Solid Forms, Salts, and Polymorphs of Antifibrotic Compounds

Abstract

This disclosure relates to crystalline and other solid forms and salts of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, and pharmaceutical compositions containing same. Use of such solid forms, salts, and pharmaceutical compositions for treating, preventing, or ameliorating diseases or conditions associated with fibrosis, inflammation, and / or proliferation is disclosed.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of Australian Provisional Application No. 2023900229, filed January 31, 2023, U.S. Patent Application No. 18 / 354,467, filed July 18, 2023, and U.S. Patent Application No. 18 / 537,184, filed December 12, 2023, the disclosures of each of which are incorporated herein by reference in their entirety.

[0002] The present disclosure relates to solid forms and salts of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (FT011), in amorphous and crystalline form, processes for their preparation, and pharmaceutical compositions thereof. The disclosure also relates to methods of using such solid forms and salts and pharmaceutical compositions thereof for treating, preventing, or ameliorating diseases or conditions associated with fibrosis, inflammation, and / or proliferation. [Background technology]

[0003] Fibrosis is the abnormal accumulation of collagen matrix after injury or inflammation, altering the structure and function of various tissues. Regardless of the location, the primary pathology of fibrosis involves excessive deposition of collagen matrix, replacing normal tissue at that site. Progressive fibrosis in the kidney, liver, lung, heart, bone or bone marrow, and skin is a major cause of death and suffering. Although the etiology and causative mechanisms of individual fibrotic disorders can be diverse (e.g., ischemic events, exposure to chemicals, radiation, or infectious agents) and are poorly understood, they all share the common feature of abnormal and excessive deposition of extracellular matrix in affected tissues (Wynn and Ramalingam, Nat. Med. 2012, 18:1028). Fibrosis contributes to 45 percent (45%) of all deaths worldwide in developed countries, resulting in a significant unmet clinical need.

[0004] Chronic heart failure (CHF) is a growing public health problem in developed countries. It is well recognized that the causes of CHF are multifactorial. The most common risk factors include coronary heart disease (especially previous myocardial infarction), long-term hypertension, diabetes, and idiopathic cardiomyopathy. However, the impending obesity and diabetes epidemic, combined with an aging population and improved survival rates from heart attacks, signals a significant increase in the number of people with HF due to diabetes and related disorders, and the subsequent future economic health burden (Najafi et al., Eur J Heart Fail 2009;11:472).

[0005] Individuals with diabetes are at increased risk for developing CHF. Even in the absence of other comorbidities such as atherosclerosis or hypertension, diabetes alone manifests as a primary myocardial disease called diabetic cardiomyopathy (DCM). Data from the Framingham Heart Study indicate that diabetes increases the risk of developing HF by 4-5 times. In its early stages, diabetic cardiomyopathy in humans is characterized by abnormal diastolic function, along with subtle changes in systolic function, such as reduced longitudinal fiber contractility. Pathologically, DCM is associated with microvascular disease and shares important similarities with diabetic nephropathy. Examination of left ventricular (LV) biopsies from diabetic patients demonstrates that, at the cellular level, DCM is associated with cardiomyocyte hypertrophy, necrosis, apoptosis, fibroblast proliferation, and, importantly, increased deposition of fibrillar collagen in the interstitial regions (fibrosis). Elevated levels of cardiac fibrosis in these patients correlate with cardiac dysfunction, including increased end-diastolic pressure (EDP), end-diastolic pressure-volume relationship (EDPVR), and end-diastolic volume (EDV), as well as reduced ejection fraction (EF). Thus, pathological fibrosis significantly impacts ventricular compliance and leads to impaired diastolic function due to increased myocardial stiffness.

[0006] The pathological fibrosis underlying cardiac remodeling in diabetes is likely mediated by locally active cytokines such as tumor necrosis factor-α (TNF-α), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and transforming growth factor-β (TGF-β).

[0007] Current treatments for CHF (including diabetic HF) include good glycemic control and treatment with beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor blockers, all of which have been shown to reduce overall mortality and improve clinical symptoms. However, despite such therapy, cardiac dysfunction continues to progress in the majority of patients.

[0008] The increasing prevalence of diabetes and the clear suggestion that pathological fibrosis underlies the decline in diastolic function in CHF in diabetes indicate that additional therapies are needed for the treatment of DCM. Current therapies do not directly target the proinflammatory and profibrotic processes occurring in the diabetic heart.

[0009] Chronic kidney disease (CKD) is a leading cause of morbidity, rehospitalization, and premature mortality, affecting 10–11% of the population in both Europe and the United States (Hallan et al., J Am Soc Nephrol. 2006, 17:2275). In a significant proportion of such patients, deterioration of renal function leads to the development of end-stage kidney disease (ESKD), requiring dialysis or transplantation to sustain life. Research conducted approximately 20 years ago emphasized the importance of blood pressure control and blockade of the renin-angiotensin system to attenuate the progression of CKD to end-stage disease. Unfortunately, although considerable progress has been made in understanding renal pathophysiology, there has been little progress in terms of new therapeutic approaches since then.

[0010] Persistent or repeated injury to the kidney, which has limited capacity for regeneration, leads to the deposition of excessive amounts of extracellular matrix in both the glomerulus and tubulointerstitium. These widespread pathological changes, recognized histologically as glomerular sclerosis and tubulointerstitial fibrosis, infiltrate surrounding structures, inevitably leading to capillary rarefaction, resulting in hypoxia, tubular atrophy, and inflammatory cell infiltration. These structural changes subsequently lead to a decline in glomerular filtration rate (GFR), which is often, but not always, accompanied by worsening proteinuria. This final common pathway, which occurs in most forms of chronic kidney disease, continues largely regardless of the primary etiology and develops in seemingly diverse disorders, including metabolic, immunological, and infectious causes.

[0011] Over the past decade, research has consistently demonstrated a key role for the pro-fibrotic growth factor transforming growth factor-β (TGF-β) in renal fibrosis and dysfunction. However, other locally active growth factors are also involved in the fibrogenic process, particularly platelet-derived growth factor (PDGF), a potent inducer of matrix synthesis and proliferation of fibrogenic mesenchymal cells, such as fibroblasts and mesangial cells. Consistent with these actions, increased expression of components of both the TGF-β and PDGF pathways has been demonstrated in kidney tissues from a variety of human and experimental kidney diseases. Consequently, each has become an important therapeutic target in efforts to develop new treatments for chronic kidney disease.

[0012] There continues to be a need for new therapies to ameliorate, treat, and / or prevent diseases or conditions associated with fibrosis, inflammation, and / or proliferation, such as diabetic cardiac fibrosis, chronic kidney disease, or cancer. [Prior art documents] [Non-patent literature]

[0013] [Non-Patent Document 1] Wynn and Ramalingam, Nat.Med.2012,18:1028 [Non-patent document 2] Najafi et al.,Eur J Heart Fail 2009;11:472 [Non-patent document 3] Hallan et al.,J Am Soc Nephrol.2006,17:2275 Summary of the Invention

[0014]

[0001] The present disclosure relates, in part, to solid forms and pharmaceutically acceptable salts of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, including crystalline forms thereof. In some embodiments, the pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid is selected from the group consisting of potassium, meglumine, ethanolamine, tris(hydroxymethyl)aminomethane, tert-butylamine, ammonium, and lysine salts of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. In some embodiments, the pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid is the ethanolamine salt or the tert-butylamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. In certain embodiments, the pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid is the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (also referred to herein as ethanolammonium (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoate).

[0015] The novel salts described herein of the antifibrotic, anti-inflammatory compound (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, such as the ethanolamine salt and tert-butylamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, are solids possessing excellent chemical and physical properties, such as high thermal stability and low hygroscopicity, and possess excellent pharmacokinetic properties, such as high bioavailability. They are therefore particularly valuable as therapeutic agents for the treatment, prevention, or amelioration of fibrotic, inflammatory, or proliferative diseases or conditions, and are particularly adapted for use in a variety of pharmaceutical dosage forms, including those designed for oral, topical, or parenteral administration.

[0016] The compound (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has the formula (I): [ka] It has the following structure.

[0017] Thus, in one aspect of the present disclosure, a compound of formula (I): [ka] wherein the crystalline form has a water sorption of less than 1.7% at 25° C. and 80% relative humidity as determined by dynamic vapor sorption.

[0018] In embodiments, the crystalline form has a weight loss of 0.07% to 8.94% when heated from 25° C. to 120° C. as determined by thermogravimetric analysis.

[0019] In embodiments, the crystalline form has a weight loss of 0.07% to 8.94%, or 0.07% to 0.94%, when heated from 25° C. to 120° C., as determined by thermogravimetric analysis.

[0020] In embodiments, the crystalline form has the following characteristics: - solubility of 2.5 mg / ml to more than 5.0 mg / ml in FaSSIF medium (pH 7.5) in 24 hours; - solubility of 3.4 mg / ml to more than 5.0 mg / ml in 24 hours in FeSSIF medium (pH 7.8); - a solubility of 0.07 mg / ml to 0.090 mg / ml in 24 hours in a medium having a pH of 6.8.

[0021] In embodiments, the crystalline form has a bioavailability of between 39F% and 82F%, between 50F% and 82F%, or between 64F% and 82F%.

[0022] In embodiments, the pharmaceutically acceptable salt is selected from the group consisting of meglumine salts, ethanolamine salts, tris(hydroxymethyl)aminomethane salts, and tert-butylamine salts.

[0023] In embodiments, a pharmaceutical composition comprises a crystalline form disclosed herein and a pharmaceutically acceptable carrier. In embodiments, the pharmaceutical composition is suitable for oral administration.

[0024] Also, the formula (I): [ka] A crystalline form of the ethanolamine salt of the compound of formula (I) is provided, wherein the crystalline form has a bioavailability that is at least about 1.5 times greater than the bioavailability of the free form of the compound of formula (I).

[0025] In embodiments, the crystalline form has a bioavailability that is at least about 1.8-fold, at least about 2.0-fold, or at least about 2.3-fold greater than the bioavailability of the free form of the compound of Formula (I).

[0026] In embodiments, the crystalline form has a bioavailability of about 82 F%.

[0027] In an embodiment, the crystalline form has a moisture sorption of 0.49% at 25° C. and 80% relative humidity as determined by dynamic vapor sorption.

[0028] In an embodiment, the crystalline form has an endothermic onset of 176° C. as measured by differential scanning calorimetry.

[0029] In an embodiment, the crystalline form has a melting point of 178° C. as measured by differential scanning calorimetry.

[0030] In an embodiment, the crystalline form has a weight loss of 0.10% when heated from 25° C. to 120° C. as determined by thermogravimetric analysis.

[0031] In embodiments, the crystalline form has the following characteristics: - solubility of more than 7.99 mg / ml in FaSSIF medium (pH 7.5) in 24 hours, - solubility of more than 8.02 mg / ml in 24 hours in FeSSIF medium (pH 7.8), - a solubility of 0.088 mg / ml in 24 hours in a medium of pH 6.8.

[0032] In embodiments, a pharmaceutical composition comprises a crystalline form disclosed herein and a pharmaceutically acceptable carrier. In embodiments, the pharmaceutical composition is for oral administration.

[0033] Also, the formula (I): [ka] wherein the crystalline form exhibits an X-ray powder diffraction pattern having at least one peak selected from 6.6±0.2, 11.7±0.2, 15.0±0.2, 15.9±0.2, 17.7±0.2, 18.7±0.2, 19.2±0.2, 23.7±0.2, and 26.6±0.2 degrees 2θ.

[0034] In embodiments, the crystalline form exhibits an X-ray powder diffraction pattern with at least two, at least three, at least four, or at least five peaks selected from 6.6±0.2, 11.7±0.2, 15.0±0.2, 15.9±0.2, 17.7±0.2, 18.7±0.2, 19.2±0.2, 23.7±0.2, and 26.6±0.2 degrees 2θ.

[0035] In embodiments, the crystalline form exhibits an X-ray powder diffraction pattern having at least one peak selected from 6.6±0.2, 11.7±0.2, 15.0±0.2, 15.9±0.2, 17.7±0.2, 18.7±0.2, and 19.2±0.2 degrees 2θ.

[0036] In embodiments, the crystalline form exhibits an X-ray powder diffraction pattern having at least one peak selected from 6.6±0.2, 15.0±0.2, 18.7±0.2, and 19.2±0.2 degrees 2θ.

[0037] In embodiments, the crystalline form exhibits an X-ray powder diffraction pattern having at least two peaks selected from 6.6±0.2, 15.0±0.2, 18.7±0.2, and 19.2±0.2 degrees 2θ.

[0038] In embodiments, the crystalline form exhibits an X-ray powder diffraction pattern having at least three peaks selected from 6.6±0.2, 15.0±0.2, 18.7±0.2, and 19.2±0.2 degrees 2θ.

[0039] In an embodiment, the crystalline form exhibits an X-ray powder diffraction pattern with peaks at 6.6±0.2, 15.0±0.2, 18.7±0.2, and 19.2±0.2 degrees 2θ.

[0040] In embodiments, the crystalline form exhibits the following parameters: [Table 1] Single X-ray crystallography with

[0041] In embodiments, the compound of formula (I): [ka] The crystalline form of the ethanolamine salt of the compound of formula (I) is determined according to the following parameters: [Table 2] Single X-ray crystallography with

[0042] In an embodiment, the crystalline form has an endothermic onset of 176° C. as measured by differential scanning calorimetry.

[0043] In embodiments, a pharmaceutical composition comprises a crystalline form disclosed herein and a pharmaceutically acceptable carrier. In embodiments, the pharmaceutical composition is for oral administration.

[0044] Also provided is a pharmaceutical composition comprising a crystalline form disclosed herein and a pharmaceutically acceptable excipient.

[0045] In embodiments, the pharmaceutical composition is formulated for single dosage administration.

[0046] In embodiments, the pharmaceutical composition is formulated as an oral, parenteral, or intravenous dosage form. In some embodiments, the pharmaceutical composition is formulated as an oral dosage form. In some embodiments, the oral dosage form is a tablet or capsule.

[0047] In embodiments, the pharmaceutical composition comprises about 1 to about 2000 mg of a crystalline form disclosed herein, hi embodiments, the pharmaceutical composition comprises about 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, or 1500 mg of a crystalline form disclosed herein. In embodiments, the pharmaceutical composition comprises about 20, about 30, about 40, about 50, about 100, about 150, about 200, about 250, about 300, about 350, or about 400 mg of a crystalline form disclosed herein. In embodiments, the pharmaceutical composition comprises about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 mg of a crystalline form disclosed herein.

[0048] In embodiments, the pharmaceutical composition comprises a crystalline form disclosed herein in an amount effective to provide a dose of the compound of Formula (I) of from about 1 mg / kg to about 500 mg / kg. In embodiments, the pharmaceutical composition comprises a crystalline form disclosed herein in an amount effective to provide a dose of about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, about 240, about 250, about 260, about 270, about 280, about 290, about 300, about 310, about 320, about 330, about 340, about 350, about 360, about 370, about 380, about 390, or about 400 mg / kg of the compound of Formula (I). In embodiments, the pharmaceutical composition comprises a crystalline form disclosed herein in an amount effective to provide a dose of about 10 to about 400 mg / kg, or about 50 to about 300 mg / kg, or about 100 to about 250 mg / kg of the compound of Formula (I). In embodiments, the pharmaceutical composition comprises a crystalline form disclosed herein in an amount effective to provide a dose of about 200 mg / kg of the compound of Formula (I).

[0049] In embodiments, the pharmaceutical composition comprises a crystalline form disclosed herein in an amount effective to provide a concentration of the compound of Formula (I) at its site of action of 10 μM to 200 μM, or 10 μM to 100 μM, or 10 μM to 50 μM. In embodiments, the pharmaceutical composition comprises a crystalline form disclosed herein in an amount effective to provide a concentration of the compound of Formula (I) at its site of action of about 20 to about 40 μM, about 25 to about 35 μM, or about 30 μM.

[0050] Also provided is a method of treating, preventing, or ameliorating a fibrotic, inflammatory, or proliferative disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of a crystalline form as defined herein, or a pharmaceutical composition as defined herein.

[0051] In embodiments, the fibrotic, inflammatory, or proliferative disease or condition is selected from fibrosis of the skin, lung, heart, kidney, pancreas, eye, and liver.

[0052] In embodiments, the fibrotic, inflammatory, or proliferative disease or condition is selected from diabetic cardiomyopathy, congestive heart failure, ischemic heart disease, hypertension, peripheral arterial disease, cerebrovascular disease, kidney disease, systemic sclerosis (scleroderma), hypertrophic scars, keloids, pulmonary fibrosis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC).

[0053] In an embodiment, the fibrotic, inflammatory, or proliferative disease or condition is a kidney disease.

[0054] In embodiments, the fibrotic, inflammatory, or proliferative disease or condition is selected from chronic kidney disease, progressive kidney disease, diabetic nephropathy, diabetic nephropathy, glomerulonephritis, focal segmental glomerulosclerosis, systemic lupus, lupus nephritis, primary glomerulonephritis, membranous nephropathy, membranoproliferative glomerulonephritis, diffuse proliferative glomerulonephritis, membranous focal segmental glomerulosclerosis, secondary glomerulonephritis, membranous nephropathy, IgA nephropathy, or ischemic nephropathy.

[0055] In an embodiment, the fibrotic, inflammatory, or proliferative disease or condition is chronic kidney disease.

[0056] In embodiments, the fibrotic, inflammatory, or proliferative disease or condition is diabetic nephropathy.

[0057] In embodiments, the fibrotic, inflammatory, or proliferative disease or condition is focal segmental glomerulosclerosis.

[0058] In embodiments, the fibrotic, inflammatory, or proliferative disease or condition is diabetic cardiomyopathy, congestive heart failure, or ischemic heart disease.

[0059] In embodiments, the fibrotic, inflammatory, or proliferative disease or condition is systemic sclerosis or scleroderma.

[0060] In embodiments, the fibrotic, inflammatory, or proliferative disease or condition is pulmonary fibrosis. In embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF).

[0061] In embodiments, the fibrotic, inflammatory, or proliferative disease or condition is selected from chronic obstructive pulmonary disease (COPD), asthma, and cystic fibrosis.

[0062] In embodiments, the fibrotic, inflammatory, or proliferative disease or condition is a fibrotic eye disease, hi embodiments, the fibrotic eye disease is selected from diabetic retinopathy, wet age-related macular degeneration, and diabetic macular edema.

[0063] In embodiments, the fibrotic, inflammatory, or proliferative disease or condition is cancer, hi embodiments, the cancer is selected from breast cancer, skin cancer (melanoma), pancreatic cancer, lung cancer, prostate cancer, colon cancer, liver cancer (hepatocellular carcinoma), head and neck cancer, ovarian cancer, and kidney cancer.

[0064] In embodiments, the fibrotic, inflammatory, or proliferative disease or condition is selected from diabetic retinopathy, diabetic macular edema, macular degeneration, retinopathy of prematurity (ROP), and proliferative vitreoretinopathy (PVR).

[0065] In embodiments, the fibrotic, inflammatory, or proliferative disease or condition is an autoimmune disease or condition, hi embodiments, the autoimmune disease or condition is selected from systemic lupus erythematosus (SLE), inflammatory bowel disease, Crohn's disease, ulcerative colitis, graft-versus-host disease, multiple sclerosis, and rheumatoid arthritis.

[0066] In embodiments, the crystalline forms disclosed herein, or the pharmaceutical compositions defined herein, are administered orally.

[0067] In embodiments, the crystalline forms disclosed herein, or the pharmaceutical compositions defined herein, are administered daily.

[0068] In embodiments, the crystalline forms disclosed herein, or pharmaceutical compositions defined herein, are administered at a dose of about 10 to about 400 mg / kg / day, or about 50 to about 300 mg / kg / day, or 100 to 250 mg / kg / day of the compound of Formula (I). In embodiments, the crystalline forms disclosed herein, or pharmaceutical compositions defined herein, are administered at a dose of about 200 mg / kg / day of the compound of Formula (I).

[0069] In embodiments, the subject is a human. [Brief explanation of the drawings]

[0070] [Figure 1] 1 shows an exemplary X-ray powder diffraction (XRPD) pattern for a sample of crystalline Form I of the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. [Figure 2] 1 shows an exemplary thermogravimetric analysis (TGA) thermogram of a sample of the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. [Figure 3]1 shows an exemplary thermogravimetric analysis (TGA) thermogram of a sample of the tert-butylamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. [Figure 4]

[0023] Figure 1 shows an exemplary dynamic vapor sorption (DVS) of a sample of the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. The DVS isotherm plot (top) and DVS mass change plot (bottom) are shown. [Figure 5]

[0023] Figure 1 shows an exemplary dynamic vapor sorption (DVS) of a sample of the tert-butylamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. The DVS isotherm plot (top) and DVS mass change plot (bottom) are shown. [Figure 6] 1 shows an exemplary differential scanning calorimetry (DSC) diffractogram of a sample of the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. [Figure 7] 1 shows an exemplary differential scanning calorimetry (DSC) diffractogram of a sample of the tert-butylamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. [Figure 8] 1 shows an exemplary X-ray powder diffraction (XRPD) pattern for a sample of the tert-butylamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid in crystalline Form II. [Figure 9] 1 shows an exemplary X-ray powder diffraction (XRPD) pattern for a sample of crystalline Form III of the meglumine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. [Figure 10]1 shows an exemplary X-ray powder diffraction (XRPD) pattern for a sample of the tris(hydroxymethyl)aminomethane (Tris) salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid in crystalline form IV. [Figure 11] 1 shows an exemplary X-ray powder diffraction (XRPD) pattern for a sample of the potassium salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid in crystalline form V. [Figure 12] 1 shows an exemplary X-ray powder diffraction (XRPD) pattern for a sample of the ammonium salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid in crystalline form VI. [Figure 13] 1 shows an exemplary X-ray powder diffraction (XRPD) pattern for a sample of crystalline Form VII of the lysine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. [Figure 14] 14A and 14B show an overlay of XRPD patterns for the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid after one week (Figure 14A) or two weeks (Figure 14B) of stability testing under accelerated storage conditions. Shown are the XRPD patterns for the starting material (lower trace), material held at 40°C and 75% relative humidity (middle trace), and material held at 60°C (top trace). [Figure 15] 1 shows an overlay of XRPD patterns of the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid at the start (lower pattern) and after 36 days of storage at room temperature (upper pattern). [Figure 16]1 shows a plot of the plasma concentration over time of the free form of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid when administered orally at 20 mg / kg body weight to Sprague-Dawley rats. [Figure 17] 1 shows a plot of the plasma concentration over time of the potassium salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid when administered orally to Sprague-Dawley rats at 20 mg / kg body weight. [Figure 18] 1 shows a plot of plasma concentrations over time of the meglumine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid when administered orally at 20 mg / kg body weight to Sprague-Dawley rats. [Figure 19] 1 shows a plot of plasma concentration over time of the tris(hydroxymethyl)aminomethane (Tris) salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid when administered orally at 20 mg / kg body weight to Sprague-Dawley rats. [Figure 20] 1 shows a plot of plasma concentration over time of the tert-butylamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid when administered orally at 20 mg / kg body weight to Sprague-Dawley rats. [Figure 21] 1 shows a plot of the plasma concentration over time of the ammonium salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid when administered orally at 20 mg / kg body weight to Sprague-Dawley rats. [Figure 22]1 shows a plot of the plasma concentration over time of the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid when administered orally at 20 mg / kg body weight to Sprague-Dawley rats. [Figure 23] 1 shows a plot of the plasma concentration over time of the lysine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid when administered orally at 20 mg / kg body weight to Sprague-Dawley rats. [Figure 24] 1 shows an illustrative X-ray powder diffraction (XRPD) pattern for a sample of crystalline monohydrate Form VIII of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. [Figure 25] 1 shows an illustrative X-ray powder diffraction (XRPD) pattern for a sample of crystalline anhydrous Form IX of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. DETAILED DESCRIPTION OF THE INVENTION

[0071] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, pharmacology, pharmaceutical science, and medicine described herein are those well known and commonly used in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art.

[0072] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein, e.g., with reference to a mammalian subject, e.g., a human subject, in one embodiment, a human.

[0073] The terms "treat," "treating," and "treatment" are meant to include alleviating or abolishing a disorder, disease, or condition, or one or more symptoms associated with the disorder, disease, or condition, or alleviating or eradicating the cause of the disorder, disease, or condition itself.

[0074] The terms "prevent," "preventing," and "prevention" are meant to include methods of delaying and / or eliminating the onset of a disorder, disease, or condition, and / or its attendant symptoms, preventing a subject from contracting a disorder, disease, or condition, or reducing a subject's risk of contracting a disorder, disease, or condition.

[0075] As used herein, and unless otherwise specified, the terms "manage," "managing," and "management" refer to preventing or slowing the progression, spread, or worsening of a disease, disorder, or condition, or one or more symptoms thereof. Often, the beneficial effects a subject derives from a prophylactic and / or therapeutic agent do not result in a cure of the disease or disorder. In this regard, the term "managing" encompasses treating a subject afflicted with a particular disease to prevent or minimize recurrence of the disease.

[0076] As used herein, amelioration of symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any relief, whether permanent or temporary, lasting or transient, that can be attributed to or associated with administration of the composition.

[0077] As used herein, the term "disorder" is intended to be generally synonymous with, and is used interchangeably with, the terms "disease," "syndrome," and "condition" (as in medical condition), in that it reflects an abnormal condition of the human or animal body or parts thereof that impairs normal function and is typically manifested by prominent signs and symptoms.

[0078] The term "therapeutically effective amount" is meant to include an amount of a compound that, when administered, is sufficient to prevent the onset of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated. The term "therapeutically effective amount" also refers to an amount of a compound sufficient to elicit the biological or medical response in a biological molecule (e.g., protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human that is sought by a researcher, veterinarian, medical doctor, or clinician.

