Salts and esters of APX3330 and their therapeutic uses

Abstract

The present invention relates to salts and esters of Compound 1 (APX3330). The present invention also provides compositions comprising a salt or ester of Compound 1. The present invention also provides compounds of Formula (I) and Formula (II), and pharmaceutically acceptable salts thereof. The present invention further provides compositions comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or vehicle. The present invention also provides a method for treating or preventing a disease, such as cancer, liver disease, eye disease, cardiovascular disease, fibrosis, or inflammatory disease, comprising administering an effective amount of a salt or ester of Compound 1, or a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 375,647, filed September 14, 2022, the entire disclosure of which is incorporated herein by reference.

[0002] The present invention relates to salts and esters of Compound 1 (APX3330), as well as processes for preparing the salts and esters of Compound 1. The present invention also provides compositions comprising salts or esters of Compound 1. The present invention also provides compounds of Formula (I) and Formula (II), and pharmaceutically acceptable salts thereof. The present invention further provides compositions comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof. The present invention also provides a method for treating or preventing a disease, such as cancer, liver disease, eye disease, cardiovascular disease, fibrosis, or inflammatory disease, comprising administering an effective amount of a salt or ester of Compound 1, or a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, to a subject in need thereof. [Background technology]

[0003] Compound 1 (APX3330), also known as (2E)-2-[(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)methylene]undecanoic acid, (2E)-2-[(4,5-dimethoxy-2-methyl-3,6-dioxocyclohexa-1,4-dien-1-yl)methylidene]undecanoic acid, (2E)-3-[2-(5,6-dimethoxy-3-methyl-1,4-benzoquinoyl)]-2-nonylpropenoic acid, "APX-3330," or "E3330," is currently undergoing clinical trials to evaluate its safety and efficacy in the treatment of diabetic retinopathy and diabetic macular edema. Summary of the Invention

[0004] The present invention provides a calcium salt of Compound 1, which exhibits an X-ray powder diffraction (XRPD) pattern including a peak at 5.8±0.2 degrees 2θ and a peak at 6.3±0.2 degrees 2θ.

[0005] The present invention further provides a calcium salt of Compound 1, which exhibits an XRPD pattern comprising a peak at 5.8±0.2 degrees 2θ, a peak at 6.3±0.2 degrees 2θ, a peak at 13.7±0.2 degrees 2θ, or a peak at 14.1±0.2 degrees 2θ.

[0006] The present invention further provides a calcium salt of Compound 1, exhibiting an XRPD pattern comprising a peak at 4.1±0.2 degrees 2θ, a peak at 5.3±0.2 degrees 2θ, and a peak at 6.3±0.2 degrees 2θ.

[0007] The present invention further provides a calcium salt of Compound 1, which exhibits an XRPD pattern substantially the same as that depicted in Figure 1A.

[0008] The present invention further provides a calcium salt of Compound 1 exhibiting an XRPD pattern comprising the peaks of Table 1 having a relative intensity of at least 10%.

[0009] The present invention further provides a calcium salt of Compound 1, exhibiting an XRPD pattern comprising a peak at 8.0±0.2 degrees 2θ and a peak at 10.1±0.2 degrees 2θ.

[0010] The present invention further provides a calcium salt of Compound 1, which exhibits an XRPD pattern comprising a peak at 8.0±0.2 degrees 2θ, a peak at 10.1±0.2 degrees 2θ, a peak at 13.3±0.2 degrees 2θ, or a peak at 14.6±0.2 degrees 2θ.

[0011] The present invention further provides a calcium salt of Compound 1, exhibiting an XRPD pattern comprising a peak at 5.1±0.2 degrees 2θ, a peak at 5.3±0.2 degrees 2θ, and a peak at 10.1±0.2 degrees 2θ.

[0012] The present invention further provides a calcium salt of Compound 1, which exhibits an XRPD pattern substantially the same as that depicted in Figure 2A.

[0013] The present invention further provides a calcium salt of Compound 1 exhibiting an XRPD pattern comprising the peaks in Table 3 having a relative intensity of at least 10%.

[0014] The present invention further provides an L-arginine salt of Compound 1, exhibiting an XRPD pattern comprising a peak at 11.9±0.2 degrees 2θ, a peak at 19.7±0.2 degrees 2θ, and a peak at 20.2±0.2 degrees 2θ.

[0015] The present invention further provides an L-arginine salt of Compound 1, which exhibits an XRPD pattern substantially the same as that depicted in Figure 4A.

[0016] The present invention further provides an L-arginine salt of Compound 1, exhibiting an XRPD pattern comprising a peak at 3.9±0.2 degrees 2θ, a peak at 13.1±0.2 degrees 2θ, and a peak at 20.3±0.2 degrees 2θ.

[0017] The present invention further provides an L-arginine salt of Compound 1, which exhibits an XRPD pattern substantially the same as that depicted in Figure 4B.

[0018] The present invention further provides the L-phenylalanine salt of Compound 1.

[0019] The present invention further provides an L-histidine salt of Compound 1.

[0020] The present invention further provides an ester of Compound 1, which is a compound having the structure: [ka] where R is C 10 ~C 24 It is a hydrocarbyl group.

[0021] Each of the above compounds is a "compound of the invention."

[0022] The present invention further provides compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier or vehicle (each composition is a "composition of the present invention").

[0023] The present invention further provides a method for treating or preventing an ocular disease, the method comprising administering an effective amount of a compound of the present invention, a composition of the present invention, a compound of formula (I), [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 are each independently H, C1-C6 alkyl, or —C(O)(C1-C6 alkyl), a compound of formula (II), [ka] or a pharmaceutically acceptable salt thereof (wherein R 2 is C1~C 24 The present invention includes administering to a subject in need thereof a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is a hydroxyl group, ...

[0024] The present invention further provides a method for treating or preventing cancer, cardiovascular disease, inflammation, chronic inflammatory disease, rheumatoid arthritis, idiopathic pulmonary fibrosis, acute adult respiratory distress syndrome, asthma, endometriosis, keloid, systemic sclerosis, chemotherapy-induced peripheral neuropathy, stroke, gastrointestinal dysfunction, chronic gastroesophageal reflux disease, von Hippel-Lindau syndrome, or a skin disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention, a composition of the present invention, a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a compound of Formula (II) or a pharmaceutically acceptable salt thereof, a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, or a composition comprising a compound of Formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle.

[0025] The present invention further provides a method for inhibiting angiogenesis, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention, a composition of the present invention, a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a compound of Formula (II) or a pharmaceutically acceptable salt thereof, a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, or a composition comprising a compound of Formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle.

[0026] The present invention further provides a method for inhibiting expression of vascular endothelial growth factor (VEGF) or VEGF protein, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention, a composition of the present invention, a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a compound of Formula (II) or a pharmaceutically acceptable salt thereof, a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, or a composition comprising a compound of Formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle.

[0027] The present invention further provides a method for inhibiting capillary formation, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention, a composition of the present invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof, a compound of formula (II) or a pharmaceutically acceptable salt thereof, a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, or a composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle.

[0028] The present invention further provides a method for treating or preventing liver disease, the method comprising administering an effective amount of a compound of the present invention or a composition of the present invention to a subject in need thereof.

[0029] The present invention further provides a method for suppressing neurological hypersensitivity, the method comprising administering an effective amount of a compound of the present invention, a composition of the present invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof, a compound of formula (II) or a pharmaceutically acceptable salt thereof, a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, or a composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle to a subject in need thereof.

[0030] The present invention further provides a method for treating pain, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention, a composition of the present invention, a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a compound of Formula (II) or a pharmaceutically acceptable salt thereof, a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, or a composition comprising a compound of Formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle.

[0031] The present invention further provides a method for improving DNA base excision repair, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention, a composition of the present invention, a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a compound of Formula (II) or a pharmaceutically acceptable salt thereof, a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, or a composition comprising a compound of Formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle.

[0032] The present invention further provides a method for improving neural DNA repair function, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention, a composition of the present invention, a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a compound of Formula (II) or a pharmaceutically acceptable salt thereof, a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, or a composition comprising a compound of Formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle.

[0033] The present invention further provides a method for treating or preventing geographic atrophy, choroidal neovascularization, or corneal transplant rejection, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention, a composition of the present invention, a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a compound of Formula (II) or a pharmaceutically acceptable salt thereof, a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, or a composition comprising a compound of Formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle.

[0034] The present invention further provides a method for treating diabetic retinopathy (DR), comprising administering to a subject in need thereof an effective amount of the calcium salt of Compound 1, wherein the calcium salt exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 5.8±0.2 degrees 2θ and a peak at 6.3±0.2 degrees 2θ.

[0035] The present invention further provides a method for treating diabetic retinopathy (DR), comprising administering to a subject in need thereof an effective amount of the calcium salt of Compound 1, wherein the calcium salt exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 4.1±0.2 degrees 2θ, a peak at 5.3±0.2 degrees 2θ, and a peak at 6.3±0.2 degrees 2θ.

[0036] The present invention further provides a method for treating diabetic retinopathy (DR), comprising administering to a subject in need thereof an effective amount of the calcium salt of Compound 1, wherein the calcium salt exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 8.0±0.2 degrees 2θ and a peak at 10.1±0.2 degrees 2θ.

[0037] The present invention further provides a method for treating diabetic retinopathy (DR), comprising administering to a subject in need thereof an effective amount of the calcium salt of Compound 1, wherein the calcium salt exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 5.1±0.2 degrees 2θ, a peak at 5.3±0.2 degrees 2θ, and a peak at 10.1±0.2 degrees 2θ.

[0038] The present invention further provides a method for treating diabetic macular edema (DME), comprising administering to a subject in need thereof an effective amount of the calcium salt of Compound 1, wherein the calcium salt exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 5.8±0.2 degrees 2θ and a peak at 6.3±0.2 degrees 2θ.

[0039] The present invention further provides a method for treating diabetic macular edema (DME), comprising administering to a subject in need thereof an effective amount of the calcium salt of Compound 1, wherein the calcium salt exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 4.1±0.2 degrees 2θ, a peak at 5.3±0.2 degrees 2θ, and a peak at 6.3±0.2 degrees 2θ.

[0040] The present invention further provides a method for treating diabetic macular edema (DME), comprising administering to a subject in need thereof an effective amount of the calcium salt of Compound 1, wherein the calcium salt exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 8.0±0.2 degrees 2θ and a peak at 10.1±0.2 degrees 2θ.

[0041] The present invention further provides a method for treating diabetic macular edema (DME), comprising administering to a subject in need thereof an effective amount of the calcium salt of Compound 1, wherein the calcium salt exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 5.1±0.2 degrees 2θ, a peak at 5.3±0.2 degrees 2θ, and a peak at 10.1±0.2 degrees 2θ.

[0042] Each of the above methods is a "method of the present invention." [Brief explanation of the drawings]

[0043] [Figure 1A] 1 shows the XRPD pattern of the calcium salt of Compound 1 obtained as described in Example 1. [Figure 1B] 1 shows an overlay of thermogravimetry (TG) and differential scanning calorimetry (DSC) thermograms of the calcium salt of Compound 1 obtained as described in Example 1. [Figure 1C] 1 shows the FT-IR spectrum of the calcium salt of Compound 1 obtained as described in Example 1. [Figure 1D] 1 shows the FT-IR spectrum of the calcium salt of Compound 1 obtained as described in Example 1. [Figure 1E] 1 shows the FT-Raman spectrum of the calcium salt of Compound 1 obtained as described in Example 1. [Figure 1F] 1 shows the dynamic vapor sorption (DVS) spectrum of the calcium salt of Compound 1 obtained as described in Example 1. [Figure 1G] 1 shows the 1H NMR spectrum of the calcium salt of Compound 1 obtained as described in Example 1. [Figure 2A]1 shows the XRPD pattern of the calcium salt of Compound 1 obtained as described in Example 2. [Figure 2B] 1 shows the 1H NMR spectrum of the calcium salt of Compound 1 obtained as described in Example 2. [Figure 2C] 1 shows a thermogravimetric (TG) thermogram of the calcium salt of Compound 1 obtained as described in Example 2. [Figure 2D] 1 shows a DSC thermogram of the calcium salt of Compound 1 obtained as described in Example 2. [Figure 3A] 1 shows the XRPD pattern of the calcium salt of Compound 1 obtained as described in Example 3. [Figure 3B] 1 shows an overlay of the TG and DSC thermograms of the anhydrous and predominantly amorphous calcium salt of Compound 1 obtained as described in Example 3. [Figure 4A] 1 shows the XRPD pattern of the L-arginine salt of Compound 1 obtained as described in Procedure A of Example 4. [Figure 4B] 1 shows the XRPD pattern of the L-arginine salt of Compound 1 obtained as described in Procedure B of Example 4. [Figure 4C] 1 shows the overlay of the TG and DSC thermograms of the L-arginine salt of Compound 1 obtained as described in Example 4, Procedure A. DETAILED DESCRIPTION OF THE INVENTION

[0044] definition The term "about" immediately preceding a numerical value means ±10% of that numerical value.

[0045] Throughout this specification, numerical ranges are provided for specific quantities. These ranges include all subranges therein. Thus, a range such as "50 to 80" includes all possible ranges therein (e.g., 51 to 79, 52 to 78, 53 to 77, 54 to 76, 55 to 75, 60 to 70, etc.). Furthermore, all values ​​within a given range may be endpoints of the ranges subsumed therein (e.g., a range of 50 to 80 includes ranges with endpoints such as 55 to 80, 50 to 75, etc.).

[0046] As used herein, "effective amount" refers to an amount of a compound or composition that is effective to treat or prevent ocular disease; treat or prevent cancer, cardiovascular disease, inflammation, chronic inflammatory disease, rheumatoid arthritis, idiopathic pulmonary fibrosis, acute adult respiratory distress syndrome, asthma, endometriosis, keloids, systemic sclerosis, chemotherapy-induced peripheral neuropathy, stroke, gastrointestinal dysfunction, chronic gastroesophageal reflux disease, von Hippel-Lindau syndrome, or skin disorders; inhibit angiogenesis; inhibit expression of vascular endothelial growth factor (VEGF) or VEGF protein; inhibit capillary formation; treat or prevent liver disease; suppress neuronal hypersensitivity; treat pain; improve DNA base excision repair; improve neuronal DNA repair function; or treat or prevent geographic atrophy, choroidal neovascularization, corneal transplant rejection, or Barrett's esophagus.

[0047] All weight percentages referred to herein (i.e., "weight %" and "wt %" and w / w) are relative to the total weight of the compound or composition of the invention, as the case may be, unless otherwise specified.

[0048] The term "pharmaceutically acceptable salt" includes base addition salts. Pharmaceutically acceptable salts can be obtained by reacting a compound of the present invention, which functions as an acid, with an inorganic or organic base to form a salt, such as a sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, ammonium, isopropylammonium, trimethylammonium, phenylalanine, arginine, or histidine salt. In some embodiments, a pharmaceutically acceptable salt is a monosalt. In some embodiments, a pharmaceutically acceptable salt is a di-salt. In some embodiments, a pharmaceutically acceptable salt is a tri-salt. Those skilled in the art will further recognize that pharmaceutically acceptable salts can be prepared by reacting a compound with an appropriate inorganic or organic acid or base via any of a number of known methods.

[0049] As used herein in reference to a compound of the invention, an "impurity" is a compound or substance other than the compound of the invention.

[0050] As used herein, "isolated" means isolated from a chemical synthesis reaction mixture. In some embodiments, an isolated compound is at least 95% pure by weight, moles, or volume and contains 5% or less of one or more impurities. "x% pure" means that the compound contains (100-x)% or less of one or more impurities by weight, moles, or volume. In some embodiments, an isolated compound is at least 96%, at least 97%, at least 98%, or at least 99% pure by weight, moles, or volume and contains 4%, 3%, 2%, or 1% or less of impurities, respectively. In some embodiments, one or more impurities, if present, are present in the compound as a weight percent. In some embodiments, one or more impurities, if present, are present in the compound as a mole percent. In some embodiments, one or more impurities, if present, are present in the compound as a volume percent.

[0051] As used herein, "predominantly amorphous," when used in reference to a compound, means a mixture of an amorphous form of the compound and a crystalline form of the compound, the mixture comprising at least 50% of the amorphous form of the compound, based on the weight of the mixture.

[0052] As used herein, "substantially the same as," when used in reference to an XRPD pattern, means that each peak in the XRPD pattern (having a relative intensity of at least 2%) differs from its respective peak in a reference or comparative XRPD pattern by no more than ±0.2 degrees 2θ. The most intense peak in an XRPD pattern is assigned a relative peak intensity of 100%, and the intensities of all other peaks in the XRPD pattern are measured relative to the most intense peak as a reference (relative peak intensities).

[0053] As used herein, "substantially the same as," when used in reference to a DSC thermogram, means that each peak in the DSC thermogram differs from the respective peak in a reference or comparative DSC thermogram by no more than ±3°C.

[0054] As used herein, "substantially the same as," when used in reference to a TG thermogram, means that each peak in the TG thermogram differs from the respective peak in a reference or comparative TG thermogram by no more than ±2%.

[0055] As used herein, "substantially the same as" when used in relation to an FT-IR spectrum means that each peak in the spectrum is within ±5 cm of the respective peak in the reference or comparative FT-IR spectrum. -1 The only differences are:

[0056] As used herein, "substantially the same as," when used in reference to an FT-Raman spectrum, means that each peak in the spectrum is within ±5 cm of the respective peak in a given reference or comparative FT-Raman spectrum. -1 The only differences are:

[0057] As used herein, "stable," when used in reference to a compound, means that the compound contains 10% or less decomposition products, based on the weight of the compound.

[0058] Compounds of the Invention The present invention provides salts of Compound 1, esters of Compound 1, and pharmaceutically acceptable salts of esters of Compound 1.

[0059] Compound 1 has the following structure: [ka]

[0060] In some embodiments, the salt of Compound 1 is a calcium salt of Compound 1, an L-arginine salt of Compound 1, a phenylalanine salt of Compound 1, or a histidine salt of Compound 1. In some embodiments, the salt of Compound 1 is a crystalline salt.

[0061] In some embodiments, the compound of the present invention is the calcium salt of Compound 1.

[0062] In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern including a peak at 4.1±0.2 degrees 2θ, a peak at 5.3±0.2 degrees 2θ, and a peak at 6.3±0.2 degrees 2θ. In some embodiments, the XRPD pattern further includes a peak at 5.8±0.2 degrees 2θ or a peak at 14.1±0.2 degrees 2θ. In some embodiments, the XRPD pattern further includes a peak at 12.8±0.2 degrees 2θ or a peak at 13.7±0.2 degrees 2θ. In some embodiments, the XRPD pattern further includes a peak at 10.8±0.2 degrees 2θ. In some embodiments, the XRPD pattern further includes a peak at 6.1±0.2 degrees 2θ or a peak at 11.4±0.2 degrees 2θ. In some embodiments, the XRPD pattern further includes a peak at 17.6±0.2 degrees 2θ or a peak at 20.3±0.2 degrees 2θ. In some embodiments, the XRPD pattern further comprises a peak at 3.0±0.2 degrees 2θ or a peak at 12.3±0.2 degrees 2θ, hi some embodiments, the XRPD pattern further comprises a peak at 11.4±0.2 degrees 2θ, a peak at 17.6±0.2 degrees 2θ, and a peak at 21.9±0.2 degrees 2θ.

[0063] In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern including a peak at 4.1±0.2 degrees 2θ, a peak at 5.3±0.2 degrees 2θ, and a peak at 6.3±0.2 degrees 2θ. In some embodiments, the XRPD pattern further includes a peak at 5.8±0.2 degrees 2θ or a peak at 13.7±0.2 degrees 2θ. In some embodiments, the XRPD pattern further includes a peak at 12.8±0.2 degrees 2θ or a peak at 14.1±0.2 degrees 2θ. In some embodiments, the XRPD pattern further includes a peak at 12.3±0.2 degrees 2θ. In some embodiments, the XRPD pattern further includes a peak at 11.4±0.2 degrees 2θ. In some embodiments, the XRPD pattern further includes a peak at 10.8±0.2 degrees 2θ.

