Crystalline solid meglumine salts of BCL inhibitors, and methods of making and using said inhibitors

Abstract

Crystalline solid meglumine salts of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid are provided. Pharmaceutical compositions having one or more of the crystalline solid meglumine salt compounds and methods for administering the crystalline solid meglumine salt compounds to a subject are also described. Methods for preparing the crystalline solid meglumine salt compounds are also provided.

Description

Background Art

[0001] Background Normally, mitotic cells can permanently exit the cell cycle in response to cellular stress, including dysfunctional telomeres, DNA damage, strong mitogenic signals, and disrupted chromatin. This response, termed cellular senescence, has been shown to be important, particularly for suppressing the development of cancer malignancy mechanisms, in order to inhibit the proliferation of dysfunctional or damaged cells (see Campisi J., Cell 120:513-22 (2005) (Non-Patent Document 1), Campisi J., Curr. Opin. Genet. Dev. 21:107-12 (2011) (Non-Patent Document 2)). Senescent cells are characterized by a number of cellular phenotypes, including non-responsiveness to mitogenic stimulation, flattening of morphology, increased senescence-associated β-galactosidase activity (SA-β-gal), elevated p16 expression, telomere shortening, elevated cyclin-dependent kinase inhibitor expression, changes in chromatin structure, extensive DNA damage foci, resistance to apoptosis, and activation of the inflammatory senescence-associated secretory phenotype (SASP) (see Coppe, J-P, et al., Annu Rev Pathol. 2010;5:99-118 (Non-Patent Document 3)).

[0002] Recently, the presence and accumulation of senescent cells in an individual have been shown to contribute to aging as well as age-related functional impairments and diseases, such as, for example, glaucoma, cataracts, diabetic pancreas, and osteoarthritis (see van Deursen JM., Nature. 2014 May 22;509(7501):439-446 (Non-Patent Document 4), Childs, B. et al., Nat Med. 2015 December;21(12):1424-1435 (Non-Patent Document 5)).

[0003] Senescent cells are causally involved in certain aspects of age-related health decline and may contribute to certain age-related diseases, including cancer, and thus effective therapies are being studied and developed. Small molecule drugs have been identified that selectively remove senescent cells accumulated within and around the affected area to alleviate the detrimental signs and symptoms of the resulting condition. Several intracellular pathways that are active in senescent cells, such as, inter alia, the MDM2 pathway, the Bcl pathway, the Akt pathway, and the proteasome pathway, have been shown to be suitable for targeting (see WO / 2015 / 171591 (Patent Document 1): Zhou et al., WO / 2015 / 116740 (Patent Document 2): Laberge et al., WO / 2019 / 133904 (Patent Document 3): Hudson et al.). The present disclosure addresses these needs and provides advantages.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Patent Document 3

Non-Patent Documents

[0005]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

[0006] Summary Aspects of the present disclosure include crystalline solid meglumine salts of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid. Also described are pharmaceutical compositions having one or more of the crystalline solid meglumine salt compounds of the subject matter, and methods for administering the crystalline solid meglumine salt compounds to a subject. Also provided is a method for preparing the crystalline solid meglumine salt compounds of the subject matter.

[0007] Aspect 1. Formula I: The crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid, which is the compound of TIFF0007688141000001.tif52128.

[0008] Aspect 2. The crystalline solid according to Aspect 1, wherein meglumine is present in a stoichiometric ratio of 1 to 3 in the crystalline solid.

[0009] Aspect 3. The crystalline solid according to Aspect 1 or 2, which is stable for 12 months or more at a temperature of 2°C to 8°C.

[0010] Aspect 4. Formula I: The crystalline solid meglumine salt of Form I of the compound of TIFF0007688141000002.tif52128.

[0011] Aspect 5. The crystalline solid according to Aspect 4, wherein meglumine is present in a stoichiometric ratio of 1 to 3 in the crystalline solid.

[0012] Aspect 6. The crystalline solid according to Aspect 4 or 5, having an X-ray powder diffraction pattern comprising one or more peaks at about 4.3° 2θ, about 6.1° 2θ, about 8.1° 2θ, about 8.6° 2θ, about 9.0° 2θ, about 10.1° 2θ, about 11.3° 2θ, about 12.2° 2θ, about 15.2° 2θ, about 16.2° 2θ, about 17.3° 2θ, about 18.2° 2θ, about 18.9° 2θ, about 19.3° 2θ, about 19.8° 2θ, about 20.7° 2θ, about 21.6° 2θ, about 22.1° 2θ, about 23.0° 2θ, about 24.2° 2θ, about 25.2° 2θ, about 25.5° 2θ, about 26.1° 2θ, about 27.1° 2θ, about 29.5° 2θ, or about 32.6° 2θ.

[0013] Aspect 7. The crystalline solid according to any one of Aspects 4 to 6, wherein the crystalline solid meglumine salt of Form I of the compound of Formula I is characterized by a 0.9% weight loss step at room temperature to 130 °C by thermogravimetric analysis (TGA) and a second weight loss step at about 130 °C.

[0014] Aspect 8. The crystalline solid according to any one of Aspects 4 to 7, wherein the crystalline solid meglumine salt of Form I of the compound of Formula I exhibits a first endotherm at 84 °C and a second endotherm at about 147 °C by differential scanning calorimetry (DSC).

[0015] Aspect 9. The crystalline solid according to any one of Aspects 4 to 8, which is stable for 12 months or more at a temperature of 2 °C to 8 °C.

[0016] Aspect 10. Formula I: The crystalline solid meglumine salt of Form II of the compound of TIFF0007688141000003.tif52128.

[0017] Aspect 11. The crystalline solid according to Aspect 10, wherein meglumine is present in a stoichiometric ratio of 1 to 3 in the crystalline solid.

[0018] Aspect 12. The crystalline solid according to Aspect 10 or 11, having an X-ray powder diffraction pattern comprising one or more peaks at about 3.8° 2θ, about 7.3° 2θ, about 8.3° 2θ, about 8.8° 2θ, about 13.7° 2θ, about 15.2° 2θ, about 15.4° 2θ, about 16.6° 2θ, about 17.7° 2θ, about 18.8° 2θ, about 20.0° 2θ, about 22.1° 2θ, or about 23.9° 2θ.

[0019] Aspect 13. The crystalline solid according to any one of Aspects 10 to 12, wherein the crystalline solid meglumine salt of the compound of Formula I in Form II is characterized by a 2.0% weight loss step from room temperature to 130 °C by thermogravimetric analysis (TGA) and a second weight loss step at about 130 °C.

[0020] Aspect 14. The crystalline solid according to any one of Aspects 10 to 13, wherein the crystalline solid meglumine salt of the compound of Formula I in Form II exhibits an endotherm at about 136 °C by differential scanning calorimetry (DSC).

[0021] Aspect 15. The crystalline solid according to any one of Aspects 10 to 14, which is stable for 12 months or more at a temperature of 2 °C to 8 °C.

[0022] Aspect 16. The crystalline solid meglumine salt of the compound of Formula I: TIFF0007688141000004.tif52128 in Form III.

[0023] Aspect 17. The crystalline solid according to Aspect 16, wherein meglumine is present in a stoichiometric ratio of 1 to 3 in the crystalline solid.

[0024] Aspect 18. The crystalline solid according to aspect 16 or 17, having an X-ray powder diffraction pattern comprising one or more peaks at about 3.9° 2θ, about 4.3° 2θ, about 6.1° 2θ, about 7.5° 2θ, about 7.7° 2θ, about 8.7° 2θ, about 10.4° 2θ, about 11.3° 2θ, about 11.5° 2θ, about 12.5° 2θ, about 13.9° 2θ, about 14.7° 2θ, about 15.2° 2θ, about 15.9° 2θ, about 17.7° 2θ, about 18.0° 2θ, about 18.8° 2θ, about 20.2° 2θ, about 21.7° 2θ, about 23.0° 2θ, or about 25.8° 2θ.

[0025] Aspect 19. The crystalline solid according to any one of aspects 16 - 18, wherein the crystalline solid meglumine salt of the compound of formula I in Form III is characterized by a 0.9% weight loss step at room temperature to 130 °C by thermogravimetric analysis (TGA) and a second weight loss step at about 130 °C.

[0026] Aspect 20. The crystalline solid according to any one of aspects 16 - 19, wherein the crystalline solid meglumine salt of the compound of formula I in Form III exhibits a first endotherm at about 113 °C and a second endotherm at about 142 °C by differential scanning calorimetry (DSC).

[0027] Aspect 21. The crystalline solid according to any one of aspects 16 - 20, which is stable for 12 months or more at a temperature of 2 °C to 8 °C.

[0028] Aspect 22. The crystalline solid meglumine salt of the compound of formula I: TIFF0007688141000005.tif52128 in Form IVa.

[0029] Aspect 23. The crystalline solid according to claim 22, wherein meglumine is present in a stoichiometric ratio of 1 - 3 in the crystalline solid.

[0030] Aspect 24. A crystalline solid according to aspect 22 or 23, having an X-ray powder diffraction pattern comprising one or more peaks at about 3.8° 2θ, about 4.2° 2θ, about 6.1° 2θ, about 7.4° 2θ, about 8.6° 2θ, about 10.3° 2θ, about 10.9° 2θ, about 12.7° 2θ, about 13.7° 2θ, about 14.4° 2θ, about 15.3° 2θ, about 15.7° 2θ, about 16.5° 2θ, about 17.0° 2θ, about 17.9° 2θ, about 18.5° 2θ, about 19.5° 2θ, about 20.7° 2θ, about 22.2° 2θ, about 22.5° 2θ, about 23.4° 2θ, about 24.8° 2θ, or about 28.2° 2θ.

[0031] Aspect 25. A crystalline solid according to any one of aspects 22 - 24, wherein the crystalline solid meglumine salt of the compound of formula I in Form IVa is characterized by a 3.5% weight loss step from room temperature to 130 °C by thermogravimetric analysis (TGA) and a second weight loss step at about 130 °C.

[0032] Aspect 26. A crystalline solid according to any one of aspects 22 - 25, wherein the crystalline solid meglumine salt of the compound of formula I in Form IVa exhibits a first endotherm at about 131 °C and a second endotherm at about 139 °C by differential scanning calorimetry (DSC).

[0033] Aspect 27. A crystalline solid according to any one of aspects 22 - 26, which is stable for 12 months or more at a temperature of 2 °C to 8 °C.

[0034] Aspect 28. A crystalline solid meglumine salt of the compound of formula I: TIFF0007688141000006.tif52128 in Form IV.

[0035] Aspect 29. A crystalline solid according to aspect 28, wherein meglumine is present in a stoichiometric ratio of 1 - 3 in the crystalline solid.

[0036] Aspect 30. The crystalline solid according to aspect 28 or 29, having an X-ray powder diffraction pattern comprising one or more peaks at about 4.2° 2θ, about 4.6° 2θ, about 7.9° 2θ, about 9.1° 2θ, about 10.4° 2θ, about 13.3° 2θ, about 14.5° 2θ, about 15.8° 2θ, about 16.8° 2θ, about 17.3° 2θ, about 19.5° 2θ, about 19.6° 2θ, about 20.2° 2θ, or about 27.7° 2θ.

[0037] Aspect 31. The crystalline solid according to any one of aspects 28 to 30, wherein the crystalline solid meglumine salt of the compound of formula I in Form IV is characterized by a single weight loss step at about 130 °C by thermogravimetric analysis (TGA).

[0038] Aspect 32. The crystalline solid according to any one of aspects 28 to 31, wherein the crystalline solid meglumine salt of the compound of formula I in Form IV exhibits a first endotherm at about 130 °C and a second endotherm at about 143.3 °C by differential scanning calorimetry (DSC).

[0039] Aspect 33. The crystalline solid according to any one of aspects 28 to 32, which is stable for 12 months or more at a temperature of 2 °C to 8 °C.

[0040] Aspect 34. The crystalline solid meglumine salt of the compound of formula I: TIFF0007688141000007.tif52128 in Form V.

[0041] Aspect 35. The crystalline solid according to aspect 34, wherein meglumine is present in a stoichiometric ratio of 1 to 3 in the crystalline solid.

[0042] Aspect 36. A crystalline solid according to Aspect 34 or 35, having an X-ray powder diffraction pattern comprising one or more peaks at about 4.2° 2θ, about 5.4° 2θ, about 7.3° 2θ, about 9.1° 2θ, about 12.2° 2θ, about 12.4° 2θ, about 13.4° 2θ, about 14.5° 2θ, about 16.1° 2θ, about 17.5° 2θ, about 18.1° 2θ, about 18.8° 2θ, about 19.6° 2θ, about 20.4° 2θ, about 21.2° 2θ, about 22.3° 2θ, about 23.0° 2θ, about 27.6° 2θ, or about 29.2° 2θ.

[0043] Aspect 37. A crystalline solid according to any one of Aspects 34 to 36, wherein the crystalline solid meglumine salt of the compound of Formula I in Form V is characterized by a 1.2% weight loss step at room temperature to 130 °C by thermogravimetric analysis (TGA) and a second weight loss step at about 130 °C.

[0044] Aspect 38. A crystalline solid according to any one of Aspects 34 to 37, wherein the crystalline solid meglumine salt of the compound of Formula I in Form V exhibits a first endotherm at about 115 °C and a second endotherm at about 143 °C by differential scanning calorimetry (DSC).

[0045] Aspect 39. A crystalline solid according to any one of Aspects 34 to 38, which is stable for 12 months or more at a temperature of 2 °C to 8 °C.

[0046] Aspect 40. A crystalline solid meglumine salt of the compound of Formula I: TIFF0007688141000008.tif52128 in Form VI.

[0047] Aspect 41. A crystalline solid according to Aspect 40, wherein meglumine is present in a stoichiometric ratio of 1 to 3 in the crystalline solid.

[0048] Aspect 42. A crystalline solid according to Aspect 40 or 41, having an X-ray powder diffraction pattern comprising one or more peaks at about 3.9° 2θ, about 8.5° 2θ, about 8.6° 2θ, about 8.7° 2θ, about 11.3° 2θ, about 12.7° 2θ, about 13.9° 2θ, about 14.5° 2θ, about 15.1° 2θ, about 15.9° 2θ, about 17.6° 2θ, about 17.7° 2θ, about 18.8° 2θ, about 20.0° 2θ, about 20.7° 2θ, about 23.0° 2θ, about 35.1° 2θ, about 36.1° 2θ, or about 36.8° 2θ.