[0079] As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease or disorder or prevent its recurrence. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent that, alone or in combination with one or more other agents, provides a prophylactic benefit in the prevention of a disease. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0080] "Fibrotic condition," "fibrotic disease," and "fibrotic disorder" are used interchangeably herein to refer to a condition, disease, or disorder characterized by dysregulated fibroblast proliferation or activity, and / or abnormal accumulation of fibronectin, and / or pathological or excessive accumulation of collagen tissue. Typically, any such disease, disorder, or condition is amenable to treatment by administering a compound with antifibrotic activity. Fibrotic disorders include, but are not limited to, renal fibrosis, skin fibrosis, pancreatic fibrosis, liver fibrosis (e.g., liver fibrosis associated with chronic active hepatitis), and pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and pulmonary fibrosis of known etiology.

[0081] "Cardiac fibrosis" refers to the formation of fibrous tissue, including cellular and extracellular components, in the cardiac endothelium and muscle. When present in sufficient amounts, the fibrous tissue results in decreased contractility and / or relaxation of one or more regions of the heart, resulting in functional deficits in cardiac output.

[0082] "Diabetic cardiomyopathy" refers to any one or more cardiac lesions and / or dysfunctions in a subject that are complications of either type I or type II diabetes. Diabetes may be symptomatic or asymptomatic. Cardiac lesions characteristic of diabetic cardiomyopathy include myocyte hypertrophy, myocardial fibrosis, and in some cases, left ventricular hypertrophy. The lesions considered occur independently of complications resulting from coronary artery disease, but both diabetic complications and coronary artery complications may be present in the same subject. Diastolic dysfunction, such as impaired early diastolic filling, prolonged isovolumic relaxation, and increased atrial filling, is also a characteristic of diabetic cardiomyopathy, and can be identified using Doppler methods such as Doppler two-dimensional echocardiography (e.g., Redford MM et al., "Burden of systolic and diastolic dysfunction in the community", JAMA (2003) 289:194-203) or radionuclide imaging for early or mild dysfunction, and standard echocardiography for more severe dysfunction.

[0083] As used herein, the term "kidney disease" may refer to at least one kidney disorder in a subject that impairs kidney function. Kidney disease can result from a primary kidney lesion (e.g., glomerular or tubular damage) or from another organ (e.g., the pancreas) that adversely affects the kidney's ability to perform biological functions. Kidney disease in humans can be the direct or indirect effect of disease. An example of kidney disease as a result of an indirect effect on the kidney is kidney disease as a result of diabetes or systemic lupus. Kidney disease can be the result of any change, damage, or trauma to the glomeruli, tubules, or interstitial tissue in either the renal cortex or renal medulla of the kidney. As used herein, the term "kidney disease" can refer to a progressive kidney disease that results in loss of kidney function over time (e.g., days, weeks, months, or years).

[0084] Kidney disease may include, but is not limited to, progressive glomerular kidney disease, including, but not limited to, diabetic nephropathy (e.g., as a result of type I or type II diabetes or systemic lupus), primary glomerulonephritis (e.g., membranous nephropathy, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, diffuse proliferative glomerulonephritis, membranous focal segmental glomerulosclerosis), or secondary glomerulonephritis (e.g., diabetic nephropathy, ischemic nephropathy).

[0085] As used herein, the term "renal function" refers to a physiological characteristic of the kidney, such as its ability to retain protein and thereby prevent proteinuria. Renal function can be assessed using methods known in the art, such as determining one or more of the glomerular filtration rate (e.g., creatinine clearance), urinary protein excretion, blood urea nitrogen, and serum or plasma creatinine.

[0086] Progressive kidney diseases treated by the salts, pharmaceutical compositions, and methods described herein include any kidney disease that can ultimately lead to end-stage renal disease. Progressive kidney diseases that can be treated by the compositions and methods of the invention can be associated, for example, with endogenous iron deposition in the kidney (e.g., glomeruli, tubules).

[0087] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refer to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other components of a pharmaceutical formulation and suitable for use in contact with the tissues or organs of human beings and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Remington: The Science and Practice of Pharmacy,22nd ed.;Pharmaceutical Press:2012, Handbook of Pharmaceutical Excipients,7th ed.;Rowe et al.,Eds.;The Pharmaceutical Press:2012, Handbook of Pharmaceutical Additives,3rd ed.;Ash and Ash Eds.;Gower Publishing Company:2007,Pharmaceutical Preformulation and Formulation,2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0088] As used in this specification and the appended claims, the indefinite articles "a" and "an," and the definite article "the," include plural and singular referents unless the context clearly indicates otherwise.

[0089] The term "about" or "approximately" refers to the allowable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range. In certain embodiments, with respect to the X-ray powder diffraction 2-theta peak, "about" or "approximately" means within ±0.2°.

[0090] The terms "active ingredient" and "active substance" refer to a compound that is administered to a subject, alone or in combination with one or more pharmaceutically acceptable excipients, to treat, prevent, or ameliorate one or more symptoms of a disorder, disease, or condition. As used herein, "active ingredient" and "active substance" may be an optically active isomer or isotopic variant of a compound described herein.

[0091] The term "anti-solvent" refers to a liquid that is added to a solvent to reduce the solubility of a compound in that solvent, in some instances resulting in precipitation of the compound.

[0092] The terms "drug," "therapeutic agent," and "chemotherapeutic agent" refer to a chemical compound, or pharmaceutical composition thereof, that is administered to a subject to treat, prevent, or ameliorate one or more symptoms of a disorder, disease, or condition.

[0093] The term "solvate" refers to a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided herein, and one or more molecules of a solvent present in stoichiometric or non-stoichiometric amounts. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in a non-crystalline form. When the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.

[0094] The term "solid form" of a compound can refer to any crystalline form or any amorphous form of the compound as a free acid, the compound as a free base, an acid addition salt of the compound, a base addition salt of the compound, a complex of the compound, a solvate (including hydrates) of the compound, or a co-crystal of the compound. The term "crystalline form" of a compound can refer to any crystalline form of the compound as a free acid, the compound as a free base, an acid addition salt of the compound, a base addition salt of the compound, a complex of the compound, a solvate (including hydrates) of the compound, or a co-crystal of the compound. In many cases, the terms "crystalline form" and "solid form" can refer to pharmaceutically acceptable forms, including, for example, pharmaceutically acceptable addition salts, pharmaceutically acceptable complexes, pharmaceutically acceptable solvates, pharmaceutically acceptable co-crystals, and pharmaceutically acceptable co-precipitates.

[0095] Additionally, the compounds disclosed herein may exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included within the scope of the compounds disclosed herein, including any polymorphic forms.

[0096] As used herein, "pharmaceutically acceptable salt" refers to any salt of a compound provided herein that retains the biological properties of the compound and is not toxic or otherwise undesirable for pharmaceutical use. Such salts can be derived from a variety of organic and inorganic counterions well known in the art. Such salts include, but are not limited to, salts formed when an acidic proton present in the parent compound is replaced (a) by a metal ion, such as an alkali metal ion, alkaline earth ion, or aluminum ion, or a hydroxide of an alkali metal or alkaline earth metal, such as sodium, potassium, or magnesium, or (b) by reaction with an organic base, such as an aliphatic, alicyclic, or aromatic organic amine, such as ammonia, ethanolamine (also known as monoethanolamine or "MEA"), lysine, arginine, choline, meglumine, tert-butylamine (also known as "TBA", 2-methylpropan-2-amine, or 2-amino-2-methylpropane), tris(hydroxymethyl)aminomethane (also known as "Tris" or "Tris base"). As used in this disclosure, the term "pharmaceutically acceptable salts" excludes piperidinium salts.

[0097] The terms "substantially pure" and "substantially homogeneous" mean sufficiently homogeneous to be free of readily detectable impurities as determined by standard analytical methods used by those of skill in the art, including, but not limited to, thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR), and mass spectrometry (MS), or sufficiently pure that further purification would not detectably alter the physical, chemical, biological, and / or pharmacological properties of the substance, such as enzymatic and biological activity. In certain embodiments, the terms "substantially pure" and "substantially homogeneous" refer to a population of molecules wherein at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% by weight of the molecules are a single compound, including a single enantiomer, a racemic mixture, a mixture of enantiomers, or a diastereomeric mixture thereof, as determined by standard analytical methods.

[0098] Unless otherwise stated, X-ray powder diffraction (XRPD) data provided herein was determined using a Cu Kα radiation source. XRPD peaks reported herein should be understood to reflect an accuracy of ±0.2 for 2θ peaks and an equivalent accuracy for d-spacings according to Bragg's law.

[0099] The term "moisture sorption" refers to the change in moisture content observed during the course of an experiment, as determined by dynamic vapor sorption (DVS), of a sample of a form of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, including the solid form, crystalline form, or pharmaceutically acceptable salts thereof, as described herein, thereby demonstrating hygroscopicity. The change in moisture content is stated as a percent change in mass of the starting sample, and all such moisture sorption (DVS) values ​​stated herein are understood to expressly include values ​​within a variance of + / - 0.2%. When a hygroscopicity value is stated at a specific humidity, this refers to the value measured during a sorption cycle, such as when the stated humidity value was reached during the process of increasing humidity from 0% RH to 95% RH in the presence of the sample.

[0100] The term "weight loss" refers to the observed weight loss, as determined by thermogravimetric analysis (TGA), of a sample of a form of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, including the solid form, crystalline form, or pharmaceutically acceptable salts of either, described herein. Weight loss is reported as the % loss of mass of the starting sample, and all such weight loss values ​​reported herein are understood to expressly include values ​​within a mass unit variation of + / - 0.2%.

[0101] The term "bioavailability" refers to the bioavailability in plasma of one or more forms of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid described herein, including solid forms, crystalline forms, and pharmaceutically acceptable salts of any thereof. Bioavailability is measured using the equation AUC=F·D / CL T where AUC is the area under the plasma concentration plot, F is the absolute bioavailability, D is the dose, and CL is the Tis the total body clearance. Furthermore, the term bioavailability refers to the bioavailability determined according to the experiments described in Example 6 and referenced in Table 22, where the bioavailability (F) is the extrapolated area under the curve (AUC inf ) Bioavailability values ​​set forth herein are understood to expressly include values ​​within a variance of + / - 10%.

[0102] The term "endothermic onset" refers to the temperature at which an endothermic event occurs as measured by differential scanning calorimetry (DSC) of a sample of a form of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, including the solid form, crystalline form, or pharmaceutically acceptable salts of either thereof, as described herein. Endothermic onset values ​​described herein are understood to expressly include values ​​within a variance of + / - 2.0°C.

[0103] The term "melting point" refers to the temperature, as measured by differential scanning calorimetry (DSC), at which a change of state from solid to liquid occurs in a sample of a form of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, including the solid form, crystalline form, or pharmaceutically acceptable salts of either, as described herein. Melting point values ​​described herein are understood to expressly include values ​​within a variance of + / - 2.0°C.

[0104] The term "FaSSIF medium" refers to a fasted-state simulated intestinal fluid medium prepared using FaSSIF powder and buffer concentrate obtained from the commercial source Biorelevant (London, UK; biorelevant.com). FaSSIF powder contains sodium taurocholate, lecithin, sodium chloride, sodium dihydrogen phosphate, and sodium hydroxide. FaSSIF medium is prepared as described at https: / / biorelevant.com / learning_center / what-is-fassif / . Briefly, a pH 6.5 buffer solution containing 0.42 g of NaOH, 3.95 g of NaH2PO4·H2O, and 6.19 g of NaCl was dissolved in 0.9 L of purified water, the pH of the solution was adjusted to 6.5 using 1 N sodium hydroxide or 1 N hydrochloric acid, and the volume was adjusted to 1 L with purified water at room temperature. Dissolve 2.24 g of FaSSIF powder in 0.5 L of pH 6.5 buffer, stir until the powder is completely dissolved, and then bring to volume with the buffer at room temperature (1 L). The prepared medium contains 3.0 mM sodium taurocholate, 0.75 mM lecithin, 106 mM sodium chloride, and 28.4 mM sodium dihydrogen phosphate. If necessary, prepare FaSSIF (pH 7.5) medium as described and adjust to the desired pH using 1 N sodium hydroxide or 1 N hydrochloric acid.

[0105] The term "FeSSIF medium" refers to a fed-state simulated intestinal fluid medium prepared using FeSSIF powder and buffer concentrate obtained from the commercial source Biorelevant (London, UK, biorelevant.com). The FeSSIF powder contains sodium taurocholate, lecithin, sodium chloride, sodium hydroxide, and acetic acid. The FeSSIF medium is prepared as described at https: / / biorelevant.com / learning_center / what-is-fessif / . Briefly, a pH 5.0 buffer solution containing 44.04 g of NaOH, 8.65 g of glacial acetic acid, and 11.87 g of NaCl was dissolved in 0.9 L of purified water, the pH of the solution was adjusted to 5.0 using 1 N sodium hydroxide or 1 N hydrochloric acid, and the solution was made to volume with purified water at room temperature (1 L). 11.20 g of FeSSIF powder was dissolved in 0.5 L of pH 5.0 buffer, stirred until the powder was completely dissolved, and then made to volume with the buffer at room temperature (1 L). The prepared medium contained 15.0 mM sodium taurocholate, 3.75 mM lecithin, 203 mM sodium chloride, and 144 mM acetic acid. If necessary, FeSSIF (pH 7.8) medium was prepared as described and adjusted to the desired pH using 1 N sodium hydroxide or 1 N hydrochloric acid.

[0106] solid form The present disclosure relates, in part, to solid forms (e.g., crystalline forms) of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof that have useful physicochemical and / or pharmacokinetic properties. The present disclosure also relates to certain pharmaceutically acceptable salts of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, and solid or crystalline forms of these salts, which, as described herein, may offer one or more surprising advantages over (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, also referred to herein as the "non-salt form," the "free form," or the "free acid form" of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. Some embodiments disclosed herein include crystalline forms of certain pharmaceutically acceptable salts of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0107] The compound (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, also known as, for example, (E)-2-(3-(3-methoxy-4-(prop-2-yn-1-yloxy)phenyl)acrylamido)benzoic acid, (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, 3-methoxy-4-propargyloxycinnamoylanthranilic acid, or "FT011," is described in International Patent Application WO 2008 / 003141, the disclosure of which is incorporated herein by reference in its entirety.

[0108] The solid forms, pharmaceutically acceptable salts, and crystalline forms thereof described herein can be characterized using several methods known to those of skill in the art, including thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR), and mass spectrometry (MS), single crystal X-ray diffraction, X-ray powder diffraction (XRPD), microscopy (e.g., scanning electron microscopy (SEM)), thermal analysis (e.g., differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and hot stage microscopy), and spectroscopy (e.g., infrared, Raman, solid-state nuclear magnetic resonance). In the case of solid forms, particle size and size distribution can be determined by conventional methods such as laser light scattering techniques. The purity of the solid forms, pharmaceutically acceptable salts, and crystalline forms thereof provided herein can be determined by standard analytical methods such as thin layer chromatography (TLC), gel electrophoresis, gas chromatography, high performance liquid chromatography (HPLC), and mass spectrometry (MS).

[0109] In embodiments, provided herein is a solid form of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. In some embodiments, the solid form is crystalline.

[0110] In some embodiments, the solid form of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid is a solid form of a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. In some embodiments, the solid form of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid is a crystalline form of a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a solvate thereof.

[0111] In any of the embodiments described herein, the term "pharmaceutically acceptable salts" excludes piperidinium salts.

[0112] A pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid can be selected from, but is not limited to, a potassium salt, a meglumine salt, an ethanolamine salt, a tris(hydroxymethyl)aminomethane (Tris) salt, a tert-butylamine (TBA) salt, an ammonium salt, or a lysine salt. In some embodiments, the pharmaceutically acceptable salt is a meglumine salt, an ethanolamine salt, a tris(hydroxymethyl)aminomethane (Tris) salt, or a tert-butylamine (TBA) salt. In some embodiments, the pharmaceutically acceptable salt is an ethanolamine salt or a tert-butylamine salt. In certain embodiments, the pharmaceutically acceptable salt is an ethanolamine salt.

[0113] In some embodiments, a solid form (e.g., a crystalline form) of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein may be solvated. In various embodiments, the solvent in the solvate is pharmaceutically acceptable. In one embodiment, the solvent in the solvate is an alcohol. In another embodiment, the solvent in the solvate is methanol, ethanol, isopropanol (IPA), 1-propanol, 1-butanol, 2-butanol, t-butanol, 3-methyl-1-butanol, 1-pentanol, 2-methoxyethanol, 2-ethoxyethanol, or ethylene glycol. In yet another embodiment, the solvent in the solvate is methanol or ethanol. In other embodiments, the solvent in the solvate is water, methanol, ethanol, n-propanol, isopropanol, acetic acid, or ethyl acetate. In yet other embodiments, the solvent in the solvate is acetic acid or ethyl acetate. In some embodiments, a solid form (e.g., a crystalline form) of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein is not solvated.

[0114] In some embodiments, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein may be a hydrate. Thus, in one embodiment, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein may be a hemihydrate. In another embodiment, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein may be a monohydrate. In another embodiment, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein may be a dihydrate. In yet another embodiment, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein may be a trihydrate. In yet another embodiment, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein may be a tetrahydrate. In yet another embodiment, a solid form (e.g., a crystalline form) of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein may be a pentahydrate.

[0115] In various embodiments, the solid forms (e.g., crystalline forms) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein exhibit advantageous solubility, bioavailability, stability, processability, ease of manufacture, and / or pharmacokinetic properties. For example, the solid forms (e.g., crystalline forms) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein may provide long-term stability, low hygroscopicity, improved dissolution, and superior pharmacokinetic properties. In some embodiments, a solid form (e.g., a crystalline form) of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has an improved property selected from the group consisting of increased stability, increased solubility, increased dissolution, increased bioavailability, increased dose response, or another property described herein. In some embodiments, the increased stability is characterized by modified (e.g., reduced) moisture sorption as determined by dynamic vapor sorption (DVS), modified (e.g., increased) endothermic onset as measured by differential scanning calorimetry (DSC), and / or modified (e.g., reduced) weight loss as determined by thermogravimetric analysis (TGA).

[0116] In some embodiments, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a water sorption of less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% at 25°C and 80% relative humidity as determined by dynamic vapor sorption (DVS). In some embodiments, a solid form (e.g., a crystalline form) of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a water sorption of 0.1% to 10% at 25° C. and 80% relative humidity, as determined by dynamic vapor sorption (DVS). In one embodiment, a solid form (e.g., a crystalline form) of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a water sorption at 25° C. and 80% relative humidity of 0.1-10%, 0.1-9%, 0.1-8%, 0.1-7%, 0.1-6%, 0.1-5%, 0.1-4%, 0.1-3%, 0.1-2%, or 0.1-1%, as determined by DVS. In one embodiment, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a water sorption of 0.1 to 1.7% at 25°C and 80% relative humidity as determined by DVS. In another embodiment, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a water sorption of 0.49% to 8.82% at 25°C and 80% relative humidity as determined by DVS.In yet another embodiment, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a water sorption of 0.49% to 6.93% at 25°C and 80% relative humidity, as determined by DVS. In some embodiments, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a water sorption of 0.49% to 6.05% at 25°C and 80% relative humidity, as determined by DVS. In certain embodiments, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a water sorption of 0.49% to 1.61% at 25°C and 80% relative humidity, as determined by DVS. In certain embodiments, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a water sorption of 0.49% to 1.07% at 25°C and 80% relative humidity, as determined by DVS. In certain embodiments, a solid form (e.g., a crystalline form) of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a water sorption of 1.07% to 8.82% at 25° C. and 80% relative humidity, as determined by DVS.

[0117] In some embodiments, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a pharmaceutically acceptable salt thereof, provided herein has an endothermic onset of 29°C to 187°C as measured by differential scanning calorimetry (DSC). In some embodiments, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a pharmaceutically acceptable salt thereof, provided herein has an endothermic onset of 116°C to 187°C as measured by DSC. In some embodiments, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a melting point of 57°C to 199°C as measured by DSC. In some embodiments, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a melting point of 155°C to 199°C as measured by DSC. In some embodiments, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has an endothermic onset of 29°C to 187°C, and a melting point of 57°C to 199°C, as measured by DSC. In some embodiments, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has an endothermic onset of 116°C to 187°C, and a melting point of 155°C to 199°C, as measured by DSC.

[0118] In some embodiments, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a weight loss of less than 3%, 2.5%, 2%, 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, or 0.05% when heated from 25°C to 120°C as determined by thermogravimetric analysis (TGA). In some embodiments, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a weight loss of 0.05% to 3% when heated from 25° C. to 120° C. as determined by thermogravimetric analysis (TGA). In some embodiments, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a weight loss of 0.01% to 1% when heated from 25° C. to 120° C. as determined by TGA. In some embodiments, a solid form (e.g., a crystalline form) of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a weight loss of 0.07% to 8.94%, or 0.07% to 0.94%, when heated from 25° C. to 120° C., as determined by TGA.

[0119] In some embodiments, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a solubility of at least 2 mg / ml, 2.5 mg / ml, 3 mg / ml, 3.5 mg / ml, 4 mg / ml, 4.5 mg / ml, or 5 mg / ml in FaSSIF medium (pH 7.5) over 24 hours. g / ml, 5 mg / ml, 5.5 mg / ml, 6 mg / ml, 6.5 mg / ml, 7 mg / ml, 7.5 mg / ml, 8 mg / ml, 8.5 mg / ml, 9 mg / ml, 9.5 mg / ml, 10 mg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, 15 mg / ml, 16 mg / ml, 17 mg / ml, 18 mg / ml, 19 mg / ml, or 20 mg / ml. In some embodiments, a solid form (e.g., a crystalline form) of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a solubility in FaSSIF medium (pH 7.5) of about 2 mg / ml to about 10 mg / ml, about 2 mg / ml to about 9 mg / ml, about 2 mg / ml to about 8 mg / ml, about 2 mg / ml to about 7 mg / ml, about 2 mg / ml to about 6 mg / ml, or about 2 mg / ml to about 5 mg / ml over 24 hours. In some embodiments, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a solubility in FaSSIF medium (pH 7.5) of 2.4 mg / ml to 5.14 mg / ml over 24 hours. In some embodiments, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a solubility in FaSSIF medium (pH 7.5) of 2.4 mg / ml to greater than 5.14 mg / ml over 24 hours.

[0120] In some embodiments, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a solubility of at least 0.5 mg / ml, 1 mg / ml, 1.5 mg / ml, 2 mg / ml, 2.5 mg / ml, 3 mg / ml, 3.5 mg / ml, or 4 mg / ml in FeSSIF medium (pH 7.8) over 24 hours. 1, 4 mg / ml, 4.5 mg / ml, 5 mg / ml, 5.5 mg / ml, 6 mg / ml, 6.5 mg / ml, 7 mg / ml, 7.5 mg / ml, 8 mg / ml, 8.5 mg / ml, 9 mg / ml, 9.5 mg / ml, 10 mg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, 15 mg / ml, 16 mg / ml, 17 mg / ml, 18 mg / ml, 19 mg / ml, or 20 mg / ml. In some embodiments, a solid form (e.g., a crystalline form) of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a solubility in FeSSIF medium (pH 7.8) of about 1 mg / ml to about 10 mg / ml, about 1 mg / ml to about 9 mg / ml, about 1 mg / ml to about 8 mg / ml, about 1 mg / ml to about 7 mg / ml, about 1 mg / ml to about 6 mg / ml, or about 1 mg / ml to about 5 mg / ml over 24 hours. In some embodiments, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a solubility in FeSSIF medium (pH 7.8) of 1.2 mg / ml to 5.14 mg / ml over 24 hours. In some embodiments, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a solubility in FeSSIF medium (pH 7.8) of 1.2 mg / ml to greater than 5.14 mg / ml over 24 hours.

[0121] In some embodiments, a solid form (e.g., a crystalline form) of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a solubility of 2.4 mg / ml to 5.14 mg / ml in 24 hours in FaSSIF medium (pH 7.5) and a solubility of 1.2 mg / ml to 5.14 mg / ml in 24 hours in FeSSIF medium (pH 7.8). In some embodiments, a solid form (e.g., a crystalline form) of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a solubility of 2.4 mg / ml to greater than 5.14 mg / ml in 24 hours in FaSSIF medium (pH 7.5) and a solubility of 1.2 mg / ml to greater than 5.14 mg / ml in 24 hours in FeSSIF medium (pH 7.8).

[0122] In embodiments, the solid forms (e.g., crystalline forms) of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein have improved bioavailability.

[0123] Bioavailability is measured by the increase in AUC (area under the plot of plasma concentration), t max (time to reach peak serum concentration) or C max For example, a solid form (e.g., a crystalline form) of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein can result in higher plasma concentrations of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid when compared to a reference form.

[0124] As will be appreciated by those skilled in the art, AUC is an estimate of bioavailability and total body clearance (CL T ) is useful for estimating AUC. In some cases, AUC=F·D / CL T where D is the dose and F is the absolute bioavailability.

[0125] For example, in some embodiments, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a bioavailability of at least 39F%, 44F%, 49F%, 54F%, 59F%, 54F%, 59F%, 64F%, 69F%, 74F%, 79F%, 84F%, 89F%, 94F%, or 99F%. In some embodiments, a solid form (e.g., a crystalline form) of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a bioavailability of at least 50F%, 55F%, 60F%, 65F%, 70F%, 75F%, 80F%, 85F%, 90F%, 95F%, or 99F%. In some embodiments, a solid form (e.g., a crystalline form) of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a bioavailability of between 39F% and 99F%, between 39F% and 94F%, between 39F% and 89F%, between 39F% and 84F%, between 39F% and 79F%, between 39F% and 74F%, between 39F% and 69F%, between 39F% and 64F%, between 39F% and 59F%, between 39F% and 54F%, between 39F% and 49F%, or between 39F% and 44F%. In some embodiments, a solid form (e.g., a crystalline form) of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a bioavailability of 39 F% to 82 F%. In some embodiments, the bioavailability is oral bioavailability.