[0064] In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern including a peak at 4.1±0.2 degrees 2θ, a peak at 5.4±0.2 degrees 2θ, and a peak at 6.4±0.2 degrees 2θ. In some embodiments, the XRPD pattern further includes a peak at 5.8±0.2 degrees 2θ or a peak at 13.8±0.2 degrees 2θ. In some embodiments, the XRPD pattern further includes a peak at 12.8±0.2 degrees 2θ or a peak at 14.2±0.2 degrees 2θ. In some embodiments, the XRPD pattern further includes a peak at 12.3±0.2 degrees 2θ. In some embodiments, the XRPD pattern further includes a peak at 12.0±0.2 degrees 2θ or a peak at 11.4±0.2 degrees 2θ. In some embodiments, the XRPD pattern further includes a peak at 10.8±0.2 degrees 2θ or a peak at 20.9±0.2 degrees 2θ. In some embodiments, the XRPD pattern further comprises a peak at 13.1±0.2 degrees 2θ, a peak at 17.6±0.2 degrees 2θ, and a peak at 23.7±0.2 degrees 2θ.

[0065] In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising a peak at 4.1±0.2 degrees 2θ, a peak at 5.3±0.2 degrees 2θ, and a peak at 6.3±0.2 degrees 2θ, wherein the peaks at 4.1±0.2 degrees 2θ, 5.3±0.2 degrees 2θ, and 6.3±0.2 degrees 2θ have relative peak intensities (%) greater than 30%. In some embodiments, the XRPD pattern further comprises a peak at 5.8±0.2 degrees 2θ or a peak at 14.1±0.2 degrees 2θ, wherein the peaks at 5.8±0.2 degrees 2θ and 14.1±0.2 degrees 2θ have relative peak intensities (%) greater than 15%. In some embodiments, the XRPD pattern further comprises a peak at 12.8±0.2 degrees 2θ or a peak at 13.7±0.2 degrees 2θ, wherein the peaks at 12.8±0.2 degrees 2θ and 13.7±0.2 degrees 2θ have relative peak intensities (%) greater than 10%. In some embodiments, the XRPD pattern further comprises a peak at 10.8±0.2 degrees 2θ, wherein the peaks have relative peak intensities (%) greater than 10%. In some embodiments, the XRPD pattern further comprises a peak at 6.1±0.2 degrees 2θ or a peak at 11.4±0.2 degrees 2θ, wherein the peaks at 6.1±0.2 degrees 2θ and 11.4±0.2 degrees 2θ have relative peak intensities (%) greater than 10%. In some embodiments, the XRPD pattern further comprises a peak at 17.6±0.2 degrees 2θ or a peak at 20.3±0.2 degrees 2θ, wherein the peaks at 17.6±0.2 degrees 2θ and 20.3±0.2 degrees 2θ have relative peak intensities (%) greater than 8%. In some embodiments, the XRPD pattern further comprises a peak at 3.0±0.2 degrees 2θ or a peak at 12.3±0.2 degrees 2θ, wherein the peaks at 3.0±0.2 degrees 2θ and 12.3±0.2 degrees 2θ have relative peak intensities (%) greater than 5%. In some embodiments, the XRPD pattern further comprises a peak at 11.4±0.2 degrees 2θ, a peak at 17.6±0.2 degrees 2θ, or a peak at 21.9±0.2 degrees 2θ, wherein the peak at 11.4±0.2 degrees 2θ, the peak at 17.6±0.2 degrees 2θ, and the peak at 21.9±0.2 degrees 2θ have relative peak intensities (%) greater than 5%.

[0066] In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising a peak at 4.1±0.2 degrees 2θ, a peak at 5.4±0.2 degrees 2θ, and a peak at 6.4±0.2 degrees 2θ, wherein the peaks at 4.1±0.2 degrees 2θ, 5.4±0.2 degrees 2θ, and 6.4±0.2 degrees 2θ have relative peak intensities (%) greater than 30%. In some embodiments, the XRPD pattern further comprises a peak at 5.8±0.2 degrees 2θ or a peak at 13.8±0.2 degrees 2θ, wherein the peaks at 5.8±0.2 degrees 2θ and 13.8±0.2 degrees 2θ have relative peak intensities (%) greater than 15%. In some embodiments, the XRPD pattern further comprises a peak at 12.8±0.2 degrees 2θ or a peak at 14.2±0.2 degrees 2θ, wherein the peaks at 12.8±0.2 degrees 2θ and 14.2±0.2 degrees 2θ have relative peak intensities (%) greater than 10%. In some embodiments, the XRPD pattern further comprises a peak at 12.3±0.2 degrees 2θ, wherein the peaks have relative peak intensities (%) greater than 10%. In some embodiments, the XRPD pattern further comprises a peak at 12.0±0.2 degrees 2θ or a peak at 11.4±0.2 degrees 2θ, wherein the peaks at 12.0±0.2 degrees 2θ and 11.4±0.2 degrees 2θ have relative peak intensities (%) greater than 10%. In some embodiments, the XRPD pattern further comprises a peak at 10.8±0.2 degrees 2θ or a peak at 20.9±0.2 degrees 2θ, wherein the peaks at 10.8±0.2 degrees 2θ and 20.9±0.2 degrees 2θ have relative peak intensities (%) greater than 6%. In some embodiments, the XRPD pattern further comprises a peak at 13.1±0.2 degrees 2θ, a peak at 17.6±0.2 degrees 2θ, or a peak at 23.7±0.2 degrees 2θ, wherein the peaks at 13.1±0.2 degrees 2θ, 17.6±0.2 degrees 2θ, and 23.7±0.2 degrees 2θ have relative peak intensities (%) greater than 5%.

[0067] In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern including a peak at 6.3±0.2 degrees 2θ. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern including a peak at 5.8±0.2 degrees 2θ. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern including a peak at 13.7±0.2 degrees 2θ. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern including a peak at 14.1±0.2 degrees 2θ.

[0068] In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising a peak at 6.3±0.2 degrees 2θ and a peak at 5.8±0.2 degrees 2θ. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising a peak at 6.3±0.2 degrees 2θ and a peak at 14.1±0.2 degrees 2θ. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising a peak at 6.3±0.2 degrees 2θ, a peak at 5.8±0.2 degrees 2θ, and a peak at 14.1±0.2 degrees 2θ. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising a peak at 5.8±0.2 degrees 2θ, a peak at 6.3±0.2 degrees 2θ, and a peak at 13.7±0.2 degrees 2θ. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising a peak at 5.8±0.2 degrees 2θ, a peak at 6.3±0.2 degrees 2θ, a peak at 13.7±0.2 degrees 2θ, or a peak at 14.1±0.2 degrees 2θ. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising a peak at 5.8±0.2 degrees 2θ, a peak at 6.3±0.2 degrees 2θ, a peak at 13.7±0.2 degrees 2θ, and a peak at 14.1±0.2 degrees 2θ.

[0069] In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising a peak at 5.8±0.2 degrees 2θ and a peak at 6.3±0.2 degrees 2θ, hi some embodiments, the XRPD pattern further comprises a peak at 13.7±0.2 degrees 2θ or a peak at 14.1±0.2 degrees 2θ.

[0070] In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising a peak at 5.8±0.2 degrees 2θ and a peak at 6.3±0.2 degrees 2θ, hi some embodiments, the XRPD pattern further comprises a peak at 13.7±0.2 degrees 2θ or a peak at 14.1±0.2 degrees 2θ.

[0071] In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern including a peak at 6.4±0.2 degrees 2θ. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern including a peak at 5.8±0.2 degrees 2θ. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern including a peak at 13.8±0.2 degrees 2θ. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern including a peak at 14.2±0.2 degrees 2θ.

[0072] In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising a peak at 6.4±0.2 degrees 2θ and a peak at 5.8±0.2 degrees 2θ. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising a peak at 6.4±0.2 degrees 2θ and a peak at 14.2±0.2 degrees 2θ. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising a peak at 6.4±0.2 degrees 2θ, a peak at 5.8±0.2 degrees 2θ, and a peak at 14.2±0.2 degrees 2θ. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising a peak at 5.8±0.2 degrees 2θ, a peak at 6.4±0.2 degrees 2θ, and a peak at 13.8±0.2 degrees 2θ. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising a peak at 6.4±0.2 degrees 2θ, a peak at 5.8±0.2 degrees 2θ, a peak at 13.8±0.2 degrees 2θ, or a peak at 14.2±0.2 degrees 2θ. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising a peak at 6.4±0.2 degrees 2θ, a peak at 5.8±0.2 degrees 2θ, a peak at 13.8±0.2 degrees 2θ, and a peak at 14.2±0.2 degrees 2θ.

[0073] In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising a peak at 5.8±0.2 degrees 2θ and a peak at 6.4±0.2 degrees 2θ, hi some embodiments, the XRPD pattern further comprises a peak at 13.8±0.2 degrees 2θ or a peak at 14.2±0.2 degrees 2θ.

[0074] In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising a peak at 5.8±0.2 degrees 2θ and a peak at 6.4±0.2 degrees 2θ, hi some embodiments, the XRPD pattern further comprises a peak at 13.8±0.2 degrees 2θ or a peak at 14.2±0.2 degrees 2θ.

[0075] In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern that includes a peak at 6.3±0.2 degrees 2θ and 1, 2, 3, 4, 5, 6, 7, 8, or 9 peaks from Table 1. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern that includes a peak at 6.3±0.2 degrees 2θ and one, two, three, four, five, six, seven, eight, or nine of the following peaks: a peak at 4.1±0.2 degrees 2θ, a peak at 5.3±0.2 degrees 2θ, a peak at 5.8±0.2 degrees 2θ, a peak at 6.1±0.2 degrees 2θ, a peak at 10.8±0.2 degrees 2θ, a peak at 11.4±0.2 degrees 2θ, a peak at 12.8±0.2 degrees 2θ, a peak at 13.7±0.2 degrees 2θ, and a peak at 14.1±0.2 degrees 2θ.

[0076] In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern that includes a peak at 6.4±0.2 degrees 2θ and 1, 2, 3, 4, 5, 6, 7, 8, or 9 peaks from Table 1. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern that includes a peak at 6.4±0.2 degrees 2θ and one, two, three, four, five, six, seven, eight, or nine of the following peaks: a peak at 4.1±0.2 degrees 2θ, a peak at 5.4±0.2 degrees 2θ, a peak at 5.8±0.2 degrees 2θ, a peak at 11.4±0.2 degrees 2θ, a peak at 12.0±0.2 degrees 2θ, a peak at 12.3±0.2 degrees 2θ, a peak at 12.8±0.2 degrees 2θ, a peak at 13.8±0.2 degrees 2θ, and a peak at 14.2±0.2 degrees 2θ.

[0077] In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising the peaks in Table 1 having a relative peak intensity (%) of greater than 30%. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising the peaks in Table 1 having a relative peak intensity (%) of greater than 20%. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising the peaks in Table 1 having a relative peak intensity (%) of greater than 15%. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising the peaks in Table 1 having a relative peak intensity (%) of greater than 5%.

[0078] In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern substantially similar to that depicted in Figure 1A.

[0079] In some embodiments, the calcium salt of Compound 1 exhibits a DSC thermogram comprising an endothermic peak having a peak maximum between about 80°C and about 84°C. In some embodiments, the calcium salt of Compound 1 exhibits a DSC thermogram comprising an endothermic peak having a peak maximum between about 81°C and about 83°C. In some embodiments, the calcium salt of Compound 1 exhibits a DSC thermogram comprising an endothermic peak having a peak maximum at about 83°C. In some embodiments, the calcium salt of Compound 1 exhibits a DSC thermogram comprising an endothermic peak with an onset at about 58°C. In some embodiments, the calcium salt of Compound 1 exhibits a DSC thermogram comprising an endothermic peak with an onset at about 54°C.

[0080] In some embodiments, the calcium salt of Compound 1 exhibits a DSC thermogram comprising an exothermic peak having a peak maximum from about 213°C to about 216°C. In some embodiments, the calcium salt of Compound 1 exhibits a DSC thermogram comprising an exothermic peak having a peak maximum from about 215°C to about 216°C. In some embodiments, the calcium salt of Compound 1 exhibits a DSC thermogram comprising an exothermic peak having a peak maximum from about 208°C to about 216°C. In some embodiments, the calcium salt of Compound 1 exhibits a DSC thermogram comprising an exothermic peak having a peak maximum from about 210°C to about 214°C. In some embodiments, the calcium salt of Compound 1 exhibits a DSC thermogram comprising an exothermic peak with an onset at about 212°C.

[0081] In some embodiments, the calcium salt of Compound 1 exhibits a DSC thermogram substantially similar to that depicted in Figure 1B.

[0082] In some embodiments, the calcium salt of Compound 1 exhibits a thermogravimetric (TG) thermogram substantially similar to that depicted in Figure 1B.

[0083] In some embodiments, the calcium salt of Compound 1 has a ribozyme activity of 2700 cm -1 ~3500cm -1In some embodiments, the calcium salt of Compound 1 exhibits an FT-IR spectrum that is substantially the same as that shown in FIG. 1C in the region of the spectrum up to 560 cm. -1 ~1700cm -1 The resulting FT-IR spectrum is substantially the same as that shown in FIG. 1D in the region of the spectrum up to 1000 nm.

[0084] In some embodiments, the calcium salt of Compound 1 exhibits an FT-Raman spectrum substantially similar to that depicted in Figure 1E.

[0085] In some embodiments, the calcium salt of Compound 1 exhibits a DVS spectrum substantially similar to that depicted in Figure 1F.

[0086] In some embodiments, the calcium salt of Compound 1 is substantially the same as depicted in FIG. 1G. 1 1 H NMR spectrum.

[0087] In some embodiments, the calcium salt of Compound 1 is a monohydrate.

[0088] In some embodiments, the calcium salt of Compound 1 obtained according to Example 1 is a calcium salt monohydrate.

[0089] In some embodiments, the calcium salt of Compound 1 obtained according to Example 1 is at least about 98% pure by weight. In some embodiments, the calcium salt of Compound 1 obtained according to Example 1 is at least about 99% pure by weight.

[0090] In some embodiments, the calcium salt of Compound 1 obtained according to Example 1 is at least about 98% pure by weight. In some embodiments, the calcium salt of Compound 1 obtained according to Example 1 is at least about 99% pure by weight.

[0091] In some embodiments, the calcium salt of Compound 1 obtained according to Example 1 is at least about 98% pure by weight after exposure to 40°C / 75% RH for 1 week. In some embodiments, the calcium salt of Compound 1 obtained according to Example 1 is at least about 99% pure by weight after exposure to 40°C / 75% RH for 1 week.

[0092] In some embodiments, the calcium salt of Compound 1 exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 5.1±0.2 degrees 2θ, a peak at 5.3±0.2 degrees 2θ, and a peak at 10.1±0.2 degrees 2θ. In some embodiments, the XRPD pattern further comprises a peak at 8.0±0.2 degrees 2θ or a peak at 12.8±0.2 degrees 2θ. In some embodiments, the XRPD pattern further comprises a peak at 13.3±0.2 degrees 2θ, a peak at 17.9±0.2 degrees 2θ, or a peak at 19.6±0.2 degrees 2θ. In some embodiments, the XRPD pattern further comprises a peak at 14.6±0.2 degrees 2θ or a peak at 18.5±0.2 degrees 2θ.

[0093] In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising a peak at 5.1±0.2 degrees 2θ, a peak at 5.3±0.2 degrees 2θ, and a peak at 10.1±0.2 degrees 2θ, wherein the peaks at 5.1±0.2 degrees 2θ, 5.3±0.2 degrees 2θ, and 10.1±0.2 degrees 2θ have relative peak intensities (%) greater than 25%. In some embodiments, the XRPD pattern further comprises a peak at 8.0±0.2 degrees 2θ or a peak at 12.8±0.2 degrees 2θ, wherein the peaks at 8.0±0.2 degrees 2θ and 12.8±0.2 degrees 2θ have relative peak intensities (%) greater than 10%. In some embodiments, the XRPD pattern further comprises a peak at 13.3±0.2 degrees 2θ, a peak at 17.9±0.2 degrees 2θ, or a peak at 19.6±0.2 degrees 2θ, wherein the peaks at 13.3±0.2 degrees 2θ, 17.9±0.2 degrees 2θ, and 19.6±0.2 degrees 2θ have relative peak intensities (%) greater than 10%. In some embodiments, the XRPD pattern further comprises a peak at 14.6±0.2 degrees 2θ or a peak at 18.5±0.2 degrees 2θ, wherein the peak at 14.6±0.2 degrees 2θ or the peak at 18.5±0.2 degrees 2θ have relative peak intensities (%) greater than 8%.

[0094] In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern including a peak at 10.1±0.2 degrees 2θ. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern including a peak at 8.0±0.2 degrees 2θ. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern including a peak at 13.3±0.2 degrees 2θ. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern including a peak at 14.6±0.2 degrees 2θ.

[0095] In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising a peak at 8.0±0.2 degrees 2θ and a peak at 10.1±0.2 degrees 2θ. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising a peak at 10.1±0.2 degrees 2θ and a peak at 14.6±0.2 degrees 2θ. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising a peak at 8.0±0.2 degrees 2θ, a peak at 10.1±0.2 degrees 2θ, and a peak at 13.3±0.2 degrees 2θ. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising a peak at 8.0±0.2 degrees 2θ, a peak at 10.1±0.2 degrees 2θ, and a peak at 14.6±0.2 degrees 2θ. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising a peak at 8.0±0.2 degrees 2θ, a peak at 10.1±0.2 degrees 2θ, a peak at 13.3±0.2 degrees 2θ, or a peak at 14.6±0.2 degrees 2θ. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising a peak at 8.0±0.2 degrees 2θ, a peak at 10.1±0.2 degrees 2θ, a peak at 13.3±0.2 degrees 2θ, and a peak at 14.6±0.2 degrees 2θ.

[0096] In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern that includes a peak at 10.1±0.2 degrees 2θ and 1, 2, 3, 4, 5, 6, 7, 8, or 9 peaks from Table 3. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern that includes a peak at 10.1±0.2 degrees 2θ and one, two, three, four, five, six, seven, eight, or nine of the following peaks: a peak at 5.1±0.2 degrees 2θ, a peak at 5.3±0.2 degrees 2θ, a peak at 7.9±0.2 degrees 2θ, a peak at 12.8±0.2 degrees 2θ, a peak at 13.3±0.2 degrees 2θ, a peak at 14.6±0.2 degrees 2θ, a peak at 17.9±0.2 degrees 2θ, a peak at 18.5±0.2 degrees 2θ, and a peak at 19.6±0.2 degrees 2θ.

[0097] In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising peaks from Table 3 having a relative peak intensity (%) of greater than 25%. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising peaks from Table 3 having a relative peak intensity (%) of greater than 15%. In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern comprising peaks from Table 3 having a relative peak intensity (%) of greater than 12%.

[0098] In some embodiments, the calcium salt of Compound 1 exhibits an XRPD pattern substantially similar to that depicted in Figure 2A.

[0099] In some embodiments, the calcium salt of Compound 1 exhibits a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak with a peak maximum from about 80°C to about 105°C. In some embodiments, the calcium salt of Compound 1 exhibits a DSC thermogram comprising an endothermic peak with a peak maximum from about 90°C to about 105°C. In some embodiments, the calcium salt of Compound 1 exhibits a DSC thermogram comprising an endothermic peak with a peak maximum from about 95°C to about 105°C. In some embodiments, the calcium salt of Compound 1 exhibits a DSC thermogram comprising an endothermic peak with a peak maximum from about 98°C to about 103°C. In some embodiments, the calcium salt of Compound 1 exhibits a DSC thermogram comprising an endothermic peak with a peak maximum at about 101°C. In some embodiments, the calcium salt of Compound 1 exhibits a DSC thermogram comprising an endothermic peak with an onset of about 77°C.