[0049] Aspect 43. A crystalline solid according to any one of Aspects 40 - 42, wherein the meglumine salt of the crystalline solid of Form VI of the compound of Formula I is characterized by a 1.0% weight loss step from room temperature to 130 °C by thermogravimetric analysis (TGA) and a second weight loss step at about 130 °C.

[0050] Aspect 44. A crystalline solid according to any one of Aspects 40 - 43, wherein the meglumine salt of the crystalline solid of Form VI of the compound of Formula I exhibits a first endotherm at about 110 °C and a second endotherm at about 142 °C by differential scanning calorimetry (DSC).

[0051] Aspect 45. A crystalline solid according to any one of Aspects 28 - 30, which is stable for 12 months or more at a temperature of 2 °C to 8 °C.

[0052] Aspect 46. A method for producing a crystalline solid meglumine salt compound according to any one of Aspects 1 to 45, comprising: generating a transparent solution containing a meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid; contacting an aliquot of the transparent solution with a seed composition and a solvent composition to generate a first suspension; contacting the first suspension with a second aliquot of the transparent solution and the solvent composition to generate a slurry composition; and filtering a crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid from the slurry composition.

[0053] Aspect 47. Meglumine and (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid are contacted in a first solvent composition to produce a first solution containing solubilized (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid meglumine salt; contacting the first composition with a second solvent composition to produce a transparent solution; contacting a first aliquot of the transparent solution with a third solvent composition and a seed composition to produce a first suspension; contacting the first suspension with a fourth solvent composition to produce a second suspension; contacting the second suspension with a fifth solvent composition to produce a third suspension; contacting a second aliquot of the transparent solution and a sixth solvent composition with the third suspension to produce a slurry precursor composition; contacting the slurry precursor composition with a seventh solvent composition to produce a slurry composition; and filtering the crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid from the slurry composition, the method according to aspect 46.

[0054] Aspect 48. The method according to aspect 47, wherein the first solvent composition comprises two or more polar solvents.

[0055] Aspect 49. The method according to aspect 48, wherein the first solvent composition comprises an aprotic polar solvent and a protic polar solvent.

[0056] Aspect 50. The method according to aspect 48 or 49, wherein the first solvent composition comprises tetrahydrofuran and water.

[0057] Aspect 51. The method according to aspect 50, wherein the first solvent composition comprises tetrahydrofuran and water in a ratio of about 9 / 1 v / v.

[0058] Aspect 52. The method according to any one of aspects 47 to 51, wherein the second solvent composition comprises a polar solvent.

[0059] Aspect 53. The method according to aspect 52, wherein the second solvent composition comprises a protic polar solvent.

[0060] Aspect 54. The method according to aspect 53, wherein the second solvent composition comprises ethanol.

[0061] Aspect 55. The method according to any one of aspects 47 to 54, wherein the second solvent composition comprises an aprotic polar solvent.

[0062] Aspect 56. The method according to aspect 55, wherein the second solvent composition comprises ethyl acetate.

[0063] Aspect 57. The method according to any one of aspects 47 to 56, wherein contacting the first composition with the second solvent composition comprises contacting the first composition with a protic polar solvent and subsequently contacting it with an aprotic polar solvent.

[0064] Aspect 58. The method according to aspect 57, wherein contacting the first composition with the second solvent composition comprises contacting the first composition with ethanol and subsequently contacting it with ethyl acetate.

[0065] Aspect 59. The method according to any one of aspects 47 to 58, wherein the first aliquot constitutes about 5% to about 15% by volume of the clear solution.

[0066] Aspect 60. The method according to aspect 59, wherein the first aliquot constitutes about 10% by weight of the transparent solution.

[0067] Aspect 61. The method according to aspect 59, wherein the seed composition constitutes about 0.9% by weight.

[0068] Aspect 62. The method according to claim 59, wherein the first aliquot constitutes about 7.5% to about 10% by weight.

[0069] Aspect 63. The method according to any one of aspects 47 to 62, wherein the fourth solvent composition comprises a polar protic solvent and a polar aprotic solvent.

[0070] Aspect 64. The method according to aspect 63, wherein the fourth solvent composition comprises ethanol and ethyl acetate.

[0071] Aspect 65. The method according to aspect 63, wherein contacting the first suspension with the fourth solvent composition comprises contacting the first suspension with a mixed solvent composition and then contacting it with a polar aprotic solvent.

[0072] Aspect 66. The method according to aspect 65, wherein contacting the first suspension with the fourth solvent composition comprises contacting the first suspension with a mixed solvent composition of ethanol and ethyl acetate and then contacting it with ethyl acetate.

[0073] Aspect 67. The method according to any one of aspects 47 to 66, wherein the fifth solvent composition comprises three or more solvents.

[0074] Aspect 68. The method according to aspect 67, wherein the fifth solvent composition comprises tetrahydrofuran, water, ethanol, and ethyl acetate.

[0075] Aspect 69. The method according to any one of aspects 47 to 68, wherein the sixth solvent composition comprises a polar protic solvent and a polar aprotic solvent.

[0076] Aspect 70. The method according to aspect 69, wherein the sixth solvent composition comprises ethanol and ethyl acetate.

[0077] Aspect 71. The method according to any one of aspects 47 to 70, wherein the seventh solvent composition comprises an aprotic polar solvent.

[0078] Aspect 72. The method according to aspect 71, wherein the aprotic polar solvent comprises ethyl acetate.

[0079] Aspect 73. A composition comprising a crystalline solid meglumine salt according to any one of aspects 1 to 45 and a pharmaceutically acceptable excipient.

[0080] Aspect 74. Use of a crystalline solid meglumine salt according to any one of aspects 1 to 45 in the treatment of a subject.

[0081] Aspect 75. Use of a crystalline solid meglumine salt according to any one of aspects 1 to 45 in the treatment of age-related macular degeneration.

[0082] Aspect 76. Use of a crystalline solid meglumine salt according to any one of aspects 1 to 45 in the treatment of diabetic macular edema.

[0083] Aspect 77. Use of a crystalline solid meglumine salt according to any one of aspects 1 to 45 in the treatment of diabetic retinopathy.

[0084] Aspect 78. Use of a crystalline solid meglumine salt according to any one of aspects 1 to 45 in the treatment of an aging-related condition.

[0085] Aspect 79. The use according to aspect 76, wherein the condition is osteoarthritis.

[0086] Aspect 80. The use according to aspect 76, wherein the condition is a pulmonary disease condition.

[0087] Aspect 81. A method comprising administering to a subject in need thereof a crystalline solid meglumine salt according to any one of Aspects 1 to 45 in an amount.

[0088] Aspect 82. A method for treating an ocular condition of a subject, the method comprising administering to the subject a crystalline solid meglumine salt according to any one of Aspects 1 to 45 in an amount.

[0089] Aspect 83. A method for treating age-related macular degeneration of a subject, the method comprising administering to the subject a crystalline solid meglumine salt according to any one of Aspects 1 to 45 in an amount.

[0090] Aspect 84. A method for treating diabetic macular edema of a subject, the method comprising administering to the subject a crystalline solid meglumine salt according to any one of Aspects 1 to 45 in an amount.

[0091] Aspect 85. A method for treating diabetic retinopathy of a subject, the method comprising administering to the subject a crystalline solid meglumine salt according to any one of Aspects 1 to 45 in an amount.

[0092] Aspect 86. A method for treating an aging-related condition of a subject, the method comprising administering to the subject a crystalline solid meglumine salt according to any one of Aspects 1 to 45 in an amount.

[0093] Aspect 87. The method according to Aspect 86, wherein the condition is osteoarthritis.

[0094] Aspect 88. The method according to Aspect 86, wherein the condition is a pulmonary disease condition.

[0095] Aspect 89. Use of a crystalline solid meglumine salt according to any one of Aspects 1 to 45 in the manufacture of a medicament for treating a subject.

[0096] Aspect 90. Use of a crystalline solid meglumine salt according to any one of Aspects 1 to 45 in the manufacture of a medicament for treating age-related macular degeneration of a subject.

[0097] Aspect 91. Use of the crystalline solid meglumine salt according to any one of Aspects 1 to 45 in the manufacture of a medicament for treating diabetic macular edema in a subject.

[0098] Aspect 92. Use of the crystalline solid meglumine salt according to any one of Aspects 1 to 45 in the manufacture of a medicament for treating an aging-related condition in a subject.

[0099] Aspect 93. The use according to Aspect 92, wherein the condition is osteoarthritis.

