Solid forms, salts and polymorphs of anti-fibrosis compounds

Abstract

The present disclosure relates to solid forms and salts (crystals and other forms) of (-2-[[3-(3-methoxy-4-propargyl) phenyl)-1-oxo-2-propenyl] amino] benzoic acid and pharmaceutical compositions comprising the same. The use of such solid forms, salts and pharmaceutical compositions for the treatment, prevention or amelioration of diseases or conditions associated with fibrosis, inflammation and / or proliferation is disclosed.

Description

[0001] Cross Reference to Related Applications

[0002] This application claims the benefit of Australian Provisional Application No. 2023900229, filed on January 31, 2023; U.S. Patent Application No. 18 / 354,467, filed on July 18, 2023; and U.S. Patent Application No. 18 / 537,184, filed on December 12, 2023; the disclosure of each of these applications is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure relates to ( Solid forms and salts of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (FT011), methods for preparing the same, and pharmaceutical compositions thereof. The present disclosure also relates to methods for using such solid forms and salts, and pharmaceutical compositions thereof, to treat, prevent, or ameliorate diseases or conditions associated with fibrosis, inflammation, and / or proliferation. Background Art

[0004] Fibrosis is the abnormal accumulation of collagen matrix following injury or inflammation, which alters the structure and function of various tissues. Regardless of the location, the primary pathology of fibrosis involves excessive deposition of collagen matrix that replaces normal tissue at the site. Progressive fibrosis in the kidneys, liver, lungs, heart, bone or bone marrow, and skin is a major cause of death and suffering. While the etiology and pathogenic mechanisms of individual fibrotic conditions may vary (e.g., ischemic events, exposure to chemicals, radiation, or infectious agents) and are poorly understood, they all share the common characteristic of abnormal and excessive deposition of extracellular matrix in affected tissues (Wynn and Ramalingam, Nat. Med. 2012, 18:1028). Fibrosis presents a significant and unmet clinical need, accounting for 45 percent (45%) of all deaths worldwide in the industrialized world.

[0005] Chronic heart failure (CHF) is a growing public health problem in industrialized countries. The causes of CHF are well-known to be multifactorial. The most common risk factors include coronary artery disease (particularly prior myocardial infarction), long-standing hypertension, diabetes mellitus, and idiopathic cardiomyopathy. However, the impending epidemics of obesity and diabetes, coupled with an aging population and improved heart attack survival rates, suggest a significant increase in the number of people with heart failure due to diabetes and related conditions, and the subsequent future economic and health burden (Najafi et al., Eur J Heart Fail 2009;11:472).

[0006] Individuals with diabetes have a high risk of developing CHF. Even in the absence of other co-morbid conditions such as atherosclerosis or hypertension, diabetes alone manifests as a primary cardiomyopathy called diabetic cardiomyopathy (DCM), with data from the Framingham Heart Study indicating that diabetes increases the risk of HF 4- to 5-fold. Human diabetic cardiomyopathy is characterized by diastolic dysfunction in its early stages and subtle changes in systolic function, such as decreased longitudinal fiber contractility. Pathologically, DCM is associated with microvascular disease and shares important similarities with diabetic nephropathy. Examination of left ventricular (LV) biopsies from patients with diabetes indicates that, at the cellular level, DCM is associated with myocyte hypertrophy, necrosis, apoptosis, fibroblast proliferation, and, more importantly, increased fibrocollagen deposition in the interstitial space (fibrosis). The elevated levels of cardiac fibrosis in these patients are associated with cardiac dysfunction, including elevated end diastolic pressure (EDP), end diastolic pressure-volume relationship (EDPVR), and end diastolic volume (EDV) and decreased ejection fraction (EF). Thus, pathological fibrosis greatly affects ventricular compliance, impairing diastolic function due to increased myocardial stiffness.

[0007] Pathological fibrosis underlying cardiac remodeling in diabetes can be mediated by locally active cytokines such as tumor necrosis factor-alpha (TNF-alpha), nuclear factor kappa-light chain enhancer of activated B cells (NF-kappaB), and transforming growth factor-beta (TGF-beta).

[0008] Current treatment of CHF, including diabetic HF, includes good glycemic control and treatment with beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, and mineralocorticoid receptor blockers, all of which have been shown to decrease overall mortality and improve clinical symptoms. However, despite such therapies, cardiac dysfunction continues to progress in most patients.

[0009] The increasing prevalence of diabetes and the clear indication that pathological fibrosis is underlying the decline in diastolic function in CHF in diabetes suggests the need for additional therapies to treat DCM. Current therapies do not directly target the proinflammatory and profibrotic processes that occur in the diabetic heart.

[0010] Chronic kidney disease (CKD) is a major cause of morbidity, recurrent hospitalization, and accelerated mortality, affecting 10-11% of the population in Europe and the United States (Hallan et al., J Am Soc Nephrol. 2006, 17:2275). In a substantial proportion of such patients, worsening renal function leads to progression to end-stage kidney disease (ESKD), necessitating dialysis or transplantation to sustain life. Studies conducted nearly 20 years ago underscored the importance of blood pressure control and blockade of the renin-angiotensin system in attenuating progression of CKD to end-stage. Unfortunately, despite substantial advances in understanding of the pathophysiology of kidney disease, there have been few new ways of therapy since then.

[0011] Due to the limited regenerative capacity, sustained or repeated injury to the kidney leads to excess deposition of extracellular matrix in both the glomerulus and the tubulointerstitium. These extensive pathologic changes, histologically recognized as glomerulosclerosis and tubulointerstitial fibrosis, encroach on the surrounding structures, inevitably leading to capillary rarefaction, with consequent hypoxia, tubular atrophy, and inflammatory cell infiltration. These structural changes in turn lead to loss of GFR, often (but not always) accompanied by worsening proteinuria. This final common pathway that occurs in most forms of chronic kidney disease occurs almost irrespective of the primary etiology, developing in response to seemingly diverse conditions including metabolic, immunologic, and infectious etiologies.

[0012] Studies conducted over the past decade have consistently shown that the pro- sclerotic growth factor, transforming growth factor-beta (TGF-beta), plays a major role in kidney fibrosis and dysfunction. However, other locally active growth factors are also implicated 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 roles, kidney tissue from a range of human and experimental kidney diseases shows increased expression in components of both the TGF-beta and PDGF pathways, making each pathway an important therapeutic target in attempts to develop new therapies for chronic kidney disease.

[0013] There is a continuing 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. SUMMARY

[0014] The present disclosure is directed, in part, to solid forms and pharmaceutically acceptable salts of (R)-2-[[3-(3-methoxy-4- propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, including crystalline forms thereof. In some embodiments, (R)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2- ) a pharmaceutically acceptable salt of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1- oxoprop-2-yl]amino]benzoic acid selected from the group consisting of ( ) a potassium salt, a meglumine salt, an ethanolamine salt, a tris(hydroxymethyl) aminomethane salt, a tert-butylamine salt, an ammonium salt, and a lysine salt of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxoprop-2-yl]amino]benzoic acid. In some embodiments, ( ) a pharmaceutically acceptable salt of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1- oxoprop-2-yl]amino]benzoic acid is a potassium salt, a meglumine salt, an ethanolamine salt, a tris(hydroxymethyl) aminomethane salt, a tert-butylamine salt, an ammonium salt, and a lysine salt of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxoprop-2-yl]amino]benzoic acid. ) an ethanolamine salt or a tert-butylamine salt of 2-[[3-(3-methoxy-4- propargyloxy)phenyl)-1-oxoprop-2-yl]amino]benzoic acid. In certain embodiments, ( ) a pharmaceutically acceptable salt of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1- oxoprop-2-yl]amino]benzoic acid is a potassium salt, a meglumine salt, an ethanolamine salt, a tris(hydroxymethyl) aminomethane salt, a tert-butylamine salt, an ammonium salt, and a lysine salt of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxoprop-2-yl]amino]benzoic acid. ) an ethanolamine salt of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxoprop-2- yl]amino]benzoic acid (also referred to herein as ( ) ethanolammonium 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxoprop-2- yl]amino]benzoate.

[0015] Anti-fibrotic, anti-inflammatory compounds ) the novel salts of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxoprop-2- yl]amino]benzoic acid described herein, such as ( ) the ethanolamine salt and the tert-butylamine salt of 2-[[3-(3-methoxy-4- propargyloxy)phenyl)-1-oxoprop-2-yl]amino]benzoic acid are solids with excellent chemical and physical properties (such as high thermal stability and low hygroscopicity) and have superior 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 suitable for use in various pharmaceutical dosage forms, including pharmaceutical dosage forms designed for oral, topical or parenteral administration.

[0016] The compounds ) 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxoprop-2-yl]amino]benzoic acid has the structure of formula (I):

[0017]

[0018] Formula (I).

[0019] Thus, in one aspect of the disclosure, there is provided a crystalline form of a pharmaceutically acceptable salt of a compound of Formula (I):

[0020]

[0021] Formula (I),

[0022] wherein the crystalline form has a water uptake of less than 1.7% at 25°C and 80% relative humidity, as determined by dynamic vapor sorption.

[0023] 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.

[0024] 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.

[0025] In embodiments, the crystalline form has one or more of the following properties:

[0026] - a solubility of 2.5 mg / ml to greater than 5.0 mg / ml at 24 hours in FaSSIF media (pH 7.5);

[0027] - a solubility of 3.4 mg / ml to greater than 5.0 mg / ml at 24 hours in FeSSIF media (pH 7.8);

[0028] - a solubility of 0.07 mg / ml to 0.090 mg / ml at 24 hours in media at pH 6.8.

[0029] In embodiments, the crystalline form has a bioavailability of 39 F% to 82 F%, 50 F% to 82 F%, or 64 F% to 82 F%.

[0030] In embodiments, the pharmaceutically acceptable salt is selected from the group consisting of a meglumine salt, an ethanolamine salt, a tris(hydroxymethyl)aminomethane salt, and a t-butylamine salt.

[0031] 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.

[0032] Also provided is a crystalline form of an ethanolamine salt of a compound of Formula (I):

[0033]

[0034] Formula (I),

[0035] wherein the bioavailability of the crystalline form is at least about 1.5x compared to the bioavailability of the free form of the compound of Formula (I).

[0036] In embodiments, the bioavailability of the crystalline form is at least about 1.8x, at least about 2.0x, or at least about 2.3x compared to the bioavailability of the free form of the compound of Formula (I).

[0037] In embodiments, the bioavailability of the crystalline form is about 82 F%.

[0038] In embodiments, the crystalline form has a water uptake of 0.49% at 25 °C and 80% relative humidity, as determined by dynamic vapor sorption.

[0039] In embodiments, the crystalline form has an endothermic onset temperature of 176 °C, as measured by differential scanning calorimetry.

[0040] In embodiments, the crystalline form has a melting point of 178 °C, as measured by differential scanning calorimetry.

[0041] In embodiments, the crystalline form has a weight loss of 0.10% when heated from 25 °C to 120 °C, as determined by thermogravimetric analysis.

[0042] In embodiments, the crystalline form has one or more of the following properties:

[0043] - solubility in FaSSIF media (pH 7.5) at 24 hours is greater than 7.99 mg / ml;

[0044] - solubility in FeSSIF media (pH 7.8) at 24 hours is greater than 8.02 mg / ml;

[0045] - solubility in media at pH 6.8 at 24 hours is 0.088 mg / ml.

[0046] 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.

[0047] Also provided is a crystalline form of an ethanolamine salt of a compound of Formula (I):

[0048]

[0049] Formula (I),

[0050] wherein the crystalline form exhibits an X-ray powder diffraction pattern having at least one peak selected from the group consisting of 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 ° 2Θ.

[0051] In embodiments, the crystalline form exhibits an X-ray powder diffraction pattern having at least two, at least three, at least four, or at least five peaks selected from the group consisting of 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 ° 2Θ.

[0052] In embodiments, the crystalline form exhibits an X-ray powder diffraction pattern having at least one peak selected from the group consisting of 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 ° 2Θ.

[0053] In embodiments, the crystalline form exhibits an X-ray powder diffraction pattern having at least one peak selected from the group consisting of 6.6 ± 0.2, 15.0 ± 0.2, 18.7 ± 0.2, and 19.2 ± 0.2 ° 2Θ.

[0054] In embodiments, the crystalline form exhibits an X-ray powder diffraction pattern having at least two peaks selected from the group consisting of 6.6 ± 0.2, 15.0 ± 0.2, 18.7 ± 0.2, and 19.2 ± 0.2 ° 2Θ.

[0055] In embodiments, the crystalline form exhibits an X-ray powder diffraction pattern having at least three peaks selected from the group consisting of 6.6 ± 0.2, 15.0 ± 0.2, 18.7 ± 0.2, and 19.2 ± 0.2 ° 2Θ.

[0056] In embodiments, the crystalline form exhibits an X-ray powder diffraction pattern having peaks at 6.6 ± 0.2, 15.0 ± 0.2, 18.7 ± 0.2, and 19.2 ± 0.2 ° 2Θ.

[0057] In embodiments, the crystalline form exhibits a single X-ray crystallographic analysis having the following parameters:

[0058]

[0059] In embodiments, a crystalline form of an ethanolamine salt of a compound of Formula (I):

[0060]

[0061] Formula (I),

[0062] exhibits a single X-ray crystallographic analysis with the following parameters:

[0063]

[0064] In embodiments, the crystalline form has an endothermic onset temperature of 176 °C, as measured by differential scanning calorimetry.

[0065] 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.

[0066] Also provided is a pharmaceutical composition comprising a crystalline form disclosed herein and a pharmaceutically acceptable excipient.

[0067] In embodiments, the pharmaceutical composition is formulated for single dose administration.

[0068] 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 a capsule.

[0069] In embodiments, the pharmaceutical composition comprises about 1 mg to about 2000 mg of a crystalline form disclosed herein. In embodiments, the pharmaceutical composition comprises about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, or about 1500 mg of a crystalline form disclosed herein. In embodiments, the pharmaceutical composition comprises about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or about 400 mg of a crystalline form disclosed herein. In embodiments, the pharmaceutical composition comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg of a crystalline form disclosed herein.

[0070] In embodiments, the pharmaceutical composition comprises an amount of a crystalline form disclosed herein effective to provide a dose of the compound of Formula (I) of about 1 mg / kg to about 500 mg / kg. In embodiments, the pharmaceutical composition comprises an amount of a crystalline form disclosed herein effective to provide a dose of the compound of Formula (I) of about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 40 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 110 mg / kg, about 120 mg / kg, about 130 mg / kg, about 140 mg / kg, about 150 mg / kg, about 160 mg / kg, about 170 mg / kg, about 180 mg / kg, about 190 mg / kg, about 200 mg / kg, about 210 mg / kg, about 220 mg / kg, about 230 mg / kg, about 240 mg / kg, about 250 mg / kg, about 260 mg / kg, about 270 mg / kg, about 280 mg / kg, about 290 mg / kg, about 300 mg / kg, about 310 mg / kg, about 320 mg / kg, about 330 mg / kg, about 340 mg / kg, about 350 mg / kg, about 360 mg / kg, about 370 mg / kg, about 380 mg / kg, about 390 mg / kg, or about 400 mg / kg. In embodiments, the pharmaceutical composition comprises an amount of a crystalline form disclosed herein effective to provide a dose of the compound of Formula (I) of about 10 mg / kg to about 400 mg / kg, or about 50 mg / kg to about 300 mg / kg, or about 100 mg / kg to about 250 mg / kg. In embodiments, the pharmaceutical composition comprises an amount of a crystalline form disclosed herein effective to provide a dose of the compound of Formula (I) of about 200 mg / kg.

[0071] In embodiments, the pharmaceutical composition comprises a crystalline form disclosed herein effective to provide a concentration of the compound of Formula (I) of 10 µM to 200 µM, or 10 µM to 100 µM, or 10 µM to 50 µM at its site of action. In embodiments, the pharmaceutical composition comprises a crystalline form disclosed herein effective to provide a concentration of the compound of Formula (I) of about 20 µM to about 40 µM, about 25 µM to about 35 µM, or about 30 µM at its site of action.

[0072] Also provided is a method of treating, preventing or ameliorating a fibrotic, inflammatory or proliferative disease or condition in a subject, the method comprising administering to the subject a therapeutically effective amount of a crystalline form as defined herein or a pharmaceutical composition as defined herein.

[0073] In embodiments, the fibrotic, inflammatory or proliferative disease or condition is selected from fibrosis of the skin, lung, heart, kidney, pancreas, eye and liver.

[0074] 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, nephropathy, systemic sclerosis (scleroderma), hypertrophic scarring, keloids, pulmonary fibrosis, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC).

[0075] In embodiments, the fibrotic, inflammatory or proliferative disease or condition is nephropathy.

[0076] In 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, membranous proliferative glomerulonephritis, diffuse proliferative glomerulonephritis, membranous focal segmental glomerulosclerosis, secondary glomerulonephritis, membranous nephropathy, IgA nephropathy or ischemic nephropathy.

[0077] In embodiments, the fibrotic, inflammatory or proliferative disease or condition is chronic kidney disease.

[0078] In embodiments, the fibrotic, inflammatory or proliferative disease or condition is diabetic nephropathy.

[0079] In embodiments, the fibrotic, inflammatory or proliferative disease or condition is focal segmental glomerulosclerosis.