[0100] In some embodiments, the calcium salt of Compound 1 exhibits a DSC thermogram comprising an exothermic peak having a peak maximum from about 210°C to about 216°C. In some embodiments, the calcium salt of Compound 1 exhibits a DSC thermogram comprising an exothermic peak having a peak maximum from about 212°C to about 215°C. In some embodiments, the calcium salt of Compound 1 exhibits a DSC thermogram comprising an exothermic peak having a peak maximum from about 213°C to about 215°C. In some embodiments, the calcium salt of Compound 1 exhibits a DSC thermogram comprising an exothermic peak having a peak maximum at about 214°C. In some embodiments, the calcium salt of Compound 1 exhibits a DSC thermogram comprising an exothermic peak with an onset at about 211°C.

[0101] In some embodiments, the calcium salt of Compound 1 exhibits a DSC thermogram substantially similar to that depicted in Figure 2D.

[0102] In some embodiments, the calcium salt of Compound 1 exhibits a thermogravimetric (TG) thermogram substantially similar to that depicted in Figure 2C.

[0103] In some embodiments, the calcium salt of Compound 1 obtained according to Example 2 is a monohydrate.

[0104] In some embodiments, the calcium salt of Compound 1 obtained according to Example 2 is at least about 98% pure by weight. In some embodiments, the calcium salt of Compound 1 obtained according to Example 2 is at least about 99% pure by weight.

[0105] In some embodiments, the calcium salt of Compound 1 obtained according to Example 2 is at least about 98% pure by weight after exposure to 40°C / 75% RH for 1 week. In some embodiments, the calcium salt of Compound 1 obtained according to Example 2 is at least about 99% pure by weight after exposure to 40°C / 75% RH for 1 week.

[0106] In some embodiments, the calcium salt of Compound 1 has a solubility of about 500 μg / mL to about 600 μg / mL at pH 5 and 37° C., as measured by high performance liquid chromatography (HPLC) at 236 nm or 266 nm, after addition to a solution of fed-state simulated intestinal fluid (FeSSIF) at pH 5 and 37° C. for 4 hours. In some embodiments, the calcium salt of Compound 1 has a solubility of about 600 μg / mL to about 700 μg / mL at pH 5 and 37° C., as measured by HPLC at 236 nm or 266 nm, after addition to a solution of FeSSIF at pH 5 and 37° C. for 24 hours.

[0107] In some embodiments, the calcium salt of Compound 1 has a solubility of about 250 μg / mL to about 350 μg / mL at pH 5 and 25° C., as measured by HPLC at 236 nm or 266 nm, after addition to a solution of FeSSIF at pH 5 and 25° C. for 4 hours. In some embodiments, the calcium salt of Compound 1 has a solubility of about 250 μg / mL to about 350 μg / mL at pH 5 and 25° C., as measured by HPLC at 236 nm or 266 nm, after addition to a solution of FeSSIF at pH 5 and 25° C. for 24 hours.

[0108] In some embodiments, the calcium salt of Compound 1 has a solubility of about 350 μg / mL to about 450 μg / mL at pH 6.5 and 37° C., as measured by HPLC at 236 nm or 266 nm, after addition to a solution of fasted-state simulated intestinal fluid (FaSSIF) at pH 6.5 and 37° C. for 4 hours. In some embodiments, the calcium salt of Compound 1 has a solubility of about 300 μg / mL to about 400 μg / mL at pH 6.5 and 37° C., as measured by HPLC at 236 nm or 266 nm, after addition to a solution of FaSSIF at pH 6.5 and 37° C. for 24 hours.

[0109] In some embodiments, the calcium salt of Compound 1 has a solubility of about 300 μg / mL to about 400 μg / mL at pH 6.5 and 25° C., as measured by HPLC at 236 nm or 266 nm, after addition to a solution of FaSSIF at pH 6.5 and 25° C. for 4 hours. In some embodiments, the calcium salt of Compound 1 has a solubility of about 200 μg / mL to about 300 μg / mL at pH 6.5 and 25° C., as measured by HPLC at 236 nm or 266 nm, after addition to a solution of FaSSIF at pH 6.5 and 25° C. for 24 hours.

[0110] In some embodiments, the calcium salt of Compound 1 is at least about 98% pure by weight, and the calcium salt contains about 2% or less impurities based on the weight of the calcium salt. In some embodiments, the calcium salt of Compound 1 is about 95.0% to 100% pure by weight, and the calcium salt contains 0% to about 5% impurities based on the weight of the calcium salt. In some embodiments, the calcium salt of Compound 1 is about 98% to 100% pure by weight, and the calcium salt contains 0% to about 2% impurities based on the weight of the calcium salt. In some embodiments, the calcium salt of Compound 1 is about 98%, about 98.5%, about 99%, about 99.5%, or 100% pure by weight, and the calcium salt contains about 2%, about 1.5%, about 1%, about 0.5%, or 0% impurities, respectively, based on the weight of the calcium salt. In some embodiments, the calcium salt of Compound 1 is about 99.5%, about 99.9%, or about 99.95% pure by weight, and the calcium salt contains about 0.5%, about 0.1%, or 0.05% impurities, respectively, based on the weight of the calcium salt. In some embodiments, the purity or impurities are determined by high performance liquid chromatography (HPLC). In some embodiments, the purity or impurities are determined by HPLC at 236 nm. In some embodiments, the purity or impurities are determined by HPLC at 266 nm. In some embodiments, the purity or impurities are determined by titration.

[0111] In some embodiments, the calcium salt of Compound 1 is at least about 98% pure by weight after exposure to 40° C. / 75% RH for 1 week. In some embodiments, the calcium salt of Compound 1 is at least about 99% pure by weight after exposure to 40° C. / 75% RH for 1 week.

[0112] In some embodiments, the calcium salt of Compound 1 is amorphous.

[0113] In some embodiments, the calcium salt of Compound 1 is predominantly amorphous, and the predominantly amorphous calcium salt exhibits an XRPD pattern comprising a peak at 4.5±0.2 degrees 2θ and a peak at 6.0±0.2 degrees 2θ.

[0114] In some embodiments, the predominantly amorphous calcium salt of Compound 1 exhibits an XRPD pattern predominantly similar to that depicted in Figure 3A.

[0115] In some embodiments, the predominantly amorphous calcium salt of Compound 1 is anhydrous. In some embodiments, the predominantly amorphous calcium salt of Compound 1 obtained according to Example 3 is anhydrous calcium salt.

[0116] In some embodiments, the predominantly amorphous calcium salt of Compound 1 obtained according to Example 3 is at least 50% amorphous by weight. In some embodiments, the predominantly amorphous calcium salt of Compound 1 obtained according to Example 3 is at least 60% amorphous by weight. In some embodiments, the predominantly amorphous calcium salt of Compound 1 obtained according to Example 3 is at least 70% amorphous by weight. In some embodiments, the predominantly amorphous calcium salt of Compound 1 obtained according to Example 3 is at least 80% amorphous by weight. In some embodiments, the predominantly amorphous calcium salt of Compound 1 obtained according to Example 3 is at least 90% amorphous by weight. In some embodiments, the predominantly amorphous calcium salt of Compound 1 obtained according to Example 3 is at least 95% amorphous by weight. In some embodiments, the predominantly amorphous calcium salt of Compound 1 obtained according to Example 3 is predominantly amorphous.

[0117] In some embodiments, the predominantly amorphous calcium salt of Compound 1 is an anhydrous calcium salt.

[0118] In some embodiments, the compound of the invention is the L-arginine salt of Compound 1. In some embodiments, the L-arginine salt of Compound 1 is crystalline.

[0119] In some embodiments, the L-arginine salt of Compound 1 exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 11.9±0.2 degrees 2θ, a peak at 19.7±0.2 degrees 2θ, and a peak at 20.2±0.2 degrees 2θ. In some embodiments, the L-arginine salt of Compound 1 exhibits an XRPD pattern comprising a peak at 11.9±0.2 degrees 2θ, a peak at 19.7±0.2 degrees 2θ, and a peak at 20.2±0.2 degrees 2θ, wherein the peak at 20.2±0.2 degrees 2θ is the most intense peak in the XRPD pattern. In some embodiments, the XRPD pattern further comprises a peak at 13.1±0.2 degrees 2θ or a peak at 22.7±0.2 degrees 2θ. In some embodiments, the XRPD pattern further comprises a peak at 10.4±0.2 degrees 2θ, 11.6±0.2 degrees 2θ, or 21.7±0.2 degrees 2θ. In some embodiments, the XRPD pattern further comprises a peak at 23.5±0.2 degrees 2θ. In some embodiments, the XRPD pattern further comprises a peak at 3.9±0.2 degrees 2θ or a peak at 19.3±0.2 degrees 2θ. In some embodiments, the XRPD pattern further comprises a peak at 3.9±0.2 degrees 2θ. In some embodiments, the XRPD pattern further comprises a peak at 12.8±0.2 degrees 2θ or a peak at 18.3±0.2 degrees 2θ. In some embodiments, the XRPD pattern further comprises a peak at 15.4±0.2 degrees 2θ, a peak at 18.4±0.2 degrees 2θ, a peak at 21.5±0.2 degrees 2θ, and a peak at 23.5±0.2 degrees 2θ.

[0120] In some embodiments, the L-arginine salt of Compound 1 exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks from Table 5A. In some embodiments, the L-arginine salt of Compound 1 exhibits an XRPD pattern that includes one, two, three, four, five, six, seven, eight, nine, or ten of the following peaks: a peak at 10.4±0.2 degrees 2θ, a peak at 11.6±0.2 degrees 2θ, a peak at 11.9±0.2 degrees 2θ, a peak at 13.1±0.2 degrees 2θ, a peak at 19.3±0.2 degrees 2θ, a peak at 19.7±0.2 degrees 2θ, a peak at 20.2±0.2 degrees 2θ, a peak at 21.7±0.2 degrees 2θ, a peak at 22.7±0.2 degrees 2θ, and a peak at 23.5±0.2 degrees 2θ.

[0121] In some embodiments, the L-arginine salt of Compound 1 exhibits an XRPD pattern comprising the peaks of Table 5A having a relative peak intensity (%) of greater than 50%. In some embodiments, the L-arginine salt of Compound 1 exhibits an XRPD pattern comprising the peaks of Table 5A having a relative peak intensity (%) of greater than 35%. In some embodiments, the L-arginine salt of Compound 1 exhibits an XRPD pattern comprising the peaks of Table 5A having a relative peak intensity (%) of greater than 20%. In some embodiments, the L-arginine salt of Compound 1 exhibits an XRPD pattern comprising the peaks of Table 5A having a relative peak intensity (%) of greater than 15%. In some embodiments, the L-arginine salt of Compound 1 exhibits an XRPD pattern comprising the peaks of Table 5A having a relative peak intensity (%) of greater than 10%.

[0122] In some embodiments, the L-arginine salt of Compound 1 exhibits an XRPD pattern substantially similar to that depicted in Figure 4A.

[0123] In some embodiments, the L-arginine salt of Compound 1 exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 3.9±0.2 degrees 2θ, a peak at 13.1±0.2 degrees 2θ, and a peak at 20.3±0.2 degrees 2θ. In some embodiments, the L-arginine salt of Compound 1 exhibits an XRPD pattern comprising a peak at 3.9±0.2 degrees 2θ, a peak at 13.1±0.2 degrees 2θ, and a peak at 20.3±0.2 degrees 2θ, wherein the peak at 3.9±0.2 degrees 2θ is the most intense peak in the XRPD pattern. In some embodiments, the L-arginine salt of Compound 1 exhibits an XRPD pattern further comprising a peak at 19.8±0.2 degrees 2θ, a peak at 19.9±0.2 degrees 2θ, or a peak at 20.4±0.2 degrees 2θ. In some embodiments, the L-arginine salt of Compound 1 exhibits an XRPD pattern further comprising a peak at 10.4±0.2 degrees 2θ, a peak at 11.9±0.2 degrees 2θ, or a peak at 20.4±0.2 degrees 2θ.

[0124] In some embodiments, the L-arginine salt of Compound 1 exhibits an XRPD pattern that includes 1 peak, 2 peaks, 3 peaks, 4 peaks, 5 peaks, 6 peaks, 7 peaks, 8 peaks, 9 peaks, or 10 peaks from Table 5B. In some embodiments, the L-arginine salt of Compound 1 exhibits an XRPD pattern that includes one, two, three, four, five, six, seven, eight, nine, or ten of the following peaks: a peak at 3.9±0.2 degrees 2θ, a peak at 10.4±0.2 degrees 2θ, a peak at 11.9±0.2 degrees 2θ, a peak at 12.8±0.2 degrees 2θ, a peak at 13.1±0.2 degrees 2θ, a peak at 19.8±0.2 degrees 2θ, a peak at 19.9±0.2 degrees 2θ, a peak at 20.3±0.2 degrees 2θ, a peak at 20.4±0.2 degrees 2θ, and a peak at 21.7±0.2 degrees 2θ. In some embodiments, the L-arginine salt of Compound 1 exhibits an XRPD pattern that includes one, two, three, four, five, six, seven, eight, nine, or ten of the following peaks: a peak at 10.4±0.2 degrees 2θ, a peak at 11.7±0.2 degrees 2θ, a peak at 11.9±0.2 degrees 2θ, a peak at 13.1±0.2 degrees 2θ, a peak at 19.8±0.2 degrees 2θ, a peak at 19.9±0.2 degrees 2θ, a peak at 20.3±0.2 degrees 2θ, a peak at 20.4±0.2 degrees 2θ, a peak at 21.7±0.2 degrees 2θ, and a peak at 22.8±0.2 degrees 2θ.

[0125] In some embodiments, the L-arginine salt of Compound 1 exhibits an XRPD pattern comprising the peaks of Table 5B having a relative peak intensity (%) of greater than 65%. In some embodiments, the L-arginine salt of Compound 1 exhibits an XRPD pattern comprising the peaks of Table 5B having a relative peak intensity (%) of greater than 60%. In some embodiments, the L-arginine salt of Compound 1 exhibits an XRPD pattern comprising the peaks of Table 5B having a relative peak intensity (%) of greater than 50%. In some embodiments, the L-arginine salt of Compound 1 exhibits an XRPD pattern comprising the peaks of Table 5B having a relative peak intensity (%) of greater than 40%. In some embodiments, the L-arginine salt of Compound 1 exhibits an XRPD pattern comprising the peaks of Table 5B having a relative peak intensity (%) of greater than 30%.

[0126] In some embodiments, the L-arginine salt of Compound 1 exhibits an XRPD pattern substantially similar to that depicted in Figure 4B.

[0127] In some embodiments, the L-arginine salt of Compound 1 exhibits a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak with a peak maximum between about 58°C and about 63°C. In some embodiments, the L-arginine salt of Compound 1 exhibits a DSC thermogram comprising an endothermic peak with a peak maximum between about 60°C and about 62°C. In some embodiments, the L-arginine salt of Compound 1 exhibits a DSC thermogram comprising an endothermic peak with a peak maximum at about 61°C. In some embodiments, the L-arginine salt of Compound 1 exhibits a DSC thermogram comprising an endothermic peak with an onset at about 54°C. In some embodiments, the L-arginine salt of Compound 1 exhibits a DSC thermogram comprising an endothermic peak with an onset at about 55°C.

[0128] In some embodiments, the L-arginine salt of Compound 1 exhibits a DSC thermogram comprising an exothermic peak having a peak maximum of about 148°C to about 152°C. In some embodiments, the L-arginine salt of Compound 1 exhibits a DSC thermogram comprising an exothermic peak having a peak maximum of about 149°C to about 151°C. In some embodiments, the L-arginine salt of Compound 1 exhibits a DSC thermogram comprising an exothermic peak having a peak maximum of about 150°C. In some embodiments, the L-arginine salt of Compound 1 exhibits a DSC thermogram comprising an exothermic peak with an onset at about 143°C. In some embodiments, the L-arginine salt of Compound 1 exhibits a DSC thermogram comprising an exothermic peak with an onset at about 145°C.

[0129] In some embodiments, the L-arginine salt of Compound 1 exhibits a DSC thermogram substantially similar to that depicted in Figure 4C.

[0130] In some embodiments, the L-arginine salt of Compound 1 exhibits a thermogravimetric (TG) thermogram substantially similar to that depicted in Figure 4C.

[0131] In some embodiments, the L-arginine salt of Compound 1 is anhydrous. In some embodiments, the L-arginine salt of Compound 1 obtained according to Procedure A of Example 4 is anhydrous. In some embodiments, the L-arginine salt of Compound 1 obtained according to Procedure B of Example 4 is anhydrous.

[0132] In some embodiments, the L-arginine salt of Compound 1 is at least about 85% pure by weight. In some embodiments, the L-arginine salt of Compound 1 is at least about 90% pure by weight. In some embodiments, the L-arginine salt of Compound 1 is at least about 95% pure by weight. In some embodiments, the L-arginine salt of Compound 1 is at least about 98% pure by weight. In some embodiments, the L-arginine salt of Compound 1 is at least about 99% pure by weight. In some embodiments, purity or impurities are determined by HPLC. In some embodiments, purity or impurities are determined by HPLC at 236 nm. In some embodiments, purity or impurities are determined by HPLC at 266 nm. In some embodiments, purity or impurities are determined by titration.

[0133] In some embodiments, the L-arginine salt of Compound 1 obtained according to Procedure A of Example 4 is at least about 85% pure by weight. In some embodiments, the L-arginine salt of Compound 1 obtained according to Procedure A of Example 4 is at least about 90% pure by weight. In some embodiments, the L-arginine salt of Compound 1 obtained according to Procedure A of Example 4 is at least about 95% pure by weight. In some embodiments, the L-arginine salt of Compound 1 obtained according to Procedure A of Example 4 is at least about 98% pure by weight. In some embodiments, the L-arginine salt of Compound 1 obtained according to Procedure A of Example 4 is at least about 99% pure by weight.

[0134] In some embodiments, the L-arginine salt of Compound 1 obtained according to Procedure B of Example 4 is at least about 85% pure by weight. In some embodiments, the L-arginine salt of Compound 1 obtained according to Procedure B of Example 4 is at least about 90% pure by weight. In some embodiments, the L-arginine salt of Compound 1 obtained according to Procedure B of Example 4 is at least about 95% pure by weight. In some embodiments, the L-arginine salt of Compound 1 obtained according to Procedure B of Example 4 is at least about 98% pure by weight. In some embodiments, the L-arginine salt of Compound 1 obtained according to Procedure B of Example 4 is at least about 99% pure by weight.

[0135] In some embodiments, the compound of the present invention is the phenylalanine salt of Compound 1.

[0136] In some embodiments, the phenylalanine salt of Compound 1 is a racemic phenylalanine salt. In some embodiments, the phenylalanine salt of Compound 1 is an L-phenylalanine salt.

[0137] In some embodiments, the phenylalanine salt of Compound 1 is crystalline.

[0138] In some embodiments, the compound of the present invention is a histidine salt of Compound 1.

[0139] In some embodiments, the histidine salt of Compound 1 is a racemic histidine salt. In some embodiments, the histidine salt of Compound 1 is an L-histidine salt.

[0140] In some embodiments, the histidine salt of Compound 1 is crystalline.

[0141] In some embodiments, the salt of Compound 1 comprises less than 5% Compound 1 by weight of the salt. In some embodiments, the salt of Compound 1 comprises less than 4% Compound 1 by weight of the salt. In some embodiments, the salt of Compound 1 comprises less than 3% Compound 1 by weight of the salt. In some embodiments, the salt of Compound 1 comprises less than 2% Compound 1 by weight of the salt. In some embodiments, the salt of Compound 1 comprises less than 1% Compound 1 by weight of the salt.

