Polymorphic Compounds and Uses Thereof

Abstract

The present invention provides free base and salt forms, compositions and methods thereof, useful for treating a variety of conditions in which aldehyde toxicity is implicated in the pathogenesis by administering small molecule therapeutic agents that act as scavengers of toxic aldehydes. In general, the salt or free base forms, and pharmaceutically acceptable compositions thereof, are useful for treating or lessening the severity of a variety of diseases or disorders, as described in detail herein.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present application relates to various forms and compositions and methods useful for treating a variety of conditions in which aldehyde toxicity is implicated in the pathogenesis by administration of small molecule therapeutic agents that act as scavengers of toxic aldehydes. [Background technology]

[0002] 2. Background of the Invention Metabolic and inflammatory processes in cells give rise to toxic aldehydes, such as malondialdehyde (MDA), 4-hydroxyl-2-nonenal (4HNE), glyoxal and methylglyoxal. These aldehydes are highly reactive with proteins, carbohydrates, lipids and DNA, leading to chemically modified biological molecules, activation of inflammatory mediators, such as NF-kappa B, and damage to a wide variety of organs. For example, retinaldehyde can react with phosphatidylethanolamine (PE) to form a highly toxic compound called A2E, a component of lipofuscin that is thought to be involved in the development and progression of age-related macular degeneration (AMD). Many body defense mechanisms function to remove or reduce the levels of toxic aldehydes, including metabolism by aldehyde dehydrogenases, buffering by molecules such as GSH, and removal from potential toxic sites by transporters, such as ABCA4. Novel small molecule therapeutics can be used to scavenge the "escaped" retinaldehyde in the retina, thus reducing the formation of A2E and lowering the risk of AMD (Jordan et al., 2006).

[0003] Aldehydes are known to be involved in a wide variety of pathological conditions, such as dry eye, cataracts, keratoconus, Fuchs endothelial dystrophy in the cornea, uveitis, allergic conjunctivitis, ocular cicatricial pemphigoid, photorefractive keratomileusis (PRK) healing or other conditions associated with corneal healing, conditions associated with tear lipid breakdown or lacrimal gland dysfunction, inflammatory eye conditions, such as ocular rosacea (with or without meibomian gland dysfunction), and non-ocular disorders or conditions, such as skin cancer, psoriasis, contact dermatitis. , atopic dermatitis, acne vulgaris, Sjögren-Larsson syndrome, ischemia-reperfusion injury, inflammation, diabetes, neurodegeneration (e.g., Parkinson's disease), scleroderma, amyotrophic lateral sclerosis, autoimmune disorders (e.g., lupus), cardiovascular disorders (e.g., atherosclerosis), and conditions associated with the damaging effects of blister agents (Negre-Salvagre et al., 2008; Nakamura et al., 2007; Batista et al., 2012; Kenney et al., 2003; Int J Dermatol 43:494 (2004); Invest Ophthalmol Vis Sci 48:1552 (2007); Graefe's Clin Exp Ophthalmol 233:694 (1994); Molecular Vision 18:194 (2012). Thus, reducing or eliminating aldehydes should alleviate symptoms and slow the progression of these pathological conditions.

[0004] MDA, HNE and other toxic aldehydes arise through a wide variety of metabolic mechanisms, including fatty alcohol, sphingolipid, glycolipid, phytol, fatty acid, arachidonic acid metabolism (Rizzo, 2007), polyamine metabolism (Wood et al., 2006), lipid peroxidation, oxidative metabolism (Buddi et al., 2002; Zhou et al., 2005), and glucose metabolism (Pozzi et al., 2009). Aldehydes can crosslink with primary amino groups and other chemical moieties on proteins, phospholipids, carbohydrates, and DNA, often resulting in toxic outcomes, such as mutagenesis and carcinogenesis (Marnett, 2002). MDA is associated with diseased corneas in conditions such as keratoconus, bullous keratopathy and other keratopathy, and Fuchs endothelial dystrophy (Buddi et al., 2002). Also, dysfunction of the skin's water barrier in skin disorders, such as Sjögren-Larsson syndrome, may be associated with the accumulation of fatty aldehydes, such as octadecanal and hexadecanal (Rizzo et al., 2010). Furthermore, increased lipid peroxidation and the resulting production of aldehydes are associated with the toxic effects of blister agents (Sciuto et al., 2004 and Pal et al., 2009).

[0005] There has been no suggestion in the art to treat various conditions associated with toxic aldehydes by administering small molecule therapeutics that act as scavengers for aldehydes, such as MDA and / or HNE.Therefore, there is a need to treat, prevent, and / or reduce the risk of diseases or disorders in which aldehyde toxicity is involved in the pathogenesis.The present invention addresses such a need. Thus, there remains a need for methods of treating, preventing, and / or reducing the risk of diseases, disorders, or conditions in which aldehyde toxicity is implicated in the pathogenesis. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Int J Dermatol, 43:494 (2004) [Non-Patent Document 2] Invest Ophthalmol Vis Sci, 48:1552 (2007) [Non-Patent Document 3] Graefe's Clin Exp Ophthalmol, vol. 233: p. 694 (1994) [Non-Patent Document 4] Molecular Vision, 18:194 (2012) Summary of the Invention [Means for solving the problem]

[0007] Summary of the Invention It has now been found that the compounds of the present invention and compositions thereof are useful for treating, preventing and / or reducing the risk of diseases, disorders or conditions in which aldehyde toxicity is involved in the pathogenesis.Generally, the salt or free base forms and pharmacologic acceptable compositions thereof are useful for treating or reducing the severity of various diseases or disorders as detailed herein.Such compounds have the following chemical structure, represented as Compound A: [ka] or a pharma- ceutically acceptable salt thereof.

[0008] The compounds of the present invention and pharma- ceutically acceptable compositions thereof are useful for treating a variety of diseases, disorders, or conditions associated with toxic aldehydes, including those described herein.

[0009] The compounds provided by the present invention are also useful in the study of certain aldehydes in biological and pathological phenomena. In certain embodiments, for example, the following are provided: (Item 1) Compound 1:

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[0010] [Figure 1] FIG. 1 illustrates the XRPD pattern of Form A of Compound A.

[0011] [Diagram 2] FIG. 2 illustrates the DSC thermogram and TGA trace of Compound A Form A.

[0012] [Diagram 3] FIG. 3 illustrates the XRPD pattern of Form B of Compound A.

[0013] [Figure 4]FIG. 4 illustrates the DSC thermogram and TGA trace of Compound A Form B.

[0014] [Diagram 5] FIG. 5 illustrates the XRPD pattern of Compound 1, Form A.

[0015] [Figure 6] FIG. 6 illustrates the DSC thermogram and TGA trace of Compound 1, Form A.

[0016] [Figure 7] FIG. 7 illustrates the XRPD pattern of Form B of Compound 1.

[0017] [Figure 8] FIG. 8 illustrates the DSC thermogram and TGA trace of Compound 1, Form B.

[0018] [Figure 9] FIG. 9 illustrates the XRPD pattern of Form A of Compound 2.

[0019] [Figure 10] FIG. 10 illustrates the DSC thermogram and TGA trace of Compound 2, Form A.

[0020] [Figure 11] FIG. 11 illustrates the XRPD pattern of Form B of Compound 2.

[0021] [Figure 12] FIG. 12 illustrates the XRPD pattern of Form A of Compound 3.

[0022] [Figure 13] FIG. 13 illustrates the DSC thermogram and TGA trace of compound 3, Form A.

[0023] [Figure 14]FIG. 14 illustrates the XRPD pattern of Form A of Compound 4.

[0024] [Figure 15] FIG. 15 illustrates the DSC thermogram and TGA trace of compound 4, Form A.

[0025] [Figure 16] FIG. 16 illustrates the XRPD pattern of Form A of Compound 5.

[0026] [Figure 17] FIG. 17 illustrates the DSC thermogram and TGA trace of compound 5, Form A.

[0027] [Figure 18] FIG. 18 illustrates the XRPD pattern of Form A of Compound 6.

[0028] [Figure 19] FIG. 19 illustrates the DSC thermogram and TGA trace of compound 6, Form A.

[0029] [Figure 20] FIG. 20 illustrates the XRPD pattern of Form A of Compound 7.

[0030] [Figure 21] FIG. 21 illustrates the DSC thermogram and TGA trace of Form A of Compound 7.

[0031] [Figure 22] FIG. 22 illustrates the XRPD pattern of Form A of Compound 8.

[0032] [Figure 23] FIG. 23 illustrates the DSC thermogram and TGA trace of Form A of Compound 8.

[0033] [Figure 24]FIG. 24 illustrates the XRPD pattern of Form A of Compound 9.

[0034] [Diagram 25] FIG. 25 illustrates the DSC thermogram and TGA trace of Form A of Compound 9. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] Detailed Description of the Invention General Description of Certain Aspects of the Invention U.S. Patent Application No. US13 / 709,802, filed December 10, 2012, and published July 25, 2013 as US2013 / 0190500 ("the '500 publication," which is incorporated herein by reference in its entirety), describes certain aldehyde scavenging compounds. Such compounds include Compound A: [ka] Includes.

[0036] Compound A, (6-chloro-3-amino-2-(2-hydroxypropyl)-1-azanaphthalene), is designated as Compound A in the '500 publication, and the synthesis of Compound A is described in detail in Example 5 of the '500 publication, which is reproduced herein for ease of reference.

[0037] It would be desirable to provide a solid form of Compound A (e.g., as its free base or a salt thereof) that offers improved characteristics, such as aqueous solubility, stability, and ease of formulation. Thus, the present invention provides both the free base and salt forms of Compound A.

[0038] Free base form of compound A It is contemplated that compound A can exist in various physical forms. For example, compound A can exist in solution, suspension, or solid form. In certain embodiments, compound A is in solid form. When compound A is in solid form, said compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0039] In some embodiments, the present invention provides a form of compound A that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain a significant amount of extraneous material. Such extraneous material may include different forms of compound A, residual solvent, or any other impurities that may result from the preparation and / or isolation of compound A. In certain embodiments, the form of compound A is present at least about 95% by weight. In yet other embodiments of the present invention, the form of compound A is present at least about 99% by weight.

[0040] According to one embodiment, the compound A form is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent, where percentages are based on the total weight of the composition. According to another embodiment, the compound A form contains less than about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than about 1.5 HPLC area percent of total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, the compound A form contains less than about 1.0% HPLC area percent of any single impurity, less than about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than about 0.5 HPLC area percent of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0041] The structures depicted for forms of Compound A are also intended to include all tautomeric forms of Compound A. Additionally, the structures depicted herein are also intended to include compounds which differ only by the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure except for the replacement of a carbon with a C-rich carbon are within the scope of this invention.

[0042] It has been found that Compound A can exist in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0043] As used herein, the term "polymorph" refers to the different crystal structures in which a compound, or a salt or solvate thereof, may crystallize.

[0044] In certain embodiments, compound A is a crystalline solid. In other embodiments, compound A is a crystalline solid that is substantially free of amorphous compound A. As used herein, the term "substantially free of amorphous compound A" means that the compound does not contain a significant amount of amorphous compound A. In certain embodiments, crystalline compound A is present at least about 95% by weight. In yet other embodiments of the present invention, crystalline compound A is present at least about 99% by weight.

[0045] It has been found that Compound A can exist in at least two distinct polymorphic forms. In certain embodiments, the present invention provides a polymorphic form of Compound A, herein referred to as Form A. In certain embodiments, the present invention provides a polymorphic form of Compound A, herein referred to as Form B.

[0046] In some embodiments, Compound A is amorphous. In some embodiments, Compound A is amorphous and substantially free of crystalline Compound A.

[0047] Form A of Compound A In some embodiments, Form A of Compound A has at least one, two, three, four or five spectral peaks selected from the peaks listed in Table 1 below. [Table 1-1]

[0048] In some embodiments, Form A of Compound A is characterized by having one or more peaks in its X-ray powder diffraction (XRPD) pattern selected from peaks at about 5.4, about 10.8, and about 16.6 degrees 2θ. In some embodiments, Form A of Compound A is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 5.4, about 10.8, and about 16.6 degrees 2θ. In some embodiments, Form A of Compound A is characterized by having all three peaks in its X-ray powder diffraction pattern selected from peaks at about 5.4, about 10.8, and about 16.6 degrees 2θ. As used herein, the term "about," when used in reference to degree 2θ values, refers to the determined value ±0.2 degrees 2θ.

[0049] In certain embodiments, the powder X-ray diffraction pattern is substantially similar to the XRPD presented in FIG.

[0050] A method for preparing Form A of Compound A is described below.

[0051] Form B of Compound A In some embodiments, Form B of Compound A has at least one, two, three, four or five spectral peaks selected from the peaks listed in Table 2 below. [Table 2-1]

[0052] In some embodiments, Form B of Compound A is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 11.6, about 23.3, and about 35.3 degrees 2θ. In some embodiments, Form B of Compound A is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 11.6, about 23.3, and about 35.3. In some embodiments, Form B of Compound A is characterized by having all three peaks in its X-ray powder diffraction pattern selected from peaks at about 11.6, about 23.3, and about 35.3.

[0053] In certain embodiments, the powder X-ray diffraction pattern is substantially similar to the XRPD presented in FIG.

[0054] A method for preparing Form B of Compound A is described below.

[0055] In some embodiments, the present invention provides a method for the preparation of compound A: [ka] The present invention provides a crystalline compound A.

[0056] In some embodiments, the present invention provides Compound A, wherein Compound A is substantially free of amorphous Compound A.

[0057] In some embodiments, the present invention provides compound A, wherein the compound A is substantially free of impurities.

[0058] In some embodiments, the present invention provides Compound A having one or more peaks in its XRPD selected from peaks at about 5.4, about 10.8, and about 16.6 degrees 2θ. In some such embodiments, the present invention provides Compound 1 having at least two peaks in its XRPD selected from peaks at about 5.4, about 10.8, and about 16.6 degrees 2θ. In some such embodiments, the present invention provides Compound A, which is a compound of Form A.

[0059] In some embodiments, the present invention provides compound A, having an XRPD substantially similar to the XRPD depicted in FIG.

[0060] In some embodiments, the present invention provides Compound A having one or more peaks in its XRPD selected from peaks at about 5.4, about 10.8, and about 16.6 degrees 2θ. In some such embodiments, the present invention provides Compound A having at least two peaks in its XRPD selected from peaks at about 5.4, about 10.8, and about 16.6 degrees 2θ. In some such embodiments, the present invention provides Compound A, which is Form B of the compound.

[0061] In some embodiments, the present invention provides compound A, having an XRPD substantially similar to the XRPD depicted in FIG.

[0062] In some embodiments, the invention provides a composition comprising Compound A and a pharma- ceutically acceptable carrier or excipient.

[0063] In some embodiments, the present invention provides a method of inhibiting or preventing accumulation of A2E in a patient, comprising administering to said patient Compound A or a composition thereof.

[0064] In some embodiments, the present invention provides methods of treating various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to said patient Compound A or a composition thereof. In some embodiments, Compound A is Form B of the compound. In some embodiments, the present invention provides methods of treating one or more of the diseases, disorders, or conditions described herein.

[0065] Salt form of compound A In some embodiments, the acid and compound A are ionically bonded to form one of compounds 1-9 described below. It is contemplated that compounds 1-9 can exist in various physical forms. For example, compounds 1-9 can exist in a solution, a suspension, or in a solid form. In certain embodiments, compounds 1-9 are in a solid form. When compounds 1-9 are in a solid form, the compounds may be amorphous, crystalline, or a mixture thereof. Exemplary such solid forms of compounds 1-9 are described in more detail below.

[0066] Compound 1 (mesylate of compound A) According to one embodiment, the present invention provides a mesylate salt of compound A, represented by compound 1: [ka] to provide.

[0067] It is understood by those skilled in the art that methanesulfonic acid and compound A are ionically bonded to form compound 1. It is contemplated that compound 1 can exist in various physical forms. For example, compound 1 can exist in a solution, a suspension, or in a solid form. In certain embodiments, compound 1 is in a solid form. When compound 1 is in a solid form, the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0068] In some embodiments, the present invention provides Compound 1 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain a significant amount of extraneous material. Such extraneous material may include excess methanesulfonic acid, excess Compound A, residual solvent, or any other impurities that may result from the preparation and / or isolation of Compound 1. In certain embodiments, Compound 1 is present at least about 95% by weight. In yet other embodiments of the present invention, Compound 1 is present at least about 99% by weight.

[0069] According to one embodiment, compound 1 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 percent by weight, where the percentages are based on the total weight of the composition. According to another embodiment, compound 1 contains less than about 3.0 HPLC area percent of total organic impurities relative to the total area of ​​the HPLC chromatogram, and in certain embodiments, less than about 1.5 HPLC area percent of total organic impurities. In other embodiments, compound 1 contains less than about 1.0% HPLC area percent of any single impurity, less than about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than about 0.5 HPLC area percent of any single impurity relative to the total area of ​​the HPLC chromatogram.

[0070] The depicted structures of Compound 1 are also intended to include all tautomeric forms of Compound 1. Additionally, the depicted structures herein are also intended to include compounds which differ only by the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure except for the replacement of a carbon with a C-rich carbon are within the scope of this invention.

[0071] It has been discovered that Compound 1 can exist in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0072] In certain embodiments, compound 1 is a crystalline solid. In other embodiments, compound 1 is a crystalline solid that is substantially free of amorphous compound 1. As used herein, the term "substantially free of amorphous compound 1" means that the compound does not contain a significant amount of amorphous compound 1. In certain embodiments, crystalline compound 1 is present at least about 95% by weight. In yet other embodiments of the present invention, crystalline compound 1 is present at least about 99% by weight.