[0126] In some embodiments, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein is (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. The bioavailability of the aromatic acid is at least about 1.1-fold, about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 1.6-fold, about 1.7-fold, about 1.8-fold, about 1.9-fold, about 2.0-fold, about 2.1-fold, about 2.2-fold, about 2.3-fold, about 2.4-fold, about 2.5-fold, about 2.6-fold, about 2.7-fold, about 2.8-fold, about 2.9-fold, or about 3.0-fold greater than the bioavailability of the free form of the aromatic acid. In some embodiments, a solid form (e.g., a crystalline form) of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein has a bioavailability that is at least about 1.4-fold, about 1.6-fold, about 1.8-fold, about 2.0-fold, or about 2.3-fold greater than the bioavailability of the free form of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. In some embodiments, the bioavailability is oral bioavailability.

[0127] Salts and solid or crystalline forms of salts In some embodiments, provided herein are pharmaceutically acceptable salts of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, and solid or crystalline forms thereof. In various embodiments, the pharmaceutically acceptable salt can be selected from, but is not limited to, a potassium salt, a meglumine salt, an ethanolamine salt, a tris(hydroxymethyl)aminomethane (Tris) salt, a tert-butylamine (TBA) salt, an ammonium salt, or a lysine salt. In some embodiments, the pharmaceutically acceptable salt is a meglumine salt, an ethanolamine salt, a tris(hydroxymethyl)aminomethane (Tris) salt, or a tert-butylamine (TBA) salt. In some embodiments, the pharmaceutically acceptable salt is an ethanolamine salt or a tert-butylamine salt. In certain embodiments, the pharmaceutically acceptable salt is an ethanolamine salt.

[0128] In some embodiments, provided herein is the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, including solid or crystalline forms thereof.

[0129] As used herein, the term "ethanolamine" refers to the compound (and related salts formed using said compound), which is also known, for example, as 2-aminoethan-1-ol, 2-aminoethanol, monoethanolamine, or "MEA."

[0130] In some embodiments, the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has the formula (II): [ka] It can be expressed as:

[0131] In some embodiments, provided herein is the tert-butylamine (TBA) salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, including solid or crystalline forms thereof.

[0132] In some embodiments, provided herein is the meglumine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, including solid or crystalline forms thereof.

[0133] In some embodiments, provided herein is the tris(hydroxymethyl)aminomethane (Tris) salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, including solid or crystalline forms thereof.

[0134] In some embodiments, provided herein is the potassium salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, including solid or crystalline forms thereof.

[0135] In some embodiments, provided herein is the ammonium salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, including its solid or crystalline forms.

[0136] In some embodiments, provided herein is a lysine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, including solid or crystalline forms thereof.

[0137] In various embodiments, the pharmaceutically acceptable salts of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or solid or crystalline forms thereof, advantageously exhibit improved solubility, bioavailability, stability, processability, ease of manufacture, and / or pharmacokinetic properties. As a result, the pharmaceutically acceptable salts of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or solid or crystalline forms thereof, may provide long-term stability, reduced hygroscopicity, improved dissolution, and superior pharmacokinetic properties compared to the free form of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. In some embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has improved properties compared to the free form of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, wherein the improved properties are selected from the group consisting of increased stability, increased solubility, increased dissolution, increased bioavailability, increased dose response, or another property described herein. In some embodiments, the increased stability is characterized by modified (e.g., reduced) moisture sorption as determined by dynamic vapor sorption (DVS), modified (e.g., increased) endothermic onset as measured by differential scanning calorimetry (DSC), and / or modified (e.g., reduced) weight loss as determined by thermogravimetric analysis (TGA).

[0138] In some embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein has a water sorption of less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% at 25°C and 80% relative humidity as determined by dynamic vapor sorption (DVS). In one embodiment, a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein has a water sorption at 25° C. and 80% relative humidity of 0.1-10%, 0.1-9%, 0.1-8%, 0.1-7%, 0.1-6%, 0.1-5%, 0.1-4%, 0.1-3%, 0.1-2%, or 0.1-1%, as determined by DVS. In another embodiment, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a water sorption of 0.49% to 8.82% at 25°C and 80% relative humidity, as determined by DVS. In yet another embodiment, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a water sorption of 0.49% to 6.93% at 25°C and 80% relative humidity, as determined by DVS. In some embodiments, a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein has a water sorption of 0.49% to 6.05% at 25° C. and 80% relative humidity as determined by DVS.In certain embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a water sorption of 0.49% to 1.61% at 25°C and 80% relative humidity, as determined by DVS. In certain embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a water sorption of 0.49% to 1.07% at 25°C and 80% relative humidity, as determined by DVS.

[0139] In some embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has an endothermic onset of 29° C. to 203° C. as measured by differential scanning calorimetry (DSC). In some embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has an endothermic onset of 116° C. to 203° C. as measured by DSC. In some embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a melting point, as measured by DSC, of ​​57°C to 204°C. In some embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a melting point, as measured by DSC, of ​​155°C to 204°C. In some embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has an endothermic onset of 29°C to 203°C, and a melting point of 57°C to 204°C, as measured by DSC. In some embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has an endothermic onset of 116°C to 203°C, and a melting point of 155°C to 204°C, as measured by DSC.

[0140] In some embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein has a weight loss of less than 3%, 2.5%, 2%, 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, or 0.05% when heated from 25°C to 120°C as determined by thermogravimetric analysis (TGA). In some embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a weight loss of 0.05% to 3% when heated from 25° C. to 120° C., as determined by thermogravimetric analysis (TGA). In some embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a weight loss of 0.07% to 5.24% when heated from 25° C. to 120° C., as determined by TGA. In some embodiments, a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein has a weight loss of 0.07% to 8.94%, or 0.07% to 0.94%, when heated from 25° C. to 120° C., as determined by TGA.

[0141] In some embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, exhibits a cytotoxicity of at least 2 mg / ml, 2.5 mg / ml, 3 mg / ml, 3.5 mg / ml, 4 mg / ml, 4.5 mg / ml, or 5 mg / ml in FaSSIF medium (pH 7.5) over 24 hours. ml, 5 mg / ml, 5.5 mg / ml, 6 mg / ml, 6.5 mg / ml, 7 mg / ml, 7.5 mg / ml, 8 mg / ml, 8.5 mg / ml, 9 mg / ml, 9.5 mg / ml, 10 mg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, 15 mg / ml, 16 mg / ml, 17 mg / ml, 18 mg / ml, 19 mg / ml, or 20 mg / ml. In some embodiments, a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a solubility in FaSSIF medium (pH 7.5) of about 2 mg / ml to about 10 mg / ml, about 2 mg / ml to about 9 mg / ml, about 2 mg / ml to about 8 mg / ml, about 2 mg / ml to about 7 mg / ml, about 2 mg / ml to about 6 mg / ml, or about 2 mg / ml to about 5 mg / ml over 24 hours. In some embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a solubility of 2.4 mg / ml to 5.14 mg / ml in FaSSIF medium (pH 7.5) over 24 hours. In some embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a solubility of 2.4 mg / ml to greater than 5.14 mg / ml in FaSSIF medium (pH 7.5) over 24 hours.

[0142] In some embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, exhibits a cytotoxicity of at least 0.5 mg / ml, 1 mg / ml, 1.5 mg / ml, 2 mg / ml, 2.5 mg / ml, 3 mg / ml, 3.5 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, 10 mg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, 15 mg / ml, 16 mg / ml, 17 mg / ml, 18 mg / ml, 19 mg / ml, 20 mg / ml, 21 mg / ml, 22 mg / ml, 23 mg / ml, 24 mg / ml, 25 mg / ml, 26 mg / ml, 27 mg / ml, 28 mg / ml, 29 mg / ml, 30 mg / ml, 31 mg / ml, 32 mg / ml, 33 mg / ml, 34 mg / ml, 35 mg / ml, 36 mg / ml, 37 mg / ml, 38 mg / ml, 39 mg / ml, 40 mg / ml, 41 mg / ml, 42 mg / ml, 43 mg / ml, 44 mg / ml, 45 mg / ml, 46 mg / ml, 47 mg / ml, 48 mg / ml, 49 mg / ml, 50 mg / ml, 51 mg / ml, 52 mg / ml, 53 mg / ml, 54 mg / ml, 55 mg / ml, 56 mg / ml, 57 mg / ml, 58 mg / ml, 59 mg / ml, having a solubility of 4 mg / ml, 4.5 mg / ml, 5 mg / ml, 5.5 mg / ml, 6 mg / ml, 6.5 mg / ml, 7 mg / ml, 7.5 mg / ml, 8 mg / ml, 8.5 mg / ml, 9 mg / ml, 9.5 mg / ml, 10 mg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, 15 mg / ml, 16 mg / ml, 17 mg / ml, 18 mg / ml, 19 mg / ml, or 20 mg / ml. In some embodiments, a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a solubility in FeSSIF medium (pH 7.8) of about 1 mg / ml to about 10 mg / ml, about 1 mg / ml to about 9 mg / ml, about 1 mg / ml to about 8 mg / ml, about 1 mg / ml to about 7 mg / ml, about 1 mg / ml to about 6 mg / ml, or about 1 mg / ml to about 5 mg / ml over 24 hours. In some embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a solubility in FeSSIF medium (pH 7.8) of 1.2 mg / ml to 5.14 mg / ml over 24 hours. In some embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a solubility in FeSSIF medium (pH 7.8) of 1.2 mg / ml to greater than 5.14 mg / ml over 24 hours.

[0143] In some embodiments, a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein has a solubility of 2.4 mg / ml to 5.14 mg / ml in 24 hours in FaSSIF medium (pH 7.5) and a solubility of 1.2 mg / ml to 5.14 mg / ml in 24 hours in FeSSIF medium (pH 7.8). In some embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein has a solubility of 2.4 mg / ml to greater than 5.14 mg / ml in 24 hours in FaSSIF medium (pH 7.5) and a solubility of 1.2 mg / ml to greater than 5.14 mg / ml in 24 hours in FeSSIF medium (pH 7.8).

[0144] In some embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein has a solubility of at least 0.04 mg / ml, 0.05 mg / ml, 0.06 mg / ml, 0.07 mg / ml, 0.08 mg / ml, 0.09 mg / ml, 0.1 mg / ml, 0.2 mg / ml, 0.3 mg / ml, 0.4 mg / ml, 0.5 mg / ml, 0.6 mg / ml, 0.7 mg / ml, 0.8 mg / ml, 0.9 mg / ml, or 1 mg / ml in a pH 6.8 medium over 24 hours. In certain embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a solubility of at least 0.06 mg / ml in a medium having a pH of 6.8 over 24 hours. In some embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a solubility of 0.048 mg / ml to 0.090 mg / ml over 24 hours in a medium having a pH of 6.8.

[0145] In embodiments, a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein has improved bioavailability.

[0146] In some embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein has a bioavailability of at least 39F%, 44F%, 49F%, 54F%, 59F%, 54F%, 59F%, 64F%, 69F%, 74F%, 79F%, 84F%, 89F%, 94F%, or 99F%. In some embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein has a bioavailability of at least 50F%, 55F%, 60F%, 65F%, 70F%, 75F%, 80F%, 85F%, 90F%, 95F%, or 99F%. In some embodiments, a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a bioavailability of 39F% to 99F%, 39F% to 94F%, 39F% to 89F%, 39F% to 84F%, 39F% to 79F%, 39F% to 74F%, 39F% to 69F%, 39F% to 64F%, 39F% to 59F%, 39F% to 54F%, 39F% to 49F%, or 39F% to 44F%. In some embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein has a bioavailability of 39 F% to 82 F%. In some embodiments, the bioavailability is oral bioavailability.

[0147] In some embodiments, the pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, is (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid The bioavailability of the compound of formula (I) is at least about 1.1-fold, about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 1.6-fold, about 1.7-fold, about 1.8-fold, about 1.9-fold, about 2.0-fold, about 2.1-fold, about 2.2-fold, about 2.3-fold, about 2.4-fold, about 2.5-fold, about 2.6-fold, about 2.7-fold, about 2.8-fold, about 2.9-fold, or about 3.0-fold greater than the bioavailability of the free form of the compound of formula (I). In some embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein has a bioavailability that is at least about 1.4-fold, about 1.6-fold, about 1.8-fold, about 2.0-fold, or about 2.3-fold greater than the bioavailability of the free form of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. In some embodiments, a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a bioavailability that is 1.1-fold to 3.0-fold that of the free form of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. In some embodiments, a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a bioavailability that is 1.4-fold to 2.3-fold that of the free form of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.In some embodiments, the bioavailability is oral bioavailability.

[0148] In some embodiments, a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, may be solvated. In various embodiments, the solvent in the solvate is pharmaceutically acceptable. In one embodiment, the solvent in the solvate is an alcohol. In another embodiment, the solvent in the solvate is methanol, ethanol, isopropanol (IPA), 1-propanol, 1-butanol, 2-butanol, t-butanol, 3-methyl-1-butanol, 1-pentanol, 2-methoxyethanol, 2-ethoxyethanol, or ethylene glycol. In yet another embodiment, the solvent in the solvate is methanol or ethanol. In other embodiments, the solvent in the solvate is water, methanol, ethanol, n-propanol, isopropanol, acetic acid, or ethyl acetate. In yet other embodiments, the solvent in the solvate is acetic acid or ethyl acetate. In some embodiments, a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein is not solvated.

[0149] In some embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, can be a hydrate. Thus, in one embodiment, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, can be a hemihydrate. In another embodiment, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, can be a monohydrate. In another embodiment, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, can be a dihydrate. In yet another embodiment, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, can be a trihydrate. In yet another embodiment, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, can be a tetrahydrate. In yet another embodiment, a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein can be a pentahydrate.

[0150] In some embodiments, the pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein is an isolated pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof.

[0151] In some embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a chemical purity of at least 90%, at least 95%, at least 98%, or at least 99%. In some embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, wherein the salt is selected from meglumine salt, ethanolamine salt, tris(hydroxymethyl)aminomethane (Tris) salt, or tert-butylamine (TBA) salt, has a chemical purity of at least 90%, at least 95%, at least 98%, or at least 99%.

[0152] In embodiments, the pharmaceutically acceptable salts of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein are crystalline.

[0153] Ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, and its solid or crystalline forms In embodiments, provided herein is the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, including its solid and crystalline forms.

[0154] In embodiments, provided herein is a solid form of the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0155] In some embodiments, the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid is unsolvated.

[0156] In some embodiments, provided herein is a crystalline form of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. In one embodiment, the crystalline form is a non-solvated ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0157] In some embodiments, the crystalline form of the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein is crystalline Form I.

[0158] In some embodiments, crystalline Form I of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has an X-ray powder diffraction (XRPD) pattern. Figure 1 shows an example of an XRPD pattern of crystalline Form I. In some embodiments, the XRPD pattern of crystalline Form I of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid includes at least one diffraction peak selected from 6.6, 11.7, 15.9, 17.7, 23.7, and 26.6 degrees 2θ (±0.2 degrees 2θ). In some embodiments, crystalline Form I of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising at least two peaks selected from 6.6, 11.7, 15.9, 17.7, 23.7, and 26.6 degrees two-theta (± 0.2 degrees two-theta). In some embodiments, crystalline Form I of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising at least three peaks selected from 6.6, 11.7, 15.9, 17.7, 23.7, and 26.6 degrees two-theta (± 0.2 degrees two-theta). In some embodiments, crystalline Form I of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising peaks at 6.6, 11.7, 15.9, 17.7, 23.7, and 26.6 degrees two-theta (± 0.2 degrees two-theta). In some embodiments, crystalline Form I of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising at least one peak selected from 6.6, 11.7, 15.0, 15.9, 17.7, 18.7, and 19.2 degrees two-theta (± 0.2 degrees two-theta).In some embodiments, crystalline Form I of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising at least two peaks selected from 6.6, 11.7, 15.0, 15.9, 17.7, 18.7, and 19.2 degrees two-theta (± 0.2 degrees two-theta). In some embodiments, crystalline Form I of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising at least three peaks selected from 6.6, 11.7, 15.0, 15.9, 17.7, 18.7, and 19.2 degrees two-theta (± 0.2 degrees two-theta). In some embodiments, crystalline Form I of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising peaks at 6.6, 11.7, 15.0, 15.9, 17.7, 18.7, and 19.2 degrees two-theta (±0.2 degrees two-theta). In some embodiments, crystalline Form I of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has an X-ray diffraction pattern substantially as shown in Figure 1.

[0159] As will be understood by those skilled in the art, due to experimental variability when X-ray diffraction patterns are measured on different instruments, peak positions are considered to be equal if the two theta (2θ) values ​​match within a certain degree of variability. For example, the United States Pharmacopoeia states that identity is confirmed when the angular positions of the 10 most intense diffraction peaks match those of a reference material within ±0.2 degrees, and the relative intensities of the peaks do not vary by more than 20%. Thus, in some embodiments, the peak positions described herein include a variation within ±0.2 degrees 2θ.

[0160] In certain embodiments, the crystalline form of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid comprises at least 80%, at least 85%, at least 88%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% of crystalline Form I of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein.

[0161] In certain embodiments, in a pharmaceutical composition comprising the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, at least 80%, at least 85%, at least 88%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid is crystalline Form I of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein.

[0162] In some embodiments, a solid form (e.g., a crystalline form) of the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein has a thermogravimetric analysis (TGA) plot: In some embodiments, a solid form (e.g., a crystalline form) of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid exhibits a weight loss of less than 3%, less than 2.5%, less than 2%, less than 1.9%, less than 1.8%, less than 1.7%, less than 1.6%, less than 1.5%, less than 1.4%, less than 1.3%, less than 1.2%, less than 1.1%, less than 1.0%, less than 0.9%, less than 0.8%, less than 0.7%, less than 0.6%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, or less than 0.15% when heated from about 25°C to about 120°C. In some embodiments, a solid form (e.g., a crystalline form) of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein has a thermogravimetric analysis (TGA) plot that exhibits a weight loss of 0.15% to 3% when heated from about 25°C to about 120°C. In some embodiments, a solid form (e.g., a crystalline form) of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid exhibits a weight loss of 0.10% when heated from about 25° C. to about 120° C. In certain embodiments, a solid form (e.g., a crystalline form) of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has a TGA plot substantially as shown in FIG.Thus, the solid forms (e.g., crystalline forms) of the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein can be characterized as thermally stable.

[0163] In some embodiments, a solid form (e.g., a crystalline form) of the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein has a dynamic vapor sorption (DVS) plot. In some embodiments, a solid form (e.g., a crystalline form) of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid exhibits a mass gain (e.g., water sorption) of less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1.9%, less than 1.8%, less than 1.7%, less than 1.6%, less than 1.5%, less than 1.4%, less than 1.3%, less than 1.2%, less than 1.1%, less than 1%, less than 0.90%, less than 0.80%, less than 0.70%, less than 0.60%, or less than 0.55% when exposed to an increase in relative humidity from about 0% to about 80% relative humidity at 25°C. In some embodiments, a solid form (e.g., a crystalline form) of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein has a dynamic vapor sorption (DVS) plot that exhibits a mass gain (e.g., moisture sorption) of 0.55% to 10% when exposed to increasing relative humidity from about 0% to about 80% relative humidity at 25°C. In some embodiments, a solid form (e.g., a crystalline form) of the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid exhibits a mass gain (e.g., water sorption) of about 0.49% when exposed to an increase in relative humidity from about 0% to about 80% relative humidity at 25° C.In certain embodiments, a solid form (e.g., a crystalline form) of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid exhibits a DVS plot substantially as shown in Figure 4. Accordingly, the solid form (e.g., a crystalline form) of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein can be characterized as having extremely low hygroscopicity and being stable over a wide range of humidity.

[0164] In some embodiments, a solid form (e.g., a crystalline form) of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein has a differential scanning calorimetry (DSC) thermogram. In some embodiments, a solid form (e.g., a crystalline form) of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein has a DSC thermogram comprising an endothermic event with an onset temperature of about 176°C and a peak (melting point) at about 178°C. In certain embodiments, a solid form (e.g., a crystalline form) of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid exhibits a DSC thermogram substantially as shown in Figure 6. Thus, the solid form (e.g., a crystalline form) of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein can be characterized as having a relatively high melting point and being thermally stable.

[0165] In some embodiments, the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein exhibits a solubility of 1 mg / ml, 1.5 mg / ml, 2 mg / ml, 2.5 mg / ml, 3 mg / ml, 3.5 mg / ml, 4 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, 10 mg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, 15 mg / ml, 16 mg / ml, 17 mg / ml, 18 mg / ml, 19 mg / ml, 20 mg / ml, 21 mg / ml, 22 mg / ml, 23 mg / ml, 24 mg / ml, 25 mg / ml, 26 mg / ml, 27 mg / ml, 28 mg / ml, 29 mg / ml, 30 mg / ml, 31 mg / ml, 32 mg / ml, 33 mg / ml, 34 mg / ml, 35 mg / ml, 36 mg / ml, 37 mg / ml, 38 mg / ml, 39 mg / ml, 40 mg / ml, 41 mg / ml, 42 mg / ml, 43 mg / ml, 44 mg / ml, 45 mg / ml, 46 mg / ml, 47 mg / ml, 48 mg / ml, 49 mg / ml, 50 mg / ml, 51 mg / ml, 52 mg / ml, 53 mg / ml, 54 mg / ml, 55 mg / ml, 56 mg / ml, 57 mg / ml, 58 mg / ml, 59 mg / ml, 60 mg / ml, and having a solubility of greater than 0.5mg / ml, 5mg / ml, 5.5mg / ml, 6mg / ml, 6.5mg / ml, 7mg / ml, 7.5mg / ml, 8mg / ml, 8.5mg / ml, 9mg / ml, 9.5mg / ml, 10mg / ml, 11mg / ml, 12mg / ml, 13mg / ml, 14mg / ml, 15mg / ml, 16mg / ml, 17mg / ml, 18mg / ml, 19mg / ml, or 20mg / ml. In some embodiments, the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein has a solubility of greater than 1 mg / ml, 1.5 mg / ml, 2 mg / ml, 2.5 mg / ml, 3 mg / ml, 3.5 mg / ml, 4 mg / ml, 4.5 mg / ml, 5 mg / ml, 5.5 mg / ml, 6 mg / ml, 6.5 mg / ml, 7 mg / ml, 7.5 mg / ml, 8 mg / ml, 8.5 mg / ml, 9 mg / ml, 9.5 mg / ml, or 10 mg / ml in FaSSIF medium (pH 7.5) at 24 hours. In some embodiments, the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a solubility of greater than 7.99 mg / ml in FaSSIF medium (pH 7.5) at 24 hours.

[0166] In some embodiments, the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, exhibits a solubility of at least 0.5 mg / ml, 1 mg / ml, 1.5 mg / ml, 2 mg / ml, 2.5 mg / ml, 3 mg / ml, 3.5 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, 10 mg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, 15 mg / ml, 16 mg / ml, 17 mg / ml, 18 mg / ml, 19 mg / ml, 20 mg / ml, 21 mg / ml, 22 mg / ml, 23 mg / ml, 24 mg / ml, 25 mg / ml, 26 mg / ml, 27 mg / ml, 28 mg / ml, 29 mg / ml, 30 mg / ml, 31 mg / ml, 32 mg / ml, 33 mg / ml, 34 mg / ml, 35 mg / ml, 36 mg / ml, 37 mg / ml, 38 mg / ml, 39 mg / ml, 40 mg / ml, 41 mg / ml, 42 mg / ml, 43 mg / ml, 44 mg / ml, 45 mg / ml, 46 mg / ml, 47 mg / ml, 48 mg / ml, 49 mg / ml, 50 mg / ml, 51 mg / ml, 52 mg / ml, 53 mg / ml, 54 mg / ml, 55 mg / ml, 56 mg / ml, 57 mg / ml, 58 mg / ml, 59 mg / ml, 6 10 mg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, 15 mg / ml, 16 mg / ml, 17 mg / ml, 18 mg / ml, 19 mg / ml, or 20 mg / ml. In some embodiments, the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a solid or crystalline form thereof, provided herein has a solubility of at least 0.5 mg / ml, 1 mg / ml, 1.5 mg / ml, 2 mg / ml, 2.5 mg / ml, 3 mg / ml, 3.5 mg / ml, 4 mg / ml, 4.5 mg / ml, 5 mg / ml, 5.5 mg / ml, 6 mg / ml, 6.5 mg / ml, 7 mg / ml, 7.5 mg / ml, 8 mg / ml, 8.5 mg / ml, 9 mg / ml, 9.5 mg / ml, or 10 mg / ml in FeSSIF medium (pH 7.8) over 24 hours. In some embodiments, the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a solubility of greater than 8.02 mg / ml in FeSSIF medium (pH 7.8) at 24 hours.

[0167] In some embodiments, the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein has a solubility of greater than 7.99 mg / ml in 24 hours in FaSSIF medium (pH 7.5) and greater than 8.02 mg / ml in 24 hours in FeSSIF medium (pH 7.8).

[0168] In some embodiments, the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a solubility of at least 0.04 mg / ml, 0.05 mg / ml, 0.06 mg / ml, 0.07 mg / ml, 0.08 mg / ml, 0.09 mg / ml, 0.1 mg / ml, 0.2 mg / ml, 0.3 mg / ml, 0.4 mg / ml, 0.5 mg / ml, 0.6 mg / ml, 0.7 mg / ml, 0.8 mg / ml, 0.9 mg / ml, or 1 mg / ml in a pH 6.8 medium over 24 hours. In certain embodiments, the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a solubility of at least 0.06 mg / ml in a medium having a pH of 6.8 over 24 hours. In some embodiments, the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a solubility of 0.088 mg / ml in a medium having a pH of 6.8 over 24 hours.

[0169] In certain embodiments, the solid form (e.g., crystalline form) of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid can be characterized by particle analysis. In yet other embodiments, a sample of the solid form (e.g., crystalline form) of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid contains particles having lengths of about 100, about 90, about 80, about 70, about 60, about 50, about 40, about 30, about 20, about 10, or about 5 µm. In some embodiments, a sample of a solid form (e.g., a crystalline form) of the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid comprises particles having lengths of about 100, about 70, about 60, about 40, about 20, or about 10 μM.