[0142] In some embodiments, the salt of Compound 1 is greater than 90% pure based on the relative peak areas in the HPLC chromatogram according to the HPLC chromatogram. In some embodiments, the salt of Compound 1 is greater than 95% pure based on the relative peak areas in the HPLC chromatogram according to the HPLC chromatogram. In some embodiments, the salt of Compound 1 is greater than 98% pure based on the relative peak areas in the HPLC chromatogram according to the HPLC chromatogram. In some embodiments, the salt of Compound 1 is greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99% pure based on the relative peak areas in the HPLC chromatogram according to the HPLC chromatogram. In some embodiments, purity is determined according to HPLC at 236 nm. In some embodiments, purity is determined according to HPLC at 266 nm.

[0143] In some embodiments, the salt of Compound 1 is stable at 25° C. / 60% RH for at least 1 week. In some embodiments, the salt of Compound 1 is stable at 25° C. / 60% RH for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, or at least 36 months. In some embodiments, 1 month is 28 days, 29 days, 30 days, or 31 days.

[0144] In some embodiments, the salt of Compound 1 is stable at 40° C. / 75% RH for at least 1 week. In some embodiments, the salt of Compound 1 is stable at 40° C. / 75% RH for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months. In some embodiments, 1 month is 28 days, 29 days, 30 days, or 31 days.

[0145] In some embodiments, the compound of the invention is an ester of Compound 1, having the structure: [ka] where R is C 10 ~C 24 It is a hydrocarbyl.

[0146] In some embodiments of the esters of the present invention, R is a C 10 ~C 24 In some embodiments of the esters of the present invention, R is a C group which may be linear or branched. 10 ~C 24 In some embodiments of the esters of the present invention, R is a C which may contain cyclic moieties. 10 ~C 24 It is a hydrocarbyl.

[0147] In some embodiments of the esters of the present invention, R is C 10 ~C 24 Alkyl or C 10 ~C 24 In some embodiments, R is C 12 ~C 24 Alkyl or C 12 ~C 24 It is alkenyl.

[0148] In some embodiments of the esters of the present invention, R is [ka] In some embodiments, R is stearyl, palmitoyl, myristyl, lauryl, palmitoleyl, oleyl, linoleyl, or linolenyl.

[0149] In some embodiments, the esters of the present invention are crystalline.

[0150] In some embodiments, the esters of the present invention contain less than 5% Compound 1 by weight of the ester. In some embodiments, the esters of the present invention contain less than 4% Compound 1 by weight of the ester. In some embodiments, the esters of the present invention contain less than 3% Compound 1 by weight of the ester. In some embodiments, the esters of the present invention contain less than 2% Compound 1 by weight of the ester. In some embodiments, the esters of the present invention contain less than 1% Compound 1 by weight of the ester.

[0151] In some embodiments, the compounds of the present invention are greater than 90% pure based on the relative peak areas of their HPLC chromatograms. In some embodiments, the compounds of the present invention are greater than 95% pure based on the relative peak areas of their HPLC chromatograms. In some embodiments, the compounds of the present invention are greater than 98% pure based on the relative peak areas of their HPLC chromatograms. In some embodiments, the compounds of the present invention are greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, or greater than 99% pure based on the relative peak areas of their HPLC chromatograms. In some embodiments, the purity is determined according to the HPLC chromatogram of the compound obtained at 236 nm. In some embodiments, the purity is determined according to the HPLC chromatogram of the compound obtained at 266 nm.

[0152] In some embodiments, the compounds of the present invention are stable at 25° C. / 60% RH for at least 1 week. In some embodiments, the compounds of the present invention are stable at 25° C. / 60% RH for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, or at least about 36 months.

[0153] In some embodiments, the compounds of the present invention are stable at 40° C. / 75% RH for at least about 1 week. In some embodiments, the compounds of the present invention are stable at 40° C. / 75% RH for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, or at least about 6 months.

[0154] In some embodiments, the compounds of the present invention are crystalline.

[0155] In some embodiments, the compounds of the present invention are compounds.

[0156] In some embodiments, the compounds of the present invention are at least about 98% pure by weight, and the compounds of the present invention contain about 2% or less impurities based on the weight of the compound of the present invention. In some embodiments, the compounds of the present invention are about 95.0% to 100% pure by weight, and the compounds of the present invention contain 0% to about 5% impurities based on the weight of the compound of the present invention. In some embodiments, the compounds of the present invention are about 98% to 100% pure by weight, and the compounds of the present invention contain 0% to about 2% impurities based on the weight of the compound of the present invention. In some embodiments, the compounds of the present invention are about 98%, about 98.5%, about 99%, about 99.5%, or 100% pure by weight, and the compounds of the present invention contain about 2%, about 1.5%, about 1%, about 0.5%, or 0% impurities, respectively, based on the weight of the compound of the present invention. In some embodiments, the compounds of the present invention are about 99.5%, about 99.9%, or about 99.95% pure by weight, and the compounds of the present invention contain about 0.5%, about 0.1%, or 0.05% impurities, respectively, based on the weight of the compound of the present invention. In some embodiments, the compounds of the present invention are about 98%, about 98.5%, about 99%, about 99.5%, or 100% pure by weight, and the compounds of the present invention contain about 2%, about 1.5%, about 1%, about 0.5%, or 0% impurities, respectively, based on the weight of the compound of the present invention. In some embodiments, the compounds of the present invention are about 99.5%, about 99.9%, or about 99.95% pure by weight, and the compounds of the present invention contain about 0.5%, about 0.1%, or 0.05% impurities, respectively, based on the weight of the compound of the present invention. In some embodiments, the compounds of the present invention are about 98%, about 98.5%, about 99%, about 99.5%, or 100% pure by weight, and the compounds of the present invention contain about 2%, about 1.5%, about 1%, about 0.5%, or 0% impurities, respectively, based on the weight of the compound of the present invention. In some embodiments, the impurities are determined by high performance liquid chromatography (HPLC). In some embodiments, the impurities are determined according to the HPLC chromatogram of the compound obtained at about 236 nm to about 266 nm. In some embodiments, the impurities are determined by titration.

[0157] In some embodiments, the compounds of the present invention contain less than about 1% impurities based on the weight of the compound of the present invention. In some embodiments, the compounds of the present invention contain less than about 0.5% impurities based on the weight of the compound of the present invention. In some embodiments, the compounds of the present invention contain less than about 1%, less than about 0.9%, less than about 0.8%, less than about 0.7%, less than about 0.6%, less than about 0.5%, less than about 0.4%, less than about 0.3%, or less than about 0.2% impurities based on the weight of the compound of the present invention.

[0158] In some embodiments, the compounds of the present invention are dried.

[0159] In some embodiments, the compounds of the invention are purified. In some embodiments, the compounds of the invention are isolated.

[0160] method

[0161] The present invention further provides a method for treating or preventing an ocular disease, the method comprising administering an effective amount of a compound of the present invention, a composition of the present invention, a compound of formula (I), [ka] or a pharmaceutically acceptable salt thereof (wherein R 1 are each independently H, C1-C6 alkyl, or —C(O)(C1-C6 alkyl), a compound of formula (II), [ka] or a pharmaceutically acceptable salt thereof (wherein R 2 is C1~C 24 The present invention includes administering to a subject in need thereof a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is a hydroxyl group, ...

[0162] In some embodiments, the ocular disease is diabetic retinal disease. In some embodiments, the diabetic retinal disease is diabetic retinopathy (DR) or diabetic macular edema (DME). In some embodiments, the DR is moderately severe non-proliferative DR or mildly proliferative DR. In some embodiments, the DME is DME without central vision loss.

[0163] In some embodiments, the ocular disease is retinopathy of prematurity, DR, pathological myopia, hypertensive retinopathy, occlusive vasculitis, polypoidal choroidal vasculopathy, diabetic macular edema, uveitis macular edema, retinal vein occlusion, ocular neovascularization, ocular histoplasmosis, neovascular glaucoma, retinoblastoma, macular degeneration, retrolental fibroplasia, retinal angiomatous proliferation, dry eye disease, uveitis, thyroid eye disease, or sickle cell retinopathy. In some embodiments, the ocular disease is DR, and the DR is proliferative diabetic retinopathy. In some embodiments, the ocular disease is macular degeneration, and the macular degeneration is advanced macular degeneration. In some embodiments, the macular degeneration is wet age-related macular degeneration. In some embodiments, the macular degeneration is dry age-related macular degeneration. In some embodiments, the ocular disease is ocular neovascularization, and the ocular neovascularization is corneal neovascularization or retinal neovascularization. In some embodiments, the retinal vein occlusion is a central retinal vein occlusion or a branch retinal vein occlusion.

[0164] The present invention further provides a method for treating diabetic retinopathy (DR), comprising administering to a subject in need thereof an effective amount of the calcium salt of Compound 1, wherein the calcium salt exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 5.8±0.2 degrees 2θ and a peak at 6.3±0.2 degrees 2θ.

[0165] The present invention further provides a method for treating diabetic retinopathy (DR), comprising administering to a subject in need thereof an effective amount of the calcium salt of Compound 1, wherein the calcium salt exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 4.1±0.2 degrees 2θ, a peak at 5.3±0.2 degrees 2θ, and a peak at 6.3±0.2 degrees 2θ.

[0166] The present invention further provides a method for treating diabetic retinopathy (DR), comprising administering to a subject in need thereof an effective amount of the calcium salt of Compound 1, wherein the calcium salt exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 8.0±0.2 degrees 2θ and a peak at 10.1±0.2 degrees 2θ.

[0167] The present invention further provides a method for treating diabetic retinopathy (DR), comprising administering to a subject in need thereof an effective amount of the calcium salt of Compound 1, wherein the calcium salt exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 5.1±0.2 degrees 2θ, a peak at 5.3±0.2 degrees 2θ, and a peak at 10.1±0.2 degrees 2θ.

[0168] The present invention further provides a method for treating diabetic macular edema (DME), comprising administering to a subject in need thereof an effective amount of the calcium salt of Compound 1, wherein the calcium salt exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 5.8±0.2 degrees 2θ and a peak at 6.3±0.2 degrees 2θ.

[0169] The present invention further provides a method for treating diabetic macular edema (DME), comprising administering to a subject in need thereof an effective amount of the calcium salt of Compound 1, wherein the calcium salt exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 4.1±0.2 degrees 2θ, a peak at 5.3±0.2 degrees 2θ, and a peak at 6.3±0.2 degrees 2θ.

[0170] The present invention further provides a method for treating diabetic macular edema (DME), comprising administering to a subject in need thereof an effective amount of the calcium salt of Compound 1, wherein the calcium salt exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 8.0±0.2 degrees 2θ and a peak at 10.1±0.2 degrees 2θ.

[0171] The present invention further provides a method for treating diabetic macular edema (DME), comprising administering to a subject in need thereof an effective amount of the calcium salt of Compound 1, wherein the calcium salt exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 5.1±0.2 degrees 2θ, a peak at 5.3±0.2 degrees 2θ, and a peak at 10.1±0.2 degrees 2θ.

[0172] The present invention further provides a method for treating or preventing geographic atrophy, choroidal neovascularization, or corneal transplant rejection, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention, a composition of the present invention, a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a compound of Formula (II) or a pharmaceutically acceptable salt thereof, a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, or a composition comprising a compound of Formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle.

[0173] The present invention further provides a method for treating or preventing Barrett's esophagus (BE), the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention, a composition of the present invention, a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a compound of Formula (II) or a pharmaceutically acceptable salt thereof, a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, or a composition comprising a compound of Formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle. In some embodiments, the BE is metaplastic BE.

[0174] The present invention further provides a method for treating or preventing cancer, cardiovascular disease, inflammation, chronic inflammatory disease, rheumatoid arthritis, idiopathic pulmonary fibrosis, acute adult respiratory distress syndrome, asthma, endometriosis, keloid, systemic sclerosis, chemotherapy-induced peripheral neuropathy, stroke, gastrointestinal dysfunction, chronic gastroesophageal reflux disease, von Hippel-Lindau syndrome, or a skin disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention, a composition of the present invention, a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a compound of Formula (II) or a pharmaceutically acceptable salt thereof, a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, or a composition comprising a compound of Formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle.

[0175] In some embodiments, the cancer is liver cancer, breast cancer, prostate cancer, pancreatic cancer, colon cancer, cervical cancer, germ cell tumor, adult glioma, pediatric glioma, osteosarcoma, rhabdomyosarcoma, non-small cell lung cancer, leukemia, or multiple myeloma. In some embodiments, the cancer is a solid tumor, blood cancer, leukemia, or lymphoma. In some embodiments, the cancer is hepatocellular carcinoma (HCC). In some embodiments, the compounds of the present invention are useful for treating solid tumors, comprising administering an effective amount of a compound of the present invention or a composition of the present invention to a subject in need thereof. In some embodiments, the cancer is not liver cancer. In some embodiments, the cancer is breast cancer, prostate cancer, pancreatic cancer, colon cancer, cervical cancer, germ cell tumor, adult glioma, pediatric glioma, osteosarcoma, rhabdomyosarcoma, non-small cell lung cancer, leukemia, or multiple myeloma.

[0176] In some embodiments, the cancer is a solid tumor, and solid tumors include fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelioma, lymphangiosarcoma, lymphangioendothelioma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer, oral cancer, nasal cancer, throat cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland cancer, sebaceous gland cancer, and the like. carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, hepatocarcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, small cell lung cancer, bladder cancer, lung cancer, epithelial carcinoma, glioma, glioblastoma multiforme, astrocytoma medulloblastoma, craniopharyngioma, ependymoma pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, skin cancer, melanoma, neuroblastoma, retinoblastoma, or hepatocellular carcinoma (HCC).

[0177] In some embodiments, the cancer is a blood cancer, and the blood cancer is leukemia, lymphoma, or myeloma. In some embodiments, the leukemia is acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute monoblastic leukemia, acute erythroleukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocytic leukemia, acute anaplastic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, or hairy cell leukemia. In some embodiments, the leukemia is acute leukemia or chronic leukemia. In some embodiments, the acute leukemia or chronic leukemia is lymphoblastic leukemia, myeloid leukemia, lymphocytic leukemia, or myelocytic leukemia. In some embodiments, the lymphoma is Hodgkin's disease, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, heavy chain disease, or polycythemia vera. In some embodiments, the myeloma is solitary plasmacytoma, extramedullary plasmacytoma, or multiple myeloma.

[0178] In some embodiments, the cancer is eye cancer. In certain embodiments, the cancer is a solid tumor. In certain embodiments, the cancer is a cancer originating from a human myeloid leukemia mononuclear cell line (THP-1). In certain embodiments, the cancer is esophageal adenocarcinoma.

[0179] In some embodiments, the skin disorder is an inflammatory skin disorder, hi some embodiments, the skin disorder is psoriasis, atopic dermatitis, or rosacea.

[0180] The present invention further provides a method for inhibiting angiogenesis, the method comprising administering an effective amount of a compound of the present invention, a composition of the present invention, a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a compound of Formula (II) or a pharmaceutically acceptable salt thereof, a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, or a composition comprising a compound of Formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle to a subject in need thereof. In some embodiments, the angiogenesis is ocular angiogenesis. In some embodiments, inhibiting angiogenesis slows or stops tumor growth. In some embodiments, inhibiting angiogenesis treats cancer.

[0181] The present invention further provides a method for inhibiting expression of vascular endothelial growth factor (VEGF) or a VEGF protein, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention, a composition of the present invention, a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a compound of Formula (II) or a pharmaceutically acceptable salt thereof, a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, or a composition comprising a compound of Formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle. In some embodiments, inhibiting expression of vascular endothelial growth factor (VEGF) or a VEGF protein inhibits angiogenesis. In some embodiments, the angiogenesis is ocular angiogenesis. In some embodiments, inhibiting expression of vascular endothelial growth factor (VEGF) or a VEGF protein slows or stops tumor growth. In some embodiments, inhibiting expression of vascular endothelial growth factor (VEGF) or a VEGF protein treats cancer.

[0182] The present invention further provides a method for inhibiting capillary formation, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention, a composition of the present invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof, a compound of formula (II) or a pharmaceutically acceptable salt thereof, a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, or a composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle.

[0183] The present invention also provides a method for treating or preventing liver disease, the method comprising administering an effective amount of the compound of the present invention or the composition of the present invention to a subject in need thereof.In some embodiments, the liver disease is hepatitis, toxic liver damage, jaundice, cirrhosis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD) or alcoholic steatosis.In some embodiments, the liver disease is hepatitis, and the hepatitis is chronic hepatitis, acute hepatitis, viral hepatitis or alcoholic hepatitis.

[0184] The present invention further provides a method for suppressing neurological hypersensitivity, the method comprising administering an effective amount of a compound of the present invention, a composition of the present invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof, a compound of formula (II) or a pharmaceutically acceptable salt thereof, a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, or a composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle to a subject in need thereof.

[0185] The present invention further provides a method for treating pain, the method comprising administering an effective amount of a compound of the present invention, a composition of the present invention, a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a compound of Formula (II) or a pharmaceutically acceptable salt thereof, a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, or a composition comprising a compound of Formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle to a subject in need thereof. In some embodiments, the pain is inflammatory or chronic pain.

[0186] The present invention further provides a method for improving DNA base excision repair, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention, a composition of the present invention, a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a compound of Formula (II) or a pharmaceutically acceptable salt thereof, a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, or a composition comprising a compound of Formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle.

[0187] The present invention further provides a method for improving neural DNA repair function, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention, a composition of the present invention, a compound of Formula (I) or a pharmaceutically acceptable salt thereof, a compound of Formula (II) or a pharmaceutically acceptable salt thereof, a composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, or a composition comprising a compound of Formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle.

[0188] In some embodiments of the methods of the present invention, the subject has obesity, diabetes, asthma, arthritis, chronic periodontitis, ulcerative colitis, Crohn's disease, chronic sinusitis, chronic active hepatitis, chronic peptic ulcer, diverticulitis, fibromyalgia, irritable bowel syndrome, irritable bowel disease, Alzheimer's disease, Parkinson's disease, atherosclerosis, or tuberculosis. In some embodiments, the subject has diabetes.

[0189] In some embodiments, in the compound of Formula (II) or a pharmaceutically acceptable salt thereof, R 1 are each H. In some embodiments, R 1 Each is methyl. In some embodiments, R 1 are -C(O)CH3, respectively.

[0190] In some embodiments, in the compound of Formula (I) or a pharmaceutically acceptable salt thereof, R 1 are each independently C1-C6 alkyl or —C(O)(C1-C6 alkyl).

[0191] In some embodiments, in the compound of Formula (II) or a pharmaceutically acceptable salt thereof, R 2 is C1~C 10 In some embodiments, in the compound of formula (II) or a pharmaceutically acceptable salt thereof, R 2 is C1-C8 alkyl. In some embodiments, in the compound of formula (II) or a pharmaceutically acceptable salt thereof, R 2 is a C1-C6 alkyl.

[0192] In some embodiments, in the compound of Formula (II) or a pharmaceutically acceptable salt thereof, R 2 is C 10 ~C 24 In some embodiments, in the compound of formula (II) or a pharmaceutically acceptable salt thereof, R 2 is C 12 ~C 20In some embodiments, in the compound of formula (II) or a pharmaceutically acceptable salt thereof, R 2 is C 12 ~C 18 It is alkyl.

[0193] In the compound of formula (II) or a pharmaceutically acceptable salt thereof, R 2 C 10 ~C 24 The hydrocarbyl may be saturated or unsaturated. 2 C 10 ~C 24 The hydrocarbyl may be linear or branched. In some embodiments, C 10 ~C 24 Hydrocarbyl includes cyclic moieties.

[0194] In the compound of formula (II) or a pharmaceutically acceptable salt thereof, R 2 C 12 ~C 24 The hydrocarbyl may be saturated or unsaturated. 2 C 12 ~C 24 The hydrocarbyl may be linear or branched. In some embodiments, C 12 ~C 24 Hydrocarbyl includes cyclic moieties.