[0100] Aspect 94. The use according to Aspect 92, wherein the condition is a pulmonary disease condition. [The present invention 1001] Formula I: TIFF0007688141000009.tif52128 A crystalline solid meglumine salt of the compound of. [The present invention 1002] The crystalline solid of the present invention 1001, wherein meglumine is present in the crystalline solid in a stoichiometric ratio of 1 to 3. [The present invention 1003] The crystalline solid of the present invention 1001 or 1002, which is stable for 12 months or more at a temperature of 2 °C to 8 °C. [The present invention 1004] Formula I: TIFF0007688141000010.tif52128 A crystalline solid meglumine salt of the compound of, in Form I. [The present invention 1005] The crystalline solid of the present invention 1004, wherein meglumine is present in the crystalline solid in a stoichiometric ratio of 1 to 3. [The present invention 1006] The crystalline solid of the present invention 1004 or 1005, having an X-ray powder diffraction pattern comprising one or more peaks at about 4.3° 2θ, about 6.1° 2θ, about 8.1° 2θ, about 8.6° 2θ, about 9.0° 2θ, about 10.1° 2θ, about 11.3° 2θ, about 12.2° 2θ, about 15.2° 2θ, about 16.2° 2θ, about 17.3° 2θ, about 18.2° 2θ, about 18.9° 2θ, about 19.3° 2θ, about 19.8° 2θ, about 20.7° 2θ, about 21.6° 2θ, about 22.1° 2θ, about 23.0° 2θ, about 24.2° 2θ, about 25.2° 2θ, about 25.5° 2θ, about 26.1° 2θ, about 27.1° 2θ, about 29.5° 2θ, or about 32.6° 2θ. [The present invention 1007] The crystalline solid of any one of the present inventions 1004 to 1006, wherein the crystalline solid meglumine salt of the compound of Formula I, in Form I, is characterized by a 0.9% weight loss step at room temperature to 130 °C by thermogravimetric analysis (TGA) and a second weight loss step at about 130 °C. [The present invention 1008] The crystalline solid of any one of the present inventions 1004 to 1007, wherein the crystalline solid meglumine salt of the compound of Formula I, in Form I, exhibits a first endotherm at 84 °C and a second endotherm at about 147 °C by differential scanning calorimetry (DSC). [The present invention 1009] The crystalline solid of any one of the present inventions 1004 to 1008, which is stable for 12 months or more at a temperature of 2 °C to 8 °C. [The present invention 1010] Formula I: TIFF0007688141000011.tif52128 A crystalline solid meglumine salt of the compound of, in Form II. [The present invention 1011] The crystalline solid of the present invention 1010, wherein meglumine is present in the crystalline solid in a stoichiometric ratio of 1 to 3. [The present invention 1012] A crystalline solid of the present invention 1010 or 1011 having an X-ray powder diffraction pattern containing one or more peaks at about 3.8° 2θ, about 7.3° 2θ, about 8.3° 2θ, about 8.8° 2θ, about 13.7° 2θ, about 15.2° 2θ, about 15.4° 2θ, about 16.6° 2θ, about 17.7° 2θ, about 18.8° 2θ, about 20.0° 2θ, about 22.1° 2θ, or about 23.9° 2θ. [The present invention 1013] A crystalline solid of any one of the present inventions 1010 to 1012, wherein the crystalline solid meglumine salt of the compound of formula I in form II is characterized by a 2.0% weight loss step at room temperature to 130 °C by thermogravimetric analysis (TGA) and a second weight loss step at about 130 °C. [The present invention 1014] A crystalline solid of any one of the present inventions 1010 to 1013, wherein the crystalline solid meglumine salt of the compound of formula I in form II exhibits an endotherm at about 136 °C by differential scanning calorimetry (DSC). [The present invention 1015] A crystalline solid of any one of the present inventions 1010 to 1014, which is stable for 12 months or more at a temperature of 2 °C to 8 °C. [The present invention 1016] [Formula I: TIFF0007688141000012.tif52128 A crystalline solid meglumine salt of the compound of [The present invention 1017] A crystalline solid of the present invention 1016, wherein meglumine is present in a stoichiometric ratio of 1 to 3 in the crystalline solid. [The present invention 1018] A crystalline solid of the present invention 1016 or 1017 having an X-ray powder diffraction pattern containing one or more peaks at about 3.9° 2θ, about 4.3° 2θ, about 6.1° 2θ, about 7.5° 2θ, about 7.7° 2θ, about 8.7° 2θ, about 10.4° 2θ, about 11.3° 2θ, about 11.5° 2θ, about 12.5° 2θ, about 13.9° 2θ, about 14.7° 2θ, about 15.2° 2θ, about 15.9° 2θ, about 17.7° 2θ, about 18.0° 2θ, about 18.8° 2θ, about 20.2° 2θ, about 21.7° 2θ, about 23.0° 2θ, or about 25.8° 2θ. [The present invention 1019] A crystalline solid of any one of the present inventions 1016 to 1018, wherein the crystalline solid meglumine salt of the compound of formula I in form III is characterized by a 0.9% weight loss step at room temperature to 130 °C by thermogravimetric analysis (TGA) and a second weight loss step at about 130 °C. [The present invention 1020] A crystalline solid of any one of the present inventions 1016 to 1019, wherein the crystalline solid meglumine salt of the compound of formula I in form III exhibits a first endotherm at about 113 °C and a second endotherm at about 142 °C by differential scanning calorimetry (DSC). [The present invention 1021] A crystalline solid according to any one of the present inventions 1016 to 1020, which is stable at a temperature of 2°C to 8°C for 12 months or more. [The present invention 1022] Formula I: TIFF0007688141000013.tif52128 A crystalline solid meglumine salt of the compound of formula (IVa). [The present invention 1023] A crystalline solid according to the present invention 1022, wherein meglumine is present in the crystalline solid in a stoichiometric ratio of 1 to 3. [The present invention 1024] A crystalline solid according to the present invention 1022 or 1023, having an X-ray powder diffraction pattern comprising one or more peaks at about 3.8° 2θ, about 4.2° 2θ, about 6.1° 2θ, about 7.4° 2θ, about 8.6° 2θ, about 10.3° 2θ, about 10.9° 2θ, about 12.7° 2θ, about 13.7° 2θ, about 14.4° 2θ, about 15.3° 2θ, about 15.7° 2θ, about 16.5° 2θ, about 17.0° 2θ, about 17.9° 2θ, about 18.5° 2θ, about 19.5° 2θ, about 20.7° 2θ, about 22.2° 2θ, about 22.5° 2θ, about 23.4° 2θ, about 24.8° 2θ, or about 28.2° 2θ. [The present invention 1025] A crystalline solid according to any one of the present inventions 1022 to 1024, wherein the crystalline solid meglumine salt of the compound of formula I has a 3.5% weight loss step at room temperature to 130°C and a second weight loss step at about 130°C by thermogravimetric analysis (TGA). [The present invention 1026] A crystalline solid according to any one of the present inventions 1022 to 1025, wherein the crystalline solid meglumine salt of the compound of formula I exhibits a first endotherm at about 131°C and a second endotherm at about 139°C by differential scanning calorimetry (DSC). [The present invention 1027] A crystalline solid according to any one of the present inventions 1022 to 1026, which is stable at a temperature of 2°C to 8°C for 12 months or more. [The present invention 1028] Formula I: TIFF0007688141000014.tif52128 A crystalline solid meglumine salt of the compound of formula (IV). [The present invention 1029] A crystalline solid according to the present invention 1028, wherein meglumine is present in the crystalline solid in a stoichiometric ratio of 1 to 3. [The present invention 1030] A crystalline solid according to the present invention 1028 or 1029, having an X-ray powder diffraction pattern comprising one or more peaks at about 4.2° 2θ, about 4.6° 2θ, about 7.9° 2θ, about 9.1° 2θ, about 10.4° 2θ, about 13.3° 2θ, about 14.5° 2θ, about 15.8° 2θ, about 16.8° 2θ, about 17.3° 2θ, about 19.5° 2θ, about 19.6° 2θ, about 20.2° 2θ, or about 27.7° 2θ. [The present invention 1031] A crystalline solid meglumine salt of the compound of formula I in Form IV, which is any of crystalline solids of the present invention 1028 - 1030, characterized by a single weight loss step at about 130 °C by thermogravimetric analysis (TGA). [The present invention 1032] A crystalline solid meglumine salt of the compound of formula I in Form IV, which is any of crystalline solids of the present invention 1028 - 1031, showing a first endotherm at about 130 °C and a second endotherm at about 143.3 °C by differential scanning calorimetry (DSC). [The present invention 1033] Any of crystalline solids of the present invention 1028 - 1032, which is stable for 12 months or more at a temperature of 2 °C to 8 °C. [The present invention 1034] [Formula I: TIFF0007688141000015.tif52128 A crystalline solid meglumine salt of the compound in Form V. [The present invention 1035] The crystalline solid of the present invention 1034, wherein meglumine is present in a stoichiometric ratio of 1 - 3 in the crystalline solid. [The present invention 1036] The crystalline solid of the present invention 1034 or 1035, having an X - ray powder diffraction pattern containing one or more peaks at about 4.2° 2θ, about 5.4° 2θ, about 7.3° 2θ, about 9.1° 2θ, about 12.2° 2θ, about 12.4° 2θ, about 13.4° 2θ, about 14.5° 2θ, about 16.1° 2θ, about 17.5° 2θ, about 18.1° 2θ, about 18.8° 2θ, about 19.6° 2θ, about 20.4° 2θ, about 21.2° 2θ, about 22.3° 2θ, about 23.0° 2θ, about 27.6° 2θ, or about 29.2° 2θ. [The present invention 1037] A crystalline solid meglumine salt of the compound of formula I in Form V, which is any of crystalline solids of the present invention 1034 - 1036, characterized by a 1.2% weight loss step from room temperature to 130 °C and a second weight loss step at about 130 °C by thermogravimetric analysis (TGA). [The present invention 1038] A crystalline solid meglumine salt of the compound of formula I in Form V, which is any of crystalline solids of the present invention 1034 - 1037, showing a first endotherm at about 115 °C and a second endotherm at about 143 °C by differential scanning calorimetry (DSC). [The present invention 1039] Any of crystalline solids of the present invention 1034 - 1038, which is stable for 12 months or more at a temperature of 2 °C to 8 °C. [The present invention 1040] [Formula I: TIFF0007688141000016.tif52128 A crystalline solid meglumine salt of the compound in Form VI. [The present invention 1041] The crystalline solid of the present invention 1040, wherein meglumine is present in a stoichiometric ratio of 1 - 3 in the crystalline solid. [The present invention 1042] A crystalline solid of the invention 1040 or 1041 having an X-ray powder diffraction pattern containing one or more peaks at about 3.9° 2θ, about 8.5° 2θ, about 8.6° 2θ, about 8.7° 2θ, about 11.3° 2θ, about 12.7° 2θ, about 13.9° 2θ, about 14.5° 2θ, about 15.1° 2θ, about 15.9° 2θ, about 17.6° 2θ, about 17.7° 2θ, about 18.8° 2θ, about 20.0° 2θ, about 20.7° 2θ, about 23.0° 2θ, about 35.1° 2θ, about 36.1° 2θ, or about 36.8° 2θ. [The invention 1043] A crystalline solid of any one of the inventions 1040 - 1042, wherein the crystalline solid meglumine salt of the compound of formula I in Form VI is characterized by a 1.0% weight loss step at room temperature to 130 °C and a second weight loss step at about 130 °C by thermogravimetric analysis (TGA). [The invention 1044] A crystalline solid of any one of the inventions 1040 - 1043, wherein the crystalline solid meglumine salt of the compound of formula I in Form VI exhibits a first endotherm at about 110 °C and a second endotherm at about 142 °C by differential scanning calorimetry (DSC). [The invention 1045] A crystalline solid of any one of the inventions 1028 - 1030 that is stable for 12 months or more at a temperature of 2 °C to 8 °C. [The invention 1046] A method for preparing a crystalline solid meglumine salt compound of any one of the inventions 1001 - 1045, comprising: generating a clear solution containing the meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid; contacting an aliquot of the clear solution with a seed composition and a solvent composition to produce a first suspension; contacting the first suspension with a second aliquot of the clear solution and a solvent composition to produce a slurry composition. Filtering a crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid from the slurry composition The method comprising the above. [Inventive concept 1047] Contacting meglumine and (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid in a first solvent composition to produce a first solution comprising solubilized (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid meglumine salt Contacting the first composition with a second solvent composition to produce a clear solution Contacting a first aliquot of the clear solution with a third solvent composition and a seed composition to produce a first suspension Contacting the first suspension with a fourth solvent composition to produce a second suspension Contacting the second suspension with a fifth solvent composition to produce a third suspension Contacting a second aliquot of the clear solution and a sixth solvent composition with the third suspension to produce a slurry precursor composition Contacting the slurry precursor composition with a seventh solvent composition to produce a slurry composition Filtering the crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid from the slurry composition The method of the present invention 1046 comprising this. [The present invention 1048] The method of the present invention 1047, wherein the first solvent composition comprises two or more polar solvents. [The present invention 1049] The method of the present invention 1048, wherein the first solvent composition comprises an aprotic polar solvent and a protic polar solvent. [The present invention 1050] The method of the present invention 1048 or 1049, wherein the first solvent composition comprises tetrahydrofuran and water. [The present invention 1051] The method of the present invention 1050, wherein the first solvent composition comprises tetrahydrofuran and water at about 9 / 1 v / v. [The present invention 1052] The method according to any one of the present inventions 1047 to 1051, wherein the second solvent composition comprises a polar solvent. [The present invention 1053] The method of the present invention 1052, wherein the second solvent composition comprises a protic polar solvent. [The present invention 1054] The method of the present invention 1053, wherein the second solvent composition comprises ethanol. [The present invention 1055] The method according to any one of the present inventions 1047 to 1054, wherein the second solvent composition comprises an aprotic polar solvent. [The present invention 1056] The method of the present invention 1055, wherein the second solvent composition comprises ethyl acetate. [The present invention 1057] The method according to any one of the present inventions 1047 to 1056, wherein contacting the first composition with the second solvent composition comprises contacting the first composition with a protic polar solvent and subsequently contacting with an aprotic polar solvent. [The present invention 1058] The method of the present invention 1057, wherein contacting the first composition with the second solvent composition comprises contacting the first composition with ethanol and subsequently contacting with ethyl acetate. [The present invention 1059] The method according to any one of the present inventions 1047 to 1058, wherein the first aliquot constitutes about 5% to about 15% by volume of the clear solution. [The present invention 1060] The method of the present invention 1059, wherein the first aliquot constitutes about 10% by weight of the clear solution. [The present invention 1061] The method of the present invention 1059, wherein the seed composition constitutes about 0.9% by weight. [The present invention 1062] The method of the present invention 1059, wherein the first aliquot constitutes about 7.5% to about 10% by weight. [The present invention 1063] The method according to any one of the present inventions 1047 to 1062, wherein the fourth solvent composition comprises a polar protic solvent and a polar aprotic solvent. [The present invention 1064] The method of the present invention 1063, wherein the fourth solvent composition comprises ethanol and ethyl acetate. [The present invention 1065] The method of the present invention 1063, wherein contacting the first suspension with the fourth solvent composition comprises contacting the first suspension with a mixed solvent composition and subsequently contacting with a polar aprotic solvent. [The present invention 1066] The method of the present invention 1065, wherein contacting the first suspension with the fourth solvent composition comprises contacting the first suspension with a mixed solvent composition of ethanol and ethyl acetate and subsequently contacting with ethyl acetate. [The present invention 1067] The method according to any one of the present inventions 1047 to 1066, wherein the fifth solvent composition comprises three or more solvents. [The present invention 1068] The method of the present invention 1067, wherein the fifth solvent composition comprises tetrahydrofuran, water, ethanol, and ethyl acetate. [The present invention 1069] The method according to any one of the present inventions 1047 to 1068, wherein the sixth solvent composition comprises a polar protic solvent and a polar aprotic solvent. [The present invention 1070] The method of the present invention 1069, wherein the sixth solvent composition comprises ethanol and ethyl acetate. [The present invention 1071] The method according to any one of the present inventions 1047 to 1070, wherein the seventh solvent composition comprises a polar aprotic solvent. [The present invention 1072] The method of the present invention 1071, wherein the polar aprotic solvent comprises ethyl acetate. [The present invention 1073] Any crystalline solid meglumine salt of the present inventions 1001 to 1045, and a pharmaceutically acceptable excipient comprising a composition. [The present invention 1074] Use of any crystalline solid meglumine salt of the present inventions 1001 to 1045 in the treatment of a subject. [The present invention 1075] Use of any crystalline solid meglumine salt of the present inventions 1001 to 1045 in the treatment of age-related macular degeneration. [The present invention 1076] Use of any crystalline solid meglumine salt of the present inventions 1001 to 1045 in the treatment of diabetic macular edema. [The present invention 1077] Use of any of the crystalline solid meglumine salts of the present invention 1001 to 1045 in the treatment of diabetic retinopathy. [The present invention 1078] Use of any of the crystalline solid meglumine salts of the present invention 1001 to 1045 in the treatment of age-related conditions. [The present invention 1079] Use of the present invention 1078, wherein the condition is osteoarthritis. [The present invention 1080] Use of the present invention 1078, wherein the condition is a pulmonary disease condition. [The present invention 1081] A method comprising administering to a subject in need thereof an amount of any of the crystalline solid meglumine salts of the present invention 1001 to 1045. [The present invention 1082] A method for treating an ocular condition of a subject, the method comprising administering to the subject an amount of any of the crystalline solid meglumine salts of the present invention 1001 to 1045. [The present invention 1083] A method for treating age-related macular degeneration of a subject, the method comprising administering to the subject an amount of any of the crystalline solid meglumine salts of the present invention 1001 to 1045. [The present invention 1084] A method for treating diabetic macular edema of a subject, the method comprising administering to the subject an amount of any of the crystalline solid meglumine salts of the present invention 1001 to 1045. [The present invention 1085] A method for treating diabetic retinopathy of a subject, the method comprising administering to the subject an amount of any of the crystalline solid meglumine salts of the present invention 1001 to 1045. [The present invention 1086] A method for treating an age-related condition of a subject, the method comprising administering to the subject an amount of any of the crystalline solid meglumine salts of the present invention 1001 to 1045. [The present invention 1087] The method of the present invention 1086, wherein the condition is osteoarthritis. [The present invention 1088] The method of the present invention 1086, wherein the condition is a pulmonary disease condition. [The present invention 1089] Use of any of the crystalline solid meglumine salts of the present invention 1001 to 1045 in the manufacture of a medicament for treating a subject. [The present invention 1090] Use of any of the crystalline solid meglumine salts of the present invention 1001 to 1045 in the manufacture of a medicament for treating age-related macular degeneration of a subject. [The present invention 1091] Use of any of the crystalline solid meglumine salts of the present invention 1001 to 1045 in the manufacture of a medicament for treating diabetic macular edema of a subject. [The present invention 1092] Use of any of crystalline solid meglumine salts of the invention Nos. 1001 to 1045 in the manufacture of a medicament for treating a target aging-related condition. [Invention No. 1093] Use of the invention No. 1092, wherein the condition is osteoarthritis. [Invention No. 1094] Use of the invention No. 1092, wherein the condition is a pulmonary disease condition.

Brief Description of the Drawings

[0101] The present invention can be best understood from the following detailed description when read in conjunction with the accompanying drawings. The drawings include the following figures.

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Mode for Carrying Out the Invention

[0102] Detailed Description Aspects of the present disclosure include crystalline solid meglumine salts of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid. Also described are pharmaceutical compositions having one or more of the crystalline solid meglumine salt compounds of the subject matter, and methods for administering the crystalline solid meglumine salt compounds to a subject. Also provided are methods for preparing the crystalline solid meglumine salt compounds of the subject matter.