[0080] In embodiments, the fibrotic, inflammatory or proliferative disease or condition is diabetic cardiomyopathy, congestive heart failure or ischemic heart disease.

[0081] In embodiments, the fibrotic, inflammatory or proliferative disease or condition is systemic sclerosis or scleroderma.

[0082] In embodiments, the fibrotic, inflammatory, or proliferative disease or condition is pulmonary fibrosis. In embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF).

[0083] In embodiments, the fibrotic, inflammatory, or proliferative disease or condition is selected from chronic obstructive pulmonary disorder (COPD), asthma, and cystic fibrosis.

[0084] In embodiments, the fibrotic, inflammatory, or proliferative disease or condition is a fibrotic eye disease. In embodiments, the fibrotic eye disease is selected from diabetic retinopathy, wet age-related macular degeneration, and diabetic macular edema.

[0085] In embodiments, the fibrotic, inflammatory, or proliferative disease or condition is cancer. In 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.

[0086] 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).

[0087] In embodiments, the fibrotic, inflammatory, or proliferative disease or condition is an autoimmune disease or condition. In 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.

[0088] In embodiments, the crystalline form or pharmaceutical composition as defined herein is administered orally.

[0089] In embodiments, the crystalline form or pharmaceutical composition as defined herein is administered daily.

[0090] In embodiments, the crystalline form or pharmaceutical composition as defined herein is administered at a dose of about 10 mg / kg / day to about 400 mg / kg / day, or about 50 mg / kg / day to about 300 mg / kg / day, or 100 mg / kg / day to 250 mg / kg / day of the compound of Formula (I). In embodiments, the crystalline form or pharmaceutical composition as defined herein is administered at a dose of about 200 mg / kg / day of the compound of Formula (I).

[0091] In embodiments, the subject is a human. BRIEF DESCRIPTION OF DRAWINGS

[0092] Figure 1 The crystalline form I is shown ( Exemplary X-ray powder diffraction (XRPD) pattern of a sample of the ethanolamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0093] Figure 2 Shown ( Exemplary thermogravimetric analysis (TGA) thermogram of a sample of the ethanolamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0094] Figure 3 Shown ( Exemplary thermogravimetric analysis (TGA) thermogram of a sample of the tert-butylamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0095] Figure 4 Shown ( Example dynamic vapor sorption (DVS) of a sample of the ethanolamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. A DVS isotherm plot (top) and a DVS mass change plot (bottom) are shown.

[0096] Figure 5 Shown ( Example dynamic vapor sorption (DVS) of a sample of the tert-butylamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. A DVS isotherm plot (top) and a DVS mass change plot (bottom) are shown.

[0097] Figure 6 Shown ( Exemplary differential scanning calorimetry (DSC) diffraction pattern of a sample of the ethanolamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0098] Figure 7 Shown ( Exemplary differential scanning calorimetry (DSC) diffraction pattern of a sample of the tert-butylamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0099] Figure 8 The crystalline form II is shown ( Exemplary X-ray powder diffraction (XRPD) pattern of a sample of the tert-butylamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0100] Figure 9 shows that ( Exemplary X-ray powder diffraction (XRPD) pattern of a sample of the meglumine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0101] Figure 10 The crystalline form IV is shown ( Exemplary X-ray powder diffraction (XRPD) pattern of a sample of the tris(hydroxymethyl)aminomethane (Tris) salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0102] Figure 11 The crystalline form V is shown ( Exemplary X-ray powder diffraction (XRPD) pattern of a sample of the potassium salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0103] Figure 12 The crystalline form VI is shown ( Exemplary X-ray powder diffraction (XRPD) pattern of a sample of the ammonium salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0104] Figure 13 The crystalline form VII is shown ( An exemplary X-ray powder diffraction (XRPD) pattern of a sample of the lysine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0105] Figure 14 Shown ( Stability test of the ethanolamine salt of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid under accelerated storage conditions for 1 week ( Figure 14 A) or 2 weeks ( Figure 14 B) Overlay of the XRPD patterns after HPLC. Shown are the XRPD patterns of the starting material (bottom pattern), the material held at 40°C and 75% relative humidity (middle pattern), and the material held at 60°C (top pattern).

[0106] Figure 15 An overlay of XRPD patterns of the ethanolamine salt of ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid is shown at the start (bottom pattern) and after storage at room temperature for 36 days (top pattern).

[0107] Figure 16 A plot of the plasma concentration of the free form of ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid over time is shown when dosed orally at 20 mg / kg body weight in Sprague-Dawley rats.

[0108] Figure 17 A plot of the plasma concentration of the potassium salt of ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid over time is shown when dosed orally at 20 mg / kg body weight in Sprague-Dawley rats.

[0109] Figure 18 A plot of the plasma concentration of the meglumine salt of ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid over time is shown when dosed orally at 20 mg / kg body weight in Sprague-Dawley rats.

[0110] Figure 19 A plot of the plasma concentration of the tris(hydroxymethyl)aminomethane (Tris) salt of ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid over time is shown when dosed orally at 20 mg / kg body weight in Sprague-Dawley rats.

[0111] Figure 20 A plot of the plasma concentration of the tert-butylamine salt of ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid over time is shown when dosed orally at 20 mg / kg body weight in Sprague-Dawley rats.

[0112] Figure 21 A plot of the plasma concentration of the tert-butylamine salt of ( A plot of plasma concentration of the ethanolamine salt of -2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid versus time following oral administration at 20 mg / kg body weight in Sprague-Dawley rats.

[0113] Figure 22 A plot of plasma concentration of the lysine salt of -2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid versus time following oral administration at 20 mg / kg body weight in Sprague-Dawley rats is shown.

[0114] Figure 23 A plot of plasma concentration of the lysine salt of -2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid versus time following oral administration at 20 mg / kg body weight in Sprague-Dawley rats is shown. A plot of plasma concentration of the lysine salt of -2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid versus time following oral administration at 20 mg / kg body weight in Sprague-Dawley rats is shown.

[0115] Figure 24 A plot of plasma concentration of the lysine salt of -2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid versus time following oral administration at 20 mg / kg body weight in Sprague-Dawley rats is shown. An exemplary X-ray powder diffraction (XRPD) pattern of a sample of crystalline anhydrous Form IX of -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2- propenyl]amino]benzoic acid is shown.

[0116] Figure 25 An exemplary X-ray powder diffraction (XRPD) pattern of a sample of crystalline anhydrous Form IX of -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2- propenyl]amino]benzoic acid is shown. DETAILED DESCRIPTION

[0117] Generally, the nomenclature used herein, and the laboratory procedures in organic chemistry, medicinal chemistry, pharmacology, formulation science and medical sciences described herein are those well-known and commonly used in the art. Unless defined otherwise, all technical and scientific terms and any acronyms used herein have the same meanings as those generally understood by one of ordinary skill in the art.

[0118] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), a cow, a pig, a sheep, a goat, a horse, a dog, a cat, a rabbit, a rat, or a mouse. The terms "subject" and "patient" are used interchangeably herein, for example, to refer to a mammalian subject, such as a human subject, in one embodiment, a human.

[0119] ​​The terms "treat," "treating," and "treatment" are intended to include one or more of the reduction or elimination of a disorder, disease, or condition; or one or more symptoms associated with the disorder, disease, or condition; or the reduction or elimination of the cause of the disorder, disease, or condition itself.

[0120] The terms "prevent," "preventing," and "prevention" are intended to include a method of delaying and / or precluding the onset of a disorder, disease, or condition and / or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing the risk of a subject acquiring a disorder, disease, or condition.

[0121] As used herein, and unless otherwise indicated, 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. Typically, a subject derives a beneficial effect from a prophylactic and / or therapeutic agent that does not cure the disease or disorder. In this regard, the term "manage" encompasses treating a subject already suffering from a particular disease in an attempt to prevent or minimize recurrence of the disease.

[0122] As used herein, ameliorating a symptom of a particular disorder by administration of a particular pharmaceutical composition refers to any alleviation, whether permanent or temporary, lasting or transient, that can be attributed to or associated with the administration of the composition.

[0123] As used herein, the term "disorder" is intended to be synonymous with, and used interchangeably with, the terms "disease," "syndrome," and "condition" (e.g., medical condition), as all reflect an abnormal condition of the body or one of its parts that impairs normal function, typically manifested by certain signs and symptoms.

[0124] The term "therapeutically effective amount" is intended to include an amount of a compound that, when administered, is sufficient to prevent the development of, or to alleviate to some extent, one or more symptoms of a disorder, disease, or condition being treated. The term "therapeutically effective amount" also refers to the amount of a compound that a researcher, veterinarian, doctor or clinician is seeking to have a biological or medical response in an organism (e.g., a protein, enzyme, RNA or DNA), cell, tissue, system, animal, or human.

[0125] As used herein, and unless otherwise indicated, a "prophylactically effective amount" of a compound is an amount sufficient to prevent aspects of a disease or condition, or to prevent recurrence of the same. A prophylactically effective amount of a compound means an amount of a therapeutic agent alone or in combination with one or more other agents that provides a prophylactic benefit in the prevention of the disease. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

[0126] "Fibrotic condition," "fibrotic disease," and "fibrotic disorder" are used interchangeably herein to refer to a condition, disease, or disorder characterized by dysregulation of fibroblast proliferation or activity and / or abnormal accumulation of fibronectin and / or pathological or excessive accumulation of collagenous tissue. Typically, any such disease, disorder, or condition is susceptible to treatment by administration of a compound having anti-fibrotic activity. Fibrotic disorders include, but are not limited to, renal fibrosis, dermal 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 from known etiologies.

[0127] "Cardiac fibrosis" refers to the formation of fibrous tissue, including cellular and extracellular components, in the intima and muscle of the heart. If present in sufficient amounts, the fibrous tissue will result in a reduction in contractility and / or diastolic compliance of one or more regions of the heart, resulting in a functional deficit in cardiac output.

[0128] "Diabetic cardiomyopathy" refers to any one or more of the cardiac pathologies and / or functional impairments of a subject that are a complication of Type I or Type II diabetes in the subject. The diabetes can be symptomatic or asymptomatic. Cardiac pathologies that are characteristic of diabetic cardiomyopathy include myocyte hypertrophy, myocardial fibrosis, and, in some cases, left ventricular hypertrophy. The pathologies contemplated arise independently of complications caused by coronary artery disease, although both diabetic and coronary artery complications can be present in the same subject. Diastolic impairments, such as impairment of early diastolic filling, prolongation of isovolumic relaxation, and increased atrial filling, are also characteristic of diabetic cardiomyopathy and can be identified using Doppler methods, such as Doppler 2-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 impairments and by standard echocardiographic testing for more severe impairments.

[0129] As used herein, the term "kidney disease" can refer to a condition in a subject that impairs kidney function of at least one kidney. Kidney disease can be caused by a primary pathology of the kidney (e.g., glomerular or tubular injury) or another organ (e.g., pancreas) that adversely affects the ability of the kidney to perform biological functions. Kidney disease in a human can be a direct or indirect effect of a disease. An example of kidney disease that is an indirect effect or consequence of a kidney is kidney disease that is a result of diabetes or systemic lupus. Kidney disease can be a result or consequence of any change, injury, or trauma to the glomerulus, tubule, or interstitial tissue in the renal cortex or 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, years).

[0130] Kidney disease can include, but is not limited to, progressive glomerulonephropathy, including, but not limited to, diabetic nephropathy (e.g., due to 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).

[0131] As used herein, the term "kidney function" refers to the physiological properties of the kidney, such as the ability to retain protein thereby preventing proteinuria. Kidney function can be assessed using methods known in the art, such as determining one or more of glomerular filtration rate (e.g., creatinine clearance), excretion of protein in the urine, blood urea nitrogen, and serum or plasma creatinine.

[0132] Progressive kidney disease treated by the salts, pharmaceutical compositions, and methods described herein include any kidney disease that can ultimately result in end-stage renal disease. Progressive kidney disease that can be treated by the compositions and methods of the present application can be associated with, for example, endogenous iron deposition in the kidney (e.g., glomerulus, tubule).

[0133] 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 ingredients of a pharmaceutical formulation for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications commensurate with a reasonable benefit / risk ratio. See Remington: The Science and Practice of Pharmacy, 22ndEdition, Pharmaceutical Press: 2012; Handbook of Pharmaceutical Excipients, 7thEdition; Rowe et al. Eds.; Pharmaceutical Press: 2012; Handbook of Pharmaceutical Additives, 3rdEdition; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2ndEdition; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0134] As used in the specification and the appended claims, the indefinite articles “a” and “an” and the definite article “the” include the plural as well as the singular, unless the context clearly dictates otherwise.

[0135] The term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is being 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, “about” or “approximately” with respect to X-ray powder diffraction 2-theta peaks means within ± 0.2°.

[0136] 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, for the treatment, prevention, or amelioration of one or more symptoms of a disorder, disease, or condition. As used herein, "active ingredient" and "active substance" can be an optically active isomer or an isotopic variant of a compound described herein.

[0137] The term "anti-solvent" refers to a liquid that is added to a solvent to decrease the solubility of a compound in the solvent, in some cases, resulting in precipitation of the compound.

[0138] The terms "drug," "therapeutic agent," and "chemotherapeutic agent" refer to a compound or a pharmaceutical composition thereof that is administered to a subject for the treatment, prevention, or amelioration of one or more symptoms of a disorder, disease, or condition.

[0139] The term "solvate" refers to a complex or aggregate formed by one or more solute molecules (e.g., a compound provided herein) and one or more solvent molecules, present in a stoichiometric or non-stoichiometric amount. 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 crystalline form. In another embodiment, the complex or aggregate is in 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.

[0140] The term "solid form" of a compound can refer to any crystalline form of a compound or any amorphous form of a compound, such as a free acid, a free base, an acid addition salt of a compound, a base addition salt of a compound, a complex of a compound, or a solvate of a compound (including a hydrate) or a co-precipitate of a compound. The term "crystalline form" of a compound can refer to any crystalline form of a compound, such as a free acid, a free base, an acid addition salt of a compound, a base addition salt of a compound, a complex of a compound, a solvate of a compound (including a hydrate) or a co-crystal of a compound. In many cases, the terms "crystalline form" and "solid form" can refer to a pharmaceutically acceptable form, including, for example, a pharmaceutically acceptable addition salt, a pharmaceutically acceptable complex, a pharmaceutically acceptable solvate, a pharmaceutically acceptable co-crystal, and a pharmaceutically acceptable co-precipitate.

[0141] In addition, the compounds disclosed herein can exist in one or more crystalline or amorphous forms. Unless otherwise indicated, all such forms are included in the scope of the compounds disclosed herein, including any polymorphic forms.

[0142] As used herein, “pharmaceutically acceptable salt” refers to any salt of a compound provided herein that retains its biological properties and is not toxic or otherwise undesirable for pharmaceutical use. Such salts can be derived from various organic and inorganic counter-ions well known in the art. Such salts include, but are not limited to, salts formed from acid protons (a) present in the parent compound by replacement with a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion) or an alkali or alkaline earth metal hydroxide, 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, t-butylamine (also known as ‘TBA’, 2-methylpropan-2-amine, or 2-amino-2-methylpropane), tris(hydroxymethyl)aminomethane (also known as ‘Tris’ or ‘Tris base’), and the like. As used in the present disclosure, the term “pharmaceutically acceptable salt” does not include piperidinium salts.

[0143] The terms “substantially pure” and “substantially homogeneous” refer to a sufficient degree of homogeneity as to be suitable for its intended purpose, as determined by standard analytical methods used by one of ordinary 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 a sufficient degree of purity such that further purification would not detectably alter the physical, chemical, biological, and / or pharmacological properties, such as enzymatic activity and biological activity, of the substance. In certain embodiments, “substantially pure” or “substantially homogeneous” refers to a collection of molecules in which at least about 50% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 98% by weight, at least about 99% by weight, 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 mixture of diastereomers thereof, as determined by standard analytical methods.

[0144] Unless otherwise indicated, X-ray powder diffraction (XRPD) data provided herein were determined using a Cu Kα radiation source. XRPD peaks cited herein should be understood to reflect an accuracy of ± 0.2 of the 2θ peak, and an equivalent accuracy of the d-spacing according to Bragg's law.

[0145] The term “water absorption” refers to the change in water content observed during the course of the experiment and is thus indicative of the water uptake by the material (g / g). - hygroscopicity of a sample of a form of 2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid, including solid forms, crystalline forms as described herein, or a pharmaceutically acceptable salt of any thereof, as determined by dynamic vapor sorption (DVS). Water content change is recited as a change in mass of the starting sample in %, and all such water sorption (DVS) values recited herein will be understood to expressly include numerical values within + / - 0.2% variance. When a hygroscopicity value at a particular humidity is recited, this refers to the value measured during an adsorption cycle, for example when the humidity value is reached during a process in which the humidity is increased from 0% RH to 95% RH in the presence of the sample.

[0146] The term "weight loss" refers to the loss in mass of a sample of a form of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid, including solid forms, crystalline forms as described herein, or a pharmaceutically acceptable salt of any thereof, as determined by thermogravimetric analysis (TGA). - observed weight loss of a sample of a form of 2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid, including solid forms, crystalline forms as described herein, or a pharmaceutically acceptable salt of any thereof. Weight loss is recited as a loss in mass of the starting sample in %, and all such weight loss values recited herein will be understood to expressly include numerical values within + / - 0.2% mass unit variance.