[0195] In some embodiments, in the compound of Formula (II) or a pharmaceutically acceptable salt thereof, R 2 is C1~C 10 In some embodiments, R 2 is C1-C6 alkyl. In some embodiments, R 2 is C1-C4 alkyl. In some embodiments, R 2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. 2 is methyl, ethyl, or tert-butyl.

[0196] In the compound of formula (II) or a pharmaceutically acceptable salt thereof, R 2 C 10 ~C 24 Hydrocarbyl is C1-C 24 Alkyl or C2-C 24 In the compound of formula (II) or a pharmaceutically acceptable salt thereof, R 2 C 10 ~C 24 Hydrocarbyl is C 10 ~C 24 Alkyl or C 10 ~C 24 It may also be alkenyl.

[0197] In some embodiments, in the compound of Formula (II) or a pharmaceutically acceptable salt thereof, R 2 teeth, [ka] In some embodiments, R 2 is stearyl, palmitoyl, myristyl, lauryl, palmitoleyl, oleyl, linoleyl, or linolenyl.

[0198] In some embodiments, the salt of the compound of Formula (I) or the compound of Formula (II) is a calcium salt. In some embodiments, the salt of the compound of Formula (I) or the compound of Formula (II) is an L-arginine salt. In some embodiments, the salt of the compound of Formula (I) or the compound of Formula (II) is a phenylalanine salt. In some embodiments, the salt of the compound of Formula (I) or the compound of Formula (II) is a histidine salt.

[0199] In some embodiments, administration is by topical instillation into the subject's eye.

[0200] In some embodiments, the administration is oral administration. In some embodiments, the administration is oral administration of the composition in an oral dosage form, for example, a tablet or capsule form.

[0201] In some embodiments, an effective amount is the amount that is administered or can be administered to a subject per day.

[0202] In some embodiments, the effective amount of the compound is about 0.01 mg to about 100 mg per day. In some embodiments, the effective amount of the compound is about 0.05 mg to about 50 mg per day. In some embodiments, the effective amount of the compound is about 0.1 mg to about 100 mg per day. In some embodiments, the effective amount of the compound is about 1 mg to about 25 mg per day. In some embodiments, the effective amount of the compound is about 5 mg to about 10 mg per day.

[0203] In some embodiments, an effective amount of the compound is the molar equivalent of about 10 mg to about 1000 mg of Compound 1 (378.48 g / mol) per day. In some embodiments, an effective amount of the compound is the molar equivalent of about 10 mg to about 800 mg of Compound 1 per day. In some embodiments, an effective amount of the compound is the molar equivalent of about 10 mg to about 650 mg of Compound 1 per day. In some embodiments, an effective amount of the compound is the molar equivalent of about 120 mg to about 600 mg of Compound 1 per day. In some embodiments, an effective amount of the compound is the molar equivalent of about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 100 mg, about 120 mg, about 150 mg, about 180 mg, about 200 mg, about 240 mg, about 250 mg, about 300 mg, about 350 mg, about 360 mg, about 400 mg, about 420 mg, about 450 mg, about 480 mg, about 500 mg, about 540 mg, about 550 mg, about 600 mg, or about 650 mg of Compound 1 per day.

[0204] In some embodiments, the effective amount of the calcium salt of Compound 1 is about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 100 mg, about 120 mg, about 150 mg, about 180 mg, about 200 mg, about 240 mg, about 250 mg, about 300 mg, about 350 mg, about 360 mg, about 400 mg, about 420 mg, about 450 mg, about 480 mg, about 500 mg, about 540 mg, about 550 mg, about 600 mg, or about 650 mg per day.

[0205] In some embodiments, the effective amount of the L-arginine salt of Compound 1 is about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 100 mg, about 120 mg, about 150 mg, about 180 mg, about 200 mg, about 240 mg, about 250 mg, about 300 mg, about 350 mg, about 360 mg, about 400 mg, about 420 mg, about 450 mg, about 480 mg, about 500 mg, about 540 mg, about 550 mg, about 600 mg, or about 650 mg per day.

[0206] In some embodiments, the effective amount of the L-phenylalanine salt of Compound 1 is about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 100 mg, about 120 mg, about 150 mg, about 180 mg, about 200 mg, about 240 mg, about 250 mg, about 300 mg, about 350 mg, about 360 mg, about 400 mg, about 420 mg, about 450 mg, about 480 mg, about 500 mg, about 540 mg, about 550 mg, about 600 mg, or about 650 mg per day.

[0207] In some embodiments, the effective amount of the L-histidine salt of Compound 1 is about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 100 mg, about 120 mg, about 150 mg, about 180 mg, about 200 mg, about 240 mg, about 250 mg, about 300 mg, about 350 mg, about 360 mg, about 400 mg, about 420 mg, about 450 mg, about 480 mg, about 500 mg, about 540 mg, about 550 mg, about 600 mg, or about 650 mg per day.

[0208] In some embodiments, the effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, is about 10 mg, about 20 mg, about 30 mg, about 50 mg, about 60 mg, about 100 mg, about 120 mg, about 150 mg, about 180 mg, about 200 mg, about 240 mg, about 250 mg, about 300 mg, about 350 mg, about 360 mg, about 400 mg, about 420 mg, about 450 mg, about 480 mg, about 500 mg, about 540 mg, about 550 mg, about 600 mg, or about 650 mg per day.

[0209] In some embodiments, the effective amount of the compound is the molar equivalent of about 120 mg to about 600 mg of Compound 1 per day. In some embodiments, the effective amount of the compound is the molar equivalent of about 600 mg of Compound 1 per day. In some embodiments, the effective amount of the compound is the molar equivalent of about 480 mg of Compound 1 per day. In some embodiments, the effective amount of the compound is the molar equivalent of about 360 mg of Compound 1 per day. In some embodiments, the effective amount of the compound is the molar equivalent of about 300 mg of Compound 1 per day. In some embodiments, the effective amount of the compound is the molar equivalent of about 240 mg of Compound 1 per day. In some embodiments, the effective amount of the compound is the molar equivalent of about 120 mg of Compound 1 per day.

[0210] In some embodiments, the effective amount is a daily dose of 600 mg (based on an amount that is the molar equivalent of 600 mg of Compound 1). In some embodiments, the daily dose can be divided into one or more oral dosage forms, such as tablets or capsules. In some embodiments, the daily dose is five 120 mg tablets (based on an amount that is the molar equivalent of 120 mg of Compound 1). In some embodiments, administration comprises administering to a subject three 120 mg tablets in the morning and two 120 mg tablets in the evening, where 120 mg is based on an amount that is the molar equivalent of 120 mg of Compound 1.

[0211] In some embodiments, the effective amount is a daily dose of 300 mg (based on an amount that is the molar equivalent of 300 mg of Compound 1). In some embodiments, the daily dose can be divided into one or more oral dosage forms, such as tablets. In some embodiments, the daily dose is five 60 mg tablets (based on an amount that is the molar equivalent of 60 mg of Compound 1). In some embodiments, administration comprises administering to a subject three 60 mg tablets in the morning and two 60 mg tablets in the evening, where 60 mg is based on an amount that is the molar equivalent of 60 mg of Compound 1.

[0212] In some embodiments, an effective amount of the calcium salt of Compound 1 is a daily dose of 600 mg, based on an amount that is the molar equivalent of 600 mg of Compound 1. In some embodiments, the daily dose can be divided into one or more oral dosage forms, such as tablets or capsules. In some embodiments, the daily dose is five 120 mg tablets (based on an amount that is the molar equivalent of 120 mg of Compound 1). In some embodiments, administration comprises administering to a subject three 120 mg tablets in the morning and two 120 mg tablets in the evening, based on an amount that is the molar equivalent of 120 mg of Compound 1.

[0213] In some embodiments, an effective amount of the calcium salt of Compound 1 is a daily dose of 300 mg, based on an amount that is the molar equivalent of 300 mg of Compound 1. In some embodiments, the daily dose can be divided into one or more oral dosage forms, such as tablets. In some embodiments, the daily dose is five 60 mg tablets (based on an amount that is the molar equivalent of 60 mg of Compound 1). In some embodiments, administration comprises administering to a subject three 60 mg tablets in the morning and two 60 mg tablets in the evening, based on an amount that is the molar equivalent of 60 mg of Compound 1.

[0214] In some embodiments, the effective amount of the L-arginine salt of Compound 1 is a daily dose of 600 mg, based on an amount that is the molar equivalent of 600 mg of Compound 1. In some embodiments, the daily dose can be divided into one or more oral dosage forms, such as tablets or capsules. In some embodiments, the daily dose is five 120 mg tablets (based on an amount that is the molar equivalent of 120 mg of Compound 1). In some embodiments, administration comprises administering to a subject three 120 mg tablets in the morning and two 120 mg tablets in the evening, based on an amount that is the molar equivalent of 120 mg of Compound 1.

[0215] In some embodiments, an effective amount of the L-arginine salt of Compound 1 is a daily dose of 300 mg, based on an amount that is the molar equivalent of 300 mg of Compound 1. In some embodiments, the daily dose can be divided into one or more oral dosage forms, such as tablets. In some embodiments, the daily dose is five 60 mg tablets (based on an amount that is the molar equivalent of 60 mg of Compound 1). In some embodiments, administration comprises administering to a subject three 60 mg tablets in the morning and two 60 mg tablets in the evening, based on an amount that is the molar equivalent of 60 mg of Compound 1.

[0216] In some embodiments, an effective amount of the L-phenylalanine salt of Compound 1 is a daily dose of 600 mg, based on an amount that is the molar equivalent of 600 mg of Compound 1. In some embodiments, the daily dose can be divided into one or more oral dosage forms, such as tablets or capsules. In some embodiments, the daily dose is five 120 mg tablets (based on an amount that is the molar equivalent of 120 mg of Compound 1). In some embodiments, administration comprises administering to a subject three 120 mg tablets in the morning and two 120 mg tablets in the evening, based on an amount that is the molar equivalent of 120 mg of Compound 1.

[0217] In some embodiments, an effective amount of the L-phenylalanine salt of Compound 1 is a daily dose of 300 mg, based on an amount that is the molar equivalent of 300 mg of Compound 1. In some embodiments, the daily dose can be divided into one or more oral dosage forms, such as tablets. In some embodiments, the daily dose is five 60 mg tablets (based on an amount that is the molar equivalent of 60 mg of Compound 1). In some embodiments, administration comprises administering to a subject three 60 mg tablets in the morning and two 60 mg tablets in the evening, based on an amount that is the molar equivalent of 60 mg of Compound 1.

[0218] In some embodiments, an effective amount of the L-histidine salt of Compound 1 is a daily dose of 600 mg, based on an amount that is the molar equivalent of 600 mg of Compound 1. In some embodiments, the daily dose can be divided into one or more oral dosage forms, such as tablets or capsules. In some embodiments, the daily dose is five 120 mg tablets (based on an amount that is the molar equivalent of 120 mg of Compound 1). In some embodiments, administration comprises administering to a subject three 120 mg tablets in the morning and two 120 mg tablets in the evening, based on an amount that is the molar equivalent of 120 mg of Compound 1.

[0219] In some embodiments, an effective amount of the L-histidine salt of Compound 1 is a daily dose of 300 mg, based on an amount that is the molar equivalent of 300 mg of Compound 1. In some embodiments, the daily dose can be divided into one or more oral dosage forms, such as tablets. In some embodiments, the daily dose is five 60 mg tablets (based on an amount that is the molar equivalent of 60 mg of Compound 1). In some embodiments, administration comprises administering to a subject three 60 mg tablets in the morning and two 60 mg tablets in the evening, based on an amount that is the molar equivalent of 60 mg of Compound 1.

[0220] In some embodiments, an effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, is a daily dose of 600 mg, based on an amount that is the molar equivalent of 600 mg of Compound 1. In some embodiments, the daily dose can be divided into one or more oral dosage forms, such as tablets or capsules. In some embodiments, the daily dose is five 120 mg tablets (based on an amount that is the molar equivalent of 120 mg of Compound 1). In some embodiments, administration comprises administering to a subject three 120 mg tablets in the morning and two 120 mg tablets in the evening, based on an amount that is the molar equivalent of 120 mg of Compound 1.

[0221] In some embodiments, an effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, is a daily dose of 300 mg, based on an amount that is the molar equivalent of 300 mg of Compound 1. In some embodiments, the daily dose can be divided into one or more oral dosage forms, such as tablets. In some embodiments, the daily dose is five 60 mg tablets (based on an amount that is the molar equivalent of 60 mg of Compound 1). In some embodiments, administration comprises administering to a subject three 60 mg tablets in the morning and two 60 mg tablets in the evening, based on an amount that is the molar equivalent of 60 mg of Compound 1.

[0222] In some embodiments, the effective amount of the compound is a daily dose. In some embodiments, the effective amount of the compound is administered once a day, twice a day, or three times a day.

[0223] In some embodiments, the effective amount of the compound is administered in a single composition or in multiple compositions, hi some embodiments, the composition is a tablet or capsule.

[0224] composition In some embodiments, the compositions are formulated for administration by various means, including orally, parenterally, by inhalation spray, topically, or rectally.

[0225] In some embodiments, the composition is in the form of a solution, suspension, emulsion, tablet, pill, capsule, powder, cream, or gel.

[0226] In some embodiments, the composition is in the form of eye drops, or the composition is coated onto or incorporated into an eye drop delivery device.

[0227] In some embodiments, the composition is in the form of a tablet or capsule.

[0228] In some embodiments, the composition comprises an amount of the compound disclosed herein that is the molar equivalent of about 20 mg to about 600 mg of Compound 1 (378.48 g / mol). In some embodiments, the composition comprises an amount of the compound disclosed herein that is the molar equivalent of about 50 mg to about 600 mg of Compound 1. In some embodiments, the composition comprises an amount of the compound that is the molar equivalent of about 50 mg to about 400 mg of Compound 1. In some embodiments, the composition comprises an amount of the compound that is the molar equivalent of about 50 mg to about 200 mg of Compound 1. In some embodiments, the composition comprises an amount of the compound that is the molar equivalent of about 50 mg to about 150 mg of Compound 1.

[0229] In some embodiments, the composition comprises an amount of the compound that is the molar equivalent of about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, or about 150 mg of Compound 1. In some embodiments, the composition comprises an amount of the compound that is the molar equivalent of about 60 mg or about 120 mg of Compound 1.

[0230] In some embodiments, the composition comprises a calcium salt of Compound 1 in an amount equivalent to about 20 mg to about 600 mg of Compound 1. In some embodiments, the composition comprises a calcium salt of Compound 1 in an amount equivalent to about 50 mg to about 600 mg of Compound 1. In some embodiments, the composition comprises a calcium salt of Compound 1 in an amount equivalent to about 50 mg to about 400 mg of Compound 1. In some embodiments, the composition comprises a calcium salt of Compound 1 in an amount equivalent to about 50 mg to about 200 mg of Compound 1. In some embodiments, the composition comprises a calcium salt of Compound 1 in an amount equivalent to about 50 mg to about 150 mg of Compound 1.

[0231] In some embodiments, the composition comprises a molar equivalent of the calcium salt of Compound 1 equivalent to about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, or about 150 mg of Compound 1. In some embodiments, the composition comprises a molar equivalent of the calcium salt of Compound 1 equivalent to about 60 mg or about 120 mg of Compound 1.

[0232] In some embodiments, the composition comprises an L-arginine salt of Compound 1 in an amount equivalent to about 20 mg to about 600 mg of Compound 1. In some embodiments, the composition comprises an L-arginine salt of Compound 1 in an amount equivalent to about 50 mg to about 600 mg of Compound 1. In some embodiments, the composition comprises an L-arginine salt of Compound 1 in an amount equivalent to about 50 mg to about 400 mg of Compound 1. In some embodiments, the composition comprises an L-arginine salt of Compound 1 in an amount equivalent to about 50 mg to about 200 mg of Compound 1. In some embodiments, the composition comprises an L-arginine salt of Compound 1 in an amount equivalent to about 50 mg to about 150 mg of Compound 1.

[0233] In some embodiments, the composition comprises the L-arginine salt of Compound 1 in an amount equivalent to about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, or about 150 mg of Compound 1. In some embodiments, the composition comprises the L-arginine salt of Compound 1 in an amount equivalent to about 60 mg or about 120 mg of Compound 1.

[0234] In some embodiments, the composition comprises an L-phenylalanine salt of Compound 1 in an amount equivalent to about 20 mg to about 600 mg of Compound 1. In some embodiments, the composition comprises an L-phenylalanine salt of Compound 1 in an amount equivalent to about 50 mg to about 600 mg of Compound 1. In some embodiments, the composition comprises an L-phenylalanine salt of Compound 1 in an amount equivalent to about 50 mg to about 400 mg of Compound 1. In some embodiments, the composition comprises an L-phenylalanine salt of Compound 1 in an amount equivalent to about 50 mg to about 200 mg of Compound 1. In some embodiments, the composition comprises an L-phenylalanine salt of Compound 1 in an amount equivalent to about 50 mg to about 150 mg of Compound 1.

[0235] In some embodiments, the composition comprises the L-phenylalanine salt of Compound 1 in a molar equivalent amount equivalent to about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, or about 150 mg of Compound 1. In some embodiments, the composition comprises the L-phenylalanine salt of Compound 1 in a molar equivalent amount equivalent to about 60 mg or about 120 mg of Compound 1.

[0236] In some embodiments, the composition comprises an L-histidine salt of Compound 1 in an amount equivalent to about 20 mg to about 600 mg of Compound 1. In some embodiments, the composition comprises an L-histidine salt of Compound 1 in an amount equivalent to about 50 mg to about 600 mg of Compound 1. In some embodiments, the composition comprises an L-histidine salt of Compound 1 in an amount equivalent to about 50 mg to about 400 mg of Compound 1. In some embodiments, the composition comprises an L-histidine salt of Compound 1 in an amount equivalent to about 50 mg to about 200 mg of Compound 1. In some embodiments, the composition comprises an L-histidine salt of Compound 1 in an amount equivalent to about 50 mg to about 150 mg of Compound 1.

[0237] In some embodiments, the composition comprises the L-histidine salt of Compound 1 in a molar equivalent amount corresponding to about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, or about 150 mg of Compound 1. In some embodiments, the composition comprises the L-histidine salt of Compound 1 in a molar equivalent amount corresponding to about 60 mg or about 120 mg of Compound 1.

[0238] In some embodiments, the composition comprises a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, in a molar equivalent amount corresponding to about 20 mg to about 600 mg of Compound 1. In some embodiments, the composition comprises a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, in a molar equivalent amount corresponding to about 50 mg to about 600 mg of Compound 1. In some embodiments, the composition comprises a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, in a molar equivalent amount corresponding to about 50 mg to about 400 mg of Compound 1. In some embodiments, the composition comprises a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, in a molar equivalent amount corresponding to about 50 mg to about 200 mg of Compound 1. In some embodiments, the composition comprises a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, in a molar equivalent amount corresponding to about 50 mg to about 150 mg of Compound 1.

[0239] In some embodiments, the composition comprises a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, in an amount equivalent to about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, or about 150 mg of Compound 1. In some embodiments, the composition comprises a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, in an amount equivalent to about 60 mg or about 120 mg of Compound 1.

[0240] In some embodiments, a composition comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, comprises a pharmaceutically acceptable vehicle or carrier.

[0241] In some embodiments, the composition is stable at 25° C. / 60% RH for at least 1 week. In some embodiments, the composition is stable when stored at 25° C. / 60% RH for at least about 6 months. In some embodiments, the composition is stable at 25° C. / 60% RH for at least about 12 months. In some embodiments, the composition is stable at 25° C. / 60% RH for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, or at least about 36 months.

[0242] In some embodiments, the composition is stable at 40°C / 75% RH for at least about 1 week. In some embodiments, the composition is stable at 40°C / 75% RH for at least about 6 months. In some embodiments, the composition is stable at 40°C / 75% RH for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months. In some embodiments, the composition is stable at 40°C / 75% RH for at least about 36 months. In some embodiments, the composition is stored in an open container under stable conditions.