[0170] In certain embodiments, a solid form (e.g., a crystalline form) of the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid can contain about 95% by weight or more, about 97% by weight or more, about 98% by weight or more, about 99% by weight or more, or about 99.5% by weight or more of the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0171] In certain embodiments, the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a concentration of about 0.1% by weight or less, about 0.11% by weight or less, about 0.12% by weight or less, about 0.13% by weight or less, about 0.14% by weight or less, about 0.15% by weight or less Less than or equal to about 0.16 weight%, less than or equal to about 0.17 weight%, less than or equal to about 0.18 weight%, less than or equal to about 0.19 weight%, less than or equal to about 0.2 weight%, less than or equal to about 0.21 weight%, less than or equal to about 0.22 weight%, about 0.23 % by weight or less, 0.24% by weight or less, 0.25% by weight or less, 0.26% by weight or less, 0.27% by weight or less, 0.28% by weight or less, 0.29% by weight or less, 0.3% by weight or less, about 0. 31 weight% or less, about 0.32 weight% or less, about 0.33 weight% or less, about 0.34 weight% or less, about 0.35 weight% or less, about 0.36 weight% or less, about 0.37 weight% or less, about 0.38 weight% or less , about 0.39% by weight or less, about 0.4% by weight or less, about 0.5% by weight or less, about 0.6% by weight or less, about 0.7% by weight or less, about 0.8% by weight or less, about 0.9% by weight or less, about 1% by weight or less, about 2% by weight %, about 3% or less, about 4% or less, about 5% or less, about 6% or less, about 7% or less, about 8% or less, about 9% or less, about 10% or less, about 11% or less, about 12% or less, about 13% or less, about 14% or less, about 15% or less, about 16% or less, about 17% or less, about 18% or less, about 19% or less, or about 20% or less by weight of water.

[0172] In embodiments, the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein exhibits superior pharmacokinetic properties compared to the free form of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or compared to other pharmaceutically acceptable salts of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0173] In some embodiments, the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein has a bioavailability of at least 50F%, 55F%, 60F%, 65F%, 70F%, 75F%, 80F%, 85F%, 90F%, 95F%, or 99F%. In some embodiments, the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a bioavailability of about 70F%, about 72F%, about 74F%, about 76F%, about 78F%, about 80F%, about 81F%, about 82F%, about 83F%, about 84F%, about 85F%, about 86F%, about 87F%, about 88F%, about 89F%, about 90F%, about 92F%, about 94F%, about 96F%, or about 98F%. In some embodiments, the bioavailability is oral bioavailability.

[0174] In some embodiments, the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, exhibits improved bioavailability compared to the free form of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. Unexpectedly, the inventors have found that the bioavailability of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, is improved compared to the free form of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. It has been found that the bioavailability of the benzoic acid in the free form is advantageously improved by at least about 1.1-fold, about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 1.6-fold, about 1.7-fold, about 1.8-fold, about 1.9-fold, about 2.0-fold, about 2.1-fold, about 2.2-fold, about 2.3-fold, about 2.4-fold, about 2.5-fold, about 2.6-fold, about 2.7-fold, about 2.8-fold, about 2.9-fold, or about 3.0-fold compared to the bioavailability of the benzoic acid in the free form. In certain embodiments, the bioavailability of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein is improved by about 2.3-fold compared to the bioavailability of the free form of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. In some embodiments, the bioavailability is oral bioavailability.

[0175] In some embodiments, the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein provides improved bioavailability compared to other pharmaceutically acceptable salts of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. Surprisingly, the inventors have found that the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a solid or crystalline form thereof, provided herein advantageously exhibits superior bioavailability compared to other salts of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, including the potassium(I), meglumine, tris(hydroxymethyl)aminomethane ("Tris"), tert-butylamine, ammonium, and lysine salts of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0176] The superior bioavailability of the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or its solid or crystalline form provided herein relative to the free form of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid as well as the other salts tested, particularly other amino salts of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, was unexpected and may offer distinct advantages, such as enhanced therapeutic efficacy, reduced dosage, less frequent administration, reduced undesirable side effects, and improved patient compliance.

[0177] tert-butylamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, and its solid or crystalline forms In embodiments, provided herein is the tert-butylamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, including its solid and crystalline forms.

[0178] In embodiments, provided herein is a solid form of the tert-butylamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0179] In some embodiments, provided herein is a crystalline form of the tert-butylamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0180] In some embodiments, the crystalline form of the tert-butylamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein is crystalline Form II.

[0181] In some embodiments, crystalline Form II of the tert-butylamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has an X-ray powder diffraction (XRPD) pattern. Figure 8 shows an example of an XRPD pattern for crystalline Form II. In some embodiments, the XRPD pattern for crystalline Form II of the tert-butylamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid includes at least one diffraction peak selected from 8.36, 13.96, and 17.50 degrees 2θ (±0.2 degrees 2θ). In some embodiments, crystalline Form II of the tert-butylamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising at least two peaks selected from 8.36, 13.96, and 17.50 degrees 2θ (±0.2 degrees 2θ). In some embodiments, crystalline Form II of the tert-butylamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising peaks at 8.36, 13.96, and 17.50 degrees 2θ (±0.2 degrees 2θ). In some embodiments, crystalline Form II of the tert-butylamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has an X-ray diffraction pattern substantially as shown in FIG. 8.

[0182] In certain embodiments, the crystalline form of the tert-butylamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid comprises at least 80%, at least 85%, at least 88%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% of crystalline Form II of the tert-butylamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein.

[0183] In certain embodiments, in a composition comprising the tert-butylamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, at least 80%, at least 85%, at least 88%, at least 90%, or at least 100% of the tert-butylamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid is at least 80%, at least 85%, at least 88%, at least 90%, or at least 100% of the tert-butylamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. %, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, or at least 99.9% is crystalline Form II of the tert-butylamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein.

[0184] In some embodiments, a solid form (e.g., a crystalline form) of the tert-butylamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein has a thermogravimetric analysis (TGA) plot: In some embodiments, a solid form (e.g., a crystalline form) of the tert-butylamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid exhibits a weight loss of less than 3%, less than 2.5%, less than 2%, less than 1.9%, less than 1.8%, less than 1.7%, less than 1.6%, less than 1.5%, less than 1.4%, less than 1.3%, less than 1.2%, less than 1.1%, less than 1.0%, less than 0.9%, less than 0.8%, less than 0.7%, less than 0.6%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, or less than 0.15% when heated from about 25°C to about 120°C, as determined by thermogravimetric analysis. In some embodiments, a solid form (e.g., a crystalline form) of the tert-butylamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid exhibits a weight loss of 0.15% to 3% when heated from about 25° C. to about 120° C. as measured by TGA. In some embodiments, a solid form (e.g., a crystalline form) of the tert-butylamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid exhibits a weight loss of 0.94% when heated from about 25° C. to about 120° C. as determined by thermogravimetric analysis. In certain embodiments, a solid form (e.g., a crystalline form) of the tert-butylamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has a TGA plot substantially as shown in Figure 3. Thus, a solid form (e.g., a crystalline form) of the tert-butylamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein can be characterized as thermally stable.

[0185] In some embodiments, a solid form (e.g., a crystalline form) of the tert-butylamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein has a dynamic vapor sorption (DVS) plot. In some embodiments, a solid form (e.g., a crystalline form) of the tert-butylamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid exhibits a mass increase (e.g., water sorption) of less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1.9%, less than 1.8%, less than 1.7%, less than 1.6%, less than 1.5%, less than 1.4%, less than 1.3%, or less than 1.2% when exposed to an increase in relative humidity from about 0% to about 80% relative humidity at 25° C. In some embodiments, a solid form (e.g., a crystalline form) of the tert-butylamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid exhibits a mass gain (e.g., water sorption) of 1.2% to 10% when exposed to an increase in relative humidity from about 0% to about 80% relative humidity at 25° C. In some embodiments, a solid form (e.g., a crystalline form) of the tert-butylamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid exhibits a mass gain (e.g., water sorption) of about 1.07% when exposed to an increase in relative humidity from about 0% to about 80% relative humidity at 25° C. In certain embodiments, a solid form (e.g., a crystalline form) of the tert-butylamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid exhibits a DVS plot substantially as shown in Figure 5. Thus, the solid form (e.g., a crystalline form) of the tert-butylamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein can be characterized as having extremely low hygroscopicity and being stable over a wide range of humidity.

[0186] In some embodiments, a solid form (e.g., a crystalline form) of the tert-butylamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein has a differential scanning calorimetry (DSC) thermogram. In some embodiments, a solid form (e.g., a crystalline form) of the tert-butylamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein has a DSC thermogram that includes an endothermic event with an onset temperature of about 175°C and a peak at about 180°C, and another endothermic event with an onset temperature of about 187°C and a peak at about 199°C. In certain embodiments, a solid form (e.g., a crystalline form) of the tert-butylamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid exhibits a DSC thermogram substantially as shown in Figure 7. Thus, the solid form (e.g., a crystalline form) of the tert-butylamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein can be characterized as having good thermal stability.

[0187] In some embodiments, the tert-butylamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein exhibits a cytotoxicity of 1 mg / ml, 1.5 mg / ml, 2 mg / ml, 2.5 mg / ml, 3 mg / ml, 3.5 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, 10 mg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, 15 mg / ml, 16 mg / ml, 17 mg / ml, 18 mg / ml, 19 mg / ml, 20 mg / ml, 21 mg / ml, 22 mg / ml, 23 mg / ml, 24 mg / ml, 25 mg / ml, 26 mg / ml, 27 mg / ml, 28 mg / ml, 29 mg / ml, 30 mg / ml, 31 mg / ml, 32 mg / ml, 33 mg / ml, 34 mg / ml, 35 mg / ml, 36 mg / ml, 37 mg / ml, 38 mg / ml, 39 mg / ml, 40 mg / ml, 41 mg / ml, 42 mg / ml, 43 mg / ml, 44 mg / ml, 45 mg / ml, 46 mg / ml, 47 mg / ml, 48 mg / ml, 49 mg / ml, 50 mg / ml, 51 mg / ml, 52 mg / ml, 53 mg / ml, 54 mg / ml, 55 mg / ml, 56 mg / ml, 57 mg / ml, 58 mg / ml, 59 mg / ml, 60 mg / ml, 61 having a solubility of greater than 4.5 mg / ml, 5 mg / ml, 5.5 mg / ml, 6 mg / ml, 6.5 mg / ml, 7 mg / ml, 7.5 mg / ml, 8 mg / ml, 8.5 mg / ml, 9 mg / ml, 9.5 mg / ml, 10 mg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, 15 mg / ml, 16 mg / ml, 17 mg / ml, 18 mg / ml, 19 mg / ml, or 20 mg / ml. In some embodiments, the tert-butylamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein has a solubility of greater than 1 mg / ml, 1.5 mg / ml, 2 mg / ml, 2.5 mg / ml, 3 mg / ml, 3.5 mg / ml, 4 mg / ml, 4.5 mg / ml, 5 mg / ml, 5.5 mg / ml, 6 mg / ml, 6.5 mg / ml, 7 mg / ml, 7.5 mg / ml, 8 mg / ml, 8.5 mg / ml, 9 mg / ml, 9.5 mg / ml, or 10 mg / ml in FaSSIF medium (pH 7.5) at 24 hours. In some embodiments, the tert-butylamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein has a solubility of greater than 2.52 mg / ml in FaSSIF medium (pH 7.5) at 24 hours.

[0188] In some embodiments, the tert-butylamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, exhibits a solubility of at least 0.5 mg / ml, 1 mg / ml, 1.5 mg / ml, 2 mg / ml, 2.5 mg / ml, 3 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, 10 mg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, 15 mg / ml, 16 mg / ml, 17 mg / ml, 18 mg / ml, 19 mg / ml, 20 mg / ml, 21 mg / ml, 22 mg / ml, 23 mg / ml, 24 mg / ml, 25 mg / ml, 26 mg / ml, 27 mg / ml, 28 mg / ml, 29 mg / ml, 30 mg / ml, 31 mg / ml, 32 mg / ml, 33 mg / ml, 34 mg / ml, 35 mg / ml, 36 mg / ml, 37 mg / ml, 38 mg / ml, 39 mg / ml, 40 mg / ml, 41 mg / ml, 42 mg / ml, 43 mg / ml, 44 mg / ml, 45 mg / ml, 46 mg / ml, 47 mg / ml, 48 mg / ml, 49 mg / ml, 50 mg / ml, 51 mg / ml, 52 mg / ml, 53 mg / ml, 54 mg / ml, 55 mg / ml, 56 mg / ml, 57 mg / ml, 58 mg / ml, 59 mg / ml, 60 mg / ml, , 4 mg / ml, 4.5 mg / ml, 5 mg / ml, 5.5 mg / ml, 6 mg / ml, 6.5 mg / ml, 7 mg / ml, 7.5 mg / ml, 8 mg / ml, 8.5 mg / ml, 9 mg / ml, 9.5 mg / ml, 10 mg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, 15 mg / ml, 16 mg / ml, 17 mg / ml, 18 mg / ml, 19 mg / ml, or 20 mg / ml. In some embodiments, the tert-butylamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a solid or crystalline form thereof, provided herein has a solubility of at least 0.5 mg / ml, 1 mg / ml, 1.5 mg / ml, 2 mg / ml, 2.5 mg / ml, 3 mg / ml, 3.5 mg / ml, 4 mg / ml, 4.5 mg / ml, 5 mg / ml, 5.5 mg / ml, 6 mg / ml, 6.5 mg / ml, 7 mg / ml, 7.5 mg / ml, 8 mg / ml, 8.5 mg / ml, 9 mg / ml, 9.5 mg / ml, or 10 mg / ml in FeSSIF medium (pH 7.8) over 24 hours. In some embodiments, the tert-butylamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a solubility of greater than 3.42 mg / ml in FeSSIF medium (pH 7.8) at 24 hours.

[0189] In some embodiments, the tert-butylamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein has a solubility of greater than 2.52 mg / ml in 24 hours in FaSSIF medium (pH 7.5) and greater than 3.42 mg / ml in 24 hours in FeSSIF medium (pH 7.8).

[0190] In some embodiments, the tert-butylamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a solubility of at least 0.04 mg / ml, 0.05 mg / ml, 0.06 mg / ml, 0.07 mg / ml, 0.08 mg / ml, 0.09 mg / ml, 0.1 mg / ml, 0.2 mg / ml, 0.3 mg / ml, 0.4 mg / ml, 0.5 mg / ml, 0.6 mg / ml, 0.7 mg / ml, 0.8 mg / ml, 0.9 mg / ml, or 1 mg / ml in a pH 6.8 medium over 24 hours. In certain embodiments, the tert-butylamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a solubility of at least 0.07 mg / ml in a medium having a pH of 6.8 over 24 hours. In some embodiments, the tert-butylamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a solubility of 0.071 mg / ml in a medium having a pH of 6.8 over 24 hours.

[0191] In some embodiments, the tert-butylamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a bioavailability of at least 50F%, 55F%, 60F%, 65F%, 70F%, 75F%, 80F%, 85F%, 90F%, 95F%, or 99F%. In some embodiments, the tert-butylamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, has a bioavailability of about 60F%. In some embodiments, the tert-butylamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein has a bioavailability of 59 F%. In some embodiments, the bioavailability is oral bioavailability.

[0192] Meglumine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, and solid or crystalline forms thereof In embodiments, provided herein is the meglumine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, including its solid and crystalline forms.

[0193] In embodiments, provided herein is a solid form of the meglumine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0194] In some embodiments, provided herein is a crystalline form of the meglumine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0195] In some embodiments, the crystalline form of the meglumine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein is crystalline Form III.

[0196] In some embodiments, crystalline Form III of the meglumine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has an X-ray powder diffraction (XRPD) pattern. Figure 9 shows an example of an XRPD pattern for crystalline Form III. In some embodiments, the XRPD pattern for crystalline Form III of the meglumine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid includes at least one diffraction peak selected from 6.6, 11.7, 15.9, 17.7, 23.7, and 26.6 degrees 2θ (±0.2 degrees 2θ). In some embodiments, crystalline Form III of the meglumine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising at least two peaks selected from 6.6, 11.7, 15.9, 17.7, 23.7, and 26.6 degrees 2Θ (± 0.2 degrees 2Θ). In some embodiments, crystalline Form III of the meglumine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising at least three peaks selected from 6.6, 11.7, 15.9, 17.7, 23.7, and 26.6 degrees 2Θ (± 0.2 degrees 2Θ). In some embodiments, crystalline Form III of the meglumine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising peaks at 6.6, 11.7, 15.9, and 17.7 degrees two-theta (±0.2 degrees two-theta). In some embodiments, crystalline Form III of the meglumine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has an X-ray diffraction pattern substantially as shown in Figure 9.

[0197] Tris(hydroxymethyl)aminomethane (Tris) salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, and its solid or crystalline forms In embodiments, provided herein is the tris(hydroxymethyl)aminomethane salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, including its solid and crystalline forms.

[0198] In embodiments, provided herein is a solid form of the tris(hydroxymethyl)aminomethane salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0199] In some embodiments, provided herein is a crystalline form of the tris(hydroxymethyl)aminomethane salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0200] In some embodiments, the crystalline form of the tris(hydroxymethyl)aminomethane salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein is crystalline Form IV.

[0201] In some embodiments, crystalline Form IV of the tris(hydroxymethyl)aminomethane salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has an X-ray powder diffraction (XRPD) pattern. Figure 10 shows an example of an XRPD pattern for crystalline Form IV. In some embodiments, the XRPD pattern for crystalline Form IV of the tris(hydroxymethyl)aminomethane salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid includes at least one diffraction peak selected from 5.78, 12.18, 15.94, and 17.24 degrees 2θ (±0.2 degrees 2θ). In some embodiments, crystalline Form IV of the tris(hydroxymethyl)aminomethane salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising at least two peaks selected from 5.78, 12.18, 15.94, and 17.24 degrees 2Θ (± 0.2 degrees 2Θ). In some embodiments, crystalline Form IV of the tris(hydroxymethyl)aminomethane salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising at least three peaks selected from 5.78, 12.18, 15.94, and 17.24 degrees 2Θ (± 0.2 degrees 2Θ). In some embodiments, crystalline Form IV of the tris(hydroxymethyl)aminomethane salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising peaks at 5.78, 12.18, 15.94, and 17.24 degrees two-theta (±0.2 degrees two-theta). In some embodiments, crystalline Form IV of the tris(hydroxymethyl)aminomethane salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has an X-ray diffraction pattern substantially as shown in Figure 10.

[0202] Potassium salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, and its solid or crystalline forms In embodiments, provided herein is the potassium salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, including its solid and crystalline forms.

[0203] In embodiments, provided herein is a solid form of the potassium salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0204] In some embodiments, provided herein is a crystalline form of the potassium salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0205] In some embodiments, the crystalline form of the potassium salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein is crystalline form V.

[0206] In some embodiments, crystalline Form V of the potassium salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has an X-ray powder diffraction (XRPD) pattern. Figure 11 shows an example of an XRPD pattern of crystalline Form V. In some embodiments, the XRPD pattern of crystalline Form V of the potassium salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid includes at least one diffraction peak selected from 9.84, 10.56, 14.10, and 25.06 degrees 2θ (±0.2 degrees 2θ). In some embodiments, crystalline Form V of the potassium salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising at least two peaks selected from 9.84, 10.56, 14.10, and 25.06 degrees two-theta (±0.2 degrees two-theta). In some embodiments, crystalline Form V of the potassium salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising at least three peaks selected from 9.84, 10.56, 14.10, and 25.06 degrees two-theta (±0.2 degrees two-theta). In some embodiments, crystalline Form V of the potassium salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising peaks at 9.84, 10.56, 14.10, and 25.06 degrees two-theta (±0.2 degrees two-theta). In some embodiments, crystalline Form V of the potassium salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has an X-ray diffraction pattern substantially as shown in Figure 11.

[0207] Ammonium salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, and its solid or crystalline forms In embodiments, provided herein is the ammonium salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, including its solid and crystalline forms.

[0208] In embodiments, provided herein is a solid form of the ammonium salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0209] In some embodiments, provided herein is a crystalline form of the ammonium salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0210] In some embodiments, the crystalline form of the ammonium salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein is crystalline Form VI.

[0211] In some embodiments, crystalline Form VI of the ammonium salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has an X-ray powder diffraction (XRPD) pattern. Figure 12 shows an example of an XRPD pattern for crystalline Form VI. In some embodiments, the XRPD pattern for crystalline Form VI of the ammonium salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid includes at least one diffraction peak selected from 8.10, 11.66, 17.62, and 26.64 degrees two-theta (±0.2 degrees two-theta). In some embodiments, crystalline Form VI of the ammonium salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising at least two peaks selected from 8.10, 11.66, 17.62, and 26.64 degrees 2Θ (± 0.2 degrees 2Θ). In some embodiments, crystalline Form VI of the ammonium salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising at least three peaks selected from 8.10, 11.66, 17.62, and 26.64 degrees 2Θ (± 0.2 degrees 2Θ). In some embodiments, crystalline Form VI of the ammonium salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising peaks at 8.10, 11.66, 17.62, and 26.64 degrees two-theta (±0.2 degrees two-theta). In some embodiments, the XRPD pattern of crystalline Form VI of the ammonium salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid comprises at least one diffraction peak selected from 8.10, 11.66, and 17.62 degrees two-theta (±0.2 degrees two-theta).In some embodiments, crystalline Form VI of the ammonium salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising at least two peaks selected from 8.10, 11.66, and 17.62 degrees 2Θ (± 0.2 degrees 2Θ). In some embodiments, crystalline Form VI of the ammonium salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising peaks at 8.10, 11.66, and 17.62 degrees 2Θ (± 0.2 degrees 2Θ). In some embodiments, crystalline Form VI of the ammonium salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has an X-ray diffraction pattern substantially as shown in FIG. 12.

[0212] Lysine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, and solid or crystalline forms thereof In embodiments, provided herein is the lysine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, including solid and crystalline forms thereof.

[0213] In embodiments, provided herein is a solid form of the lysine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0214] In some embodiments, provided herein is a crystalline form of the lysine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0215] In some embodiments, the crystalline form of the lysine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein is crystalline Form VII.

[0216] In some embodiments, crystalline Form VII of the lysine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has an X-ray powder diffraction (XRPD) pattern. Figure 13 shows an example of an XRPD pattern for crystalline Form VII. In some embodiments, the XRPD pattern for crystalline Form VII of the lysine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid comprises at least one diffraction peak selected from 11.76, 14.48, 18.60, and 27.22 degrees 2θ (±0.2 degrees 2θ). In some embodiments, crystalline Form VII of the lysine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising at least two peaks selected from 11.76, 14.48, 18.60, and 27.22 degrees two-theta (± 0.2 degrees two-theta). In some embodiments, crystalline Form VII of the lysine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising at least three peaks selected from 11.76, 14.48, 18.60, and 27.22 degrees two-theta (± 0.2 degrees two-theta). In some embodiments, crystalline Form VII of the lysine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising peaks at 11.76, 14.48, 18.60, and 27.22 degrees two-theta (± 0.2 degrees two-theta). In some embodiments, crystalline Form VII of the lysine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising at least one peak selected from 11.76, 14.48, and 18.60 degrees two-theta (± 0.2 degrees two-theta).In some embodiments, crystalline Form VII of the lysine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising at least two peaks selected from 11.76, 14.48, and 18.60 degrees 2Θ (± 0.2 degrees 2Θ). In some embodiments, crystalline Form VII of the lysine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising peaks at 11.76, 14.48, and 18.60 degrees 2Θ (± 0.2 degrees 2Θ). In some embodiments, crystalline Form VII of the lysine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has an X-ray diffraction pattern substantially as shown in FIG. 13.

[0217] Preparation Process Also provided herein are processes for preparing the solid forms, pharmaceutically acceptable salts, and crystalline forms thereof described herein.

[0218] Pharmaceutically acceptable salts of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (e.g., the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid) and crystalline forms thereof provided herein can be prepared by a process comprising contacting (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a salt or solvate thereof, with a suitable counterion source (e.g., ethanolamine), or a salt or solvate thereof, in a solvent at a first predetermined temperature.

[0219] In certain embodiments, in the contacting step to form a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, the molar ratio of the counterion source, or salt or solvate thereof, to (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or salt or solvate thereof, is about 1. In certain embodiments, the contacting step to form a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein is carried out in the presence of an excess amount of the counterion source, or salt or solvate thereof, relative to the (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or salt or solvate thereof, to maximize the yield of the process. In certain embodiments, the molar ratio of the counterion source, or salt or solvate thereof to the (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or salt or solvate thereof, is about 1.01 or greater, about 1.05 or greater, about 1.1 or greater, or about 1.2 or greater. In certain embodiments, the molar ratio of the counterion source, or salt or solvate thereof, to (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or salt or solvate thereof, is in the range of about 1.00 to about 10, about 1.05 to about 8, about 1.05 to about 5, about 1.1 to about 5, about 1.1 to about 3, about 1.1 to about 8, or about 1.2 to about 2.5.