[0073] It has been found that Compound 1 can exist in at least two distinct polymorphic forms. In some embodiments, the present invention provides a polymorphic form of Compound 1, referred to herein as Form A. In certain embodiments, the present invention provides a polymorphic form of Compound 1, referred to herein as Form B.

[0074] In some embodiments, Compound 1 is amorphous. In some embodiments, Compound 1 is amorphous and substantially free of crystalline Compound 1.

[0075] Form A of Compound 1 In some embodiments, Form A of Compound 1 has at least one, two, three, four or five spectral peaks selected from the peaks listed in Table 3 below. [Table 3-1]

[0076] In some embodiments, Form A of Compound 1 is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 9.3, about 16.9, and about 26.4 degrees 2θ. In some embodiments, Form A of Compound 1 is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 9.3, about 16.9, and about 26.4 degrees 2θ. In some embodiments, Form A of Compound 1 is characterized by having all three peaks in its X-ray powder diffraction pattern selected from peaks at about 9.3, about 16.9, and about 26.4 degrees 2θ.

[0077] In certain embodiments, the powder X-ray diffraction pattern is substantially similar to the XRPD presented in FIG.

[0078] A method for preparing Form A of Compound 1 is described below.

[0079] Form B of Compound 1 In some embodiments, Form B of Compound 1 has at least one, two, three, four or five spectral peaks selected from the peaks listed in Table 4 below. [Table 4-1]

[0080] In some embodiments, Form B of Compound 1 is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 9.6, about 19.1, and about 28.8 degrees 2θ. In some embodiments, Form B of Compound 1 is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 9.6, about 19.1, and about 28.8 degrees 2θ. In some embodiments, Form B of Compound 1 is characterized by having all three peaks in its X-ray powder diffraction pattern selected from peaks at about 9.6, about 19.1, and about 28.8 degrees 2θ.

[0081] In certain embodiments, the powder X-ray diffraction pattern is substantially similar to the XRPD presented in FIG.

[0082] A method for preparing Form B of Compound 1 is described below.

[0083] In some embodiments, the present invention provides a method for the preparation of compound 1: [ka] to provide.

[0084] In some embodiments, the present invention provides compound 1, wherein compound 1 is crystalline.

[0085] In some embodiments, the present invention provides Compound 1, which is a crystalline solid that is substantially free of amorphous Compound 1.

[0086] In some embodiments, the present invention provides compound 1, wherein compound 1 is substantially free of impurities.

[0087] In some embodiments, the present invention provides Compound 1 having one or more peaks in its XRPD selected from peaks at about 9.3, about 16.9, and about 26.4 degrees 2θ. In some such embodiments, the present invention provides Compound 1 having at least two peaks in its XRPD selected from peaks at about 9.3, about 16.9, and about 26.4 degrees 2θ. In some such embodiments, the present invention provides Compound 1, which is Form A of the compound.

[0088] In some embodiments, the present invention provides compound 1, having an XRPD substantially similar to the XRPD depicted in FIG.

[0089] In some embodiments, the present invention provides Compound 1 having one or more peaks in its XRPD selected from peaks at about 9.6, about 19.1, and about 28.8 degrees 2θ. In some such embodiments, the present invention provides Compound 1 having at least two peaks in its XRPD selected from peaks at about 9.6, about 19.1, and about 28.8 degrees 2θ. In some such embodiments, the present invention provides Compound 1, which is Form B of the compound.

[0090] In some embodiments, the present invention provides compound 1, having an XRPD substantially similar to the XRPD depicted in FIG.

[0091] In some embodiments, the present invention provides a composition comprising Compound 1 and a pharma- ceutically acceptable carrier or excipient.

[0092] In some embodiments, the present invention provides a method of inhibiting or preventing accumulation of A2E in a patient, comprising administering to the patient Compound 1, or a composition thereof.

[0093] In some embodiments, the present invention provides methods of treating various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to the patient Compound 1 or a composition thereof, wherein Compound 1 is in a crystalline form as described herein. In some embodiments, the present invention provides methods of treating one or more of the diseases, disorders, or conditions described herein.

[0094] Compound 2 (besylate of compound A) According to one embodiment, the present invention provides a besylate salt of compound A, represented by compound 2: [ka] to provide.

[0095] It is understood by those skilled in the art that benzenesulfonic acid and compound A are ionically bonded to form compound 2. It is contemplated that compound 2 can exist in various physical forms. For example, compound 2 can exist in a solution, a suspension, or in a solid form. In certain embodiments, compound 2 is in a solid form. When compound 2 is in a solid form, the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0096] In some embodiments, the present invention provides compound 2 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain a significant amount of extraneous material. Such extraneous material can include excess benzenesulfonic acid, excess compound A, residual solvent, or any other impurities that may result from the preparation and / or isolation of compound 2. In certain embodiments, compound 2 is present at least about 95% by weight. In yet other embodiments of the present invention, compound 2 is present at least about 99% by weight.

[0097] According to one embodiment, compound 2 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 percent by weight, where the percentages are based on the total weight of the composition. According to another embodiment, compound 2 contains less than about 3.0 HPLC area percent of total organic impurities relative to the total area of ​​the HPLC chromatogram, and in certain embodiments, less than about 1.5 HPLC area percent of total organic impurities. In other embodiments, compound 2 contains less than about 1.0% HPLC area percent of any single impurity, less than about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than about 0.5 HPLC area percent of any single impurity relative to the total area of ​​the HPLC chromatogram.

[0098] The depicted structure of compound 2 is also intended to include all tautomeric forms of compound 2. Additionally, the depicted structures herein are also intended to include compounds which differ only by the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure except for the replacement of a carbon with a C-rich carbon are within the scope of this invention.

[0099] It has been discovered that Compound 2 can exist in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0100] In certain embodiments, compound 2 is a crystalline solid. In other embodiments, compound 2 is a crystalline solid that is substantially free of amorphous compound 2. As used herein, the term "substantially free of amorphous compound 2" means that the compound does not contain a significant amount of amorphous compound 2. In certain embodiments, crystalline compound 2 is present at least about 95% by weight. In yet other embodiments of the present invention, crystalline compound 2 is present at least about 99% by weight.

[0101] It has been found that Compound 2 can exist in at least two distinct polymorphic forms. In some embodiments, the present invention provides a polymorphic form of Compound 2, referred to herein as Form A. In certain embodiments, the present invention provides a polymorphic form of Compound 2, referred to herein as Form B.

[0102] In some embodiments, Compound 2 is amorphous. In some embodiments, Compound 2 is amorphous and substantially free of crystalline Compound 2.

[0103] Form A of Compound 2 In some embodiments, Form A of Compound 2 has at least one, two, three, four or five spectral peaks selected from the peaks listed in Table 5 below. [Table 5-1]

[0104] In some embodiments, Compound 2 Form A is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 8.4, about 14.0, and about 25.4 degrees 2θ. In some embodiments, Compound 2 Form A is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 8.4, about 14.0, and about 25.4 degrees 2θ. In some embodiments, Compound 2 Form A is characterized by having all three peaks in its X-ray powder diffraction pattern selected from peaks at about 8.4, about 14.0, and about 25.4 degrees 2θ.

[0105] In certain embodiments, the powder X-ray diffraction pattern is substantially similar to the XRPD presented in FIG.

[0106] A method for preparing Form A of Compound 2 is described below.

[0107] Form B of Compound 2 In some embodiments, Form B of Compound 2 has at least one, two, three, four or five spectral peaks selected from the peaks listed in Table 6 below. [Table 6-1]

[0108] In some embodiments, Form B of Compound 2 is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 8.4, about 26.8, and about 29.3 degrees 2θ. In some embodiments, Form B of Compound 2 is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 8.4, about 26.8, and about 29.3 degrees 2θ. In some embodiments, Form B of Compound 2 is characterized by having all three peaks in its X-ray powder diffraction pattern selected from peaks at about 8.4, about 26.8, and about 29.3 degrees 2θ.

[0109] In certain embodiments, the powder X-ray diffraction pattern is substantially similar to the XRPD presented in FIG.

[0110] A method for preparing Form B of Compound 2 is described below.

[0111] In some embodiments, the present invention provides a method for the preparation of compound 2: [ka] to provide.

[0112] In some embodiments, the present invention provides compound 2, wherein compound 2 is crystalline.

[0113] In some embodiments, the present invention provides compound 2, which is a crystalline solid that is substantially free of amorphous compound 2.

[0114] In some embodiments, the present invention provides compound 2, wherein compound 2 is substantially free of impurities.

[0115] In some embodiments, the present invention provides Compound 2 having one or more peaks in its XRPD selected from peaks at about 8.4, about 14.0, and about 25.4 degrees 2θ. In some such embodiments, the present invention provides Compound 2 having at least two peaks in its XRPD selected from peaks at about 8.4, about 14.0, and about 25.4 degrees 2θ. In some such embodiments, the present invention provides Compound 2, which is Form A of the compound.

[0116] In some embodiments, the present invention provides compound 2, having an XRPD substantially similar to the XRPD depicted in FIG.

[0117] In some embodiments, the present invention provides Compound 2 having one or more peaks in its XRPD selected from peaks at about 8.4, about 26.8, and about 29.3 degrees 2θ. In some such embodiments, the present invention provides Compound 2 having at least two peaks in its XRPD selected from peaks at about 8.4, about 26.8, and about 29.3 degrees 2θ. In some such embodiments, the present invention provides Compound 2, which is Form B of the compound.

[0118] In some embodiments, the present invention provides compound 2, having an XRPD substantially similar to the XRPD depicted in FIG.

[0119] In some embodiments, the invention provides a composition comprising Compound 2 and a pharma- ceutically acceptable carrier or excipient.

[0120] In some embodiments, the present invention provides a method of inhibiting or preventing accumulation of A2E in a patient, comprising administering to the patient Compound 2, or a composition thereof.

[0121] In some embodiments, the present invention provides methods of treating various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to said patient Compound 2 or a crystalline form as described herein. In some embodiments, the present invention provides methods of treating one or more of the diseases, disorders, or conditions described herein.

[0122] Compound 3 (sulfate of compound A) According to one embodiment, the present invention provides a sulfate salt of compound A, represented by compound 3: [ka] to provide.

[0123] It is understood by those skilled in the art that sulfuric acid and compound A are ionically bonded to form compound 3. It is contemplated that compound 3 can exist in various physical forms. For example, compound 3 can exist in a solution, a suspension, or in a solid form. In certain embodiments, compound 3 is in a solid form. When compound 3 is in a solid form, the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0124] In some embodiments, the present invention provides compound 3 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain a significant amount of extraneous material. Such extraneous material may include excess sulfuric acid, excess compound A, residual solvent, or any other impurities that may result from the preparation and / or isolation of compound A. In certain embodiments, the form of compound 3 is present at least about 95% by weight. In yet other embodiments of the present invention, compound 3 is present at least about 99% by weight.

[0125] According to one embodiment, compound 3 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 percent by weight, where the percentages are based on the total weight of the composition. According to another embodiment, compound 3 contains less than about 3.0 HPLC area percent of total organic impurities relative to the total area of ​​the HPLC chromatogram, and in certain embodiments, less than about 1.5 HPLC area percent of total organic impurities. In other embodiments, compound 3 contains less than about 1.0% HPLC area percent of any single impurity, less than about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than about 0.5 HPLC area percent of any single impurity relative to the total area of ​​the HPLC chromatogram.

[0126] The depicted structure for compound 3 is also intended to include all tautomeric forms of compound 3. Additionally, the depicted structures herein are also intended to include compounds which differ only by the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure except for the replacement of a carbon with a C-rich carbon are within the scope of this invention.

[0127] It has been discovered that Compound 3 can exist in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0128] In certain embodiments, compound 3 is a crystalline solid. In other embodiments, compound 3 is a crystalline solid that is substantially free of amorphous compound A. As used herein, the term "substantially free of amorphous compound 3" means that the compound does not contain a significant amount of amorphous compound 3. In certain embodiments, crystalline compound 3 is present at least about 95% by weight. In yet other embodiments of the present invention, crystalline compound 3 is present at least about 99% by weight.

[0129] In some embodiments, compound 3 is amorphous. In some embodiments, compound 3 is amorphous and substantially free of crystalline compound 3.

[0130] Form A of Compound 3 In some embodiments, Form A of compound 3 has at least one, two, three, four or five spectral peaks selected from the peaks listed in Table 7 below. [Table 7-1]

[0131] In some embodiments, Form 3 of Compound A is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 17.2, about 23.8, and about 25.5 degrees 2θ. In some embodiments, Form A of Compound 3 is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 17.2, about 23.8, and about 25.5 degrees 2θ. In some embodiments, Form A of Compound 3 is characterized by having all three peaks in its X-ray powder diffraction pattern selected from peaks at about 17.2, about 23.8, and about 25.5 degrees 2θ.

[0132] In certain embodiments, the powder X-ray diffraction pattern is substantially similar to the XRPD presented in FIG.

[0133] A method for preparing Form A of Compound 3 is described below.

[0134] In some embodiments, the present invention provides a method for the preparation of compound 3: [ka] to provide.

[0135] In some embodiments, the present invention provides compound 3, wherein compound 3 is crystalline.

[0136] In some embodiments, the present invention provides compound 3, which is a crystalline solid that is substantially free of amorphous compound 3.

[0137] In some embodiments, the present invention provides compound 3, wherein the compound 3 is substantially free of impurities.

[0138] In some embodiments, the present invention provides compound 3 having one or more peaks in its XRPD selected from peaks at about 17.2, about 23.8, and about 25.5 degrees 2θ. In some such embodiments, the present invention provides compound 3 having at least two peaks in its XRPD selected from peaks at about 17.2, about 23.8, and about 25.5 degrees 2θ. In some such embodiments, the present invention provides compound 3, which is Form A of the compound.

[0139] In some embodiments, the present invention provides compound 3, having an XRPD substantially similar to the XRPD depicted in FIG.

[0140] In some embodiments, the invention provides a composition comprising Compound 3 and a pharma- ceutically acceptable carrier or excipient.

[0141] In some embodiments, the present invention provides a method of inhibiting or preventing accumulation of A2E in a patient, comprising administering to the patient Compound 3, or a composition thereof.

[0142] In some embodiments, the present invention provides methods of treating various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to said patient compound 3 or a crystalline form described herein. In some embodiments, the present invention provides methods of treating one or more of the diseases, disorders, or conditions described herein.

[0143] Compound 4 (tosylate of compound A) According to one embodiment, the present invention provides a tosylate salt of compound A, represented by compound 4: [ka] to provide.

[0144] By "tosylate" is meant p-toluenesulfonate, i.e., an ionic form of p-toluenesulfonic acid. It will be understood by those skilled in the art that p-toluenesulfonic acid and compound A are ionically bonded to form compound 4. It is contemplated that compound 4 can exist in various physical forms. For example, compound 4 can exist in a solution, a suspension, or in a solid form. In certain embodiments, compound 4 is in a solid form. When compound 4 is in a solid form, the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0145] In some embodiments, the present invention provides compound 4 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain a significant amount of extraneous material. Such extraneous material can include excess p-toluenesulfonic acid, excess compound A, residual solvent, or any other impurities that may result from the preparation and / or isolation of compound 4. In certain embodiments, compound 4 is present at least about 95% by weight. In yet other embodiments of the present invention, compound 4 is present at least about 99% by weight.

[0146] According to one embodiment, compound 4 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 percent by weight, where the percentages are based on the total weight of the composition. According to another embodiment, compound 4 contains less than about 3.0 HPLC area percent of total organic impurities relative to the total area of ​​the HPLC chromatogram, and in certain embodiments, less than about 1.5 HPLC area percent of total organic impurities. In other embodiments, compound 4 contains less than about 1.0% HPLC area percent of any single impurity, less than about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than about 0.5 HPLC area percent of any single impurity relative to the total area of ​​the HPLC chromatogram.

[0147] The depicted structure of compound 4 is also intended to include all tautomeric forms of compound 4. Additionally, the depicted structures herein are also intended to include compounds which differ only by the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure except for the replacement of a carbon with a C-rich carbon are within the scope of this invention.

[0148] It has been discovered that compound 4 can exist in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0149] In certain embodiments, compound 4 is a crystalline solid. In other embodiments, compound 4 is a crystalline solid that is substantially free of amorphous compound 4. As used herein, the term "substantially free of amorphous compound 4" means that the compound does not contain a significant amount of amorphous compound 4. In certain embodiments, crystalline compound 4 is present at least about 95% by weight. In yet other embodiments of the present invention, crystalline compound 4 is present at least about 99% by weight.

[0150] In some embodiments, compound 4 is amorphous. In some embodiments, compound 4 is amorphous and substantially free of crystalline compound 4.

[0151] Form A of Compound 4 In some embodiments, Form A of compound 4 has at least one, two, three, four or five spectral peaks selected from the peaks listed in Table 8 below. [Table 8-1]

[0152] In some embodiments, Compound 4 Form A is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 13.4, about 17.0, and about 25.9 degrees 2θ. In some embodiments, Compound 4 Form A is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 13.4, about 17.0, and about 25.9 degrees 2θ. In some embodiments, Compound 4 Form A is characterized by having all three peaks in its X-ray powder diffraction pattern selected from peaks at about 13.4, about 17.0, and about 25.9 degrees 2θ.

[0153] In certain embodiments, the powder X-ray diffraction pattern is substantially similar to the XRPD presented in FIG.