[0103] Prior to further description of the invention, it is to be understood that the invention is not limited to the specific embodiments described, and accordingly may vary. It is also to be understood that the terms used herein are for the purpose of describing particular embodiments only and are not intended to be limiting, as the scope of the invention is limited only by the appended claims.

[0104] Where a range of values is provided, unless the context clearly dictates otherwise, each intervening value between the upper and lower limits of that range to one tenth of the unit of the lower limit, and any other stated value or intervening value within the stated range, is included within the invention. The upper and lower limits of these smaller ranges may independently be included within the smaller ranges and are also included within the invention, subject to any specifically excluded limitation within the stated range. Where the stated range includes one or both of the limits, ranges excluding either one or both of those included limits are also included in the invention.

[0105] For the sake of clarity, it is understood that certain features of the invention described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, various features of the invention described in the context of a single embodiment for the sake of brevity may also be provided separately or in any suitable partial combination. All combinations of embodiments belonging to the invention are specifically embraced by the invention and are disclosed herein to the extent that each and every combination includes an object that is, for example, a compound that is a stable compound (i.e., a compound that can be made, isolated, characterized, and tested for biological activity) as if such combinations were individually and explicitly disclosed. In addition, all partial combinations of various embodiments and elements of various embodiments (such as such variable elements recited in embodiments that describe elements of chemical groups) are also specifically embraced by the invention and are disclosed herein as if each and every such partial combination were individually and explicitly disclosed herein.

[0106] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, but the methods and materials of choice are set forth herein. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials related to the cited publications.

[0107] As used in this specification and the appended claims, it should be noted that the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. It should further be noted that the claims may be drafted to exclude any optional element. Accordingly, this description is intended to serve as a basis for the use of exclusive terms such as "solely", "only", etc. or the use of "negative" limitations in connection with the recitation of claim elements.

[0108] For clarity, it is understood that specific features of the invention described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, various features of the invention described in the context of a single embodiment for brevity may also be provided separately or in any suitable partial combination.

[0109] Publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention. Further, the dates of the publications provided may be different from the actual publication dates which may need to be independently confirmed.

[0110] Unless otherwise noted, the methods and techniques of this embodiment are generally carried out according to conventional methods well known in the art and as described in various general and more specific references cited and discussed throughout this specification. For example, see Loudon, Organic Chemistry, Fourth Edition, New York: Oxford University Press, 2002, pp. 360 - 361, 1084 - 1085; Smith and March, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley - Interscience, 2001.

[0111] The nomenclature used herein to name the compounds of the present subject matter is illustrated in the examples herein. When possible, this nomenclature has generally been derived using commercially available AutoNom software (MDL, San Leandro, Calif.).

[0112] Many general reference works are available that provide generally known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds (see, for example, Smith and March, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001, or Vogel, A Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis, Fourth Edition, New York: Longman, 1978).

[0113] The compounds described herein can be purified by any of the means known in the art, including chromatographic means such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography, and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reverse phases as well as ion exchange resins. See, for example, Introduction to Modern Liquid Chromatography, 2nd Edition, ed. L.R. Snyder and J.J. Kirkland, John Wiley and Sons, 1979, and Thin Layer Chromatography, ed E. Stahl, Springer-Verlag, New York, 1969.

[0114] During any of the processes for preparing the compounds of the present disclosure, it may be necessary and / or desirable to protect sensitive or reactive groups in any of the related molecules. This can be achieved by conventional protecting groups as described in standard studies such as T.W. Greene and P.G.M. Wuts, “Protective Groups in Organic Synthesis”, Fourth edition, Wiley, New York 2006. The protecting groups can be removed in convenient subsequent steps using methods known in the art.

[0115] The compounds described herein can contain one or more chiral centers and / or double bonds and can therefore exist as stereoisomers such as double bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. Accordingly, all possible enantiomers and stereoisomers of the compounds, including stereoisomerically pure (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) forms, and mixtures of enantiomers and stereoisomers, are included in the description of the compounds herein. Mixtures of enantiomers and stereoisomers can be resolved into the component enantiomers or stereoisomers of the mixture of enantiomers and stereoisomers using separation techniques or chiral synthesis techniques well known to those skilled in the art. Compounds can also exist in several tautomeric forms including enol forms, keto forms, and mixtures thereof. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the exemplified compounds. The compounds described also include isotopically labeled compounds, in which one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17Examples include, but are not limited to, O. Compounds can exist in non-solvated form and in solvated forms including hydrated forms. Generally, compounds can be hydrated or solvated. A compound can exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent for the intended uses herein and are intended to be within the scope of this disclosure.

[0116] Aspects of the present disclosure include a crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid. The term "crystalline" is used herein in its conventional meaning to refer to a solid material in which the molecules forming the solid are arranged in a highly regular microscopic geometric configuration that extends in three dimensions (e.g., forms a regular lattice type structure). In embodiments, the crystalline solids described herein are not amorphous, and the crystalline solids are characterized by an undefined structural regularity and microscopic configuration lacking a regular geometric arrangement in three dimensions.

[0117] As described herein, the compound (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid has the formula I: It is the compound of TIFF0007688141000017.tif52128.

[0118] The compound meglumine has the following structure: Refers to a glucose-derived amino sugar having TIFF0007688141000018.tif27128, (2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentol.

[0119] In some embodiments, meglumine is present in the crystalline solid of the present subject matter in a stoichiometric ratio with (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid that ranges from 1:10 to, for example, 1:9 to, for example, 1:8 to, for example, 1:7 to, for example, 1:6 to, for example, 1:5 to, for example, 1:4 to, for example, 1:3 to, for example, 1:2 to and includes 1:1. In other embodiments, meglumine is present in the crystalline solid of the present subject matter in a stoichiometric ratio with (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid that ranges from 10:1 to, for example, 9:1 to, for example, 8:1 to, for example, 7:1 to, for example, 6:1 to, for example, 5:1 to, for example, 4:1 to, for example, 3:1 to and includes 2:1.

[0120] The present disclosure uses the term "form" to identify different crystalline forms of crystalline (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid meglumine salt or liquid crystalline forms. The differences in forms are discernible by structure such as X-ray powder diffraction, properties such as hygroscopicity or thermal behavior, and / or both. The use of the term "Form I" means the crystalline (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid meglumine salt of Form I. Similarly, "Form II" means the crystalline (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid meglumine salt of Form II. Similarly, Form III, Form IV, Form IVa, Form V, and Form VI mean the crystalline (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid meglumine salt of Form III, Form IV, Form IVa, Form V, and Form VI, respectively.

[0121] In an embodiment, the crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid has polymorphic purity (i.e., exists as a polymorph as demonstrated by X-ray powder diffraction (XRPD) analysis, thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC) analysis described in detail below), and the polymorphic purity is 90% or more, for example, 95% or more, for example, 97% or more, for example, 99% or more and includes 99.9% or more. In some embodiments, the polymorphic form of the meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid described herein is present in 100% purity in the crystalline solid.In some embodiments, the crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid provided herein exhibits improved solubility and reactivity compared to crystalline (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid and other salts of amorphous (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid (e.g., sodium, potassium). In some embodiments, the crystalline solid meglumine salt of the present subject matter is stable for 3 months or more, such as 6 months or more, such as 9 months or more, such as 12 months or more, such as 18 months or more, such as 24 months or more, such as 36 months or more, such as 48 months or more at a temperature of 2°C to 8°C, including being stable for 60 months or more at a temperature of 2°C to 8°C.

[0122] (R)-5-(4-Chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid crystalline solid meglumine salt can be analyzed by X-ray powder diffraction. The X-ray powder diffraction pattern is an x-y graph having °2θ (diffraction angle) on the x-axis and intensity on the y-axis. The pattern contains peaks that can be used to characterize the crystalline solid meglumine salt of the subject matter. The peaks are usually represented and referenced by the position of the peaks on the x-axis rather than the intensity of the peaks on the y-axis because the peak intensity can be particularly sensitive to sample orientation (see Pharmaceutical Analysis, Lee & Web, pp. 255-257 (2003)). Thus, intensity is typically not used to characterize the solid form.

[0123] Data from X-ray powder diffraction can be used in multiple ways to characterize crystalline forms. For example, the entire X-ray powder diffraction pattern output from a diffractometer can be used to characterize the crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid. However, smaller subsets of such data can also be suitable, and typically are suitable, for characterizing the crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid. For example, a collection of one or more peaks from such a pattern can be used to characterize the crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid. In this application, all reported peak values are peak values at 2θ in Cu-Kα radiation. In fact, often a single X-ray powder diffraction peak can also be used to characterize such a crystalline form.The crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid is characterized by "one or more peaks" in the X-ray powder diffraction pattern, and when such peaks are listed, generally what is meant is that any combination of the listed peaks can be used to characterize the crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid. Further, the presence of other peaks in the X-ray powder diffraction pattern generally does not negate or otherwise limit this characterization.

[0124] In addition to the variability in peak intensity, there can also be variability in the position of the peaks on the x-axis. However, this variability can typically be taken into account when reporting the position of the peaks for characterization. Such variability in the position of the peaks along the x-axis can arise from several sources (e.g., sample preparation, particle size, moisture content, solvent content, instrument parameters, data analysis software, and sample orientation). For example, samples of the same crystalline material prepared under different conditions can yield slightly different diffractograms, and different X-ray instruments can operate using different parameters, which can result in slightly different diffraction patterns from the same crystalline solid.

[0125] Due to such sources of variability, it is common to enumerate X-ray diffraction peaks using the word "about" before the peak value at °2θ. For the data reported herein, this value is generally ±0.1°2θ. This generally means that for well-maintained equipment, the variability of peak measurements is expected to be ±0.1°2θ. Unless otherwise specified, the X-ray powder diffraction peaks described herein are generally reported with this variability of ±0.1°2θ and are generally intended to be reported with such variability whenever disclosed herein, whether or not the word "about" is present, although in some cases the variability can be at a height of ±0.2°2θ or higher depending on the instrument conditions or even higher than ±0.2°2θ.

[0126] Aspects of the present disclosure include the meglumine salt of the crystalline solid of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid, Form I. In embodiments, the crystalline solid (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid meglumine salt of polymorphic Form I exhibits an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at about 4.3° 2θ, about 6.1° 2θ, about 8.1° 2θ, about 8.6° 2θ, about 9.0° 2θ, about 10.1° 2θ, about 11.3° 2θ, about 12.2° 2θ, about 15.2° 2θ, about 16.2° 2θ, about 17.3° 2θ, about 18.2° 2θ, about 18.9° 2θ, about 19.3° 2θ, about 19.8° 2θ, about 20.7° 2θ, about 21.6° 2θ, about 22.1° 2θ, about 23.0° 2θ, about 24.2° 2θ, about 25.2° 2θ, about 25.5° 2θ, about 26.1° 2θ, about 27.1° 2θ, about 29.5° 2θ, or about 32.6° 2θ. For a given crystal form, the relative intensities of the diffraction peaks can vary, for example, due to the orientation of the crystals with respect to the X-rays from the crystalline morphology. In embodiments, the intensity of the X-ray powder diffraction peaks at 2θ can vary from crystal to crystal, but the characteristic peak positions for the polymorphic form remain the same.The crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid, polymorphic form I, provided herein, in some cases, is characterized by a 0.9% weight loss step at room temperature to 130 °C by thermogravimetric analysis (TGA) and a second weight loss step at about 130 °C. Differential scanning calorimetry (DSC) measures the transition temperature of a crystalline solid when the crystal absorbs or releases heat due to a change in the crystal's structure or due to melting. DSC provides for distinguishing between different crystalline forms (e.g., different polymorphs). Different crystalline forms can be identified according to their different characteristic transition temperatures. In some embodiments, the crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid, polymorphic form I, provided herein, exhibits a first endotherm at about 84 °C and a second endotherm at about 147 °C by differential scanning calorimetry (DSC).

[0127] Aspects of the present disclosure include the meglumine salt of the crystalline solid of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid, in polymorphic form II. In embodiments, the crystalline solid (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid meglumine salt of polymorphic form II exhibits an X-ray powder diffraction (XRPD) pattern that includes one or more peaks at about 3.8° 2θ, about 7.3° 2θ, about 8.3° 2θ, about 8.8° 2θ, about 13.7° 2θ, about 15.2° 2θ, about 15.4° 2θ, about 16.6° 2θ, about 17.7° 2θ, about 18.8° 2θ, about 20.0° 2θ, about 22.1° 2θ, or about 23.9° 2θ. The crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid provided herein, in polymorphic form II, is in some cases characterized by a 2.0% weight loss step from room temperature to 130° C. by thermogravimetric analysis (TGA) and a second weight loss step at about 130° C.In some embodiments, the crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid, polymorphic form II, exhibits an endotherm at about 136 °C by differential scanning calorimetry (DSC).

[0128] Aspects of the present disclosure include the meglumine salt of the crystalline solid of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid, in polymorphic form III. In embodiments, the crystalline solid (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid meglumine salt of polymorphic form III exhibits an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at about 3.9° 2θ, about 4.3° 2θ, about 6.1° 2θ, about 7.5° 2θ, about 7.7° 2θ, about 8.7° 2θ, about 10.4° 2θ, about 11.3° 2θ, about 11.5° 2θ, about 12.5° 2θ, about 13.9° 2θ, about 14.7° 2θ, about 15.2° 2θ, about 15.9° 2θ, about 17.7° 2θ, about 18.0° 2θ, about 18.8° 2θ, about 20.2° 2θ, about 21.7° 2θ, about 23.0° 2θ, or about 25.8° 2θ. The crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid provided herein, in polymorphic form III, is characterized in some cases by a 0.9% weight loss step from room temperature to 130° C. and a second weight loss step at about 130° C. by thermogravimetric analysis (TGA).In some embodiments, the crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid, polymorphic form III, exhibits a first endotherm at about 113 °C and a second endotherm at about 142 °C by differential scanning calorimetry (DSC).