[0220] Suitable solvents for use in the contacting step to form a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein include hydrocarbons including petroleum ether, pentane, hexane, heptane, octane, isooctane, cyclopentane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, tetralin, and cumene; dichloromethane (DCM), 1,2-dichloroethane, 1,1-dichloroethene, 1,2-dichloroethane, 1,1-dichloroethene, 1,2-dichloroethane, 1,2-dichloroethane, 1,1-dichloroethane, 1,2 ... Chlorinated hydrocarbons including chloroethene, chloroform, trichloroethane, trichloroethene, carbon tetrachloride, chlorobenzene, and trifluoromethylbenzene; alcohols including methanol, ethanol, isopropanol (IPA), 1-propanol, 1-butanol, 2-butanol, t-butanol, 3-methyl-1-butanol, 1-pentanol, 2-methoxyethanol, 2-ethoxyethanol, and ethylene glycol; diethyl ether, diisopropyl ether, methyl t-butyl ether (MTBE), diphenyl ether Ethers including ether, 1,2-dimethoxyethane, bi(2-methoxyethyl)ether, 1,1-dimethoxymethane, 2,2-dimethoxypropane, and anisole; ketones including acetone, butanone, methyl ethyl ketone (MEK), methyl isopropyl ketone, methyl butyl ketone, and methyl isobutyl ketone (MIBK); esters including methyl acetate, ethyl formate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, and butyl acetate; carbonates including ethylene carbonate and propylene carbonate; formamide, N,N-diisopropyl ether ... Amides, including methylformamide (DMF) and N,N-dimethylacetamide; nitriles, including acetonitrile (ACN); sulfoxides, such as dimethyl sulfoxide (DMSO); sulfones, such as sulfolane; nitro compounds, such as nitromethane and nitrobenzene; heterocycles, such as N-methylpyrrolidinone, 2-methyltetrahydrofuran, tetrahydrofuran (THF), dioxane, and pyridine; carboxylic acids, such as acetic acid, trichloroacetic acid, and trifluoroacetic acid; phosphoramides, such as hexamethylphosphoramide; carbon sulfide; water;and mixtures thereof;

[0221] In certain embodiments, the solvent for the contacting step to form a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein is acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, N,N-dimethylformamide, dimethyl sulfoxide, a lower alkanol (e.g., methanol, ethanol, n-propanol, isopropanol, sec-butanol, or 2-methoxyethanol), methyl acetate, ethyl acetate, ethyl formate, isopropyl acetate, isobutyl acetate, chloroform, dichloromethane, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, petroleum ether, hexane, heptane, toluene, water, or a mixture thereof. In another embodiment, the solvent for the contacting step to form a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein is C 1-5 In yet another embodiment, the solvent for the contacting step to form a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein comprises methanol, ethanol, propanol, isopropanol, sec-butanol, 2-methoxyethanol, or a mixture thereof.

[0222] In certain embodiments, the solvent for the contacting step to form a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein is selected from methanol, ethanol, isopropanol, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, tetrahydrofuran, toluene, n-heptane, 1,4-dioxane, water, dichloromethane, acetic acid, or a mixture thereof.

[0223] In some embodiments, the contacting step to form a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein is carried out at a temperature ranging from about −10 to about 150° C., about 10 to about 110° C., or about 20 to about 100° C., e.g., about 20° C., about 30° C., about 40° C., about 50° C., about 60° C., about 70° C., about 80° C., about 90° C., or about 100° C.

[0224] In some embodiments, the processes provided herein each further include preparing a solid form of a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein (e.g., the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid) at a second predetermined temperature. Solid forms of the pharmaceutically acceptable salts of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein can be prepared from a solution or slurry of the pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid in a solvent using conventional methods, including, but not limited to, cooling, chilling, solvent evaporation, or addition of an antisolvent. Other formation methods, including spray drying, roller drying, freeze drying, and melt crystallization, can also be applied.

[0225] In some embodiments, the processes provided herein each further include a step of crystallizing a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein (e.g., the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid) at a second predetermined temperature.

[0226] The process for preparing a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (e.g., the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid) in amorphous or crystalline form comprises the steps of: The process may further comprise contacting the compound with a solvent, wherein fine particles of the pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid in amorphous form, or a solid or crystalline form of the pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solvate thereof, may be formed from the solution or may be converted from one solid form to another. The process may further comprise an isolation step, wherein the compound is isolated by conventional methods such as filtration and centrifugation, followed by washing with a solvent and then drying (e.g., vacuum oven drying, air drying, or desiccator drying).

[0227] Suitable solvents for use in preparing the pharmaceutically acceptable salts of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein (e.g., the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid) in amorphous or crystalline form include petroleum ether, pentane, hexane, heptane, octane, isooctane, cyclopentane, cyclohexane, methylcyclohexane, benzoic acid ... Hydrocarbons including benzene, toluene, xylene, tetralin, and cumene; chlorinated hydrocarbons including dichloromethane (DCM), 1,2-dichloroethane, 1,1-dichloroethene, 1,2-dichloroethene, chloroform, trichloroethane, trichloroethene, carbon tetrachloride, chlorobenzene, and trifluoromethylbenzene; methanol, ethanol, isopropanol (IPA), 1-propanol, 1-butanol, 2-butanol, t-butanol, 3-methyl-1-butanol, 1-pentanol, 2-methoxyethanol, 2-ethoxyethanol alcohols, including diethanol, and ethylene glycol; ethers, including diethyl ether, diisopropyl ether, methyl t-butyl ether (MTBE), diphenyl ether, 1,2-dimethoxyethane, bi(2-methoxyethyl) ether, 1,1-dimethoxymethane, 2,2-dimethoxypropane, and anisole; ketones, including acetone, butanone, methyl ethyl ketone (MEK), methyl isopropyl ketone, methyl butyl ketone, and methyl isobutyl ketone (MIBK); methyl acetate, ethyl formate, ethyl acetate, propyl acetate, isopropyl acetate, and methyl methyl ether. esters including isopropyl, isobutyl acetate, and butyl acetate; carbonates including ethylene carbonate and propylene carbonate; amides including formamide, N,N-dimethylformamide (DMF), and N,N-dimethylacetamide; nitriles including acetonitrile (ACN); sulfoxides such as dimethyl sulfoxide (DMSO); sulfones such as sulfolane; nitro compounds such as nitromethane and nitrobenzene; heterocycles such as N-methylpyrrolidinone, 2-methyltetrahydrofuran, tetrahydrofuran (THF), dioxane, and pyridine;These include, but are not limited to, carboxylic acids such as acetic acid, trichloroacetic acid, and trifluoroacetic acid; phosphoramides such as hexamethylphosphoramide; carbon sulfide; water; and mixtures thereof.

[0228] In various embodiments, the solvent for preparing a crystalline form of a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein (e.g., the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid) is acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, N,N-dimethylformamide, dimethyl sulfoxide, a lower alkanol (e.g., methanol, ethanol, n-propanol, isopropanol, sec-butanol, or 2-methoxyethanol), methyl acetate, ethyl acetate, ethyl formate, isopropyl acetate, isobutyl acetate, chloroform, dichloromethane, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, petroleum ether, hexane, heptane, toluene, water, or a mixture thereof. In one embodiment, the solvent for crystallization comprises a C1-5 alkanol, hi another embodiment, the solvent for crystallization comprises methanol, ethanol, propanol, isopropanol, sec-butanol, 2-methoxyethanol, or a mixture thereof.

[0229] In certain embodiments, crystallization is carried out using conventional methods, including, but not limited to, cooling, chilling, solvent evaporation, anti-solvent addition, or anti-solvent back-addition. In certain embodiments, crystallization is carried out at a temperature ranging from about −50 to about 100° C., about −30 to about 50° C., or about −10 to about 30° C. In certain embodiments, the process further comprises a seeding step to accelerate crystallization. In certain embodiments, the process further comprises an isolation step, in which the formed solid is isolated by conventional methods, such as filtration and centrifugation, followed by washing with a solvent and then drying.

[0230] In certain embodiments, crystallization is achieved by cooling a solution containing a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein (e.g., the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein) to room temperature or below, or by solvent evaporation. In certain embodiments, crystallization is carried out by adding an anti-solvent to a solution containing a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or by adding a solution containing a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid to an anti-solvent.

[0231] Suitable anti-solvents include hydrocarbons including petroleum ether, pentane, hexane, heptane, octane, isooctane, cyclopentane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, tetralin, and cumene; chlorinated hydrocarbons including dichloromethane, 1,2-dichloroethane, 1,1-dichloroethene, 1,2-dichloroethene, chloroform, trichloroethane, trichloroethene, carbon tetrachloride, chlorobenzene, and trifluoromethylbenzene; alcohols including isopropanol, 1-propanol, 1-butanol, 2-butanol, t-butanol, 3-methyl-1-butanol, 1-pentanol, 2-ethoxyethanol, and ethylene glycol; ethers including diethyl ether, diisopropyl ether, methyl t-butyl ether (MTBE), diphenyl ether, 1,2-dimethoxyethane, bi(2-methoxyethyl)ether, 1,1-dimethoxymethane, 2,2-dimethoxypropane, and anisole; acetone. ketones including butanone, methyl ethyl ketone (MEK), methyl isopropyl ketone, methyl butyl ketone, and methyl isobutyl ketone (MIBK); esters including methyl acetate, ethyl formate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, and butyl acetate; carbonates including ethylene carbonate and propylene carbonate; amides including formamide, N,N-dimethylformamide (DMF), and N,N-dimethylacetamide; nitriles including acetonitrile (ACN); sulfoxides such as dimethyl sulfoxide (DMSO); sulfones such as sulfolane; nitro compounds such as nitromethane and nitrobenzene; heterocycles such as N-methylpyrrolidinone, 2-methyltetrahydrofuran, tetrahydrofuran (THF), dioxane, and pyridine; carboxylic acids such as acetic acid, trichloroacetic acid, and trifluoroacetic acid; phosphoramides such as hexamethylphosphoramide; carbon sulfide; water; and mixtures thereof.

[0232] When two solvents are used as a solvent / antisolvent pair, a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (e.g., the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid) has a higher solubility in the solvent than in the antisolvent. Optionally, the solvent and antisolvent in the solvent / antisolvent pair are at least partially miscible.

[0233] In some embodiments, a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein (e.g., the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid) or a solid or crystalline form thereof exhibits ease of manufacture or processing, and / or improved solidification and / or crystallization properties. As a result, in some embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein (e.g., the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid) or a solid or crystalline form thereof is obtained in higher yield or via fewer preparation or purification steps compared to the free form of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or compared to other pharmaceutically acceptable salts of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. In some embodiments, a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein (e.g., the ethanolamine salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid) or a solid or crystalline form thereof is obtained in greater purity (e.g., substantially pure or substantially homogeneous) compared to the free form of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or compared to other pharmaceutically acceptable salts of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0234] Pharmaceutical Composition Also provided herein are pharmaceutical compositions comprising a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein (e.g., the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid), or a solid or crystalline form thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0235] The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on the solubility and stability of the active ingredient, and the nature of the dosage form.

[0236] The pharmaceutical compositions provided herein can be formulated into various dosage forms for oral, parenteral, and topical administration. The pharmaceutical compositions can also be formulated as modified-release dosage forms, including delayed-release, sustained-release, extended-release, sustained-release, pulsed-release, controlled-release, accelerated-release, rapid-release, targeted-release, programmed-release, and gastroretentive dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see Remington: The Science and Practice of Pharmacy (supra); Modified-Release Drug Delivery Technology, 2nd Edition, Rathbone et al., Eds., Marcel Dekker, Inc.: New York, NY, 2008).

[0237] In one embodiment, the pharmaceutical compositions provided herein are formulated in a dosage form for oral administration, which comprises a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, and one or more pharmaceutically acceptable excipients.

[0238] In one embodiment, an oral pharmaceutical composition comprises a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein or a solid or crystalline form thereof, and one or more pharmaceutically acceptable excipients, each of which is independently selected from candelilla wax, cellulose acetate, crospovidone or povidone, dibutyl sebacate, ethylcellulose, glyceryl behenate, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol (e.g., PEG 400 or PEG 8000), polyvinyl alcohol, polysorbate (e.g., polysorbate 80), sodium carboxymethylcellulose, sodium dioxide, sodium lauryl sulfate, synthetic black iron oxide, titanium dioxide, triacetin, hydrochloric acid, potassium bicarbonate, calcium saccharin, xylitol, water, and cherry flavor.

[0239] In another embodiment, an oral pharmaceutical composition comprises a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein or a solid or crystalline form thereof, and one, two, or more pharmaceutically acceptable excipients, each of which is independently selected from candelilla wax, cellulose acetate, corn starch, crospovidone or povidone, dibutyl sebacate, ethylcellulose, glyceryl behenate, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, polysorbate, sodium carboxymethylcellulose, sodium dioxide, sodium lauryl sulfate, synthetic black iron oxide, titanium dioxide, and triacetin.

[0240] In one embodiment, the oral pharmaceutical composition is a tablet. In another embodiment, the oral pharmaceutical composition is a sustained release tablet. In yet another embodiment, the oral pharmaceutical composition is a coated tablet.

[0241] In another embodiment, the pharmaceutical compositions provided herein are formulated in a dosage form for parenteral administration, comprising a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, and one or more pharmaceutically acceptable excipients. In one embodiment, the pharmaceutical compositions provided herein are formulated in a dosage form for intravenous administration. In another embodiment, the pharmaceutical compositions provided herein are formulated in a dosage form for intramuscular administration. In yet another embodiment, the pharmaceutical compositions provided herein are formulated in a dosage form for subcutaneous administration.

[0242] In yet another embodiment, the pharmaceutical compositions provided herein are formulated in a dosage form for topical administration, which comprises a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein or a solid or crystalline form thereof, and one or more pharmaceutically acceptable excipients.

[0243] The pharmaceutical compositions provided herein may be provided in unit-dosage form or multiple-dosage form. As used herein, unit-dosage form refers to a physically discrete unit suitable for administration to human and animal subjects and packaged individually as known in the art. Each unit dose contains a predetermined amount of active ingredient sufficient to produce the desired therapeutic effect, in association with the necessary pharmaceutical carriers or excipients. Examples of unit-dosage forms include ampoules, syringes, and individually packaged tablets and capsules. A unit-dosage form may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dosage form. Examples of multiple-dosage forms include vials, bottles of tablets or capsules, or bottles of pints or gallons.

[0244] In certain embodiments, the pharmaceutical compositions provided herein contain, in each unit dosage form, an amount in the range of about 10 to about 10,000 mg of a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof. In certain embodiments, the pharmaceutical compositions provided herein comprise, in each unit dosage form, a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, in an amount of about 10, about 50, about 100, about 200, about 300, about 400, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 850, about 900, about 950, about 1000, about 1050, about 1100, about 1150, about 1200, about 1250, about 1300, about 1350, about 1400, about 1450, and about 1500 mg.

[0245] In some embodiments, the pharmaceutical compositions provided herein comprise, in each unit dosage form, an amount of about 10, about 50, about 100, about 150, about 200, about 250, about 300, about 400, about 450, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 850, about 900, about 950, about 1000, about 1050, about 1100, about 1150, about 1200, about 1250, about 1300, about 1350, about 1400, about 1450, or about 1500 mg of a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof.

[0246] In some embodiments, the pharmaceutical compositions provided herein comprise, in each unit dosage form, about 20, about 30, about 40, about 50, about 100, about 150, about 200, about 250, about 300, about 350, or about 400 mg of a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof.

[0247] In certain embodiments, the pharmaceutical compositions provided herein comprise, in each unit dosage form, a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, in an amount ranging from about 1 to about 100, about 1 to about 50, about 2 to about 20, or about 2 to about 10 mg. In certain embodiments, the pharmaceutical compositions provided herein comprise, in each unit dosage form, an amount of about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 mg of a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof.

[0248] In some embodiments, the pharmaceutical compositions provided herein comprise a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, in an amount of about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 210, about 220, about 230, about 240, about 250, about 260, about 270, about 280, about 290, about 300, about 310, about 320, about 330, about 340, about 350, about 360, about 370, about 380, about 390, about 410, about 420, about 430, about 440, about 450, about 460, about 470, about 480, about 490, about 500, about 510, about 520, about 530, about 540, about 550, about 560, about 570, about 580, about 590, about 600, about 610, about 620, about 630, about 640, about 650, about 660, about 670, about 680, about 690, about 700, about 710, about 720, about 730, about 740, about 750, about 760, about 7 , about 180, about 190, about 200, about 210, about 220, about 230, about 240, about 250, about 260, about 270, about 280, about 290, about 300, about 310, about 320, about 330, about 340, about 350, about 360, about 370, about 380, about 390, or about 400 mg / kg of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. In some embodiments, the pharmaceutical compositions provided herein comprise a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, in an amount effective to provide a dose of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid of about 10 to about 400 mg / kg, about 50 to about 300 mg / kg, or about 100 to about 250 mg / kg. In certain embodiments, the pharmaceutical compositions provided herein comprise a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, in an amount effective to provide a dose of about 200 mg / kg of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0249] In some embodiments, the pharmaceutical compositions provided herein comprise a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, in an amount effective to provide a concentration of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid at its site of action of 10 μM to 200 μM, 10 μM to 100 μM, or 10 μM to 50 μM. In some embodiments, the pharmaceutical compositions provided herein comprise a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein, or a solid or crystalline form thereof, in an amount effective to provide a concentration of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid at its site of action of about 20 to about 40 μM, about 25 to about 35 μM, or about 30 μM.

[0250] As used herein, the "site of action" of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid may refer to a cell or tissue affected by fibrosis, inflammation, and / or proliferation, or a cell or tissue involved in the progression of fibrosis, inflammation, and / or proliferation.

[0251] The pharmaceutical compositions provided herein can be administered once or multiple times at intervals.It is understood that the exact dosage and duration of treatment may vary depending on the age, weight and condition of the patient being treated, and can be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro testing or diagnostic data.It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual's needs and the professional judgment of the person administering or prescribing the formulation.

[0252] The pharmaceutical compositions provided herein are intended to be administered by a suitable route, including oral administration in the form of a liquid formulation, including capsules, tablets, granules, powders, or syrups; parenteral administration (as a sterile injectable aqueous or non-aqueous solution or suspension) by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques; intranasal administration, such as by inhalation spray; topical administration in the form of a cream or ointment; rectal administration, such as in the form of a suppository; liposomal administration; and topical administration. The compositions may be in liquid, semi-liquid, or solid form and are formulated in a manner suitable for each administration route. In certain embodiments, administration of the formulations includes parenteral and oral administration modes. In various embodiments, the pharmaceutical compositions provided herein are administered orally. In one embodiment, the pharmaceutical compositions provided herein are administered directly into the eye by injection.

[0253] Oral administration The pharmaceutical compositions for oral administration provided herein can be provided in solid, semi-solid, or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, fast melts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups. In addition to the active ingredient, the pharmaceutical composition may contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, dye transfer inhibitors, sweeteners, flavoring agents, emulsifiers, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and carbon dioxide sources.

[0254] Binders or granulating agents impart cohesive properties to the tablet to ensure that the tablet remains intact after compression. Suitable binders or granulating agents include starches such as corn starch, potato starch, and pregelatinized starch (e.g., STARCH 1500); gelatin; sugars such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums such as acacia, alginic acid, alginates, Irish moss extract, panwar gum, ghatti gum, isagol shell mucilage, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses such as ethylcellulose, cellulose acetate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC); AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC) Microcrystalline cellulose, such as cellulose acetate (Cellulose, Inc., Marcus Hook, PA); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler may be present in the pharmaceutical compositions provided herein at about 50 to about 99% by weight.

[0255] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.When present in sufficient amounts, certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, can impart properties to some compressed tablets that allow them to disintegrate in the oral cavity by chewing.Such compressed tablets can be used as chewable tablets.The amount of diluent in the pharmaceutical compositions provided herein varies depending on the type of formulation, and is easily recognizable to those skilled in the art.

[0256] Suitable disintegrants include, but are not limited to, agar, bentonite, celluloses such as methylcellulose and carboxymethylcellulose, wood products, natural sponge, cation exchange resins, alginic acid, gums such as guar gum and Vee gum HV, citrus pulp, cross-linked celluloses such as croscarmellose, cross-linked polymers such as crospovidone, cross-linked starch, calcium carbonate, microcrystalline cellulose such as sodium starch glycolate, polacrilin potassium, starches such as corn starch, potato starch, tapioca starch, and pregelatinized starch, clays, aligns, and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions provided herein varies depending on the type of formulation and is readily discernible to those skilled in the art. The pharmaceutical compositions provided herein may contain about 0.5 to about 15% by weight or about 1 to about 5% by weight of disintegrant.

[0257] Suitable lubricants include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, glycols such as glycerol behenate and polyethylene glycol (PEG), stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil, zinc stearate, ethyl oleate, ethyl laurate, agar, starch, lycopodium, silica or silica gel such as AEROSIL® 200 and CAB-O-SIL®, and mixtures thereof. The pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant.

[0258] Suitable glidants include colloidal silicon dioxide, CAB-O-SIL® (Cabot Co., Boston, MA), and asbestos-free talc. Coloring agents include any of the approved certified water-soluble FD&C dyes and water-insoluble FD&C dyes suspended in alumina hydroxide, as well as color lakes and mixtures thereof. Color lakes are combinations of water-soluble dyes adsorbed onto hydrous oxides of heavy metals, resulting in an insoluble form of the dye. Flavoring agents include natural flavors extracted from plants such as fruits, and synthetic blends of compounds that produce a pleasant taste, such as peppermint and methyl salicylate. Sweetening agents include sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners such as saccharin and aspartame. Suitable emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate (TWEEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEEN® 80), and triethanolamine oleate. Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate, and alcohol. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Organic acids include citric acid and tartaric acid. Carbon dioxide sources include sodium bicarbonate and sodium carbonate.

[0259] It will be appreciated that many carriers and excipients may serve several functions, even within the same formulation.

[0260] The pharmaceutical compositions provided herein may be provided as compressed tablets, powder tablets, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coated, sugar-coated, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the action of stomach acid but dissolves or disintegrates in the intestine, thus protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylates, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can be beneficial for masking objectionable tastes or odors and protecting the tablets from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings impart general properties similar to those of sugar coatings. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets and press-coated or dry-coated tablets.

[0261] Tablet dosage forms may be prepared from the active ingredient in powdered, crystalline, or granular form, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and / or coloring agents. Flavoring and sweetening agents are particularly useful in the formation of chewable tablets and lozenges.

[0262] The pharmaceutical compositions provided herein may be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFCs), consist of two sections, one over the other, thus completely enclosing the active ingredient. Soft elastic capsules (SECs) are soft, spherical shells, such as gelatin shells plasticized by the addition of glycerin, sorbitol, or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives are those described herein, including methylparaben and propylparaben, and sorbic acid. The liquid, semisolid, and solid dosage forms provided herein may be encapsulated. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Patent Nos. 4,328,245, 4,409,239, and 4,410,545. The capsules can also be coated as known to those skilled in the art to modify or sustain dissolution of the active ingredient.

[0263] The pharmaceutical compositions provided herein may be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. Emulsions are two-phase systems in which one liquid is dispersed in the form of small globules throughout another liquid and may be oil-in-water or water-in-oil. Emulsions may contain a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. Suspensions may contain a pharmaceutically acceptable suspending agent and preservative. Hydroalcoholic solutions may contain a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde (the term "lower" means an alkyl having 1 to 6 carbon atoms), e.g., acetaldehyde diethyl acetal, and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, e.g., sucrose, and may also contain a preservative. For a liquid dosage form, the solution, for example, for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, eg, water, to be conveniently measured for administration.

[0264] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredients provided herein and dialkylated mono- or polyalkylene glycols, including 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, and polyethylene glycol-750-dimethyl ether (350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol). These formulations may further contain one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

[0265] The pharmaceutical compositions for oral administration provided herein may also be provided in the form of liposomes, micelles, microspheres, or nanosystems. Micelle dosage forms can be prepared as described in U.S. Patent No. 6,350,458.

[0266] The pharmaceutical compositions provided herein may be provided as non-effervescent or effervescent granules and powders to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may include organic acids and a carbon dioxide source.

[0267] Coloring and flavoring agents may be used in all of the above dosage forms.

[0268] The pharmaceutical compositions provided herein may be formulated as immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release forms.

[0269] The pharmaceutical compositions provided herein may also be combined with other active ingredients that do not impair the desired therapeutic action, or with substances that complement the desired action.

[0270] Parenteral administration The pharmaceutical compositions provided herein can be administered parenterally by injection, infusion, or implantation for local or systemic administration. As used herein, parenteral administration includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.

[0271] The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for dissolution or suspension in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical sciences (see Remington: The Science and Practice of Pharmacy, supra).

[0272] Pharmaceutical compositions intended for parenteral administration may contain one or more pharmaceutically acceptable carriers and excipients including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against microbial growth, stabilizers, solubility enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestrating or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.

[0273] Suitable aqueous vehicles include, but are not limited to, water, saline, normal saline or phosphate-buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water for injection, dextrose and lactated Ringer's injection. Non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil and palm seed oil. Water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycols (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethyl sulfoxide.

[0274] Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercury, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoate, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl and propylparaben, and sorbic acid. Suitable isotonicity agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphates and citrates. Suitable antioxidants include those described herein, including bisulfites and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents include those described herein, including sodium carboxymethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents include those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH adjusters include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, and sulfobutylether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, KS).

[0275] The pharmaceutical compositions provided herein may be formulated for single or multiple doses. Single dose formulations are packaged in ampoules, vials, or syringes. Multi-dose parenteral formulations must contain bacteriostatic or fungistatic concentrations of antibacterial agents. All parenteral formulations must be sterile, as known and practiced in the art.

[0276] In one embodiment, pharmaceutical compositions for parenteral administration are provided as ready-to-use sterile solutions. In another embodiment, pharmaceutical compositions are provided as sterile dry soluble products, including lyophilized powders and subcutaneous tablets, to be reconstituted with a vehicle before use. In yet another embodiment, pharmaceutical compositions are provided as ready-to-use sterile suspensions. In yet another embodiment, pharmaceutical compositions are provided as sterile dry insoluble products to be reconstituted with a vehicle before use. In yet another embodiment, pharmaceutical compositions are provided as ready-to-use sterile emulsions.

[0277] The pharmaceutical compositions provided herein may be formulated as immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release forms.

[0278] The pharmaceutical compositions may be formulated as a suspension, solid, semi-solid, or thixotropic liquid for administration as an implanted depot. In one embodiment, the pharmaceutical compositions provided herein are dispersed in a solid inner matrix surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredients in the pharmaceutical composition to diffuse through.

[0279] Suitable inner matrices include polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.

[0280] Suitable outer polymeric membranes include polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl acetate, vinylidene chloride, ethylene and vinyl chloride copolymers with propylene, ionomeric polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyloxyethanol copolymers.

[0281] Topical administration The pharmaceutical compositions provided herein may be administered topically to the skin, orifices, or mucosa. As used herein, topical administration includes cutaneous (intradermal), intraconjunctival, intracorneal, intraocular, ophthalmic, otic, transdermal, nasal, vaginal, urethral, ​​respiratory, and rectal administration.

