-KB Reporter Cell Line

[0130] The ability of the compounds of Formula I in Table 1, below, to inhibit TNFoc- induced activation of the NF-KB pathway was tested in an NF-KB reporter cell line.Table 1.Procedure

[0131] HEK-Blue-Lucia™ TNFoc cells were purchased from InvivoGen and cultured according to manufacturer’s protocols. NF-KB reporter activity was measured in response to TNFot (20 ng / mL) in the presence of the compounds of Formula I in Table 1, above. Test groups were as follows, where all but the first control group were treated with TNFa:1. Control,2. Control, without test compound vehicle,3. Control, with test compound vehicle (0.1% DMSO),4. Test compound, 2.5 pM,5. Test compound, 5.0 pM, and6. Test compound, 10.0 pM.Results

[0132] The test compounds of Formula I, APX2009 and APX2014, each showed a dosedependent, statistically significant inhibition of TNFa-induced activation of the NF -KB pathway, based on relative luminescence (Fig. 1, where results for test groups #1-6 described in the procedure section above are depicted in order from left to right).EXAMPLE 2 — Cytoprotection of Retinal Pigment Epithelium Cells Using Exemplary Compounds Under NalOs-Induced Oxidative-Stress Conditions

[0133] The cytoprotective effects of the compounds of Formula I in Table 1, above, were tested in human induced-pluripotent stem cell derived retinal pigment epithelium (iPSC-RPE) cells under exogenously applied oxidative stress (NalOs-induction).Procedure

[0134] Cells (iCell iPSC-RPE) from Fujifilm Cellular Dynamics were cultured for 22 days according to the manufacturer’s protocols. The cells were then treated for 24 hours with NalCE (2.5-10 pM) either alone, or in the presence of APX2009 or APX2014 (1 or 5 pM). Cytotoxicity was measured based on LDH release using CyQUANT LDH cytotoxicity assay (Invitrogen) according to the manufacturer’s protocol.Results

[0135] The test compounds of Formula I, APX2009 and APX2014, each showed a statistically significant reduction in cytotoxicity in iPSC-RPE cells under exogenously applied, NalCh-induced oxidative stress (Fig. 2). Specifically, APX2009 at 5 pM showed a statistically significant effect at 5 and 10 pM NalCh, and APX2014 at 1 pM showed a statistically significant effect at 5 pM NalCh.EXAMPLE 3 - Therapeutic Effect of Exemplary Compounds in NalOj Murine Model of Retinal Pigment Endothelium Degeneration

[0136] The therapeutic effects of the test compounds of Formula I set forth in Table 1 in Example 1 were investigated in the NalCf murine model of retinal pigment epithelium (RPE)degeneration, a mouse model of dry AMD. The endpoint measurements were Fundus, optical coherence tomography (OCT), fluorescein angiography, retinal thickness, and electroradiography (ERG). The effects were compared to the effects of the following compound, APX3330:Procedure

[0137] Prior to the study, mice (C57BL / 6J, 8-week-old, males and females; 8 mice per group) were allowed to acclimate to the laboratory for 7 days. Mice were then treated for 10 days as described in the following table:

[0138] The mouse anti-C5 antibody binds the fifth component of mouse complement and was purchased from HycultBiotech (catalog # HM1073).

[0139] On day 3 of the study, mice were treated with NaKh (35 mg / kg). On day 10 of the study, mice were examined via OCT and ERG. On day 11 of the study, mice were euthanized. Retina, RPE, choroid, and sclera samples were then collected from the mice’s left eyes. The mice’s right eyes were fixed in paraffin for embedding, then sectioned and stained (H&E).Results

[0140] Retinal function as measured by ERG (Fig. 3 and 4) showed a trend toward improvement for compounds APX2009 and APX2014, particularly in rod-mediated scotopic-b amplitudes. Retinal function also showed a statistically significant improvement for the mouse anti-C5 antibody, in both scotopic-b and photopic-b amplitudes. A two-way ANOVA test was used for significance analysis between groups. (*P<0.05)