[0129] Aspects of the present disclosure include a crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid in polymorphic form IVa. In embodiments, the crystalline solid (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid meglumine salt of polymorphic form IVa exhibits an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at about 3.8° 2θ, about 4.2° 2θ, about 6.1° 2θ, about 7.4° 2θ, about 8.6° 2θ, about 10.3° 2θ, about 10.9° 2θ, about 12.7° 2θ, about 13.7° 2θ, about 14.4° 2θ, about 15.3° 2θ, about 15.7° 2θ, about 16.5° 2θ, about 17.0° 2θ, about 17.9° 2θ, about 18.5° 2θ, about 19.5° 2θ, about 20.7° 2θ, about 22.2° 2θ, about 22.5° 2θ, about 23.4° 2θ, about 24.8° 2θ, or about 28.2° 2θ. The crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid in polymorphic form IVa provided herein is, in some cases, characterized by a 3.5% weight loss step from room temperature to 130° C. and a second weight loss step at about 130° C. by thermogravimetric analysis (TGA).In some embodiments, the crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid, polymorphic form IVa, exhibits a first endotherm at about 113 °C and a second endotherm at about 142 °C by differential scanning calorimetry (DSC).

[0130] Aspects of the present disclosure include the meglumine salt of the crystalline solid of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid, in polymorphic form IV. In embodiments, the crystalline solid (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid meglumine salt of polymorphic form IV exhibits an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at about 4.2° 2θ, about 4.6° 2θ, about 7.9° 2θ, about 9.1° 2θ, about 10.4° 2θ, about 13.3° 2θ, about 14.5° 2θ, about 15.8° 2θ, about 16.8° 2θ, about 17.3° 2θ, about 19.5° 2θ, about 19.6° 2θ, about 20.2° 2θ, or about 27.7° 2θ. The crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid provided herein, in polymorphic form IV, is in some cases characterized by a single weight loss step at about 130° C. by thermogravimetric analysis (TGA).In some embodiments, the crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid, polymorphic form IV, exhibits a first endotherm at about 130 °C and a second endotherm at about 143.3 °C by differential scanning calorimetry (DSC).

[0131] Aspects of the present disclosure include the meglumine salt of the crystalline solid of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid, Form V. In embodiments, the crystalline solid (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid meglumine salt of polymorphic Form V exhibits an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at about 4.2° 2θ, about 5.4° 2θ, about 7.3° 2θ, about 9.1° 2θ, about 12.2° 2θ, about 12.4° 2θ, about 13.4° 2θ, about 14.5° 2θ, about 16.1° 2θ, about 17.5° 2θ, about 18.1° 2θ, about 18.8° 2θ, about 19.6° 2θ, about 20.4° 2θ, about 21.2° 2θ, about 22.3° 2θ, about 23.0° 2θ, about 27.6° 2θ, or about 29.2° 2θ. The crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid, polymorphic Form V, provided herein is, in some cases, characterized by a 1.2% weight loss step from room temperature to 130° C. and a second weight loss step at about 130° C. by thermogravimetric analysis (TGA).In some embodiments, the crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid, polymorphic form V, exhibits a first endotherm at about 115 °C and a second endotherm at about 143 °C by differential scanning calorimetry (DSC).

[0132] Aspects of the present disclosure include the meglumine salt of the crystalline solid of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid, in polymorphic form VI. In embodiments, the crystalline solid (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid meglumine salt of polymorphic form VI exhibits an X-ray powder diffraction (XRPD) pattern comprising one or more peaks at about 3.9° 2θ, about 8.5° 2θ, about 8.6° 2θ, about 8.7° 2θ, about 11.3° 2θ, about 12.7° 2θ, about 13.9° 2θ, about 14.5° 2θ, about 15.1° 2θ, about 15.9° 2θ, about 17.6° 2θ, about 17.7° 2θ, about 18.8° 2θ, about 20.0° 2θ, about 20.7° 2θ, about 23.0° 2θ, about 35.1° 2θ, about 36.1° 2θ, or about 36.8° 2θ. The crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid, in polymorphic form VI, provided herein is, in some cases, characterized by a 1.0% weight loss step from room temperature to 130° C. and a second weight loss step at about 130° C. by thermogravimetric analysis (TGA).In some embodiments, the crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid, polymorphic form VI, exhibits a first endotherm at about 110 °C and a second endotherm at about 142 °C by differential scanning calorimetry (DSC).

[0133] A method for preparing a crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid is also provided. In practicing the method according to certain embodiments, a clear solution of the meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid is produced by dissolving the free acid and meglumine in a solvent. In some embodiments, the solvent comprises a polar protic solvent. In other embodiments, the solvent comprises an aprotic polar solvent. In still other embodiments, the solvent is a mixture of a polar protic solvent and an aprotic polar solvent. Exemplary polar protic solvents can include, but are not limited to, ammonia, t-butanol, n-propanol, ethanol, methanol, acetic acid, water. Exemplary aprotic polar solvents can include tetrahydrofuran, methyltetrahydrofuran, dimethylformamide (DMF), acetone, dimethylsulfoxide (DMSO), and acetonitrile, dichloromethane, ethyl acetate, and combinations thereof. In some cases, the solvent is a combination of an aprotic polar solvent and a polar protic solvent.When the solvent is a combination of an aprotic polar solvent and a protic polar solvent, the volume ratio of the aprotic polar solvent to the protic polar solvent can be in the range of 100:1 to 1:1, for example, 90:1 to 1:1, for example, 80:1 to 1:1, for example, 70:1 to 1:1, for example, 60:1 to 1:1, for example, 50:1 to 1:1, for example, 40:1 to 1:1, for example, 30:1 to 1:1, for example, 20:1 to 1:1, for example, 10:1 to 1:1, for example, 10:1, or 9:1, or 8:1, or 7:1, or 6:1, or 5:1, or 4:1, or 3:1, or 2:1. In other embodiments, the volume ratio of the aprotic polar solvent to the protic polar solvent is in the range of 1:100 to 1:1, for example, 1:90 to 1:1, for example, 1:80 to 1:1, for example, 1:70 to 1:1, for example, 1:60 to 1:1, for example, 1:50 to 1:1, for example, 1:40 to 1:1, for example, 1:30 to 1:1, for example, 1:20 to 1:1, for example, 1:10 to 1:1, for example, 1:9, or 1:8, or 1:7, or 1:6, or 1:5, or 1:4, or 1:3, or 1:2, including the range of 1:1. In some cases, a clear solution of meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid is produced by dissolving the free acid and meglumine in a solvent containing tetrahydrofuran and water at a volume ratio of, for example, 9:1 v / v.

[0134] In some embodiments, generating a transparent solution comprises contacting the meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid (e.g., dissolved in THF / water) with a second solvent. The solvents of interest can include, but are not limited to, ammonia, t-butanol, n-propanol, ethanol, methanol, acetic acid, water, tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate, ethyl acetate, 1,2-dichloroethane (DCE), dimethylformamide (DMF), acetone, dimethylacetamide, dimethylsulfoxide (DMSO), acetonitrile, toluene, 2-methylbutan-2-ol (tAmOH), and N-methyl-2-pyrrolidone (NMP), and combinations thereof. In certain embodiments, the solvent is a polar protic solvent. In some cases, the solvent is ethanol. In some cases, the method further comprises contacting the composition with a third solvent. The solvents of interest can include, but are not limited to, ammonia, t-butanol, n-propanol, ethanol, methanol, acetic acid, water, tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate, ethyl acetate, 1,2-dichloroethane (DCE), dimethylformamide (DMF), acetone, dimethylacetamide, dimethylsulfoxide (DMSO), acetonitrile, toluene, 2-methylbutan-2-ol (tAmOH), and N-methyl-2-pyrrolidone (NMP), and combinations thereof. In certain embodiments, the solvent is a polar aprotic solvent. In some cases, the third solvent is ethyl acetate.

[0135] In the method of the present subject matter, an aliquot of the transparent solution is contacted with a seed composition of meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid. The aliquot can be 0.1 wt% or more of the transparent solution, for example, 0.5 wt% or more, for example, 1.0 wt% or more, for example, 2.0 wt% or more, for example, 3.0 wt% or more, for example, 4.0 wt% or more, for example, 5.0 wt% or more, for example, 6.0 wt% or more, for example, 7.0 wt% or more, for example, 8.0 wt% or more, for example, 9.0 wt% or more of the transparent solution, and can include 10 wt% or more. In some cases, the aliquot is in the range of 0.1 wt% to 25 wt% of the transparent solution, for example, 0.2 wt% to 20 wt% of the transparent solution, for example, 0.3 wt% to 15 wt%, for example, 0.4 wt% to 14 wt%, for example, 0.5 wt% to 13 wt%, for example, 0.6 wt% to 12 wt%, for example, 0.7 wt% to 11 wt% of the transparent solution, and includes 0.8 wt% to 10 wt% of the transparent solution. In certain embodiments, the aliquot is about 10 wt% of the transparent solution.

[0136] In some embodiments, the seed composition is contacted with a clear solution and a solvent. The solvent of interest can include, but is not limited to, ammonia, t-butanol, n-propanol, ethanol, methanol, acetic acid, water, tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate, ethyl acetate, 1,2-dichloroethane (DCE), dimethylformamide (DMF), acetone, dimethylacetamide, dimethyl sulfoxide (DMSO), acetonitrile, toluene, 2-methylbutan-2-ol (tAmOH), and N-methyl-2-pyrrolidone (NMP), and combinations thereof. In some embodiments, the solvent is a mixture of two or more solvents, e.g., a mixture of three or more solvents, e.g., a mixture of four or more solvents, e.g., a mixture of five or more solvents, including a mixture of six or more solvents. In certain embodiments, the seed composition is contacted with an aliquot of the clear solution and a solvent mixture comprising tetrahydrofuran, water, ethanol, and ethyl acetate. In some cases, the seed composition is contacted with an aliquot of the clear solution and a solvent mixture comprising 9 / 1 v / v tetrahydrofuran / water:ethanol:ethyl acetate (2 / 1 / 2 v / v / v). In these embodiments, the seed suspension can be 0.5 wt% or greater, e.g., 0.6 wt% or greater, e.g., 0.7 wt% or greater, e.g., 0.8 wt% or greater, e.g., 0.9 wt% or greater, e.g., 1.0 wt% or greater, e.g., 1.5 wt% or greater, e.g., 2.0 wt% or greater, e.g., 3.0 wt% or greater, e.g., 4.0 wt% or greater, e.g., 5.0 wt% or greater, e.g., 6.0 wt% or greater, e.g., 7.0 wt% or greater, e.g., 8.0 wt% or greater, e.g., 9.0 wt% or greater, e.g., 10 wt% or greater, e.g., 15 wt% or greater, including 20 wt% or greater. In certain embodiments, the seed composition is a 0.9 wt% seed composition. In embodiments, contacting the aliquot of the clear solution with the seed composition and the solvent produces a first suspension.

[0137] The first suspension is contacted with a solvent to form a slurry. The solvent of interest can include, but is not limited to, ammonia, t-butanol, n-propanol, ethanol, methanol, acetic acid, water, tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate, ethyl acetate, 1,2-dichloroethane (DCE), dimethylformamide (DMF), acetone, dimethylacetamide, dimethyl sulfoxide (DMSO), acetonitrile, toluene, 2-methylbutan-2-ol (tAmOH), and N-methyl-2-pyrrolidone (NMP), as well as combinations thereof. In some embodiments, the solvent is a mixture of two or more solvents, for example, a mixture of three or more solvents, for example, a mixture of four or more solvents, for example, a mixture of five or more solvents, including a mixture of six or more solvents. For example, the first suspension can be contacted with a mixture of ethanol and ethyl acetate.

[0138] In some cases, the method comprises contacting a first suspension with a first solvent and slurrying for a first predetermined period, and subsequently contacting with a second solvent and slurrying for a second predetermined period. In these embodiments, the second solvent can be ammonia, t-butanol, n-propanol, ethanol, methanol, acetic acid, water, tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate, ethyl acetate, 1,2-dichloroethane (DCE), dimethylformamide (DMF), acetone, dimethylacetamide, dimethyl sulfoxide (DMSO), acetonitrile, toluene, 2-methylbutan-2-ol (tAmOH), and N-methyl-2-pyrrolidone (NMP), or a combination thereof. For example, the second solvent can be ethyl acetate. For example, the method can comprise contacting the first suspension with a solvent mixture of ethanol / ethyl acetate and slurrying for a first predetermined period, and subsequently contacting with ethyl acetate and slurrying for a second predetermined period. In these embodiments, the first predetermined period and the second predetermined period can independently be 1 minute or more, for example, 2 minutes or more, for example, 3 minutes or more, for example, 4 minutes or more, for example, 5 minutes or more, for example, 10 minutes or more, for example, 15 minutes or more, for example, 30 minutes or more, for example, 45 minutes or more, for example, 60 minutes or more, for example, 2 hours or more, for example, 3 hours or more, for example, 4 hours or more, for example, 8 hours or more, for example, 12 hours or more, and can include 16 hours or more.

[0139] In some embodiments, the slurry suspension composition further contacts the solvent composition. In these embodiments, the solvent composition can include one or more of ammonia, t-butanol, n-propanol, ethanol, methanol, acetic acid, water, tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate, ethyl acetate, 1,2-dichloroethane (DCE), dimethylformamide (DMF), acetone, dimethylacetamide, dimethyl sulfoxide (DMSO), acetonitrile, toluene, 2-methylbutan-2-ol (tAmOH), and N-methyl-2-pyrrolidone (NMP), or combinations thereof. In one embodiment, the slurried suspension composition contacts a solvent mixture that includes tetrahydrofuran, water, ethanol, and ethyl acetate. In some cases, the slurried suspension composition contacts a solvent mixture that includes tetrahydrofuran / water at 9 / 1 v / v:ethanol:ethyl acetate (2 / 1 / 2 v / v / v).