[0282] The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for topical administration for local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, washes, sprays, suppositories, bandages, and skin patches. Topical formulations of the pharmaceutical compositions provided herein can also include liposomes, micelles, microspheres, nanosystems, and mixtures thereof.

[0283] Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations provided herein include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against microbial growth, stabilizers, solubility enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestrating or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.

[0284] Pharmaceutical compositions may also be administered locally by electroporation, iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection, e.g., POWDERJECT™ (Chiron Corp., Emeryville, CA), and BIOJECT™ (Bioject Medical Technologies Inc., Tualatin, OR).

[0285] The pharmaceutical compositions provided herein can be provided in the form of ointment, cream, and gel.Suitable ointment vehicles include oily or hydrocarbon vehicles, including lard, benzoic lard, olive oil, cottonseed oil, and other oils, white petrolatum; emulsifying or absorbing vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles, such as hydrophilic ointments; water-soluble ointment vehicles, including polyethylene glycols of various molecular weights; emulsion vehicles, such as water-in-oil (W / O) emulsion or oil-in-water (O / W) emulsion, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid (see Remington: The Science and Practice of Pharmacy, supra).These vehicles are emollient, but generally require the addition of antioxidants and preservatives.

[0286] Suitable cream bases can be oil-in-water or water-in-oil.Suitable cream vehicles can be water-washable and contain an oil phase, an emulsifier, and an aqueous phase.The oil phase, also called the "internal" phase, is generally composed of petrolatum and fatty alcohols such as cetyl or stearyl alcohol.The aqueous phase usually, but not necessarily, exceeds the oil phase in volume and generally contains a moisturizer.The emulsifier in a cream formulation can be a nonionic, anionic, cationic, or amphoteric surfactant.

[0287] Gels are semi-solid suspension-type systems. Single-phase gels contain organic polymers dispersed substantially uniformly throughout the liquid carrier. Suitable gelling agents include, but are not limited to, cross-linked acrylic acid polymers such as carbomer, carboxypolyalkylene, and CARBOPOL®; hydrophilic polymers such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymer, and polyvinyl alcohol; cellulose-based polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, and methylcellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin. To prepare a uniform gel, dispersants such as alcohol or glycerin can be added, or the gelling agent can be dispersed by grinding, mechanical mixing, and / or stirring.

[0288] The pharmaceutical compositions provided herein may be administered rectally, urethrally, vaginally, or perivaginally in the form of a suppository, pessary, bougie, poultices or cataplasm, paste, powder, dressing, cream, plaster, contraceptive, ointment, solution, emulsion, suspension, tampon, gel, foam, spray, or enema. These dosage forms can be prepared using conventional processes, such as those described in Remington: The Science and Practice of Pharmacy, supra.

[0289] Rectal, urethral, ​​and vaginal suppositories are solids for insertion into body orifices. They are solid at room temperature but melt or soften at body temperature, releasing the active ingredient into the orifice. Pharmaceutically acceptable carriers used in rectal and vaginal suppositories include bases or vehicles, such as stiffening agents, that, when formulated with the pharmaceutical compositions provided herein, produce melting points close to body temperature, as well as antioxidants, as described herein, including bisulfite and sodium metabisulfite. Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow waxes, and appropriate mixtures of mono-, di-, and triglycerides of fatty acids, as well as hydrogels such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid. Combinations of various vehicles can also be used. Rectal and vaginal suppositories can be prepared by compression or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g.

[0290] The pharmaceutical compositions provided herein may be administered ophthalmically in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solution, gels, ocular inserts, and implants.

[0291] The pharmaceutical compositions provided herein can be administered intranasally or by inhalation into the respiratory tract. The pharmaceutical compositions can be provided in the form of an aerosol or solution, alone or in combination with a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, for delivery using a pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to generate a fine mist, or nebulizer. The pharmaceutical compositions can also be provided as dry powders for insufflation, alone or in combination with an inert carrier, such as lactose or phospholipids, and as nasal drops. For intranasal use, the powder can include a bioadhesive agent, including chitosan or cyclodextrin.

[0292] Solutions or suspensions for use in pressurized containers, pumps, sprays, atomizers, or nebulizers can be formulated to contain ethanol, aqueous ethanol, or a suitable substitute, a propellant as a solvent, and / or a surfactant such as sorbitan trioleate, oleic acid, or oligolactic acid to disperse, solubilize, or extend the release of the active ingredients provided herein.

[0293] The pharmaceutical compositions provided herein can be micronized to a size suitable for delivery by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less. Particles of such sizes can be prepared using comminution methods known to those skilled in the art, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

[0294] Capsules, blisters, and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mix of the pharmaceutical composition provided herein, a suitable powder base such as lactose or starch, and a performance modifier such as l-leucine, mannitol, or magnesium stearate. Lactose can be anhydrous or in the form of the monohydrate. Other suitable excipients or carriers include, but are not limited to, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The pharmaceutical compositions provided herein for inhaled / intranasal administration can further comprise a suitable flavoring agent, such as menthol and levomenthol, and / or a sweetener, such as saccharin or saccharin sodium.

[0295] The pharmaceutical compositions provided herein for topical administration may be formulated to be immediate or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release.

[0296] controlled release The pharmaceutical compositions provided herein may be formulated as modified-release dosage forms. As used herein, the term "modified-release" refers to a dosage form in which the release rate or location of the active ingredient is different from that of an immediate-release dosage form when administered by the same route. Modified-release dosage forms include, but are not limited to, delayed-release, sustained-release, extended-release, sustained-release, pulsed-release, controlled-release, accelerated-release and rapid-release, targeted-release, programmed-release, and gastroretentive dosage forms. Pharmaceutical compositions in modified-release dosage forms may be prepared using various modified-release devices and methods known to those skilled in the art, including, but not limited to, matrix-controlled release devices, osmotic-controlled release devices, multiparticulate-controlled release devices, ion-exchange resins, enteric coatings, multilayer coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient can also be adjusted by changing the particle size and polymorphism of the active ingredient.

[0297] The controlled-release dosage forms of the pharmaceutical compositions provided herein can be prepared using matrix controlled-release devices known to those skilled in the art (see Takada et al. in "Encyclopedia of Controlled Drug Delivery," Vol. 2, Mathiowitz Ed., Wiley, 1999).

[0298] In certain embodiments, the pharmaceutical compositions provided herein in modified release dosage form are formulated using erodible matrix devices that are water-swellable, erodible, or soluble polymers, including, but not limited to, synthetic polymers and naturally occurring polymers and derivatives such as polysaccharides and proteins.

[0299] Materials useful for forming erodible matrices include chitin, chitosan, dextran, and pullulan; agar gum, gum arabic, gum karaya, locust bean gum, tragacanth gum, carrageenan, ghatti gum, guar gum, xanthan gum, and scleroglucan; starches such as dextrin and maltodextrin; hydrophilic colloids such as pectin; phosphatides such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl ... Cellulose-based materials such as hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methylcellulose acetate trimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm Copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolic acid copolymers; poly-D-(-)-3-hydroxybutyric acid; and other acrylic acid derivatives such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate, and (trimethylaminoethyl) methacrylate chloride.

[0300] In certain embodiments, the pharmaceutical compositions provided herein are formulated in a non-erodible matrix device. The active ingredient is dissolved or dispersed in an inert matrix and, upon administration, is released primarily by diffusion through the inert matrix. Materials suitable for use as a non-erodible matrix device include polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, polybutyl methacrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methacrylate copolymer, ethylene-vinyl acetate copolymer, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, vinyl acetate, vinylidene chloride, vinyl chloride copolymers with ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubber, and epichlorohydrin rubber. Insoluble plastics such as ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, ethylene / vinyloxyethanol copolymers, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane, and silicone carbonate copolymers; hydrophilic polymers such as ethyl cellulose, cellulose acetate, crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate; and fatty compounds such as carnauba wax, microcrystalline wax, and triglycerides.

[0301] In matrix controlled release systems, the desired release kinetics can be controlled, for example, through the type of polymer used, the polymer viscosity, the particle size of the polymer and / or the active ingredient, the ratio of active ingredient to polymer, and other excipients or carriers in the composition.

[0302] The pharmaceutical compositions provided herein in modified release dosage form can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt granulation followed by compression.

[0303] The pharmaceutical compositions provided herein in modified release dosage forms can be manufactured using osmotic controlled release devices, including, but not limited to, one-chamber systems, two-chamber systems, asymmetric membrane technology (AMT), and extruded core systems (ECS). Generally, such devices have at least two components: (a) a core containing an active ingredient, and (b) a semipermeable membrane with at least one delivery port that encapsulates the core. The semipermeable membrane controls the influx of water from an aqueous environment into the core during use, allowing drug release to occur by extrusion through the delivery port.

[0304] In addition to the active ingredient, the core of the osmotic device optionally contains an osmotic agent that generates a driving force for transporting water from the environment of use into the core of the device. One class of osmotic agents are water-swellable hydrophilic polymers, also referred to as "osmopolymers" and "hydrogels." Water-swellable hydrophilic polymers suitable as osmotic agents include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymers, PVA / PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, croscarmellose sodium, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.

[0305] Another class of osmotic agents is osmogens, which can absorb water and affect the osmotic pressure gradient across the barrier of the surrounding coating. Suitable osmogens include, but are not limited to, inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and mixtures thereof.

[0306] Osmotic agents with different dissolution rates can be used to affect how rapidly the active ingredient is initially delivered from the dosage form. For example, amorphous sugars such as MANNOGEM™ EZ (SPI Pharma, Lewis, DE) can be used to provide faster delivery in the first few hours to rapidly produce the desired therapeutic effect, with the remaining amount gradually and continuously released to maintain the desired level of therapeutic or prophylactic effect over an extended period of time. In this case, the active ingredient is released at a rate that replaces the amount of active ingredient that is metabolized and excreted.

[0307] The core can also include various other excipients and carriers as described herein to improve the performance of the dosage form or to facilitate stability or processing.

[0308] Materials useful for forming semipermeable membranes include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulose derivatives that are water-permeable and water-insoluble at physiologically relevant pH or that are susceptible to being made water-insoluble by chemical alteration, such as crosslinking. Examples of suitable polymers useful for forming coatings include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta-glucan acetate, beta-glucan acetate, and the like. triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxylated ethylene vinyl acetate, EC, PEG, PPG, PEG / PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly(methacrylic) acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halides, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0309] The semipermeable membrane may also be a hydrophobic microporous membrane, in which the pores are substantially gas-filled and not wetted by aqueous media but are permeable to water vapor, as disclosed in U.S. Patent No. 5,798,119. Such hydrophobic but water vapor permeable membranes are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0310] Delivery ports in the semipermeable membrane can be formed after coating by mechanical or laser drilling. Delivery ports can also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over a depression in the core. In addition, delivery ports can be formed during the coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Patent Nos. 5,612,059 and 5,698,220.

[0311] The total amount and rate of release of the active ingredient can be substantially controlled by the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and location of the delivery ports.

[0312] The osmotic controlled-release dosage form of the pharmaceutical composition may further comprise additional conventional excipients or carriers as described herein to facilitate performance or processing of the formulation.

[0313] The pharmaceutical compositions provided herein in modified-release dosage forms can be manufactured as multiparticulate controlled-release devices comprising a multiplicity of particles, granules, or pellets ranging in diameter from about 10 μm to about 3 mm, from about 50 μm to about 2.5 mm, or from about 100 μm to about 1 mm. Such multiparticulates can be made by processes known to those skilled in the art, including wet and dry granulation, extrusion / spheronization, roller compaction, melt congealing, and spray coating of seed cores. See, e.g., Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994, and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

[0314] Other excipients or carriers as described herein can be blended with the pharmaceutical composition to aid in the processing and formation of the multiparticulates. The resulting particles can themselves constitute the multiparticulate device or can be coated with various film-forming materials, such as enteric polymers, water-swellable, and water-soluble polymers. The multiparticulates can be further processed as capsules or tablets.

[0315] The pharmaceutical compositions provided herein can also be formulated to target specific tissues, receptors, or other areas of the body of the subject being treated, such as liposome-, resealed red blood cell-, and antibody-based delivery systems.

[0316] How to use Further provided herein is a method of using a solid form disclosed herein, a pharmaceutically acceptable salt, or crystalline form thereof, or a pharmaceutical composition disclosed herein, to treat, prevent, or ameliorate a fibrotic, inflammatory, or proliferative disease or condition in a subject, the method comprising administering to the subject a therapeutically effective amount of a solid form disclosed herein, a pharmaceutically acceptable salt, or crystalline form thereof, or a pharmaceutical composition disclosed herein.

[0317] In some embodiments, provided herein are methods of treating, preventing, or ameliorating a fibrotic, inflammatory, or proliferative disease or condition in a subject, the methods comprising administering to the subject a therapeutically effective amount of a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein (e.g., (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a pharmaceutical composition comprising a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (e.g., the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid) or a solid or crystalline form thereof provided herein.

[0318] In various embodiments, the subject is an animal, including, but not limited to, a primate (e.g., a human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. In some embodiments, the subject is a human.

[0319] In some embodiments, the fibrotic, inflammatory, or proliferative disease or condition is selected from fibrosis of the skin, lung, heart, kidney, pancreas, eye, and liver.

[0320] In certain embodiments, the fibrotic, inflammatory, or proliferative disease or condition is selected from diabetic cardiomyopathy, congestive heart failure, ischemic heart disease, hypertension, peripheral arterial disease, cerebrovascular disease, kidney disease, systemic sclerosis, scleroderma, hypertrophic scars, keloids, pulmonary fibrosis, interstitial lung disease (ILD), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC).

[0321] In certain embodiments, fibrotic, inflammatory, or proliferative diseases or conditions treatable with the pharmaceutically acceptable salts and / or pharmaceutical compositions thereof provided herein include, but are not limited to, fibrotic ocular diseases such as diabetic retinopathy, wet age-related macular degeneration, and diabetic macular edema. In some embodiments, the fibrotic ocular disease is proliferative vitreoretinopathy, corneal edema, anterior and posterior uveitis, pterygium, corneal disease, dry eye, conjunctivitis, allergic and laser-induced exudation, non-age-related macular degeneration, macular edema, age-related macular degeneration, or ocular von Hippel-Lindau disease.

[0322] In certain embodiments, the fibrotic, inflammatory, or proliferative disease or condition is a kidney disease. In some embodiments, the fibrotic, inflammatory, or proliferative disease or condition is selected from chronic kidney disease, progressive kidney disease, diabetic nephropathy, diabetic kidney disease, glomerulonephritis, focal segmental glomerulosclerosis, systemic lupus, lupus nephritis, primary glomerulonephritis, membranous nephropathy, membranoproliferative glomerulonephritis, diffuse proliferative glomerulonephritis, membranous focal segmental glomerulosclerosis, secondary glomerulonephritis, membranous nephropathy, IgA nephropathy, ischemic nephropathy, or Alport syndrome. In certain embodiments, the fibrotic, inflammatory, or proliferative disease or condition is a chronic kidney disease. In some embodiments, the kidney disease can include, but is not limited to, progressive glomerular kidney diseases, including, but not limited to, diabetic nephropathy (e.g., as a result of type 1 or type 11 diabetes or systemic lupus), primary glomerulonephritis (e.g., membranous nephropathy, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, diffuse proliferative glomerulonephritis, membranous focal segmental glomerulosclerosis), or secondary glomerulonephritis (e.g., diabetic nephropathy, ischemic nephritis). In some embodiments, the kidney disease can include progressive kidney diseases primarily of tubulointerstitial origin. In some embodiments, the kidney disease can include, for example, chronic interstitial nephritis, autosomal dominant tubulointerstitial fibrosis, or reflux nephropathy.

[0323] In certain embodiments, the fibrotic, inflammatory, or proliferative disease or condition is diabetic nephropathy.

[0324] In certain embodiments, the fibrotic, inflammatory, or proliferative disease or condition is focal segmental glomerulosclerosis.

[0325] In certain embodiments, the fibrotic, inflammatory, or proliferative disease or condition is diabetic cardiomyopathy, congestive heart failure, or ischemic heart disease.

[0326] In certain embodiments, the fibrotic, inflammatory, or proliferative disease or condition is systemic sclerosis or scleroderma.

[0327] In certain embodiments, the fibrotic, inflammatory, or proliferative disease or condition is pulmonary fibrosis, hi some embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF).

[0328] In certain embodiments, the fibrotic, inflammatory, or proliferative disease or condition is chronic obstructive pulmonary disease (COPD), asthma, or cystic fibrosis.

[0329] In some embodiments, the fibrotic, inflammatory, or proliferative disease or condition includes, but is not limited to, a disease selected from fibrotic skin diseases such as keloids, hypertrophic scars, and scleroderma; lung diseases such as pulmonary fibrosis; heart diseases such as ischemic heart disease, valvular heart disease, and hypertensive heart disease, diabetic cardiomyopathy, and heart failure due to hypertension; and liver diseases such as cirrhosis.

[0330] In some embodiments, the fibrotic, inflammatory, or proliferative disease or condition is a kidney disease, such as chronic kidney disease. In some embodiments, the kidney disease is progressive kidney disease. In some embodiments, the progressive kidney disease is due to glomerulonephritis or diabetic nephropathy. In some embodiments, the kidney disease is selected from one or more of progressive kidney disease, glomerulonephritis, diabetic kidney disease, diabetic nephropathy, systemic lupus, primary glomerulonephritis, membranous nephropathy, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, diffuse proliferative glomerulonephritis, membranous focal segmental glomerulosclerosis, secondary glomerulonephritis, or ischemic nephropathy. In certain embodiments, the present application provides a method of treating focal segmental glomerulosclerosis. In certain embodiments, the present application provides a method of treating inflammation.

[0331] In some embodiments, the fibrotic, inflammatory, or proliferative disease or condition is diabetic heart disease or diabetic kidney disease. In some embodiments, the fibrotic, inflammatory, or proliferative disease or condition is diabetic cardiomyopathy. In some embodiments, the kidney disease is chronic kidney disease. In some embodiments, the kidney disease is a progressive glomerular kidney disease, including, but not limited to, diabetic nephropathy (e.g., as a result of type 1 or type 11 diabetes or systemic lupus), primary glomerulonephritis (e.g., membranous nephropathy, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, diffuse proliferative glomerulonephritis, membranous focal segmental glomerulosclerosis), or secondary glomerulonephritis (e.g., diabetic nephropathy, ischemic nephritis).

[0332] In some embodiments, the pharmaceutically acceptable salts and / or pharmaceutical compositions thereof provided herein are useful for treating an inflammatory disease or condition.

[0333] Generally, the inflammatory diseases or conditions treatable with the solid forms, pharmaceutically acceptable salts, or crystalline forms thereof provided herein, or pharmaceutical compositions thereof provided herein, relate to any disease or condition characterized by an abnormal, irregular, excessive, unwarranted, or inappropriate inflammatory response.

[0334] In some embodiments, the inflammatory disease or condition is the result of tissue damage, hi some embodiments, the inflammatory disease, disorder, or condition is the result of an autoimmune condition, while in further embodiments, the inflammatory disease, disorder, or condition is the result of a bacterial or viral infection or the presence of a toxin.

[0335] The solid forms, pharmaceutically acceptable salts, or crystalline forms thereof provided herein, or pharmaceutical compositions thereof provided herein, may have anti-inflammatory and / or immunomodulatory activity, and may be used in the treatment of septic shock, hemodynamic shock, sepsis syndrome, post-ischemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, transplant rejection, cancer such as cutaneous T-cell lymphoma, diseases involving angiogenesis, autoimmune diseases, inflammatory skin diseases, inflammatory bowel diseases such as Crohn's disease and colitis, ankylosing spondylitis, psoriatic arthritis, adult Still's disease, uveitis, Wegener's granulomatosis, Beche's disease, Sjogren's syndrome, sarcoidosis, , polymyositis, dermatomyositis, multiple sclerosis, sciatica, complex regional pain syndrome, radiation injury, hyperoxic alveolar damage, periodontal disease, HIV, non-insulin dependent diabetes mellitus, systemic lupus erythematosus, glaucoma, sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, retinal disease, scleroderma, osteoporosis, renal ischemia, myocardial infarction, stroke, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, idiopathic fibrosing alveolitis, psoriasis, transplant rejection, atopic dermatitis, vasculitis, allergies, seasonal allergic rhinitis, reversible airway obstruction, adult respiratory distress syndrome, asthma, chronic obstructive pulmonary disease (COPD) and / or bronchitis. The solid forms, pharmaceutically acceptable salts, or crystalline forms thereof provided herein, or pharmaceutical compositions thereof provided herein, and methods provided herein may be useful in treating one or more of these diseases, disorders, or conditions.

[0336] In some embodiments, the inflammatory disease or condition is at least one inflammatory disease or condition selected from the group consisting of inflammatory bowel disease, celiac disease, colitis, irritable bowel syndrome, intestinal hyperplasia, metabolic syndrome, obesity, diabetes, rheumatoid arthritis, liver disease, hepatic steatosis, fatty liver disease, non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH).

[0337] In some embodiments, the inflammatory disease or condition is arthritis, osteoarthritis, psoriatic arthritis, rheumatoid arthritis, diabetic retinopathy, retinal inflammation, retinitis, Sjogren's syndrome, macular degeneration, gout, pseudogout, pericarditis, or uveitis.

[0338] In some embodiments, the inflammatory disease or condition is focal segmental glomerulosclerosis, lupus nephritis, membranous nephropathy, IgA nephropathy, chronic obstructive pulmonary disease (COPD), asthma, or cystic fibrosis.

[0339] In some embodiments, the inflammatory disease or condition is an autoimmune disease or condition, hi some embodiments, the autoimmune disease or condition treatable with the pharmaceutically acceptable salts and / or pharmaceutical compositions thereof provided herein is systemic lupus erythematosus (SLE), inflammatory bowel disease, Crohn's disease, ulcerative colitis, graft-versus-host disease, multiple sclerosis, or rheumatoid arthritis.

[0340] In some embodiments, the solid forms, pharmaceutically acceptable salts, or crystalline forms thereof provided herein, or pharmaceutical compositions thereof provided herein, are useful for treating proliferative diseases or conditions.

[0341] Generally, proliferative diseases or conditions treatable with the solid forms, pharmaceutically acceptable salts, or crystalline forms thereof provided herein, or pharmaceutical compositions thereof provided herein, relate to any disease or condition characterized by abnormal cell proliferation. Cell proliferation can be autogenous, including inappropriate or excessive wound healing responses. Cell proliferation can increase the influx of inflammatory cytokines and inflammatory cells, and is therefore associated with inflammation and / or degeneration.

[0342] Proliferative diseases or conditions treatable with the solid forms, pharmaceutically acceptable salts, or crystalline forms thereof provided herein, or pharmaceutical compositions thereof provided herein, include, but are not limited to, various retinopathies.

[0343] In some embodiments, proliferative diseases or conditions suitable for treatment by the methods provided herein include, but are not limited to, diabetic retinopathy, diabetic macular edema, macular degeneration, retinopathy of prematurity (ROP), and proliferative vitreoretinopathy (PVR).

[0344] Proliferative diseases or conditions treatable with the solid forms, pharmaceutically acceptable salts, or crystalline forms thereof provided herein, or pharmaceutical compositions thereof provided herein, further include, but are not limited to, various tumors and cancers, benign or malignant, metastatic or non-metastatic.

[0345] Cancers treatable with the solid forms, pharmaceutically acceptable salts, or crystalline forms thereof provided herein, or pharmaceutical compositions thereof provided herein, include various cancers, including breast cancer, skin cancer, ovarian cancer, renal cancer, gastrointestinal cancer, kidney cancer, bladder cancer, pancreatic cancer, lung squamous cell carcinoma, and adenocarcinoma, among others.

[0346] In some embodiments, the cancer is characterized by the presence of one or more tumors in a subject. Examples of cancers suitable for treatment with the solid forms, pharmaceutically acceptable salts, or crystalline forms thereof provided herein, or pharmaceutical compositions thereof provided herein, include, but are not limited to, metastatic melanoma, metastatic prostate cancer, metastatic breast cancer, triple-negative breast cancer, bladder cancer, brain cancer, esophageal cancer, liver cancer, head and neck cancer, squamous cell lung cancer, non-small cell lung cancer, Merkel cell carcinoma, sarcoma, hepatocellular carcinoma, multiple myeloma, pancreatic cancer, colorectal cancer, cervical cancer, gastric cancer, kidney cancer, metastatic renal cell carcinoma, leukemia, ovarian cancer, and malignant glioma. In certain embodiments, the cancer is metastatic melanoma, metastatic prostate cancer, or metastatic breast cancer. In some embodiments, the subject has received an allogeneic tissue transplant associated with cancer treatment, for example, after a hematopoietic stem cell transplant used to treat leukemia.

[0347] In some embodiments, the cancer suitable for treatment with the solid forms, pharmaceutically acceptable salts, or crystalline forms thereof provided herein, or the pharmaceutical compositions thereof provided herein, is breast cancer, skin cancer (melanoma), pancreatic cancer, lung cancer, prostate cancer, colon cancer, liver cancer (hepatocellular carcinoma), head and neck cancer, ovarian cancer, or kidney cancer.

[0348] In some embodiments, treating a disease or condition described herein with a solid form, a pharmaceutically acceptable salt, or a crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, results in an increase in the mean survival time of a population of treated subjects compared to a population of untreated subjects. Preferably, the mean survival time is increased by more than about 30 days, more preferably more than about 60 days, more preferably more than about 90 days, and even more preferably more than about 120 days. The increase in the survival time of a population can be measured by any reproducible means. In some embodiments, the increase in the mean survival time of a population can be measured, for example, by calculating the mean survival time of the population after initiation of treatment with a solid form, a pharmaceutically acceptable salt, or a crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein. In another embodiment, the increase in the mean survival time of a population can also be measured, for example, by calculating the mean survival time of the population after completion of a first round of treatment with a solid form, a pharmaceutically acceptable salt, or a crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein.

