Methods and compositions for treating and preventing the progression of intermediate age-related macular degeneration and related conditions

Abstract

The invention provides methods, compositions, and kits containing a first therapeutic agent that is a substituted 2,3-dimethoxyquinone of Formula I, a compound of Formula II, or a pharmaceutically acceptable salt thereof, for treating and / or preventing the progression of intermediate age-related macular degeneration and / or other conditions.

Description

METHODS AND COMPOSITIONS FOR TREATING AND PREVENTING THE PROGRESSION OF INTERMEDIATE AGE-RELATED MACULAR DEGENERATION AND RELATED CONDITIONSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to United States Provisional Patent Application serial number 63 / 691,862, filed September 6, 2024; 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 first therapeutic agent that is a substituted 2,3 -dimethoxy quinone of Formula I, a compound of Formula II, or a pharmaceutically acceptable salt thereof, for treating and / or preventing the progression of intermediate age-related macular degeneration and / or other conditions.BACKGROUND

[0003] Age-related macular degeneration (AMD) is a leading cause of central visual impairment, which, in advanced stages, can result in blurred vision or complete loss of vision in the center of the visual field. It is particularly prevalent among older individuals. Existing therapies for AMD are not effective for all patients and / or have undesirable side effects. For example, vitamin and mineral supplementation was reported to reduce the likelihood of disease progression, but only for a fraction of the patients tested. Typical treatments for advanced AMD require frequent intravitreal injections, which carry a risk of intraocular infection and can be costly, uncomfortable for patients, and time-consuming for caregivers.

[0004] Exemplary compounds that inhibit reduction-oxidation factor 1-apurunic / apyrimidinic endonuclease (Ref-l / APEl) are described in, for example, international patent application publication WO 2009 / 042544, WO 2009 / 042542, WO 2012 / 167122, WO 2018 / 175429, WO 2018 / 194976, WO 2019 / 157163, WO 2012 / 162589, and WO 2022 / 232597. The compound (E)-2-((4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-l,4-dien-l- yl)methylene)undecanoic acid, which has the following chemical formula, is described in, for example, WO 2009 / 042542 and WO 2022 / 232597:133482596 399256-OPI-012WO (211257)Procedures for treating, preventing, and / or preventing the progression of intermediate age-related macular degeneration and / or other disorders using a Ref-l / APEl inhibitor compound would benefit patients, particularly if they allow for systemic, oral treatment.

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

[0006] The invention provides methods, compositions, and kits containing a first therapeutic agent that is a substituted 2,3-dimethoxyquinone of Formula I, a compound of Formula IT, or a pharmaceutically acceptable salt thereof, for treating and / or preventing the progression of intermediate age-related macular degeneration and / or other conditions.

[0007] For example, one aspect of the invention provides a method of treating intermediate age-related macular degeneration, comprising orally administering to a human patient in need thereof a therapeutically effective amount of a first therapeutic agent to thereby treat intermediate age-related macular degeneration, wherein the first therapeutic agent is a compound of Formula I or II or a pharmaceutically acceptable salt thereof:(I) (II) wherein the variables are as defined in the detailed description. Exemplary compounds of Formula II are also provided in the detailed description. The compound of Formula I or II or a pharmaceutically acceptable salt thereof may be formulated in a pharmaceutical composition. Additional features of the method are described in the detailed description.233482596 399256-OPI-012WO (211257)

[0008] In certain embodiments, the method further comprises the step of identifying a human patient with intermediate age-related macular degeneration that would benefit from therapy that treats intermediate age-related macular degeneration.

[0009] Another aspect of the invention provides a method of preventing the progression of intermediate age-related macular degeneration, comprising orally administering to a human patient in need thereof a therapeutically effective amount of a first therapeutic agent to thereby prevent the progression of intermediate age-related macular degeneration, wherein the first therapeutic agent is a compound of Formula I or II or a pharmaceutically acceptable salt thereof:wherein the variables are as defined in the detailed description. Exemplary compounds of Formula II are also provided in the detailed description. The compound of Formula I or II or a pharmaceutically acceptable salt thereof may be formulated in a pharmaceutical composition. Additional features of the method are described in the detailed description.

[0010] In certain embodiments, the method further comprises the step of identifying a human patient with intermediate age-related macular degeneration that would benefit from therapy that prevents the progression of intermediate age-related macular degeneration.

[0011] Another aspect of the invention provides a method of reducing the rate of progression of intermediate age-related macular degeneration, comprising orally administering to a human patient in need thereof a therapeutically effective amount of a first therapeutic agent to thereby reduce the rate of progression of intermediate age-related macular degeneration, wherein the first therapeutic agent is a compound of Formula I or II or a pharmaceutically acceptable salt thereof333482596 399256-OPI-012WO (211257)wherein the variables are as defined in the detailed description. Exemplary compounds of Formula II are also provided in the detailed description. The compound of Formula I or II or a pharmaceutically acceptable salt thereof may be formulated in a pharmaceutical composition. Additional features of the method are described in the detailed description.

[0012] In certain embodiments, the method further comprises the step of identifying a human patient with intermediate age-related macular degeneration that would benefit from therapy that reduces the rate of progression of intermediate age-related macular degeneration.

[0013] In certain embodiments, the effects of the above methods may be observed on (i) geographic atrophy, vision loss, and / or loss of visual acuity in the human patient and / or (ii) photoreceptors, choriocapillaries, retinal pigment epithelium cells, and / or retinal degradation (as measured by electroradiography, optical coherence tomography, fluorescein angiography, and or retinal thickness) in the eye of the human patient.BRIEF DESCRIPTION OF FIGURES

[0014] Fig. 1A shows an XRPD pattern of Compound 1 hemicalcium salt monohydrate obtained as described in Example 3.

[0015] Fig. IB shows an overlay of a thermo-gravimetric (TG) thermogram and a differential scanning calorimetry (DSC) thermogram of Compound 1 hemicalcium salt monohydrate obtained as described in Example 3.

[0016] Fig. 1C shows a dynamic vapor sorption (DVS) spectrum of Compound 1 hemicalcium salt monohydrate obtained as described in Example 3.

[0017] Fig. 2A shows an XRPD pattern of Compound 1 hemicalcium salt monohydrate obtained as described in Example 4.433482596 399256-OPI-012WO (211257)

[0018] Fig. 2B shows aJH NMR spectrum of Compound 1 hemicalcium salt monohydrate obtained as described in Example 4.

[0019] Fig. 2C shows a thermo-gravimetric (TG) thermogram of Compound 1 hemicalcium salt monohydrate obtained as described in Example 4.

[0020] Fig. 2D shows a DSC thermogram of Compound 1 hemicalcium salt monohydrate obtained as described in Example 4.

[0021] Fig. 3A shows an XRPD pattern of the anhydrous and predominantly amorphous Compound 1 hemicalcium salt obtained as described in Example 5.

[0022] Fig. 3B shows an overlay of a TG thermogram and a DSC thermogram of the anhydrous and predominantly amorphous Compound 1 hemicalcium salt obtained as described in Example 5.

[0023] Fig. 4 shows results for retinal function as measured by scotopic electroradiography (ERG), as described in Example 2, where results are presented in the table in the order of, from left to right at each stimulus luminace value, G1 -propylene glycol (vehicle control), G2- APX3330, G3-APX2009, G4-APX2014, and G5-Anti C5 antibody).

[0024] Fig. 5 shows results for retinal function as measured by photopic ERG, as described in Example 2, where results are presented in the table in the order of, from left to right at each stimulus luminace value, Gl-propylene glycol (vehicle control), G2-APX3330, G3-APX2009, G4-APX2014, and G5-Anti C5 antibody).

[0025] Fig. 6 shows results for retinal thickness as measured by optical coherence tomography (OCT), as described in Example 2.DETAILED DESCRIPTION OF THE INVENTION

[0026] The invention provides methods, compositions, and kits containing a first therapeutic agent that is a substituted 2,3 -dimethoxy quinone of Formula 1, a compound of Formula II, or a pharmaceutically acceptable salt thereof, for treating and / or preventing the progression of intermediate age-related macular degeneration and / or other conditions:533482596 399256-OPI-012WO (211257)wherein the variables are as defined herein below.

[0027] In certain embodiments, the effects of the above methods may be observed on (i) geographic atrophy, vision loss, and / or loss of visual acuity in the human patient and / or (ii) photoreceptors, choriocapillaries, retinal pigment epithelium cells, and / or retinal degradation (as measured by electroradiography, optical coherence tomography, fluorescein angiography, and or retinal thickness) in the eye of the human patient. In certain embodiments, the first therapeutic agent is a compound of Formula I. In certain embodiments, the first therapeutic agent is a calcium salt of the compound of Formula I. In certain embodiments, the method further comprises administering to the patient an additional therapeutic agent that is a vitamin, mineral, vascular endothelial growth factor inhibitor, complement inhibitor, retinal gene therapy, and / or retinal cell therapy. Additional features of the method are described in the detailed description.

[0028] 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

[0029] To facilitate an understanding of the present invention, a number of terms and phrases are defined below.

[0030] The terms “a,” “an” and “the” as used herein mean “one or more” and include the plural unless the context is inappropriate.

[0031] 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.

[0032] 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.,633482596 399256-OPI-012WO (211257)murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans.

[0033] 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.

[0034] 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.

[0035] 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] ,

[0036] 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.733482596 399256-OPI-012WO (211257)

[0037] Examples of bases include, but are not limited to, alkali metals (e.g., sodium) hydroxides, alkaline earth metals (e.g., magnesium or calcium), hydroxides, ammonia, and compounds of formula NW3, wherein W is C1-4 alkyl, and the like.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.833482596 399256-OPI-012WO (211257)

[0042] 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

[0043] One aspect of the invention provides methods using a first therapeutic agent that is a substituted 2,3 -dimethoxy quinone of Formula I, a compound of Formula II, or a pharmaceutically acceptable salt thereof, for treating and / or preventing the progression of intermediate age-related macular degeneration. 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

[0044] One aspect of the invention provides a method of treating intermediate age-related macular degeneration, comprising orally administering to a human patient in need thereof a therapeutically effective amount of a first therapeutic agent to thereby treat intermediate age- related macular degeneration, wherein the first therapeutic agent is a compound of Formula I or II or a pharmaceutically acceptable salt thereofwherein: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 2.933482596 399256-OPI-012WO (211257)

[0045] The method may be further characterized by additional features, such as additional steps that the method comprises. For example, in certain embodiments, the method further comprises the step of identifying a human patient with intermediate age-related macular degeneration that would benefit from therapy that treats intermediate age-related macular degeneration.

[0046] In certain embodiments, the first therapeutic agent is a compound of Formula I or a pharmaceutically acceptable salt thereof. In certain embodiments, the first therapeutic agent is a compound of Formula II or a pharmaceutically acceptable salt thereof.B. Second Method

[0047] Another aspect of the invention provides a method of preventing the progression of intermediate age-related macular degeneration, comprising orally administering to a human patient in need thereof a therapeutically effective amount of a first therapeutic agent to thereby prevent the progression of intermediate age-related macular degeneration, wherein the first therapeutic agent is a compound of Formula I or II or a pharmaceutically acceptable salt thereof:(I) (II) wherein:R1represents independently for each occurrence C1-4 alkyl;R2is Ci-4 alkyl;R3is Ci-6 alkyl;R4is Ci-6 alkyl or hydrogen;R is Ci-6 alkyl or Ci-4alkoxyl; and n is 0, 1, or 2.