[0140] (With the solvent composition added) the suspension contacts a second aliquot of the clear solution and the solvent composition and is slurried. The second aliquot can be 10 wt% or more of the clear solution, such as 20 wt% or more, such as 30 wt% or more, such as 40 wt% or more, such as 50 wt% or more, such as 60 wt% or more, such as 70 wt% or more, such as 75 wt% or more, such as 80 wt% or more, such as 85 wt% or more, and can include 90 wt% or more. In some cases, the aliquot is in the range of 10 wt% to 90 wt% of the clear solution, such as 11 wt% to 89 wt% of the clear solution, such as 12 wt% to 88 wt% of the clear solution, such as 13 wt% to 87 wt% of the clear solution, such as 14 wt% to 86 wt% of the clear solution, such as 15 wt% to 85 wt% of the clear solution, such as 16 wt% to 84 wt% of the clear solution, such as 17 wt% to 83 wt% of the clear solution, such as 18 wt% to 82 wt% of the clear solution, such as 19 wt% to 81 wt% of the clear solution, and includes 20 wt% to 80 wt%. In one embodiment, the second aliquot is about 90 wt% of the clear solution.

[0141] The solvent of interest can include, but is not limited to, ammonia, t-butanol, n-propanol, ethanol, methanol, acetic acid, water, tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate, ethyl acetate, 1,2-dichloroethane (DCE), dimethylformamide (DMF), acetone, dimethylacetamide, dimethyl sulfoxide (DMSO), acetonitrile, toluene, 2-methylbutan-2-ol (tAmOH), and N-methyl-2-pyrrolidone (NMP), as well as combinations thereof. In some embodiments, the solvent is a mixture of two or more solvents, for example, a mixture of three or more solvents, for example, a mixture of four or more solvents, for example, a mixture of five or more solvents, including mixtures of six or more solvents. For example, a suspension having a second aliquot of a clear solution can be contacted with a mixture of ethanol and ethyl acetate.

[0142] In some cases, the method includes contacting a second aliquot of the suspension and the clear solution with a first solvent, slurrying for a first predetermined period, and then contacting with a second solvent and slurrying for a second predetermined period. In these embodiments, the second solvent can be ammonia, t-butanol, n-propanol, ethanol, methanol, acetic acid, water, tetrahydrofuran, methyltetrahydrofuran, dichloromethane, isopropyl acetate, ethyl acetate, 1,2-dichloroethane (DCE), dimethylformamide (DMF), acetone, dimethylacetamide, dimethyl sulfoxide (DMSO), acetonitrile, toluene, 2-methylbutan-2-ol (tAmOH), and N-methyl-2-pyrrolidone (NMP), or combinations thereof. For example, the second solvent can be ethyl acetate. For example, the method can include contacting a second aliquot of the suspension and the clear solution with a solvent mixture of ethanol / ethyl acetate, slurrying for a first predetermined period, and then contacting with ethyl acetate and slurrying for a second predetermined period. In these embodiments, the first predetermined period and the second predetermined period can independently be 1 minute or more, for example, 2 minutes or more, for example, 3 minutes or more, for example, 4 minutes or more, for example, 5 minutes or more, for example, 10 minutes or more, for example, 15 minutes or more, for example, 30 minutes or more, for example, 45 minutes or more, for example, 60 minutes or more, for example, 2 hours or more, for example, 3 hours or more, for example, 4 hours or more, for example, 8 hours or more, for example, 12 hours or more, and can include 16 hours or more.

[0143] In an embodiment, the crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid is isolated by filtration (e.g., vacuum filtration), or the solvent can be removed by heating or rotary evaporation. In certain embodiments, the crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid is isolated by filtration and subsequently subjected to drying at room temperature under a nitrogen atmosphere or under vacuum.

[0144] The components used in each step of the methods of the present subject matter can be, if desired, purified compositions or crude compositions. The term "purified" is used in its conventional sense of the term "purified" to refer to a composition in which at least some isolation or purification process, such as filtration of a reaction mixture or aqueous workup, etc., has been performed. In some cases, purification includes liquid chromatography, recrystallization, distillation (e.g., azeotropic distillation), or other types of compound purification. In some embodiments, the mixture is used as a crude mixture in subsequent steps in the methods described herein, in which no purification or other workup of the reaction mixture has been performed. In some cases, the crude composition reaction mixture contains the compound of interest in sufficient purity, e.g., the crude composition contains the compound of interest at a purity of 90% or more, such as 95% or more, such as 97% or more and including 99% or more, as determined by high performance liquid chromatography (HPLC), proton nuclear magnetic resonance spectroscopy ( 1 1H NMR), or a combination thereof.

[0145] Aspects of the present disclosure include a composition comprising one or more of the crystalline solid meglumine salts of the above (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid, and a pharmaceutically acceptable excipient. A wide variety of pharmaceutically acceptable excipients are known in the art and need not be considered in detail herein. Pharmaceutically acceptable excipients are described in detail in a variety of publications, for example, A. Gennaro (2000) “Remington: The Science and Practice of Pharmacy”, 20th edition, Lippincott, Williams, & Wilkins, Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H. C. Ansel et al., eds 7th ed., Lippincott, Williams, & Wilkins, and Handbook of Pharmaceutical Excipients (2000) A. H. Kibbe et al., eds., 3rd ed. Amer. Pharmaceutical Assoc.For example, the one or more excipients may include sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, or calcium carbonate, binders (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, poly(ethylene glycol), sucrose, or starch), disintegrants (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, sodium hydrogen carbonate, calcium phosphate, or calcium citrate), lubricants (e.g., magnesium stearate, light anhydrous silicic acid, talc, or sodium lauryl sulfate), flavoring agents (e.g., citric acid, menthol, glycine, or orange powder), preservatives (e.g., sodium benzoate, sodium bisulfite, methyl paraben, or propyl paraben), stabilizers (e.g., citric acid, sodium citrate, or acetic acid), suspending agents (e.g., methylcellulose, polyvinylpyrrolidone, or aluminum stearate), dispersing agents (e.g., hydroxypropylmethylcellulose), diluents (e.g., water), and base waxes (e.g., cocoa butter, white petrolatum, or polyethylene glycol).

[0146] (R)-5-(4-Chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid crystalline solid meglumine salt can be formulated into a composition suitable for delivery to a subject by combination with a suitable pharmaceutically acceptable carrier or diluent, and can be formulated into preparations in solid, semi-solid, liquid, or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, and aerosols.

[0147] In some cases, the composition of interest is formulated for injection by subcutaneous injection, intramuscular injection, intravitreal injection, intracisternal injection, or intrathecal injection, among others. In other cases, the composition is formulated for oral administration to the subject. In still other cases, the composition is formulated for intraocular administration to the subject. In yet other cases, the composition is formulated for topical or transdermal administration to the subject.

[0148] In some embodiments, the composition of interest comprises an aqueous buffer. Suitable aqueous buffers include, but are not limited to, acetate buffer, succinate buffer, citrate buffer, and phosphate buffer, the strength of which varies from about 5 mM to about 100 mM. In some embodiments, the aqueous buffer comprises a reagent that provides an isotonic solution. Such reagents include, but are not limited to, sodium chloride, as well as sugars such as mannitol, dextrose, and sucrose. In some embodiments, the aqueous buffer further comprises a nonionic surfactant such as polysorbate 20 or 80. In some cases, the composition of interest further comprises a preservative. Suitable preservatives include, but are not limited to, benzyl alcohol, phenol, chlorobutanol, and benzalkonium chloride. In many cases, the composition is stored at about 4°C. The formulation can also be lyophilized, in which case the formulation generally comprises a cryoprotectant such as sucrose, trehalose, lactose, maltose, and mannitol. The lyophilized formulation can be stored for extended periods even at ambient temperature.

[0149] In some embodiments, the composition comprises other additives such as lactose, mannitol, corn starch, or potato starch, together with a binder such as crystalline cellulose, cellulose derivative, acacia, corn starch, or gelatin, a disintegrant such as corn starch, potato starch, or sodium carboxymethyl cellulose, and a lubricant such as talc or magnesium stearate, and, if desired, a diluent, a buffering agent, a wetting agent, a preservative, and a flavoring agent.

[0150] When the composition is formulated for injection, the crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid can be formulated by dissolving, suspending, or emulsifying the crystalline solid meglumine salt in an aqueous or non-aqueous solvent such as vegetable oil or other similar oils, synthetic fatty acid glycerides, esters of higher fatty acids, or propylene glycol, together with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers, and preservatives, if desired.

[0151] The dosage used in the treatment of a subject varies depending on the clinical goal to be achieved. However, a suitable dosage range for the compounds of the present subject matter is from a maximum of about 0.0001 mg to about 5000 mg, for example, a dosage range that provides from about 1 mg to about 25 mg, about 25 mg to about 50 mg, about 50 mg to about 100 mg, about 100 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 500 mg, about 500 mg to about 1000 mg, or about 1000 mg to about 5000 mg of the active agent, which can be administered in a single dose. It will be readily understood by those skilled in the art that the dosage levels can vary as a function of the particular compound, the severity of the symptoms, and the subject's susceptibility to side effects.

[0152] In some embodiments, suitable dosages of the crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid are in the range of about 1 mg / kg body weight to about 500 mg / kg body weight, for example, about 5 mg / kg body weight to about 500 mg / kg body weight, about 10 mg / kg body weight to about 500 mg / kg body weight, about 20 mg / kg body weight to about 500 mg / kg body weight, about 30 mg / kg body weight to about 500 mg / kg body weight, about 40 mg / kg body weight to about 500 mg / kg body weight, about 50 mg / kg body weight to about 500 mg / kg body weight, about 60 mg / kg body weight to about 500 mg / kg body weight, about 70 mg / kg body weight to about 500 mg / kg body weight, about 80 mg / kg body weight to about 500 mg / kg body weight, about 90 mg / kg body weight to about 500 mg / kg body weight, about 100 mg / kg body weight to about 500 mg / kg body weight, about 200 mg / kg body weight to about 500 mg / kg body weight, about 300 mg / kg body weight to about 500 mg / kg body weight, or about 400 mg / kg body weight to about 500 mg / kg body weight.

[0153] In some embodiments, suitable dosages of the crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid are in the range of about 1 mg / kg body weight to about 5 mg / kg body weight, for example, about 5 mg / kg body weight to about 10 mg / kg body weight, about 10 mg / kg body weight to about 20 mg / kg body weight, about 20 mg / kg body weight to about 30 mg / kg body weight, about 30 mg / kg body weight to about 40 mg / kg body weight, about 40 mg / kg body weight to about 50 mg / kg body weight, about 50 mg / kg body weight to about 100 mg / kg body weight, or about 100 mg / kg body weight to about 500 mg / kg body weight.

[0154] In some embodiments, a single dose of the crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid is administered. In other embodiments, multiple doses are administered. When multiple doses are administered over a period of time, the compound is administered over a period of time, for example, twice a day (qid), daily (qd), every other day (qod), every three days, three times a week (tiw), or twice a week (biw). For example, the compounds of the present subject matter are administered qid, qd, qod, tiw, or biw over a period of from 1 day to about 2 years or more. For example, the compound is administered for 1 week, 2 weeks, 1 month, 2 months, 6 months, 1 year, or 2 years, or 2 years or more, at any of the above frequencies, depending on various factors.

[0155] The dosage units of the present disclosure can be prepared using manufacturing methods available in the art and can be dosage units in various forms suitable for parenteral administration (including in a large tank, intrathecal, intravenous, intramuscular, subcutaneous, and dermal), for example, dosage units as solutions, suspensions, solutions, lyophilized agents, or emulsions. The dosage units can contain conventional ingredients in a pharmaceutical preparation, for example, one or more carriers, binders, lubricants, excipients (for example, to impart controlled release characteristics), pH adjusters, colorants, or additional active agents.

[0156] Dosage units provided as liquid dosage units can have a total weight of from about 1 μg to about 1 g, can be from about 5 μg to 1.5 g, from about 50 μg to 1 g, from 100 μg to 1 g, 50 μg to 750 mg, and can be from about 1 μg to 2 g.

[0157] Dosage units can contain the components in any relative amounts. For example, a dosage unit can be about 0.1 wt% to 99 wt% of the active ingredient (i.e., the crystalline solid meglumine salt compound) per total weight of the dosage unit. In some embodiments, the dosage unit can be 10 wt% to 50 wt%, 20 wt% to 40 wt%, or about 30 wt% of the active ingredient per total weight dosage unit.

[0158] Dosage units can be provided in a variety of different forms and, optionally, in a manner suitable for storage. For example, a dosage unit can be disposed within a container suitable for containing a pharmaceutical composition. The container can be, for example, a bottle (e.g., one having a closure device such as a cap), a vial, an ampoule (for single dosage units), a dropper, a film, and a tube, etc.

[0159] The container can include a cap (e.g., a screw cap), the cap being removably connected to the container over an opening, and the dosage unit disposed within the container can be accessed through the opening.

[0160] The container can include a seal, the seal being able to function as a tamper-evident and / or tamper-resistant element, and the seal being broken when the dosage unit disposed within the container is accessed. Such a seal element can be, for example, a frangible element, and when the dosage unit disposed within the container is accessed, the frangible element is damaged or otherwise altered. Examples of such frangible seal elements include a seal, the seal being located over the container opening, whereby access to the dosage unit within the container requires breaking of the seal (e.g., by peeling off the seal and / or making a hole in the seal). Examples of frangible seal elements include a frangible ring, the frangible ring being disposed around the container opening and connected to the cap, whereby the ring is damaged when the cap is opened to access the dosage unit disposed within the container.

[0161] A liquid dosage unit can be placed within a container (e.g., a bottle or an ampoule) sized and configured to maintain the stability of the dosage unit over the period during which the dosage unit is dispensed and becomes a prescription drug. For example, the container can be sized and configured to hold 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, or more than 100 single liquid dosage units. The container can be sealed or resealable. The container can be packaged within a carton (e.g., for shipping from the manufacturer to a pharmacy or other dispensing facility). Such a carton can be in the form of a box, a tube, or other configuration and can be made from any material (e.g., cardboard and plastic, etc.). The packaging system and / or container disposed within the carton can have one or more affixed labels (e.g., to provide information such as lot number, dosage unit type, and manufacturer, etc.).

[0162] The container can include a moisture barrier and / or a light barrier, for example, to facilitate maintaining the stability of the active ingredient in the dosage unit contained within the container. The container can be adapted to hold a single dosage unit or multiple dosage units. The container can include a dispensing control mechanism such as a lockout mechanism to facilitate maintaining the dosing schedule.