[0349] In some embodiments, treating a disease or condition described herein with a solid form, a pharmaceutically acceptable salt, or a crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, results in a reduction in mortality in the population of treated subjects compared to a population of subjects administered carrier alone. In another embodiment, treating a disease or condition described herein with a solid form, a pharmaceutically acceptable salt, or a crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, results in a reduction in mortality in the population of treated subjects compared to an untreated population. In a further embodiment, treating a disease or condition described herein with a solid form, a pharmaceutically acceptable salt, or a crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, results in a reduction in mortality in the population of treated subjects compared to a population receiving monotherapy with a drug other than a solid form, a pharmaceutically acceptable salt, or a crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein. Preferably, the mortality rate is reduced by more than about 2%, more preferably by more than about 5%, more preferably by more than about 10%, and most preferably by more than about 25%.

[0350] In certain embodiments, treating a disease or condition described herein with a solid form, a pharmaceutically acceptable salt, or a crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, results in a decrease in the rate of cell proliferation. Preferably, after treatment with a solid form, a pharmaceutically acceptable salt, or a crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, the rate of cell proliferation is reduced by at least about 5%, more preferably at least about 10%, more preferably at least about 20%, more preferably at least about 30%, more preferably at least about 40%, more preferably at least about 50%, even more preferably at least about 60%, and most preferably at least about 75%. The rate of cell proliferation can be measured by any reproducible means of measurement. In some embodiments, the rate of cell proliferation is measured, for example, by measuring the number of dividing cells in a tissue sample per unit time.

[0351] In another embodiment, treating a disease or condition described herein with a solid form, a pharmaceutically acceptable salt, or a crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, results in a decrease in the proportion of proliferating cells. Preferably, after treatment with a solid form, a pharmaceutically acceptable salt, or a crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, the proportion of proliferating cells is reduced by at least about 5%, more preferably at least about 10%, more preferably at least about 20%, more preferably at least about 30%, more preferably at least about 40%, more preferably at least about 50%, even more preferably at least about 60%, and most preferably at least about 75%. The proportion of proliferating cells can be measured by any reproducible means of measurement. In some embodiments, the proportion of proliferating cells is measured, for example, by quantifying the number of dividing cells relative to the number of non-dividing cells in a tissue sample. In another embodiment, the proportion of proliferating cells is equivalent to the mitotic index.

[0352] In another embodiment, treating a disease or condition described herein with a solid form, a pharmaceutically acceptable salt, or a crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, results in a decrease in the size of the area or zone of cellular proliferation. Preferably, after treatment with a solid form, a pharmaceutically acceptable salt, or a crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, the size of the area or zone of cellular proliferation is reduced by at least 5% compared to its size before treatment, more preferably by at least about 10%, more preferably by at least about 20%, more preferably by at least about 30%, more preferably by at least about 40%, more preferably by at least about 50%, even more preferably by at least about 60%, and most preferably by at least about 75%. The size of the area or zone of cellular proliferation can be measured by any reproducible means of measurement. In some embodiments, the size of the area or zone of cellular proliferation can be measured as the diameter or width of the area or zone of cellular proliferation.

[0353] Depending on the disease to be treated and the condition of the subject, the solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or pharmaceutical composition thereof provided herein, for example, the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein or a solid or crystalline form thereof, or pharmaceutical composition thereof provided herein, may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) administration route, and may be formulated in a suitable dosage unit, either alone or with pharmaceutically acceptable carriers, adjuvants, and vehicles appropriate for each administration route. Also provided is administration of the solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, for example, the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, in a depot formulation in which the active ingredient is released over a predetermined period of time.

[0354] In the context of the methods provided herein, a therapeutically or prophylactically effective amount of the solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, for example, the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, can be readily determined by one of ordinary skill in the art using conventional techniques and by observing results obtained under analogous circumstances. In determining a therapeutically effective amount, several factors are taken into account, including, but not limited to, the subject's species, its size, age, and general health, the particular condition involved, the severity of the condition, the subject's response to treatment, the mode of administration, the bioavailability of the administered preparation, the selected dose regime, the use of other drugs, and other relevant circumstances.

[0355] One of ordinary skill in the art will be able, by routine experimentation, to determine the effective, non-toxic amount of a solid form, a pharmaceutically acceptable salt, or a crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, such as the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, required to treat, prevent, or ameliorate a fibrotic, inflammatory, or proliferative disease or condition described herein.

[0356] In some embodiments, the therapeutically effective dosage level of a solid form, a pharmaceutically acceptable salt, or a crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, for example, a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein (e.g., the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid), or a solid or crystalline form thereof, is in the range of about 0.01 to about 1000 mg per kilogram of body weight per day, or about 0.1 to about 100 mg per kilogram of body weight per day, or about 1 to about 10 mg per kilogram of body weight per day, or about 5 mg per kilogram of body weight per day. Small doses (0.01-1 mg / kg per day) may be administered initially, followed by increasing the dose up to about 1000 mg / kg per day. If the subject does not respond adequately at such doses, higher doses (or higher effective doses via a different, more localized delivery route) may be used, as tolerated by the patient. A typical therapeutically or prophylactically effective amount of a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein (e.g., the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid) or a solid or crystalline form thereof can range from 1 to 300 mg per kilogram of body weight per day, 1 to 200 mg per kilogram of body weight per day, or 1 to 100 mg per kilogram of body weight per day. A suitable dose can be administered in multiple sub-doses per day.

[0357] In some embodiments, suitable dosage levels of a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein (e.g., the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid) or a solid or crystalline form thereof suitable for the treatment, prevention, or amelioration of a fibrotic, inflammatory, or proliferative disease or condition generally range from about 10 to about 5000, about 100 to about 3000, or about 200 to about 2500 mg per day (mg / day), which can be administered in single or multiple doses. Within this range, the dosage can be about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 600, about 700, about 800, about 900, about 1000, about 1100, about 1200, about 1300, about 1400, about 1500, about 1600, about 1700, about 1800, about 1900, about 2000, about 2100, about 2200, about 2300, about 2400, or about 2500 mg per day.

[0358] In certain embodiments, suitable dosage levels for the treatment, prevention, or amelioration of a fibrotic, inflammatory, or proliferative disease or condition provided herein for a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (e.g., the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid), or a solid or crystalline form thereof, range from about 1 to about 100, about 1 to about 50, about 2 to about 20, or about 2 to about 10 mg per kg of body weight per day (mg / kg / day), which may be administered in single or multiple doses. Within this range, the dosage can be about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 mg / kg / day.

[0359] In certain embodiments, a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein (e.g., the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid) or a solid or crystalline form thereof, or a pharmaceutical composition provided herein, is administered at a dose of about 10 to about 400 mg / kg / day, or about 50 to about 300 mg / kg / day, or 100 to 250 mg / kg / day of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. In some embodiments, a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein (e.g., the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid) or a solid or crystalline form thereof, or a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein The pharmaceutical composition is administered at a dose of about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, about 240, about 250, about 260, about 270, about 280, about 290, or about 300 mg / kg / day of the compound (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0360] For oral administration, the pharmaceutical compositions provided herein contain 10 to 10,000 mg of a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein (e.g., the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid) or a solid or crystalline form thereof, particularly about 100, about 200, about 300, about 400, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 850, about 900, about 950, or about 1 ... The compositions can be provided in the form of tablets containing about 0, about 1000, about 1050, about 1100, about 1150, about 1200, about 1250, about 1300, about 1350, about 1400, about 1450, and about 1500 mg of a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (e.g., the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid) or a solid or crystalline form thereof, for adjustment of dosage depending on the symptoms of the patient being treated. The compositions can be administered one to four times per day, for example, once, twice, three times, and four times per day.

[0361] In certain embodiments, for oral administration, the pharmaceutical compositions provided herein are in the form of tablets containing 1 to 100 mg of a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein (e.g., the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid) or a solid or crystalline form thereof, particularly about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 mg of the active ingredient, for adjustment of dosage depending on the condition of the patient being treated. The compositions may be administered on a regimen of 1 to 4 times per day, for example, 1, 2, 3, or 4 times per day.

[0362] It will be understood, however, that the specific dose level and frequency of administration for any particular patient may vary and will depend upon a variety of factors, including the activity of the particular compound used, the metabolic stability and length of action of that compound, the patient's age, weight, general health, sex, and diet, the mode and time of administration, rate of excretion, drug combination, and the severity of the particular condition.

[0363] In certain embodiments, kits are also provided herein which, when used by a physician, can simplify the administration to a subject of an appropriate amount of a solid form provided herein, a pharmaceutically acceptable salt, or a crystalline form thereof, or a pharmaceutical composition thereof provided herein, e.g., a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein (e.g., the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid) or a solid or crystalline form thereof. In certain embodiments, the kits provided herein include a container and a dosage form of a solid form, a pharmaceutically acceptable salt, or a crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, such as a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein (e.g., the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid), or a solid or crystalline form thereof.

[0364] The kits provided herein can further include a device used to administer the solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, such as a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein (e.g., the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid) or a solid or crystalline form thereof. Examples of such devices include, but are not limited to, a syringe, a needleless injector, an infusion bag, a patch, and an inhaler.

[0365] The kits provided herein can further include a pharmaceutically acceptable vehicle that can be used to administer the solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, e.g., a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid provided herein (e.g., the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid) or a solid or crystalline form thereof. For example, when the solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein is provided in a solid form that must be reconstituted for parenteral administration, the kit can include a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particle-free, sterile solution suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include aqueous vehicles, including, but not limited to, Water for Injection USP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles, including, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, including, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0366] It will be understood by those skilled in the art that numerous variations and / or modifications may be made to the above-described embodiments without departing from the broad general scope of the present disclosure, and the present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

[0367] The following numbered embodiments are disclosed herein:

[0368] Embodiment 1: A solid form of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a salt thereof, having a water sorption of 0.49% to 1.61% at 80% relative humidity as determined by dynamic vapor sorption.

[0369] Embodiment 2: A solid form of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a salt thereof, having an endothermic onset of 29°C to 187°C as measured by differential scanning calorimetry.

[0370] Embodiment 3: A solid form of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a salt thereof, having a melting point of 57°C to 199°C as measured by differential scanning calorimetry.

[0371] Embodiment 4: A solid form of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a salt thereof, having an endothermic onset of 29°C to 187°C, and a melting point of 57°C to 199°C, as measured by differential scanning calorimetry.

[0372] Embodiment 5: A solid form of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a salt thereof, having a weight loss of 0.07% to 8.94%, or 0.07% to 0.94%, when heated from 25° C. to 120° C., as determined by thermogravimetric analysis.

[0373] Embodiment 6: A solid form of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a salt thereof, having a solubility of 2.4 mg / ml to 5.14 mg / ml in 24 hours in FaSSIF medium (pH 7.5).

[0374] Embodiment 7: A solid form of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a salt thereof, having a solubility of 2.4 mg / ml to greater than 5.14 mg / ml in 24 hours in FaSSIF medium (pH 7.5).

[0375] Embodiment 8: A solid form of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a salt thereof, having a solubility of 1.2 mg / ml to 5.14 mg / ml in 24 hours in FeSSIF medium (pH 7.8).

[0376] Embodiment 9: A solid form of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a salt thereof, having a solubility in FeSSIF medium (pH 7.8) of 1.2 mg / ml to greater than 5.14 mg / ml in 24 hours.

[0377] Embodiment 10: A solid form of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a salt thereof, having a solubility of 2.4 mg / ml to 5.14 mg / ml in 24 hours in FaSSIF medium (pH 7.5) and 1.2 mg / ml to 5.14 mg / ml in 24 hours in FeSSIF medium (pH 7.8).

[0378] Embodiment 11: A solid form of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a salt thereof, having a solubility in FaSSIF medium (pH 7.5) of 2.4 mg / ml to greater than 5.14 mg / ml in 24 hours, and in FeSSIF medium (pH 7.8) of 1.2 mg / ml to greater than 5.14 mg / ml in 24 hours.

[0379] Embodiment 12: A solid form of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a salt thereof, having a bioavailability of 39F% to 82F%.

[0380] Embodiment 13: The solid form of embodiment 12, having a bioavailability of at least 50F%, at least 55F%, at least 60F%, at least 65F%, at least 70F%, at least 75F%, or at least 80F%.

[0381] Embodiment 14: The solid form has the following characteristics: Moisture sorption of 0.49% to 1.61% at 80% relative humidity, as determined by dynamic vapor sorption; Endothermic onset of 29°C to 187°C as measured by differential scanning calorimetry; A melting point of 57°C to 199°C as measured by differential scanning calorimetry; a weight loss of 0.07% to 8.94%, or 0.07% to 0.94%, when heated from 25°C to 120°C, as determined by thermogravimetric analysis; Solubility of 2.4 mg / ml to 5.14 mg / ml in 24 hours in FaSSIF medium (pH 7.5), Solubility of 2.4 mg / ml to over 5.14 mg / ml in 24 hours in FaSSIF medium (pH 7.5); Solubility in FeSSIF medium (pH 7.8) ranges from 1.2 mg / ml to 5.14 mg / ml in 24 hours. Solubility of 1.2 mg / ml to over 5.14 mg / ml in 24 hours in FeSSIF medium (pH 7.8); 14. The solid form of any one of embodiments 1 to 13, having any two or more of the following bioavailability: a bioavailability of 39F% to 82F%.

[0382] Embodiment 15: The solid form of any one of embodiments 1-14, wherein the solid form is a crystalline form of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0383] Embodiment 16: The solid form of any one of embodiments 1 to 15, wherein the solid form is a crystalline form of a salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0384] Embodiment 17: The solid form of any one of embodiments 1-16, wherein the solid form is a crystalline form of a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0385] Embodiment 18: A solid form of a salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, having a water sorption of 0.49% to 8.82% at 80% relative humidity as determined by dynamic vapor sorption.

[0386] Embodiment 19: A solid form of a salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, having an endotherm onset of 29°C to 203°C as measured by differential scanning calorimetry.

[0387] Embodiment 20: A solid form of a salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, having a melting point of 57° C. to 204° C. as measured by differential scanning calorimetry.

[0388] Embodiment 21: A solid form of a salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, having an endotherm onset of 29°C to 203°C, and a melting point of 57°C to 204°C, as measured by differential scanning calorimetry.

[0389] Embodiment 22: A solid form of a salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, having a weight loss of 0.07% to 5.24% when heated from 25° C. to 120° C. as determined by thermogravimetric analysis.

[0390] Embodiment 23: A solid form of a salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, having a solubility in FaSSIF medium (pH 7.5) of 2.4 mg / ml to 5.14 mg / ml in 24 hours.

[0391] Embodiment 24: A solid form of a salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, having a solubility of 2.4 mg / ml to greater than 5.14 mg / ml in 24 hours in FaSSIF medium (pH 7.5).

[0392] Embodiment 25: A solid form of a salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, having a solubility in FeSSIF medium (pH 7.8) of 1.2 mg / ml to 5.14 mg / ml in 24 hours.

[0393] Embodiment 26: A solid form of a salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, having a solubility in FeSSIF medium (pH 7.8) of 1.2 mg / ml to greater than 5.14 mg / ml in 24 hours.

[0394] Embodiment 27: A solid form of a salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, having a solubility in FaSSIF medium (pH 7.5) of 2.4 mg / ml to 5.14 mg / ml in 24 hours, and in FeSSIF medium (pH 7.8) of 1.2 mg / ml to 5.14 mg / ml in 24 hours.

[0395] Embodiment 28: A solid form of a salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, having a solubility in FaSSIF medium (pH 7.5) of 2.4 mg / ml to greater than 5.14 mg / ml in 24 hours, and in FeSSIF medium (pH 7.8) of 1.2 mg / ml to greater than 5.14 mg / ml in 24 hours.

[0396] Embodiment 29: A solid form of a salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, having a solubility of 0.048 mg / ml to 0.090 mg / ml in 24 hours in a medium of pH 6.8.

[0397] Embodiment 30: A solid form of a salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, having a bioavailability of 39F% to 82F%.

[0398] Embodiment 31: A solid form according to embodiment 30, having a bioavailability of at least 50F%, at least 55F%, at least 60F%, at least 65F%, at least 70F%, at least 75F%, or at least 80F%.

[0399] Embodiment 32: The solid form has the following characteristics: Moisture sorption of 0.49% to 8.82% at 80% relative humidity, as determined by dynamic vapor sorption; Endothermic onset of 29°C to 203°C as measured by differential scanning calorimetry; Melting point of 57°C to 204°C as measured by differential scanning calorimetry; Weight loss of 0.07% to 5.24% when heated from 25°C to 120°C, as determined by thermogravimetric analysis; Solubility of 2.4 mg / ml to 5.14 mg / ml in 24 hours in FaSSIF medium (pH 7.5), Solubility of 2.4 mg / ml to over 5.14 mg / ml in 24 hours in FaSSIF medium (pH 7.5); Solubility in FeSSIF medium (pH 7.8) ranges from 1.2 mg / ml to 5.14 mg / ml in 24 hours. Solubility of 1.2 mg / ml to over 5.14 mg / ml in 24 hours in FeSSIF medium (pH 7.8); Solubility of 0.048 mg / ml to 0.090 mg / ml in 24 hours in a medium with a pH of 6.8; A solid form according to any one of embodiments 18 to 31, having any two or more of the following bioavailability: a bioavailability of 39F% to 82F%.

[0400] Embodiment 33: The solid form of any one of embodiments 18 to 32, wherein the solid form is a crystalline form of a salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0401] Embodiment 34: The solid form of any one of embodiments 18 to 33, wherein the solid form is a crystalline form of a pharmaceutically acceptable salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0402] Embodiment 35: The solid form of any one of embodiments 18 to 34, wherein the solid form is a crystalline form of a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid selected from the group consisting of potassium, meglumine, tris(hydroxymethyl)aminomethane, ethanolamine, tert-butylamine, ammonium, and lysine salts of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0403] Embodiment 36: The solid form of any one of embodiments 18 to 35, wherein the solid form is a crystalline form of a pharmaceutically acceptable salt of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid selected from the group consisting of meglumine, tris(hydroxymethyl)aminomethane, ethanolamine, and tert-butylamine salts of (£)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0404] Embodiment 37: The solid form of any one of embodiments 18 to 36, wherein the solid form is a crystalline form of the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0405] Embodiment 38: Formula (I): [ka] 1. A crystalline form of a pharmaceutically acceptable salt of the compound of formula (I), wherein the crystalline form has a water sorption of less than 1.7% at 25° C. and 80% relative humidity as determined by dynamic vapor sorption.

[0406] Embodiment 39: The crystalline form of embodiment 38, wherein the crystalline form has a weight loss of 0.07% to 8.94%, or 0.07% to 0.94%, when heated from 25°C to 120°C, as determined by thermogravimetric analysis.

[0407] Embodiment 40: The crystalline form of embodiment 38, wherein the crystalline form has a solubility of 2.5 mg / ml to greater than 5.0 mg / ml in 24 hours in FaSSIF medium (pH 7.5).

[0408] Embodiment 41: The crystalline form of embodiment 38, wherein the crystalline form has a solubility in FeSSIF medium (pH 7.8) of 3.4 mg / ml to greater than 5.0 mg / ml in 24 hours.

[0409] Embodiment 42: The crystalline form of embodiment 38, wherein the crystalline form has a solubility of 0.07 mg / ml to 0.090 mg / ml in 24 hours in a medium at pH 6.8.

[0410] Embodiment 43: The crystalline form of embodiment 38, wherein the crystalline form has a bioavailability of 39F% to 82F%.

[0411] Embodiment 44: The crystalline form of embodiment 38, wherein the pharmaceutically acceptable salt is selected from the group consisting of meglumine salt, ethanolamine salt, tris(hydroxymethyl)aminomethane salt, and tert-butylamine salt.

[0412] Embodiment 45: A pharmaceutical composition comprising the crystalline form of embodiment 38 and at least one pharmaceutically acceptable excipient.

[0413] Embodiment 46: Formula (I): [ka] 1. A crystalline form of a pharmaceutically acceptable salt of the compound of formula (I), wherein the crystalline form has a bioavailability of 39F% to 82F%.

[0414] Embodiment 47: The crystalline form of embodiment 46, wherein the pharmaceutically acceptable salt is selected from the group consisting of potassium salts, meglumine salts, ethanolamine salts, tris(hydroxymethyl)aminomethane salts, tert-butylamine salts, ammonium salts, and lysine salts.

[0415] Embodiment 48: The crystalline form of embodiment 46, wherein the crystalline form has a bioavailability of 50F% to 82F%.

[0416] Embodiment 49: The crystalline form of embodiment 46, wherein the crystalline form has a bioavailability of 64F% to 82F%.

[0417] Embodiment 50: A pharmaceutical composition comprising the crystalline form of embodiment 46 and at least one pharmaceutically acceptable excipient.

[0418] Embodiment 51: Formula (I): [ka] 1. A crystalline form of the ethanolamine salt of the compound of formula (I), wherein the crystalline form has a bioavailability that is at least about 1.5 times greater than the bioavailability of the free form of the compound of formula (I).

[0419] Embodiment 52: The crystalline form of embodiment 51, wherein the crystalline form has a bioavailability that is at least about 2-fold greater than the bioavailability of the free form of the compound of formula (I).

[0420] Embodiment 53: The crystalline form of embodiment 51, wherein the crystalline form has a bioavailability of from 82 F%.

[0421] Embodiment 54: The crystalline form of embodiment 51, wherein the crystalline form has a water sorption of 0.49% at 25° C. and 80% relative humidity, as determined by dynamic vapor sorption.

[0422] Embodiment 55: The crystalline form of embodiment 51, wherein the crystalline form has an endothermic onset of 176° C. as measured by differential scanning calorimetry.

[0423] Embodiment 56: The crystalline form of embodiment 51, wherein the crystalline form has a melting point of 178°C as measured by differential scanning calorimetry.

[0424] Embodiment 57: The crystalline form of embodiment 51, wherein the crystalline form has a weight loss of 0.10% when heated from 25°C to 120°C as determined by thermogravimetric analysis.

[0425] Embodiment 58: The crystalline form of embodiment 51, wherein the crystalline form has a solubility of greater than 7.99 mg / ml in FaSSIF medium (pH 7.5) in 24 hours.

[0426] Embodiment 59: The crystalline form of embodiment 51, wherein the crystalline form has a solubility of greater than 8.02 mg / ml in 24 hours in FeSSIF medium (pH 7.8).

[0427] Embodiment 60: The crystalline form of embodiment 51, wherein the crystalline form has a solubility of 0.088 mg / ml in 24 hours in a medium at pH 6.8.

[0428] Embodiment 61: A pharmaceutical composition comprising the crystalline form of embodiment 51 and at least one pharmaceutically acceptable excipient.

[0429] Embodiment 62: Formula (I): [ka] 1. A crystalline form of the ethanolamine salt of the compound of formula (I), wherein the crystalline form exhibits an X-ray powder diffraction pattern having at least one peak selected from 6.6±0.2, 11.7±0.2, 15.0±0.2, 15.9±0.2, 17.7±0.2, 18.7±0.2, 19.2±0.2, 23.7±0.2, and 26.6±0.2 degrees two-theta.

[0430] Embodiment 63: The crystalline form of embodiment 62, wherein the crystalline form exhibits an X-ray powder diffraction pattern with at least two peaks selected from 6.6±0.2, 11.7±0.2, 15.0±0.2, 15.9±0.2, 17.7±0.2, 18.7±0.2, 19.2±0.2, 23.7±0.2, and 26.6±0.2 degrees 2θ.

[0431] Embodiment 64: The crystalline form of embodiment 62, wherein the crystalline form exhibits an X-ray powder diffraction pattern with at least three peaks selected from 6.6±0.2, 11.7±0.2, 15.0±0.2, 15.9±0.2, 17.7±0.2, 18.7±0.2, 19.2±0.2, 23.7±0.2, and 26.6±0.2 degrees 2θ.

[0432] Embodiment 65: The crystalline form of embodiment 62, wherein the crystalline form exhibits an X-ray powder diffraction pattern with at least four peaks selected from 6.6±0.2, 11.7±0.2, 15.0±0.2, 15.9±0.2, 17.7±0.2, 18.7±0.2, 19.2±0.2, 23.7±0.2, and 26.6±0.2 degrees 2θ.

[0433] Embodiment 66: The crystalline form of embodiment 62, wherein the crystalline form exhibits an X-ray powder diffraction pattern with at least five peaks selected from 6.6±0.2, 11.7±0.2, 15.0±0.2, 15.9±0.2, 17.7±0.2, 18.7±0.2, 19.2±0.2, 23.7±0.2, and 26.6±0.2 degrees 2θ.

[0434] Embodiment 67: The crystalline form of embodiment 62, wherein the crystalline form exhibits an X-ray powder diffraction pattern with at least one peak selected from 6.6±0.2, 11.7±0.2, 15.0±0.2, 15.9±0.2, 17.7±0.2, 18.7±0.2, and 19.2±0.2 degrees 2θ.

[0435] Embodiment 68: The crystalline form of embodiment 62, wherein the crystalline form exhibits an X-ray powder diffraction pattern with at least two peaks selected from 6.6±0.2, 11.7±0.2, 15.0±0.2, 15.9±0.2, 17.7±0.2, 18.7±0.2, and 19.2±0.2 degrees 2θ.

[0436] Embodiment 69: The crystalline form of embodiment 62, wherein the crystalline form exhibits an X-ray powder diffraction pattern with at least three peaks selected from 6.6±0.2, 11.7±0.2, 15.0±0.2, 15.9±0.2, 17.7±0.2, 18.7±0.2, and 19.2±0.2 degrees 2θ.

[0437] Embodiment 70: Formula (I): [ka] 1. A crystalline form of the ethanolamine salt of the compound of claim 1, wherein the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks at 6.6±0.2, 11.7±0.2, 15.0±0.2, 15.9±0.2, 17.7±0.2, 18.7±0.2, and 19.2±0.2 degrees 2θ.

[0438] Embodiment 71: Formula (I): [ka] 1. A crystalline form of the ethanolamine salt of the compound of claim 1, wherein the crystalline form exhibits an X-ray powder diffraction pattern comprising peaks at 6.6±0.2, 11.7±0.2, 15.0±0.2, 15.9±0.2, 17.7±0.2, 18.7±0.2, 19.2±0.2, 23.7±0.2, and 26.6±0.2 degrees 2θ.