[0147] The term "bioavailability" refers to the fraction of an active ingredient that reaches the general circulation after administration. - bioavailability of one or more forms of 2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid, including solid forms, crystalline forms as described herein, and a pharmaceutically acceptable salt of any thereof, in plasma. Bioavailability is determined according to the equation AUC = F • D / CL T , where AUC is the area under the curve of plasma concentration, F is the absolute bioavailability, D is the dose, and CL T is the total clearance. Furthermore, the term bioavailability refers to the bioavailability determined according to the experiment recited in Example 6, and reference is made to Table 22, wherein bioavailability (F) is calculated using the extrapolated area under the curve (AUC inf ) of plasma concentration. Bioavailability values as recited herein will be understood to expressly include numerical values within + / - 10% variance.

[0148] The term "endothermic onset temperature" refers to the temperature at which the endothermic transition begins, as measured by differential scanning calorimetry (DSC). ) -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid forms, including solid forms, crystalline forms, or pharmaceutically acceptable salts of any thereof, in which an endothermic event occurs. Melting point values as recited herein will be understood to expressly include values within + / - 2.0 °C variance.

[0149] 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 ) -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid forms, including solid forms, crystalline forms, or pharmaceutically acceptable salts of any thereof, in which a change of state from solid to liquid occurs. Melting point values as recited herein will be understood to expressly include values within + / - 2.0 °C variance.

[0150] The term "FaSSIF medium" refers to a fasted state simulated intestinal fluid medium prepared using FaSSIF powder and buffer concentrates obtained from commercial source Biorelevant (Biorelevant, London, UK, biorelevant.com). The FaSSIF powder contains sodium taurocholate, lecithin, sodium chloride, sodium dihydrogen phosphate, and sodium hydroxide. The FaSSIF medium is prepared as described at https: / / biorelevant.com / learning_center / what-is-fassif / . In brief, a pH 6.5 buffer containing 0.42 g NaOH, 3.95 g NaH2PO4-H2O, and 6.19 g NaCl is dissolved in 0.9 L purified water, and the pH of the solution is adjusted to 6.5 using 1 N sodium hydroxide or 1 N hydrochloric acid and made up to volume (1 L) with purified water at room temperature. 2.24 g of FaSSIF powder is dissolved in 0.5 L of pH 6.5 buffer, stirred until the powder is completely dissolved, and then made up to volume (1 L) with buffer at room temperature. The prepared medium contains sodium taurocholate at a concentration of 3.0 mM, lecithin at a concentration of 0.75 mM, sodium chloride at a concentration of 106 mM, and sodium dihydrogen phosphate at a concentration of 28.4 mM. When needed, FaSSIF (pH 7.5) medium is prepared as described and adjusted to the desired pH using 1 N sodium hydroxide or 1 N hydrochloric acid.

[0151] The term "FeSSIF medium" refers to a fed state simulated intestinal fluid medium prepared using FeSSIF powder and buffer concentrates obtained from commercial source Biorelevant (Biorelevant, London, UK, biorelevant.com) and buffer concentrate to prepare fed-state simulated intestinal fluid medium. FeSSIF powder contains sodium taurocholate, lecithin, sodium chloride, sodium hydroxide, and acetic acid. FeSSIF medium was prepared as described at https: / / biorelevant.com / learning_center / what-is-fessif / . Briefly, pH 5.0 buffer containing 44.04 g NaOH, 8.65 g glacial acetic acid, and 11.87 g 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 volume was made up to 1 L with purified water at room temperature. 11.20 g FeSSIF powder was dissolved in 0.5 L of pH 5.0 buffer, stirred until the powder was completely dissolved, and then made up to 1 L with buffer at room temperature. The prepared medium contained 15.0 mM sodium taurocholate, 3.75 mM lecithin, 203 mM sodium chloride, and 144 mM acetic acid. When 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.

[0152] Solid forms

[0153] The present disclosure relates, in part, to ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid form (e.g., a crystalline form) of a pharmaceutically acceptable salt thereof. 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 may provide advantages over ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (also referred to herein as ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid in "non-salt form", "free form" or "free acid form"). Some embodiments disclosed herein include ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid in crystalline form.

[0154] The compound has been described in the international patent application WO 2008 / 003141 ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, also known as, for example, ( )-2-(3-(3-methoxy-4-(prop-2-yn-1-yloxy)phenyl)acrylamide)benzoic acid, ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, 3-methoxy-4-propargyloxycinnamoylanthranilic acid or 'FT011', including its preparation and biological evaluation, the disclosure of which is incorporated herein by reference in its entirety.

[0155] The solid forms, pharmaceutically acceptable salts, and crystalline forms thereof described herein can be characterized using a variety of methods known to those skilled 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). For solid forms, particle size and size distribution can be determined by conventional methods (e.g., 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).

[0156] In the embodiments, provided herein are ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. In some embodiments, the solid form is crystalline.

[0157] In some embodiments, ( The solid form of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid is ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid in solid form. In some embodiments, ( The solid form of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid is ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a crystalline form of a pharmaceutically acceptable salt thereof or a solvate thereof.

[0158] In any embodiment described herein, the term "pharmaceutically acceptable salt" does not include piperidinium salts.

[0159] ( The pharmaceutically acceptable salt of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid can be selected from, but is not limited to, potassium salt, meglumine salt, ethanolamine salt, tris(hydroxymethyl)aminomethane (Tris) salt, tert-butylamine (TBA) salt, ammonium salt, or lysine salt. In some embodiments, the pharmaceutically acceptable salt is meglumine salt, ethanolamine salt, tris(hydroxymethyl)aminomethane (Tris) salt, or tert-butylamine (TBA) salt. In some embodiments, the pharmaceutically acceptable salt is ethanolamine salt or tert-butylamine salt. In certain embodiments, the pharmaceutically acceptable salt is ethanolamine salt.

[0160] In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid form (e.g., a crystalline form) of a pharmaceutically acceptable salt thereof can 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, isopropyl alcohol (IPA), 1-propanol, 1-butanol, 2-butanol, tert-butyl alcohol, 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, isopropyl alcohol, acetic acid, or ethyl acetate. In other embodiments, the solvent in the solvate is acetic acid or ethyl acetate. In some embodiments, provided herein ( The solid form (eg, crystalline form) of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof is unsolvated.

[0161] In some embodiments, provided herein ( The solid form (e.g., crystalline form) of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof may be a hydrate. Thus, in one embodiment, the ( In various embodiments, a solid form (e.g., a crystalline form) of -2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein can be a hemihydrate. In another embodiment, a solid form (e.g., a crystalline form) of -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein can be a monohydrate. In another embodiment, a solid form (e.g., a crystalline form) of -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein can be a dihydrate. In yet another embodiment, a solid form (e.g., a crystalline form) of -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein can be a trihydrate. In yet another embodiment, a solid form (e.g., a crystalline form) of -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein can be a tetrahydrate. In still another embodiment, a solid form (e.g., a crystalline form) of -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein can be a pentahydrate.

[0162] In various embodiments, a solid form (e.g., a crystalline form) of -2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein exhibits advantageous solubility, bioavailability, stability, processability, ease of manufacture, and / or pharmacokinetic properties. For example, a solid form (e.g., a crystalline form) of -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid provided herein can provide long-term stability, low hygroscopicity, improved dissolution, and superior pharmacokinetic properties. In some embodiments, a solid form (e.g., a crystalline form) of -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid provided herein can provide long-term stability, low hygroscopicity, improved dissolution, and superior pharmacokinetic properties. ​​​​​​​)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof has a solid form (e.g., a crystalline form) with 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 a modulated (e.g., decreased) water uptake as determined by dynamic vapor sorption (DVS), a modulated (e.g., increased) endothermic onset temperature as determined by differential scanning calorimetry (DSC), and / or a modulated (e.g., decreased) weight loss as determined by thermogravimetric analysis (TGA).

[0163] In some embodiments, the solid forms of -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein have a water uptake at 25 °C and 80% relative humidity 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%, as determined by dynamic vapor sorption (DVS). In some embodiments, the solid forms of -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein have a water uptake at 25 °C and 80% relative humidity 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%, as determined by dynamic vapor sorption (DVS). In some embodiments, the solid forms of -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein have a water uptake at 25 °C and 80% relative humidity 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%, as determined by dynamic vapor sorption (DVS). In some embodiments, the solid forms of -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein have a water uptake at 25 °C and 80% relative humidity 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%, as determined by dynamic vapor sorption (DVS). )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof in a solid form (e.g., a crystalline form) has a water absorption of 0.1% to 1.7% at 25° C. and 80% relative humidity, as determined by DVS. In another embodiment, provided herein is ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof in a solid form (e.g., a crystalline form) has a water absorption of 0.49% to 8.82% at 25° C. and 80% relative humidity, as determined by DVS. In yet another embodiment, provided herein is ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof in a solid form (e.g., a crystalline form) has a water absorption of 0.49% to 6.93% at 25° C. and 80% relative humidity, as determined by DVS. In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof in a solid form (e.g., a crystalline form) has a water absorption of 0.49% to 6.05% at 25° C. and 80% relative humidity, as determined by DVS. In certain embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof in a solid form (e.g., a crystalline form) has a water absorption of 0.49% to 1.61% at 25° C. and 80% relative humidity, as determined by DVS. In certain embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof in a solid form (e.g., a crystalline form) has a water absorption of 0.49% to 1.07% at 25° C. and 80% relative humidity, as determined by DVS. In certain embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof has a water absorption of 1.07% to 8.82% at 25° C. and 80% relative humidity, as determined by DVS.

[0164] In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof has an endothermic onset temperature of 29° C. to 187° C. as measured by differential scanning calorimetry (DSC). In some embodiments, the ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof has an endothermic onset temperature of 116° C. to 187° C. as measured by DSC. In some embodiments, provided herein are ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof has a solid form (e.g., a crystalline form) having a melting point of 57° C. to 199° C. as measured by DSC. In some embodiments, provided herein are ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof has a melting point of 155° C. to 199° C. as measured by DSC. In some embodiments, provided herein are ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof has an endothermic onset temperature of 29° C. to 187° C. and a melting point of 57° C. to 199° C. as measured by DSC. In some embodiments, provided herein are ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof has an endothermic onset temperature of 116° C. to 187° C. and a melting point of 155° C. to 199° C., as measured by DSC.

[0165] In some embodiments, when heated from 25°C to 120°C, the ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof, wherein the weight loss of the solid form (e.g., crystalline form) is 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% as determined by thermogravimetric analysis (TGA). In some embodiments, when heated from 25° C. to 120° C., the ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof, the weight loss of the solid form (e.g., crystalline form) is 0.05% to 3% as determined by thermogravimetric analysis (TGA). In some embodiments, when heated from 25° C. to 120° C., the ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof, the weight loss of the solid form (e.g., crystalline form) is 0.01% to 1% as determined by TGA. In some embodiments, when heated from 25° C. to 120° C., the ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof, the weight loss of the solid form (e.g., crystalline form) is 0.07% to 8.94% or 0.07% to 0.94%, as determined by TGA.

[0166] In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof 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, 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 FaSSIF medium (pH 7.5) at 24 hours. In some embodiments, provided herein are ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof in a solid form (e.g., a crystalline form) having a solubility 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 in FaSSIF medium (pH 7.5) at 24 hours. In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof in a solid form (e.g., a crystalline form) in FaSSIF medium (pH 7.5) at a solubility of 2.4 mg / ml to 5.14 mg / ml at 24 hours. In some embodiments, provided herein ( The solubility of 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 in FaSSIF medium (pH 7.5) at 24 hours is 2.4 mg / ml to greater than 5.14 mg / ml.

[0167] In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof in FeSSIF medium (pH 7.8) at 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, 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, provided herein are )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof in a solid form (e.g., a crystalline form) having a solubility 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 in FeSSIF medium (pH 7.8) at 24 hours. In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof in a solid form (e.g., a crystalline form) in FeSSIF medium (pH 7.8) at a solubility of 1.2 mg / ml to 5.14 mg / ml at 24 hours. In some embodiments, provided herein ( The solubility of 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 in FeSSIF medium (pH 7.8) at 24 hours is 1.2 mg / ml to greater than 5.14 mg / ml.

[0168] In some embodiments, provided herein ( ) -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid or a solid form (e.g., a crystalline form) of a pharmaceutically acceptable salt thereof has an improved bioavailability. ) -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid or a solid form (e.g., a crystalline form) of a pharmaceutically acceptable salt thereof has an improved bioavailability.

[0169] In embodiments, a solid form (e.g., a crystalline form) of ) -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof has an improved bioavailability.

[0170] Bioavailability can be improved by increasing the AUC (area under the plasma concentration curve), decreasing the time to reach t max (maximum serum level) or increasing C max For example, a solid form (e.g., a crystalline form) of ) -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof provided herein can produce a higher ) -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid plasma concentration than a reference form.

[0171] As will be appreciated by one of skill in the art, AUC is useful in estimating bioavailability and in estimating total clearance (CL T ) of a drug. In some cases, AUC = F • D / CL T , where D is the dose and F is the absolute bioavailability.

[0172] 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 has a bioavailability of at least 39 F%, 44 F%, 49 F%, 54 F%, 59 F%, 54 F%, 59 F%, 64 F%, 69 F%, 74 F%, 79 F%, 84 F%, 89 F%, 94 F%, or 99 F%. In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof has a bioavailability of at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%. In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof has a bioavailability of 39 F% to 99 F%, 39 F% to 94 F%, 39 F% to 89 F%, 39 F% to 84 F%, 39 F% to 79 F%, 39 F% to 74 F%, 39 F% to 69 F%, 39 F% to 64 F%, 39 F% to 59 F%, 39 F% to 54 F%, 39 F% to 49 F%, or 39 F% to 44 F%. In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof has a bioavailability of 39 F% to 82 F%. In some embodiments, the bioavailability is oral bioavailability.

[0173] In some embodiments, )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, compared to the bioavailability of the free form of ( about 2.0x, about 2.1x, about 2.2x, about 2.3x, about 2.4x, about 2.5x, about 2.6x, about 2.7x, about 2.8x, about 2.9x, or about 3.0x. In some embodiments, the bioavailability is oral bioavailability. about 2.0x, about 2.1x, about 2.2x, about 2.3x, about 2.4x, about 2.5x, about 2.6x, about 2.7x, about 2.8x, about 2.9x, or about 3.0x. In some embodiments, the bioavailability is oral bioavailability. about 2.0x, about 2.1x, about 2.2x, about 2.3x, about 2.4x, about 2.5x, about 2.6x, about 2.7x, about 2.8x, about 2.9x, or about 3.0x. In some embodiments, the bioavailability is oral bioavailability.

[0174] Salts and solid forms or crystalline forms of salts

[0175] In some embodiments, provided herein are pharmaceutically acceptable salts of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1- oxo-2-propenyl]amino]benzoic acid, and solid forms or crystalline forms thereof. In various embodiments, the pharmaceutically acceptable salt can be selected from, but not limited to, a potassium salt, a meglumine salt, an ethanolamine salt, a tris(hydroxymethyl)aminomethane (Tris) salt, a t-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 t-butylamine (TBA) salt. In some embodiments, the pharmaceutically acceptable salt is an ethanolamine salt or a t-butylamine salt. In certain embodiments, the pharmaceutically acceptable salt is an ethanolamine salt.

[0176] In some embodiments, provided herein are ethanolamine salts of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2- propenyl]amino]benzoic acid, including solid forms or crystalline forms thereof.

[0177] As used herein, the term “ethanolamine” refers to the compound (and related salts formed using the compound), also known as, for example, 2-aminoethan-1-ol, 2-aminoethanol, monoethanolamine, or “MEA.”

[0178] In some embodiments, provided herein is a salt of 2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid, including solid forms or crystalline forms thereof. In some embodiments, provided herein is a salt of 2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid, including solid forms or crystalline forms thereof.

[0179]

[0180] In some embodiments, provided herein is a salt of 2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid, including solid forms or crystalline forms thereof.

[0181] In some embodiments, provided herein is a salt of 2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid, including solid forms or crystalline forms thereof. In some embodiments, provided herein is a salt of 2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid, including solid forms or crystalline forms thereof.

[0182] In some embodiments, provided herein is a salt of 2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid, including solid forms or crystalline forms thereof.

[0183] In some embodiments, provided herein is a salt of 2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid, including solid forms or crystalline forms thereof. In some embodiments, provided herein is a salt of 2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid, including solid forms or crystalline forms thereof.

[0184] In some embodiments, provided herein is a salt of 2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid, including solid forms or crystalline forms thereof.

[0185] In some embodiments, provided herein is a salt of 2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid, including solid forms or crystalline forms thereof. In some embodiments, provided herein is a salt of 2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid, including solid forms or crystalline forms thereof.

[0186] In some embodiments, provided herein is a salt of 2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid, including solid forms or crystalline forms thereof.

[0187] In some embodiments, provided herein is a salt of 2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid, including solid forms or crystalline forms thereof. ​​​)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof, or a solid or crystalline form thereof, advantageously exhibits improved solubility, bioavailability, stability, processability, ease of manufacture and / or pharmacokinetic properties. Compared to the free form of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, the ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof or a solid form or a crystalline form thereof can provide long-term stability, low hygroscopicity, improved solubility and superior pharmacokinetic properties. In some embodiments, Compared to the free form of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, the ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a solid or crystalline form thereof, has improved properties, wherein the improved property is 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 a modified (e.g., decreased) water uptake as determined by dynamic vapor sorption (DVS), a modified (e.g., increased) endothermic onset temperature as determined by differential scanning calorimetry (DSC), and / or a modified (e.g., decreased) weight loss as determined by thermogravimetric analysis (TGA).