[0243] In some embodiments, the composition is stable to exposure to light for at least about 6 months. In some embodiments, the composition is stable to exposure to visible light for at least about 6 months.

[0244] In some embodiments, the composition is an eye drop suitable for intraocular administration or ophthalmic use, hi some embodiments, the eye drop is suitable for topical, subconjunctival, intravitreal, retrobulbar, intracameral, or systemic administration.

[0245] In some embodiments, the composition is an ophthalmic solution suitable for intravitreal administration and further comprises α,α-trehalose dihydrate or polysorbate 20. In some embodiments, the composition is an ophthalmic solution suitable for intravitreal administration and further comprises water for injection. In some embodiments, the composition is an ophthalmic solution suitable for intravitreal administration and further comprises a buffer.

[0246] In some embodiments, the composition comprises a salt of Compound 1, an ester of Compound 1 or a pharmaceutically acceptable salt thereof, or a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises a calcium salt of Compound 1, an L-arginine salt of Compound 1, an L-phenylalanine salt of Compound 1, an L-histidine salt of Compound 1, or a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof.

[0247] In some embodiments, the composition comprises a calcium salt of Compound 1, obtainable according to the method of Example 1. In some embodiments, the composition comprises a calcium salt of Compound 1, obtainable according to the method of Example 2. In some embodiments, the composition comprises a calcium salt of Compound 1, obtainable according to the method of Example 3. In some embodiments, the composition comprises an L-arginine salt of Compound 1, obtainable according to the method of Example 4, Procedure A. In some embodiments, the composition comprises an L-arginine salt of Compound 1, obtainable according to the method of Example 4, Procedure B.

[0248] In some embodiments, compositions comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, are suitable for topical, subconjunctival, intravitreal, retrobulbar, intracameral, or systemic administration. In some embodiments, compositions comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, are suitable for intravitreal administration.

[0249] In some embodiments, a composition comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, is suitable for intraocular administration or ophthalmic use. In some embodiments, the composition is an eye drop. In some embodiments, the eye drop is suitable for topical, subconjunctival, intravitreal, retrobulbar, intracameral, or systemic administration. In some embodiments, the composition is an eye drop, or the composition is coated on or incorporated into an eye drop delivery device.

[0250] In some embodiments, the pharmaceutically acceptable carrier or vehicle is a stabilizer, binder, filler, diluent, disintegrant, wetting agent, lubricant, glidant, colorant, dye transfer inhibitor, sweetener, flavoring agent, viscosity modifier, pH adjuster, buffer, osmotic agent, chelating agent, surfactant, or cosolvent. In some embodiments, the pharmaceutically acceptable carrier or vehicle is a binder, diluent, disintegrant, and / or lubricant.

[0251] In some embodiments, the diluent is sugar, mannitol, lactose, lactose monohydrate, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, microfine cellulose, or starch. In some embodiments, the starch is corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, or porous starch. In some embodiments, the diluent is lactose monohydrate, microcrystalline cellulose, dicalcium phosphate dihydrate, calcium carbonate, or partially pregelatinized maize starch. In some embodiments, the microcrystalline cellulose has an average particle size of about 50 μm to about 200 μm. In some embodiments, the microcrystalline cellulose has an average particle size of about 50 μm or about 100 μm.

[0252] In some embodiments, the disintegrant is carboxymethylcellulose, starch, pregelatinized starch, partially pregelatinized starch, crospovidone, sodium starch glycolate, or hydroxypropylcellulose. In some embodiments, the disintegrant is sodium carboxymethylcellulose. In some embodiments, the disintegrant is low-substituted hydroxypropylcellulose.

[0253] In some embodiments, the binder is methylcellulose, hydroxypropyl cellulose, hypromellose (hydroxypropyl methylcellulose), ethyl cellulose, povidone (polyvinylpyrrolidone), polyvinyl alcohol, powdered acacia, gelatin, or pullulan. In some embodiments, the viscosity of the methylcellulose is about 25 cP.

[0254] In some embodiments, the glidant is talc.

[0255] In some embodiments, the lubricant is magnesium stearate, calcium stearate, talc, or sodium stearyl fumarate.

[0256] In some embodiments, the viscosity modifier is polyvinyl alcohol, poloxamer, hyaluronic acid, carbomer, and polysaccharides, i.e., cellulose derivatives, gellan gum, or xanthan gum.

[0257] In some embodiments, the composition comprises lactose monohydrate, microcrystalline cellulose, starch, sodium carboxymethylcellulose, methylcellulose, and / or magnesium stearate. In some embodiments, the starch is partially pregelatinized maize starch.

[0258] In some embodiments, the pharmaceutically acceptable carrier or vehicle is sterile water, sterile buffer, or sterile saline.

[0259] In some embodiments, the pharmaceutically acceptable carrier or vehicle comprises or is mannitol or sodium acetate.

[0260] In some embodiments, the composition comprises a preservative, hi some embodiments, the preservative is benzalkonium chloride, cetrimide, polyquaternium-1, thimerosal, sodium perborate, stabilized oxychloro complex, stabilized chlorite peroxide, chlorhexidine, chlorobutanol, phenylethanol, or methylparaben.

[0261] In some embodiments, the composition does not contain a preservative. In some embodiments, the composition is preservative-free.

[0262] In some embodiments, the compositions of the present invention are in the form of a tablet. In some embodiments, the tablet comprises a coating. In some embodiments, the coating is a film coating.

[0263] In some embodiments, the compositions of the present invention are in the form of tablets having a tablet hardness ranging from about 5 kp to about 15 kp. In some embodiments, the tablet hardness is about 5 kp, about 6 kp, about 7 kp, about 8 kp, about 9 kp, about 10 kp, about 11 kp, about 12 kp, about 13 kp, about 14 kp, or about 15 kp. In some embodiments, the tablet hardness is about 6 kp to about 12 kp. In some embodiments, the tablet hardness is about 8 kp to about 14 kp.

[0264] In some embodiments, the compositions of the present invention are in the form of tablets having a tablet thickness ranging from about 3.0 mm to about 7.0 mm. In some embodiments, the tablet thickness is about 3.0 mm, about 3.5 mm, about 4.0 mm, about 4.5 mm, about 5.0 mm, about 5.5 mm, about 6.0 mm, about 6.5 mm, or about 7.0 mm. In some embodiments, the tablet hardness is about 4.0 mm to about 4.3 mm. In some embodiments, the tablet thickness is about 4.0 mm, about 4.1 mm, about 4.2 mm, or about 4.3 mm. In some embodiments, the tablet hardness is about 4.8 mm to about 5.1 mm. In some embodiments, the tablet thickness is about 4.8 mm, about 4.9 mm, about 5.0 mm, or about 5.1 mm.

[0265] In some embodiments, the compositions of the present invention are in the form of tablets with a friability (% weight loss) of less than about 1%. In some embodiments, the tablet friability is less than about 0.9%. In some embodiments, the tablet friability is less than about 0.8%.

[0266] In some embodiments, the compositions of the present invention are in the form of tablets, the tablets have a target weight, and the tablet weight variation is ±10% of the tablet's target weight.

[0267] In some embodiments, the compositions of the present invention are in the form of tablets, and the average solubility of the compound of the present invention from the tablets at 15 minutes in phosphate buffer at pH 6.8 at 37°C is about 4% to about 10% by weight of the total amount of the compound of the present invention in the tablets. In some embodiments, the average solubility of the compound of the present invention from the tablets at 15 minutes in phosphate buffer at pH 6.8 at 37°C is about 5% to about 7% by weight of the total amount of the compound of the present invention in the tablets. In some embodiments, the average solubility of the compound of the present invention from the tablets at 15 minutes in phosphate buffer at pH 6.8 at 37°C is about 6% by weight of the total amount of the compound of the present invention in the tablets. In some embodiments, the solubility is measured using USP Apparatus 2 (paddle) set at 100 rpm. In some embodiments, the solubility of the compound of the present invention is analyzed by HPLC based on Compound 1.

[0268] In some embodiments, the compositions of the present invention are in the form of tablets, and the average solubility of the compound of the present invention from the tablets at 30 minutes in phosphate buffer at pH 6.8 at 37°C is about 10% to about 25% by weight of the total amount of the compound of the present invention in the tablets. In some embodiments, the average solubility of the compound of the present invention from the tablets at 30 minutes in phosphate buffer at pH 6.8 at 37°C is about 10% to about 20% by weight of the total amount of the compound of the present invention in the tablets. In some embodiments, the average solubility of the compound of the present invention from the tablets at 30 minutes in phosphate buffer at pH 6.8 at 37°C is about 15% by weight of the total amount of the compound of the present invention in the tablets. In some embodiments, the solubility is measured using USP Apparatus 2 (paddle) set at 100 rpm. In some embodiments, the solubility of the compound of the present invention is analyzed by HPLC based on Compound 1.

[0269] In some embodiments, the compositions of the present invention are in the form of tablets, and the average solubility of the compound of the present invention from the tablets at 45 minutes in phosphate buffer at pH 6.8 at 37°C is about 15% to about 35% by weight of the total amount of the compound of the present invention in the tablets. In some embodiments, the average solubility of the compound of the present invention from the tablets at 45 minutes in phosphate buffer at pH 6.8 at 37°C is about 20% to about 30% by weight of the total amount of the compound of the present invention in the tablets. In some embodiments, the average solubility of the compound of the present invention from the tablets at 45 minutes in phosphate buffer at pH 6.8 at 37°C is about 24% by weight of the total amount of the compound of the present invention in the tablets. In some embodiments, the solubility is measured using USP Apparatus 2 (paddle) set at 100 rpm. In some embodiments, the solubility of the compound of the present invention is analyzed by HPLC based on Compound 1.

[0270] In some embodiments, the compositions of the present invention are in the form of tablets, and the average solubility of the compound of the present invention from the tablets at 60 minutes in phosphate buffer at pH 6.8 at 37°C is about 23% to about 50% by weight of the total amount of the compound of the present invention in the tablets. In some embodiments, the average solubility of the compound of the present invention from the tablets at 60 minutes in phosphate buffer at pH 6.8 at 37°C is about 30% to about 40% by weight of the total amount of the compound of the present invention in the tablets. In some embodiments, the average solubility of the compound of the present invention from the tablets at 60 minutes in phosphate buffer at pH 6.8 at 37°C is about 35% by weight of the total amount of the compound of the present invention in the tablets. In some embodiments, the solubility is measured using USP Apparatus 2 (paddle) set at 100 rpm. In some embodiments, the solubility of the compound of the present invention is analyzed by HPLC based on Compound 1.

[0271] In some embodiments, the compositions of the present invention are in the form of tablets, and the average solubility of the compound of the present invention from the tablets at 90 minutes in phosphate buffer at pH 6.8 at 37°C is about 40% to about 75% by weight of the total amount of the compound of the present invention in the tablets. In some embodiments, the average solubility of the compound of the present invention from the tablets at 90 minutes in phosphate buffer at pH 6.8 at 37°C is about 50% to about 65% by weight of the total amount of the compound of the present invention in the tablets. In some embodiments, the average solubility of the compound of the present invention from the tablets at 90 minutes in phosphate buffer at pH 6.8 at 37°C is about 57% by weight of the total amount of the compound of the present invention in the tablets. In some embodiments, the solubility is measured using USP Apparatus 2 (paddle) set at 100 rpm. In some embodiments, the solubility of the compound of the present invention is analyzed by HPLC based on Compound 1.

[0272] In some embodiments, the compositions of the present invention have a pH of about 4 to about 8.6. In some embodiments, the compositions have a pH of about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, or about 8.5. In some embodiments, the compositions of the present invention have a pH of about 4 to about 6. In some embodiments, the compositions of the present invention have a pH of about 4.5 to about 5.3. In some embodiments, the compositions have a pH of about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, or about 5.3. In some embodiments, the compositions of the present invention have a pH of 4 to 6. In some embodiments, the compositions of the present invention have a pH of 4.5 to 5.3. In some embodiments, the compositions have a pH of 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, or 5.3.

[0273] In some embodiments, the compositions of the present invention are contained in a capsule.

[0274] In some embodiments, the compositions of the present invention are contained in a sealed container. In some embodiments, the sealed container further contains an inert gas. In some embodiments, the inert gas is argon or nitrogen. [Example]

[0275] General Procedure: Unless otherwise noted, X-ray powder diffraction (XRPD) analysis was performed using a Bruker D8 Discover diffractometer in DAVINCI configuration in transmission mode (scan type: 2θ or offset-coupled 2θ / θ) scanning samples (approximately 2-3 mg) from 1.5 to 45 degrees 2θ angles. The following measurement characteristics were used: acquisition time was 7.58 min, increment per step was 0.01 degrees, time per step was 0.1 seconds, generator voltage / generator amperage was 40 mA / 40 kV, and power reached 1.6 kW. The XRPD system was used in parallel beam geometry (Gobel mirror) with a Cu anode and a LynxEye-type detector. The XRPD system also used a goniometer type θ / θ in a vertical operating position with a measurement circle diameter of 560 mm. In transmission mode, a single 1 mm UBC collimator magnetic holder was attached to the primary optics.

[0276] The raw XRPD data were imported into Diffrac.EVA5.0 software and processed using the following parameters: background subtraction and Kα2 stripping were performed before peak determination, and a peak search operation was performed with a threshold of 1 and a peak width of 0.153 in all examples except for Examples 2 and 3, which were performed with a threshold of 0.78 and a peak width of 0.242 (or 0.153). All resulting peaks with a relative intensity of 2% or greater were considered.

[0277] The XRPD data for Example 2 were obtained using a Bruker AXS in a D2 Phaser 2nd generation configuration (part number: A26X1-A2B0B1C) in reflectance mode (scan type: coupled 2θ / θ) scanning the sample from 3 to 40 degrees 2θ angles, with the following measurement characteristics: increment per step was 0.02 degrees, time per step was 0.3 seconds, generator voltage / generator amperage was 10 mA / 30 kV, reaching a power of 0.3 kW, detector type was LynxEye A17-B60, and goniometer type was θ / θ. XRPD data were collected using DIFFRAC.MEASURMENT 8.6.3.0 software and processed with DIFFRAC.EVA 6.0.0.8 software.

[0278] Compound 1 can be obtained according to US Pat. No. 5,210,239.

[0279] Example 1. Synthesis of the calcium salt of compound 1 Approximately 20 g of compound 1 (1 equivalent) was weighed into a 1 L glass reactor and mixed with HO:MeOH (1:1 v / v) at room temperature to obtain a fine suspension with a concentration of 36.3 g of compound per 1 L of HO:MeOH (1:1 v / v). The suspension was stirred at 300 rpm for 30 minutes using an OS-20 mechanical stirrer equipped with a rod and a PTFE propeller. Calcium hydroxide (95%, 2.0953 g, 0.5 equivalents) was added, and the resulting mixture was stirred at 500 rpm for 2 hours at room temperature. After 2 hours, the resulting precipitate was vacuum filtered and washed with 400 mL of HO:MeOH (1:1 v / v). The washed precipitate was dried in a fume hood at 25 °C under atmospheric pressure for approximately 45 hours to obtain the calcium salt of compound 1 as a pale orange-yellow solid (89.06% yield).

[0280] The purity of the calcium salt of compound 1 was determined by HPLC chromatography using an Agilent 1260 Infinity HPLC system and a HiChrom C18 column (4.6 x 100 mm, 3.5 μm) at 30 °C. The HPLC system was connected to a UV-Vis diode array detector (HPLC-DAD). Analysis was performed using a gradient method (described in the table below) with 0.1% formic acid in purified MilliQ water (mobile phase A) and 0.1% formic acid in HPLC-grade acetonitrile (mobile phase B). The flow rate was 1 mL / min, and the injection volume was 5 μL. UV detection was performed at 236 nm and 266 nm. The sample was dissolved in MilliQ purified water. The purity of the calcium salt of compound 1, as determined by HPLC, was 99.7% at 236 nm and 99.8% at 266 nm. [Table 1]

[0281] The calcium salt of compound 1 was analyzed by XRPD and thermogravimetry (TG) / differential scanning calorimetry (DSC).

[0282] FIG. 1A shows the XRPD diffractogram (with the background removed) of the calcium salt of Compound 1 obtained as described in this example, and Table 1 lists the XRPD peaks represented in FIG. 1A. [Table 2]

[0283] TG / DSC Analysis: A sample (approximately 5.3 mg) of the calcium salt of Compound 1 obtained according to this example was weighed into an open aluminum pan and loaded into a Setaram LABSYS EVO simultaneous thermogravimetry / differential scanning calorimeter (TG-DTA / DSC) and held at 30°C for 15 minutes. The sample was then heated from 30°C to 550°C, during which the change in sample weight was recorded along with all differential thermal events. Nitrogen was introduced at 180 cm 3 HCl was used as the purge gas at a flow rate of 10 °C / min. Prior to analysis, the mass loss and temperature of the instrument were calibrated using copper sulfate pentahydrate and reference standards (lead and indium), respectively. Sample analysis was performed using CALISTO software, and the corresponding mass loss and temperature of the thermal event were quoted as the measured onset temperature according to the manufacturer's specifications. Analysis was performed at a heating rate of 10 °C / min, and the background was subtracted before further processing.

[0284] TG / DSC analysis of the calcium salt of Compound 1 obtained according to this example showed one small endothermic event between 50 and 89°C (peak maximum at approximately 82°C) and one exothermic event starting at approximately 208°C (peak maximum at approximately 213°C) (Figure 1B). Corresponding to the endothermic event, a mass loss of approximately 5% was observed on the TG curve. Based on the TG / DSC data, the calcium salt of Compound 1 obtained according to this example is a monohydrate.

[0285] The calcium salt of compound 1 obtained generally according to this method was analyzed by FT-IR, FT-Raman, dynamic vapor sorption (DVS), and 1 H Further analysis was carried out by NMR.

[0286] The FT-IR spectrum of the calcium salt of compound 1 (Figures 1C and 1D) shows a peak between 3500 and 50 cm -1 Recorded between the following wavenumbers (cm -1 ) showed important bands designated as: 2924 (m) and 2853 (m) (characteristic of asymmetric -CH2-, symmetric -CH3 and -CH2- stretching vibrations); 1636 (st) (characteristic of -C=O stretching vibrations and some =CH stretching vibrations); 1603 (st) (characteristic of -C=C- stretching vibrations and -CC- skeletal vibrations); 1556 (st) (which is characteristic of -CO- vibrations (e.g. in -COOR groups) or aromatic -C=C- 1418 (st) (characteristic of -C-C- stretching (intracyclic) aromatic or -C-H bending vibrations); 1298 (m), 1261 (st), 1203 (st), and 1157 (m) (characteristic of -C-O or -C(O)-O stretching vibrations); 1094 (m), 997 (m), 951 (w), 787 (w), 739 (m), and 636 (w) (characteristic of C-H out-of-plane bending or -C-C- bending vibrations). The intensities of the absorption bands are indicated as follows: (w) = weak, (m) = medium, (st) = strong intensity.

[0287] The FT-Raman spectrum of the calcium salt of compound 1 (Figure 1E) shows a peak at 4000 to 150 cm -1The data were recorded between 1000 and 1000 m / s and showed the following important bands, expressed in wavenumbers (cm-1): 2927 (m) and 2858 (m) (assigned to -CH2 and -CH3 vibrations); 1652 (st) (assigned to the -C=O group), 1600 (m) (attributed to -C=C- vibrations); 1440 (m), 1384 (m), 1337 (st), and 1303 (m) (attributed to ring deformation and -C-O- vibrations); 957 (w), 874 (w), 499 (m), 443 (m), and 344 (w) (assigned to -C-C vibrations and ring breathing). The intensities of the absorption bands are indicated as follows: (w) = weak, (m) = moderate, (st) = strong intensity. The tolerance for all FT-Raman absorption bands is ±2 cm. -1 is.