[0163] Dosage units can be provided within the container in which the dosage unit is disposed and can be provided as part of a packaging system (optionally, together with instructions for use). For example, dosage units containing different amounts of the crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid can be provided in separate containers, and these containers can be disposed within a larger container (e.g., to facilitate protection of the dosage units for shipping). For example, one or more dosage units described herein can be provided in separate containers, in which case dosage units of different compositions are provided in separate containers, and the separate containers are disposed within a package for dispensing.

[0164] The crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid described herein can be used for the prevention or treatment of various diseases such as age-related conditions. Such conditions typically (but not necessarily) are characterized by an excess of such cells (such as cells expressing p16 and other senescence markers) or an excess of such expression within or surrounding the site of the condition, compared to the frequency of senescent cells (such as cells expressing p16 and other senescence markers) in non-affected tissue or the level of expression of p16 and other senescence markers.

[0165] In certain embodiments, the crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid described herein can be used for the prevention or treatment of an ocular condition of interest, whereby the severity of at least one sign or symptom of the disease is reduced. Such conditions include both diseases of the posterior segment of the eye and diseases of the anterior segment of the eye. Ocular diseases that can be treated according to the present disclosure include presbyopia, macular degeneration (including exudative or dry AMD), macular edema, ischemic or vascular conditions such as diabetic retinopathy, glaucomatous retinopathy, ischemic arteritic optic neuropathy, and vascular diseases characterized by arterial and venous occlusion, retinopathy of prematurity and sickle cell retinopathy, glaucoma, degenerative conditions such as dermatochalasis, ptosis, dry keratitis, Fuchs corneal dystrophy, presbyopia, cataract, exudative age-related macular degeneration (exudative AMD), dry age-related macular degeneration (dry AMD); vitreomacular traction (VMT) syndrome, macular hole, epiretinal membrane (ERM), retinal tear, retinal detachment, and degenerative vitreous disorders including proliferative vitreoretinopathy (PVR), genetic conditions such as retinitis pigmentosa, Stargardt disease, Best disease, and Leber hereditary optic neuropathy (LHON), conditions caused by bacterial, fungal, or viral infections such as conditions caused or induced by pathogens such as herpes zoster varicella (HZV), herpes simplex, cytomegalovirus (CMV), and human immunodeficiency virus (HIV), inflammatory conditions such as punctate inner choroiditis (PIC), multifocal choroiditis (MIC), and serpiginous choroidopathy, and iatrogenic conditions such as post-vitrectomy cataract and radiation retinopathy.

[0166] In other embodiments, the crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid described herein can be developed for treating osteoarthritis. Degenerative joint diseases of osteoarthritis are characterized by fibrosis of cartilage, osteosclerosis, and hypertrophy of the synovium and joint capsule at sites of high mechanical stress. Fibrosis is a local surface tissue disruption accompanied by splitting of the surface layer of cartilage. The early splitting is tangential to the cartilage surface and subsequently tangential to the axis of the dominant collagen fiber bundles. The collagen in the cartilage breaks down and proteoglycans are lost from the cartilage surface. In the absence of the protective and lubricating effects of proteoglycans in the joint, the collagen fibers are more prone to degradation and mechanical failure occurs. Predisposing risk factors for developing osteoarthritis include aging, obesity, previous joint injury, overuse of joints, weak thigh muscles, and genetics. Symptoms of osteoarthritis include painful or stiff joints after inactivity or overuse, particularly in the hips, knees, and lower back, stiffness after rest that resolves after movement, and pain that worsens after activity or towards the end of the day.

[0167] In still other embodiments, the crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid described herein can be used to reduce or inhibit the loss or erosion of the proteoglycan layer in joints, and to reduce inflammation in affected joints, and to promote, induce, enhance, or induce the production of collagen, such as type II collagen. The compound can cause a reduction in the amount or level of inflammatory cytokines, such as IL-6, produced in joints, and the inflammation is reduced. The compound can be used to treat osteoarthritis and / or to induce the production of collagen, such as type II collagen, in the joints of a subject. The compound can also be used to decrease, inhibit, or reduce the production of matrix metalloproteinase 13 (MMP-13), which degrades collagen in joints, and to restore the proteoglycan layer, or to inhibit the loss and / or degradation of the proteoglycan layer. Treatment with the compound can also reduce the likelihood of bone erosion, inhibit bone erosion, or decrease or slow down bone erosion. The compound can be administered directly to the joints affected by osteoarthritis, for example, by intra-articular, topical, transdermal, intradermal, or subcutaneous administration. The compound can also restore, improve, or inhibit the deterioration of joint strength and reduce joint pain.

[0168] In yet other embodiments, the crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid described herein is used to prevent or treat a target lung disease. Lung disease conditions that can be treated in accordance with the present disclosure include idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, bronchiectasis, and emphysema.

[0169] In certain embodiments, the crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid described herein can be used to treat aging-related conditions such as those described in International Patent Application No. WO2019 / 213160, which is incorporated herein by reference.

Examples

[0170] The following examples are presented to provide a complete disclosure and description of the methods of making and using the present invention to those skilled in the art, and are not intended to limit the scope of what the inventors regard as their invention, nor are they intended to represent that the following experiments are all or the only experiments performed. Although efforts have been made to ensure accuracy with respect to the numerical values used (e.g., amounts, temperatures, etc.), some experimental error and deviation should be considered. Unless otherwise indicated, parts are by weight, molecular weight is weight-average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric pressure. "Average" means arithmetic mean. Standard abbreviations such as bp, base pair; kb, kilobase; pl, picoliter; s or sec, second; min, minute; h or hr, hour; aa, amino acid; kb, kilobase; bp, base pair; nt, nucleotide; i.m., intramuscularly; i.p., intraperitoneally; and s.c., subcutaneously, etc. may be used.

[0171] Example 1 - Salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid Different salts were prepared from the free acid of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid. The free acid compound was purified and the free acid compound was amorphous. Formation of the salt compounds was tested in eight different bases (KOH, NaOH, meglumine, L-arginine, ammonia, nicotinamide, L-lysine, and calcium acetate). Salts with low crystallinity or amorphous were obtained in L-arginine, ammonia, nicotinamide, L-lysine, and calcium acetate. The sodium and potassium salts of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid were unstable. The meglumine salt showed high crystallinity and high solubility in water.

[0172] Materials and Methods An appropriate amount of eight bases was dissolved and diluted to 10 mL with different solvent combinations (e.g., MeOH or MeOH / H₂O) to prepare a 0.1 M solution. (R)-5-(4-Chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid was dissolved in MeOH or THF / H₂O to prepare a 20 or 30 mg / mL solution. The compound solution was dispensed into a 96-well plate. Each well contained 100 μL of the free acid solution and 26 μL or 72 μL of each base solution. After evaporation to dryness, 200 μL of solvent was added. The wells were covered with parafilm having one pinhole and evaporated under ambient conditions. One sample of each line was characterized by ¹H NMR to confirm salt formation. The obtained solid samples were characterized by XRPD to reveal whether the solid samples were crystalline. The bases and solvents used are shown in Tables 1 and 2 below.

[0173] (Table 1) Base TIFF0007688141000019.tif27141

[0174] (Table 2) Solvent TIFF0007688141000020.tif46141

[0175] Analysis method X-ray powder diffraction (XRPD ) - The solid samples were examined using a D8 ADVANCE X-ray diffractometer (Bruker). The X-ray diffractometer was equipped with a LynxEye detector. In XRPD analysis, the samples were scanned from 3 to 40° 2θ in steps of 0.02° 2θ. The tube voltage and current were 40 kV and 40 mA, respectively.

[0176] Polarizing microscope (PLM) - PLM analysis was performed using a polarized light microscope ECLIPSE LV100POL (Nikon, JPN).

[0177] Thermogravimetric analysis (TGA) - TGA was carried out using a Discovery TGA 55 (TA Instruments, US). The sample was placed in an open tar aluminum pan, automatically weighed, and inserted into the TGA furnace. The sample was heated to the final temperature at 10 °C / min.

[0178] Differential scanning calorimetry (DSC) - DSC analysis was performed using a Discovery DSC 250 (TA Instruments, US). The weighed sample was placed in a DSC pinhole pan, and the weight was accurately recorded. The sample was heated to the final temperature at 10 °C / min.

[0179] Dynamic vapor sorption (DVS) - DVS was determined using an IGA Sorp (Hiden Isochema, UK). The sample was tested in step mode at a target RH of 0 - 90% full cycle. The analysis was performed in 10% RH increments.

[0180] Results In a 96-well plate, 1 equivalent or 3 equivalents of 0.1 M base were added into the wells together with the free acid solution respectively. After drying, some solid samples appeared in the 96-well plate. One sample in each column of the 96-well plate was analyzed by 1H-NMR, and the solid samples were characterized by PLM and XRPD.

[0181] Chemical shifts were observed by NMR for all samples, indicating successful salt formation. For samples with 1 equivalent of base, no crystallinity was observed. Samples of sodium and calcium salts with 3 equivalents of base are crystalline with low crystallinity. The calcium salt shows diffraction peaks similar to calcium acetate in the XRPD pattern, suggesting that the calcium salt might not have been prepared. All the remaining samples are amorphous.

[0182] Preparation of salts Preparation of potassium salt - The potassium salt was prepared with either 1 equivalent or 3 equivalents of KOH. A summary of the results is shown in Table 3 below. The XRPD results indicate that Form 1 and Form 2 were prepared in THF / W / EtOH and MeOH / W / IPA, respectively. After slurrying in acetone or heptane, the sample became amorphous. Form 1 shows a weight loss of approximately 4.7% before 190 °C by TGA. Two endothermic peaks at 138.43 °C and 217.52 °C were observed by DSC, suggesting that Form 1 might be a solvate. Only a small amount of Form 2 was obtained and it was not further characterized. The free acid was not stable in the presence of strong base.

[0183] (Table 3) Preparation of potassium salt TIFF0007688141000021.tif55146

[0184] Preparation of arginine salt - The arginine salt was prepared with either 1 equivalent or 3 equivalents of L-arginine. A summary of the results is shown in Table 4 below. The arginine salt could not be prepared.

[0185] (Table 4) Preparation of arginine salt TIFF0007688141000022.tif35146

[0186] Preparation of sodium salt - The sodium salt was prepared with either 1 equivalent or 3 equivalents of NaOH. A summary of the results is shown in Table 5 below. A crystalline solid was prepared from THF / W / EtOH and designated as Form 1. The monosodium salt was first prepared with a purity of over 99.0% by process chemistry. The salt and the free acid were not stable in the presence of strong base.

[0187] (Table 5) Preparation of sodium salt TIFF0007688141000023.tif35146

[0188] Preparation of meglumine salt - The meglumine salt was prepared with either 1 equivalent or 3 equivalents of meglumine. The summary of the results is shown in Table 6 below. The XRPD results indicated that the form prepared in MeOH / THF / W / EtOH / EA was reproducible and was designated as Form 1. Form 1 showed a weight loss of approximately 0.9% before 130 °C by TGA. Two endothermic peaks at 84.1 and 147.4 °C were observed by DSC, suggesting that Form 1 might be an anhydrate with a small amount of solvent residue. The DVS analysis of Form 1 showed water adsorption of 16.1% at 0% - 80% RH (23% at 90% RH).

[0189] (Table 6) Preparation of meglumine salt TIFF0007688141000024.tif61146

[0190] Preparation of calcium salt - The calcium salt was prepared with either 1 equivalent or 3 equivalents of calcium acetate. The summary of the results is shown in Table 7 below. A crystalline solid was obtained. XRPD showed that the characteristic diffraction peaks of the calcium salt were similar to those of calcium acetate, suggesting that the calcium salt might not have been prepared by the reaction.

[0191] (Table 7) Preparation of calcium salt TIFF0007688141000025.tif41146

[0192] Preparation of ammonium salt - The ammonium salt was prepared with either 1 equivalent or 3 equivalents of ammonium. The summary of the results is shown in Table 8 below. A solid of the ammonium salt was not obtained.

[0193] (Table 8) Preparation of ammonium salt TIFF0007688141000026.tif22146

[0194] Preparation of nicotinamide salt - The nicotinamide salt was prepared with either 1 equivalent or 3 equivalents of nicotinamide. The summary of the results is shown in Table 9 below. No solid of the nicotinamide salt was obtained.

[0195] (Table 9) Preparation of nicotinamide salt TIFF0007688141000027.tif22146

[0196] Preparation of lysine salt - The lysine salt was prepared with either 1 equivalent or 3 equivalents of lysine. The summary of the results is shown in Table 10 below. No solid of the lysine salt was obtained.

[0197] (Table 10) Preparation of lysine salt TIFF0007688141000028.tif28145

[0198] Conclusion The salt was prepared from the free acid of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid with 8 bases including KOH, NaOH, L-arginine, meglumine, calcium acetate, ammonium, nicotinamide, and L-lysine. Three crystalline salts (potassium salt, sodium salt, and meglumine salt) were obtained with the sodium salt and meglumine salt showing good crystallinity. However, the free acid was not stable in the presence of KOH or NaOH. The meglumine salt was chemically stable under the experimental conditions and showed good crystallinity and high solubility in water (about 26 mg / mL).

[0199] Example 2 - Polymorphs of crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid (R)-5-(4-Chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid crystalline solid meglumine salt polymorphs were prepared. Six different forms were shown to be crystalline and characterized by XRPD, TGA, DSC, DVS, and HPLC. An overview of the properties of the six isolated forms is listed in Table 11.

[0200] (Table 11) Polymorph TIFF0007688141000029.tif111151

[0201] Materials and Methods Solvent for screening - Solvents for preparing polymorphs and screening polymorph properties are listed in Table 12.

[0202] (Table 12) Solvent for screening TIFF0007688141000030.tif46141

[0203] Estimation of solubility - A preliminary solubility investigation of each meglumine salt compound was carried out visually. The solvents tested are listed in Table 13.

[0204] (Table 13) Solvent for estimating solubility TIFF0007688141000031.tif107139

[0205] Reactive crystallization - Meglumine salts were prepared using different ratios of free acid and meglumine. Attempts were made to obtain crystalline materials using different solvents.