[0188] In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a pharmaceutically acceptable salt thereof, or a solid or crystalline form thereof, has a water absorption 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, provided herein is ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a pharmaceutically acceptable salt thereof in a solid or crystalline form thereof, has a water absorption at 25° C. and 80% relative humidity of 0.1 to 10%, 0.1 to 9%, 0.1 to 8%, 0.1 to 7%, 0.1 to 6%, 0.1 to 5%, 0.1 to 4%, 0.1 to 3%, 0.1 to 2% or 0.1 to 1%, as determined by DVS. In another embodiment, provided herein is ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a pharmaceutically acceptable salt thereof in a solid or crystalline form thereof, has a water absorption of 0.49% to 8.82% at 25° C. and 80% relative humidity, as determined by DVS. In yet another embodiment, provided herein is ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a pharmaceutically acceptable salt thereof in a solid or crystalline form thereof, has a water absorption of 0.49% to 6.93% at 25° C. and 80% relative humidity, as determined by DVS. In some embodiments, provided herein are ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a pharmaceutically acceptable salt thereof in a solid or crystalline form thereof, has a water absorption of 0.49% to 6.05% at 25° C. and 80% relative humidity, as determined by DVS. In certain embodiments, provided herein are ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a pharmaceutically acceptable salt thereof in a solid or crystalline form thereof, has a water absorption of 0.49% to 1.61% at 25° C. and 80% relative humidity, as determined by DVS. In certain embodiments, provided herein are ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a pharmaceutically acceptable salt thereof, or a solid or crystalline form thereof, has a water absorption of 0.49% to 1.07% at 25° C. and 80% relative humidity, as determined by DVS.

[0189] In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a pharmaceutically acceptable salt thereof in a solid or crystalline form thereof, has an endothermic onset temperature of 29° C. to 203° C., as measured by differential scanning calorimetry (DSC). In some embodiments, the ( pharmaceutically acceptable salt of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l- oxoprop-2-yl]amino]benzoic acid or a solid form or crystalline form thereof has an endothermic onset temperature 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)-l- oxoprop-2-yl]amino]benzoic acid or a solid form or crystalline form thereof provided herein has a melting point of 57 °C to 204 °C, as determined by DSC. In some embodiments, a pharmaceutically acceptable salt of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l- oxoprop-2-yl]amino]benzoic acid or a solid form or crystalline form thereof provided herein has a melting point of 155 °C to 204 °C, as measured by DSC. In some embodiments, a pharmaceutically acceptable salt of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l- oxoprop-2-yl]amino]benzoic acid or a solid form or crystalline form thereof provided herein has an endothermic onset temperature 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)-l- oxoprop-2-yl]amino]benzoic acid or a solid form or crystalline form thereof provided herein has an endothermic onset temperature of 116 °C to 203 °C and a melting point of 155 °C to 204 °C, as measured by DSC.

[0190] In some embodiments, a pharmaceutically acceptable salt of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxoprop-2-yl]amino]benzoic acid or a solid form 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)-l-oxoprop-2-yl]amino]benzoic acid or a solid form 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). ​​​​​)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a pharmaceutically acceptable salt thereof, or a solid or crystalline form thereof, has a weight loss of 0.05% to 3% as determined by thermogravimetric analysis (TGA). In some embodiments, when heated from 25° C. to 120° C., the ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a pharmaceutically acceptable salt thereof, or a solid or crystalline form thereof, has a weight loss of 0.07% to 5.24% as determined by TGA. In some embodiments, when heated from 25° C. to 120° C., the ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a solid or crystalline form thereof, with a weight loss of 0.07% to 8.94% or 0.07% to 0.94%, as determined by TGA.

[0191] In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a solid or crystalline form thereof, 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, 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 FaSSIF medium (pH 7.5) at 24 hours. In some embodiments, provided herein are ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof, or a solid form or a crystalline form thereof, has a solubility 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 in FaSSIF medium (pH 7.5) at 24 hours. In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof or a solid form or a crystalline form thereof has a solubility of 2.4 mg / ml to 5.14 mg / ml in FaSSIF medium (pH 7.5) at 24 hours. In some embodiments, provided herein ( The solubility of a pharmaceutically acceptable salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid form or a crystalline form thereof in FaSSIF medium (pH 7.5) at 24 hours is 2.4 mg / ml to greater than 5.14 mg / ml.

[0192] In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a solid or crystalline form thereof, 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, 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, mg / ml or 20 mg / ml. In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof, or a solid form or a crystalline form thereof, has a solubility 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 in FeSSIF medium (pH 7.8) at 24 hours. In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof or a solid form or a crystalline form thereof has a solubility of 1.2 mg / ml to 5.14 mg / ml in FeSSIF medium (pH 7.8) at 24 hours. In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a solid form or a crystalline form thereof, has a solubility in FeSSIF medium (pH 7.8) of 1.2 mg / ml to greater than 5.14 mg / ml at 24 hours.

[0193] In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof in a solid form or a crystalline form thereof has a solubility of 2.4 mg / ml to 5.14 mg / ml in FaSSIF medium (pH 7.5) at 24 hours and a solubility of 1.2 mg / ml to 5.14 mg / ml in FeSSIF medium (pH 7.8) at 24 hours. In some embodiments, provided herein are ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a solid form or a crystalline form thereof, has a solubility of 2.4 mg / ml to greater than 5.14 mg / ml in FaSSIF medium (pH 7.5) at 24 hours, and a solubility of 1.2 mg / ml to greater than 5.14 mg / ml in FeSSIF medium (pH 7.8) at 24 hours.

[0194] In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, 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 culture medium at pH 6.8 at 24 hours. In certain embodiments, provided herein are ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof, or a solid or crystalline form thereof, has a solubility of at least 0.06 mg / ml in a medium at pH 6.8 at 24 hours. In some embodiments, provided herein are ( The solubility of a pharmaceutically acceptable salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid form or a crystalline form thereof in a medium at pH 6.8 at 24 hours is 0.048 mg / ml to 0.090 mg / ml.

[0195] In the examples provided herein ( A pharmaceutically acceptable salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid form or a crystalline form thereof has improved bioavailability.

[0196] In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a solid or crystalline form thereof, has a bioavailability of at least 39 F%, 44 F%, 49 F%, 54 F%, 59 F%, 54 F%, 59 F%, 64 F%, 69 F%, 74 F%, 79 F%, 84 F%, 89 F%, 94 F%, or 99 F%. In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a solid or crystalline form thereof, has a bioavailability of at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%. In some embodiments, provided herein are ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a solid or crystalline form thereof, has a bioavailability of 39 F% to 99 F%, 39 F% to 94 F%, 39 F% to 89 F%, 39 F% to 84 F%, 39 F% to 79 F%, 39 F% to 74 F%, 39 F% to 69 F%, 39 F% to 64 F%, 39 F% to 59 F%, 39 F% to 54 F%, 39 F% to 49 F%, or 39 F% to 44 F%. In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a solid or crystalline form thereof, has a bioavailability of 39 F% to 82 F%. In some embodiments, the bioavailability is oral bioavailability.

[0197] In some embodiments, )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, compared to the bioavailability of the free form of ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a solid or crystalline form thereof, has a bioavailability of at least about 1.1×, about 1.2×, about 1.3×, about 1.4×, about 1.5×, about 1.6×, about 1.7×, about 1.8×, about 1.9×, about 2.0×, about 2.1×, about 2.2×, about 2.3×, about 2.4×, about 2.5×, about 2.6×, about 2.7×, about 2.8×, about 2.9×, or about 3.0×. In some embodiments, the bioavailability of the pharmaceutically acceptable salt of ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, compared to the bioavailability of the free form of ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof has a bioavailability of at least about 1.4x, about 1.6x, about 1.8x, about 2.0x, or about 2.3x. In some embodiments, ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid form or crystalline form thereof has a bioavailability of 1.1× to 3.0×. In some embodiments, ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, provided herein ( The bioavailability of 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 is 1.4× to 2.3×. In some embodiments, the bioavailability is oral bioavailability.

[0198] In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof or a solid form or crystalline form thereof can 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, isopropyl alcohol (IPA), 1-propanol, 1-butanol, 2-butanol, tert-butyl alcohol, 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, isopropyl alcohol, acetic acid or ethyl acetate. In other embodiments, the solvent in the solvate is acetic acid or ethyl acetate. In some embodiments, provided herein ( 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 is unsolvated.

[0199] In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or its solid form or crystalline form can be a hydrate. Therefore, in one embodiment, provided herein is ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof in solid form or crystalline form may be a hemihydrate. In another embodiment, provided herein is ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof in solid form or crystalline form may be a monohydrate. In another embodiment, provided herein is ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof in solid form or crystalline form may be a dihydrate. In yet another embodiment, provided herein is ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof in solid form or crystalline form may be a trihydrate. In yet another embodiment, provided herein is ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof in solid form or crystalline form may be a tetrahydrate. In yet another embodiment, provided herein is ( The pharmaceutically acceptable salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or its solid form or crystalline form may be a pentahydrate.

[0200] In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof in solid or crystalline form is isolated ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a pharmaceutically acceptable salt thereof in a solid form or a crystalline form thereof.

[0201] In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof, 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, provided herein are ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a pharmaceutically acceptable salt thereof having a chemical purity of at least 90%, at least 95%, at least 98% or at least 99% in a solid or crystalline form thereof, wherein the salt is selected from the group consisting of a meglumine salt, an ethanolamine salt, a tris(hydroxymethyl)aminomethane (Tris) salt or a tert-butylamine (TBA) salt.

[0202] In the examples provided herein ( The pharmaceutically acceptable salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid is crystalline.

[0203] ( Ethanolamine salt of (R)-2-[[3-(3-methoxy-4- propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid and solid forms or crystalline forms thereof Figure 1

[0204] In the examples provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, including solid and crystalline forms thereof.

[0205] In the examples provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid in solid form.

[0206] In some embodiments, ( The ethanolamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid is unsolvated.

[0207] In some embodiments, provided herein are ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid ethanolamine salt crystalline form. In one embodiment, the crystalline form is ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, unsolvated ethanolamine salt.

[0208] In some embodiments, provided herein ( The crystalline form of the ethanolamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid is crystalline Form I.

[0209] In some embodiments, ( The 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 An example of an XRPD pattern of crystalline Form I is depicted. In some embodiments, ( The XRPD pattern of the crystalline Form I of the ethanolamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid comprises at least one diffraction peak selected from the group consisting of: 6.6, 11.7, 15.9, 17.7, 23.7, and 26.6° 2θ (± 0.2° 2θ). In some embodiments, ( )-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 the group consisting of 6.6, 11.7, 15.9, 17.7, 23.7, and 26.6° 2θ (± 0.2° 2θ). In some embodiments, ( )-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 the group consisting of 6.6, 11.7, 15.9, 17.7, 23.7, and 26.6° 2θ (± 0.2° 2θ). In some embodiments, ( )-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, 17.7, 23.7, and 26.6° 2θ (± 0.2° 2θ). In some embodiments, ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising at least one peak selected from the group consisting of: 6.6, 11.7, 15.0, 15.9, 17.7, 18.7, and 19.2° 2θ (± 0.2° 2θ). In some embodiments, ( 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 °2Θ (+ 0.2 °2Θ). In some embodiments, the 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 °2Θ (+ 0.2 °2Θ). In some embodiments, the 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, 15.0, 15.9, 17.7, 18.7, and 19.2 °2Θ (+ 0.2 °2Θ). In some embodiments, the crystalline Form I of the ethanolamine salt of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid has an X-ray diffraction pattern substantially as shown in Figure 2

[0210] As will be understood by those skilled in the art, due to experimental variability when measuring X-ray diffraction patterns on different instruments, two theta (2 theta) values are assumed to be equivalent if they agree within a certain degree of variability. For example, the United States Pharmacopeia provides that identity is confirmed if the angles of the 10 most intense diffraction peaks agree within ± 0.2° with the angles of the reference material, and the relative intensities of the peaks vary by no more than 20%. Thus, in some embodiments, the peak positions recited herein include variability within ± 0.2° 2 theta.

[0211] In certain embodiments, the crystalline form of the ethanolamine salt of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-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 the ​​​​​) ethanolamine salt of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l- oxoprop-2-yl]amino]benzoic acid.

[0212] In certain embodiments, in a pharmaceutical composition comprising In certain embodiments, in a pharmaceutical composition comprising ) ethanolamine salt of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l- oxoprop-2-yl]amino]benzoic acid. ) ethanolamine salt of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l- oxoprop-2-yl]amino]benzoic acid.

[0213] In some embodiments, a solid form (e.g., crystalline form) of the In some embodiments, a solid form (e.g., crystalline form) of the In some embodiments, a solid form (e.g., crystalline form) of the In some embodiments, a solid form (e.g., crystalline form) of the 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 exhibits a weight loss of 0.15% to 3%. In some embodiments, upon heating from about 25° C. to about 120° C., ( 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 exhibits a weight loss of 0.10%. 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 has substantially the same Figure 4 Therefore, the TGA plots provided in this paper ( The solid form (eg, crystalline form) of the ethanolamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid can be characterized as being thermally stable.

[0214] In some embodiments, provided herein ( 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 dynamic vapor sorption (DVS) plot. In some embodiments, ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid exhibits a mass increase (e.g., water absorption) 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 subjected to an increase in relative humidity from about 0% to about 80% relative humidity at 25°C. In some embodiments, provided herein ( 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 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 increase (e.g., water absorption) of 0.55% to 10% when subjected 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 exhibits a mass increase (e.g., water absorption) of about 0.49% when subjected to an increase in relative humidity from about 0% to about 80% relative humidity at 25° C. 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 exhibits substantially the same Figure 6 Therefore, the DVS plots provided in this paper ( 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 as having very low hygroscopicity and being stable over a wide range of humidity.

[0215] In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid ethanolamine salt solid form (e.g., crystalline form) has a differential scanning calorimetry (DSC) thermogram. In some embodiments, provided herein ( 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 DSC thermogram comprising an endothermic event with an onset temperature of about 176° C. and a peak at about 178° C. (melting point). 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 exhibits substantially the same Tert-butylamine salt of (R)-2-[[3-(3-methoxy-4- propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid and solid forms or crystalline forms thereof Therefore, the DSC thermogram provided in this paper ( 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 as thermally stable with a relatively high melting point.

[0216] In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a solid or crystalline form thereof, 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, 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 FaSSIF medium (pH 7.5) at 24 hours. In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof 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, provided herein ( The solubility of the ethanolamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid form or a crystalline form thereof in FaSSIF medium (pH 7.5) is greater than 7.99 mg / ml at 24 hours.

[0217] In some embodiments, provided herein ( The solubility 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 in FeSSIF medium (pH 7.8) at 24 hours is 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, 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, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof 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) at 24 hours. In some embodiments, provided herein are ( The solubility of the ethanolamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid form or a crystalline form thereof in FeSSIF medium (pH 7.8) is greater than 8.02 mg / ml at 24 hours.

[0218] In some embodiments, provided herein ( The solubility of the ethanolamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid form or a crystalline form thereof in FaSSIF medium (pH 7.5) is greater than 7.99 mg / ml at 24 hours and in FeSSIF medium (pH 7.8) is greater than 8.02 mg / ml at 24 hours.

[0219] In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid 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 culture medium at pH 6.8 at 24 hours. In certain embodiments, provided herein are ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof has a solubility of at least 0.06 mg / ml in a medium at pH 6.8 for 24 hours. In some embodiments, provided herein are ( The solubility of the ethanolamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or its solid form or crystalline form in a medium at pH 6.8 at 24 hours is 0.088 mg / ml.

[0220] 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 another embodiment, ( A sample of 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 comprises particles having a length of about 100 μM, about 90 μM, about 80 μM, about 70 μM, about 60 μM, about 50 μM, about 40 μM, about 30 μM, about 20 μM, about 10 μM, about 5 μM. In some 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 comprises particles having a length of about 100 µM, about 70 µM, about 60 µM, about 40 µM, about 20 µM, or about 10 µM.

[0221] 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 may contain not less than about 95%, not less than about 97%, not less than about 98%, not less than about 99%, or not less than about 99.5% by weight of ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, ethanolamine salt.

[0222] In certain embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof may contain no more than about 0.1% by weight, no more than about 0.11% by weight, no more than about 0.12% by weight, no more than about 0.13% by weight, no more than about 0.14% by weight, no more than about 0.15% by weight, no more than about 0.16% by weight, no more than about 0.17% by weight, no more than about 0.18% by weight , not more than about 0.19 wt %, not more than about 0.2 wt %, not more than about 0.21 wt %, not more than about 0.22 wt %, not more than about 0.23 wt %, not more than about 0.24 wt %, not more than about 0.25 wt %, not more than about 0.26 wt %, not more than about 0.27 wt %, not more than about 0.28 wt %, not more than about 0.29 wt %, not more than about 0.3 wt %, not more than about 0.31 wt %, not more than about 0.32 wt %, not more than about %, not more than about 0.33 wt %, not more than about 0.34 wt %, not more than about 0.35 wt %, not more than about 0.36 wt %, not more than about 0.37 wt %, not more than about 0.38 wt %, not more than about 0.39 wt %, not more than about 0.4 wt %, not more than about 0.5 wt %, not more than about 0.6 wt %, not more than about 0.7 wt %, not more than about 0.8 wt %, not more than about 0.9 wt %, not more than about 1 wt %, not more than about 2 wt %, not more than about 3 wt %, not more than about 4 wt %, not more than about 5 wt %, not more than about 6 wt %, not more than about 7 wt %, not more than about 8 wt %, not more than about 9 wt %, not more than about 10 wt %, not more than about 11 wt %, not more than about 12 wt %, not more than about 13 wt %, not more than about 14 wt %, not more than about 15 wt %, not more than about 16 wt %, not more than about 17 wt %, not more than about 18 wt %, not more than about 19 wt %, or not more than about 20 wt % water.