[0048] The method may be further characterized by additional features, such as additional steps that the method comprises. For example, in certain embodiments, the method further comprises the step of identifying a human patient with intermediate age-related macular33482596 399256-OPI-012WO (211257)degeneration that would benefit from therapy that prevents the progression of intermediate age- related macular degeneration.

[0049] In certain embodiments, the first therapeutic agent is a compound of Formula I or a pharmaceutically acceptable salt thereof. In certain embodiments, the first therapeutic agent is a compound of Formula II or a pharmaceutically acceptable salt thereof.C. Third Method

[0050] Another aspect of the invention provides a method of reducing the rate of progression of intermediate age-related macular degeneration, comprising orally administering to a human patient in need thereof a therapeutically effective amount of a first therapeutic agent to thereby reduce the rate of progression of intermediate age-related macular degeneration, wherein the first therapeutic agent is a compound of Formula I or II or a pharmaceutically acceptable salt thereof:(I) (II) 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-4 alkoxyl; and n is 0, 1, or 2.

[0051] The method may be further characterized by additional features, such as additional steps that the method comprises. For example, in certain embodiments, the method further comprises the step of identifying a human patient with intermediate age-related macular degeneration that would benefit from therapy that prevents the progression of intermediate age- related macular degeneration.1133482596 399256-OPI-012WO (211257)

[0052] The method may be further characterized by effects of the method. For example, in certain embodiments, the method reduces the rate of development of geographic atrophy in the human patient. In certain embodiments, the method reduces the rate of loss of photoreceptors in the eye of the human patient. In certain embodiments, the method reduces the rate of loss of choriocapillaries in the eye of the human patient. In certain embodiments, the method reduces the rate of loss of retinal pigment epithelium cells in the eye of the human patient. In certain embodiments, the method reduces the rate of vision loss by the patient. In certain embodiments, the method reduces the rate of loss of visual acuity by the patient.

[0053] In certain embodiments, the method reduces the rate of retinal degradation in the eye of the human patient. The retinal degradation in the eye of the human patient may be measured by one or more of a variety of methods. For example, in certain embodiments, the retinal degradation in the eye of the human patient is measured by electroradiography. In certain embodiments, the retinal degradation in the eye of the human patient is measured by optical coherence tomography. In certain embodiments, the retinal degradation in the eye of the human patient is measured by fluorescein angiography. In certain embodiments, the retinal degradation in the eye of the human patient is measured by retinal thickness.

[0054] In certain embodiments, the first therapeutic agent is a compound of Formula I or a pharmaceutically acceptable salt thereof. In certain embodiments, the first therapeutic agent is a compound of Formula II or a pharmaceutically acceptable salt thereof.D. Fourth Method

[0055] Another aspect of the invention provides a method of treating intermediate age- related macular degeneration, comprising orally administering to a human patient in need thereof therapeutically effective amount of a Ref-l / APEl inhibitor to thereby treat intermediate age- related macular degeneration.

[0056] Another aspect of the invention provides a method of preventing the progression of intermediate age-related macular degeneration, comprising orally administering to a human patient in need thereof a therapeutically effective amount of a Ref- 1 / APE 1 inhibitor to thereby prevent the progression of intermediate age-related macular degeneration.1233482596 399256-OPI-012WO (211257)

[0057] Another aspect of the invention provides a method of reducing the rate of progression of intermediate age-related macular degeneration, comprising orally administering to a human patient in need thereof a therapeutically effective amount of a Ref-l / APEl inhibitor to thereby reduce the rate of progression of intermediate age-related macular degeneration.

[0058] The method may be further characterized by additional features, such as additional steps that the method comprises. For example, in certain embodiments, the method further comprises the step of identifying a human patient with intermediate age-related macular degeneration that would benefit from therapy that treats, prevents, or reduces the rate of progression of intermediate age-related macular degeneration.

[0059] In certain embodiments, the Ref-l / APEl inhibitor is a first therapeutic agent. In certain embodiments, the method further comprises administering to the patient an additional therapeutic agent.E. Additional Features of the First, Second, and Fourth Therapeutic Methods

[0060] The First, Second, and Fourth Therapeutic Methods may be further characterized by additional features, such as the effects of the methods. For example, in certain embodiments, the method prevents development of geographic atrophy in the human patient. In certain embodiments, the method prevents loss of photoreceptors in the eye of the human patient. In certain embodiments, the method prevents loss of choriocapillaries in the eye of the human patient. In certain embodiments, the method prevents loss of retinal pigment epithelium cells in the eye of the human patient. In certain embodiments, the method prevents vision loss by the patient. In certain embodiments, the method prevents loss of visual acuity by the patient.

[0061] In certain embodiments, the method prevents retinal degradation in the eye of the human patient. The retinal degradation in the eye of the human patient may be measured by one or more of a variety of methods. For example, in certain embodiments, the retinal degradation in the eye of the human patient is measured by electroradiography. In certain embodiments, the retinal degradation in the eye of the human patient is measured by optical coherence tomography. In certain embodiments, the retinal degradation in the eye of the human patient is measured by fluorescein angiography. In certain embodiments, the retinal degradation in the eye of the human patient is measured by retinal thickness.1333482596 399256-OPI-012WO (211257)F. General Considerations for Therapeutic Methods

[0062] General considerations that may be applied to therapeutic methods described herein (e.g., the methods described in Parts A through E, above) are provided below and include, for example, any additional effects produced by the first therapeutic agent, the dosing regimen of the first therapeutic agent, the identity of the human patient, and the identity of the first therapeutic agent. A more thorough description of such features is provided below. The invention embraces all permutations and combinations of these features.Additional Effects Produced by the First Therapeutic Agent

[0063] The methods may be further characterized according to any additional effects produced by the first therapeutic agent on the human patient. For example, in certain embodiments, any increase in blood plasma concentration of alanine aminotransferase in the human patient due to the first therapeutic agent is no greater than 50%. In certain embodiments, any increase in blood plasma concentration of alanine aminotransferase in the human patient due to the first therapeutic agent is no greater than 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 percent. In certain embodiments, any increase in blood plasma concentration of alanine aminotransferase in the human patient due to the first therapeutic agent is no greater than 30, 40, 50, 60, 70, 80 or 90 percent.

[0064] In certain embodiments, blood plasma concentration of alanine aminotransferase in the human patient is reduced due to the first therapeutic agent. In certain embodiments, the reduction is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 15 percent. In certain embodiments, the reduction is at least 10 percent.

[0065] In certain embodiments, any increase in blood plasma concentration of aspartate aminotransferase in the human patient due to the first therapeutic agent is no greater than 50%. In certain embodiments, any increase in blood plasma concentration of aspartate aminotransferase in the human patient due to the first therapeutic agent is no greater than 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 25 percent. In certain embodiments, any increase in blood plasma concentration of aspartate aminotransferase in the human patient due to the first therapeutic agent is no greater than 30, 40, 50, 60, 70, 80 or 90 percent.1433482596 399256-OPI-012WO (211257)

[0066] In certain embodiments, blood plasma concentration of aspartate aminotransferase in the human patient is reduced due to the first therapeutic agent. In certain embodiments, the reduction is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 15 percent. In certain embodiments, the reduction is at least 10 percent.

[0067] In certain embodiments, any reduction in glomerular filtration rate in the human patient is no greater than 25%. In certain embodiments, any reduction in glomerular filtration rate in the human patient is no greater than 15%. In certain embodiments, any reduction in glomerular filtration rate in the human patient is no greater than 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 percent.

[0068] In certain embodiments, the incidence of any eye disorder due to the first therapeutic agent occurs no more frequently than one human patient for every ten human patients subjected to the same treatment. In certain embodiments, the incidence of any eye disorder due to the first therapeutic agent occurs no more frequently than one human patient for every twenty human patients subjected to the same treatment. In certain embodiments, the incidence of any eye disorder due to the first therapeutic agent occurs no more frequently than one human patient for every 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, or 40 human patients subjected to the same treatment.

[0069] In certain embodiments, the incidence of any gastrointestinal disorder due to the first therapeutic agent occurs no more frequently than one human patient for every ten human patients subjected to the same treatment. In certain embodiments, the incidence of any gastrointestinal disorder due to the first therapeutic agent occurs no more frequently than one human patient for every 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, or 40 human patients subjected to the same treatment.

[0070] In certain embodiments, the incidence of any nervous system disorder due to the first therapeutic agent occurs no more frequently than one human patient for every twenty human patients subjected to the same treatment. In certain embodiments, the incidence of any nervous system disorder due to the first therapeutic agent occurs no more frequently than one human patient for every 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, or 40 human patients subjected to the same treatment.1533482596 399256-OPI-012WO (211257)Dosing Regimen of the First Therapeutic Agent

[0071] The methods may be further characterized according to the dosing regimen. For example, in certain embodiments, a first dose of the first therapeutic agent and a second dose of the first therapeutic agent are orally administered to the human patient on the same day. In certain embodiments, the first therapeutic agent is orally administered to a human patient only once per day.

[0072] In certain embodiments, the first therapeutic agent is orally administered to the human patient in an amount of from about 480 mg to about 600 mg per day. In certain embodiments, the first therapeutic agent is orally administered to the human patient in an amount of about 600 mg per day.

[0073] In certain embodiments, about 360 mg of the first therapeutic agent is orally administered to the human patient in the morning, and about 240 mg of the first therapeutic agent is orally administered to the human patient in the evening. In certain embodiments, about 360 mg of the first therapeutic agent is orally administered to the human patient, and then at a time that is from about 8 hours to about 16 hours later about 240 mg of the first therapeutic agent is orally administered to the human patient. In certain embodiments, about 360 mg of the first therapeutic agent is orally administered to the human patient, and then at a time that is from about 10 hours to about 14 hours later about 240 mg of the first therapeutic agent is orally administered to the human patient.

[0074] In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the human patient in the morning, and about 360 mg of the first therapeutic agent is orally administered to the human patient in the evening. In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the human patient, and then at a time that is from about 8 hours to about 16 hours later about 360 mg of the first therapeutic agent is orally administered to the human patient. In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the human patient, and then at a time that is from about 10 hours to about 14 hours later about 360 mg of the first therapeutic agent is orally administered to the human patient.

[0075] In certain embodiments, about 300 mg of the first therapeutic agent is orally administered to the human patient in the morning, and about 300 mg of the first therapeutic agent1633482596 399256-OPI-012WO (211257)is orally administered to the human patient in the evening. In certain embodiments, about 300 mg of the first therapeutic agent is orally administered to the human patient, and then at a time that is from about 8 hours to about 16 hours later about 300 mg of the first therapeutic agent is orally administered to the human patient. In certain embodiments, about 300 mg of the first therapeutic agent is orally administered to the human patient, and then at a time that is from about 10 hours to about 14 hours later about 300 mg of the first therapeutic agent is orally administered to the human patient.

[0076] In certain embodiments, if the human patient experiences an adverse event due to the first therapeutic agent, then thereafter for a period of at least two days the first therapeutic agent is orally administered to the human patient in the reduced-daily amount of from about 300 mg to about 480 mg per day. In certain embodiments, if the human patient experiences an adverse event due to the first therapeutic agent, then thereafter for a period of at least two days the first therapeutic agent is orally administered to the human patient in the reduced-daily amount of about 480 mg per day.