[0154] A method for preparing Form A of compound 4 is described below.

[0155] In some embodiments, the present invention provides compound 4: [ka] to provide.

[0156] In some embodiments, the present invention provides compound 4, wherein compound 4 is crystalline.

[0157] In some embodiments, the present invention provides compound 4, which is a crystalline solid that is substantially free of amorphous compound 4.

[0158] In some embodiments, the present invention provides compound 4, wherein the compound 4 is substantially free of impurities.

[0159] In some embodiments, the present invention provides compound 4 having one or more peaks in its XRPD selected from peaks at about 13.4, about 17.0, and about 25.9 degrees 2θ. In some such embodiments, the present invention provides compound 4 having at least two peaks in its XRPD selected from peaks at about 13.4, about 17.0, and about 25.9 degrees 2θ. In some such embodiments, the present invention provides compound 4, which is Form A of the compound.

[0160] In some embodiments, the present invention provides compound 4, having an XRPD substantially similar to the XRPD depicted in FIG.

[0161] In some embodiments, the invention provides a composition comprising compound 4 and a pharma- ceutically acceptable carrier or excipient.

[0162] In some embodiments, the present invention provides a method of inhibiting or preventing accumulation of A2E in a patient, comprising administering to the patient compound 4, or a composition thereof.

[0163] In some embodiments, the present invention provides methods of treating various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to said patient compound 4 or a crystalline form as described herein. In some embodiments, the present invention provides methods of treating one or more of the diseases, disorders, or conditions described herein.

[0164] Compound 5 (hydrochloride of compound A) According to one embodiment, the present invention provides the hydrochloride salt of compound A, represented by compound 5: [ka] to provide.

[0165] It will be understood by those skilled in the art that hydrochloric acid and compound A are ionically bonded to form compound 5. It is contemplated that compound 5 can exist in various physical forms. For example, compound 5 can exist in a solution, a suspension, or in a solid form. In certain embodiments, compound 5 is in a solid form. When compound 5 is in a solid form, the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0166] In some embodiments, the present invention provides compound 5 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain a significant amount of extraneous material. Such extraneous material can include excess hydrochloric acid, excess compound A, residual solvent, or any other impurities that may result from the preparation and / or isolation of compound 5. In certain embodiments, compound 5 is present at least about 95% by weight. In yet other embodiments of the present invention, compound 5 is present at least about 99% by weight.

[0167] According to one embodiment, compound 5 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 percent by weight, where the percentages are based on the total weight of the composition. According to another embodiment, compound 5 contains less than about 3.0 HPLC area percent of total organic impurities relative to the total area of ​​the HPLC chromatogram, and in certain embodiments, less than about 1.5 HPLC area percent of total organic impurities. In other embodiments, compound 5 contains less than about 1.0% HPLC area percent of any single impurity, less than about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than about 0.5 HPLC area percent of any single impurity relative to the total area of ​​the HPLC chromatogram.

[0168] The depicted structure of compound 5 is also intended to include all tautomeric forms of compound 5. Additionally, the depicted structures herein are also intended to include compounds which differ only by the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure except for the replacement of a carbon with a C-rich carbon are within the scope of this invention.

[0169] It has been discovered that compound 5 can exist in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0170] In certain embodiments, compound 5 is a crystalline solid. In other embodiments, compound 5 is a crystalline solid that is substantially free of amorphous compound 5. As used herein, the term "substantially free of amorphous compound 5" means that the compound does not contain a significant amount of amorphous compound 5. In certain embodiments, crystalline compound 5 is present at least about 95% by weight. In yet other embodiments of the present invention, crystalline compound 5 is present at least about 99% by weight.

[0171] In some embodiments, compound 5 is amorphous. In some embodiments, compound 5 is amorphous and substantially free of crystalline compound 5.

[0172] Form A of Compound 5 In some embodiments, Form A of compound 5 has at least one, two, three, four or five spectral peaks selected from the peaks listed in Table 9 below. [Table 9-1]

[0173] In some embodiments, Compound 5 Form A is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 17.0, about 22.6, and about 26.1 degrees 2θ. In some embodiments, Compound 5 Form A is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 17.0, about 22.6, and about 26.1 degrees 2θ. In some embodiments, Compound 5 Form A is characterized by having all three peaks in its X-ray powder diffraction pattern selected from peaks at about 17.0, about 22.6, and about 26.1 degrees 2θ.

[0174] In certain embodiments, the powder X-ray diffraction pattern is substantially similar to the XRPD presented in FIG.

[0175] A method for preparing Form A of compound 5 is described below.

[0176] In some embodiments, the present invention provides compound 5: [ka] to provide.

[0177] In some embodiments, the present invention provides compound 5, wherein compound 5 is crystalline.

[0178] In some embodiments, the present invention provides compound 5, which is a crystalline solid that is substantially free of amorphous compound 5.

[0179] In some embodiments, the present invention provides compound 5, wherein the compound 5 is substantially free of impurities.

[0180] In some embodiments, the present invention provides compound 5, which has one or more peaks in its XRPD selected from peaks at about 17.0, about 22.6, and about 26.1 degrees 2θ. In some such embodiments, the present invention provides compound 5, which has at least two peaks in its XRPD selected from peaks at about 17.0, about 22.6, and about 26.1 degrees 2θ. In some such embodiments, the present invention provides compound 5, which is Form A of the compound.

[0181] In some embodiments, the present invention provides compound 5, having an XRPD substantially similar to the XRPD depicted in FIG.

[0182] In some embodiments, the present invention provides a composition comprising compound 5 and a pharma- ceutically acceptable carrier or excipient.

[0183] In some embodiments, the present invention provides a method of inhibiting or preventing accumulation of A2E in a patient, comprising administering to the patient compound 5, or a composition thereof.

[0184] In some embodiments, the present invention provides methods of treating various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to said patient compound 5 or a crystalline form as described herein. In some embodiments, the present invention provides methods of treating one or more of the diseases, disorders, or conditions described herein.

[0185] Compound 6 (Oxalate of Compound A) According to one embodiment, the present invention provides an oxalate salt of compound A, represented by compound 6: [ka] to provide.

[0186] It is understood by those skilled in the art that oxalic acid and compound A are ionically bonded to form compound 6. It is contemplated that compound 6 can exist in various physical forms. For example, compound 6 can exist in a solution, a suspension, or in a solid form. In certain embodiments, compound 6 is in a solid form. When compound 6 is in a solid form, the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0187] In some embodiments, the present invention provides compound 6 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain a significant amount of extraneous material. Such extraneous material can include excess oxalic acid, excess compound A, residual solvent, or any other impurities that may result from the preparation and / or isolation of compound 6. In certain embodiments, compound 6 is present at least about 95% by weight. In yet other embodiments of the present invention, compound 6 is present at least about 99% by weight.

[0188] According to one embodiment, compound 6 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 percent by weight, where the percentages are based on the total weight of the composition. According to another embodiment, compound 6 contains less than about 3.0 HPLC area percent of total organic impurities relative to the total area of ​​the HPLC chromatogram, and in certain embodiments, less than about 1.5 HPLC area percent of total organic impurities. In other embodiments, compound 6 contains less than about 1.0% HPLC area percent of any single impurity, less than about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than about 0.5 HPLC area percent of any single impurity relative to the total area of ​​the HPLC chromatogram.

[0189] The depicted structure of compound 6 is also intended to include all tautomeric forms of compound 6. Additionally, the depicted structures herein are also intended to include compounds which differ only by the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure except for the replacement of a carbon with a C-rich carbon are within the scope of this invention.

[0190] It has been discovered that compound 6 can exist in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0191] In certain embodiments, compound 6 is a crystalline solid. In other embodiments, compound 6 is a crystalline solid that is substantially free of amorphous compound 6. As used herein, the term "substantially free of amorphous compound 6" means that the compound does not contain a significant amount of amorphous compound 6. In certain embodiments, crystalline compound 6 is present at least about 95% by weight. In yet other embodiments of the present invention, crystalline compound 6 is present at least about 99% by weight.

[0192] In some embodiments, compound 6 is amorphous. In some embodiments, compound 6 is amorphous and substantially free of crystalline compound 6.

[0193] Form A of Compound 6 In some embodiments, Form A of compound 6 has at least one, two, three, four or five spectral peaks selected from the peaks listed in Table 10 below. [Table 10-1]

[0194] In some embodiments, Form A of Compound 6 is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 16.9, about 19.8, and about 25.3 degrees 2θ. In some embodiments, Form A of Compound 6 is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 16.9, about 19.8, and about 25.3 degrees 2θ. In some embodiments, Form A of Compound 6 is characterized by having all three peaks in its X-ray powder diffraction pattern selected from peaks at about 16.9, about 19.8, and about 25.3 degrees 2θ.

[0195] In certain embodiments, the powder X-ray diffraction pattern is substantially similar to the XRPD presented in FIG.

[0196] A method for preparing Form A of compound 6 is described below.

[0197] In some embodiments, the present invention provides compound 6: [ka] to provide.

[0198] In some embodiments, the present invention provides compound 6, where compound 6 is crystalline.

[0199] In some embodiments, the present invention provides compound 6, which is a crystalline solid that is substantially free of amorphous compound 6.

[0200] In some embodiments, the present invention provides compound 6, wherein the compound 6 is substantially free of impurities.

[0201] In some embodiments, the present invention provides compound 6, which has one or more peaks in its XRPD selected from peaks at about 16.9, about 19.8, and about 25.3 degrees 2θ. In some such embodiments, the present invention provides compound 6, which has at least two peaks in its XRPD selected from peaks at about 16.9, about 19.8, and about 25.3 degrees 2θ. In some such embodiments, the present invention provides compound 6, which is Form A of the compound.

[0202] In some embodiments, the present invention provides compound 6, having an XRPD substantially similar to the XRPD depicted in FIG.

[0203] In some embodiments, the present invention provides a composition comprising compound 6 and a pharma- ceutically acceptable carrier or excipient.

[0204] In some embodiments, the present invention provides a method of inhibiting or preventing accumulation of A2E in a patient, comprising administering to the patient compound 6, or a composition thereof.

[0205] In some embodiments, the present invention provides methods of treating various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to said patient compound 6 or a crystalline form as described herein. In some embodiments, the present invention provides methods of treating one or more of the diseases, disorders, or conditions described herein.

[0206] Compound 7 (phosphate salt of compound A) According to one embodiment, the present invention provides a phosphate salt of compound A, represented by compound 7: [ka] to provide.

[0207] It will be understood by those skilled in the art that phosphate and compound A are ionically bonded to form compound 7. It is contemplated that compound 7 can exist in various physical forms. For example, compound 7 can exist in a solution, a suspension, or in a solid form. In certain embodiments, compound 7 is in a solid form. When compound 7 is in a solid form, the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0208] In some embodiments, the present invention provides compound 7 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of extraneous material. Such extraneous material can include excess phosphoric acid, excess compound A, residual solvent, or any other impurities that may result from the preparation and / or isolation of compound 7. In certain embodiments, compound 7 is present at least about 95% by weight. In yet other embodiments of the present invention, compound 7 is present at least about 99% by weight.

[0209] According to one embodiment, compound 7 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 percent by weight, where the percentages are based on the total weight of the composition. According to another embodiment, compound 7 contains less than about 3.0 HPLC area percent of total organic impurities relative to the total area of ​​the HPLC chromatogram, and in certain embodiments, less than about 1.5 HPLC area percent of total organic impurities. In other embodiments, compound 7 contains less than about 1.0% HPLC area percent of any single impurity, less than about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than about 0.5 HPLC area percent of any single impurity relative to the total area of ​​the HPLC chromatogram.

[0210] The depicted structure of compound 7 is also intended to include all tautomeric forms of compound 7. Additionally, the depicted structures herein are also intended to include compounds which differ only by the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure except for the replacement of a carbon with a C-rich carbon are within the scope of this invention.

[0211] It has been discovered that compound 7 can exist in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0212] In certain embodiments, compound 7 is a crystalline solid. In other embodiments, compound 7 is a crystalline solid that is substantially free of amorphous compound 7. As used herein, the term "substantially free of amorphous compound 7" means that the compound does not contain a significant amount of amorphous compound 7. In certain embodiments, crystalline compound 7 is present at least about 95% by weight. In yet other embodiments of the invention, crystalline compound 7 is present at least about 99% by weight.

[0213] In some embodiments, compound 7 is amorphous. In some embodiments, compound 7 is amorphous and substantially free of crystalline compound 7.

[0214] Form A of compound 7 In some embodiments, Form A of compound 7 has at least one, two, three, four or five spectral peaks selected from the peaks listed in Table 11 below. [Table 11-1]

[0215] In some embodiments, Form A of Compound 7 is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 16.8, about 24.3, and about 27.8 degrees 2θ. In some embodiments, Form A of Compound 7 is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 16.8, about 24.3, and about 27.8 degrees 2θ. In some embodiments, Form A of Compound 7 is characterized by having all three peaks in its X-ray powder diffraction pattern selected from peaks at about 16.8, about 24.3, and about 27.8 degrees 2θ.

[0216] In certain embodiments, the powder X-ray diffraction pattern is substantially similar to the XRPD presented in FIG.

[0217] A method for preparing Form A of compound 7 is described below.

[0218] In some embodiments, the present invention provides compound 7: [ka] to provide.

[0219] In some embodiments, the present invention provides compound 7, where compound 7 is crystalline.

[0220] In some embodiments, the present invention provides compound 7, which is a crystalline solid that is substantially free of amorphous compound 7.

[0221] In some embodiments, the present invention provides compound 7, wherein the compound 7 is substantially free of impurities.

[0222] In some embodiments, the present invention provides compound 7, which has one or more peaks in its XRPD selected from peaks at about 16.8, about 24.3, and about 27.8 degrees 2θ. In some such embodiments, the present invention provides compound 7, which has at least two peaks in its XRPD selected from peaks at about 16.8, about 24.3, and about 27.8 degrees 2θ. In some such embodiments, the present invention provides compound 7, which is Form A of the compound.

[0223] In some embodiments, the present invention provides compound 7, having an XRPD substantially similar to the XRPD depicted in FIG.

[0224] In some embodiments, the invention provides a composition comprising compound 7 and a pharma- ceutically acceptable carrier or excipient.

[0225] In some embodiments, the present invention provides a method of inhibiting or preventing accumulation of A2E in a patient, comprising administering to the patient compound 7, or a composition thereof.

[0226] In some embodiments, the present invention provides methods of treating various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to said patient compound 7 or a crystalline form as described herein. In some embodiments, the present invention provides methods of treating one or more of the diseases, disorders, or conditions described herein.

[0227] Compound 8 (camsylate salt of Compound A) According to one embodiment, the present invention provides a camsylate salt of compound A, represented by compound 8: [ka] to provide.

[0228] It will be understood by those skilled in the art that camphorsulfonic acid and compound A are ionically bonded to form compound 8. It is contemplated that compound 8 can exist in various physical forms. For example, compound 8 can exist in a solution, a suspension, or in a solid form. In certain embodiments, compound 8 is in a solid form. When compound 8 is in a solid form, the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0229] In some embodiments, the present invention provides compound 8 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain a significant amount of extraneous material. Such extraneous material may include excess camphorsulfonic acid, excess compound A, residual solvent, or any other impurities that may result from the preparation and / or isolation of compound 8. In certain embodiments, compound 8 is present at least about 95% by weight. In yet other embodiments of the present invention, compound 8 is present at least about 99% by weight.

[0230] According to one embodiment, compound 8 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 percent by weight, where the percentages are based on the total weight of the composition. According to another embodiment, compound 8 contains less than about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than about 1.5 HPLC area percent of total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, compound 8 contains less than about 1.0% HPLC area percent of any single impurity, less than about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than about 0.5 HPLC area percent of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0231] The depicted structure of compound 8 is also intended to include all tautomeric forms of compound 8. Additionally, the depicted structures herein are also intended to include compounds which differ only by the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure except for the replacement of a carbon with a C-rich carbon are within the scope of this invention.

[0232] It has been discovered that compound 8 can exist in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0233] In certain embodiments, compound 8 is a crystalline solid. In other embodiments, compound 8 is a crystalline solid that is substantially free of amorphous compound 8. As used herein, the term "substantially free of amorphous compound 8" means that the compound does not contain a significant amount of amorphous compound 8. In certain embodiments, crystalline compound 8 is present at least about 95% by weight. In yet other embodiments of the invention, crystalline compound 8 is present at least about 99% by weight.

[0234] In some embodiments, compound 8 is amorphous. In some embodiments, compound 8 is amorphous and substantially free of crystalline compound 8.

[0235] Form A of Compound 8 In some embodiments, Form A of compound 8 has at least one, two, three, four or five spectral peaks selected from the peaks listed in Table 12 below. [Table 12-1]

[0236] In some embodiments, Form A of Compound 8 is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.1, about 17.2, and about 18.4 degrees 2θ. In some embodiments, Form A of Compound 8 is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.1, about 17.2, and about 18.4 degrees 2θ. In some embodiments, Form A of Compound 8 is characterized by having all three peaks in its X-ray powder diffraction pattern selected from peaks at about 7.1, about 17.2, and about 18.4 degrees 2θ.

[0237] In certain embodiments, the powder X-ray diffraction pattern is substantially similar to the XRPD presented in FIG.

[0238] A method for preparing Form A of compound 8 is described below.

[0239] In some embodiments, the present invention provides compound 8: [ka] to provide.

[0240] In some embodiments, the present invention provides compound 8, wherein compound 8 is crystalline.