[0223] In the embodiment, )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid in its free form or compared to ( Compared with other pharmaceutically acceptable salts of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, the ( The ethanolamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or its solid form or crystalline form exhibits excellent pharmacokinetic properties.

[0224] In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof has a bioavailability of at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%. In some embodiments, provided herein ( 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, is about 70 F%, about 72 F%, about 74 F%, about 76 F%, about 78 F%, about 80 F%, about 81 F%, about 82 F%, about 83 F%, about 84 F%, about 85 F%, about 86 F%, about 87 F%, about 88 F%, about 89 F%, about 90 F%, about 92 F%, about 94 F%, about 96 F%, or about 98 F%. In some embodiments, the bioavailability is oral bioavailability.

[0225] In some embodiments, Compared to the free form of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, the ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or its solid form or crystalline form shows improved bioavailability. Unexpectedly, the inventors found that ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, compared to the bioavailability of the free form of ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a solid or crystalline form thereof, advantageously has an improved bioavailability of at least about 1.1x, about 1.2x, about 1.3x, about 1.4x, about 1.5x, about 1.6x, about 1.7x, about 1.8x, about 1.9x, about 2.0x, about 2.1x, about 2.2x, about 2.3x, about 2.4x, about 2.5x, about 2.6x, about 2.7x, about 2.8x, about 2.9x, or about 3.0x. In certain embodiments, compared to ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, compared to the bioavailability of the free form of ( 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 is improved by about 2.3 times. In some embodiments, the bioavailability is oral bioavailability.

[0226] In some embodiments, Compared with other pharmaceutically acceptable salts of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, the ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or its solid or crystalline form provides improved bioavailability. Surprisingly, the inventors have found that ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (including ( Compared to the potassium (I) salt, meglumine salt, tris (hydroxymethyl) aminomethane ('tri') salt, tert-butylamine salt, ammonium salt and lysine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, the ( The ethanolamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid form or a crystalline form thereof advantageously exhibits excellent bioavailability.

[0227] This article provides )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid ethanolamine salt or its solid form or crystalline form relative to ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid in its free form and other tested salts, particularly ( The superior bioavailability of other amino salts of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid is unpredictable and may provide significant advantages such as enhanced therapeutic efficacy, reduced dosage, reduced dosage frequency, reduced undesirable side effects, and improved patient compliance.

[0228] ( Figure 8 Figure 8

[0229] In the examples provided herein ( )-tert-butylamine salt of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, including solid and crystalline forms thereof.

[0230] In the examples provided herein ( A solid form of the tert-butylamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0231] In some embodiments, provided herein are ( A crystalline form of the tert-butylamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0232] In some embodiments, provided herein ( The crystalline form of the tert-butylamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid is crystalline Form II.

[0233] In some embodiments, ( The 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 X-ray powder diffraction (XRPD) pattern. Figure 3 An example of an XRPD pattern of crystalline Form II is depicted. In some embodiments, ( The XRPD pattern of the crystalline Form II of the tert-butylamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid comprises at least one diffraction peak selected from the group consisting of 8.36, 13.96, and 17.50° 2θ (± 0.2° 2θ). In some embodiments, ( )-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 the group consisting of: 8.36, 13.96, and 17.50° 2θ (± 0.2° 2θ). In some embodiments, ( )-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 2θ (± 0.2° 2θ). In some embodiments, ( The crystalline form II of the tert-butylamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has substantially the same Figure 5 The X-ray diffraction pattern is shown in .

[0234] In certain embodiments, ( The crystalline form of the tert-butylamine salt 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 the ( Crystalline Form II of the tert-butylamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0235] In certain embodiments, in the case 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 ( The tert-butylamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid is provided herein ( Crystalline Form II of the tert-butylamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0236] In some embodiments, provided herein ( 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 thermogravimetric analysis (TGA) plot. In some embodiments, when heated from about 25° C. to about 120° C., ( )-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%, as determined by thermogravimetric analysis. In some embodiments, when heated from about 25° C. to about 120° C., ( The solid form (e.g., 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% as measured by TGA. In some embodiments, when heated from about 25° C. to about 120° C., ( The solid form (e.g., 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% as determined by thermogravimetric analysis. In certain embodiments, ( The solid form (e.g., crystalline form) of the tert-butylamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has substantially the same Figure 7 Therefore, the TGA plots provided in this paper ( The solid form (eg, crystalline form) of the tert-butylamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid can be characterized as being thermally stable.

[0237] In some embodiments, provided herein ( 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 dynamic vapor sorption (DVS) 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 mass increase (e.g., water absorption) 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 subjected 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 increase (e.g., water absorption) of 1.2% to 10% when subjected 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 increase (e.g., water absorption) of about 1.07% when subjected to an increase in relative humidity from about 0% to about 80% relative humidity at 25° C. In certain embodiments, ( The solid form (e.g., crystalline form) of the tert-butylamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid exhibits substantially the same Glycine salt of (R)-2-[[3-(3-methoxy-4- propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid and solid forms or crystalline forms thereof Therefore, the DVS plots provided in this paper ( The solid form (e.g., crystalline form) of the tert-butylamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid can be characterized as having very low hygroscopicity and being stable over a wide range of humidity.

[0238] In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid solid form (e.g., crystalline form) has a differential scanning calorimetry (DSC) thermogram. In some embodiments, provided herein ( 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 DSC thermogram comprising 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, ( The solid form (e.g., crystalline form) of the tert-butylamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid exhibits substantially the same Figure 9 Therefore, the DSC thermogram provided in this paper ( The solid form (eg, crystalline form) of the tert-butylamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid can be characterized as being thermally stable.

[0239] In some embodiments, provided herein ( The solubility of 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, in FaSSIF medium (pH 7.5) at 24 hours is 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, 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, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a solid or crystalline form thereof, 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, provided herein are ( The solubility of the tert-butylamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid form or a crystalline form thereof in FaSSIF medium (pH 7.5) is greater than 2.52 mg / ml at 24 hours.

[0240] In some embodiments, provided herein ( The solubility of 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 in FeSSIF medium (pH 7.8) at 24 hours is 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, 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, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a solid or crystalline form thereof, 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) at 24 hours. In some embodiments, provided herein are ( The solubility of the tert-butylamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid form or a crystalline form thereof in FeSSIF medium (pH 7.8) is greater than 3.42 mg / ml at 24 hours.

[0241] In some embodiments, provided herein ( The solubility of the tert-butylamine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid form or a crystalline form thereof in FaSSIF medium (pH 7.5) is greater than 2.52 mg / ml at 24 hours, and the solubility in FeSSIF medium (pH 7.8) is greater than 3.42 mg / ml at 24 hours.

[0242] In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, 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 culture medium at pH 6.8 at 24 hours. In certain embodiments, provided herein are ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a solid or crystalline form thereof has a solubility of at least 0.07 mg / ml in a medium at pH 6.8 at 24 hours. In some embodiments, provided herein are ( The solubility of 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 in a medium at pH 6.8 at 24 hours is at least 0.071 mg / ml.

[0243] In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a solid or crystalline form thereof, has a bioavailability of at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%. In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or its solid form or crystalline form has a bioavailability of about 60% by weight. In some embodiments, provided herein ( The bioavailability of 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 is 59 F%. In some embodiments, the bioavailability is oral bioavailability.

[0244] ( Figure 9 Tris salt of (R)-2-[[3-(3-methoxy-4- propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid and solid forms or crystalline forms thereof

[0245] In the examples provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, including solid and crystalline forms thereof.

[0246] In the examples provided herein ( A solid form of the meglumine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0247] In some embodiments, provided herein are ( A crystalline form of the meglumine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0248] In some embodiments, provided herein ( The crystalline form of the meglumine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid is crystalline Form III.

[0249] In some embodiments, ( The 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 powder diffraction (XRPD) pattern. Figure 10 An example of an XRPD pattern of crystalline Form III is depicted. In some embodiments, ( The XRPD pattern of the crystalline Form III of the meglumine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid comprises at least one diffraction peak selected from the group consisting of: 6.6, 11.7, 15.9, 17.7, 23.7, and 26.6° 2θ (± 0.2° 2θ). In some embodiments, ( )-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 the group consisting of 6.6, 11.7, 15.9, 17.7, 23.7, and 26.6° 2θ (± 0.2° 2θ). In some embodiments, ( )-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 the group consisting of 6.6, 11.7, 15.9, 17.7, 23.7, and 26.6° 2θ (± 0.2° 2θ). In some embodiments, ( )-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° 2θ (± 0.2° 2θ). In some embodiments, ( The crystalline form III of the meglumine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has substantially the Figure 10 The X-ray diffraction pattern is shown in .

[0250] ( Potassium salt of (R)-2-[[3-(3-methoxy-4- propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid and solid forms or crystalline forms thereof Figure 11

[0251] In the examples provided herein ( tris(hydroxymethyl)aminomethane salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, including solid and crystalline forms thereof.

[0252] In the examples provided herein ( A solid form of the tris(hydroxymethyl)aminomethane salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0253] In some embodiments, provided herein are ( A crystalline form of the tris(hydroxymethyl)aminomethane salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0254] In some embodiments, provided herein ( The crystalline form of the tris(hydroxymethyl)aminomethane salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid is crystalline Form IV.

[0255] In some embodiments, ( The 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 powder diffraction (XRPD) pattern. Figure 11 An example of an XRPD pattern of crystalline Form IV is depicted. In some embodiments, ( The XRPD pattern of the crystalline Form IV of the tris(hydroxymethyl)aminomethane salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid comprises at least one diffraction peak selected from the group consisting of: 5.78, 12.18, 15.94, and 17.24° 2θ (± 0.2° 2θ). In some embodiments, ( Form IV of the potassium salt of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l- oxo-2-propenyl]amino]benzoic acid, including solid forms and crystalline forms thereof, has an XRPD pattern comprising at least two peaks selected from 5.78, 12.18, 15.94, and 17.24 °2Q (+ 0.2 °2Q). In some embodiments, Form IV of the potassium salt of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid, including solid forms and crystalline forms thereof, has an XRPD pattern comprising at least three peaks selected from 5.78, 12.18, 15.94, and 17.24 °2Q (+ 0.2 °2Q). In some embodiments, Form IV of the potassium salt of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid, including solid forms and crystalline forms thereof, has an XRPD pattern comprising peaks at 5.78, 12.18, 15.94, and 17.24 °2Q (+ 0.2 °2Q). In some embodiments, Form IV of the potassium salt of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid, including solid forms and crystalline forms thereof, has an X-ray diffraction pattern substantially as shown in Figure 22. Ammonium salt of (R)-2-[[3-(3-methoxy-4- propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid and solid forms or crystalline forms thereof

[0256] ( Figure 12 Figure 12

[0257] In embodiments, provided herein are: In embodiments, provided herein are: In embodiments, provided herein are:

[0258] In embodiments, provided herein are: In embodiments, provided herein are:

[0259] In some embodiments, provided herein are: In some embodiments, provided herein are:

[0260] In some embodiments, provided herein are: ​​​) -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid potassium salt crystalline Form V is crystalline Form V.

[0261] In some embodiments, ) -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid potassium salt crystalline Form V has an X-ray powder diffraction (XRPD) pattern. Lysine salt of (R)-2-[[3-(3-methoxy-4- propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid and solid forms or crystalline forms thereof An example of an XRPD pattern of crystalline Form V is depicted. In some embodiments, ) -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid potassium salt crystalline Form V has an XRPD pattern comprising at least one diffraction peak selected from the group consisting of: 9.84, 10.56, 14.10, and 25.06° 2Q (± 0.2° 2Q). In some embodiments, ) -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid potassium salt crystalline Form V has an XRPD pattern comprising at least two peaks selected from the group consisting of: 9.84, 10.56, 14.10, and 25.06° 2Q (± 0.2° 2Q). In some embodiments, ) -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid potassium salt crystalline Form V has an XRPD pattern comprising at least three peaks selected from the group consisting of: 9.84, 10.56, 14.10, and 25.06° 2Q (± 0.2° 2Q). In some embodiments, ) -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid potassium salt crystalline Form V has an XRPD pattern comprising peaks at 9.84, 10.56, 14.10, and 25.06° 2Q (± 0.2° 2Q). In some embodiments, ) -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid potassium salt crystalline Form V has an X-ray diffraction pattern substantially as shown in Figure 13 FIG. 1.

[0262] ( Figure 13 Preparation methods

[0263] In embodiments, provided herein is )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid.

[0264] In embodiments, provided herein are )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid.

[0265] In embodiments, provided herein are )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid.

[0266] In embodiments, provided herein are )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid.

[0267] In embodiments, provided herein are )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid. Pharmaceutical compositions An example of an XRPD pattern of crystalline Form VI is depicted. In embodiments, provided herein are )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid. )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid. )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid. )-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° 2θ (±0.2° 2θ). In some embodiments, ( The XRPD pattern of the 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 the group consisting of: 8.10, 11.66, and 17.62° 2θ (± 0.2° 2θ). In some embodiments, ( )-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 the group consisting of: 8.10, 11.66, and 17.62° 2θ (± 0.2° 2θ). In some embodiments, ( )-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, and 17.62° 2θ (± 0.2° 2θ). In some embodiments, ( The crystalline form VI of the ammonium salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has substantially the Methods of use The X-ray diffraction pattern is shown in .

[0268] ( Example 1. General experimental Reagents and materials

[0269] In the examples provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid lysine salt, including solid and crystalline forms thereof.

[0270] In the examples provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid in solid form of the lysine salt.

[0271] In some embodiments, provided herein are ( A crystalline form of the lysine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0272] In some embodiments, provided herein ( The crystalline form of the lysine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid is crystalline Form VII.

[0273] In some embodiments, ( The crystalline Form VII of the lysine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has an X-ray powder diffraction (XRPD) pattern. Instruments An example of an XRPD pattern of crystalline Form VII is depicted. In some embodiments, ( The XRPD pattern of the crystalline Form VII of the lysine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid comprises at least one diffraction peak selected from the group consisting of: 11.76, 14.48, 18.60, and 27.22° 2θ (± 0.2° 2θ). In some embodiments, ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid lysine salt crystalline Form VII has an XRPD pattern comprising at least two peaks selected from the group consisting of: 11.76, 14.48, 18.60, and 27.22° 2θ (±0.2° 2θ). In some embodiments, ( )-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 the group consisting of: 11.76, 14.48, 18.60, and 27.22° 2θ (± 0.2° 2θ). In some embodiments, ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising peaks at 11.76, 14.48, 18.60, and 27.22° 2θ (± 0.2° 2θ). In some embodiments, ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising at least one peak selected from the group consisting of: 11.76, 14.48, and 18.60° 2θ (± 0.2° 2θ). In some embodiments, ( )-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 the group consisting of: 11.76, 14.48, and 18.60° 2θ (± 0.2° 2θ). In some embodiments, ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has an XRPD pattern comprising peaks at 11.76, 14.48, and 18.60° 2θ (± 0.2° 2θ). In some embodiments, ( The crystalline form VII of the lysine salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has substantially the Instrument parameters The X-ray diffraction pattern is shown in .

[0274] X-ray powder diffraction (XRPD)

[0275] Also provided herein are methods for preparing the solid forms, pharmaceutically acceptable salts, and crystalline forms thereof described herein.

[0276] This article provides )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid pharmaceutically acceptable salt (for example, ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid ethanolamine salt) and its crystalline form can be prepared by a method comprising the steps of: )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a salt or solvate thereof, is contacted with a suitable counterion source (e.g., ethanolamine), or a salt or solvate thereof, in a solvent at a first predetermined temperature.

[0277] In certain embodiments, in the formation of the ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, in the step of contacting the counter ion source or its salt or solvate with ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a salt or solvate thereof is about 1. In certain embodiments, the molar ratio of the contacting step of a pharmaceutically acceptable salt of 2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid is conducted in the presence of an excess of a counterion source or salt or solvate thereof to form -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid or a salt or solvate thereof, thereby maximizing the yield of the process. In certain embodiments, the molar ratio of the counterion source or salt or solvate thereof to -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid or a salt or solvate thereof is not less than about 1.01, not less than about 1.05, not less than about 1.1, or not less than about 1.2. In certain embodiments, the molar ratio of the counterion source or salt or solvate thereof to -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid or a salt or solvate thereof ranges from 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.