[0077] In certain embodiments, the first therapeutic agent is orally administered to a human patient in an amount of about 480 mg per day. In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the human patient in the morning, and about 240 mg of the first therapeutic agent is orally administered to the human patient in the evening. In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the human patient, and then at a time that is from about 8 hours to about 16 hours later about 240 mg of the first therapeutic agent is orally administered to the human patient. In certain embodiments, about 240 mg of the first therapeutic agent is orally administered to the human patient, and then at a time that is from about 10 hours to about 14 hours later about 240 mg of the first therapeutic agent is orally administered to the human patient.

[0078] In certain embodiments, if the human patient experiences an adverse event due to the first therapeutic agent, then thereafter for a period of at least two days the first therapeutic agent is orally administered to the human patient in the reduced-daily amount of about 300 mg per day. In certain embodiments, the first therapeutic agent is orally administered to the human patient in the morning.1733482596 399256-OPI-012WO (211257)Duration of Daily Administration of the First Therapeutic Agent

[0079] The methods may be further characterized according to the duration of daily oral administration of the first therapeutic agent.

[0080] In certain embodiments, the first therapeutic agent is orally administered to the human patient daily for at least 1 week. In certain embodiments, the first therapeutic agent is orally administered to the human patient daily for at least 2 weeks. In certain embodiments, the first therapeutic agent is orally administered to the human patient daily for at least 4 weeks. In certain embodiments, the first therapeutic agent is orally administered to the human patient daily for at least 6 weeks. In certain embodiments, the first therapeutic agent is orally administered to the human patient daily for at least 8 weeks. In certain embodiments, the first therapeutic agent is orally administered to the human patient daily for at least 10 weeks. In certain embodiments, the first therapeutic agent is orally administered to the human patient daily for at least 12 weeks. In certain embodiments, of the first therapeutic agent is orally administered to the human patient daily for at least 24 weeks. In certain embodiments, of the first therapeutic agent is orally administered to the human patient daily for at least 36 weeks. In certain embodiments, of the first therapeutic agent is orally administered to the human patient daily for at least 48 weeks. In certain embodiments, of the first therapeutic agent is orally administered to the human patient daily for at least 52 weeks. In certain embodiments, of the first therapeutic agent is orally administered to the human patient daily for at least 96 weeks. In certain embodiments, the first therapeutic agent is orally administered to the human patient daily for at least 30, 32, 34, 36, 38 40, 42, 44, 46, 48, 50, or 52 weeks.

[0081] In certain embodiments, the amount of the first therapeutic agent is orally administered to the human patient daily for at least 1 week. In certain embodiments, the amount of the first therapeutic agent is orally administered to the human patient daily for at least 2 weeks. In certain embodiments, the amount of the first therapeutic agent is orally administered to the human patient daily for at least 4 weeks. In certain embodiments, the amount of the first therapeutic agent is orally administered to the human patient daily for at least 6 weeks. In certain embodiments, the amount of the first therapeutic agent is orally administered to the human patient daily for at least 8 weeks. In certain embodiments, the amount of the first therapeutic agent is orally administered to the human patient daily for at least 10 weeks. In certain1833482596 399256-OPI-012WO (211257)embodiments, the amount of the first therapeutic agent is orally administered to the human patient daily for at least 12 weeks. In certain embodiments, the amount of the first therapeutic agent is orally administered to the human patient daily for at least 24 weeks. In certain embodiments, the amount of the first therapeutic agent is orally administered to the human patient daily for at least 48 weeks. In certain embodiments, the amount of the first therapeutic agent is orally administered to the human patient daily for at least 52 weeks. In certain embodiments, the amount of the first therapeutic agent is orally administered to the human patient daily for at least 96 weeks. In certain embodiments, the amount of the first therapeutic agent is orally administered to the human patient daily for at least 30, 32, 34, 36, 38 40, 42, 44, 46, 48, 50, or 52 weeks.Additional Considerations

[0082] The methods may be further characterized according to additional considerations, such as the form in which the first therapeutic agent is administered and the identity of the human patient.

[0083] For example, in certain embodiments, the first therapeutic agent is orally administered to the patient in the form of an extended-release pharmaceutical composition, in certain embodiments, the first therapeutic agent is orally administered to the patient in the form of an extended-release pharmaceutical composition that provides release of the first therapeutic agent for duration of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours. In certain embodiments, the first therapeutic agent is orally administered to the patient in the form of an immediate- release pharmaceutical composition. Pharmaceutical compositions are described in further detail in Section III below.

[0084] In certain embodiments, the human patient is an adult human patient. In certain embodiments, the human patient is a geriatric human patient.

[0085] Another aspect of the invention provides for the use of the first therapeutic agent described herein in the manufacture of a medicament. In certain embodiments, the medicament is for treating and / or preventing a medical disorder described herein, for example, for treating, preventing, and / or preventing the progression of intermediate age-related macular degeneration and / or other disorders.1933482596 399256-OPI-012WO (211257)

[0086] Another aspect of the invention provides for the use of the first therapeutic agent described herein for treating and / or preventing a medical disorder, such as a medical disorder described herein, for example, for treating, preventing, and / or preventing the progression of intermediate age-related macular degeneration and / or other disorders.Identity of the First Therapeutic Agent

[0087] The methods may be further characterized according to the identity of the first therapeutic agent.A. Compound of Formula I or Pharmaceutically Acceptable Salt Thereof

[0088] In certain embodiments, the first therapeutic agent is a compound of Formula I or a pharmaceutically acceptable salt thereof. In certain embodiments, the first therapeutic agent is a compound of Formula I. In certain embodiments, the first therapeutic agent is a pharmaceutically acceptable salt of the compound of Formula I. In certain embodiments, the first therapeutic agent is an alkaline earth metal salt of the compound of Formula I. In certain embodiments, the first therapeutic agent is a calcium salt of the compound of Formula I.

[0089] In certain embodiments, the first therapeutic agent is crystalline.

[0090] In certain embodiments, the first therapeutic agent is in the form of a hydrate. In certain embodiments, the calcium salt of compound of Formula I is a monohydrate. In certain embodiments, the first therapeutic agent is a hemicalcium salt of a compound of Formula I in the form of a hydrate.

[0091] The hemicalcium salt of a compound of Formula I in the form of a monohydrate may be represented by:

[0092] In certain embodiments, the first therapeutic agent is described by reference to Compound 1. Compound 1 has the following structure:2033482596 399256-OPI-012WO (211257)

[0093] In certain embodiments, the first therapeutic agent is described by reference to a hemicalcium salt of Compound 1. Said hemicalcium salt of Compound 1 may be represented by:

[0094] In certain embodiments, the first therapeutic agent is Compound 1 hemicalcium salt monohydrate in crystalline form. In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 4.1 ± 0.2 degrees 2-theta, a peak at 5.3 ± 0.2 degrees 2-theta, and a peak at 6.3 ± 0.2 degrees 2-theta. In certain embodiments, the XRPD pattern further comprises a peak at 5.8 ± 0.2 degrees 2-theta or a peak at 14.1 ± 0.2 degrees 2-theta. In certain embodiments, the XRPD pattern further comprises a peak at 12.8 ± 0.2 degrees 2-theta or a peak at 13.7 ± 0.2 degrees 2-theta. In certain embodiments, the XRPD pattern further comprises a peak at 10.8 ± 0.2 degrees 2-theta. In certain embodiments, the XRPD pattern further comprises a peak at 6.1 ± 0.2 degrees 2-theta or a peak at 11.4 ± 0.2 degrees 2-theta. In certain embodiments, the XRPD pattern further comprises a peak at 17.6 ± 0.2 degrees 2-theta or a peak at 20.3 ± 0.2 degrees 2-theta. In certain embodiments, the XRPD pattern further comprises a peak at 3.0 ± 0.2 degrees 2-theta or a peak at 12.3 ± 0.2 degrees 2-theta. In certain embodiments, the XRPD pattern further comprises a peak at 11.4 ± 0.2 degrees 2-theta, a peak at 17.6 ± 0.2 degrees 2-theta, and a peak at 21.9 ± 0.2 degrees 2-theta.

[0095] In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 4.1 ± 0.2 degrees 2-theta, a peak at 5.3 ± 0.2 degrees 2-theta, and a peak at 6.3 ± 0.2 degrees 2-theta. In certain embodiments, the XRPD pattern further comprises a peak at 5.8 ± 0.2 degrees 2-theta or a peak at 13.7 ± 0.2 degrees 2- theta. In certain embodiments, the XRPD pattern further comprises a peak at 12.8 ± 0.2 degrees21 33482596 399256-OPI-012WO (211257)2-theta or a peak at 14.1 ± 0.2 degrees 2-theta. In certain embodiments, the XRPD pattern further comprises a peak at 12.3 ± 0.2 degrees 2-theta. In certain embodiments, the XRPD pattern further comprises a peak at 11.4 ± 0.2 degrees 2-theta. In certain embodiments, the XRPD pattern further comprises a peak at 10.8 ± 0.2 degrees 2-theta.

[0096] In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 4.1 ± 0.2 degrees 2-theta, a peak at 5.4 ± 0.2 degrees 2-theta, and a peak at 6.4 ± 0.2 degrees 2-theta. In certain embodiments, the XRPD pattern further comprises a peak at 5.8 ± 0.2 degrees 2-theta or a peak at 13.8 ± 0.2 degrees 2- theta. In certain embodiments, the XRPD pattern further comprises a peak at 12.8 ± 0.2 degrees 2-theta or a peak at 14.2 ± 0.2 degrees 2-theta. In certain embodiments, the XRPD pattern further comprises a peak at 12.3 ± 0.2 degrees 2-theta. In certain embodiments, the XRPD pattern further comprises a peak at 12.0 ± 0.2 degrees 2-theta or a peak at 11.4 ± 0.2 degrees 2-theta. In certain embodiments, the XRPD pattern further comprises a peak at 10.8 ± 0.2 degrees 2-theta or a peak at 20.9 ± 0.2 degrees 2-theta. In certain embodiments, the XRPD pattern further comprises a peak at 13.1 ± 0.2 degrees 2-theta, a peak at 17.6 ± 0.2 degrees 2-theta, and a peak at 23.7 ± 0.2 degrees 2-theta.