[0288] DVS analysis: The water content of the calcium salt of compound 1 was 0.39% and was equilibrated to 0% before starting the analysis. DVS analysis of the calcium salt of compound 1 (Figure 1F) showed that the maximum water adsorption at 82% RH was approximately 1.52%, whereas at the end of the desorption branch, the calcium salt of compound 1 retained 0.19% water. Subsequent XRPD analysis revealed the same peaks, albeit with slightly lower intensity, confirming that the post-DVS sample of calcium salt of compound 1 maintained the same crystalline morphology as the pre-DVS sample of calcium salt of compound 1.

[0289] of the calcium salt of compound 1 1 The H-NMR spectrum was obtained (Figure 1G), and the peak of the -COOH group (approximately 12 ppm) was not observed. 1 H (600MHz, DMSO-d6): 0.84 (3H), 1.12 (6H), 1.18 (4H), 1.23 (2H), 1.33 (2H), 1.83 (3H), 1.98 (2H), 3.88 (3H), 3.91 (3H), 6.85 (1H).

[0290] Example 2: Synthesis of the calcium salt of compound 1 Approximately 75 g (0.198 mol) of compound 1 (1 equivalent) was charged to a 5 L jacketed reactor. 2025 mL (27.0 volumes) of 2:1 HO:MeOH (v / v) was charged to the 5 L jacketed reactor at room temperature. The reaction mixture was stirred at 25 ± 5 °C for 25 minutes to obtain a fine suspension. Calcium hydroxide (7.3 g, 0.5 equivalents) was charged to the reactor in small portions over 25 minutes. The resulting mixture was thick but remained stirrable, and some shelling was observed near the top of the reactor. The shelled material was scraped off. The mixture was stirred at 25 ± 5 °C for 2 hours, at which point the mixture became very thick. A sample was taken, and XRPD analysis confirmed the formation of the calcium salt of compound 1.

[0291] The resulting solid was collected by vacuum filtration and washed twice with 2:1 water / methanol (900 mL, 12.0 vol). The solid was dried under vacuum until the moisture content was approximately 12%, and then dried using humidified drying. Humidified drying was performed using a vacuum oven attached to a household vacuum system emitting a small amount of water-vapor-saturated nitrogen. The water-vapor-saturated nitrogen was obtained by bubbling nitrogen through water, with a humidity of 100% at 20 ± 5 °C. Humidified drying was continued until the moisture content of the solid was 4-6% (Table 2), yielding the calcium salt of compound 1 as an orange-yellow solid (80.41 g, 97.2% yield). The purity, as determined by HPLC at 262 nm, was 99.9%. The HPLC parameters and conditions were as follows: Mobile phase A: 0.1% TFA in water Mobile phase B: 0.1% TFA in acetonitrile Diluent: acetonitrile and water; 80:20 v / v Sample concentration: 0.7 mg / mL [Table 3]

[0292] The calcium salt of compound 1 was analyzed by XRPD, TGA, DSC, and 1 H The product was analyzed by NMR (Figures 2A-2D). [Table 4]

[0293] FIG. 2A shows the XRPD diffractogram of the calcium salt of Compound 1 obtained as described in this example, and Table 3 lists the XRPD peaks represented in FIG. 2A. [Table 5]

[0294] TGA analysis: A sample (approximately 2-5 mg) of the calcium salt of Compound 1 obtained generally according to this example was weighed into an aluminum pan (70 μL) and loaded into a Mettler Toledo TGA 2 Star System (sampling interval: 1 s). The sample was then heated from 25°C to 350°C (heating rate 10 K / min), and the change in sample weight was recorded. Sample analysis was performed using STAR 16.20 software.

[0295] DSC Analysis: A sample (approximately 3-6 mg) of the calcium salt of Compound 1, obtained generally according to this example, was weighed into an aluminum pan (40 μL) and loaded into a Mettler Toledo DSC 1 Star System (sampling interval: 1 s). The sample was then heated from 25°C to 350°C (heating rate 10°C / min) while recording all differential thermal events. Nitrogen was introduced at 80 cm 3 1000kJ / min. Sample analysis was performed using STAR 16.10 software.

[0296] 1 H NMR analysis: 1 H NMR spectra were acquired on a Bruker Advance III HD 300 MHz NMR Spectrometer (sample size: approximately 8 mg / mL in DMSO-d6) and analyzed with TopSpin 3.6.4 software.

[0297] Example 3. Synthesis of the calcium salt of compound 1 (mainly amorphous) The calcium salt of Compound 1, prepared generally according to Example 1, was heated at approximately 60° C. under atmospheric pressure for 1 hour. The resulting calcium salt of Compound 1 was determined to be anhydrous and predominantly (>50%) amorphous, based on the presence of few XRPD peaks.

[0298] FIG. 3A shows the XRPD diffractogram (with background removed) of the anhydrous and predominantly amorphous calcium salt of Compound 1 obtained upon heating at about 60° C. under atmospheric pressure for 1 hour, and Table 4 lists the XRPD peaks shown in FIG. 3A. [Table 6]

[0299] TG / DSC analysis of the predominantly amorphous calcium salt of Compound 1 showed only one exothermic event starting at approximately 210 °C, which was attributed to the salt decomposition process (Figure 3B). There was no mass loss due to the thermal event. Based on the TG / DSC data, the predominantly amorphous calcium salt of Compound 1 is anhydrous.

[0300] Hydration experiment: To approximately 200 mg of the calcium salt of Compound 1 (anhydrous and primarily amorphous) obtained above was added water (1.60 mL). The resulting mixture was stirred at 700 rpm for 1 hour. The resulting mixture was heated at approximately 40°C under atmospheric pressure for 2 hours, followed by heating at 50°C under atmospheric pressure for 4 hours. The resulting solid exhibited an XRPD pattern and TG / DSC consistent with the calcium salt monohydrate of Compound 1 obtained generally according to Example 1.

[0301] Example 4 - Synthesis of L-arginine salt of compound 1 Procedure A: Approximately 100 mg of compound 1 (1 equivalent) was placed in a flask and mixed with acetonitrile at room temperature to provide a solution having a concentration of 100.94 mg of compound 1 per mL of acetonitrile. The solution was stirred (500 rpm) for 1 hour. L-arginine (1.1 equivalents) was added, and the resulting mixture was stirred at room temperature for 3 hours. The resulting precipitate was filtered, washed with 4 mL of acetonitrile, and dried under vacuum (30 °C and 22 mbar) overnight to give a dark yellow solid (88.81% yield).

[0302] The purity of the calcium salt of compound 1 was determined by HPLC chromatography using an Agilent 1260 Infinity HPLC system and a HiChrom C18 column (4.6 x 100 mm, 3.5 μm) at 30 °C. The HPLC system was connected to a UV-Vis diode array detector (HPLC-DAD). The analysis was performed using a gradient method with 0.1% formic acid in purified MilliQ water (mobile phase A) and 0.1% formic acid in HPLC-grade acetonitrile (mobile phase B). The gradient started with 50% phase A for 3 min, switched to 10% phase A after 10 min, followed by a 3-min hold at 10% phase A and then back to 50% phase A for 15 min. The flow rate was 1 mL / min and the injection volume was 5 μL. UV detection was performed at 236 nm and 266 nm. Samples were dissolved in MilliQ purified water.

[0303] The HPLC purity of the L-arginine salt of Compound 1 obtained by Procedure A of this Example was 98.9% at 236 nm and 99.6% at 266 nm.

[0304] FIG. 4A shows the XRPD diffractogram (with background removed) of the L-arginine salt of Compound 1 obtained as described in Procedure A, and Table 5A lists the XRPD peaks represented in FIG. 4A. [Table 7]

[0305] Procedure B: Approximately 20 mg of compound 1 (1 equivalent) was placed in a 2 mL vial containing acetonitrile to provide a solution having a concentration of approximately 101.00 mg of compound 1 per mL of acetonitrile. The resulting solution was stirred (500 rpm) for 1 hour. L-arginine (1.1 equivalents) was added at room temperature, and the resulting mixture was stirred at room temperature for 4 hours. The resulting precipitate was filtered and dried under vacuum (30 °C, 21 mbar) for 4 hours to obtain the L-arginine salt of compound 1 as a yellow solid (yield not determined).

[0306] The HPLC purity of the L-arginine salt of Compound 1 obtained by Procedure B (see Procedure A for HPLC conditions) was 89.4% at 236 nm and 93.0% at 266 nm.

[0307] FIG. 4B shows the XRPD diffractogram (with background removed) of the L-arginine salt of Compound 1 obtained as described in Procedure B, and Table 5B lists the XRPD peaks represented in FIG. 4B. [Table 8]

[0308] The L-arginine salt of compound 1 obtained as described in procedure A (HPLC purity 98.9% at 236 nm and 99.6% at 266 nm) was analyzed by TG / DSC.

[0309] TG / DSC analysis of the L-arginine salt of compound 1 obtained as described in Procedure A showed one small endothermic event between 55 and 66 °C (peak maximum at approximately 61 °C) and one exothermic event starting at approximately 146 °C (peak maximum at approximately 150 °C) (Figure 4C). There was no mass loss due to the first thermal event. Based on the TG / DSC data, the L-arginine salt of compound 1 obtained according to Procedure A is anhydrous.

[0310] The threshold solubility of the L-arginine salt of Compound 1 obtained according to Procedure A in Milli-Q® water (c=1 mg / mL concentration, 37°C, stirring for 24 hours) was determined by HPLC to be approximately 630 μg / mL after 24 hours at 37°C (release efficiency >90%).

[0311] Example 5. Synthesis of L-phenylalanine salt of compound 1 and L-histidine salt of compound 1 An ethanol solution of compound 1 (concentration 201.60 mg / mL) was distributed into six vials, each containing approximately 25 mg of compound 1 (1 equivalent). Solid L-phenylalanine (1.1 equivalents) or solid L-histidine (1.1 equivalents) and a base or a mixture of bases (9.21 μL triethylamine, 2.64 mg NaOH, or 3.71 mg KOH) were added to each vial containing compound 1. The resulting mixture was stirred at approximately 25–27 °C for 4 h. A precipitate formed and was collected.

[0312] The L-phenylalanine salt of compound 1 was obtained as a dark yellow solid.

[0313] The L-histidine salt of compound 1 was obtained as a dark yellow solid, a brown solid, or a dark red solid.

[0314] Example 6. Preparation of tablets containing a salt of Compound 1 Tablets are prepared containing a salt of Compound 1, such as the calcium salt of Compound 1, as disclosed herein. Steps in the manufacturing process include premixing, granulating, milling, blending, tableting, and coating.

[0315] Granulation process: Compound 1 salt and one or more excipients, such as diluents, binders, disintegrants, anti-caking agents, surfactants, and lubricants, are individually de-lumped and collected in suitable tared containers. The combined powders are then loaded into a fluid-bed granulator and sprayed with the granulating solution. After the granulating solution is applied, additional purified water is sprayed onto the fluidized powder until a visually acceptable endpoint is reached. At this endpoint, the liquid spray is stopped and drying begins. The granulated powder is dried in the fluid bed until the loss on drying (LOD) is 3% or less.

[0316] The bulk dry granulation is milled and blended. The combined granulation is milled to prepare for the blending process. Approximately half of the granulation is added to a V-blender. One or more excipients, such as diluents, binders, or disintegrants, are de-lumped and subsequently added to the V-blender. The remaining half of the granulation is then added to the V-blender, and the powders are pre-blended. A visually equivalent amount of the pre-blend is added to a container of one or more excipients, such as a lubricant, and bag-blended. This blend is de-lumped by manually passing it through a 30-mesh screen and adding it to the V-blender for blending. The completed final blend is discharged and weighed prior to tablet compression.

[0317] Compression: The granulation is compressed on a press equipped with a force feeder and appropriate circular compression tooling. As the final blend is added to the press, tablet weights are established. The main compression force is then adjusted to achieve the target tablet hardness (approximately 8-14 kp) and thickness (approximately 5.0 mm). After initial start-up sample testing confirms acceptable weight variation, hardness, thickness, and friability, the bulk final blend is compressed into tablet cores. The cores are tared and collected into a double-lined fiber drum. During the compression run, tablets are collected every 10 minutes, and the composite weight of 10 tablets is recorded, along with the break load and thickness of five tablets. From this in-process sample, five tablets are placed in a composite sample container for end-of-batch tablet physical testing.

[0318] Coating: Prepare a coating suspension using Opadry® Yellow coating and purified water. Tablets are coated to achieve a target weight gain of approximately 4.0-5.0%.

[0319] Table 6 shows the in-process controls. [Table 9]

[0320] Example 7. Safety and Efficacy Study of the Calcium Salt of Compound 1 in Patients with Ophthalmic Disease This study is a randomized, placebo-controlled, double-blind study of the safety and efficacy of the calcium salt of Compound 1, prepared according to any one of Examples 2-4, administered orally twice daily for 24 weeks in subjects with an ocular disease described herein, such as moderately severe to severe nonproliferative diabetic retinopathy (NPDR), or mild proliferative diabetic retinopathy (PDR).

[0321] The study will involve a 1:1 randomization (placebo:calcium salt of Compound 1) with stratification by level of disease severity.

[0322] Calcium salt of Compound 1 group: 600 mg / day of calcium salt of Compound 1 is orally administered in divided doses in the morning and evening (eg, 360 mg every morning and 240 mg every evening). Placebo group: The placebo tablets are identical to the calcium salt tablets of Compound 1, except that there is no calcium salt of Compound 1. Five placebo tablets are taken orally as follows: three tablets every morning and two tablets every evening.

[0323] Study medication is to be taken at approximately the same time each day and may be taken with or without food. If a subject considers discontinuing the study due to an adverse event, a dose reduction from 600 mg to 480 mg per day (two tablets in the morning and two tablets in the evening) may be offered. The screening visit (Visit 1) occurs 1–21 days before the eligibility / baseline visit (Visit 2), which occurs before dosing on Day 1. Three treatment site visits are scheduled: Visit 4 at Week 4 (± 2 days), Visit 6 at Week 12 (± 2 days), and Visit 9 at Week 24 (± 2 days). Between these visits, subjects will be contacted by phone at Visit 3 at Week 1 (± 2 days), Visit 5 at Week 8 (± 2 days), Visit 7 at Week 16 (± 2 days), and Visit 8 at Week 20 (± 2 days) for safety assessments, including adverse events (AEs), concomitant medications, and compliance.

[0324] Efficacy Analysis: For analyses of the primary efficacy endpoint, appropriate imputation methods will be performed, where applicable, for missing observations or subjects requiring rescue. If analyses using the per-protocol (PP) population show a positive effect of the calcium salt of Compound 1 at a significance level of 0.05, the primary endpoint will be considered met. Confirmatory analyses may be performed using the entire randomized population, with imputation for missing data. If necessary, confirmatory analyses with imputation for missing data or subjects requiring rescue will also be performed for secondary efficacy endpoints.

[0325] For all efficacy endpoints, baseline values ​​are defined as the last observation before randomization. The primary efficacy endpoint is the difference between treatment groups in the proportion of subjects achieving an improvement of 2 or more grades from baseline in a disease severity score, such as the Diabetic Retinopathy Severity Score, from the study's perspective at week 24. The primary efficacy endpoint is analyzed using a logistic regression model with treatment as a factor and baseline severity score as a covariate. The proportion of subjects meeting criteria in each treatment group, odds ratios (OR) with 95% confidence intervals (CI), and p-values ​​are provided.

Claims

1. The calcium salt of Compound 1 exhibits an X-ray powder diffraction (XRPD) pattern including a peak at 5.8±0.2 degrees 2θ and a peak at 6.3±0.2 degrees 2θ.

2. 2. The calcium salt of Compound 1 of claim 1, wherein the XRPD pattern further comprises a peak at 13.7±0.2 degrees 2θ or a peak at 14.1±0.2 degrees 2θ.

3. The calcium salt of Compound 1 exhibits an X-ray powder diffraction (XRPD) pattern including a peak at 4.1±0.2 degrees 2θ, a peak at 5.3±0.2 degrees 2θ, and a peak at 6.3±0.2 degrees 2θ.

4. 4. The calcium salt of Compound 1 of claim 3, wherein the XRPD pattern further comprises a peak at 5.8±0.2 degrees 2θ or a peak at 14.1±0.2 degrees 2θ.

5. 5. The calcium salt of Compound 1 of claim 3 or 4, wherein the XRPD pattern further comprises a peak at 12.8±0.2 degrees 2θ or 13.7±0.2 degrees 2θ.

6. The calcium salt of Compound 1 exhibits an XRPD pattern substantially the same as that depicted in Figure 1A.

7. A calcium salt of Compound 1 exhibiting an XRPD pattern containing the peaks in Table 1 having a relative intensity of at least 10%.

8. The calcium salt of Compound 1 exhibits an X-ray powder diffraction (XRPD) pattern including a peak at 8.0±0.2 degrees 2θ and a peak at 10.1±0.2 degrees 2θ.

9. 9. The calcium salt of Compound 1 of claim 8, wherein the XRPD pattern further comprises a peak at 13.3±0.2 degrees 2θ or a peak at 14.6 degrees 2θ.

10. The calcium salt of Compound 1 exhibits an X-ray powder diffraction (XRPD) pattern including a peak at 5.1±0.2 degrees 2θ, a peak at 5.3±0.2 degrees 2θ, and a peak at 10.1±0.2 degrees 2θ.

11. 11. The calcium salt of Compound 1 of claim 10, wherein the XRPD pattern further comprises a peak at 8.0±0.2 degrees 2θ or a peak at 12.8±0.2 degrees 2θ.

12. 12. The calcium salt of Compound 1 of claim 10 or 11, wherein the XRPD pattern further comprises peaks at 13.3±0.2 degrees 2θ, 17.9±0.2 degrees 2θ, and 19.6±0.2 degrees 2θ.

13. The calcium salt of Compound 1 exhibits an XRPD pattern substantially the same as that depicted in Figure 2A.

14. The calcium salt of Compound 1 exhibiting an XRPD pattern containing the peaks in Table 3 having a relative intensity of at least 10%.

15. The L-arginine salt of Compound 1 exhibits an X-ray powder diffraction (XRPD) pattern including a peak at 11.9±0.2 degrees 2θ, a peak at 19.7±0.2 degrees 2θ, and a peak at 20.2±0.2 degrees 2θ.

16. 16. The L-arginine salt of Compound 1 of claim 15, wherein the XRPD pattern further comprises a peak at 13.1±0.2 degrees 2θ or a peak at 22.7±0.2 degrees 2θ.

17. 17. The L-arginine salt of Compound 1 of claim 15 or 16, wherein the XRPD pattern further comprises a peak at 10.4±0.2 degrees 2θ, 11.6±0.2 degrees 2θ, or 21.7±0.2 degrees 2θ.

18. The L-arginine salt of Compound 1 exhibits an XRPD pattern substantially the same as that depicted in Figure 4A.

19. The L-arginine salt of Compound 1 exhibits an X-ray powder diffraction (XRPD) pattern including a peak at 3.9±0.2 degrees 2θ, a peak at 13.1±0.2 degrees 2θ, and a peak at 20.3±0.2 degrees 2θ.

20. 20. The L-arginine salt of Compound 1 of claim 19, wherein the XRPD pattern further comprises a peak at 19.8±0.2 degrees 2θ, 19.9±0.2 degrees 2θ, or 20.4±0.2 degrees 2θ.

21. 21. The L-arginine salt of Compound 1 of claim 19 or 20, wherein the XRPD pattern further comprises a peak at 10.4±0.2 degrees 2θ, 11.9±0.2 degrees 2θ, or 20.4±0.2 degrees 2θ.

22. The L-arginine salt of Compound 1 exhibited an XRPD pattern substantially the same as that depicted in Figure 4B.

23. L-phenylalanine salt of Compound 1.

24. L-histidine salt of Compound 1.

25. 25. The salt of Compound 1 according to claim 23 or 24, which is crystalline.

26. 26. The salt of any one of claims 1 to 25, comprising less than 5% of Compound 1, based on the weight of the salt.

27. 27. The salt of claim 26, comprising less than 1% of Compound 1 by weight of the salt.