[0141] Retinal thickness as measured by OCT (Fig. 5) did not show an improvement in any of the treatment groups.INCORPORATION BY REFERENCE

[0142] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes.EQUIVALENTS

[0143] The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

Claims:

1. A method of treating geographic atrophy, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, in order to treat the geographic atrophy, wherein Formula is represented by:or a pharmaceutically acceptable salt thereof, wherein:R1represents independently for each occurrence C1-4 alkyl;R2is Ci-4 alkyl;R3is Ci-6 alkyl;R4is Ci-6 alkyl or hydrogen;R5is Ci-6 alkyl or Ci-4alkoxyl; and n is 0, 1, or 3.

2. The method of claim 1, wherein the patient has more than one geographic atrophy lesion.

3. A method of inhibiting the progression of geographic atrophy in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, in order to inhibit the progression of geographic atrophy, wherein Formula I is represented by:or a pharmaceutically acceptable salt thereof, wherein:R1represents independently for each occurrence Ci-4 alkyl;R2is Ci-4 alkyl;R3is Ci-6 alkyl;R4is Ci-6 alkyl or hydrogen;R5is Ci-6 alkyl or C1-4 alkoxyl; and n is 0, 1, or 3.

4. A method of reducing the size of a geographic atrophy lesion in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, in order to reduce the size of the geographic atrophy lesion, wherein Formula I is represented by:or a pharmaceutically acceptable salt thereof, wherein:R1represents independently for each occurrence Ci-4 alkyl;R2is Ci-4 alkyl;R3is Ci-6 alkyl;R4is Ci-6 alkyl or hydrogen;R3is Ci-6 alkyl or Ci-4 alkoxyl; and n is 0, 1, or 3.

5. The method of any one of claims 1-4, wherein the patient has a geographic atrophy lesion in the foveal region of the retina.

6. The method of any one of claims 1 -4, wherein the patient does not have a geographic atrophy lesion in the foveal region of the retina.

7. The method of any one of claims 1-6, wherein any geographic atrophy lesions in the patient have a size of less than 1 mm2.

8. The method of any one of claims 1-6, wherein any geographic atrophy lesions in the patient have a size of less than 2 mm2.

9. The method of any one of claims 1-6, wherein any geographic atrophy lesions in the patient have a size of less than 3 mm2.

10. The method of any one of claims 1-6, wherein any geographic atrophy lesions in the patient have a size of less than 5 mm2.

11. The method of any one of claims 1-6, wherein any geographic atrophy lesions in the patient have a size of less than 10 mm2.

12. The method of any one of claims 1-6, wherein any geographic atrophy lesions in the patient have a size of less than 20 mm2.

13. The method of any one of claims 1-6, wherein at least one geographic atrophy lesion in the patient has a size of greater than 2 mm2.

14. The method of any one of claims 1-6, wherein at least one geographic atrophy lesion in the patient has a size of greater than 5 mm2.

15. The method of any one of claims 1-6, wherein at least one geographic atrophy lesion in the patient has a size of greater than 10 mm2.

16. The method of any one of claims 1-6, wherein the patient has at least one geographic atrophy lesion at a size in the range of from about 0.5 mm2to about 3 mm2.

17. The method of any one of claims 1-6, wherein the patient has at least one geographic atrophy lesion at a size in the range of from about 2 mm2to about 5 mm2.

18. The method of any one of claims 1-6, wherein the patient has at least one geographic atrophy lesion at a size in the range of from about 5 mm2to about 10 mm2.

19. The method of any one of claims 1 -6, wherein the patient has at least one geographic atrophy lesion at a size in the range of from about 10 mm2to about 15 mm2.

20. The method of any one of claims 1-19, wherein the patient has at least one geographic atrophy lesion that prior to receiving a compound of Formula I is increasing in size at a rate of at least 1 mm2per year.

21. The method of any one of claims 1-19, wherein the patient has at least one geographic atrophy lesion that prior to receiving a compound of Formula I is increasing in size at a rate of at least 2 mm2per year.