[0097] In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 4.1 ± 0.2 degrees 2-theta, a peak at 5.3 ± 0.2 degrees 2-theta, and a peak at 6.3 ± 0.2 degrees 2-theta, wherein the peak at 4.1 ± 0.2 degrees 2- theta, the peak at 5.3 ± 0.2 degrees 2-theta, and the peak at 6.3 ± 0.2 degrees 2-theta, have a relative peak intensity (%) of greater than 30%. In certain embodiments, the XRPD pattern further comprises a peak at 5.8 ± 0.2 degrees 2-theta or a peak at 14.1 ± 0.2 degrees 2-theta, wherein the peak at 5.8 ± 0.2 degrees 2-theta and the peak at 14.1 ± 0.2 degrees 2-theta have a relative peak intensity (%) of greater than 15%. In certain embodiments, the XRPD pattern further comprises a peak at 12.8 ± 0.2 degrees 2-theta or a peak at 13.7 ± 0.2 degrees 2-theta, wherein the peak at 12.8 ± 0.2 degrees 2-theta and the peak at 13.7 ± 0.2 degrees 2-theta have a relative peak intensity (%) of greater than 10%. In certain embodiments, the XRPD pattern further comprises a peak at 10.8 ± 0.2 degrees 2-theta, wherein the peak has a relative peak intensity (%) of greater than 10%. In certain embodiments, the XRPD pattern further comprises a peak at 6.1 ± 0.2 degrees 2-theta or a peak at 11.4 ± 0.2 degrees 2-theta, wherein the peak at 6.12233482596 399256-OPI-012WO (211257)± 0.2 degrees 2-theta and the peak at 1 1 .4 ± 0.2 degrees 2-theta have a relative peak intensity (%) of greater than 10%. In certain embodiments, the XRPD pattern further comprises a peak at 17.6 ± 0.2 degrees 2-theta or a peak at 20.3 ± 0.2 degrees 2-theta, wherein the peak at 17.6 ± 0.2 degrees 2-theta and the peak at 20.3 ± 0.2 degrees 2-theta have a relative peak intensity (%) of greater than 8%. In certain embodiments, the XRPD pattern further comprises a peak at 3.0 ± 0.2 degrees 2-theta or a peak at 12.3 ± 0.2 degrees 2-theta, wherein the peak at 3.0 ± 0.2 degrees 2- theta and the peak at 12.3 ± 0.2 degrees 2-theta have a relative peak intensity (%) of greater than 5%. In certain embodiments, the XRPD pattern further comprises a peak at 11.4 ± 0.2 degrees 2- theta, a peak at 17.6 ± 0.2 degrees 2-theta, or a peak at 21.9 ± 0.2 degrees 2-theta, wherein the peak at 11.4 ± 0.2 degrees 2-theta, the peak at 17.6 ± 0.2 degrees 2-theta, and the peak at 21.9 ± 0.2 degrees 2-theta have a relative peak intensity (%) of greater than 5%.

[0098] In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 4.1 ± 0.2 degrees 2-theta, a peak at 5.4 ± 0.2 degrees 2-theta, and a peak at 6.4 ± 0.2 degrees 2-theta, wherein the peak at 4.1 ± 0.2 degrees 2- theta, the peak at 5.4 ± 0.2 degrees 2-theta, and the peak at 6.4 ± 0.2 degrees 2-theta have a relative peak intensity (%) of greater than 30%. In certain embodiments, the XRPD pattern further comprises a peak at 5.8 ± 0.2 degrees 2-theta or a peak at 13.8 ± 0.2 degrees 2-theta, wherein the peak at 5.8 ± 0.2 degrees 2-theta and the peak at 13.8 ± 0.2 degrees 2-theta have a relative peak intensity (%) of greater than 15%. In certain embodiments, the XRPD pattern further comprises a peak at 12.8 ± 0.2 degrees 2-theta or a peak at 14.2 ± 0.2 degrees 2-theta, wherein the peak at 12.8 ± 0.2 degrees 2-theta and the peak at 14.2 ± 0.2 degrees 2-theta have a relative peak intensity (%) of greater than 10%. In certain embodiments, the XRPD pattern further comprises a peak at 12.3 ± 0.2 degrees 2-theta, wherein the peak has a relative peak intensity (%) of greater than 10%. In certain embodiments, the XRPD pattern further comprises a peak at 12.0 ± 0.2 degrees 2-theta or a peak at 11.4 ± 0.2 degrees 2-theta, wherein the peak at 12.0 ± 0.2 degrees 2-theta and the peak at 11.4 ± 0.2 degrees 2-theta have a relative peak intensity (%) of greater than 10%. In certain embodiments, the XRPD pattern further comprises a peak at 10.8 ± 0.2 degrees 2-theta or a peak at 20.9 ± 0.2 degrees 2-theta, wherein the peak at 10.8 ± 0.2 degrees 2-theta and the peak at 20.9 ± 0.2 degrees 2-theta have a relative peak intensity (%) of greater than 6%. In certain embodiments, the XRPD pattern further comprises a peak at 13.1 ± 0.2 degrees 2-theta, a peak at 17.6 ± 0.2 degrees 2-theta, or a peak at 23.7 ± 0.22333482596 399256-OPI-012WO (211257)degrees 2-theta, wherein the peak at 13.1 ± 0.2 degrees 2-theta, the peak at 17.6 ± 0.2 degrees 2- theta, and the peak at 23.7 ± 0.2 degrees 2-theta have a relative peak intensity (%) of greater than 5%.

[0099] In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 6.3 ± 0.2 degrees 2-th eta. In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 5.8 ± 0.2 degrees 2-theta. In certain embodiments, the crystalline Compound 1 hemi calcium salt monohydrate exhibits an XRPD pattern comprising a peak at 13.7 ± 0.2 degrees 2-theta. In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 14.1 ± 0.2 degrees 2-theta.

[0100] In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 6.3 ± 0.2 degrees 2-theta and a peak at 5.8 ± 0.2 degrees 2-theta. In certain embodiments, the crystalline Compound 1 hemi calcium salt monohydrate exhibits an XRPD pattern comprising a peak at 6.3 ± 0.2 degrees 2-theta and a peak at 14.1 ± 0.2 degrees 2-theta. In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 6.3 ± 0.2 degrees 2-theta, a peak at 5.8 ± 0.2 degrees 2-theta, and a peak at 14.1 ± 0.2 degrees 2-theta. In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 5.8 ± 0.2 degrees 2-theta, a peak at 6.3 ± 0.2 degrees 2-theta, and a peak at 13.7 ± 0.2 degrees 2-theta. In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 5.8 ± 0.2 degrees 2-theta, a peak at 6.3 ± 0.2 degrees 2-theta, a peak at 13.7 ± 0.2 degrees 2-theta, or a peak at 14.1 ± 0.2 degrees 2-theta. In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 5.8 ± 0.2 degrees 2-theta, a peak at 6.3 ± 0.2 degrees 2-theta, a peak at 13.7 ± 0.2 degrees 2-theta, and a peak at 14.1 ± 0.2 degrees 2- theta.

[0101] In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 5.8 ± 0.2 degrees 2-theta and a peak at 6.3 ± 0.2 degrees 2-theta. In certain embodiments, the XRPD pattern further comprises a peak at 13.7 ± 0.2 degrees 2-theta or a peak at 14.1 ± 0.2 degrees 2-theta.2433482596 399256-OPI-012WO (211257)

[0102] In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 5.8 ± 0.2 degrees 2-theta and a peak at 6.3 ± 0.2 degrees 2-theta. In certain embodiments, the XRPD pattern further comprises a peak at 13.7 ± 0.2 degrees 2-theta or a peak at 14.1 ± 0.2 degrees 2-theta.

[0103] In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 6.4 ± 0.2 degrees 2-theta. In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 5.8 ± 0.2 degrees 2-theta. In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 13.8 ± 0.2 degrees 2-theta. In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 14.2 ± 0.2 degrees 2-theta.

[0104] In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 6.4 ± 0.2 degrees 2-theta and a peak at 5.8 ± 0.2 degrees 2-theta. In certain embodiments, the crystalline Compound 1 hemi calcium salt monohydrate exhibits an XRPD pattern comprising a peak at 6.4 ± 0.2 degrees 2-theta and a peak at 14.2 ± 0.2 degrees 2-theta. In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 6.4 ± 0.2 degrees 2-theta, a peak at 5.8 ± 0.2 degrees 2-theta, and a peak at 14.2 ± 0.2 degrees 2-theta. In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 5.8 ± 0.2 degrees 2-theta, a peak at 6.4 ± 0.2 degrees 2-theta, and a peak at 13.8 ± 0.2 degrees 2-theta. In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 6.4 ± 0.2 degrees 2-theta, a peak at 5.8 ± 0.2 degrees 2-theta, a peak at 13.8 ± 0.2 degrees 2-theta, or a peak at 14.2 ± 0.2 degrees 2-theta. In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 6.4 ± 0.2 degrees 2-theta, a peak at 5.8 ± 0.2 degrees 2-theta, a peak at 13.8 ± 0.2 degrees 2-theta, and a peak at 14.2 ± 0.2 degrees 2- theta.

[0105] In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 5.8 ± 0.2 degrees 2-theta and a peak at 6.4 ± 0.22533482596 399256-OPI-012WO (211257)degrees 2-theta. In certain embodiments, the XRPD pattern further comprises a peak at 13.8 ± 0.2 degrees 2-theta or a peak at 14.2 ± 0.2 degrees 2-theta.

[0106] In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 5.8 ± 0.2 degrees 2-theta and a peak at 6.4 ± 0.2 degrees 2-theta. In certain embodiments, the XRPD pattern further comprises a peak at 13.8 ± 0.2 degrees 2-theta or a peak at 14.2 ± 0.2 degrees 2-theta.

[0107] In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 6.3 ± 0.2 degrees 2-theta and 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, or 9 peaks of Table 1 in Example 3. In certain embodiments, the calcium salt of compound of Formula I exhibits an XRPD pattern comprising a peak at 6.3 ± 0.2 degrees 2-theta and 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, or 9 peaks of the following peaks: a peak at 4.1 ± 0.2 degrees 2-theta, a peak at5.3 ± 0.2 degrees 2-theta, a peak at 5.8 ± 0.2 degrees 2-theta, a peak at 6.1 ± 0.2 degrees 2-theta, a peak at 10.8 ± 0.2 degrees 2-theta, a peak at 11.4 ± 0.2 degrees 2-theta, a peak at 12.8 ± 0.2 degrees 2-theta, a peak at 13.7 ± 0.2 degrees 2-theta, and 14.1 ± 0.2 degrees 2-theta.

[0108] In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 6.4 ± 0.2 degrees 2-theta and 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, or 9 peaks of Table 1 in Example 3. In certain embodiments, the calcium salt of compound of Formula I exhibits an XRPD pattern comprising a peak at 6.4 ± 0.2 degrees 2-theta and 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, or 9 peaks of the following peaks: a peak at 4.1 ± 0.2 degrees 2-theta, a peak at5.4 ± 0.2 degrees 2-theta, a peak at 5.8 ± 0.2 degrees 2-theta, a peak at 11.4 ± 0.2 degrees 2-theta, a peak at 12.0 ± 0.2 degrees 2-theta, a peak at 12.3 ± 0.2 degrees 2-theta, a peak at 12.8 ± 0.2 degrees 2-theta, a peak at 13.8 ± 0.2 degrees 2-theta, and 14.2 ± 0.2 degrees 2-theta.

[0109] In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak from Table 1 in Example 3 having a relative peak intensity (%) of greater than 30%. In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak from Table 1 in Example 3 having a relative peak intensity (%) of greater than 20%. In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a2633482596 399256-OPI-012WO (211257)peak from Table 1 in Example 3 having a relative peak intensity (%) of greater than 15%. In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak from Table 1 in Example 3 having a relative peak intensity (%) of greater than 5%.

[0110] In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern that is substantially the same as that depicted in Fig. 1A.