[0278] Suitable solvents for use in forming the pharmaceutically acceptable salts of The solvent for the contacting step of preparing a pharmaceutically acceptable salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid includes, but is not limited to, hydrocarbons including petroleum ether, pentane, hexane, heptane, octane, isooctane, cyclopentane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, tetralin and cumene; chlorinated hydrocarbons including dichloromethane (DCM), 1,2-dichloroethane, 1,1-dichloroethylene, 1, 2-Dichloroethylene, chloroform, trichloroethane, trichloroethylene, carbon tetrachloride, chlorobenzene, and trifluoromethylbenzene; alcohols, including methanol, ethanol, isopropyl alcohol (IPA), 1-propanol, 1-butanol, 2-butanol, tert-butanol, 3-methyl-1-butanol, 1-pentanol, 2-methoxyethanol, 2-ethoxyethanol, and ethylene glycol; ethers, including diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), diphenyl ether, 1,2-dimethoxyethane, bis(2-methoxy-1-butanol), ethyl) 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; amides including formamide, N,N-dimethyl Formamide (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; heterocyclic compounds, such as N-methylpyrrolidone, 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.

[0279] In certain embodiments, for forming the ( The solvent for the contacting step of preparing a pharmaceutically acceptable 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 another embodiment, the solvent for forming the ( The solvent in the step of contacting a pharmaceutically acceptable salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid comprises C 1-5alkanol. In yet another embodiment, the solvent of the contacting step for forming a pharmaceutically acceptable salt of (S)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l- oxo-2-propenyl]amino]benzoic acid provided herein comprises methanol, ethanol, propanol, isopropanol, sec-butanol, 2-methoxyethanol, or a mixture thereof.

[0280] In certain embodiments, the solvent of the contacting step for forming a pharmaceutically acceptable salt of (S)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l- 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.

[0281] In some embodiments, the contacting step for forming a pharmaceutically acceptable salt of (S)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid provided herein is performed at a temperature ranging from about -10 °C to about 150 °C, about 10 °C to about 110 °C, or about 20 °C to about 100 °C; for example, 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.

[0282] In some embodiments, the methods provided herein each further comprise a step of preparing a solid form of a pharmaceutically acceptable salt of (S)-2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid provided herein (e.g., a solid form of an ethanolamine salt of (S)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l- oxo-2-propenyl]amino]benzoic acid) at a second predetermined temperature. The solid form of a pharmaceutically acceptable salt of (S)-2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid provided herein can be prepared from a solution or slurry of a pharmaceutically acceptable salt of (S)-2-[[3-(3- methoxy-4-propargyloxy)phenyl)-l-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.

[0283] ​​​​​​​In some embodiments, each of the methods provided herein further comprises subjecting the ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid pharmaceutically acceptable salt (for example, ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid) ethanolamine salt step.

[0284] For the preparation of amorphous or crystalline )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid pharmaceutically acceptable salt (for example, ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid ethanolamine salt) comprising the steps of: a step of contacting a pharmaceutically acceptable salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid with a solvent, wherein the amorphous form of ( )-2-[[3-(3c-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or ( The solid or 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 can be formed from solution or converted from one solid form to another. The method can further comprise an isolation step, wherein the compound can be 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 dessicator drying).

[0285] Suitable for preparing the ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid pharmaceutically acceptable salt (for example, ( The solvents for the preparation of the pharmaceutically acceptable salts of 2-[[3-(3- methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid (e.g., the hydrochloride salt of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2- propenyl]amino]benzoic acid) include, but are not limited to, hydrocarbons, including petroleum ether, pentane, hexane, heptane, octane, isooctane, cyclopentane, cyclohexane, methylcyclohexane, benzene, toluene, xylenes, 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; alcohols, including methanol, ethanol, isopropyl alcohol (IPA), 1-propanol, 1-butanol, 2-butanol, tert-butyl alcohol, 3-methyl-l-butanol, 1-pentanol, 2-methoxyethanol, 2-ethoxyethanol, and ethylene glycol; ethers, including diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), diphenyl ether, 1,2-dimethoxyethane, bis(2-methoxyethyl) ether, 1,1-dimethoxy methane, 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; 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; heterocyclic compounds, such as N-methylpyrrolidone, 2-methyltetrahydrofuran, tetrahydrofuran (THF), dioxane, and pyridine; carboxylic acids, such as acetic acid, trichloroacetic acid, and trifluoroacetic acid; phosphoramides, such as hexamethylphosphoramide; carbon disulfide; water; and mixtures thereof.

[0286] In various embodiments, the processes for preparing the pharmaceutically acceptable salts of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid (e.g., the hydrochloride salt of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2- propenyl]amino]benzoic acid) provided herein comprise: In various embodiments, the processes for preparing the pharmaceutically acceptable salts of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid (e.g., the hydrochloride salt of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2- propenyl]amino]benzoic acid) provided herein comprise: The solvent for the crystallization of 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. In another embodiment, the solvent for crystallization comprises methanol, ethanol, propanol, isopropanol, sec-butanol, 2-methoxyethanol, or a mixture thereof.

[0287] In certain embodiments, crystallization is performed using conventional methods, including but not limited to cooling, chilling, solvent evaporation, addition of an antisolvent, or reverse addition of an antisolvent. In certain embodiments, crystallization is performed at a temperature ranging from about -50°C to about 100°C, from about -30°C to about 50°C, or from about -10°C to about 30°C. In certain embodiments, the method further comprises a seeding step to accelerate crystallization. In certain embodiments, the method further comprises a separation step, wherein the formed solid is separated by conventional methods (such as filtration and centrifugation), followed by washing with a solvent and then drying.

[0288] In certain embodiments, crystallization is performed by adding a molecule comprising a )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (e.g., provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid ethanolamine salt) is cooled to room temperature or below or by solvent evaporation. In certain embodiments, crystallization is performed by adding an antisolvent to a solution containing ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or by adding a solution containing ( The reaction is carried out by adding a solution of a pharmaceutically acceptable salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid to an antisolvent.

[0289] Suitable antisolvents include, but are not limited to, 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-dichloroethylene, 1,2-dichloroethylene, chloroform, trichloroethane, trichloroethylene, carbon tetrachloride, chlorobenzene and trifluoromethylbenzene; alcohols including isopropyl alcohol, 1-propanol, 1-butanol, 2-butanol, tert-butanol, 3-methyl-1-butanol, 1-pentanol, 2-ethoxyethanol and ethylene glycol; ethers including diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), diphenyl ether, 1,2-dimethoxyethane, bis(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; 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; heterocyclic compounds such as N-methylpyrrolidone, 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.

[0290] When two solvents are used as a solvent / antisolvent pair, ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid pharmaceutically acceptable salt (for example, (

[00145] In some embodiments, the solvent and antisolvent of the solvent / antisolvent pair are at least partially miscible.

[0291] In some embodiments, provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid pharmaceutically acceptable salt (for example, ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid ethanolamine salt) or its solid form or crystalline form exhibits ease of manufacture or processability and / or improved solidification and / or crystallization properties. Therefore, in some embodiments, with ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid in its free form or compared to ( Compared with other pharmaceutically acceptable salts of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, the ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid pharmaceutically acceptable salt (for example, ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid ethanolamine salt) or its solid form or crystalline form is obtained in higher yield or through fewer manufacturing or purification steps. In some embodiments, with ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid in its free form or compared to ( Compared with other pharmaceutically acceptable salts of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, the ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid pharmaceutically acceptable salt (for example, ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid) or its solid form or crystalline form is obtained with higher purity (e.g., substantially pure or substantially homogeneous).

[0292] Differential scanning calorimetry (DSC)

[0293] Also provided herein are pharmaceutical compositions comprising the ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid pharmaceutically acceptable salt (for example, ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid ethanolamine salt) or its solid form or crystalline form and one or more pharmaceutically acceptable carriers or excipients.

[0294] 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.

[0295] 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 into modified release dosage forms, including delayed release, extended release, long-term release, sustained release, pulsed release, controlled release, accelerated release, rapid release, targeted release, programmed release, and gastric retention 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 Pharmaceuticals, supra; Modified Release Drug Delivery Technology, supra). dR l as Drug D liv ry T chnology, 2nd ed., Rathbone et al., ed., Marcel Dekker, Inc.: New York, NY, 2008.

[0296] In one embodiment, the pharmaceutical composition provided herein is formulated into a dosage form for oral administration, the dosage form comprising the ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof in a solid form or a crystalline form and one or more pharmaceutically acceptable excipients.

[0297] In one embodiment, an oral pharmaceutical composition comprises ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a solid form or a crystalline form thereof, and one or more pharmaceutically acceptable excipients, any of which is independently selected from candellila 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, titanium dioxide, sodium lauryl sulfate, synthetic black iron oxide, titanium dioxide, glyceryl triacetate, hydrochloric acid, potassium bicarbonate, saccharin calcium, xylitol, water, and cherry flavor.

[0298] In another embodiment, an oral pharmaceutical composition comprises provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a solid form or crystalline form thereof, and one, two or more pharmaceutically acceptable excipients, any 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, titanium dioxide, sodium lauryl sulfate, synthetic black iron oxide, titanium dioxide and triacetin.

[0299] In one embodiment, the oral pharmaceutical composition is a tablet. In another embodiment, the oral pharmaceutical composition is an extended release tablet. In yet another embodiment, the oral pharmaceutical composition is a coated tablet.

[0300] In another embodiment, the pharmaceutical composition provided herein is formulated into a dosage form for parenteral administration, the dosage form comprising the ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a pharmaceutically acceptable salt thereof in solid form or crystalline form and one or more pharmaceutically acceptable excipients. In one embodiment, the pharmaceutical composition provided herein is formulated into a dosage form for intravenous administration. In another embodiment, the pharmaceutical composition provided herein is formulated into a dosage form for intramuscular administration. In yet another embodiment, the pharmaceutical composition provided herein is formulated into a dosage form for subcutaneous administration.

[0301] In yet another embodiment, the pharmaceutical compositions provided herein are formulated into a dosage form for topical administration, the dosage form comprising the ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof in a solid form or a crystalline form and one or more pharmaceutically acceptable excipients.

[0302] The pharmaceutical composition provided herein can be provided in unit dosage form or multiple dosage form. As used herein, unit dosage form refers to a physically discrete unit suitable for application to humans and animal subjects and as known in the art, individually packaged. Each unit dose contains a predetermined amount of active ingredient sufficient to produce the desired therapeutic effect, together with required pharmaceutical carriers or excipients. The example of unit dosage form includes ampoules, syringes, and individually packaged tablets and capsules. The unit dosage form can be used with its fraction or multiple. Multiple dosage form is a plurality of identical unit dosage forms packaged in a single container, pending use with separated unit dosage form. The example of multiple dosage form includes a bottle of a bottle, tablet, or capsule, or a pint or gallon bottle.

[0303] In certain embodiments, the pharmaceutical compositions provided herein comprise an amount ranging from about 10 mg to about 10,000 mg of the ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof in solid form or crystalline form. In certain embodiments, the pharmaceutical compositions provided herein comprise about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg and about 1500 mg of ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a pharmaceutically acceptable salt thereof in a solid form or a crystalline form thereof.

[0304] In some embodiments, the pharmaceutical compositions provided herein contain about 10 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, or about 1500 mg of an anti-inflammatory drug provided herein per unit dosage form. )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a pharmaceutically acceptable salt thereof in a solid form or a crystalline form thereof.

[0305] In some embodiments, the pharmaceutical compositions provided herein comprise an amount of about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or about 400 mg of a ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a pharmaceutically acceptable salt thereof in a solid form or a crystalline form thereof.

[0306] In certain embodiments, the pharmaceutical compositions provided herein comprise an amount ranging from about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 2 mg to about 20 mg, or about 2 mg to about 10 mg of a pharmaceutical composition provided herein per unit dosage form. )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof in solid or crystalline form. In certain embodiments, the pharmaceutical compositions provided herein comprise about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg or about 20 mg of ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a pharmaceutically acceptable salt thereof in a solid form or a crystalline form thereof.

[0307] In some embodiments, the pharmaceutical compositions provided herein comprise an amount of the pharmaceutical compositions provided herein effective to provide the following dosages: )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a solid or crystalline form thereof: about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 40 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 110 mg / kg, about 120 mg / kg, about 130 mg / kg, about 140 mg / kg, about 150 mg / kg, about 160 mg / kg, about 170 mg / kg, about 180 mg / kg, about 190 mg / kg, about 200 mg / kg, about 210 mg / kg, about 220 mg / kg, about 230 mg / kg, about 240 mg / kg, about 250 mg / kg, about 260 mg / kg, about 270 mg / kg, about 280 mg / kg, about 290 mg / kg, about 300 mg / kg, about 310 mg / kg, about 320 mg / kg, about 330 mg / kg, about 340 mg / kg, about 350 mg / kg, about 360 mg / kg, about 370 mg / kg, about 380 mg / kg, about 390 mg / kg or about 400 mg / kg ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. In some embodiments, the pharmaceutical compositions provided herein comprise an amount effective to provide the following dosages: )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof, or a solid or crystalline form thereof: between about 10 mg / kg and about 400 mg / kg, between about 50 mg / kg and about 300 mg / kg, between about 100 mg / kg and about 250 mg / kg ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. In certain embodiments, the pharmaceutical compositions provided herein comprise an amount effective to provide about 200 mg / kg of ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid in an amount provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a pharmaceutically acceptable salt thereof in a solid form or a crystalline form thereof.

[0308] In some embodiments, the pharmaceutical compositions provided herein comprise a composition effective to provide 10 μM to 200 μM, or 10 μM to 100 μM, or 10 μM to 50 μM of ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid in an amount as provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid or a pharmaceutically acceptable salt thereof or a solid form or crystalline form thereof. In some embodiments, the pharmaceutical compositions provided herein comprise ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid in an amount as provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a pharmaceutically acceptable salt thereof in a solid form or a crystalline form thereof.

[0309] As used herein, ( The "site of action" of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid can refer to cells or tissues affected by fibrosis, inflammation and / or proliferation, or cells or tissues involved in the progression of fibrosis, inflammation and / or proliferation.

[0310] The pharmaceutical composition provided herein can be used once, or multiple times at intervals. It should be understood that the precise dosage and duration for the treatment of can vary with the age, body weight and symptom of the patient being treated, and can be determined empirically using known testing protocols or by extrapolating from in vivo or in vitro tests or diagnostic data. It should be further understood that for any particular individual, the specific dosage regimen should be adjusted over time based on individual needs and the professional judgment of the person administering or supervising the formulation.

[0311] The pharmaceutical compositions provided herein are intended to be administered by a suitable route, including oral administration in the form of capsules, tablets, granules, powders, or liquid formulations including syrups; parenteral administration, such as subcutaneous, intravenous, intramuscular administration, using intercostal injection or infusion techniques (e.g., sterile injectable aqueous or non-aqueous solutions or suspensions); nasal, such as by inhalation spray; topical administration, such as in the form of a cream or ointment; rectal administration, such as in the form of a suppository; liposomal administration; and local administration. The compositions can be in liquid, semi-liquid, or solid form and formulated in a manner appropriate for each route of administration. In certain embodiments, administration of the formulation includes parenteral and oral modes of administration. In various embodiments, the pharmaceutical compositions provided herein are administered orally. In one embodiment, the pharmaceutical compositions provided herein are administered directly to the eye by injection.

[0312] Oral administration

[0313] The pharmaceutical compositions provided herein for oral administration 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, fastmelt, chewable tablets, capsules, pills, troches, lozenges, pastilles, cachets, granules, medicinal chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mist, solutions, emulsions, suspensions, wafers, sprays, elixirs, and syrups. In addition to the active ingredient, the pharmaceutical compositions can contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binding agents, fillers, diluents, disintegrating agents, wetting agents, lubricating agents, glidants, coloring agents, dye migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide.

[0314] A binder or granulator imparts cohesiveness to a tablet to ensure that the tablet remains intact after compression. Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch, and pre-gelatinized 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, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC); microcrystalline cellulose, such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., 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, pre-gelatinized starch, and mixtures thereof. A binder or filler can be present in the pharmaceutical compositions provided herein from about 50% to about 99% by weight.

[0315] 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. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in a sufficient amount, can impart the property of allowing some compressed tablets to disintegrate in the mouth by mastication. 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 readily discernible to one of ordinary skill in the art.

[0316] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses such as methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins; alginic acid; gums such as guar gum and Vee's gum HV; citrus pulp; cross-linked celluloses such as cross-linked carboxymethylcellulose; 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; clay; algin; 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 one of ordinary skill in the art. The pharmaceutical compositions provided herein may contain from about 0.5% to about 15% by weight or from about 1% to about 5% by weight of a disintegrant.

[0317] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols such as glyceryl behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oils, including peanut, cottonseed, sunflower, sesame, olive, corn, and soybean oils; zinc stearate; ethyl oleate; ethyl laurate; agar; starch; lycopodium; silicon dioxide or silica gel, such as AEROSIL ® 200 and CAB-O-SIL ® and mixtures thereof. The pharmaceutical compositions provided herein may contain from about 0.1% to about 5% by weight of a lubricant.

[0318] Suitable glidants include colloidal silicon dioxide, CAB-O-SIL® (Cabot Co. of Boston, MA), and asbestos-free talc. Colorants include any approved, certified water-soluble FD&C dyes and water-insoluble FD&C dyes suspended on alumina hydrate, as well as lakes and mixtures thereof. Lakes are combinations of water-soluble dyes adsorbed onto hydrated 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 sensation, such as peppermint and methyl salicylate. Sweeteners include sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifiers include gelatin, gum arabic, gum tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, gum tragacanth, Veegum, gum arabic, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Preservatives include glycerin, methyl and propyl parabens, 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, ethanol, and syrup. Examples of non-aqueous liquids used 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.