[0241] In some embodiments, the present invention provides compound 8, which is a crystalline solid that is substantially free of amorphous compound 8.

[0242] In some embodiments, the present invention provides compound 8, wherein compound 8 is substantially free of impurities.

[0243] In some embodiments, the present invention provides compound 8 having one or more peaks in its XRPD selected from peaks at about 7.1, about 17.2, and about 18.4 degrees 2θ. In some such embodiments, the present invention provides compound 8 having at least two peaks in its XRPD selected from peaks at about 7.1, about 17.2, and about 18.4 degrees 2θ. In some such embodiments, the present invention provides compound 8, which is Form A of the compound.

[0244] In some embodiments, the present invention provides compound 8, having an XRPD substantially similar to the XRPD depicted in FIG.

[0245] In some embodiments, the invention provides a composition comprising compound 8 and a pharma- ceutically acceptable carrier or excipient.

[0246] In some embodiments, the present invention provides a method of inhibiting or preventing accumulation of A2E in a patient, comprising administering to the patient compound 8, or a composition thereof.

[0247] In some embodiments, the present invention provides methods of treating various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to said patient compound 8 or a crystalline form as described herein. In some embodiments, the present invention provides methods of treating one or more of the diseases, disorders, or conditions described herein.

[0248] Compound 9 (tartrate salt of compound A) According to one embodiment, the present invention provides a tartrate salt of compound A, represented by compound 9: [ka] to provide.

[0249] It is understood by those skilled in the art that tartaric acid and compound A are ionically bonded to form compound 9. It is contemplated that compound 9 can exist in various physical forms. For example, compound 9 can exist in a solution, a suspension, or in a solid form. In certain embodiments, compound 9 is in a solid form. When compound 9 is in a solid form, the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0250] In some embodiments, the present invention provides compound 9 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain a significant amount of extraneous material. Such extraneous material can include excess tartaric acid, excess compound A, residual solvent, or any other impurities that may result from the preparation and / or isolation of compound 9. In certain embodiments, compound 9 is present at least about 95% by weight. In yet other embodiments of the present invention, compound 9 is present at least about 99% by weight.

[0251] According to one embodiment, compound 9 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 percent by weight, where the percentages are based on the total weight of the composition. According to another embodiment, compound 9 contains less than about 3.0 HPLC area percent of total organic impurities relative to the total area of ​​the HPLC chromatogram, and in certain embodiments, less than about 1.5 HPLC area percent of total organic impurities. In other embodiments, compound 9 contains less than about 1.0% HPLC area percent of any single impurity, less than about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than about 0.5 HPLC area percent of any single impurity relative to the total area of ​​the HPLC chromatogram.

[0252] The depicted structure of compound 9 is also intended to include all tautomeric forms of compound 9. Additionally, the depicted structures herein are also intended to include compounds which differ only by the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure except for the replacement of a carbon with a C-rich carbon are within the scope of this invention.

[0253] It has been discovered that compound 9 can exist in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0254] In certain embodiments, compound 9 is a crystalline solid. In other embodiments, compound 9 is a crystalline solid that is substantially free of amorphous compound 9. As used herein, the term "substantially free of amorphous compound 9" means that the compound does not contain a significant amount of amorphous compound 9. In certain embodiments, crystalline compound 9 is present at least about 95% by weight. In yet other embodiments of the present invention, crystalline compound 9 is present at least about 99% by weight.

[0255] In some embodiments, compound 9 is amorphous. In some embodiments, compound 9 is amorphous and substantially free of crystalline compound 9.

[0256] Form A of compound 9 In some embodiments, Form A of compound 9 has at least one, two, three, four or five spectral peaks selected from the peaks listed in Table 13 below. [Table 13-1]

[0257] In some embodiments, Form A of Compound 9 is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.2, about 8.1, and about 16.1 degrees 2θ. In some embodiments, Form A of Compound 9 is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from peaks at about 7.2, about 8.1, and about 16.1 degrees 2θ. In some embodiments, Form A of Compound 9 is characterized by having all three peaks in its X-ray powder diffraction pattern selected from peaks at about 7.2, about 8.1, and about 16.1 degrees 2θ.

[0258] In certain embodiments, the powder X-ray diffraction pattern is substantially similar to the XRPD presented in FIG.

[0259] A method for preparing Form A of compound 9 is described below.

[0260] In some embodiments, the present invention provides compound 9: [ka] to provide.

[0261] In some embodiments, the present invention provides compound 9, which is crystalline.

[0262] In some embodiments, the present invention provides compound 9, which is a crystalline solid that is substantially free of amorphous compound 9.

[0263] In some embodiments, the present invention provides compound 9, wherein the compound 9 is substantially free of impurities.

[0264] In some embodiments, the present invention provides compound 9 having one or more peaks in its XRPD selected from peaks at about 7.2, about 8.1, and about 16.1 degrees 2θ. In some such embodiments, the present invention provides compound 9 having at least two peaks in its XRPD selected from peaks at about 7.2, about 8.1, and about 16.1 degrees 2θ. In some such embodiments, the present invention provides compound 9, which is Form A of the compound.

[0265] In some embodiments, the present invention provides compound 9, having an XRPD substantially similar to the XRPD depicted in FIG.

[0266] In some embodiments, the invention provides a composition comprising compound 9 and a pharma- ceutically acceptable carrier or excipient.

[0267] In some embodiments, the present invention provides a method of inhibiting or preventing accumulation of A2E in a patient, comprising administering to the patient compound 9, or a composition thereof.

[0268] In some embodiments, the present invention provides a method for treating various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to the patient compound 9 or a composition thereof. In some such embodiments, various conditions in a patient in which aldehyde toxicity is implicated in the pathogenesis can include dry eye, cataracts, keratoconus, Fuchs endothelial dystrophy in the cornea, uveitis, allergic conjunctivitis, ocular cicatricial pemphigoid, conditions associated with photorefractive keratomileusis (PRK) healing or other corneal healing, conditions associated with tear lipid breakdown or lacrimal gland dysfunction, inflammatory ocular conditions, such as ocular rosacea (with or without meibomian gland dysfunction), and non-ocular disorders or conditions, such as skin cancer, psoriasis, contact dermatitis, atopic dermatitis, acne vulgaris, Sjogren-Larsson syndrome, ischemia-reperfusion injury, inflammation, diabetes, neurodegeneration (e.g., Parkinson's disease), scleroderma, amyotrophic lateral sclerosis, autoimmune disorders (e.g., lupus), cardiovascular disorders (e.g., atherosclerosis), and conditions associated with the damaging effects of blistering agents.

[0269] In some embodiments, the present invention provides a compound selected from Compound A, Form A; Compound A, Form B; Compound 1, Form A; Compound 1, Form B; Compound 2, Form A; Compound 2, Form B; Compound 3, Form A; Compound 4, Form A; Compound 5, Form A; Compound 6, Form A; Compound 7, Form A; Compound 8, Form A; and Compound 9, Form A. In some such embodiments, the present invention provides a composition comprising one of the above compound forms and a pharma- ceutically acceptable carrier or excipient. In some such embodiments, the present invention provides a method of treating one or more of the diseases, disorders, or conditions described herein.

[0270] General Method for Providing Salt Compounds Compound A is prepared according to the methods detailed in the '500 publication, which is incorporated herein by reference in its entirety. Salt compounds of general formula X, which formula encompasses salt compounds 1-9, and / or specific forms thereof, among others, are prepared from compound A according to the following general scheme: [ka]

[0271] For example, each of Compounds 1-9, and forms thereof, is prepared from Compound A by combining Compound A with an appropriate acid to form a salt of the acid. Accordingly, another aspect of the invention provides methods for preparing Compounds 1-9, and forms thereof.

[0272] As generally described above, in some embodiments, the present invention provides salt compounds of the general formula X: [ka] A method for preparing Compound A: [ka] with a suitable acid, and optionally a suitable solvent, under suitable conditions to form a salt compound of general formula X.

[0273] In some embodiments, the suitable acid is methanesulfonic acid. In some embodiments, the present invention provides a method for making a mesylate salt of compound A. In certain embodiments, the mesylate salt of compound A is compound 1. In certain embodiments, the mesylate salt of compound A is form A of compound 1. In certain embodiments, the mesylate salt of compound A is form B of compound 1.

[0274] In some embodiments, the suitable acid is benzenesulfonic acid. In some embodiments, the present invention provides a method of making a besylate salt of compound A. In certain embodiments, the besylate salt of compound A is compound 2. In certain embodiments, the besylate salt of compound A is Form A of compound 2. In certain embodiments, the besylate salt of compound A is Form B of compound 2.

[0275] In some embodiments, the suitable acid is sulfuric acid. In some embodiments, the present invention provides a method for making a sulfate salt of compound A. In certain embodiments, the sulfate salt of compound A is compound 3. In certain embodiments, the sulfate salt of compound A is form A of compound 3.

[0276] In some embodiments, the suitable acid is p-toluenesulfonic acid. In some embodiments, the present invention provides a method for making a tosylate salt of compound A. In certain embodiments, the tosylate salt of compound A is compound 4. In certain embodiments, the tosylate salt of compound A is form A of compound 4.

[0277] In some embodiments, the suitable acid is hydrochloric acid. In some embodiments, the present invention provides a method for making a hydrochloride salt of compound A. In certain embodiments, the hydrochloric salt of compound A is compound 5. In certain embodiments, the hydrochloric salt of compound A is form A of compound 5.

[0278] In some embodiments, the suitable acid is oxalic acid. In some embodiments, the present invention provides a method for making the oxalate salt of compound A. In certain embodiments, the oxalate salt of compound A is compound 6. In certain embodiments, the oxalate salt of compound A is form A of compound 6.

[0279] In some embodiments, the suitable acid is phosphoric acid. In some embodiments, the present invention provides a method for making a phosphate salt of Compound A. In certain embodiments, the phosphate salt of Compound A is Compound 7. In certain embodiments, the phosphate salt of Compound A is Form A of Compound 7.

[0280] In some embodiments, the suitable acid is camphorsulfonic acid. In some embodiments, the present invention provides a method for making a camsylate salt of compound A. In certain embodiments, the camsylate salt of compound A is compound 8. In certain embodiments, the camsylate salt of compound A is form A of compound 8.

[0281] In some embodiments, the suitable acid is tartaric acid. In some embodiments, the present invention provides a method for making the tartrate salt of compound A. In certain embodiments, the tartrate salt of compound A is compound 9. In certain embodiments, the tartrate salt of compound A is form A of compound 9.

[0282] A suitable solvent can be any solvent system (eg, a solvent or mixture of solvents) in which compound A and / or the acid are soluble or at least partially soluble.

[0283] Examples of suitable solvents useful in the present invention include, but are not limited to, protic solvents, aprotic solvents, polar aprotic solvents, or mixtures thereof. In certain embodiments, suitable solvents include ethers, esters, alcohols, ketones, or mixtures thereof. In some embodiments, the solvent is one or more organic alcohols. In some embodiments, the solvent is chlorinated. In some embodiments, the solvent is an aromatic solvent.

[0284] In certain embodiments, the suitable solvent is methanol, ethanol, isopropanol, or acetone, said solvent being anhydrous or in combination with water or heptane. In some embodiments, suitable solvents include tetrahydrofuran, dimethylformamide, dimethylsulfoxide, glyme, diglyme, methyl t-butyl ether, t-butanol, n-butanol, and acetonitrile. In some embodiments, the suitable solvent is ethanol. In some embodiments, the suitable solvent is anhydrous ethanol. In some embodiments, the suitable solvent is MTBE.

[0285] In some embodiments, the suitable solvent is ethyl acetate. In some embodiments, the suitable solvent is a mixture of methanol and methylene chloride. In some embodiments, the suitable solvent is a mixture of acetonitrile and water. In certain embodiments, the suitable solvent is methyl acetate, isopropyl acetate, acetone, or tetrahydrofuran. In certain embodiments, the suitable solvent is diethyl ether. In certain embodiments, the suitable solvent is water. In certain embodiments, the suitable solvent is methyl ethyl ketone. In certain embodiments, the suitable solvent is toluene.

[0286] In some embodiments, the present invention provides a method for preparing a salt compound of general formula X, comprising one or more steps of removing a solvent and adding a solvent. In some embodiments, the solvent added is the same as the solvent removed. In some embodiments, the solvent added is different from the solvent removed. Means of solvent removal are known in the synthetic and chemical arts, including, but not limited to, any of the means described herein and in the examples.

[0287] In some embodiments, the method for preparing the salt compound of general formula X includes one or more steps of heating or cooling the preparation.

[0288] In some embodiments, the method for preparing the salt compound of general formula X comprises one or more steps of shaking or stirring the preparation.

[0289] In some embodiments, the method for preparing a salt compound of general formula X comprises adding a suitable acid to a solution or slurry of compound A.

[0290] In some embodiments, the method for preparing a salt compound of general formula X comprises a heating step.

[0291] In certain embodiments, the salt compound of formula X precipitates from the mixture. In other embodiments, the salt compound of formula X crystallizes from the mixture. In other embodiments, the salt compound of formula X crystallizes from the solution after seeding the solution (i.e., adding crystals of the salt compound of formula X to the solution).

[0292] The salt compound of formula X can be precipitated from the reaction mixture or can be produced by methods such as removing some or all of the solvent by evaporation, distillation, filtration (e.g., nanofiltration, ultrafiltration), reverse osmosis, absorption and reaction, by adding an anti-solvent, such as heptane, by cooling, or various combinations of these methods.

[0293] As generally described above, the salt compound of formula X is optionally isolated. It is understood that the salt compound of formula X can be isolated by any suitable physical means known to those skilled in the art. In certain embodiments, the precipitated solid salt compound of formula X is separated from the supernatant by filtration. In other embodiments, the precipitated solid salt compound of formula X is separated from the supernatant by decanting the supernatant.

[0294] In certain embodiments, the salt compound of formula X is separated from the supernatant by filtration.

[0295] In certain embodiments, the isolated salt compound of formula X is dried in air. In other embodiments, the isolated salt compound of formula X is dried under reduced pressure, optionally at elevated temperature.

[0296] Uses of the Compounds and Pharmaceutically Acceptable Compositions Thereof Certain compounds described herein have been found to be useful in scavenging toxic aldehydes, such as MDA and HNE. Compounds described herein undergo Schiff base condensation with MDA, HNE, or other toxic aldehydes, forming complexes with aldehydes in energetically favorable reactions, thus reducing or eliminating the aldehydes available for reaction with proteins, lipids, carbohydrates, or DNA. Importantly, compounds described herein can react with aldehydes to form compounds with closed ring structures containing aldehydes, thus capturing aldehydes and preventing them from being released back into the cellular environment.

[0297] As used herein, the terms "treatment", "treat" and "treating" refer to reversing the progression, alleviating, delaying the onset or inhibiting a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment is administered after one or more symptoms have developed. In other embodiments, treatment is administered in the absence of symptoms. For example, treatment is administered to susceptible individuals prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment is also continued after symptoms have resolved, for example, to prevent, delay, or reduce the severity of their recurrence.

[0298] The present invention relates to compounds as described herein for treating, preventing, and / or reducing the risk of a disease, disorder, or condition in which aldehyde toxicity is implicated in the pathogenesis.

[0299] Examples of diseases, disorders, or conditions in which aldehyde toxicity is implicated include, but are not limited to, ocular diseases, disorders, or conditions, including corneal diseases (e.g., dry eye syndrome, cataracts, keratoconus, bullous and other keratopathy, and Fuchs' endothelial dystrophy), other ocular disorders or conditions (e.g., allergic conjunctivitis, ocular cicatricial pemphigoid, conditions associated with PRK healing and other corneal healing, and conditions associated with tear lipid breakdown or lacrimal gland dysfunction), and other ocular conditions associated with high aldehyde levels as a result of inflammation (e.g., uveitis, scleritis, ocular Stevens-Johnson syndrome, ocular rosacea (with or without meibomian gland dysfunction)). In one example, the ocular disease, disorder, or condition is not macular degeneration, such as age-related macular degeneration ("AMD"), or Stargardt's disease. In further examples, the ocular disease, disorder, or condition is dry eye syndrome, ocular rosacea, or uveitis.

[0300] Examples of diseases, disorders, conditions, or indications in which aldehyde toxicity is implicated also include non-ocular disorders including psoriasis, localized (disciform) lupus, contact dermatitis, atopic dermatitis, allergic dermatitis, radiation dermatitis, acne vulgaris, Sjogren-Larsson syndrome and other ichthyoses, actinic elastosis / wrinkles, skin firmness and elasticity, swelling, eczema, smoking or irritant induced skin changes, skin conditions associated with skin incisions, burns and / or wounds, lupus, scleroderma, asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, inflammatory bowel disease, sepsis, atherosclerosis, ischemia-reperfusion injury, Parkinson's disease, Alzheimer's disease, succinic semialdehyde dehydrogenase deficiency, multiple sclerosis, amyotrophic lateral sclerosis, diabetes, metabolic syndrome, age-related disorders, and fibrotic diseases. In a further example, the non-ocular disorder is a skin disease, disorder, or condition selected from contact dermatitis, atopic dermatitis, allergic dermatitis, and radiation dermatitis. In another example, the non-ocular disorder is a skin disease, disorder, or condition selected from Sjogren-Larsson syndrome and cosmetic indications associated with burns and / or wounds.

[0301] In a further example, the disease, disorder, or condition in which aldehyde toxicity is implicated is an age-related disorder. Examples of age-related diseases, disorders, or conditions include skin wrinkling, dryness, and pigmentation.