[0111] In certain embodiments, the calcium salt of compound of Formula I exhibits a DSC thermogram comprising an endothermic peak having a peak maximum of from about 80 °C to about 84 °C. In certain embodiments, the calcium salt of compound of Formula I exhibits a DSC thermogram comprising an endothermic peak having a peak maximum of from about 81 °C to about 83 °C. In certain embodiments, the calcium salt of compound of Formula I exhibits a DSC thermogram comprising an endothermic peak having a peak maximum of about 83 °C. In certain embodiments, the calcium salt of compound of Formula I exhibits a DSC thermogram comprising an endothermic peak that onsets at about 58 °C. In certain embodiments, the calcium salt of compound of Formula I exhibits a DSC thermogram comprising an endothermic peak that onsets at about 54 °C.

[0112] In certain embodiments, the calcium salt of compound of Formula I exhibits a DSC thermogram comprising an exothermic peak having a peak maximum of from about 213 °C to about 216 °C. In certain embodiments, the calcium salt of compound of Formula I exhibits a DSC thermogram comprising an exothermic peak having a peak maximum of from about 215 °C to about 216 °C. In certain embodiments, the calcium salt of compound of Formula I exhibits a DSC thermogram comprising an exothermic peak having a peak maximum of from about 208 °C to about 216 °C. In certain embodiments, the calcium salt of compound of Formula I exhibits a DSC thermogram comprising an exothermic peak having a peak maximum of from about 210 °C to about 214 °C. In certain embodiments, the calcium salt of compound of Formula I exhibits a DSC thermogram comprising an exothermic peak that onsets at about 212 °C.

[0113] In certain embodiments, the calcium salt of compound of Formula I exhibits a DSC thermogram that is substantially the same as that depicted in Fig. IB. In certain embodiments, the calcium salt of compound of Formula I exhibits a thermo-gravimetric (TG) thermogram that is substantially the same as that depicted in Fig. IB. In certain embodiments, the calcium salt of2733482596 399256-OPI-012WO (211257)compound of Formula T exhibits a DVS spectrum that is substantially the same as that depicted in Fig. 1C.

[0114] In certain embodiments, the calcium salt of compound of Formula I is a monohydrate.

[0115] In certain embodiments, the calcium salt of compound of Formula I obtained is at least about 98% pure by weight. In certain embodiments, the calcium salt of compound of Formula I is at least about 99% pure by weight.

[0116] In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 5.1 ± 0.2 degrees 2- theta, a peak at 5.3 ± 0.2 degrees 2-theta, and a peak at 10.1 ± 0.2 degrees 2-theta. In certain embodiments, the XRPD pattern further comprises a peak at a peak at 8.0 ± 0.2 degrees 2-theta or a peak at 12.8 ± 0.2 degrees 2-theta. In certain embodiments, the XRPD pattern further comprises a peak at 13.3 ± 0.2 degrees 2-theta, a peak at 17.9 ± 0.2 degrees 2-theta, or a peak at19.6 ± 0.2 degrees 2-theta. In certain embodiments, the XRPD pattern further comprises a peak at 14.6 ± 0.2 degrees 2-theta or a peak at 18.5 ± 0.2 degrees 2-theta.

[0117] In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 5.1 ± 0.2 degrees 2-theta, a peak at 5.3 ± 0.2 degrees 2-theta, and a peak at 10.1 ± 0.2 degrees 2-theta, wherein the peak at 5.1 ± 0.2 degrees 2- theta, the peak at 5.3 ± 0.2 degrees 2-theta, and the peak at 10.1 ± 0.2 degrees 2-theta have a relative peak intensity (%) of greater than 25%. In certain embodiments, the XRPD pattern further comprises a peak at 8.0 ± 0.2 degrees 2-theta or a peak at 12.8 ± 0.2 degrees 2-theta, wherein the peak at 8.0 ± 0.2 degrees 2-theta and the peak at 12.8 ± 0.2 degrees 2-theta have a relative peak intensity (%) of greater than 10%. In certain embodiments, the XRPD pattern further comprises a peak at 13.3 ± 0.2 degrees 2-theta, a peak at 17.9 ± 0.2 degrees 2-theta, or a peak at 19.6 ± 0.2 degrees 2-theta, wherein the peak at 13.3 ± 0.2 degrees 2-theta, the peak at 17.9 ± 0.2 degrees 2-theta, and the peak at 19.6 ± 0.2 degrees 2-theta have a relative peak intensity (%) of greater than 10%. In certain embodiments, the XRPD pattern further comprises a peak at 14.6 ± 0.2 degrees 2-theta or a peak at 18.5 ± 0.2 degrees 2-theta, wherein the peak at14.6 ± 0.2 degrees 2-theta or the peak at 18.5 ± 0.2 degrees 2-theta have a relative peak intensity (%) of greater than 8%.2833482596 399256-OPI-012WO (211257)

[0118] In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 10.1 ± 0.2 degrees 2-theta. In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 8.0 ± 0.2 degrees 2-theta. In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 13.3 ± 0.2 degrees 2-theta. In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 14.6 ± 0.2 degrees 2-theta.

[0119] In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 8.0 ± 0.2 degrees 2-theta and a peak at 10.1 ± 0.2 degrees 2-theta. In certain embodiments, the crystalline Compound 1 hemi calcium salt monohydrate exhibits an XRPD pattern comprising a peak at 10.1 ± 0.2 degrees 2-theta and a peak at 14.6 ± 0.2 degrees 2-theta. In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 8.0 ± 0.2 degrees 2-theta, a peak at 10.1 ± 0.2 degrees 2-theta, and a peak at 13.3 ± 0.2 degrees 2-theta. In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 8.0 ± 0.2 degrees 2-theta, a peak at 10.1 ± 0.2 degrees 2-theta, and a peak at 14.6 ± 0.2 degrees 2-theta. In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 8.0 ± 0.2 degrees 2-theta, a peak at 10.1 ± 0.2 degrees 2-theta, a peak at 13.3 ± 0.2 degrees 2-theta, or a peak at 14.6 ± 0.2 degrees 2-theta. In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 8.0 ± 0.2 degrees 2-theta, a peak at 10.1 ± 0.2 degrees 2-theta, a peak at 13.3 ± 0.2 degrees 2-theta, and a peak at 14.6 ± 0.2 degrees 2-theta.

[0120] In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak at 10.1 ± 0.2 degrees 2-theta and 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, or 9 peaks of Table 3 in Example 4. In certain embodiments, the calcium salt of compound of Formula I exhibits an XRPD pattern comprising a peak at 10.1 ± 0.2 degrees 2-theta and 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, or 9 peaks of the following peaks: a peak at 5.1 ± 0.2 degrees 2-theta, a peak at 5.3 ± 0.2 degrees 2-theta, a peak at 7.9 ± 0.2 degrees 2-theta, a peak at 12.8 ± 0.2 degrees 2-theta,2933482596 399256-OPI-012WO (211257)a peak at 13.3 ± 0.2 degrees 2-theta, a peak at 14.6 ± 0.2 degrees 2-theta, a peak at 17.9 ± 0.2 degrees 2-theta, a peak at 18.5 ± 0.2 degrees 2-theta, and a peak at 19.6 ± 0.2 degrees 2-theta.

[0121] In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak from Table 3 in Example 4 having a relative peak intensity (%) of greater than 25%. In certain embodiments, the ccrystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak from Table 3 in Example 4 having a relative peak intensity (%) of greater than 15%. In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern comprising a peak from Table 3 in Example 4 having a relative peak intensity (%) of greater than 12%.

[0122] In certain embodiments, the crystalline Compound 1 hemicalcium salt monohydrate exhibits an XRPD pattern that is substantially the same as that depicted in Fig. 2A.

[0123] In certain embodiments, the calcium salt of compound of Formula I exhibits a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak having a peak maximum of from about 80 °C to about 105 °C. In certain embodiments, the calcium salt of compound of Formula I exhibits a DSC thermogram comprising an endothermic peak having a peak maximum of from about 90 °C to about 105 °C. In certain embodiments, the calcium salt of compound of Formula I exhibits a DSC thermogram comprising an endothermic peak having a peak maximum of from about 95 °C to about 105 °C. In certain embodiments, the calcium salt of compound of Formula I exhibits a DSC thermogram comprising an endothermic peak having a peak maximum of from about 98 °C to about 103 °C. In certain embodiments, the calcium salt of compound of Formula I exhibits a DSC thermogram comprising an endothermic peak having a peak maximum of about 101 °C. In certain embodiments, the calcium salt of compound of Formula I exhibits a DSC thermogram comprising an endothermic peak that onsets at about 77 °C.

[0124] In certain embodiments, the calcium salt of compound of Formula I exhibits a DSC thermogram comprising an exothermic peak having a peak maximum of from about 210 °C to about 216 °C. In certain embodiments, the calcium salt of compound of Formula I exhibits a DSC thermogram comprising an exothermic peak having a peak maximum of from about 212 °C to about 215 °C. In certain embodiments, the calcium salt of compound of Formula I exhibits a DSC thermogram comprising an exothermic peak having a peak maximum of from about 213 °C3033482596 399256-OPI-012WO (211257)to about 215 °C. In certain embodiments, the calcium salt of compound of Formula I exhibits a DSC thermogram comprising an exothermic peak having a peak maximum at about 214 °C. In certain embodiments, the calcium salt of compound of Formula I exhibits a DSC thermogram comprising an exothermic peak that onsets at about 211 °C.

[0125] In certain embodiments, the calcium salt of compound of Formula I exhibits a DSC thermogram that is substantially the same as that depicted in Fig. 2D. In certain embodiments, the calcium salt of compound of Formula I exhibits a thermo-gravimetric (TG) thermogram that is substantially the same as that depicted in Fig. 2C.

[0126] In certain embodiments, the calcium salt of compound of Formula I has a solubility of about 500 pg / mL to about 600 pg / mL at pH 5 and 37 °C, after 4 hours of being added to a pH 5 and 37 °C solution of Fed State Simulated Intestinal Fluid (FeSSIF) when determined by high- performance liquid chromatography (HPLC) at 236 nm or at 266 nm. In certain embodiments, the calcium salt of compound of Formula I has a solubility of about 600 pg / mL to about 700 pg / mL at pH 5 and 37 °C, after 24 hours of being added to a pH 5 and 37 °C solution of FeSSIF when determined by HPLC at 236 nm or at 266 nm.

[0127] In certain embodiments, the calcium salt of compound of Formula I has a solubility of about 250 pg / mL to about 350 pg / mL at pH 5 and 25 °C, after 4 hours of being added to a pH 5 and 25 °C solution of FeSSIF when determined by HPLC at 236 nm or at 266 nm. In certain embodiments, the calcium salt of compound of Formula I has a solubility of about 250 pg / mL to about 350 pg / mL at pH 5 and 25 °C, after 24 hours of being added to a pH 5 and 25 °C solution of FeSSIF when determined by HPLC at 236 nm or at 266 nm.

[0128] In certain embodiments, the calcium salt of compound of Formula I has a solubility of about 350 pg / mL to about 450 pg / mL at pH 6.5 and 37 °C, after 4 hours of being added to a pH 6.5 and 37 °C solution of Fasted State Simulated Intestinal Fluid (FaSSIF) when determined by HPLC at 236 nm or at 266 nm. In certain embodiments, the calcium salt of compound of Formula I has a solubility of about 300 pg / mL to about 400 pg / mL at pH 6.5 and 37 °C, after 24 hours of being added to a pH 6.5 and 37 °C solution of FaSSIF when determined by HPLC at 236 nm or at 266 nm.