[0319] It will be appreciated that many carriers and excipients may serve several functions, even within the same formulation.

[0320] The pharmaceutical compositions provided herein can be provided as compressed tablets, tablet grinders, chewable lozenges, fast-dissolving tablets, multiple compressed tablets, or enteric-coated tablets, sugar-coated tablets, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the effects of gastric acid but dissolves or disintegrates in the intestines, thereby protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets coated with a sugar coating, which may be helpful in masking unpleasant tastes or odors and protecting the tablet 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 the same general properties as 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.

[0321] Tablet dosage forms can 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 colorants. Flavorings and sweeteners are particularly useful in forming chewable tablets and lozenges.

[0322] The pharmaceutical compositions provided herein can 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-fill capsules (DFCs), consist of two parts, one nested within the other, completely enclosing the active ingredient. Soft elastic capsules (SECs) are soft spherical shells, such as gelatin shells, plasticized by the addition of glycerol, sorbitol, or similar polyols. The soft gelatin shells can contain a preservative to prevent microbial growth. Suitable preservatives are those described herein, including methyl and propyl parabens and sorbic acid. Liquid, semisolid, and solid dosage forms provided herein can be encapsulated in capsules. 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. Patents Nos. 4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated as known to those skilled in the art to modify or sustain dissolution of the active ingredient.

[0323] The pharmaceutical compositions provided herein can 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, which can be oil-in-water or water-in-oil. Emulsions can include a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifying agent, and a preservative. Suspensions can include a pharmaceutically acceptable suspending agent and a preservative. Aqueous alcoholic solutions can include a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde (the term "lower" refers to an alkyl group having from 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, and water-alcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, e.g., sucrose, and can also contain a preservative. For liquid dosage forms, solutions, e.g., in polyethylene glycol, can be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to facilitate convenient measurement for administration.

[0324] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient provided herein in a dialkylated mono- or polyalkylene glycol, including 1,2-dimethoxy methane, diglycol dimethyl ether, triglycol dimethyl ether, tetraglycol dimethyl ether, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, where 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol. These formulations can further comprise 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 esters and dithioaminoo carboxylates thereof.

[0325] The pharmaceutical compositions provided herein for oral administration can also be provided in the form of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms are prepared as described in U.S. Patent No. 6,350,458.

[0326] The pharmaceutical compositions provided herein can be provided as non-effervescent or effervescent granules and powders, for reconstitution with, or without, water, respectively, into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in the non-effervescent granules or powders can include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders can include organic acids and sources of carbon dioxide.

[0327] Colorants and flavoring agents can be used in all the above-described dosage forms.

[0328] The pharmaceutical compositions provided herein can be formulated as immediate release or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release forms.

[0329] The pharmaceutical compositions provided herein can be co-formulated with other active ingredients that do not impair the desired therapeutic effect, or with substances that supplement the desired effect.

[0330] Parenteral administration

[0331] 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.

[0332] The pharmaceutical compositions provided herein can be formulated into any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solution or suspension in a liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (see Remington: The Science and Practice of Pharmaceuticals, supra).

[0333] Pharmaceutical compositions intended for parenteral administration may include 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 to combat the growth of microorganisms, stabilizers, solubility enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusters, and inert gases.

[0334] Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate-buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose, and lactated Ringer's injection. Non-aqueous vehicles include, but are not limited to, fixed oils of plant origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, 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-butylene glycol, liquid polyethylene glycols (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethyl sulfoxide.

[0335] Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, m-cresol, mercurial agents, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl and propyl parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphate and citrate. Suitable antioxidants are antioxidants as described herein, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are suspending and dispersing agents as described herein, including sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents are emulsifying agents 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 modifiers 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 a-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and sulfobutyl ether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, KS).

[0336] The pharmaceutical compositions provided herein can be formulated for single or multiple dosage administration. Single dose formulations are packaged in ampules, vials, or syringes. Multiple dose parenteral formulations must contain a bacteriostatic or fungistatic concentration of an antimicrobial agent. All parenteral formulations must be sterile, as known and practiced in the art.

[0337] In one embodiment, the pharmaceutical composition for parenteral administration is provided as a ready-to-use, sterile solution. In another embodiment, the pharmaceutical composition is provided as a sterile, dry dissolvable product, including a lyophilized powder and a subcutaneous injection tablet, to be reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use, sterile suspension. In yet another embodiment, the pharmaceutical composition is provided as a sterile, dry, insoluble product to be reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use, sterile emulsion.

[0338] The pharmaceutical compositions provided herein can be formulated as immediate or modified release dosage forms, including delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release forms.

[0339] The pharmaceutical composition can be formulated as a suspension, solid, semisolid or thixotropic liquid for administration as an implantable reservoir. In one embodiment, the pharmaceutical composition provided herein is dispersed in a solid inner matrix that is surrounded by an outer polymer membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical composition to diffuse through.

[0340] 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 copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic acid and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.

[0341] Suitable outer polymer films include polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, chloroprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyloxyethanol copolymers.

[0342] Topical application

[0343] The pharmaceutical compositions provided herein can be topically administered to the skin, orifices, or mucous membranes. As used herein, topical administration includes (intra)dermal, conjunctival, intracorneal, intraocular, ophthalmic, otic, transdermal, nasal, vaginal, urethral, ​​respiratory, and rectal administration.

[0344] The pharmaceutical compositions provided herein can be formulated into any dosage form suitable for topical administration to achieve local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, douches, sprays, suppositories, bandages, and skin patches. Topical formulations of the pharmaceutical compositions provided herein can also comprise liposomes, micelles, microspheres, nanosystems, and mixtures thereof.

[0345] 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 to combat the growth of microorganisms, stabilizers, solubility enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.

[0346] Typically, the pharmaceutical composition is also administered topically by electroporation, iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp., Emeryville, CA) and BIOJECT™ (Bioject Medical Technologies Inc., Tualatin, OR).

[0347] The pharmaceutical compositions provided herein can be provided in the form of ointments, creams, and gels. Suitable ointment vehicles include oily or hydrocarbon vehicles, including lard, benzoated lard, olive oil, cottonseed oil and other oils, and white petrolatum; emulsifiable or absorbent 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 varying molecular weights; and emulsion vehicles, either water-in-oil (W / O) or oil-in-water (O / W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid (see Remington: The Science and Practice of Pharmacy, supra). These vehicles are emollients, but typically require the addition of antioxidants and preservatives.

[0348] Suitable cream bases can be oil-in-water or water-in-oil. Suitable cream vehicles can be washable and contain an oil phase, an emulsifier and an aqueous phase. The oil phase is also referred to as the "inner" phase, which is usually composed of vaseline and fatty alcohols such as cetyl alcohol or stearyl alcohol. The aqueous phase usually (but not necessarily) exceeds the oil phase in volume and usually contains a wetting agent. The emulsifier in the cream formulation can be a nonionic surfactant, anionic surfactant, cationic surfactant or amphoteric surfactant.

[0349] Gels are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout a liquid carrier. Suitable gelling agents include, but are not limited to, cross-linked acrylic acid polymers such as carbomers, carboxypolyalkylenes, and carbopols. ®Examples of the present invention include hydrophilic polymers such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymers, and polyvinyl alcohol; cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin. To prepare a uniform gel, a dispersant such as alcohol or glycerin may be added, or the gelling agent may be dispersed by grinding, mechanical mixing, and / or stirring.

[0350] The pharmaceutical compositions provided herein can be administered rectally, urethrally, vaginally, or perivabally in the form of suppositories, pessaries, bougies, poultices or poultices, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or enemas. These dosage forms can be prepared using conventional methods as described in Remington: The Science and Practice of Pharmacy, supra.

[0351] Rectal suppositories, urethral suppositories, and vaginal suppositories are solid bodies for insertion into body orifices that are solid at room temperature but melt or soften at body temperature to release the active ingredient within the orifice. Pharmaceutically acceptable carriers used in rectal and vaginal suppositories include a base or vehicle, such as a hardening agent, which, when formulated with the pharmaceutical compositions provided herein, produces a melting point near body temperature; and antioxidants, such as those described herein, including bisulfites and sodium metabisulfite. Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil); glycerinated gelatin; carbowax (polyethylene glycol); spermaceti; paraffin wax; white and yellow wax; and suitable 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 may also be used. Rectal and vaginal suppositories can be prepared by compression or molding. Typical weights for rectal and vaginal suppositories are from about 2 g to about 3 g.

[0352] The pharmaceutical compositions provided herein can be administered ophthalmically in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ocular inserts, and implants.

[0353] 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 for delivery using a pressurized container, pump, spray, atomizer, a nebulizer, or inhaler. The pharmaceutical compositions can be delivered alone, or in combination with a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoro propane. The pharmaceutical compositions can also be provided as a dry powder for insufflation, alone or in combination with an inert carrier such as lactose or phospholipid; and as drops for nasal administration. For intranasal use, the powder can include a bioadhesive including chitosan or cyclodextrin.

[0354] Solutions or suspensions employed in pressurized containers, pumps, sprayers, atomizers, or nebulizers can be formulated to contain ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or prolonging release of the active ingredients provided herein; a propellant as a solvent; and / or a surfactant, such as sorbitan trioleate, oleic acid, or oligomeric lactic acid.

[0355] The pharmaceutical compositions provided herein can be micronized to a size suitable for delivery by inhalation, such as about 50 microns or less, or about 10 microns or less. Particles of such size can be prepared using comminution methods known to those of skill in the art, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

[0356] Capsules, blisters and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mix of the pharmaceutical compositions provided herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as lactose can be anhydrous or in the form of a 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 inhalation / intranasal administration can further comprise a suitable flavor, such as menthol and levomenthol; and / or a sweetener, such as saccharin and sodium saccharin.

[0357] The pharmaceutical compositions provided herein for topical administration can be formulated for immediate release or modified release, including delayed release,

[0358] sustained release, pulsatile release, controlled release, targeted release, and programmed release.

[0359] modified release

[0360] The pharmaceutical compositions provided herein can be formulated as modified release dosage forms. As used herein, the term "modified release" refers to a dosage form whose rate or location of release of an active ingredient is different from an immediate dosage form when administered by the same route. Modified release dosage forms include, but are not limited to, delayed release, extended release, prolonged release, sustained release, pulsatile release, controlled release, accelerated release and fast release, targeted release, programmed release, and gastric residence dosage forms. Pharmaceutical compositions in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those of ordinary skill 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, multiple coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient can also be altered by varying the particle size and polymorphism of the active ingredient.

[0361] The pharmaceutical compositions provided herein in modified release dosage forms can be manufactured using matrix controlled release devices known to those of skill in the art (see Takada et al. "Encyclopedia of Controlled Drug Delivery", Vol. 2, Mathiowitz, Ed., Wiley, 1999).

[0362] In certain embodiments, the pharmaceutical compositions provided herein in modified release dosage forms are formulated using erodible matrix devices, which 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.

[0363] Materials that can be used to form erodible matrices include, but are not limited to, chitin, chitosan, dextran, and pullulan; agar gum, gum arabic, gum karaya, gum tragacanth, gum xanthan, carrageenan, ghatti gum, guar gum, xanthan gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrocolloids, such as pectin; phospholipids, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; celluloses, such as ethyl cellulose (EC), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethyl acrylate or methacrylic acid (EUDRAGIT®); and combinations thereof.® , Rohm America, Inc., Piscataway, NJ); poly(2-hydroxyethyl methacrylate); polylactide; copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolic acid copolymer; 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.

[0364] In certain embodiments, the pharmaceutical compositions provided herein are formulated using a non-erodible matrix device. The active ingredient is dissolved or dispersed in the inert matrix and released upon administration primarily by diffusion through the inert matrix. Materials suitable for use as non-erodible matrix devices include, but are not limited to, insoluble plastics such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, polybutyl methacrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate copolymers, ethylene-vinyl acetate copolymers, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, copolymers of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, ethylene / ethyleneoxyethanol copolymers, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane, and silicone carbonate copolymers; hydrophilic polymers such as ethylcellulose, cellulose acetate, crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate; and fatty compounds such as carnauba wax, microcrystalline wax, and triglycerides.

[0365] In matrix controlled release systems, the desired release kinetics can be controlled, for example, by the type of polymer used, polymer viscosity, particle size of the polymer and / or active ingredient, the ratio of active ingredient to polymer, and other excipients or carriers in the composition.

[0366] The pharmaceutical compositions provided herein in modified release dosage forms 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.

[0367] The pharmaceutical compositions provided herein in modified release dosage forms can be manufactured using osmotic controlled release devices, including but not limited to single-chamber systems, dual-chamber systems, asymmetric membrane technology (AMT), and extruded core systems (ECS). Typically, such devices have at least two components: (a) a core containing the active ingredient; and (b) a semipermeable membrane with at least one delivery port, which encapsulates the core. The semipermeable membrane controls the influx of water from the aqueous environment of use into the core, thereby causing drug release by extrusion through the delivery port.

[0368] In addition to the active ingredient, the core of the osmotic device optionally includes an osmotic agent that generates a driving force to transport water from the environment of use into the core of the device. One class of osmotic agents are water-swellable hydrophilic polymers, which are also referred to as "osmopolymers" and "hydrogels." Suitable water-swellable hydrophilic polymers 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), polyvinyl pyrrolidone (PVP), cross-linked 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, cross-linked sodium carboxymethylcellulose, carrageenan, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) and carboxyethylcellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.

[0369] Another class of osmogens is osmogens, which are capable of absorbing water to affect an 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.

[0370] Osmotic agents with different dissolution rates can be used to affect the rate at which the active ingredient is initially delivered from the dosage form. For example, amorphous sugars (such as MANNOGEM ™EZ (SPI Pharma, Lewes, DE) can be used to provide faster delivery during the first few hours to quickly produce the desired therapeutic effect and gradually and continuously release the remaining amount 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 to replace the amount of active ingredient that is metabolized and excreted.

[0371] The core may also include various other excipients and carriers as described herein to enhance the performance of the dosage form or to facilitate stability or processing.

[0372] Materials that can be used to form the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulose derivatives that are water permeable at physiologically relevant pH and insoluble in water or readily rendered water insoluble by chemical alteration, such as cross-linking. Examples of suitable polymers that can be used to form the coating include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA urethane, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methylsulfonate, CA butylsulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta glucan ethyl Acid esters, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxylated ethylene vinyl acetate, EC, PEG, PPG, PEG / PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMCP, HPMCAS, HPMCAT, poly(acrylic acid) and esters and poly-(methacrylic acid) and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyolefins, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halides, polyvinyl esters and ethers, natural waxes and synthetic waxes.

[0373] The semipermeable membrane may also be a hydrophobic microporous membrane in which the pores are substantially filled with gas and are 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 polyolefins, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0374] Delivery ports on the semipermeable membrane can be formed after coating by mechanical drilling 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 recess in the core. Alternatively, delivery ports can be formed during the coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Patents Nos. 5,612,059 and 5,698,220.

[0375] The total amount of active ingredient released and the rate of release can be substantially modified by the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and location of the delivery ports.

[0376] The pharmaceutical composition in the form of an osmotic controlled release dosage form may further comprise additional conventional excipients or carriers as described herein to facilitate performance or processing of the formulation.

[0377] The pharmaceutical compositions provided herein in modified release dosage forms can be manufactured as multiparticulate controlled release devices comprising a plurality of particles, granules or agglomerates having a diameter ranging 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 prepared by methods known to those skilled in the art, including wet and dry granulation, extrusion / spheronization, roller compaction, melt congealing, and by spraying seed cores. See, for example, Multiparticulate Oral Drug Delivery. Oral Drug D liv ry); Marcel Dekker: 1994; and Pharmaceutical Granulation Technology utical P ll tization T chnology”; Marcel Dekker & Co.: 1989.

[0378] Other excipients or carriers described herein can be blended with the pharmaceutical composition to aid in processing and forming multiparticulates. The resulting particles can themselves constitute the multiparticulate device or can be coated with various film-forming materials (e.g., enteric polymers, water-swellable polymers, and water-soluble polymers). The multiparticulates can be further processed into capsules or tablets.

[0379] The pharmaceutical compositions provided herein can also be formulated to target specific tissues, receptors, or other body areas of the subject to be treated, including liposome-, resealed erythrocyte-, and antibody-based delivery systems.

[0380] Thermogravimetric analysis (TGA)

[0381] Further provided herein are methods of using a solid form, a pharmaceutically acceptable salt or a crystalline form thereof disclosed herein, or a pharmaceutical composition thereof 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, a pharmaceutically acceptable salt or a crystalline form thereof disclosed herein, or a pharmaceutical composition disclosed herein.

[0382] In some embodiments, provided herein is a method for treating, preventing, or ameliorating a fibrotic, inflammatory, or proliferative disease or condition in a subject, the method comprising administering to the subject a therapeutically effective amount of a ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid pharmaceutically acceptable salt (for example, ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid ethanolamine salt) or its solid form or crystalline form, or comprising the ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid pharmaceutically acceptable salt (for example, ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid) or a pharmaceutical composition in solid or crystalline form thereof.