[0302] Examples of diseases, disorders, or conditions in which aldehyde toxicity is implicated further include conditions associated with the toxic effects of blister agents or burns from alkaline agents. The compounds described herein reduce or eliminate toxic aldehydes, thus treating, preventing, and / or reducing the risk of these diseases or disorders.

[0303] In some embodiments, the present invention relates to the treatment, prevention, and / or reduction of risk of ocular diseases, disorders, or conditions in which aldehyde toxicity is implicated in the pathogenesis, comprising administering a compound described herein to a subject in need thereof.Ocular diseases, disorders, or conditions include, but are not limited to, corneal diseases (e.g., dry eye syndrome, cataracts, keratoconus, bullous keratopathy and other keratopathy, and Fuchs' endothelial dystrophy in the cornea), other ocular disorders or conditions (e.g., allergic conjunctivitis, ocular cicatricial pemphigoid, conditions associated with PRK healing and other corneal healing, and conditions associated with tear lipid breakdown or lacrimal gland dysfunction), and other ocular conditions in which inflammation leads to high aldehyde levels (e.g., uveitis, scleritis, ocular Stevens-Johnson syndrome, ocular rosacea (with or without meibomian gland dysfunction)).Ocular diseases, disorders, or conditions do not include macular degeneration, e.g., AMD, or Stargardt's disease. In one example, in ocular disease, disorder or condition, the amount or concentration of MDA or HNE is increased in ocular tissue or cell.For example, the amount or concentration of aldehyde (e.g., MDA or HNE) is increased by at least 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 2-fold, 2.5-fold, 5-fold, 10-fold when compared with that in normal ocular tissue or cell.Compounds described herein, such as Compound 1, reduce aldehyde (e.g., MDA and HNE) concentration in a time-dependent manner.The amount or concentration of aldehyde (e.g., MDA or HNE) can be measured by methods or techniques known in the art, such as those described in Tukozkan et al., Furat Tip Dergisi, vol. 11:88-92 (2006).

[0304] In one class, the ocular disease, disorder, or condition is dry eye syndrome. In a second class, the ocular disease, disorder, or condition is a condition associated with PRK healing and other corneal healing. For example, the present invention is directed to ongoing PRK healing or other corneal healing, comprising administering a compound described herein to a subject in need thereof. In a third class, the ocular disease, disorder, or condition is an ocular condition associated with high aldehyde levels resulting from inflammation, such as uveitis, scleritis, ocular Stevens-Johnson syndrome, and ocular rosacea (with or without meibomian gland dysfunction). In a fourth class, the ocular disease, disorder, or condition is keratoconus, cataract, bullous keratopathy and other keratopathy, Fuchs endothelial dystrophy, ocular cicatricial pemphigoid, or allergic conjunctivitis. The compounds described herein may be administered topically or systemically as described herein below.

[0305] In a second embodiment, the present invention relates to the treatment, prevention, and / or reduction of risk of skin disorders or conditions, or cosmetic signs, in which aldehyde toxicity is implicated in the pathogenesis, comprising administering a compound as described herein to a subject in need thereof. Skin disorders or conditions include, but are not limited to, psoriasis, scleroderma, localized (disciform) lupus, contact dermatitis, atopic dermatitis, allergic dermatitis, radiation dermatitis, acne vulgaris, and Sjogren-Larsson syndrome and other ichthyoses, and cosmetic signs include actinic elastosis / wrinkles, skin color and firmness, swelling, eczema, smoking or irritant-induced skin changes, skin incisions, or skin conditions associated with burns and / or wounds. In some embodiments, the present invention relates to age-related diseases, disorders, or conditions of the skin, as described herein.

[0306] Various skin disorders or conditions, such as atopic dermatitis, localized (disciform) lupus, psoriasis, and scleroderma, are characterized by high MDA and HNE levels (Br J Dermatol, 149:248 (2003); JEADV, 26:833 (2012); Clin Rheumatol, 25:320 (2006)). In addition, ichthyosis, a characteristic of Sjögren-Larsson syndrome (SLS), is caused by the accumulation of fatty aldehydes, which disrupt the normal function and secretion of lamellar bodies (LBs), leading to intercellular lipid deposition in the stratum corneum (SC) and defective water barrier in skin layers (WB Rizzo et al., 2010). In SLS patients, fatty aldehyde dehydrogenase, an enzyme that metabolizes aldehydes, is dysfunctional. Thus, aldehyde-reducing or -eliminating compounds, such as those described herein, can be used to treat, prevent, and / or reduce the risk of skin disorders or conditions in which aldehyde toxicity is implicated in the pathogenesis, such as those described herein.Furthermore, with the improvement of water barrier and prevention of aldehyde-mediated inflammation, including fibrosis and elastosis (Chairpotto et al., 2005), many cosmetic indications, such as solar elastosis / wrinkles, skin color, firmness (swelling), eczema, smoking or irritant-induced skin changes and skin incision cosmetic procedures, and skin conditions associated with burns and / or wounds, can be treated using the methods of the present invention.

[0307] In one class, the skin disease, disorder or condition is psoriasis, scleroderma, localized (disciform) lupus, contact dermatitis, atopic dermatitis, allergic dermatitis, radiation dermatitis, acne vulgaris, or Sjogren-Larsson syndrome and other ichthyosis. In one example, the skin disease, disorder or condition is contact dermatitis, atopic dermatitis, allergic dermatitis, radiation dermatitis, or Sjogren-Larsson syndrome and other ichthyosis. In a second class, the cosmetic manifestation is actinic elastosis / wrinkles, skin tone, swelling, eczema, smoking or irritant-induced skin changes, skin incisions, or skin conditions associated with burns and / or wounds.

[0308] In a third embodiment, the present invention relates to the treatment, prevention, and / or reduction of the risk of conditions associated with the toxic effects of blister agents or burns from alkaline agents, where aldehyde toxicity is implicated in the pathogenesis, comprising administering to a subject in need thereof a compound as described herein.

[0309] Blistering agents include, but are not limited to, sulfur mustard, nitrogen mustard, and phosgene oxime. The toxic or damaging effects of blistering agents include pain, irritation, and / or tears in the skin, eyes, and / or mucous membranes, as well as conjunctivitis and / or corneal damage to the eye. Sulfur mustard is the compound bis(2-chloroethyl) sulfide. Nitrogen mustards include the compounds bis(2-chloroethyl)ethylamine, bis(2-chloroethyl)methylamine, and tris(2-chloroethyl)amine. Sulfur mustard or its analogs can cause oxidative stress, particularly an increase in HNE levels, and can induce an oxidative stress response by depleting the antioxidant defense system, thereby increasing lipid peroxidation, thus increasing aldehyde levels (Jafari et al. (2010); Pal et al. (2009)). Increased activity of antioxidant enzymes may be a compensatory response to reactive oxygen species generated by sulfur mustard. Antioxidants, such as silibinin, when applied topically, attenuate the skin damage induced by exposure to sulfur mustard or its analogs (Jafari et al. (2010); Tewari-Singh et al. (2012)). Furthermore, interventions that reduce free radical species have been effective post-exposure treatments for phosgene-induced lung injury (Sciuto et al. (2004)). Thus, compounds that reduce or eliminate aldehydes, such as those described herein, can be used to treat, prevent, and / or reduce the risk of conditions associated with the toxic effects of blister agents, such as sulfur mustard, nitrogen mustard, and phosgene oxime.

[0310] Alkaline agents include, but are not limited to, lime, lye, ammonia, and drain cleaners. Compounds that reduce or eliminate aldehydes, such as those described herein, can be used to treat, prevent, and / or reduce the risk of conditions associated with burns from alkaline agents.

[0311] In a fourth embodiment, the present invention relates to the treatment, prevention, and / or reduction of risk of autoimmune, immune-mediated, inflammatory, cardiovascular, or neurological diseases, disorders, or conditions, or metabolic syndrome, or diabetes, in which aldehyde toxicity is implicated in the pathogenesis, comprising administering to a subject in need thereof a compound as described herein. Autoimmune or immune-mediated diseases, disorders, or conditions include, but are not limited to, lupus, scleroderma, asthma, chronic obstructive pulmonary disease (COPD), and rheumatoid arthritis. Inflammatory diseases, disorders, or conditions include, but are not limited to, rheumatoid arthritis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), sepsis, and fibrosis (e.g., renal, hepatic, pulmonary, and cardiac fibrosis). Cardiovascular diseases, disorders, or conditions include, but are not limited to, atherosclerosis and ischemia-reperfusion injury. Diseases, disorders, or conditions of the nervous system include, but are not limited to, Parkinson's disease, Alzheimer's disease, succinic semialdehyde dehydrogenase deficiency, multiple sclerosis, amyotrophic lateral sclerosis, and neurological aspects of Sjogren-Larsson syndrome (cognitive delay and spasticity).

[0312] Those skilled in the art understand that the diseases, disorders or conditions listed herein may involve more than one pathological mechanism.For example, the diseases, disorders or conditions listed herein may involve dysregulation in immune and inflammatory responses.Therefore, the above classification of diseases, disorders or conditions is not absolute, and the diseases, disorders or conditions may be considered to be immune, inflammatory, cardiovascular, nervous system, and / or metabolic diseases, disorders or conditions.

[0313] Individuals with aldehyde dehydrogenase deficiency have been found to have high aldehyde levels and increased risk of Parkinson's disease (PNAS, 110:636 (2013)) and Alzheimer's disease (BioChem Biophys Res Commun., 273:192 (2000)). In Parkinson's disease, aldehydes specifically interfere with the physiological function of dopamine (Free Radic Biol Med, 51:1302 (2011); Mol Aspects Med, 24:293 (2003); Brain Res, 1145:150 (2007)). Additionally, aldehyde levels are elevated in multiple sclerosis, amyotrophic lateral sclerosis, autoimmune diseases such as lupus, rheumatoid arthritis, psoriasis, scleroderma, and fibrotic diseases, and increased levels of HNE, MDA, glyoxal, and methylglyoxal are associated with the progression of atherosclerosis and diabetes (J. Cell. Mol. Med. 15:1339 (2011); Arthritis Rheum 62:2064 (2010); Clin Exp Immunol 101:233 (1995); Int J Rheum Dis 14:325 (2011); JEADV 26:833 (2012); Clin Rheumatol, 25:320 (2006); Gut, 54:987 (2005); J Am Soc Nephrol, 20:2119 (2009); Curr. Aging Sci., 10:18 (2017); Oxid. Med. Cell Longev. Paper 1625130 (2017). MDA has further been implicated in the increased formation of foam cells that lead to atherosclerosis (Leibundgut et al., Current Opinion in Pharmacology, 13:168 (2013)). In addition, aldehyde-related toxicity plays an important role in the pathogenesis of many inflammatory lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD) (Bartoli et al., Mediators of Inflammation, 2011, Paper 891752).Therefore, compounds that reduce or eliminate aldehydes, such as those described herein, can be used to treat, prevent, and / or reduce the risk of autoimmune, immune-mediated, inflammatory, cardiovascular, or neurological diseases, disorders, or conditions, or metabolic syndrome, or diabetes.For example, compounds described herein prevent aldehyde-mediated cell death in neurons.In addition, compounds described herein downregulate a wide range of pro-inflammatory cytokines and / or upregulate anti-inflammatory cytokines, indicating that compounds described herein are useful for treating inflammatory diseases, such as multiple sclerosis and amyotrophic lateral sclerosis.

[0314] As discussed above, the disclosed compositions can be administered to a subject to treat or prevent macular degeneration and other forms of retinal disease whose pathogenesis involves the accumulation of A2E and / or lipofuscin. Other diseases, disorders, or conditions characterized by the accumulation of A2E can be treated similarly.

[0315] In one embodiment, a compound that reduces the formation of A2E is administered to a subject.For example, the compound can compete with PE for reaction with trans-RAL, thereby reducing the amount of A2E that is formed.In another embodiment, a compound that prevents the accumulation of A2E is administered to a subject.For example, the compound can compete with PE for reaction with trans-RAL quite successfully, and A2E is not formed.

[0316] Treated individuals are classified into three groups: (1) those who are clinically diagnosed with macular degeneration or other forms of retinal disease whose etiology involves A2E and / or lipofuscin accumulation, based on visual defects (including but not limited to dark adaptation, contrast sensitivity and acuity) as determined by visual inspection and / or electroretinography, and / or retinal health as shown by fundoscopic examination of retinal and RPE tissues for drusen accumulation, tissue atrophy and / or lipofuscin fluorescence, (2) those who are presymptomatic to macular degenerative disease but are considered to be at risk based on abnormal results on any or all of the same measures, and (3) those who are presymptomatic but are considered to be genetically at risk based on a family history of macular degenerative disease and / or genotyping results indicating one or more alleles or polymorphisms associated with the disease. The compositions are administered topically or systemically, one or more times per month, week or day. Dosage can be selected to avoid side effects in dark-adapted visual performance in some cases.Treatment continues for at least 1 month, 3 months, 6 months, or 12 months, or longer.Patients can be examined at intervals of 1 month, 3 months, 6 months, or 12 months, or longer, to evaluate safety and efficacy.Efficacy is measured by examining the above-mentioned visual performance and retinal health.

[0317] In one embodiment, the subject is diagnosed with symptoms of macular degeneration and then administered the disclosed compound. In another embodiment, the subject can be identified as at risk for developing macular degeneration (risk factors include smoking history, age, female gender, and family history) and then administered the disclosed compound. In another embodiment, the subject can have dry AMD in both eyes and then administered the disclosed compound. In another embodiment, the subject can have wet AMD in one eye but dry AMD in the other eye and then administered the disclosed compound. In yet another embodiment, the subject can be diagnosed with Stargardt's disease and then administered the disclosed compound. In another embodiment, the subject is diagnosed with symptoms of other forms of retinal disease whose etiology involves accumulation of A2E and / or lipofuscin and then administered the compound. In another embodiment, a subject may be identified as at risk of developing other forms of retinal disease whose etiology involves accumulation of A2E and / or lipofuscin, and then the disclosed compound is administered. In some embodiments, the compound is administered prophylactically. In some embodiments, a subject is diagnosed with a disease before retinal damage is evident. For example, a subject is found to carry a genetic mutation for ABCA4 and is diagnosed as at risk for Stargardt's disease before any ophthalmic signs are evident, or a subject is found to have early macular changes indicative of macular degeneration before the subject is aware of any impact on vision. In some embodiments, a human subject may know that they are in need of treatment or prevention of macular generation.

[0318] In some embodiments, the subject may be monitored for the extent of macular degeneration. The subject may be monitored in various ways, for example, by eye examination, dilated eye examination, fundus examination, visual acuity test, and / or biopsy. The monitoring may be performed at various times. For example, the subject may be monitored after the compound is administered. The monitoring may be performed, for example, one day, one week, two weeks, one month, two months, six months, one year, two years, five years, or any other period of time after the first administration of the compound. The subject may be monitored repeatedly. In some embodiments, the dose of the compound may be changed in response to the monitoring.

[0319] In some embodiments, the disclosed methods involve treating macular degeneration, or a condition in which A2E and / or A2C are implicated in the pathogenesis thereof. The present invention may be combined with other methods for treating or preventing other forms of retinal disease involving accumulation of lipofuscin, such as photodynamic therapy.For example, a patient may be treated with more than one therapy for one or more diseases or disorders.For example, a patient may have one eye suffering from dry AMD, which is treated with the compound of the present invention, and the other eye suffering from wet AMD, which is treated with, for example, photodynamic therapy.

[0320] In some embodiments, compounds for treating or preventing macular degeneration or other forms of retinal disease whose pathogenesis involves accumulation of A2E and / or lipofuscin may be administered chronically. Compounds may be administered daily, more than once a day, twice a week, three times a week, weekly, biweekly, monthly, bimonthly, semi-annually, annually, and / or biennially.

[0321] Sphingosine 1-phosphate, a bioactive signaling molecule with diverse cellular functions, is irreversibly degraded by the endoplasmic reticulum enzyme sphingosine 1-phosphate lyase to yield trans-2-hexadecenal and phosphoethanolamine. trans-2-hexadecenal has been demonstrated to cause cytoskeletal reorganization, abscission, and apoptosis in multiple cell types via a JNK-dependent pathway. See Biochem Biophys Res Commun. 2012 Jul 20;424(1):18-21. These findings and the known chemical properties of related α,β-unsaturated aldehydes raise the possibility that trans-2-hexadecenal may interact with additional cellular constituents. trans-2-Hexadecenal was shown to react readily with deoxyguanosine and DNA to produce the diastereoisomers of the cyclic 1,N(2)-deoxyguanosine adducts 3-(2-deoxy-β-d-erythro-pentofuranosyl)-5,6,7,8-tetrahydro-8R-hydroxy-6R-tridecylpyrimido[1,2-a]purin-10(3H)one and 3-(2-deoxy-β-d-erythro-pentofuranosyl)-5,6,7,8-tetrahydro-8S-hydroxy-6S-tridecylpyrimido[1,2-a]purin-10(3H)one. These findings demonstrate that trans-2-hexadecenal produced endogenously by sphingosine 1-phosphate lyase reacts directly with DNA adducts derived from DNA-forming aldehydes that potentially have mutagenic consequences.