[0129] In certain embodiments, the calcium salt of compound of Formula I has a solubility of about 300 pg / mL to about 400 pg / mL at pH 6.5 and 25 °C, after 4 hours of being added to a3133482596 399256-OPI-012WO (211257)pH 6.5 and 25 °C solution of FaSSIF when determined by HPLC at 236 nm or at 266 nm. In certain embodiments, the calcium salt of compound of Formula I has a solubility of about 200 pg / mL to about 300 pg / mL at pH 6.5 and 25 °C, after 24 hours of being added to a pH 6.5 and 25 °C solution of FaSSIF when determined by HPLC at 236 nm or at 266 nm.

[0130] In certain embodiments, the calcium salt of compound of Formula I is at least about 98% pure by weight, and the calcium salt comprises no more than about 2% of an impurity by weight of the calcium salt. In certain embodiments, the calcium salt of compound of Formula I is about 95.0% to 100% pure by weight, and the calcium salt comprises 0% to about 5% of an impurity by weight of the calcium salt. In certain embodiments, the calcium salt of compound of Formula I is about 98% to 100% pure by weight, and the calcium salt comprises 0% to about 2% of an impurity by weight of the calcium salt. In certain embodiments, the calcium salt of compound of Formula I is about 98%, about 98.5%, about 99%, about 99.5%, or 100% pure by weight, and the calcium salt comprises about 2%, about 1.5%, about 1%, about 0.5%, or 0%, respectively, of an impurity by weight of the calcium salt. In certain embodiments, the calcium salt of compound of Formula I is about 99.5%, about 99.9%, or about 99.95% pure by weight, and the calcium salt comprises about 0.5%, about 0.1%, or about 0.05%, respectively, of an impurity by weight of the calcium salt. In certain embodiments, the purity or the impurity are determined by high-performance liquid chromatography (HPLC). In certain embodiments, the purity or impurity is determined by HPLC at 236 nm. In certain embodiments, the purity or impurity is determined by HPLC at 266 nm. In certain embodiments, the purity or impurity is determined by titration.

[0131] In certain embodiments, the calcium salt of compound of Formula I is at least about 98% pure by weight after being exposed to 40 °C / 75% RH for 1 week. In certain embodiments, the calcium salt of compound of Formula I is at least about 99% pure by weight after being exposed to 40 °C / 75% RH for 1 week.

[0132] In certain embodiments, the calcium salt of compound of Formula I is amorphous.

[0133] In certain embodiments, the calcium salt of compound of Formula I is predominantly amorphous, wherein the predominantly amorphous calcium salt exhibits an XRPD pattern comprising a peak at 4.5 ± 0.2 degrees 2-theta and a peak at 6.0 ± 0.2 degrees 2-theta.3233482596 399256-OPI-012WO (211257)

[0134] In certain embodiments, the predominantly amorphous calcium salt of compound of Formula I exhibits an XRPD pattern that is predominantly the same as that depicted in Fig. 3A.

[0135] In certain embodiments, the predominantly amorphous calcium salt of compound of Formula I is an anhydrate.

[0136] In certain embodiments, the predominantly amorphous calcium salt of compound of Formula I is at least 50% amorphous by weight. In certain embodiments, the predominantly amorphous calcium salt of compound of Formula I is at least 60% amorphous by weight. In certain embodiments, the predominantly amorphous calcium salt of compound of Formula I is at least 70% amorphous by weight. In certain embodiments, the predominantly amorphous calcium salt of compound of Formula I is at least 80% amorphous by weight. In certain embodiments, the predominantly amorphous calcium salt of compound of Formula I is at least 90% amorphous by weight. In certain embodiments, the predominantly amorphous calcium salt of compound of Formula I is at least 95% amorphous by weight. In certain embodiments, the predominantly amorphous calcium salt of compound of Formula I is predominantly amorphous.

[0137] In certain embodiments, the predominantly amorphous calcium salt of compound of Formula l is a calcium salt anhydrate.B. Compound of Formula II or Pharmaceutically Acceptable Salt Thereof

[0138] In certain embodiments, the first therapeutic agent is a compound of Formula II or a pharmaceutically acceptable salt thereof. In certain embodiments, the first therapeutic agent is a compound of Formula II.

[0139] As generally defined above, Formula II is represented by:wherein:R1represents independently for each occurrence C1.4 alkyl;3333482596 399256-OPI-012WO (211257)R2is Ci-4 alkyl;R3is Ci-6 alkyl;R4is Ci-6 alkyl or hydrogen;R5is Ci -6 alkyl or Ci-4 alkoxyl; and n is 0, 1, or 2.

[0140] In certain embodiments, R1is methyl.

[0141] In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2.

[0142] In certain embodiments, R2is methyl or ethyl. In certain embodiments, R2is methyl.

[0143] In certain embodiments, R3is C3 alkyl. In certain embodiments, R3is -CH2CH2CH3.

[0144] In certain embodiments, R4is C1-6 alkyl. In certain embodiments, R4is C1-3 alkyl. In certain embodiments, R4is ethyl. In certain embodiments, R4is hydrogen.

[0145] In certain embodiments, R5is C1-6 alkyl. In certain embodiments, R5is C1-3 alkyl. In certain embodiments, R is ethyl. In certain embodiments, R5is C1-2 alkoxyl. In certain embodiments, R5is C1-4 alkoxyl. In certain embodiments, R5is methoxy.

[0146] In certain embodiments, the first therapeutic agent ipharmaceutically acceptable salt thereof. In certain embodiments, the first therapeutic agent is3433482596 399256-OPI-012WO (211257)

[0147] In certain embodiments, the first therapeutic agent ipharmaceutically acceptable salt thereof. In certain embodiments , the first therapeutic agentII. Combination Therapy

[0148] Another aspect of the invention provides for combination therapy. In certain embodiments, therapeutic methods described hereinabove may optionally further comprise administering one or more additional therapeutic agents to the patient. For example, in certain embodiments, the method further comprises administering to the patient an additional therapeutic agent for age-related macular degeneration.

[0149] In certain embodiments, the method further comprises administering to the human patient an additional therapeutic agent that is a vitamin and / or a mineral. In certain embodiments, the method further comprises orally administering to the human patient once per day an additional therapeutic agent that is a formulation comprising vitamin C, zinc, vitamin E, and copper. In certain embodiments, the method further comprises orally administering to the human patient once per day an additional therapeutic agent that is a formulation comprising vitamin C, zinc, vitamin E, copper, and beta carotene. In certain embodiments, the method further comprises orally administering to the human patient once per day an additional therapeutic agent that is a formulation comprising vitamin C (500 mg), zinc (80 mg), vitamin E (400 IU), copper (2 mg), and beta carotene (15 mg). In certain embodiments, the method further comprises orally administering to the human patient once per day an additional therapeutic agent that is a formulation comprising vitamin C, zinc, vitamin E, copper, lutein, and zeaxanthin. In certain embodiments, the method further comprises orally administering to the human patient3533482596 399256-OPI-012WO (211257)once per day an additional therapeutic agent that is a formulation comprising vitamin C (500 mg), zinc (80 mg), vitamin E (400 IU), copper (2 mg), lutein (10 mg), and zeaxanthin (2 mg).

[0150] In certain embodiments, the method further comprises administering to the human patient an additional therapeutic agent that is a vascular endothelial growth factor inhibitor. In certain embodiments, the method further comprises administering to the human patient an additional therapeutic agent that is ranibizumab, bevacizumab, brolucizumab, faricimab, and / or aflibercept.

[0151] In certain embodiments, the method further comprises administering to the human patient an additional therapeutic agent that is a complement inhibitor. In certain embodiments, the method further comprises administering to the human patient an additional therapeutic agent that is pegcetacoplan and / or avacincaptad pegol.

[0152] In certain embodiments, the method further comprises administering to the human patient an additional therapeutic agent that is a retinal gene therapy or retinal cell therapy. In certain embodiments, the method further comprises administering to the human patient an additional therapeutic agent that is a retinal gene therapy. In certain embodiments, the method further comprises administering to the human patient an additional therapeutic agent that is a retinal cell therapy.

[0153] In certain embodiments, the first therapeutic agent is the only therapeutic agent for age-related macular degeneration that is administered to the human patient.

[0154] The additional therapeutic agent and optionally further therapeutic agents may be administered separately from a compound or composition of the invention, as part of a multiple dosage regimen. Alternatively, the additional therapeutic agent and optionally further 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, the additional therapeutic agent and optionally further therapeutic agents and a compound or composition of the invention may be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or 24 hours from one another. In certain embodiments, the additional therapeutic3633482596 399256-OPI-012WO (211257)agent and optionally further therapeutic agents and a compound or composition of the invention are administered as a multiple dosage regimen more than 24 hours apart.

[0155] In certain embodiments, administration of the first therapeutic agent in combination with the additional therapeutic agent permits administering the additional therapeutic agent at a lower dose and / or less frequently. In certain embodiments, administration of the first therapeutic agent in combination with the additional therapeutic agent permits administering the additional therapeutic agent at a lower dose and / or less frequently while still achieving a therapeutic result for the patient that is as good or better than the result achieved with monotherapy using the additional therapeutic agent.III. Pharmaceutical Compositions

[0156] 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.

[0157] 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.

[0158] 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 hydroxyanisole (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.3733482596 399256-OPI-012WO (211257)

[0159] 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.

[0160] 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.

[0161] 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.

[0162] 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.

[0163] 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 / or3833482596 399256-OPI-012WO (211257)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.

[0164] 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.

[0165] 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 dissolved3933482596 399256-OPI-012WO (211257)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.

[0166] 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.

[0167] 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.

[0168] 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.

[0169] 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.

[0170] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms4033482596 399256-OPI-012WO (211257)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.

[0171] 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.

[0172] 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.

[0173] 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.

[0174] 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.g., as sensitizing agents), the effective amount may be less than when the agent is used alone.

[0175] 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.4133482596 399256-OPI-012WO (211257)

[0176] 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

[0177] Another aspect of the invention provides a medical kit comprising, for example, (i) a therapeutic agent described herein, and (ii) instructions for treating and / or preventing the progression of intermediate age-related macular degeneration and / or other disorders according to methods described herein.V. EXAMPLES

[0178] 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 - Cvtoprotection of Retina! Pigment Epithelium Ceils Using Exemplary Compounds Under NaKh-Induced Oxidative-Stress Conditions

[0179] The cytoprotective effects of the Ref-l / APEl inhibitors in Table 1 below were tested in human induced pluripotent stem cell derived retinal pigment epithelium (iPSC-RPE) cells under exogenously applied oxidative stress (NalCh -induction). The endpoint measurements were leakage of lactate dehydrogenase (LDH), cell viability, formation of reactive oxygen species (ROS), and gene expression.Table 1.4233482596 399256-OPI-012WO (211257)

[0180] Using the intracellular marker resazurin, the test compounds Compound 1 hemicalcium salt monohydrate and APX2009 did not display cytotoxic effects up to the highest dose tested (45 pM). APX2014 displayed a cytotoxic effect at 10 pM which was the highest dose tested using APX2014. In combination with 10 mM NalCh, Compound 1 hemicalcium salt monohydrate demonstrated a statistically significant decrease in ROS formation compared to vehicle across a range of concentrations of Compound 1 hemicalcium salt monohydrate (5 pM, p<0.05; 10 pM, p<0.01; 30 pM, p<0.001; 45 pM, p<0.0001).EXAMPLE 2 - Therapeutic Effect of Exemplary Compounds in alO; Murine Model of Retinal Pigment Endothelium Degeneration

[0181] The therapeutic effects of the test compounds set forth in Table 1 in Example 1 were investigated in the NalOs 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).Procedure

[0182] 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:4333482596 399256-OPI-012WO (211257)

[0183] The mouse anti-C5 antibody binds the fifth component of mouse complement and was purchased from HycultBiotech (catalog # HM1073).