28. 28. The salt of any one of claims 1 to 27, having a purity of greater than 95% by HPLC chromatogram based on relative peak areas in the HPLC chromatogram.

29. 29. The salt of claim 28, having a purity by HPLC chromatogram of greater than 98% based on relative peak areas in the HPLC chromatogram.

30. An ester of Compound 1 having the structure: 【Chemical 1】 In the formula, R is C １０ ~C ２４ An ester of Compound 1 which is a hydrocarbyl.

31. In the formula, R is C １０ ~C ２４ 31. The ester of compound 1 of claim 30, which is alkyl.

32. In the formula, R is C １０ ~C ２４ 32. An ester of compound 1 according to claim 30 or 31, which is alkenyl.

33. The ester of compound 1 according to any one of claims 30 to 32, which is crystalline.

34. 34. The ester of compound 1 according to any one of claims 30 to 33, having a purity of greater than 95% based on the relative peak area of ​​the HPLC chromatogram thereof.

35. 35. The ester of compound 1 of claim 34, whose HPLC chromatogram has a purity of greater than 98% based on relative peak areas in the HPLC chromatogram.

36. A composition comprising a salt of compound 1 according to any one of claims 1 to 29, or an ester of compound 1 according to any one of claims 30 to 35, and a pharmaceutically acceptable carrier or excipient.

37. 37. The composition of claim 36, wherein the pharmaceutically acceptable carrier or excipient is a diluent, disintegrant, binder, or lubricant.

38. 38. The composition of claim 36 or 37, in the form of a solution, suspension, emulsion, tablet, capsule, powder, cream, or gel.

39. 37. The composition of claim 36, wherein the composition is an eye drop solution, or the composition is coated on or incorporated into an eye drop delivery device.

40. 38. The composition of claim 36 or 37, which is a tablet.

41. 38. The composition of claim 36 or 37, contained within a capsule.

42. 42. The composition of any one of claims 36 to 41, comprising the salt of Compound 1 or the ester of Compound 1 in a molar equivalent amount corresponding to about 50 mg to about 600 mg of Compound 1.

43. 43. The composition of claim 42, comprising the salt of Compound 1 or the ester of Compound 1 in a molar equivalent amount corresponding to about 120 mg or about 300 mg of Compound 1.

44. 42. The composition of any one of claims 36 to 41, comprising about 50 mg to about 600 mg of the salt of Compound 1 or the ester of Compound 1.

45. 45. The composition of claim 44, comprising about 120 mg or about 300 mg of the salt of Compound 1 or the ester of Compound 1.

46. A method for treating or preventing an eye disease, comprising administering to a subject in need thereof an effective amount of a salt of compound 1 according to any one of claims 1 to 29, an ester of compound 1 according to any one of claims 30 to 35 or a pharmaceutically acceptable salt thereof, a composition according to any one of claims 36 to 45, a compound of formula (I) or a pharmaceutically acceptable salt thereof, a compound of formula (II) or a pharmaceutically acceptable salt thereof, a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, or a composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle; The compound of formula (I) has the following structure: 【Chemistry 2】 In the formula, R １ However, independently, H and C １ ~C ６ alkyl, or —C(O)(C １ ~C ６ alkyl), The compound of formula (II) has the following structure: 【Chemistry 3】 In the formula, R ２ is C １ ~C ２４ The method according to claim 1, wherein the group is a hydrocarbyl group.

47. 47. The method of claim 46, wherein the eye disease is diabetic retinal disease.

48. 48. The method of claim 46 or 47, wherein the eye disease is diabetic retinopathy (DR) or diabetic macular edema (DME).

49. 49. The method of claim 48, wherein the ocular disease is DR, and the DR is moderately severe non-proliferative DR or mild proliferative DR.

50. 49. The method of claim 48, wherein the eye disease is DME, and the DME is DME without loss of central vision.

51. 47. The method of claim 46, wherein the ocular disease is retinopathy of prematurity, diabetic retinopathy, pathologic myopia, hypertensive retinopathy, occlusive vasculitis, polypoidal choroidal vasculopathy, diabetic macular edema, uveitic macular edema, retinal vein occlusion, ocular neovascularization, ocular histoplasmosis, neovascular glaucoma, retinoblastoma, macular degeneration, retrolental fibroplasia, retinal angiomatous proliferation, dry eye disease, uveitis, thyroid eye disease, or sickle cell retinopathy.

52. 52. The method of claim 51, wherein the eye disease is diabetic retinopathy, and the diabetic retinopathy is proliferative diabetic retinopathy.

53. 52. The method of claim 51, wherein the eye disease is macular degeneration, and the macular degeneration is advanced macular degeneration.

54. 52. The method of claim 51, wherein the eye disease is macular degeneration, and the macular degeneration is wet age-related macular degeneration or dry age-related macular degeneration.

55. 52. The method of claim 51, wherein the ocular disease is ocular neovascularization, and the ocular neovascularization is corneal neovascularization or retinal neovascularization.

56. 52. The method of claim 51, wherein the retinal vein occlusion is central retinal vein occlusion or branch retinal vein occlusion.

57. 46. ​​A method for treating cancer, cardiovascular disease, inflammation, chronic inflammatory disease, rheumatoid arthritis, idiopathic pulmonary fibrosis, acute adult respiratory distress syndrome, asthma, endometriosis, keloid, systemic sclerosis, chemotherapy-induced peripheral neuropathy, stroke, gastrointestinal dysfunction, chronic gastroesophageal reflux disease, von Hippel-Lindau syndrome, or a skin disorder, comprising administering to a subject in need thereof an effective amount of a salt of compound 1 according to any one of claims 1 to 29, an ester of compound 1 according to any one of claims 30 to 35 or a pharmaceutically acceptable salt thereof, a composition according to any one of claims 36 to 45, a compound of formula (I) or a pharmaceutically acceptable salt thereof, a compound of formula (II) or a pharmaceutically acceptable salt thereof, a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, or a composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, The compound of formula (I) has the following structure: 【Chemistry 4】 In the formula, R １ However, independently, H and C １ ~C ６ alkyl, or —C(O)(C １ ~C ６ alkyl), The compound of formula (II) has the following structure: 【Chemistry 5】 In the formula, R ２ is C １ ~C ２４ The method according to claim 1, wherein the group is a hydrocarbyl group.

58. 58. The method of claim 57, wherein the method is for treating cancer, and the cancer is liver cancer, breast cancer, prostate cancer, pancreatic cancer, colon cancer, cervical cancer, germ cell tumor, adult glioma, pediatric glioma, osteosarcoma, rhabdomyosarcoma, non-small cell lung cancer, leukemia, or multiple myeloma.

59. 58. The method of claim 57, wherein the method is for treating cancer, and the cancer is a solid tumor, a blood cancer, a leukemia, or a lymphoma.

60. The method is for treating cancer, wherein the cancer is a solid tumor, and the solid tumor is selected from the group consisting of fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelioma, lymphangiosarcoma, lymphangioendothelioma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer, oral cancer, nasal cancer, throat cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, 58. The method of claim 57, wherein the cancer is sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, hepatocarcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, small cell lung cancer, bladder cancer, lung cancer, epithelial carcinoma, glioma, glioblastoma multiforme, astrocytoma medulloblastoma, craniopharyngioma, ependymoma pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, skin cancer, melanoma, neuroblastoma, or retinoblastoma.

61. 60. The method of claim 59, wherein the cancer is a blood cancer, and the blood cancer is leukemia, lymphoma, or myeloma.

62. 62. The method of claim 61, wherein the hematological cancer is leukemia, and the leukemia is acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute monoblastic leukemia, acute erythroleukemic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocytic leukemia, acute anaplastic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, or hairy cell leukemia.

63. 62. The method of claim 61, wherein the hematological cancer is leukemia, and the leukemia is acute leukemia or chronic leukemia.

64. 64. The method of claim 63, wherein the acute or chronic leukemia is lymphoblastic leukemia, myeloid leukemia, lymphocytic leukemia, or myelocytic leukemia.

65. 62. The method of claim 61, wherein the hematological cancer is lymphoma, and the lymphoma is Hodgkin's disease, non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, heavy chain disease, or polycythemia vera.

66. 62. The method of claim 61, wherein the hematological cancer is myeloma, and the myeloma is solitary plasmacytoma, extramedullary plasmacytoma, or multiple myeloma.

67. 58. The method of claim 57, wherein the method is for treating or preventing a skin disease, and the skin disease is psoriasis, atopic dermatitis, or rosacea.

68. 1. A method for inhibiting angiogenesis, comprising administering to a subject in need thereof an effective amount of a salt of compound 1 according to any one of claims 1 to 29, an ester of compound 1 according to any one of claims 30 to 35 or a pharmaceutically acceptable salt thereof, a composition according to any one of claims 36 to 45, a compound of formula (I) or a pharmaceutically acceptable salt thereof, a compound of formula (II) or a pharmaceutically acceptable salt thereof, a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, or a composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle; The compound of formula (I) has the following structure: 【Chemistry 6】 In the formula, R １ However, independently, H and C １ ~C ６ alkyl, or —C(O)(C １ ~C ６ alkyl), The compound of formula (II) has the following structure: 【Chemistry 7】 In the formula, R ２ is C １ ~C ２４ The method according to claim 1, wherein the group is a hydrocarbyl group.

69. 1. A method for inhibiting expression of a vascular endothelial growth factor protein, comprising administering to a subject in need thereof an effective amount of a salt of compound 1 according to any one of claims 1 to 29, an ester of compound 1 according to any one of claims 30 to 35 or a pharmaceutically acceptable salt thereof, a composition according to any one of claims 36 to 45, a compound of formula (I) or a pharmaceutically acceptable salt thereof, a compound of formula (II) or a pharmaceutically acceptable salt thereof, a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, or a composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle; The compound of formula (I) has the following structure: 【Chemistry 8】 In the formula, R １ However, independently, H and C １ ~C ６ alkyl, or —C(O)(C １ ~C ６ alkyl), The compound of formula (II) has the following structure: 【Chemistry 9】 In the formula, R ２ is C １ ~C ２４ The method according to claim 1, wherein the group is a hydrocarbyl group.

70. 1. A method for inhibiting capillary formation, comprising administering to a subject in need thereof an effective amount of a salt of compound 1 according to any one of claims 1 to 29, an ester of compound 1 according to any one of claims 30 to 35 or a pharmaceutically acceptable salt thereof, a composition according to any one of claims 36 to 45, a compound of formula (I) or a pharmaceutically acceptable salt thereof, a compound of formula (II) or a pharmaceutically acceptable salt thereof, a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, or a composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle; The compound of formula (I) has the following structure: 【Chemistry 10】 In the formula, R １ However, independently, H and C １ ~C ６ alkyl, or —C(O)(C １ ~C ６ alkyl), The compound of formula (II) has the following structure: 【Chemistry 11】 In the formula, R ２ is C １ ~C ２４ The method according to claim 1, wherein the group is a hydrocarbyl group.

71. A method for treating or preventing liver disease, comprising administering an effective amount of a salt of compound 1 described in any one of claims 1 to 29, an ester of compound 1 described in any one of claims 30 to 35, or a pharmaceutically acceptable salt thereof, or a composition described in any one of claims 36 to 45 to a subject in need thereof.

72. 72. The method of claim 71, wherein the liver disease is hepatitis, toxic liver disease, jaundice, cirrhosis, nonalcoholic steatohepatitis, or alcoholic steatosis.

73. 72. The method of claim 71, wherein the liver disease is hepatitis, and the hepatitis is chronic hepatitis, acute hepatitis, viral hepatitis, or alcoholic hepatitis.

74. A method for suppressing neurotic hypersensitivity, comprising administering to a subject in need thereof an effective amount of a salt of compound 1 according to any one of claims 1 to 29, an ester of compound 1 according to any one of claims 30 to 35 or a pharmaceutically acceptable salt thereof, a composition according to any one of claims 36 to 45, a compound of formula (I) or a pharmaceutically acceptable salt thereof, a compound of formula (II) or a pharmaceutically acceptable salt thereof, a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, or a composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle; The compound of formula (I) has the following structure: 【Chemistry 12】 In the formula, R １ However, independently, H and C １ ~C ６ alkyl, or —C(O)(C １ ~C ６ alkyl), The compound of formula (II) has the following structure: 【Chemistry 13】 In the formula, R ２ is C １ ~C ２４ The method according to claim 1, wherein the group is a hydrocarbyl group.

75. A method for treating pain, comprising administering to a subject in need thereof an effective amount of a salt of compound 1 according to any one of claims 1 to 29, an ester of compound 1 according to any one of claims 30 to 35 or a pharmaceutically acceptable salt thereof, a composition according to any one of claims 36 to 45, a compound of formula (I) or a pharmaceutically acceptable salt thereof, a compound of formula (II) or a pharmaceutically acceptable salt thereof, a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, or a composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle; The compound of formula (I) has the following structure: 【Chemistry 14】 In the formula, R １ However, independently, H and C １ ~C ６ alkyl, or —C(O)(C １ ~C ６ alkyl), The compound of formula (II) has the following structure: 【Chemistry 15】 In the formula, R ２ is C １ ~C ２４ The method according to claim 1, wherein the group is a hydrocarbyl group.

76. 76. The method of claim 75, wherein the pain is inflammatory or chronic pain.

77. 1. A method for improving DNA base excision repair, comprising administering to a subject in need thereof an effective amount of a salt of compound 1 according to any one of claims 1 to 29, an ester of compound 1 according to any one of claims 30 to 35 or a pharmaceutically acceptable salt thereof, a composition according to any one of claims 36 to 45, a compound of formula (I) or a pharmaceutically acceptable salt thereof, a compound of formula (II) or a pharmaceutically acceptable salt thereof, a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, or a composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle; The compound of formula (I) has the following structure: 【Chemistry 16】 In the formula, R １ However, independently, H and C １ ~C ６ alkyl, or —C(O)(C １ ~C ６ alkyl), The compound of formula (II) has the following structure: 【Chemistry 17】 In the formula, R ２ is C １ ~C ２４ The method according to claim 1, wherein the group is a hydrocarbyl group.

78. 1. A method for improving neuronal DNA repair function, comprising administering to a subject in need thereof an effective amount of a salt of compound 1 according to any one of claims 1 to 29, an ester of compound 1 according to any one of claims 30 to 35 or a pharmaceutically acceptable salt thereof, a composition according to any one of claims 36 to 45, a compound of formula (I) or a pharmaceutically acceptable salt thereof, a compound of formula (II) or a pharmaceutically acceptable salt thereof, a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, or a composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle; The compound of formula (I) has the following structure: 【Chemistry 18】 In the formula, R １ However, independently, H and C １ ~C ６ alkyl, or —C(O)(C １ ~C ６ alkyl), The compound of formula (II) has the following structure: 【Chemistry 19】 In the formula, R ２ is C １ ~C ２４ The method according to claim 1, wherein the group is a hydrocarbyl group.

79. A method for treating or preventing geographic atrophy, choroidal neovascularization, or post-corneal transplant rejection, comprising administering to a subject in need thereof an effective amount of a salt of compound 1 according to any one of claims 1 to 29, an ester of compound 1 according to any one of claims 30 to 35 or a pharmaceutically acceptable salt thereof, a composition according to any one of claims 36 to 45, a compound of formula (I) or a pharmaceutically acceptable salt thereof, a compound of formula (II) or a pharmaceutically acceptable salt thereof, a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle, or a composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or vehicle; The compound of formula (I) has the following structure: 【Chemistry 20】 In the formula, R １ However, independently, H and C １ ~C ６ alkyl, or —C(O)(C １ ~C ６ alkyl), The compound of formula (II) has the following structure: 【Chemical 21】 In the formula, R ２ is C １ ~C ２４ The method according to claim 1, wherein the group is a hydrocarbyl group.

80. In the formula, R １ is H, methyl, or —C(O)CH ３ The method according to any one of claims 46 to 70 and 74 to 79,

81. In the formula, R ２ is C １ ~C ６ The method of any one of claims 46 to 70 and 74 to 79, wherein the alkyl is alkyl.

82. In the formula, R ２ is C １０ ~C ２４ Alkyl or C １０ ~C ２４ The method of any one of claims 46 to 70 and 74 to 79, wherein the alkyl group is alkenyl.

83. 83. The method of any one of claims 46 to 82, wherein the pharmaceutically acceptable carrier or excipient is a diluent, disintegrant, binder, or lubricant.

84. 84. The method of any one of claims 46 to 83, wherein the composition is contained within a capsule.

85. 84. The method of any one of claims 46 to 83, wherein the composition is a tablet.

86. The method of any one of claims 46 to 83, wherein the composition is an eye drop.

87. 87. The method of claim 86, wherein the ophthalmic solution is suitable for topical, subconjunctival, intravitreal, retrobulbar, intracameral, or systemic administration.

88. 84. The method of any one of claims 46 to 83, wherein the composition is an eye drop solution, or the composition is coated on or incorporated into an eye drop delivery device.

89. 89. The method of any one of claims 46-88, wherein the subject has obesity, diabetes, asthma, arthritis, chronic periodontitis, ulcerative colitis, Crohn's disease, chronic sinusitis, chronic active hepatitis, chronic peptic ulcer, diverticulitis, fibromyalgia, irritable bowel syndrome, Alzheimer's disease, Parkinson's disease, atherosclerosis, or tuberculosis.

90. 89. The method of any one of claims 46 to 88, wherein the subject has diabetes.

91. A method for treating diabetic retinopathy (DR), comprising administering to a subject in need thereof an effective amount of the calcium salt of Compound 1, wherein the calcium salt exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 5.8±0.2 degrees 2θ and a peak at 6.3±0.2 degrees 2θ.

92. A method for treating diabetic retinopathy (DR), comprising administering to a subject in need thereof an effective amount of the calcium salt of Compound 1, wherein the calcium salt exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 4.1±0.2 degrees 2θ, a peak at 5.3±0.2 degrees 2θ, and a peak at 6.3±0.2 degrees 2θ.

93. A method for treating diabetic retinopathy (DR), comprising administering to a subject in need thereof an effective amount of the calcium salt of Compound 1, wherein the calcium salt exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 8.0±0.2 degrees 2θ and a peak at 10.1±0.2 degrees 2θ.

94. A method for treating diabetic retinopathy (DR), comprising administering to a subject in need thereof an effective amount of the calcium salt of Compound 1, wherein the calcium salt exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 5.1±0.2 degrees 2θ, a peak at 5.3±0.2 degrees 2θ, and a peak at 10.1±0.2 degrees 2θ.

95. A method for treating diabetic macular edema (DME), comprising administering to a subject in need thereof an effective amount of the calcium salt of Compound 1, wherein the calcium salt exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 5.8±0.2 degrees 2θ and a peak at 6.3±0.2 degrees 2θ.

96. A method for treating diabetic macular edema (DME), comprising administering to a subject in need thereof an effective amount of the calcium salt of Compound 1, wherein the calcium salt exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 4.1±0.2 degrees 2θ, a peak at 5.3±0.2 degrees 2θ, and a peak at 6.3±0.2 degrees 2θ.

97. A method for treating diabetic macular edema (DME), comprising administering to a subject in need thereof an effective amount of the calcium salt of Compound 1, wherein the calcium salt exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 8.0±0.2 degrees 2θ and a peak at 10.1±0.2 degrees 2θ.

98. A method for treating diabetic macular edema (DME), comprising administering to a subject in need thereof an effective amount of the calcium salt of Compound 1, wherein the calcium salt exhibits an X-ray powder diffraction (XRPD) pattern comprising a peak at 5.1±0.2 degrees 2θ, a peak at 5.3±0.2 degrees 2θ, and a peak at 10.1±0.2 degrees 2θ.

99. 91. The method of any one of claims 46 to 90, comprising administering to a subject in need thereof an effective amount of a salt of compound 1 of any one of claims 1 to 29.

100. 58. The method of claim 57, wherein the method is for treating cancer, and the cancer is hepatocellular carcinoma (HCC).

Images