[0322] Succinic semialdehyde dehydrogenase deficiency (SSADHD), also known as 4-hydroxybutyric aciduria or gamma-hydroxybutyric aciduria, is the most common autosomal recessive genetic disorder of GABA metabolism (Vogel et al., 2013), which presents with developmental delay and hypotonia in early childhood, and severe expressive language disorder and obsessive-compulsive disorder phenotypes in adolescence and adulthood. Epilepsy usually occurs in half of patients as generalized tonic-clonic seizures, but occasionally, absence and myoclonic seizures occur (Pearl et al., 2014). In adolescence and adulthood, more than two-thirds of patients present with potentially disabling neuropsychiatric problems (i.e., ADHD, OCD, and aggression). Metabolically, there is an accumulation of the major inhibitory neurotransmitters, GABA and gamma-hydroxybutyrate (GHB), a neuromodulatory monocarboxylic acid (Snead and Gibson, 2005). In addition, several other intermediates specific to the disorder have been detected in both patients and the corresponding murine model. Vigabatrin (VGB; γ-vinyl-GABA), an irreversible inhibitor of GABA-transaminase, is a logical choice for the treatment of SSADH deficiency, since it prevents the conversion of GABA to GHB by inhibiting GABA transaminase. Outcomes are variable, and in selected patients, treatment has led to deterioration (Good, 2011; Pellock, 2011; Escalera et al., 2010; Casarano et al., 2011; Matern et al., 1996; Al-Essa et al., 2000). Targeted therapy for SSADH deficiency remains elusive and interventions are palliative.

[0323] As discussed above, the compounds of the present disclosure are used to treat inflammatory disorders. In some embodiments, the compounds are administered to subjects in a therapeutically effective amount to treat systemic inflammatory disorders. In some embodiments, the systemic inflammatory disorders are non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), inflammatory bowel disease (IBD) Crohn's disease, ulcerative colitis (UC), psoriasis, IBS (irritable bowel syndrome or spastic colon), including spastic colon, ankylosing spondylitis, osteoporosis, rheumatoid arthritis (RA), psoriatic arthritis, chronic obstructive pulmonary disease (COPD), interstitial lung disease (including idiopathic pulmonary fibrosis), atherosclerosis, psoriatic arthritis, pulmonary arterial fibrosis, pulmonary ... Hypertension, pyridoxine-dependent epilepsy, atopic dermatitis, rosacea, multiple sclerosis (MS), systemic lupus erythematosus (SLE), lupus nephritis, sepsis, eosinophilic esophagitis, chronic kidney disease (CKD), fibrotic kidney disease, chronic eosinophilic pneumonia, extrinsic allergic alveolitis, pre-eclampsia, endometriosis, polycystic ovary syndrome (PCOS), reduced female fertility, reduced sperm viability and motility, or cyclophosphamide-induced hemorrhagic cystitis.

[0324] In some embodiments, the compound of the present disclosure is used to treat systemic disease, disorder or condition.In some embodiments, the systemic disease, disorder or condition is light chain deposition disease, IgA nephropathy, end-stage renal disease, gout, pseudogout, diabetic nephropathy, diabetic neuropathy, traumatic brain injury, noise-induced hearing loss, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, primary biliary cirrhosis, primary sclerosing cholangitis, uterine leiomyoma, sarcoidosis or chronic kidney disease.In some embodiments, the compound of the present disclosure is administered in an amount effective for treating non-alcoholic fatty liver disease (NAFLD).

[0325] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat non-alcoholic steatohepatitis (NASH).

[0326] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat inflammatory bowel disease (IBD).

[0327] In some embodiments, the compounds of the disclosure are administered in an amount effective to treat Crohn's disease.

[0328] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat ulcerative colitis (UC).

[0329] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat psoriasis.

[0330] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat IBS (irritable bowel syndrome) or spastic colon.

[0331] In some embodiments, the compounds of the disclosure are administered in an amount effective to treat ankylosing spondylitis.

[0332] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat osteoporosis.

[0333] In some embodiments, the compounds of the disclosure are administered in an amount effective to treat rheumatoid arthritis (RA).

[0334] In some embodiments, the compounds of the disclosure are administered in an amount effective to treat psoriatic arthritis.

[0335] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat chronic obstructive pulmonary disease (COPD).

[0336] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat interstitial lung disease, including idiopathic pulmonary fibrosis.

[0337] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat atherosclerosis.

[0338] In some embodiments, the compounds of the disclosure are administered in an amount effective to treat psoriatic arthritis.

[0339] In some embodiments, the compounds of the disclosure are administered in an amount effective to treat pulmonary arterial hypertension.

[0340] In some embodiments, the compounds of the disclosure are administered in an amount effective to treat pyridoxine-dependent epilepsy.

[0341] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat atopic dermatitis.

[0342] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat rosacea.

[0343] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat multiple sclerosis (MS).

[0344] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat systemic lupus erythematosus (SLE).

[0345] In some embodiments, the compounds of the disclosure are administered in an amount effective to treat lupus nephritis.

[0346] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat sepsis.

[0347] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat eosinophilic esophagitis.

[0348] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat chronic kidney disease (CKD).

[0349] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat fibrotic kidney disease.

[0350] In some embodiments, the compounds of the disclosure are administered in an amount effective to treat chronic eosinophilic pneumonia.

[0351] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat extrinsic allergic alveolitis.

[0352] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat pre-eclampsia.

[0353] In some embodiments, the compounds of the disclosure are administered in an amount effective to treat endometriosis.

[0354] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat polycystic ovary syndrome (PCOS).

[0355] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat reduced female fertility.

[0356] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat reduced sperm viability and motility.

[0357] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat cyclophosphamide-induced hemorrhagic cystitis.

[0358] In some embodiments, the inflammatory disorder is an ocular inflammatory disorder. In some embodiments, the ocular inflammatory disorder is diabetic macular edema (DME), atopic keratoconjunctivitis (AKC), vernal keratoconjunctivitis (VKC), age-related macular degeneration (AMD), dry eye disease (DED), allergic conjunctivitis (AC), dry eye disease with allergic conjunctivitis, non-infectious anterior uveitis, posterior uveitis, panuveitis, postoperative eye pain and inflammation.

[0359] In some embodiments, the compounds of the present disclosure are administered in an amount effective to prevent corneal fibrosis following radial keratotomy, to prevent corneal fibrosis following trauma or exposure to rubeogenic agents, or to prevent corneal fibrosis following infection. In some embodiments, the compound of the present disclosure is administered in an amount effective for treating diabetic macular edema (DME).In some embodiments, the diabetic macular edema for treatment is non-clinically significant macular edema (non-CSME).In some embodiments, the diabetic macular edema for treatment is clinically significant macular edema (CSME).

[0360] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat uveitis, including panuveitis, anterior uveitis, posterior uveitis, and non-infectious uveitis, which are eye disorders that may be secondary to primary underlying disorders. Some of the disorders that uveitis is sometimes associated with are Behcet's syndrome, ankylosing spondylitis, Lyme disease, sarcoidosis, and psoriasis. Uveitis is inflammation of the iris, ciliary body, and choroid. Uveitis is associated with blurred vision; seeing dark floating spots ("floats"); eye pain; redness of the eye; and sensitivity to light (photophobia). The standard course of treatment for uveitis is topical corticosteroids, and in some cases, dilators, such as cyclopentolate or immunomodulators.

[0361] In some embodiments, the compounds of the disclosure are administered in an amount effective to treat atopic keratoconjunctivitis (AKC) or vernal keratoconjunctivitis (VKC).

[0362] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat age-related macular degeneration (AMD).

[0363] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat dry eye disease (DED).

[0364] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat allergic conjunctivitis (AC).

[0365] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat dry eye disease associated with allergic conjunctivitis.

[0366] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat post-operative ocular pain and inflammation.

[0367] In some embodiments, the compounds of the present disclosure are administered in an amount effective to prevent corneal fibrosis following radial keratotomy.

[0368] In some embodiments, the compounds of the present disclosure are administered in an amount effective to prevent corneal fibrosis following trauma.

[0369] In some embodiments, the compounds of the present disclosure are administered in an amount effective to prevent corneal fibrosis following infection.

[0370] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat non-alcoholic fatty liver disease (NAFLD).

[0371] In some embodiments, the compounds of the disclosure are administered in an amount effective to treat and / or prevent light chain deposition disease.

[0372] In some embodiments, the compounds of the disclosure are administered in an amount effective to treat and / or prevent IgA nephropathy.

[0373] In some embodiments, the compounds of the disclosure are administered in an amount effective to treat and / or prevent end stage renal disease.

[0374] In some embodiments, the compounds of the disclosure are administered in an amount effective to treat and / or prevent gout.

[0375] In some embodiments, the compounds of the disclosure are administered in an amount effective to treat and / or prevent pseudogout.

[0376] In some embodiments, the compounds of the disclosure are administered in an amount effective to treat and / or prevent diabetic nephropathy.

[0377] In some embodiments, the compounds of the disclosure are administered in an amount effective to treat and / or prevent diabetic neuropathy.

[0378] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat and / or prevent traumatic brain injury.

[0379] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat and / or prevent noise-induced hearing loss.

[0380] In some embodiments, the compounds of the disclosure are administered in an amount effective to treat and / or prevent Alzheimer's disease.

[0381] In some embodiments, the compounds of the disclosure are administered in an amount effective to treat and / or prevent Parkinson's disease.

[0382] In some embodiments, the compounds of the disclosure are administered in an amount effective to treat and / or prevent Huntington's disease.

[0383] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat and / or prevent amyotrophic lateral sclerosis.

[0384] In some embodiments, the compounds of the disclosure are administered in an amount effective to treat and / or prevent primary biliary cirrhosis.

[0385] In some embodiments, the compounds of the present disclosure are administered in an amount effective to treat and / or prevent primary sclerosing cholangitis.

[0386] In some embodiments, the compounds of the disclosure are administered in an amount effective to treat and / or prevent uterine leiomyomas.

[0387] In some embodiments, the compounds of the disclosure are administered in an amount effective to treat and / or prevent sarcoidosis.

[0388] In some embodiments, the compounds of the disclosure are administered in an amount effective to treat and / or prevent chronic kidney disease.

[0389] Pharmaceutically acceptable compositions The compounds and compositions according to the method of the present invention are administered using any amount and any route of administration effective to treat or reduce the severity of the disorders presented above. The exact amount required will vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the infection, the specific drug, its mode of administration, and the like. The compounds of the present invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of drug appropriate for the patient to be treated. However, it is understood that the total daily usage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend on a variety of factors, including the disorder and severity of the disorder to be treated; the activity of the specific compound used; the specific composition used; the age, weight, general health, sex and diet of the patient; the time of administration, route of administration and excretion rate of the specific compound used; the duration of treatment; the drugs used in combination or simultaneously with the specific compound used, and similar factors well known in the medical field.

[0390] The pharma- ceutically acceptable compositions of the invention may be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (by powder, ointment or drops), orally, as an oral or nasal spray, etc., depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention are administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg, preferably about 1 mg / kg to about 25 mg / kg, of the subject's body weight per day, one or more times per day to obtain the desired therapeutic effect.

[0391] Liquid dosage forms for oral administration include, but are not limited to, pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings and aromatics.

[0392] Injectable preparations, for example, sterile aqueous or oily suspensions for injection, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Injectable sterile preparations can also be injectable sterile solutions, suspensions or emulsions, for example, in 1,3-butanediol, in parenterally acceptable non-toxic diluents or solvents. Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile non-volatile oils are commonly used as solvents or suspension media. For this purpose, any non-irritating non-volatile oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids, such as oleic acid, are used in the preparation of injectables.

[0393] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other injectable sterile medium prior to use.

[0394] In order to prolong the effect of the compounds of the present invention, it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its rate of dissolution, which in turn may depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers, such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues. Subcutaneous depot formulations are also prepared using hyaluronidase.

[0395] Compositions for rectal or vaginal administration can be prepared by mixing the compounds of the present invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or a suppository wax, which is solid at ambient temperature but liquid at body temperature and thus will melt in the rectum or vaginal cavity and release the active compound, preferably a suppository.

[0396] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharma- ceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) bulking agents or extenders, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose and acacia, c) humectants, such as glycerol, d) disintegrants, such as agar, calcium carbonate, etc. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents.

[0397] Similar types of solid compositions may also be used as fillers in soft and hard filled gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and may also be of a composition that releases the active ingredient(s) only or preferentially in a certain part of the intestinal tract, optionally with a delayed release. Examples of embedding compositions that can be used include polymeric substances and waxes. Similar types of solid compositions may also be used as fillers in soft and hard filled gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0398] As mentioned above, the active compound can also be in microencapsulated form with one or more excipients. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound can be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms can also contain additional substances other than the inert diluent, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose, as is normal practice. In the case of capsules, tablets, and pills, the dosage forms can also contain buffering agents. They can optionally contain opacifying agents and can also be of a composition that releases the active ingredient(s) only or preferentially in a certain part of the intestinal tract, optionally with a delay. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0399] Dosage forms for topical or transdermal administration of the compounds of the invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is admixed under sterile conditions with a pharma- ceutical acceptable carrier, and any necessary preservatives, or buffers, as required. Ophthalmic formulations, ear drops, and eye drops are also contemplated as being within the scope of the invention. Additionally, the invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0400] The compounds of the present invention can also be administered topically, for example, directly to the eye, for example, as eye drops or eye ointments. Eye drops typically contain an effective amount of at least one compound of the present invention and a carrier that can be safely applied to the eye. For example, eye drops are in the form of an isotonic solution, and the pH of the solution is adjusted so as not to cause eye irritation. In many cases, the epithelial barrier prevents the penetration of molecules into the eye. Therefore, most currently used ophthalmic drugs are supplemented with some form of penetration enhancer. These penetration enhancers work by loosening the tight junctions of the uppermost epithelial cells (Burstein, 1985, Trans Ophthalmol Soc UK 104(Pt4):402-9; Ashton et al., 1991, J Pharmacol Exp Ther 259(2):719-24; Green et al., 1971, Am J Ophthalmol 72(5):897-905). The most commonly used penetration enhancer is benzalkonium chloride, which also acts as a preservative against microbial contamination (Tang et al., 1994, J Pharm Sci 83(1):85-90; Burstein et al., 1980, Invest Ophthalmol Vis Sci 19(3):308-13). Benzalkonium chloride is typically added to a final concentration of 0.01-0.05%.

[0401] The term "biological sample" as used herein includes, but is not limited to, cell cultures or extracts thereof, biopsies or extracts thereof obtained from mammals, and blood, saliva, urine, stool, semen, tears or other bodily fluids, or extracts thereof.

[0402] Combination therapy Depending on the particular condition or disease being treated, additional therapeutic agents that are normally administered to treat that condition may be administered in combination with the compounds and compositions of the invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease or condition are known as "appropriate for the disease or condition being treated."

[0403] In certain embodiments, a provided compound or composition thereof is administered in combination with another therapeutic agent.

[0404] Additional therapeutic agents may be administered separately from the combination therapy provided as part of a multiple dose regimen. Alternatively, these agents may be part of a single dosage form, mixed together with the compound of the present invention in a single composition. When administered as part of a multiple dose regimen, the two active agents may be delivered simultaneously, sequentially, or within a period of each other.

[0405] As used herein, the terms "combination," "in combination," and related terms refer to simultaneous or sequential administration of therapeutic agents according to the invention. For example, the combination of the invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or may be administered together in a single unit dosage form.

[0406] The amount of additional therapeutic agent present in the compositions of the invention is no more than the amount that would normally be administered in a composition containing that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions of the present disclosure ranges from about 50% to 100% of the amount that would normally be present in a composition containing that agent as the only therapeutically active agent.

[0407] In one embodiment, the present invention provides a composition comprising a compound of formula I and one or more additional therapeutic agents. The therapeutic agent may be administered together with the compound of formula I, or before or after the compound of formula I. Suitable therapeutic agents are described in more detail below. In certain embodiments, the compound of formula I may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours or 18 hours before the therapeutic agent. In other embodiments, the compound of formula I may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours after the therapeutic agent.

[0408] In some embodiments, the present invention provides a method of treating a disorder described herein, comprising administering a provided compound or composition thereof in combination with an additional therapeutic agent, in some embodiments, the additional therapy is the standard of care for the disorder being treated.

[0409] As used herein, the term "standard of care" refers to a treatment that is accepted by medical professionals as an appropriate treatment for a particular type of disease and is widely used by medical practitioners. Also known as best practice, standard of care, and standard of care. Those skilled in the art will recognize standard of care treatment protocols for the treatment of the disorders described herein.

[0410] In another embodiment, the present invention provides a method of treating an inflammatory disease, disorder or condition by administering to a patient in need of such treatment a compound of formula I and one or more additional therapeutic agents. Such additional therapeutic agents can be small molecules or recombinant biological agents, such as nonsteroidal anti-inflammatory drugs (NSAIDS), such as anti-inflammatory agents selected from aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids, such as prednisone, prednisolone, methylprednisolone, hydrocortisone, methotrexate (Rheumatrex®), "anti-TNF" agents, such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®). , certolizumab pegol (Cimzia®) and adalimumab (Humira®), "anti-IL-1" agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), canakinumab (Ilaris®), anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab (Rituxan®), "anti-T cell" agents such as abatacept (Orencia®) or "anti-IL-6" agents such as tocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®).

[0411] In some embodiments, the present invention provides a method of treating allergic conjunctivitis in a patient in need of such treatment, comprising administering to the patient a provided compound or a composition thereof in combination with an additional therapeutic agent useful for treating allergy or at least one allergy-related symptom. In some embodiments, the additional therapeutic agent is an antihistamine. In some embodiments, the antihistamine is selected from fexofenadine (Allegra), terfenadine (Seldane), triprolidine (Zymine), brompheniramine (Lodrane), chlorpheniramine (Chlor-Trimeton), cetirizine, diphenhydramine, carbinoxamine, promethazine, loratedine (Claritin), desloratadine (Clarinex), cetirizine (Zyrtec), clemastine (Allerhist), levocetirizine (Xyzal) or hydroxyzine (Atarax).