[0184] On day 3 of the study, mice were treated with NalOs (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

[0185] Retinal function as measured by ERG (Fig. 4 and 5) 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)

[0186] Retinal thickness as measured by OCT (Fig. 6) did not show an improvement in any of the treatment groups.EXAMPLE 3 - Preparation of Compound 1 Hemicalcium Salt Monohydrate in Crystalline Form

[0187] About 20 g of Compound 1 (1 eq.) was weighed and added to a 1 L glass reactor and mixed at room temperature with H20:Me0H (1 : 1 v / v) to provide a fine suspension having a concentration of 36.3 g of Compound 1 / L of FEO McOH (1 :1 v / v). Compound 1 has the formula:4433482596 399256-OPI-012WO (211257)The suspension was allowed to stir for 30 minutes with a mechanical stirrer type OS-20 with a rod and PTFE propeller at 300 rpm. Calcium hydroxide (95%; 2.0953 g; 0.5 eq.) was added, and the resultant mixture was allowed to stir at 500 rpm at room temperature for 2 hours. After 2 hours, the resultant precipitate was vacuum filtered, washed with 400 mL of ThCfMeOH (1 : 1 v / v). The washed precipitate was dried in a fume hood at atmospheric pressure at 25 °C for about 45 hours to provide a Compound 1 hemicalcium salt monohydrate as a light orange solid (89.06% yield).

[0188] Purity of the Compound 1 hemicalcium salt monohydrate was determined by HPLC chromatography using an Agilent 1260 Infinity HPLC device, at 30°C and a HiChrom C18 column (4.6x100mm, 3.5pm). The HPLC device was coupled with a UV-Vis Diode Array Detector (HPLC-DAD). Analyses were run with a gradient method (as described in the table below) using 0.1% formic acid in purified MilliQ water (mobile phase A) and 0.1% formic acid in acetonitrile HPLC grade (mobile phase B). A flow rate was 1 mL / min and an injection volume was5 pL. UV detection was run at 236 nm and 266 nm. The sample was dissolved into MilliQ pure water. Purity of Compound 1 hemicalcium salt monohydrate determined by HPLC at 236 nm was 99.7% and at 266 nm was 99.8%.

[0189] The Compound 1 hemicalcium salt monohydrate was analyzed by XRPD and thermo-gravimetric (TG) / differential scanning calorimetric (DSC).4533482596 399256-OPI-012WO (211257)

[0190] Fig. 1 A shows an XRPD diffractogram (background subtracted) of the Compound 1 hemicalcium salt monohydrate obtained as described in this Example, and Table 1 lists XRPD peaks represented in Fig. 1A.Table 1. XRPD Data for Compound 1 hemicalcium salt monohydrate from this Example

[0191] TG / DSC analysis: A sample of the Compound 1 hemicalcium salt monohydrate (about 5.3 mg) obtained according to this Example was weighed into an open aluminum pan, loaded into a simultaneous Setaram LAB SYS EVO thermo-gravimetric / differential scanning calorimeter (TG-DTA / DSC) and maintained at 30 °C for 15 minutes. The sample was then heated from 30 °C to 550 °C, during which time a change in sample weight was recorded along with any differential thermal events. Nitrogen was used as a purge gas, at a flow rate of 180 cm3 / min. Prior to the analysis, the instrument mass loss and temperature were calibrated using4633482596 399256-OPI-012WO (211257)copper sulfate pentahydrate and reference standards (lead and indium), respectively. The sample analysis was performed using CALISTO software, where the corresponding mass loss and temperatures of thermal events were quoted as the onset temperature, measured according to the manufacturer’s specifications. The analysis was carried out with a heating rate of 10 °C / minute and the background was subtracted before further processing.

[0192] The TG / DSC analysis of the Compound 1 hemicalcium salt monohydrate obtained according to this Example showed one small endothermic event between 50 °C and 89 °C (peak maximum at about 82 °C) and one exothermic event starting at about 208 °C (peak maximum at about 213 °C) (Fig. IB). A mass loss of about 5% was observed on the TG curve, corresponding to the endothermic event. Based on the TG / DSC data, the Compound 1 hemicalcium salt obtained according to this Example is a monohydrate.

[0193] Compound 1 hemicalcium salt monohydrate obtained generally according to this method was further analyzed by FT-IR, FT-Raman, dynamic vapor sorption (DVS), andJH NMR.

[0194] An FT-IR spectrum of the Compound 1 hemicalcium salt monohydrate was recorded at between 3500 and 50 cm'1showing the following significant bands, expressed in wavenumbers (cm'1): 2924 (m) and 2853 (m) specific to asymmetric -CH2-, symmetric -CEE and -CH2- stretching vibrations; 1636 (st) characteristic to -C=O stretching and some =C-H stretching vibrations; 1603 (st) specific to -C=C- stretching and -C-C- skeletal vibrations; 1556 (st) also specific to -C-O- vibrations (e.g. in the -COOR groups) or aromatic -C=C- stretching vibrations; 1418 (st) characteristic for -C-C- stretch (in-ring) aromatics or -C-H bending vibrations; 1298 (m), 1261 (st), 1203 (st) and 1157 (m) specific to -C-0 or -C(O)-O stretching vibrations; 1094 (m), 997 (m), 951 (w), 787 (w), 739 (m) and 636 (w) characteristic for =C-H out-of-plane bending or -C-C- bending vibrations. The intensities of the absorption bands are indicated as follows: (w) = weak; (m) = medium; and (st) = strong intensities.

[0195] An FT-Raman spectrum of the Compound 1 hemicalcium salt monohydrate was recorded at between 4000 and 150 cm'1showing the following significant bands, expressed in wavenumbers (cm-1): 2927 (m) and 2858 (m) assigned to -CEE and -CEE vibrations; 1652 (st) assigned to -C=O group, 1600 (m) attributed to -C=C- vibrations; 1440 (m), 1384 (m), 1337 (st) and 1303 (m) attributed to ring deformation and -C-O- vibrations; 957 (w), 874 (w), 499 (m),4733482596 399256-OPI-012WO (211257)443 (m) and 344 (w) assigned to -C-C- vibrations and ring breathing. The intensities of the absorption bands are indicated as follows: (w) = weak; (m) = medium; and (st) = strong intensities. The error margin for all absorption bands of FT-Raman is ± 2 cm1.

[0196] DVS Analysis: Compound 1 hemicalcium salt monohydrate had a water content of 0.39 % and was equilibrated to 0 before starting the analysis. DVS analysis of the Compound 1 hemicalcium salt monohydrate (Fig. 1C) showed that the maximum water adsorption at 82% RH was about 1.52%, while at the end of the desorption branch the Compound 1 hemicalcium salt monohydrate retained 0.19% water. The pattern of a subsequent XRPD analysis revealed the same peaks, although with slightly lower intensities, and supports that post-DVS sample of the Compound 1 hemicalcium salt monohydrate maintained the same crystalline form as the pre- DVS sample of the Compound 1 hemicalcium salt monohydrate.

[0197] A1H-NMR spectrum of the Compound 1 hemicalcium salt was obtained and no - COOH group peak (~12 ppm) was observed. 5 'H (600 MHz, DMSO-de): 0.84 (3H), 1.12 (6H), 1.18 (4H), 1.23 (2H), 1.33 (2H), 1.83 (3H), 1.98 (2H), 3.88 (3H), 3.91 (3H), 6.85 (1H).EXAMPLE 4 - Preparation of Compound 1 Hemicalcium Salt Monohydrate in Crystalline Form

[0198] About 75 g (0.198 mol) of Compound 1 (1 eq.) was charged to a 5 L jacketed reactor. 2025 mb (27.0 vol) of 2: 1 H20:Me0H (v / v) was charged to the 5 L jacketed reactor at room temperature. Compound 1 has the formula:The reaction mixture was agitated for 25 minutes at 25 ± 5 °C to provide a fine suspension. Calcium hydroxide (7.3 g, 0.5 eq.) was charged to the reactor portion-wise over 25 minutes. The resultant mixture was thick but remained stirrable with some shelling observed near the top of the reactor. The shelled material was scraped down. The mixture was agitated at 25 ± 5 °C for 2 hours and the mixture became very thick. A sample was taken to confirm formation of Compound 1 hemicalcium salt monohydrate by an XRPD analysis.33482596 399256-OPI-012WO (211257)

[0199] The resultant solids were collected via vacuum filtration and were washed twice with 2: 1 water / methanol (900 mL, 12.0 vol). The solids were dried under vacuum until they had a water content of about 12% and dried using humidified drying. The humidified drying was performed using a vacuum oven attached to a house vacuum system with a small bleed of nitrogen that was saturated with water vapor. The water vapor-saturated nitrogen was obtained by bubbling nitrogen through water and had 100% humidity at 20 ± 5 °C. Humidified drying continued until the solids had a water content of 4-6% (Table 2) to provide Compound 1 hemicalcium salt monohydrate as an orange solid (80.41 g, 97.2% yield). Purity determined by HPLC at 262 nm was 99.9%. HPLC parameters and conditions are:Mobile Phase A: 0.1% TFA in WaterMobile Phase B: 0.1% TFA in AcetonitrileDiluent: Acetonitrile and Water; 80:20 v / vSample Concentration: 0.7mg / mLTable 1.4933482596 399256-OPI-012WO (211257)

[0200] The Compound 1 hemicalcium salt monohydrate was analyzed by XRPD, TGA, DSC, and1H NMR (Figs. 2A-2D). XRPD data were obtained using a Bruker AXS with D2 Phaser 2ndGen configuration (Part Number: A26X1-A2B0B1C) in reflection mode (scan type: Coupled TwoTheta / Theta) scanning the samples at between 3 and 40° 2-theta angles, and using the following measurements characteristics: increment per step was 0.02°, time per step was 0.3 s, and generator voltage / generator amperage was 10 mA / 30 kV to reach 0.3 kW power, detector type LynxEye A17-B60 and a goniometer type Theta / Theta. The XRPD data were collected using DIFFRAC.MEASURMENT 8.6.3.0 software and processed with DIFFRAC.EVA 6.0.0.8 software.Table 2. Vacuum Drying Time and Water Content5033482596 399256-OPI-012WO (211257)* Inconsistency with this time point due to solids precipitating in the system and sticking to the detector

[0201] Fig. 2A shows an XRPD diffractogram of the Compound 1 hemicalcium salt monohydrate obtained by this Example, and Table 3 lists XRPD peaks represented in Fig. 2A.Table 3. XRPD Data for Compound 1 hemicalcium salt monohydrate

[0202] TGA analysis: A sample of the Compound 1 hemi calcium salt monohydrate (about2-5 mg) obtained generally according to this Example, was weighed into an aluminum pan (70 pL), loaded into Mettler Toledo TGA 2 Star System (sampling interval: 1 s). The sample was then heated from 25 °C to 350 °C (heating rate of 10 K / min), during which time a change in sample weight was recorded. The sample analysis was performed using STAR 16.20 software.