[0206] Crystallization by slurry - An appropriate amount of the sample was added into the solvent to prepare a suspension. The suspension was continuously stirred or shaken at room temperature or a higher temperature. The solid sample was collected at intervals for XRPD analysis.

[0207] Cooling crystallization - An appropriate amount of the sample was added into the solvent to prepare a suspension, and the suspension was continuously stirred at room temperature or a higher temperature. The solid sample was collected at intervals for XRPD analysis.

[0208] Competitive slurry - A mixture of two or more crystal forms was suspended in a specific solvent at a constant temperature. If the solubility was high in the solvent or the amount of one form was very small, the solvent was first saturated with the other crystal form to ensure that the crystal form did not completely dissolve before saturation. Samples were taken from the suspension at certain time intervals to confirm polymorphic transformation.

[0209] Solid stability test - An appropriate amount of meglumine salt was placed at 60 °C and 40 °C / 75% RH for up to 1 week, and samples were taken at 0, 3, and 7 days. The samples were dissolved in the diluent to prepare a solution at 0.5 mg / mL for HPLC analysis. The solid samples were analyzed by XRPD to confirm the crystal form.

[0210] Analysis method X-ray powder diffraction (XRPD) - The solid sample was examined using a D8 ADVANCE X-ray diffractometer (Bruker). The X-ray diffractometer was equipped with a LynxEye detector. In the XRPD analysis, the sample was scanned from 3 to 40° 2θ at a step of 0.02° 2θ. The tube voltage and current were 40 KV and 40 mA, respectively.

[0211] Polarizing microscope (PLM) - PLM analysis was performed using a polarized light microscope ECLIPSE LV100POL (Nikon, JPN).

[0212] Thermogravimetric analysis (TGA) - TGA was performed using a Discovery TGA 55 (TA Instruments, US). The sample was placed in an open tar aluminum pan, automatically weighed, and inserted into the TGA furnace. The sample was heated to the final temperature at 10 °C / min.

[0213] Differential scanning calorimetry (DSC) - DSC analysis was carried out using a Discovery DSC 250 (TA Instruments, US). The weighed sample was placed in a DSC pinhole pan, and the weight was accurately recorded. The sample was heated to the final temperature at 10 °C / min.

[0214] Dynamic vapor sorption (DVS) - DVS was determined using an IGA Sorp (Hiden Isochema, UK). The sample was tested in step mode at a target RH of 0 - 90% full cycle. The analysis was performed in 10% RH increments.

[0215] HPLC - High performance liquid chromatography was performed as outlined in Table 14.

[0216] (Table 14) HPLC TIFF0007688141000032.tif62146

[0217] Results Summary of the prepared crystal forms - Seven forms were identified and defined as Forms I, II, III, IVA, IV, V, and VI. The XRPD patterns of all the discovered forms are presented in Figure 1, and the preparation methods are shown in Table 15. Form I was prepared with a low-purity free acid (95.8%) and repeated with a more pure material (99.1%). Among the crystalline solid meglumine salts prepared of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid, Forms II, III, IVA, V, and VI were identified as either hydrates or solvates. Form IV was identified as an anhydrate.

[0218] (Table 15) Summary of the prepared crystal forms TIFF0007688141000033.tif54151

[0219] Characterization of Form I - Form I shows irregular crystals with good crystallinity by PLM (Figure 2A) and XRPD (Figure 4). The TGA in Figure 2B shows a weight loss of about 0.9% from RT to 130 °C. Two endothermic peaks were observed by DSC at 84 °C and 147 °C, which may be due to solvent evaporation and melting, respectively. DVS analysis (Figure 3) shows that Form I absorbed about 15.3% (23% from 0 to 90% RH) of moisture from 0% to 80% RH, and thus Form I is very hygroscopic. As depicted by XRPD shown in Figure 4, the crystallinity decreased after the DVS test. The 2θ peaks of the XRPD of Form I are listed in Table 16.

[0220] (Table 16) 2θ peaks of XRPD of Form I TIFF0007688141000034.tif184141

[0221] Characterization of Form II- Form II exhibits an irregular morphology with low crystallinity by PLM (Figure 5A) and XRPD (Figure 6). The TGA in Figure 5B shows a 2% weight loss from RT to 130 °C. An endothermic peak at 136 °C was observed by DSC, which may be due to the melting of Form II. The ratio of free acid to meglumine was calculated as 1 to 2.7 according to 1H-NMR. The 2θ peaks of the XRPD of Form II are listed in Table 17.

[0222] (Table 17) 2θ peaks of XRPD of Form II TIFF0007688141000035.tif103146

[0223] Characterization of Form III - Form III shows irregular crystals with low crystallinity (Figure 7A). The TGA in Figure 7B shows a 0.9% weight loss from RT to 130 °C. The DSC profile shows a small endothermic event at 113 °C, followed by a large endothermic peak at 142 °C. Form IV (described below) was obtained by heating Form III to 130 °C. The chemical shift of meglumine CH 3 was observed in the 1H-NMR spectrum, which indicates salt formation. The ratio of free acid to meglumine was calculated as 1 to 2.7. DVS (Figure 8) shows that Form III absorbs about 9.4% (about 22% from 0 to 90% RH) of moisture at 0% - 80% RH. Form III is hygroscopic. According to the XRPD depicted in Figure 9, the crystallinity decreased after DVS. The 2θ peaks of the XRPD of Form III are listed in Table 18.

[0224] (Table 18) 2θ peaks of XRPD of Form III TIFF0007688141000036.tif156145

[0225] Characterization of Form IV- Form IV shows irregular crystals with high crystallinity by PLM (Figure 10A) and XRPD (Figure 12). The TGA in Figure 10B did not show significant weight loss before 130 °C. The DSC profile shows an endothermic peak at 143.3 °C, which is due to the melting of Form IV. Meglumine CH 3 The significant chemical shift of 3

[0226] (Table 19) 2θ peaks of XRPD of Form IV TIFF0007688141000037.tif103146

[0227] Characterization of Form IVA - The 2θ peaks of the XRPD of Form IVA are listed in Table 20.

[0228] (Table 20) 2θ peaks of XRPD of Form IVA TIFF0007688141000038.tif164146

[0229] Characterization of Form V - Form V shows irregular crystals with high crystallinity by PLM (Figure 13A) and XRPD (Figure 15). The TGA in Figure 13B shows a 1.2% weight loss from RT to 130 °C. The DSC results show two endothermic peaks at 115 °C and 143 °C. For Form V, residual solvent was not detected by NMR, and Form IV was obtained by heating Form V up to 130 °C. Meglumine CHshows a chemical shift in 1H-NMR, which indicates salt formation. The ratio of free acid to meglumine was calculated as 1:3. DVS (Figure 14) shows that Form V absorbed about 6.8% (about 14.5% at 0 - 90% RH) of moisture at 0% - 80% RH. Form V is hygroscopic. The crystal form remained unchanged, and as shown by the XRPD depicted in Figure 15, the crystallinity increased slightly after DVS. The 2θ peaks of the XRPD of Form V are listed in Table 21.

[0230] (Table 21) 2θ peaks of XRPD of Form V TIFF0007688141000039.tif136146

[0231] Characterization of Form VI - Form VI shows irregular crystals with low crystallinity by PLM (Figure 16A) and XRPD (Figure 18). TGA in Figure 16B shows a 1% weight loss before 130 °C. The DSC profile shows two endothermic peaks at 110 and 142 °C. Form VI was converted to Form IV after being heated to 130 °C. Meglumine CH 3 shows a chemical shift indicating salt formation. A ratio of free acid to meglumine of 1:2.7 was calculated according to NMR. DVS in Figure 17 shows that Form VI absorbed about 8.2% (about 18.2% at 0 - 90% RH) of moisture at 0% - 80% RH. Form VI is hygroscopic. According to the XRPD depicted in Figure 18, the crystallinity decreased after DVS. The 2θ peaks of the XRPD of Form VI are listed in Table 22.

[0232] (Table 22) 2θ peaks of XRPD of Form VI TIFF0007688141000040.tif137146

[0233] Solid state stability- Solid state stability investigations of Forms II, III, IV, V, and VI were conducted at 60 °C for up to 7 days. Samples were analyzed at day 0 and day 7 by XRPD (Figure 19) and HPLC (Table 23). Form IV showed the highest purity among all forms and was found to be the most stable form at 60 °C for 7 days. The other forms showed minor degradation after storage at 60 °C for 1 week. For Forms II, III, and VI, the amorphous form was obtained after 1 week of storage at 60 °C. The crystalline forms of Forms IV and V remained unchanged.

[0234] (Table 23) Stability tests measured by HPLC TIFF0007688141000041.tif47142

[0235] The stability over 12 months of the crystalline solid meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid was tested as compared with the sodium salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid. As shown in Figure 20, the meglumine salt compound shows little or no change in purity over the entire 12-month test period. On the other hand, the sodium salt shows a sharp decrease in purity, dropping to less than 95% purity within 3 months. Also, the 12-month stability of the meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamide)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid in Form IV was investigated by HPLC (HPLC conditions in the summary of Table 24). As shown in Table 25, the meglumine salt in Form IV shows little change over the entire 12 months.

[0236] (Table 24) HPLC conditions for 12-month stability tests TIFF0007688141000042.tif60141

[0237] (Table 25) HPLC results for 12-month stability tests TIFF0007688141000043.tif76146

[0238] Also, the solid state stability of Form IV at 40 °C / 75% RH was investigated. The samples were analyzed by XRPD after 3 days. The XRPD results in Figure 21 show that Form IV can be converted from Form V. For Forms III, V, and VI, heat treatment investigations were carried out. The samples were heated to 130 °C at a ramp rate of 5 °C / min and then analyzed by XRPD (Figure 22). Forms III, V, and VI were converted to Form IV upon heating.

[0239] The above invention has been described in some detail by way of illustration and example for the purpose of clarity of understanding. However, it will be readily apparent to those skilled in the art that, in light of the teachings of the present invention, certain changes and modifications can be made without departing from the spirit or scope of the appended claims.

[0240] Therefore, the above is merely an explanation of the principles of the present invention. It will be understood by those skilled in the art that, although not explicitly described or shown herein, they can embody the principles of the present invention and devise various changes within the spirit and scope of the present invention. Further, all examples and conditional terms listed herein are mainly intended to assist the reader in understanding the principles of the present invention and the concepts provided by the inventors for further advancement of the art, and should not be construed as being limited to such specifically listed examples and conditions. Furthermore, all descriptions in this specification, including the enumeration of the principles, aspects, and embodiments of the present invention, as well as its specific examples, are intended to encompass both their structural and functional equivalents. Moreover, such equivalents are intended to include both currently known equivalents and equivalents developed in the future, regardless of structure, i.e., any element developed to perform the same function. Additionally, nothing disclosed in this specification is intended to be dedicated to the public whether or not such disclosure is explicitly recited in the claims.

[0241] Accordingly, the scope of the present invention is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of the present invention are embodied by the appended claims. In the claims, 35 U.S.C. § 112(f) or 35 U.S.C. § 112, ¶ 6 are expressly defined as invoking such a limitation in a claim only when a phrase that exactly matches “means for” or “step for” begins the limitation recited in the claim, and when such an exact match phrase is not used in a limitation in the claim, neither 35 U.S.C. § 112(f) nor 35 U.S.C. § 112, ¶ 6 apply.

Claims

1. Formula I: Crystals of the meglumine salt of the compound of.

2. The crystals according to claim 1, wherein meglumine is present in the crystals in a stoichiometric ratio of 1 to 3.

3. The crystals according to claim 1, which are stable for 12 months or more at a temperature of 2°C to 8°C.

4. Crystals of Form IV of the meglumine salt of the compound of Formula I: having an X-ray powder diffraction pattern containing six or more peaks at 4.2° 2θ, 4.6° 2θ, 7.9° 2θ, 9.1° 2θ, 10.4° 2θ, 13.3° 2θ, 14.5° 2θ, 15.8° 2θ, 16.8° 2θ, 17.3° 2θ, 19.5° 2θ, 19.6° 2θ, 20.2° 2θ, or 27.7° 2θ.

5. The crystals according to claim 4, wherein meglumine is present in the crystals in a stoichiometric ratio of 1 to 3.

6. The crystals according to claim 4, characterized by a single weight loss step at 130°C by thermogravimetric analysis (TGA).

7. The crystals according to claim 4, showing a first endotherm at 130°C and a second endotherm at 143.3°C by differential scanning calorimetry (DSC).

8. The crystals according to claim 4, which are stable for 12 months or more at a temperature of 2°C to 8°C.

9. A composition comprising the crystals according to claim 1 or 4, and a pharmaceutically acceptable excipient.

10. A method for preparing the crystals according to claim 1 or 4, comprising: generating a transparent solution containing the meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid; contacting an aliquot of the transparent solution with seeds of the meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid and a polar solvent to form a first suspension; Contacting the first suspension with a second aliquot of the transparent solution and a polar solvent to produce a slurry composition; Filtering crystals of the meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid from the slurry composition; The method comprising the above. **Claim 11** Contacting meglumine with (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid in a first solvent to produce a first solution comprising solubilized meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid; Contacting the first solution with a second solvent to produce a transparent solution; Contacting a first aliquot of the transparent solution with a third solvent and a seed of the meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid to produce a first suspension; Contacting the first suspension with a fourth solvent to produce a second suspension; contacting the second suspension with a fifth solvent to produce a third suspension; contacting a second aliquot of the clear solution and a sixth solvent with the third suspension to produce a slurry precursor composition; contacting the slurry precursor composition with a seventh solvent to produce a slurry composition; filtering crystals of the meglumine salt of (R)-5-(4-chlorophenyl)-1-isopropyl-2-methyl-4-(3-(4-(4-((4-((1-(phenylthio)-4-(4-((phosphonooxy)methyl)piperidin-1-yl)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonamido)phenyl)piperazin-1-yl)phenyl)-1H-pyrrole-3-carboxylic acid from the slurry composition; comprising; each of the second, third, fourth, fifth, sixth, and seventh solvents being a polar solvent; The method according to claim 10. **Claim 12** The method according to claim 10 or 11, wherein the polar solvent is selected from ethanol (EtOH), methanol (MeOH), water, tetrahydrofuran (THF), acetone, acetonitrile (ACN), ethyl acetate (EA), and any combination thereof.

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