[0412] In some embodiments, the additional therapeutic agent is an anti-allergy agent. Such anti-allergy agents are well known in the art and include anti-inflammatory nasal sprays, eye drops, nasal decongestants (e.g., oxymetazoline, phenylephrine or pseudoephedrine) and immunotherapy (e.g., allergy shots). Such agents include mast cell inhibitors (e.g., cromolyn sodium) and leukotriene inhibitors (e.g., Singulair). In some embodiments, the additional therapeutic agent is cetirizine (e.g., Zerviate, a cetirizine ophthalmic solution).

[0413] In some embodiments, the second therapeutic agent is a leukotriene inhibitor, a nonsteroidal anti-inflammatory drug (NSAID), a steroid, a tyrosine kinase inhibitor, a receptor kinase inhibitor, a modulator of the nuclear receptor family of transcription factors, an HSP90 inhibitor, an adenosine receptor (A2A) agonist, a disease-modifying antirheumatic drug (DMARDS), a phosphodiesterase (PDE) inhibitor, a neutrophil elastase inhibitor, a modulator of Axl kinase, or a combination thereof.

[0414] In some embodiments, the second therapeutic agent is a leukotriene inhibitor. In some embodiments, the leukotriene inhibitor is montelukast, zafirlukast, pranlukast, zileuton, or a combination thereof.

[0415] In some embodiments, the second therapeutic agent is an NSAID. In some embodiments, the NSAID is acetylsalicylic acid, diflunisal, salsalate, ibuprofen, dexibuprofen, naioxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, nabumetone, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, phenylbutazone, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxib or combinations thereof.

[0416] In some embodiments, the second therapeutic agent is a steroid, hi some embodiments, the steroid is prednisone, prednisolone, methylprednisone, triamcinolone, betamethasone, dexamethasone and their prodrugs.

[0417] In some embodiments, the second therapeutic agent is a tyrosine kinase inhibitor, hi some embodiments, the tyrosine kinase inhibitor is an inhibitor of the above kinases, including, inter alia, JAK, Syk, JNK / SAPK, MAPK, PI-3K, or Ripk2. In some embodiments, the tyrosine kinase inhibitor is ruxolitinib, tofacitinib, oclactinib, filgotinib, ganotinib, lestaurtinib, momelotinib, pacritinib, upadacitinib, peficitinib, fedratinib, bentamapimod, D-JNKI-1 (XG-102, AM-111), ponatinib, WEHI-345, OD36, GSK583, idelalisib, copanlisib, taselisib, duvelisib, alpelisib, umbralisib, dactolisib, CUDC-907, entospletinib, fostamatinib, or a combination thereof.

[0418] In some embodiments, the second therapeutic agent is a receptor kinase inhibitor, including, inter alia, an inhibitor of EGFR or HER2. In some embodiments, the receptor kinase inhibitor is gefitinib, erlotinib, neratinib, lapatinib, cetuximab, panitumumab, vandetanib, necitumumab, osimertinib, trastuzumab, neratinib, lapatinib, pertuzumab, or a combination thereof.

[0419] In some embodiments, the second therapeutic agent is a modulator of the nuclear receptor family of transcription factors, including, inter alia, inhibitors of PPAR, RXR, FXR or LXR. In some embodiments, the inhibitor is pioglitazone, bexarotene, obeticholic acid, ursodeoxycholic acid, fexaramine, hypocholamide, or a combination thereof.

[0420] In some embodiments, the second therapeutic agent is an Hsp90 inhibitor. In some embodiments, the Hsp90 inhibitor is ganetespib, 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010, or a combination thereof.

[0421] In some embodiments, the second therapeutic agent is an adenosine receptor (A2A) agonist.In some embodiments, the adenosine receptor agonist is disclosed in, inter alia, US9,067,963, which is incorporated herein by reference.In some embodiments, the adenosine receptor agonist is LNC-3050, LNC-3015, LNC-3047, LNC-3052 or combinations thereof.

[0422] In some embodiments, the second therapeutic agent is a disease-modifying antirheumatic drug (DMARDS). In some embodiments, the DMARDS is, inter alia, tocilizumab, certolizumab, etanercept, adalimumab, anakinra, abatacept, infliximab, rituximab, golimumab, utesukinumab, or a combination thereof.

[0423] In some embodiments, the second therapeutic agent is a phosphodiesterase (PDE) inhibitor. In some embodiments, the phosphodiesterase inhibitor is apremilast, crisaborole, picrimilast, drotaverine, ibudurast, roflumilast, sildenafil, tadalafil, vardenafil, or a combination thereof.

[0424] In some embodiments, the second therapeutic agent is a neutrophil elastase inhibitor. In some embodiments, the neutrophil elastase inhibitor is, inter alia, sivelestat.

[0425] In some embodiments, the second therapeutic agent is a modulator of Axl kinase. In some embodiments, the modulator of Axl kinase is bemcentinib (BGB324 or R428), TP-0903, LY2801653, amuvatinib (MP-470), bosutinib (SKI-606), MGCD265, ASP2215, cabozantinib (XL184), foretinib (GSK1363089 / XL880) or SGI-7079. In some embodiments, the modulator of Axl kinase is a monoclonal antibody targeting AXL (e.g., YW327.6S2) or AXL decoy receptor (e.g., GL2I.T)) or glesatinib, merestinib or a dual Flt3-Axl inhibitor, e.g., gilteritinib.

[0426] All features of each of the aspects of the invention apply to all other aspects mutatis mutandis.

[0427] In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any way. EXAMPLES

[0428] Example As shown in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures: While the general methods are directed to the synthesis of certain specific compounds of the invention, it is understood that the following general methods, as well as other methods known to those of skill in the art, may be applied to all compounds and each subclass and species of these compounds described herein.

[0429] General Procedure Powder X-ray diffraction patterns were collected on one of two instruments, a Bruker AXS C2 GADDS diffractometer or a Bruker AXS D8 Advance diffractometer.

[0430] For powder X-ray diffraction patterns collected on a Bruker AXS C2 GADDS diffractometer, the following parameters were used: Powder X-ray diffraction patterns were collected using Cu Kα radiation (40 kV, 40 mA), an automated XYZ stage, a laser video microscope for automated sample positioning, and a HiStar 2D area detector. The X-ray lens included a single Goebel multilayer mirror connected to a 0.3 mm pinhole collimator. The instrument is qualified using a certified corundum standard (NIST 1976). The beam divergence (i.e., the effective size of the X-ray beam relative to the sample) was approximately 4 mm. A θ-θ continuous scan mode was used with a sample-to-detector distance of 20 cm, which gives an effective 2θ range of 3.2° to 29.7°. Typically, samples are exposed to the X-ray beam for 120 seconds. The software used for data collection was GADDS for XP / 2000 4.1.43 and Diffrac Plus EVA v15.0.0.0 was used to analyze and present the data.

[0431] Ambient conditions: Samples processed under ambient conditions were prepared as flat specimens using the as-obtained powder without grinding. Approximately 1-2 mg of sample was lightly pressed onto a glass slide to obtain a flat surface. Non-ambient conditions: Samples processed under non-ambient conditions were mounted onto a silicon wafer with a thermally conductive compound. The samples were then heated to the appropriate temperature at 20°C / min and subsequently held isothermal for 1 min before data collection began.

[0432] For powder X-ray diffraction patterns collected on a Bruker AXS D8 Advance diffractometer, the following parameters were used: Powder X-ray diffraction patterns were collected using Cu Kα radiation (40 kV, 40 mA), theta-2theta goniometer with V4 divergent and receiving slits, Ge monochromator and Lynxeye detector. The instrument is validated using a certified corundum standard (NIST1976). The software used for data collection was Diffrac Plus XRD Commander v2.6.1 and Diffrac Plus EVA v15.0.0.0 was used to analyze and present the data. Samples were processed under ambient conditions as flat specimens using the powder obtained as is. Samples were loosely packed into cavities cut into polished zero background (510) silicon wafers. Samples were rotated in their own plane during analysis. The details for data collection are as follows: A) angle range: 2-42° 2θ; B) step size: 0.05° 2θ; and C) collection time: 0.5 s / step.

[0433] Proton nuclear magnetic resonance (1H NMR) spectra were collected on a Bruker 400 MHz instrument equipped with an autosampler and controlled by a DRX400 console. Automated experiments were acquired using ICON-NMR v4.0.7 running on Topspin v1.3 using standard Bruker on-board experiments. For non-routine spectroscopy, data were acquired using Topspin alone. Samples were prepared in DMSO-d6 unless otherwise stated. Offline analysis was performed using an ACD Spectrus Processor 2014.

[0434] Differential scanning calorimetry (DSC) data were collected on a TA Instruments Q2000 equipped with a 50-position autosampler. Heat capacity calibration was performed using sapphire, and energy and temperature calibrations were performed using certified indium. Typically, 0.5-3 mg of each sample in a pinhole aluminum pan was heated at 10 °C / min from 25 °C to 300 °C. A purge of 50 ml / min of dry nitrogen was maintained over the sample. Temperature modulated DSC was performed using a base heating rate of 2 °C / min, and temperature adjustment parameters of ±0.318 °C (amplitude) every 60 seconds (period). The instrument control software was Advantage for Q Series v2.8.0.394 and Thermal Advantage v5.5.3, and data were analyzed using Universal Analysis v4.5A.

[0435] Thermogravimetric analysis (TGA) data were collected on a TA Instruments Q500 TGA equipped with a 16-position autosampler. The instrument was temperature calibrated using certified alumel and nickel. Typically, 5-10 mg of each sample was placed on a pre-tared aluminum DSC pan and heated at 10 °C / min from ambient to 350 °C. A nitrogen purge of 60 ml / min was maintained over the samples. The instrument control software was Advantage for Q Series v2.5.0.256 and Thermal Advantage v5.5.3, and data were analyzed using Universal Analysis v4.5A.

[0436] Example A General Preparation of Compound A [ka] The title compound was prepared according to the steps and intermediates described below and in the '500 publication (eg, Scheme 1), which is incorporated herein by reference in its entirety. [ka]

[0437] Step 1: Synthesis of intermediate A-1 A 2 L round bottom flask was charged with ethanol (220 mL) and pyridine (31 g, 392 mmol) and the resulting solution was stirred at a gentle agitation rate under nitrogen. To this solution was added ethyl bromopyruvate (76.6 g, 354 mmol) in a slow steady stream. The reaction mixture was stirred at 65±5° C. for 2 hours.

[0438] Step 2: Synthesis of intermediate A-2 Upon completion of the 2 hour stirring period in Example 1, the reaction mixture was slowly cooled to 18-22°C. The flask was vacuum purged three times, at which point 2-amino-5-chloro-benzaldehyde (ACB) (50.0 g, 321 mmol) was added as a solid directly to the reaction flask using a long plastic funnel. Pyridine (64.0 g, 809 mmol) was added, followed by an EtOH rinse (10 mL), and the reaction mixture was heated under nitrogen at 80±3°C for approximately 16 hours (overnight), at which point HPLC analysis indicated the reaction was effectively complete.

[0439] Step 3: Synthesis of intermediate A-3 The reaction mixture from Example 2 was cooled to approximately 70° C. and morpholine (76.0 g, 873 mmol) was added to a 2 L reaction flask using an addition funnel. The reaction mixture was heated at 80±2° C. for approximately 2.5 hours, at which point the reaction was deemed complete by HPLC analysis (area % of A-3 had stopped increasing). The reaction mixture was cooled to 10-15° C. for quenching, workup and isolation.

[0440] Step 4: Isolation of intermediate A-3 A 2 L reaction flask was charged with water (600 g) using a dropping funnel over 30-60 min, adjusting the rate of addition and using a cooling bath to maintain the temperature below 15 °C. The reaction mixture was stirred at 10-15 °C for an additional 45 min, and then crude A-3 was isolated by filtration using a Buchner funnel. The cake was washed with water (100 mL x 4), each time applying vacuum after percolation of the cake with water. The cake was air-dried to give crude A-3 as a nearly dry brown solid. The cake was returned to the 2 L reaction flask, heptane (350 mL) and EtOH (170 mL) were added, and the mixture was heated to 70 ± 3 °C for 30-60 min. The slurry was cooled to 0-5 °C and isolated by filtration under vacuum. A-3 was dried in a vacuum drying oven under vacuum and at 35±3° C. overnight (16-18 hours) to give A-3 as a dark green solid.

[0441] Step 5: Synthesis of compound A A 2 L round bottom flask was charged with methylmagnesium chloride (200 mL of a 3.0 M solution in THF, 600 mmol). The solution was cooled to 0-5° C. using an ice bath.

[0442] A 500 mL flask (magnetic stirring) was charged with 22.8 grams of A-3 from Example 4 and THF (365 mL), stirred to dissolve, then transferred to an addition funnel on a 2 L reaction flask. The A-3 solution was added dropwise to the reaction flask over 5.75 hours, maintaining the temperature of the reaction flask between 0-5° C. throughout the addition. At the end of the addition, the contents of the flask were stirred at 0-5° C. for an additional 15 minutes, then the cooling bath was removed and the reaction was stirred at ambient temperature overnight.

[0443] The reaction mixture was carefully quenched by cooling the flask in an ice bath and adding EtOH (39.5 g, 857 mmol) dropwise to the reaction mixture, maintaining the temperature of the reaction mixture below 15° C. during the course of the addition. An aqueous solution of NH4Cl (84.7 g NH4Cl in 415 mL water) was then carefully added and the mixture was stirred under gentle agitation for approximately 30 minutes and then transferred to a separatory funnel to separate the layers. Solids were present in the aqueous phase, so HOAc (12.5 g) was added and the contents were gently swirled to obtain a nearly homogenous aqueous phase at the bottom. The lower aqueous layer was transferred back to the 2 L reaction flask and stirred with 2-methylTHF (50 mL) for approximately 15 minutes under gentle agitation. The original upper organic layer was reduced in volume to approximately 40 mL at ≦40° C. using a rotary evaporator and under vacuum if necessary. The phases in the separatory funnel were separated and the upper 2-MeTHF phase was combined with the product residue, transferred to a 500 mL flask and vacuum distilled to a volume of approximately 25 mL. To this residue, 2-MeTHF (50 mL) was added and distilled to a volume of approximately 50 mL. The crude Compound A solution was diluted with 2-MeTHF (125 mL), cooled to 5-10 °C, 2M H2SO4 (aq) (250 mL) was added slowly and the mixture was stirred for 30 minutes to return to ambient temperature. Heptane (40 mL) was charged and the reaction mixture was stirred for an additional 15 minutes, then transferred to a separatory funnel and the layers separated. The lower aqueous product layer was extracted with additional heptane (35 mL) and the lower aqueous phase was then transferred to a 1 L reaction flask equipped with a mechanical stirrer and the mixture was cooled to 5-10 °C. The combined organic layers were discarded. A solution of 25% NaOH (aqueous) was prepared (NaOH, 47 g, water 200 mL) and added slowly to a 1 L reaction flask to achieve a pH in the range of 6.5-8.5.

[0444] EtOAc (250 mL) was added and the mixture was stirred overnight. The mixture was transferred to a separatory funnel and the lower phase was discarded. The upper organic layer was washed with brine (25 mL) and then the upper organic product layer was reduced in volume on a rotary evaporator to give crude compound A as a dark oil that solidified within minutes. Crude compound A was dissolved in EtOAc (20 mL) and filtered through a plug of silica gel (23 g) and eluted with 3 / 1 heptane / EtOAc until all compound A had eluted (approximately 420 mL was required) to remove most of the dark coloration of compound A. The solvent was removed in vacuo to give 14.7 g of compound A as a tan solid. Compound A was dissolved in EtOAc (25 mL) and eluted through a column of silica gel (72 g) using a mobile phase gradient of 7 / 1 heptane / EtOAc to 3 / 1 heptane / EtOAc (total 1400 mL). The solvent fractions containing compound A were removed, and compound A was diluted with EtOAc (120 mL) and stirred in a flask containing Darco G-60 decolorizing charcoal (4.0 g) for about 1 h. The mixture was filtered through Celite using a fitted funnel, and the cake was rinsed with EtOAc (3×15 mL). The combined filtrate was removed on a rotary evaporator, and compound A was dissolved in heptane (160 mL) / EtOAc (16 mL) at 76° C. The homogeneous solution was slowly cooled to 0-5° C. and held for 2 h, and then compound A was isolated by filtration. After drying in a vacuum oven at 35° C. under full vacuum for 5 h, compound A was obtained as a white solid. HPLC purity: 100% (AUC).

[0445] Example 1 Preparation of Free Base Forms A and B of Compound A [ka] Compound A is prepared according to the methods detailed in Examples 1-5 of the '500 publication, which are incorporated herein by reference in their entirety.

[0446] Form A of Compound A Form A of Compound A was prepared as follows.

[0447] Compound A was dissolved in dichloromethane (DCM, 15 ml). The clear solution was treated with heptane (130 ml) at ambient conditions. The resulting solid was filtered and air-dried.

[0448] Characterization of the resulting material demonstrated it to be a non-hygroscopic, unsolvated crystalline form A.

[0449] Table 1 above is reproduced below and shows the X-ray diffraction peaks observed for Compound A Form A. [Table 1-2]

[0450] FIG. 1 illustrates the XRPD pattern of Form A of Compound A.