[0203] DSC analysis: A sample of the Compound 1 hemicalcium salt monohydrate (about3-6 mg) obtained generally according to this Example, was weighed into an aluminum pan (405133482596 399256-OPI-012WO (211257)pL), loaded into Mettler Toledo DSC 1 Star System (sampling interval: 1 s). The sample was then heated from 25 °C to 350 °C (heating rate of 10 °C / min), during which any differential thermal events were recorded. Nitrogen was used as a purge gas, at a flow rate of 80 cm3 / min. The sample analysis was performed using STAR 16.10 software.

[0204] JH NMR analysis: 'H NMR spectrum was obtained on Broker Advance III HD 300 MHz NMR Spectrometer (sample size: about 8 mg / mL in DMSO-de) and analyzed with TopSpin 3.6.4 software.EXAMPLE 5 - Preparation of Hemicalcium Salt of Compound 1 (predominantly amorphous)

[0205] Compound 1 hemicalcium salt monohydrate as prepared generally according to Example 3 was heated at about 60 °C for 1 h at atmospheric pressure. The resultant Compound 1 hemicalcium salt was determined to be anhydrous and predominantly (>50%) amorphous, as evidenced by the presence of only a few XRPD peaks. Compound 1 has the formula:

[0206] X-ray powder diffraction (XRPD) analysis was carried out using a Bruker D8 Discover diffractometer with DAVINCI configuration, in transmission mode (scan type: TwoTheta or Offset Coupled TwoTheta / Theta) scanning the samples (~2-3 mg) at between 1.5 and 45° 2-theta angles, and using the following measurements characteristics: acquisition time was 7.58 minutes, increment per step was 0.01°, time per step was 0.1 s, and generator voltage / generator amperage was 40 mA / 40 kV to reach 1.6 kW power. The XRPD system was used in Parallel Beam Geometry (Gobel mirror) with an anode of Cu and a detector type LynxEye. Also, the XRPD system used a goniometer type Theta / Theta with a measuring circle diameter of 560 mm and vertical operating position. For transmission mode, 1 UBC collimator magnetic holder 1 mm was mounted to primary optics.

[0207] The raw XRPD data were imported in the Diffrac.EVA5.0 software and processed using the subsequent parameters: background subtraction and Ku.2 stripping were performed before peak determination, and the peak search operation was performed with a threshold of 0.7833482596 399256-OPI-012WO (211257)and a peak width of 0.242 (or 0.153). All resulting peaks with relative intensity greater than or equal to 2% were considered.

[0208] Fig. 3A shows an XRPD diffractogram (background subtracted) of the anhydrous and predominantly amorphous Compound 1 hemicalcium salt obtained when heated at about 60 °C for 1 h at atmospheric pressure, and Table 1 lists XRPD peaks represented in Fig. 3A.Table 1

[0209] The TG / DSC analysis of the predominantly amorphous Compound 1 hemicalcium salt showed only one exothermic event starting at about 210 °C that was attributed to the degradation process of the salt (Fig. 3B). No mass loss was attributed to the thermal event. Based on the TG / DSC data, the predominantly amorphous Compound 1 hemicalcium salt is anhydrous.

[0210] Hydration Experiment: Water (1.60 m ) was added to the Compound 1 hemicalcium salt (anhydrous and predominantly amorphous) as obtained above (about 200 mg). The resultant mixture was allowed to stir at 700 rpm for 1 h. The resultant mixture was heated at about 40 °C for 2 h at atmospheric pressure then at 50 °C for 4 h at atmospheric pressure. The resultant solids showed an XRPD pattern and a TG / DSC consistent with Compound 1 hemicalcium salt monohydrate obtained generally according to Example 3.INCORPORATION BY REFERENCE

[0211] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes.5333482596 399256-OPI-012WO (211257)EQUIVALENTS

[0212] 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.5433482596 399256-OPI-012WO (211257)

Claims

1. Claims:

1. A method of treating intermediate age-related macular degeneration, comprising orally administering to a human patient in need thereof a therapeutically effective amount of a first therapeutic agent to thereby treat intermediate age-related macular degeneration, wherein the first therapeutic agent is a compound of Formula I or II 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 2.

2. The method of claim 1, further comprising the step of identifying a human patient with intermediate age-related macular degeneration that would benefit from therapy that treats intermediate age-related macular degeneration.

3. A method of preventing the progression of intermediate age-related macular degeneration, comprising orally administering to a human patient in need thereof a therapeutically effective amount of a first therapeutic agent to thereby prevent the progression of intermediate age-5533482596 399256-OPI-012WO (211257)related macular degeneration, wherein the first therapeutic agent is a compound of Formula T or II 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 2.

4. The method of claim 3, further comprising the step of identifying a human patient with intermediate age-related macular degeneration that would benefit from therapy that prevents the progression of intermediate age-related macular degeneration.

5. The method of claim 3 or 4, wherein preventing the progression of intermediate age-related macular degeneration comprises preventing the development of geographic atrophy in the human patient.

6. The method of any one of claims 1-5, wherein the method prevents loss of photoreceptors in the eye of the human patient.5633482596 399256-OPI-012WO (211257)7. The method of any one of claims 1 -6, wherein the method prevents loss of chori ocapillaries in the eye of the human patient.

8. The method of any one of claims 1-7, wherein the method prevents loss of retinal pigment epithelium cells in the eye of the human patient.

9. The method of any one of claims 1-8, wherein the method prevents vision loss by the patient.

10. The method of any one of claims 1-9, wherein the method prevents loss of visual acuity by the patient.

11. The method of any one of claims 1-10, wherein the method prevents retinal degradation in the eye of the human patient.

12. A method of reducing the rate of progression of intermediate age-related macular degeneration, comprising orally administering to a human patient in need thereof a therapeutically effective amount of a first therapeutic agent to thereby reduce the rate of progression of intermediate age-related macular degeneration, wherein the first therapeutic agent is a compound of Formula I or II or a pharmaceutically acceptable salt thereofwherein:R1represents independently for each occurrence Ci-4 alkyl;R2is Ci-4 alkyl;R3is Ci-6 alkyl;5733482596 399256-OPI-012WO (211257)R4is Ci-6 alkyl or hydrogen;R5is Ci-6 alkyl or Ci-4 alkoxyl; and n is 0, 1, or 2.

13. The method of claim 12, further comprising the step of identifying a human patient with intermediate age-related macular degeneration that would benefit from therapy that reduces the rate of progression of intermediate age-related macular degeneration.

14. The method of claim 12 or 13, wherein the method reduces the rate of development of geographic atrophy in the human patient.

15. The method of any one of claims 1 -4 or 12-14, wherein the method reduces the rate of loss of photoreceptors in the eye of the human patient.

16. The method of any one of claims 1-4 or 12-15, wherein the method reduces the rate of loss of choriocapillaries in the eye of the human patient.

17. The method of any one of claims 1-4 or 12-16, wherein the method reduces the rate of loss of retinal pigment epithelium cells in the eye of the human patient.

18. The method of any one of claims 1-4 or 12-17, wherein the method reduces the rate of vision loss by the patient.

19. The method of any one of claims 1-4 or 12-18, wherein the method reduces the rate of loss of visual acuity by the patient.

20. The method of any one of claims 1-4 or 12-19, wherein the method reduces the rate of retinal degradation in the eye of the human patient.

21. The method of claim 11 or 20, wherein the retinal degradation in the eye of the human patient is measured by electroradiography.

22. The method of any one of claims 11, 20, or 21, wherein the retinal degradation in the eye of the human patient is measured by optical coherence tomography.

23. The method of any one of claims 11 or 20-22, wherein the retinal degradation in the eye of the human patient is measured by fluorescein angiography.

24. The method of any one of claims 11 or 20-23, wherein the retinal degradation in the eye of the human patient is measured by retinal thickness.5833482596 399256-OPI-012WO (211257)25. The method of any one of claims 1 -24, wherein any increase in blood plasma concentration of alanine aminotransferase in the human patient due to the first therapeutic agent is no greater than 50%.

26. The method of any one of claims 1-25, wherein any increase in blood plasma concentration of aspartate aminotransferase in the human patient due to the first therapeutic agent is no greater than 50%.

27. The method of any one of claims 1-26, wherein any reduction in glomerular filtration rate in the human patient is no greater than 25%.

28. The method of any one of claims 1 -27, wherein the incidence of any eye disorder due to the first therapeutic agent occurs no more frequently than one human patient for every ten human patients subjected to the same treatment.

29. The method of any one of claims 1-27, wherein the incidence of any eye disorder due to the first therapeutic agent occurs no more frequently than one human patient for every twenty human patients subjected to the same treatment.

30. The method of any one of claims 1-29, wherein the incidence of any gastrointestinal disorder due to the first therapeutic agent occurs no more frequently than one human patient for every ten human patients subjected to the same treatment.

31. The method of any one of claims 1-30, wherein the incidence of any nervous system disorder due to the first therapeutic agent occurs no more frequently than one human patient for every twenty human patients subjected to the same treatment.

32. The method of any one of claims 1-31, wherein the first therapeutic agent is a compound of Formula I.

33. The method of any one of claims 1-31, wherein the first therapeutic agent is a pharmaceutically acceptable salt of the compound of Formula I.

34. The method of any one of claims 1 -31 , wherein the first therapeutic agent is an alkaline earth metal salt of the compound of Formula I.

35. The method of any one of claims 1-31, wherein the first therapeutic agent is a calcium salt of the compound of Formula I.5933482596 399256-OPI-012WO (211257)36. The method of any one of claims 1 -31 , wherein the first therapeutic agent is a hemicalcium salt of the compound of Formula I.

37. The method of any one of claims 1-31, wherein the first therapeutic agent is a hemicalcium salt monohydrate of the compound of Formula I.

38. The method of any one of claims 1-37, further comprising administering to the human patient an additional therapeutic agent that is a vitamin and / or a mineral.

39. The method of any one of claims 1-38, further comprising administering to the human patient an additional therapeutic agent that is a vascular endothelial growth factor inhibitor.

40. The method of any one of claims 1-38, further comprising administering to the human patient an additional therapeutic agent that is ranibizumab, bevacizumab, brolucizumab, faricimab, and / or aflibercept.

41. The method of any one of claims 1-40, further comprising administering to the human patient an additional therapeutic agent that is a complement inhibitor.

42. The method of any one of claims 1-40, further comprising administering to the human patient an additional therapeutic agent that is pegcetacoplan and / or avacincaptad pegol.

43. The method of any one of claims 1-42, further comprising administering to the human patient an additional therapeutic agent that is a retinal gene therapy or retinal cell therapy.

44. The method of any one of claims 1-43, wherein the human patient is an adult human patient.

45. The method of any one of claims 1-43, wherein the human patient is a geriatric human patient.6033482596 399256-OPI-012WO (211257)

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