22. The method of any one of claims 1 -19, wherein the patient has at least one geographic atrophy lesion that prior to receiving a compound of Formula I is increasing in size at a rate of at least 5 mm2per year.

23. The method of any one of claims 1-22, wherein the patient experiences at least a 10% reduction in rate at which the size of a geographic atrophy lesion has increased over the prior 1 year, due to the patient receiving a compound of Formula I.

24. The method of any one of claims 1-22, wherein the patient experiences at least a 20% reduction in rate at which the size of a geographic atrophy lesion has increased over the prior 1 year, due to the patient receiving a compound of Formula I.

25. The method of any one of claims 1-22, wherein the patient experiences at least a 50% reduction in rate at which the size of a geographic atrophy lesion has increased over the prior 1 year, due to the patient receiving a compound of Formula I.

26. The method of any one of claims 1-23, wherein the patient experiences at least an 80% reduction in rate at which the size of a geographic atrophy lesion has increased over the prior 1 year, due to the patient receiving a compound of Formula I.

27. The method of any one of claims 23-26, wherein said reduction in rate is measured at a time that is 4 months after the patient receives a first dose of a compound of Formula I.

28. The method of any one of claims 23-26, wherein said reduction in rate is measured at a time that is 6 months after the patient receives a first dose of a compound of Formula I.

29. The method of any one of claims 23-26, wherein said reduction in rate is measured at a time that is 12 months after the patient receives a first dose of a compound of Formula I.

30. The method of any one of claims 23-26, wherein said reduction in rate is measured at a time that is 24 months after the patient receives a first dose of a compound of Formula I.

31. The method of any one of claims 1-30, wherein the method provides an improvement in visual acuity characterized by at least a one-line improvement in the patient’s vision measured using a vision chart.

32. The method of any one of claims 1-30, wherein the method results in an improvement in visual acuity characterized by at least a two-line improvement in the patient’s vision measured using a vision chart.

33. The method of any one of claims 1-32, wherein the compound is administered orally to the patient.

34. The method of any one of claims 1-32, wherein the compound is administered by injection into an eye of the patient.

35. The method of any one of claims 1-32, wherein the compound is administered by intravitreal injection into an eye of the patient.

36. The method of any one of claims 1-35, wherein the compound is administered to the patient in the morning.

37. The method of any one of claims 1-36, wherein the compound is administered to the patient in the patient in the evening.

38. The method of any one of claims 1-37, wherein the patient is a human.

39. The method of any one of claims 1-37, wherein the patient is an adult human.

40. The method of any one of claims 1-39, wherein the patient has neovascular age-related macular degeneration.

41. The method of any one of claims 1-39, wherein the patient has neovascular age-related macular degeneration in an eye other than the eye with geographic atrophy.

42. The method of any one of claims 1 -39, wherein the patient does not have neovascular age- related macular degeneration.

43. The method of any one of claims 1-42, wherein the compound is a compound of Formula I in free base form.

44. The method of any one of claims 1-43, wherein R1is methyl.

45. The method of any one of claims 1-43, wherein n is 0.

46. The method of any one of claims 1-45, wherein R2is methyl.

47. The method of any one of claims 1 -46, wherein R3is C3 alkyl.

48. The method of any one of claims 1-46, wherein R3is -CH2CH2CH3.

49. The method of any one of claims 1-48, wherein R4is C1-6 alkyl.

50. The method of any one of claims 1-48, wherein R4is ethyl.

51. The method of any one of claims 1-48, wherein R4is hydrogen.

52. The method of any one of claims 1-51, wherein R5is C1-6 alkyl.

53. The method of any one of claims 1-51, wherein R5is ethyl.

54. The method of any one of claims 1-51, wherein R5is C1-4 alkoxyl.

55. The method of any one of claims 1-51, wherein R5is methoxy.

56. The method of any one of claims 1-42, wherein the compound ipharmaceutically acceptable salt thereof.

57. The method of any one of claims 1-42, wherein the compound58. The method of any one of claims 1-42, wherein the compound ipharmaceutically acceptable salt thereof.

59. The method of any one of claims 1-42, wherein the compound i

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