[0451] FIG. 2 illustrates the DSC thermogram and TGA trace of Compound A Form A.

[0452] Form B of Compound A Form B of Compound A was prepared as follows.

[0453] Form A (obtained as described immediately above) was treated with a premixed solution of isopropyl alcohol:cyclohexane (700 μl:7 ml) at ambient conditions. The sample was heated to 75° C. and stirred at 75° C. for 5 minutes. The solution was then cooled to 5° C. at a rate of 0.3° C. per minute. After stirring at 5° C. for about 12 hours, an aliquot was analyzed by XRPD. Form A was obtained. Seeds of Form B (AB-1324-09-29) were seeded into the sample. The sample was stirred at 5° C. for 4 days and analyzed by XRPD after filtration.

[0454] Characterization of the resulting material demonstrated it to be a slightly hygroscopic unsolvated crystalline form B.

[0455] Table 2 above is reproduced below and shows the X-ray diffraction peaks observed for Compound A Form B. [Table 2-2]

[0456] FIG. 3 illustrates the XRPD pattern of Form B of Compound A.

[0457] FIG. 4 illustrates the DSC thermogram and TGA trace of Compound A Form B.

[0458] Competitive Slurry of Free Base: This series of experiments was performed using a variety of solvents and solvent combinations. Cross-seeding experiments were performed at a range of temperatures to help clarify the relationship between Form A and Form B.

[0459] Procedure: 21 cross-seeding experiments were performed by adding equal amounts of Forms A and B (wt / wt, 25 mg total). The mixture was slurried in the given solvent / system (approximately 5 volumes, 125 μl) at room temperature and then aged for 72 hours at the designated temperature (5° C., 25° C. or 50° C.). The solids were filtered, air-dried, and analyzed by XRPD. After 2 days, samples 3 and 15 were completely dry and an additional amount of their corresponding solvent was added (250 μl was added to sample 3 and 248.6 μl was added to sample 15). The resulting solids were characterized by XRPD. The results are shown in Table 14 below. [Table 14]

[0460] Competitive slurries of the two anhydrous forms (Form A and Form B) showed that Form B was the most stable form under the conditions investigated. Nevertheless, Form A is stable once isolated. The dominance of a particular form is solvent and temperature dependent. The transition temperature between Form A and Form B is below 50° C., which means that specific methods must be developed and followed to isolate a particular form.

[0461] At 5°C, the majority of the sample converted to form B. The sample from cyclohexane remained as a mixture of forms A and B. At 25°C, all of the sample converted to form B. At 50°C, the majority of the sample converted to form B. The sample from the acetone:water 10% experiment remained as a mixture of forms A and B. The sample from toluene converted to form A. One aspect to consider is that the samples were analyzed after incubation for 3 days at the specified temperature. Longer incubation times seem to favor the formation of form B, suggesting that the formation of form B is driven by kinetic factors, which in turn means that the holding time is an important parameter to consider during the crystallization progression. It was not possible to establish a monotropic or enantiotropic relationship between the two forms. If either pure form A or pure form B is isolated from this experiment, this form remains stable and does not convert to the other. However, if form A remains in the solvent medium during extended incubation, form A converts to form B.

[0462] Example 2 Preparation of Forms A and B of Compound 1 [ka] Form A of Compound 1 Compound 1 Form A was prepared as follows.

[0463] Compound A was dissolved in EtOH (10 volumes, 500 μl) at ambient conditions. The solution was heated to 50° C. and then treated with methanesulfonic acid (1.0 mol equivalent, added as a stock solution (1M) in THF). A cooling gradient of 0.1° C. / min was applied from 50° C. to 5° C. After 20 hours, the solution was treated with anti-solvent (TBME, 4 ml) at ambient conditions. If no solid was obtained after cooling, the anti-solvent solution was filtered and air-dried, and the resulting solid was further analyzed by appropriate techniques.

[0464] Characterization of the resulting material demonstrated it to be unhydrated crystalline Form A.

[0465] Table 3 above is reproduced below and shows the X-ray diffraction peaks observed for Compound 1, Form A. [Table 3-2]

[0466] FIG. 5 illustrates the XRPD pattern of Compound 1, Form A.

[0467] FIG. 6 illustrates the DSC thermogram and TGA trace of Compound 1, Form A.

[0468] Form B of Compound 1 Form B of Compound 1 was prepared as follows.

[0469] Compound A was dissolved in EtOH (10 volumes, 500 μl) at ambient conditions. This solution was treated with methanesulfonic acid (1.0 mol equivalent, added as a stock solution (1M) in THF) at ambient conditions. A cooling gradient of 0.1° C. / min was applied from 50° C. to 5° C. After 20 hours, the resulting solid was filtered, air-dried, and analyzed by XRPD. This solution was treated with anti-solvent (TBME, 4 ml) at ambient conditions. After stirring at ambient conditions for 48 hours, the resulting solid was filtered, air-dried, and analyzed by the appropriate technique.

[0470] Characterization of the resulting material demonstrated a slightly hygroscopic crystalline form B with the possible hydrated form.

[0471] Table 4 above is reproduced below and shows the X-ray diffraction peaks observed for Compound 1, Form B. [Table 4-2]

[0472] FIG. 7 illustrates the XRPD pattern of Form B of Compound 1.

[0473] FIG. 8 illustrates the DSC thermogram and TGA trace of Compound 1, Form B.

[0474] Example 3 Preparation of Forms A and B of Compound 2 [ka] Form A of Compound 2 Compound 2 Form A was prepared as follows.

[0475] Compound A was dissolved in EtOH (10 volumes, 500 μl) at ambient conditions. The solution was heated to 50° C. and then treated with benzenesulfonic acid (1.0 mol equivalent, added as a stock solution (1M) in THF). A cooling gradient of 0.1° C. / min was applied from 50° C. to 5° C. After 20 hours, the solution was treated with anti-solvent (TBME, 4 ml) at ambient conditions. If no solid was obtained after cooling, the anti-solvent solution was filtered and air-dried, and the resulting solid was further analyzed by appropriate techniques.

[0476] Characterization of the resulting material demonstrated it to be unhydrated Form A which was slightly hygroscopic.

[0477] Table 5 above is reproduced below and shows the X-ray diffraction peaks observed for Compound 2, Form A. [Table 5-2]

[0478] FIG. 9 illustrates the XRPD pattern of Form A of Compound 2.

[0479] FIG. 10 illustrates the DSC thermogram and TGA trace of Compound 2, Form A.

[0480] Form B of Compound 2 Form B of Compound 2 was prepared as follows.

[0481] Compound A was dissolved in EtOH (10 volumes, 500 μl) at ambient conditions. The solution was heated to 50° C. and then treated with benzenesulfonic acid (1.0 mol equivalent, added as a stock solution (1M) in THF). A cooling gradient of 0.1° C. / min was applied from 50° C. to 5° C. After 20 hours, the solution was treated with anti-solvent (TBME, 4 ml) at ambient conditions. If no solid was obtained after cooling, the anti-solvent solution was filtered and air-dried, and the resulting solid was further analyzed by appropriate techniques. An aliquot of the collected solid was then stored at 40° C. / 75% RH for 1 week and analyzed by XRPD.

[0482] This material was only subjected to XRPD analysis.

[0483] Table 6 above is reproduced below and shows the X-ray diffraction peaks observed for Compound 2, Form B. [Table 6-2]

[0484] FIG. 11 illustrates the XRPD pattern of Form B of Compound 2.

[0485] Example 4 Preparation of Form A of Compound 3 [ka] Form A of Compound 3 Compound 3 Form A was prepared as follows.

[0486] Compound A was dissolved in EtOH (10 volumes, 500 μl) at ambient conditions. The solution was heated to 50° C. and then treated with sulfuric acid (1.0 mol equivalent, added as a stock solution (1M) in THF). A cooling gradient of 0.1° C. / min was applied from 50° C. to 5° C. After 20 hours, the solution was treated with anti-solvent (TBME, 4 ml) at ambient conditions. If no solid was obtained after cooling, the anti-solvent solution was filtered and air-dried, and the resulting solid was further analyzed by appropriate techniques.

[0487] Characterization of the resulting material demonstrated it to be unhydrated Form A which was slightly hygroscopic.

[0488] Table 7 above is reproduced below and shows the X-ray diffraction peaks observed for Compound 3, Form A. [Table 7-2]

[0489] FIG. 12 illustrates the XRPD pattern of Form A of Compound 3.

[0490] FIG. 13 illustrates the DSC thermogram and TGA trace of compound 3, Form A.

[0491] Example 5 Preparation of Form A of Compound 4 [ka] Form A of Compound 4 Compound 4 Form A was prepared as follows.

[0492] Compound A was dissolved in EtOH (10 volumes, 500 μl) at ambient conditions. The solution was heated to 50° C. and then treated with toluenesulfonic acid (1.0 mol equivalent, added as a stock solution (1M) in THF). A cooling gradient of 0.1° C. / min was applied from 50° C. to 5° C. After 20 hours, no solid was obtained, then the solution was further cooled at −20° C. for 48 hours. No solid was obtained, then the solution was evaporated at ambient conditions, resulting in a gum. The gum was treated with 500 μl of heptane and left to age for 24 hours (50° C. / room temperature). A solid was obtained from this experiment, then the solid was filtered, air-dried, and analyzed by the appropriate technique.

[0493] Characterization of the resulting material demonstrated a crystalline, possibly hydrated form.

[0494] Table 8 above is reproduced below and shows the X-ray diffraction peaks observed for Compound 4, Form A. [Table 8-2]

[0495] FIG. 14 illustrates the XRPD pattern of Form A of Compound 4.

[0496] FIG. 15 illustrates the DSC thermogram and TGA trace of compound 4, Form A.

[0497] Example 6 Preparation of Form A of Compound 5 [ka] Form A of Compound 5 Compound 5 Form A was prepared as follows.

[0498] Compound A was dissolved in EtOH (10 volumes, 500 μl) at ambient conditions. The solution was heated to 50° C. and then treated with hydrochloric acid (1.0 mol equivalent, added as a stock solution (1 M) in THF). A cooling gradient of 0.1° C. / min was applied from 50° C. to 5° C. After 20 hours, the resulting solid was filtered, air-dried, and analyzed by the appropriate technique.

[0499] Characterization of the resulting material demonstrated it to be a hydrated, slightly hygroscopic crystalline form A.

[0500] Table 9 above is reproduced below and shows the X-ray diffraction peaks observed for Compound 5, Form A. [Table 9-2]

[0501] FIG. 16 illustrates the XRPD pattern of Form A of Compound 5.

[0502] FIG. 17 illustrates the DSC thermogram and TGA trace of compound 5, Form A.

[0503] Example 7 Preparation of Form A of Compound 6 [ka] Form A of Compound 6 Form A of compound 6 was prepared as follows.

[0504] Compound A was dissolved in EtOH (10 volumes, 500 μl) at ambient conditions. The solution was heated to 50° C. and then treated with oxalic acid (1.0 mol equivalent, added as a stock solution (1M) in THF). A cooling gradient of 0.1° C. / min was applied from 50° C. to 5° C. After 20 hours, no solid was obtained and (wand) the solution was cooled at −20° C. for 48 hours. If no solid was obtained after cooling, the solution was treated with anti-solvent (TBME, 500 μl). If no solid was obtained after 24 hours, the solution was evaporated at ambient conditions. After 24 hours, a solid was obtained and analyzed by the appropriate technique.

[0505] Characterization of the resulting material demonstrated it to be crystalline hydrated Form A.

[0506] Table 10 above is reproduced below and shows the X-ray diffraction peaks observed for Compound 6, Form A. [Table 10-2]

[0507] FIG. 18 illustrates the XRPD pattern of Form A of Compound 6.

[0508] FIG. 19 illustrates the DSC thermogram and TGA trace of compound 6, Form A.

[0509] Example 8 Preparation of Form A of Compound 7 [ka] Form A of compound 7 Form A of compound 7 was prepared as follows.

[0510] Compound A was dissolved in EtOH (10 volumes, 1 ml) at ambient conditions. The clear solution was treated with phosphoric acid (1.0 mol equivalent, added as a stock solution (1M) in THF). After the addition of the acid, a clear solution was obtained and treated with 8 ml of the given anti-solvent (heptane). The sample was stirred overnight. The sample was filtered, air-dried at ambient conditions, and analyzed by the appropriate technique.

[0511] Characterization of the resulting material demonstrated it to be a slightly hygroscopic unhydrated crystalline form A.

[0512] Table 11 above is reproduced below and shows the X-ray diffraction peaks observed for Form A of Compound 7. [Table 11-2]

[0513] FIG. 20 illustrates the XRPD pattern of Form A of Compound 7.

[0514] FIG. 21 illustrates the DSC thermogram and TGA trace of Form A of Compound 7.

[0515] Example 9 Preparation of Forms A and B of Compound 8 [ka] Form A of Compound 8 Form A of compound 8 was prepared as follows.

[0516] Compound A was dissolved in EtOH (10 volumes, 500 μl) at ambient conditions. The solution was heated to 50° C. and then treated with camphorsulfonic acid (1.0 mol equivalent, added as a stock solution (1M)). A cooling gradient of 0.1° C. / min was applied from 50° C. to 5° C. After 20 hours, the solution was treated with anti-solvent (TBME, 4 ml) at ambient conditions. If no solid was obtained after cooling, the anti-solvent solution was filtered and air-dried, and the resulting solid was further analyzed by appropriate techniques.

[0517] Characterization of the resulting material demonstrated it to be crystalline anhydrous Form A.

[0518] Table 12 above is reproduced below and shows the X-ray diffraction peaks observed for Form A of Compound 8. [Table 12-2]

[0519] FIG. 22 illustrates the XRPD pattern of Form A of Compound 8.

[0520] FIG. 23 illustrates the DSC thermogram and TGA trace of Form A of Compound 8.

[0521] Example 10 Preparation of Form A of Compound 9 [ka] Form A of compound 9 Form A of compound 9 was prepared as follows.

[0522] Compound A was dissolved in EtOH (10 volumes, 500 μl) at ambient conditions. The solution was heated to 50° C. and then treated with tartaric acid (1.0 mol equivalent, added as a stock solution (1M)). A cooling gradient of 0.1° C. / min was applied from 50° C. to 5° C. After 20 hours, no solid was obtained and (wand) the solution was cooled at −20° C. for 48 hours. If no solid was obtained after cooling, the solution was treated with anti-solvent (TBME, 500 μl). If no solid was obtained after 24 hours, the solution was evaporated at ambient conditions. After 24 hours, a solid was obtained and analyzed by the appropriate technique.

[0523] Characterization of the resulting material demonstrated it to be crystalline hydrated Form A.

[0524] Table 13 above is reproduced below and shows the X-ray diffraction peaks observed for Form A of Compound 9. [Table 13-2]

[0525] FIG. 24 illustrates the XRPD pattern of Form A of Compound 9.

[0526] FIG. 25 illustrates the DSC thermogram and TGA trace of Form A of Compound 9.

[0527] Example 11 Aqueous solubility studies on compounds 1 and 3-8 The aqueous solubility studies of salt compounds 1 and 3-8 were determined by calibration curves. Compounds 1 and 3-8 were each prepared at five different concentration levels (e.g., 0.25 mM, 0.5 mM, 0.75 mM, 1.0 mM, and 2.0 mM) and calibration curves for each salt were derived by plotting the HPLC response measurements against the salt solution concentration.

[0528] Solubility determinations were performed as follows: Salt suspensions were each made by adding 50-100 mg of material to a minimum amount of water (starting with 0.1-0.2 mL). Based on solubility, additional material was added to obtain salt suspensions. The suspensions were then filtered through a 0.25 μm filter, the filtrate was further diluted with water, and the salt solutions were analyzed by HPLC. The concentrations of the injected salt solutions were calculated using the linear equation y=mx+c (Y refers to the HPLC response obtained for the injected salt solution) derived from the calibration curve. The results are shown in Table 15 below. [Table 15]

[0529] As can be seen, compounds 1 and 3-8 were significantly more soluble than the free base compound A, with compound 1 exhibiting the highest solubility.

[0530] While the inventors have described several embodiments of the invention, it will be apparent that the inventors' basic examples may be modified to provide other embodiments that utilize the compounds and methods of the invention. It will therefore be appreciated that the scope of the invention is defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

Claims

1. Compound 1: 【Chemical 37】 The crystal has an XRPD of: 【Table 1A】 or in its XRPD, the crystals are of Form A having the following peaks: 【Table 1B】 The crystals are characterized in that they are form B crystals having a peak of where each peak is ±0.2 degrees. Crystal of compound 1.

2. A composition comprising at least 95% by weight of a crystal of compound 1 described in claim 1.

3. below: 【Chemistry 5】 2. A crystal of compound 1 according to claim 1, having an XRPD as shown in:

4. below: 【Chemistry 7】 2. A crystal of compound 1 according to claim 1, having an XRPD as shown in:

5. A pharma- ceutically acceptable composition comprising a crystal of Compound 1 according to claim 1 and a pharma- ceutically acceptable carrier, excipient or vehicle.

6. Compound 7: 【Chemistry 44】 The crystal is characterized in that the crystal is a crystal of Form A, which has an XRPD of: 【Table 8A】 The present invention is characterized by having a peak of where each peak is ±0.2 degrees. Crystal of compound 7.

7. A pharma- ceutically acceptable composition comprising the crystal of compound 7 of claim 6 and a pharma- ceutically acceptable carrier, excipient or vehicle.

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