[0439] Embodiment 72: Form I crystalline ethanolammonium (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoate.

[0440] Embodiment 73: A pharmaceutical composition comprising the crystalline form of any one of embodiments 62-72 and a pharmaceutically acceptable carrier.

[0441] Embodiment 74: A pharmaceutical composition comprising the solid or crystalline form of any one of embodiments 1 to 72 and a pharmaceutically acceptable excipient.

[0442] Embodiment 75: The pharmaceutical composition of embodiment 73 or embodiment 74, wherein the pharmaceutical composition is formulated for single-dose administration.

[0443] Embodiment 76: The pharmaceutical composition of any one of embodiments 73 to 75, wherein the pharmaceutical composition is formulated as an oral, parenteral, or intravenous dosage form.

[0444] Embodiment 77: The pharmaceutical composition of any one of embodiments 73 to 76, wherein the pharmaceutical composition is formulated as an oral dosage form.

[0445] Embodiment 78: The pharmaceutical composition of embodiment 77, wherein the oral dosage form is a tablet or capsule.

[0446] Embodiment 79: The pharmaceutical composition of any one of embodiments 73 to 78, wherein the pharmaceutical composition comprises from about 1 to about 2000 mg of the solid or crystalline form of any one of embodiments 1 to 72.

[0447] Embodiment 80: The pharmaceutical composition of any one of embodiments 73 to 79, wherein the pharmaceutical composition comprises about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 850, about 900, about 950, about 1000, about 1050, about 1100, about 1150, about 1200, about 1250, about 1300, about 1350, about 1400, about 1450, or about 1500 mg of the solid or crystalline form of any one of embodiments 1 to 72.

[0448] Embodiment 81: A pharmaceutical composition according to any one of embodiments 73 to 79, wherein the pharmaceutical composition comprises about 20, about 30, about 40, about 50, about 100, about 150, about 200, about 250, about 300, about 350, or about 400 mg of the solid or crystalline form according to any one of embodiments 1 to 72.

[0449] Embodiment 82: A pharmaceutical composition according to any one of embodiments 73 to 79, wherein the pharmaceutical composition comprises about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, or about 20 mg of the solid or crystalline form according to any one of embodiments 1 to 72.

[0450] Embodiment 83: The pharmaceutical composition of any one of embodiments 73 to 78, wherein the pharmaceutical composition comprises the solid or crystalline form of any one of embodiments 1 to 72 in an amount effective to provide a dose of the compound of Formula (I) of from about 1 mg / kg to about 500 mg / kg.

[0451] Embodiment 84: The pharmaceutical composition of embodiment 83, wherein the pharmaceutical composition comprises the solid or crystalline form of any one of embodiments 1 to 72 in an amount effective to provide a dose of about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 110, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 210, about 220, about 230, about 240, about 250, about 260, about 270, about 280, about 290, about 300, about 310, about 320, about 330, about 340, about 350, about 360, about 370, about 380, about 390, or about 400 mg / kg of the compound of Formula (I).

[0452] Embodiment 85: The pharmaceutical composition of embodiment 83 or embodiment 84, wherein the pharmaceutical composition comprises the solid or crystalline form of any one of embodiments 1 to 72 in an amount effective to provide a dose of the compound of Formula (I) of about 10 to about 400 mg / kg, or about 50 to about 300 mg / kg, or about 100 to about 250 mg / kg.

[0453] Embodiment 86: The pharmaceutical composition of any one of embodiments 83 to 85, wherein the pharmaceutical composition comprises the solid or crystalline form of any one of embodiments 1 to 72 in an amount effective to provide a dose of the compound of formula (I) of about 200 mg / kg.

[0454] Embodiment 87: The pharmaceutical composition of any one of embodiments 73 to 78, wherein the pharmaceutical composition comprises the solid or crystalline form of any one of embodiments 1 to 72 in an amount effective to provide a concentration of the compound of formula (I) at its site of action of 10 μM to 200 μM, or 10 μM to 100 μM, or 10 μM to 50 μM.

[0455] Embodiment 88: The pharmaceutical composition of any one of embodiments 73 to 78, wherein the pharmaceutical composition comprises the solid or crystalline form of any one of embodiments 1 to 72 in an amount effective to provide a concentration of the compound of formula (I) at its site of action of about 20 to about 40 μM, about 25 to about 35 μM, or about 30 μM.

[0456] Embodiment 89: A pharmaceutical composition comprising the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid and at least one pharmaceutically acceptable carrier, wherein at least about 80% of the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid is crystalline Form I of the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0457] Embodiment 90: The pharmaceutical composition of embodiment 89, wherein at least 85%, at least 88%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, or at least 95% of the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid is crystalline Form I of the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0458] Embodiment 91: The pharmaceutical composition of embodiment 90, wherein at least 96%, at least 97%, at least 98%, or at least 99% of the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid is crystalline Form I of the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0459] Embodiment 92: The pharmaceutical composition of embodiment 91, wherein at least 99.5% or at least 99.9% of the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid is crystalline Form I of the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0460] Embodiment 93: A method of treating, preventing, or ameliorating a fibrotic, inflammatory, or proliferative disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of the solid or crystalline form of any one of embodiments 1 to 72, or the pharmaceutical composition of any one of embodiments 73 to 92.

[0461] Embodiment 94: The method of embodiment 93, wherein the fibrotic, inflammatory, or proliferative disease or condition is selected from fibrosis of the skin, lung, heart, kidney, pancreas, eye, and liver.

[0462] Embodiment 95: The method of embodiment 93, wherein the fibrotic, inflammatory, or proliferative disease or condition is selected from diabetic cardiomyopathy, congestive heart failure, ischemic heart disease, hypertension, peripheral arterial disease, cerebrovascular disease, kidney disease, systemic sclerosis (scleroderma), hypertrophic scars, keloids, pulmonary fibrosis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC).

[0463] Embodiment 96: The method of embodiment 93, wherein the fibrotic, inflammatory, or proliferative disease or condition is a kidney disease.

[0464] Embodiment 97: The method of embodiment 93, wherein the fibrotic, inflammatory, or proliferative disease or condition is selected from chronic kidney disease, progressive kidney disease, diabetic nephropathy, diabetic nephropathy, glomerulonephritis, focal segmental glomerulosclerosis, systemic lupus, lupus nephritis, primary glomerulonephritis, membranous nephropathy, membranoproliferative glomerulonephritis, diffuse proliferative glomerulonephritis, membranous focal segmental glomerulosclerosis, secondary glomerulonephritis, membranous nephropathy, IgA nephropathy, or ischemic nephropathy.

[0465] Embodiment 98: The method of embodiment 93, wherein the fibrotic, inflammatory, or proliferative disease or condition is chronic kidney disease.

[0466] Embodiment 99: The method of embodiment 93, wherein the fibrotic, inflammatory, or proliferative disease or condition is diabetic nephropathy.

[0467] Embodiment 100: The method of embodiment 93, wherein the fibrotic, inflammatory, or proliferative disease or condition is focal segmental glomerulosclerosis.

[0468] Embodiment 101: The method of embodiment 93, wherein the fibrotic, inflammatory, or proliferative disease or condition is diabetic cardiomyopathy, congestive heart failure, or ischemic heart disease.

[0469] Embodiment 102: The method of embodiment 93, wherein the fibrotic, inflammatory, or proliferative disease or condition is systemic sclerosis or scleroderma.

[0470] Embodiment 103: The method of embodiment 93, wherein the fibrotic, inflammatory, or proliferative disease or condition is pulmonary fibrosis.

[0471] Embodiment 104: The method of embodiment 103, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF).

[0472] Embodiment 105: The method of embodiment 93, wherein the fibrotic, inflammatory, or proliferative disease or condition is selected from chronic obstructive pulmonary disease (COPD), asthma, and cystic fibrosis.

[0473] Embodiment 106: The method of embodiment 93, wherein the fibrotic, inflammatory, or proliferative disease or condition is a fibrotic eye disease.

[0474] Embodiment 107: The method of embodiment 106, wherein the fibrotic eye disease is selected from diabetic retinopathy, wet age-related macular degeneration, and diabetic macular edema.

[0475] Embodiment 108: The method of embodiment 93, wherein the fibrotic, inflammatory, or proliferative disease or condition is cancer.

[0476] Embodiment 109: The method of embodiment 108, wherein the cancer is selected from breast cancer, skin cancer (melanoma), pancreatic cancer, lung cancer, prostate cancer, colon cancer, liver cancer (hepatocellular carcinoma), head and neck cancer, ovarian cancer, and kidney cancer.

[0477] Embodiment 110: The method of embodiment 93, wherein the fibrotic, inflammatory, or proliferative disease or condition is selected from diabetic retinopathy, diabetic macular edema, macular degeneration, retinopathy of prematurity (ROP), and proliferative vitreoretinopathy (PVR).

[0478] Embodiment 111: The method of embodiment 93, wherein the fibrotic, inflammatory, or proliferative disease or condition is an autoimmune disease or condition.

[0479] Embodiment 112: The method of embodiment 111, wherein the autoimmune disease or condition is selected from systemic lupus erythematosus (SLE), inflammatory bowel disease, Crohn's disease, ulcerative colitis, graft-versus-host disease, multiple sclerosis, and rheumatoid arthritis.

[0480] Embodiment 113: The method of any one of embodiments 93 to 112, wherein the solid or crystalline form, or pharmaceutical composition, is administered orally.

[0481] Embodiment 114: The method of any one of embodiments 93 to 113, wherein the solid or crystalline form, or pharmaceutical composition, is administered daily.

[0482] Embodiment 115: The method of any one of embodiments 93 to 114, wherein the solid or crystalline form, or pharmaceutical composition, is administered at a dose of about 10 to about 400 mg / kg / day, or about 50 to about 300 mg / kg / day, or 100 to 250 mg / kg / day of the compound of formula (I).

[0483] Embodiment 116: The method of any one of embodiments 93 to 115, wherein the solid or crystalline form, or pharmaceutical composition is administered at a dose of about 200 mg / kg / day of the compound of Formula (I).

[0484] Embodiment 117: The method of any one of embodiments 93 to 116, wherein the subject is a human. [Example]

[0485] The present disclosure is further illustrated by the following examples, which are not intended to limit the scope of the claims.

[0486] Example 1. General Experiment Reagents and materials All inorganic reagents, organic solvents, and water are of at least analytical laboratory reagent grade standard. device [Table 3]

[0487] Instrument parameters X-ray powder diffraction (XRPD) X-ray powder diffraction (XRPD) patterns were obtained on a Shimadzu XRD-6000 instrument. XRPD bulk patterns were measured at room temperature. Samples were measured by XRPD using the following method: [Table 4]

[0488] Differential scanning calorimetry (DSC) Approximately 1 mg of sample was tested in a pinhole aluminum pan under nitrogen purge using a ramp rate of 20°C / min over the range of 30°C to 300°C (the test range was adjusted according to the decomposition temperature of the sample). [Table 5]

[0489] Thermogravimetric analysis (TGA) A sample of the compound (4-6 mg) was weighed into a pan and heated under a nitrogen purge using a ramp rate of 20°C / min over the range 30°C to 350°C, then held at 350°C for an additional 1 min. [Table 6]

[0490] Dynamic Vapor Sorption (DVS) Approximately 10 mg of sample was used to test the moisture sorption / desorption profile at 25°C during a 0% to 95% to 0% relative humidity (RH) cycle with the following parameters: [Table 7]

[0491] During DVS analysis, humidity is held at each value during a 0%-95%-0% RH cycle and changed in 5% RH increments, measuring the change in mass at each such value. For example, a sample is exposed to an increase in relative humidity from 25% RH to 30% RH, and the resulting mass change is measured. Humidity is held constant at 30% RH until the sample's mass equilibrium is reached, as determined by a weight change rate of 0.01% / min or less. The humidity is then changed to the next step value, the resulting mass change is measured, and so on. Thus, while moisture response profiles are observed over a range of conditions during a 0%-95%-0% RH cycle, a standard comparison can be provided by moisture content values ​​at a set condition, such as 80% RH. Table 11 lists the hygroscopicity values ​​of relevant samples during the sorption cycle by listing the moisture content at mass equilibrium measured at 80% RH during the ramp-up from 0 to 95% RH.

[0492] Thus, when hygroscopicity values ​​are reported herein at a particular humidity, they refer to values ​​obtained at the stated humidity level measured during a sorption cycle that increased humidity from 0% RH to 95% RH before returning to 0% RH. The hygroscopicity values ​​reported herein refer only to the total moisture gain since the start of the experiment and, therefore, do not necessarily equate to the actual total moisture content of the sample.

[0493] The hygroscopicity of the samples was classified as follows: [Table 8]

[0494] Polarized Light Microscope (PLM) Samples dispersed in silicone oil were observed using an eyepiece (10x) and an objective lens (40x) under crossed polarizers and recorded by a camera / computer system with a magnification scale.

[0495] 1 H nuclear magnetic resonance (NMR) Approximately 3 mg of sample was weighed into a nuclear magnetic tube, and 0.5 mL of deuterated dimethyl sulfoxide or deuterated methanol was added to completely dissolve the sample.

[0496] Solubility measurement Approximately 8-12 mg of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid salt (equimolar to 8 mg of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid free form) was accurately weighed into each glass vial, followed by the addition of 4 ml of the indicated medium. The samples were stirred at 37 °C using a magnetic stirrer. After stirring for 1 or 24 hours, 1 ml of each sample was withdrawn and the final pH recorded. The samples were filtered by centrifugation (12,000 rpm, 5 min). The supernatant was diluted (2x) with HPLC-grade solvent and analyzed by HPLC.

[0497] The HPLC conditions were as follows: Column: Agilent Eclipse Plus C18, 150 × 4.6 mm, 3.5 μm, Column temperature: 35 °C, Flow rate: 1.0 mL / min, Detector wavelength: 230 nm, Run time: 12 min, Injection volume: 5 μL, Diluent: Acetone, Mobile phase A (MPA): 0.1% TFA in HO, Mobile phase B (MPB): ACN.

[0498] The HPLC gradient was as follows: [Table 9]

[0499] Example 2. Preparation of salts of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid Approximately 100 mg of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid ("FT011 free form," hereinafter also referred to as "API") was accurately weighed into each glass vial. An appropriate amount of solvent selected from ethyl acetate (EA) and 90% isopropanol (90% IPA) was then added to the glass vial, and the mixture was heated to 50°C. A counterion source selected from potassium hydroxide, meglumine, ethanolamine (MEA), tris(hydroxymethyl)aminomethane (Tris base), tert-butylamine (TBA), ammonia, lysine, L-arginine, and choline was added to each vial in an appropriate molar ratio (e.g., 5% molar excess). In the case of meglumine and Tris base, they were accurately weighed and mixed with FTO11 free form, and then the solvent was added to the mixture. Each mixture was stirred at 50°C for 1 hour, then cooled to room temperature (20-25°C) and continued stirring for 24-48 hours, after which the solid precipitate was isolated by centrifugation. If no precipitate was present in the system, the clear solution was evaporated at room temperature by compressed air or nitrogen blowing. The obtained sample was dried overnight under vacuum at 40°C. The dried sample was 1 The salts were analyzed by H NMR, TGA, DSC, and PLM. The detailed procedure for the formation of the salts and their physical properties are summarized in Table 1. [Table 10-1] [Table 10-2] [Table 10-3]

[0500] Based on the experimental results, potassium hydroxide, meglumine, ethanolamine (MEA), tris(hydroxymethyl)aminomethane (Tris base), tert-butylamine (TBA), ammonia, and lysine formed crystalline solid salt forms with (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. Sodium hydroxide formed a less crystalline solid salt form, whereas L-arginine and choline did not form solid salt forms but instead formed oils.

[0501] The ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid was obtained as a crystalline solid and analyzed by X-ray powder diffraction (XRPD) and single crystal X-ray diffraction (SXRD). The X-ray powder diffraction pattern of a sample of crystalline Form I of the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid prepared as described above is shown in FIG. 1 and shows prominent XRP diffraction peaks at 6.6, 11.7, 15.9, 17.7, 23.7, and 26.6 degrees two-theta (±0.2 degrees two-theta). As used herein, "prominent peaks" are a subset of the entire observed peak list. Prominent peaks are selected from the observed peaks, preferably by identifying non-overlapping peaks with strong intensities. The observed XRP diffraction peaks are listed in Table 2a. Table 2b lists the prominent peaks calculated from SXRD. SXRD measurements of the monohydrate MEA salt were performed at -103°C (170K), while the XRPD bulk pattern was measured at room temperature. This temperature difference results in shrinkage of the crystalline form (at lower temperatures); therefore, slight changes in the crystalline structure and resulting peak positions are observed compared to those at room temperature. The overall patterns of SXRD and XRPD are consistent in terms of diffraction peaks and relative peak heights and are therefore comparable, except for the noted effect of temperature on the precise 2-theta values. Table 2c shows the calculated SXRD peaks for crystalline Form I of the ethanolamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. The variability in the values ​​is explained by the standard experimental error in measuring the relevant parameters, as understood by those skilled in the art. For example, in Table 2c, "a" (Å) is listed as 4.7710±(8), which means that values ​​from 4.7702 to 4.7718 are explicitly included; "b" (Å) is listed as 29.645±(4), which means that values ​​from 29.641 to 29.649 are explicitly included; and so on.This approach applies to all such SXRD values ​​described in the same or similar manner herein. [Table 11] [Table 12] [Table 13]

[0502] The tert-butylamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid was obtained as a crystalline solid and analyzed by X-ray powder diffraction (XRPD). The X-ray powder diffraction pattern of a sample of crystalline Form II of the tert-butylamine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid prepared as described above is shown in Figure 8 and shows prominent XRP diffraction peaks at 8.36, 13.96, and 17.50 degrees two-theta (±0.2 degrees two-theta). The observed XRP diffraction peaks are listed in Table 3. [Table 14]

[0503] The meglumine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid was obtained as a crystalline solid and analyzed by X-ray powder diffraction (XRPD). The X-ray powder diffraction pattern of a sample of crystalline Form III of the meglumine salt of (E)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid prepared as described above is shown in Figure 9 and shows prominent XRP diffraction peaks at 7.50, 12.86, 15.26, and 23.92 degrees two-theta (±0.2 degrees two-theta). The observed XRP diffraction peaks are listed in Ta...

Claims

1. Formula (I) 【Chemistry 1】 or a solvate thereof, A pharmaceutically acceptable salt or a solvate thereof, wherein the pharmaceutically acceptable salt is selected from the group consisting of an ethanolamine salt, a tert-butylamine salt, a potassium salt, a meglumine salt, a tris(hydroxymethyl)aminomethane salt, a lysine salt, and an ammonium salt.

2. 2. The pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein the pharmaceutically acceptable salt is an ethanolamine salt or a tert-butylamine salt.

3. The pharmaceutically acceptable salt or solvate thereof according to claim 1 or 2, wherein the pharmaceutically acceptable salt is an ethanolamine salt.

4. 10. A pharmaceutically acceptable salt or solvate thereof according to any one of the preceding claims, wherein the pharmaceutically acceptable salt or solvate thereof is in solid form.

5. 10. The pharmaceutically acceptable salt or solvate thereof according to any one of the preceding claims, wherein the pharmaceutically acceptable salt or solvate thereof is in crystalline form.

6. 10. A pharmaceutically acceptable salt or solvate thereof according to any one of the preceding claims, having a bioavailability of at least 39F%, or 39F% to 82F%, or 50F% to 82F%, or 64F% to 82F%.

7. 10. A pharmaceutically acceptable salt or solvate thereof according to any one of the preceding claims, having a water sorption of less than 1.7% at 25°C and 80% relative humidity as determined by dynamic vapor sorption.

8. 10. A pharmaceutically acceptable salt or solvate thereof according to any one of the preceding claims, which has a weight loss of 0.07% to 8.94% when heated from 25°C to 120°C as determined by thermogravimetric analysis.

9. 9. The pharmaceutically acceptable salt or solvate thereof of claim 8, wherein the crystalline form has a weight loss of 0.07% to 0.94% when heated from 25°C to 120°C as determined by thermogravimetric analysis.

10. The following characteristics: - solubility of 2.5 mg / ml to more than 5.0 mg / ml in 24 hours in FaSSIF medium (pH 7.5); - solubility in FeSSIF medium (pH 7.8) of 3.4 mg / ml to more than 5.0 mg / ml in 24 hours; - a solubility of 0.07 mg / ml to 0.090 mg / ml in 24 hours in a medium of pH 6.

8.

11. 10. A pharmaceutically acceptable salt or solvate thereof according to any one of the preceding claims, wherein the pharmaceutically acceptable salt or solvate thereof is a crystalline form of the ethanolamine salt of the compound of formula (I).

12. The following characteristics: - 82F% bioavailability, - 0.49% moisture sorption at 25°C and 80% relative humidity as determined by dynamic vapor sorption; - endotherm onset of 176°C as measured by differential scanning calorimetry; a melting point of 178°C measured by differential scanning calorimetry; - 0.10% weight loss when heated from 25°C to 120°C, as determined by thermogravimetric analysis; - solubility greater than 7.99 mg / ml in FaSSIF medium (pH 7.5) at 24 hours; - solubility of more than 8.02 mg / ml in 24 hours in FeSSIF medium (pH 7.8), - a solubility of 0.088 mg / ml in 24 hours in a medium of pH 6.

8.

13. 12. The pharmaceutically acceptable salt or solvate thereof of claim 11, wherein the crystalline form exhibits an X-ray powder diffraction pattern with at least one peak selected from 6.6±0.2, 11.7±0.2, 15.0±0.2, 15.9±0.2, 17.7±0.2, 18.7±0.2, 19.2±0.2, 23.7±0.2, and 26.6±0.2 degrees 2θ.

14. 14. The pharmaceutically acceptable salt or solvate thereof of claim 13, wherein the crystalline form exhibits an X-ray powder diffraction pattern with at least two, at least three, at least four, or at least five peaks selected from 6.6±0.2, 11.7±0.2, 15.0±0.2, 15.9±0.2, 17.7±0.2, 18.7±0.2, 19.2±0.2, 23.7±0.2, and 26.6±0.2 degrees 2θ.

15. The crystalline form is an ethanolamine salt of the compound of formula (I), and the crystalline form satisfies the following parameters: Table 1 12. The pharmaceutically acceptable salt or solvate thereof of claim 11, which exhibits a single X-ray crystallographic analysis having the formula:

16. A pharmaceutical composition comprising the pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 15 and a pharmaceutically acceptable excipient.

17. 17. The pharmaceutical composition of claim 16, wherein at least about 80%, at least 85%, at least 88%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, or at least 95% of the pharmaceutically acceptable salt or solvate thereof is crystalline Form I of the ethanolamine salt.

18. 18. A method of treating, preventing, or ameliorating a fibrotic, inflammatory, or proliferative disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 15, or a pharmaceutical composition according to claim 16 or 17.

19. 18. Use of a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 15, or a pharmaceutical composition according to claim 16 or 17, in the manufacture of a medicament for the treatment, prevention, or amelioration of a fibrotic, inflammatory, or proliferative disease or condition in a subject.

20. A pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 15, or a pharmaceutical composition according to claim 16 or 17, for use in the treatment, prevention, or amelioration of a fibrotic, inflammatory, or proliferative disease or condition in a subject.

21. 21. The method of claim 18, the use of claim 19, or the pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition for the use of claim 20, wherein the fibrotic, inflammatory, or proliferative disease or condition is selected from fibrosis of the skin, lung, heart, kidney, pancreas, eye, and liver.

22. 21. The method of claim 18, the use of claim 19, or the pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition for the use of claim 20, wherein the fibrotic, inflammatory, or proliferative disease or condition is selected from diabetic cardiomyopathy, congestive heart failure, ischemic heart disease, hypertension, peripheral arterial disease, cerebrovascular disease, kidney disease, systemic sclerosis (scleroderma), hypertrophic scars, keloids, pulmonary fibrosis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC).

23. 21. The method of claim 18, the use of claim 19, or the pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition for the use of claim 20, wherein the fibrotic, inflammatory, or proliferative disease or condition is a kidney disease.

24. 21. The method of claim 18, the use of claim 19, or the pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition for the use of claim 20, wherein the fibrotic, inflammatory, or proliferative disease or condition is selected from chronic kidney disease, progressive kidney disease, diabetic nephropathy, diabetic nephropathy, glomerulonephritis, focal segmental glomerulosclerosis, systemic lupus, lupus nephritis, primary glomerulonephritis, membranous nephropathy, membranoproliferative glomerulonephritis, diffuse proliferative glomerulonephritis, membranous focal segmental glomerulosclerosis, secondary glomerulonephritis, membranous nephropathy, IgA nephropathy, or ischemic nephropathy.

25. 21. The method of claim 18, the use of claim 19, or the pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition for the use of claim 20, wherein the fibrotic, inflammatory, or proliferative disease or condition is selected from chronic obstructive pulmonary disease (COPD), asthma, and cystic fibrosis.

26. 21. The method of claim 18, the use of claim 19, or the pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition for the use of claim 20, wherein the fibrotic, inflammatory, or proliferative disease or condition is cancer.

27. 27. The method, use, or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition for use according to claim 26, wherein the cancer is selected from breast cancer, skin cancer (melanoma), pancreatic cancer, lung cancer, prostate cancer, colon cancer, liver cancer (hepatocellular carcinoma), head and neck cancer, ovarian cancer, and kidney cancer.

28. 21. The method of claim 18, the use of claim 19, or the pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition for the use of claim 20, wherein the fibrotic, inflammatory, or proliferative disease or condition is an autoimmune disease or condition.

29. 29. The method, use, or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition for use according to claim 28, wherein the autoimmune disease or condition is selected from systemic lupus erythematosus (SLE), inflammatory bowel disease, Crohn's disease, ulcerative colitis, graft-versus-host disease, multiple sclerosis, and rheumatoid arthritis.

30. The method, use, or pharmaceutically acceptable salt or solvate thereof, or pharmaceutical composition for use according to any one of claims 18 to 29, wherein the subject is a human.

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