[0383] In various embodiments, the subject is an animal, including but not limited to a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. In some embodiments, the subject is human.

[0384] 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.

[0385] 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).

[0386] In certain embodiments, the fibrotic, inflammatory, or proliferative disease or condition that can be treated with the pharmaceutically acceptable salts provided herein and / or pharmaceutical compositions thereof include, but are not limited to, fibrotic eye diseases such as diabetic retinopathy, wet age-related macular degeneration, and diabetic macular edema. In some embodiments, the fibrotic eye disease is proliferative vitreoretinopathy, corneal edema, anterior uveitis and posterior uveitis, pterygium, comeal disease, dry eye, conjunctivitis, allergy, and laser-induced exudation, non-age-related macular degeneration, macular edema, age-related macular degeneration, or ocular von Hippel-Lindau disease.

[0387] 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 kidney disease, diabetic nephropathy, glomerulonephritis, focal segmental glomerulosclerosis, systemic lupus, lupus nephritis, primary glomerulonephritis, membranous nephropathy, membranous proliferative glomerulonephritis, diffuse proliferative glomerulonephritis, membranous focal segmental glomerulosclerosis, secondary glomerulonephritis, membranous nephropathy, IgA nephropathy, ischemic kidney disease, or Alports Syndrome. In certain embodiments, the fibrotic, inflammatory, or proliferative disease or condition is chronic kidney disease. In some embodiments, the kidney disease can include, but is not limited to, progressive glomerulonephropathy including, but not limited to, diabetic kidney disease (e.g., due to Type I or Type II diabetes or systemic lupus), primary glomerulonephritis (e.g., membranous nephropathy, focal segmental glomerulosclerosis, membranous proliferative glomerulonephritis, diffuse proliferative glomerulonephritis, membranous focal segmental glomerulosclerosis), or secondary glomerulonephritis (e.g., diabetic nephropathy, ischemic kidney disease). In some embodiments, the kidney disease can include progressive kidney disease primarily originating from the tubulointerstitium. In some embodiments, the kidney disease can include, for example, chronic interstitial nephritis, autosomal dominant tubulointerstitial fibrosis, or reflux nephropathy.

[0388] In certain embodiments, the fibrotic, inflammatory, or proliferative disease or condition is diabetic nephropathy.

[0389] In certain embodiments, the fibrotic, inflammatory, or proliferative disease or condition is focal segmental glomerulosclerosis.

[0390] In certain embodiments, the fibrotic, inflammatory, or proliferative disease or condition is diabetic cardiomyopathy, congestive heart failure, or ischemic heart disease.

[0391] In certain embodiments, the fibrotic, inflammatory, or proliferative disease or condition is systemic sclerosis or scleroderma.

[0392] In certain embodiments, the fibrotic, inflammatory, or proliferative disease or condition is pulmonary fibrosis. In some embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF).

[0393] In certain embodiments, the fibrotic, inflammatory, or proliferative disease or condition is chronic obstructive pulmonary disorder (COPD), asthma, or cystic fibrosis.

[0394] In some embodiments, the fibrotic, inflammatory, or proliferative disease or condition includes, but is not limited to, a disease selected from the group consisting of fibrotic skin disorders such as keloids, hypertrophic scars, and scleroderma; lung diseases such as pulmonary fibrosis; heart diseases such as heart failure due to ischemic heart disease, valvular heart disease, and hypertensive heart disease, diabetic cardiomyopathy, and hypertension; and liver diseases such as cirrhosis.

[0395] 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 a 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 the group consisting of a progressive kidney disease, glomerulonephritis, diabetic nephropathy, diabetic kidney disease, systemic lupus, primary glomerulonephritis, membranous nephropathy, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, diffuse proliferative glomerulonephritis, membranous focal segmental glomerulosclerosis, secondary glomerulonephritis, or ischemic kidney disease. 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.

[0396] 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 glomerulonephropathy, including but not limited to diabetic nephropathy (e.g., due to 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 kidney disease).

[0397] In some embodiments, the pharmaceutically acceptable salts provided herein and / or pharmaceutical compositions thereof can be used to treat an inflammatory disease or condition.

[0398] In general, the inflammatory disease or condition that can be treated with the solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or the pharmaceutical composition thereof provided herein, is any disease or condition characterized by an abnormal, irregular, excessive, undesirable, or unnecessary inflammatory response.

[0399] In some embodiments, the inflammatory disease or condition is a result of tissue damage. In some embodiments, the inflammatory disease, disorder, or condition is a result of an autoimmune condition, and in further embodiments, the inflammatory disease, disorder, or condition is a result of a bacterial or viral infection or presence of a toxin.

[0400] The solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or the pharmaceutical composition thereof provided herein, can have anti-inflammatory activity and / or immunomodulatory activity, and can be used to treat diseases or conditions including, but not limited to, septic shock, hemodynamic shock, sepsis syndrome, post-ischemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic disease, cachexia, graft rejection, cancer (such as cutaneous T-cell lymphoma), diseases involving angiogenesis, autoimmune diseases, inflammatory diseases of the skin, inflammatory bowel disease (such as Crohn’s disease and colitis), ankylosing spondylitis, psoriatic arthritis, adult Still’s disease, uveitis, Wegener’s granulomatosis, Behcet’s disease, Sjogren’s syndrome, sarcoidosis, polymyositis, dermatomyositis, multiple sclerosis, sciatica, complex regional pain syndrome, radiation injury, hyperoxic alveolar injury, 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, cerebral stroke, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, cryptogenic fibrosing alveolitis, psoriasis, transplant rejection, atopic dermatitis, vasculitis, allergy, seasonal allergic rhinitis, reversible airway obstruction, adult respiratory distress syndrome, asthma, chronic obstructive pulmonary disease (COPD), and / or bronchitis. The solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or the pharmaceutical composition thereof provided herein, as well as the methods provided herein, can be used to treat one or more of these diseases, disorders, or conditions.

[0401] 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, liver steatosis, fatty liver disease, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH).

[0402] 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.

[0403] In some embodiments, the inflammatory disease or condition is focal segmental glomerulosclerosis, lupus nephritis, membranous nephropathy, IgA nephropathy, chronic obstructive pulmonary disorder (COPD), asthma, or cystic fibrosis.

[0404] In some embodiments, the inflammatory disease or condition is an autoimmune disease or condition. In some embodiments, the autoimmune disease or condition that can be treated with the pharmaceutically acceptable salts provided herein and / or pharmaceutical compositions thereof is systemic lupus erythematosus (SLE), inflammatory bowel disease, Crohn’s disease, ulcerative colitis, graft-versus-host disease, multiple sclerosis, or rheumatoid arthritis.

[0405] In some embodiments, the solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or the pharmaceutical composition thereof provided herein, can be used to treat a proliferative disease or condition.

[0406] Generally, the proliferative disease or condition that can be treated with the solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or the pharmaceutical composition thereof provided herein, relates to any disease or condition characterized by abnormal cell proliferation. Cell proliferation can be self-replicating and includes an inappropriate or excessive wound healing response. Cell proliferation can increase the influx of inflammatory cytokines and inflammatory cells, and thus is associated with inflammation and / or degeneration.

[0407] The proliferative disease or condition that can be treated with the solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or the pharmaceutical composition thereof provided herein, includes, but is not limited to, various retinopathies.

[0408] In some embodiments, the proliferative disease or condition suitable for treatment by the methods provided herein includes, but is not limited to, diabetic retinopathy, diabetic macular edema, macular degeneration, retinopathy of prematurity (ROP), and proliferative vitreoretinopathy (PVR).

[0409] The proliferative disease or condition that can be treated with the solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or the pharmaceutical composition thereof provided herein, further includes, but is not limited to, various tumors and cancers that are benign or malignant, metastatic or non-metastatic.

[0410] Cancers treatable with the solid forms, pharmaceutically acceptable salts, or crystalline forms thereof provided herein, or the pharmaceutical compositions thereof provided herein include various cancers, including, among others, breast cancer, skin cancer, ovarian cancer, renal cancer, gastrointestinal cancer, renal cancer, bladder cancer, pancreatic cancer, squamous and adenocarcinoma of the lung.

[0411] In some embodiments, the cancer is one that is characterized by the presence of one or more tumors in the subject. Examples of cancers suitable for treatment by the solid forms, pharmaceutically acceptable salts, or crystalline forms thereof provided herein, or the 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, renal 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 graft associated with treatment of the cancer, for example, following hematopoietic stem cell transplantation for treatment of leukemia.

[0412] In some embodiments, the cancer suitable for treatment by 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 renal cancer.

[0413] In some embodiments, treatment of a disease or condition described herein with the solid forms, pharmaceutically acceptable salts, or crystalline forms thereof provided herein, or the pharmaceutical compositions thereof provided herein results in an increase in the average survival time of a population of treated subjects as compared to a population of untreated subjects. Preferably, the average survival time is increased by more than about 30 days; more preferably, by more than about 60 days; more preferably, by more than about 90 days; and even more preferably, by more than about 120 days. The increase in survival time of a population can be measured by any reproducible means. In some embodiments, the increase in average survival time of a population can be measured, for example, by calculating the average length of survival of a population following initiation of treatment with the solid forms, pharmaceutically acceptable salts, or crystalline forms thereof provided herein, or the pharmaceutical compositions thereof provided herein. In another embodiment, the increase in average survival time of a population can also be measured, for example, by calculating the average length of survival of a population following completion of a first round of treatment with the solid forms, pharmaceutically acceptable salts, or crystalline forms thereof provided herein, or the pharmaceutical compositions thereof provided herein.

[0414] In some embodiments, treatment of a disease or condition described herein with a solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, results in a decrease in mortality in the treated population of subjects compared to a population of subjects receiving the vehicle alone. In another embodiment, treatment of a disease or condition described herein with a solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, results in a decrease in mortality in the treated population of subjects compared to an untreated population. In a further embodiment, treatment of a disease or condition described herein with a solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, results in a decrease in mortality in the treated population of subjects compared to a population receiving monotherapy with a drug that is not a solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein. Preferably, the mortality is decreased by more than about 2%; more preferably, more than about 5%; more preferably, more than about 10%; and most preferably, more than about 25%.

[0415] In certain embodiments, treatment of a disease or condition described herein with a solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, results in a decrease in the rate of cell proliferation. Preferably, the rate of cell proliferation is decreased by at least about 5% after treatment with a solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein; 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.

[0416] In another embodiment, treatment of a disease or condition described herein with a solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, results in a decrease in the proportion of proliferating cells. Preferably, the proportion of proliferating cells is decreased by at least about 5% after treatment with a solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein; 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.

[0417] In another embodiment, treatment of a disease or condition described herein with a solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, results in a decrease in the size of an area or region of cell proliferation. Preferably, the size of an area or region of cell proliferation is decreased by at least 5% relative to its size prior to treatment with a solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein; 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% after treatment with a solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein. The size of an area or region of cell proliferation can be measured by any reproducible means of measurement. In some embodiments, the size of an area or region of cell proliferation can be measured as the diameter or width of an area or region of cell proliferation.

[0418] The solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein (e.g., a pharmaceutical composition provided herein comprising a solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein) can be administered to a subject in need of treatment of a disease or condition described herein in a therapeutically effective amount. )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, or a solid form or crystalline form thereof, or a pharmaceutical composition thereof as provided herein) can be administered orally, parenterally (e.g., intramuscularly, intraperitoneally, intravenously, ICV, intracisternal injection or infusion, subcutaneous injection or implantation), inhaled, nasal, vaginal, rectal, sublingually, or topically (e.g., transdermal or topical) and can be formulated into suitable dosage units, alone or with pharmaceutically acceptable carriers, adjuvants, and vehicles suitable for each route of administration. Also provided are solid forms, pharmaceutically acceptable salts, or crystalline forms thereof, or pharmaceutical compositions thereof as provided herein (e.g., ( )-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 thereof as provided herein), wherein the active ingredient is released over a predetermined period of time.

[0419] In the context of the methods provided herein, a therapeutically or prophylactically effective amount of a solid form, a pharmaceutically acceptable salt, or a crystalline form thereof, provided herein, or a pharmaceutical composition thereof, provided herein (e.g.,

[00145] The amount 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, or a pharmaceutical composition thereof as provided herein) can be readily determined by one of ordinary skill in the art by using conventional techniques and by observing results obtained under similar circumstances. In determining a therapeutically effective amount, a number of factors are considered, including, but not limited to, the species of the subject, the size, age, and general health of the subject, the specific condition involved, the severity of the condition, the subject's response to treatment, the mode of administration, the bioavailability of the administered formulation, the dosage regimen selected, the use of other medications, and other relevant circumstances.

[0420] Those skilled in the art will be able to determine the effectiveness of a solid form, a pharmaceutically acceptable salt, or a crystalline form thereof as provided herein, or a pharmaceutical composition thereof as provided herein (e.g., )-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 thereof as provided herein) in an effective, non-toxic amount that would be needed to treat, prevent or ameliorate the fibrotic, inflammatory or proliferative diseases or conditions described herein.

[0421] In some embodiments, a therapeutically effective dose level of a solid form, a pharmaceutically acceptable salt or a crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, such as provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid pharmaceutically acceptable salt (for example, ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid ethanolamine salt) or its solid form or crystalline form in the range of about 0.01 mg / kg body weight / day to about 1000 mg / kg body weight / day, or about 0.1 mg / kg body weight / day to about 100 mg / kg body weight / day, or about 1 mg / kg body weight / day to about 10 mg / kg body weight / day, or about 5 mg / kg body weight / day. Small doses (0.01-1 mg / kg / day) can be used initially, with the dosage increased subsequently to about 1000 mg / kg / day. If the response of the subject at such dosage is insufficient, even higher dosages (or effectively higher dosages given by different, more localized delivery routes) can be used within the scope of patient tolerance. Provided herein ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid pharmaceutically acceptable salt (for example, ( A typical therapeutically or prophylactically effective amount of benzophenone (ethanolamine salt of benzophenone)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid) or a solid or crystalline form thereof can be 1 mg / kg body weight / day to 300 mg / kg body weight / day, 1 mg / kg body weight / day to 200 mg / kg body weight / day, or 1 mg / kg body weight / day to 100 mg / kg body weight / day. Suitable dosages can be administered as multiple subdoses per day.

[0422] In some embodiments, the invention provides a method for treating, preventing, or ameliorating a fibrotic, inflammatory, or proliferative disease or condition. )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid pharmaceutically acceptable salt (for example, ( ) of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid in a range of about 10 mg / day to about 5000 mg / day, about 100 mg / day to about 3000 mg / day, or about 200 mg / day to about 2500 mg / day (mg / day) can be administered in a single dose or in multiple doses. Within this range, the dose can be about 150 mg / day, about 200 mg / day, about 250 mg / day, about 300 mg / day, about 350 mg / day, about 400 mg / day, about 450 mg / day, about 500 mg / day, about 600 mg / day, about 700 mg / day, about 800 mg / day, about 900 mg / day, about 1000 mg / day, about 1100 mg / day, about 1200 mg / day, about 1300 mg / day, about 1400 mg / day, about 1500 mg / day, about 1600 mg / day, about 1700 mg / day, about 1800 mg / day, about 1900 mg / day, about 2000 mg / day, about 2100 mg / day, about 2200 mg / day, about 2300 mg / day, about 2400 mg / day, or about 2500 mg / day.

[0423] In certain embodiments, the pharmaceutically acceptable salts of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid provided herein are useful in the treatment, prevention, or amelioration of a fibrotic, inflammatory, or proliferative disease or condition. ) of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid in a range of about 10 mg / day to about 5000 mg / day, about 100 mg / day to about 3000 mg / day, or about 200 mg / day to about 2500 mg / day (mg / day) can be administered in a single dose or in multiple doses. Within this range, the dose can be about 150 mg / day, about 200 mg / day, about 250 mg / day, about 300 mg / day, about 350 mg / day, about 400 mg / day, about 450 mg / day, about 500 mg / day, about 600 mg / day, about 700 mg / day, about 800 mg / day, about 900 mg / day, about 1000 mg / day, about 1100 mg / day, about 1200 mg / day, about 1300 mg / day, about 1400 mg / day, about 1500 mg / day, about 1600 mg / day, about 1700 mg / day, about 1800 mg / day, about 1900 mg / day, about 2000 mg / day, about 2100 mg / day, about 2200 mg / day, about 2300 mg / day, about 2400 mg / day, or about 2500 mg / day. Suitable dosage levels for the invention include, but are not limited to, 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, ranging from about 1 mg / kg body weight / day (mg / kg / day) to about 100 mg / kg / day, about 1 mg / kg / day to about 50 mg / kg / day, about 2 mg / kg / day to about 20 mg / kg / day, or about 2 mg / kg / day to about 10 mg / kg / day, which can be administered in single or multiple doses. Within this range, the dosage can be about 1 mg / kg / day, about 2 mg / kg / day, about 3 mg / kg / day, about 4 mg / kg / day, about 5 mg / kg / day, about 6 mg / kg / day, about 7 mg / kg / day, about 8 mg / kg / day, about 9 mg / kg / day, about 10 mg / kg / day, about 11 mg / kg / day, about 12 mg / kg / day, about 13 mg / kg / day, about 14 mg / kg / day, about 15 mg / kg / day, about 16 mg / kg / day, about 17 mg / kg / day, about 18 mg / kg / day, about 19 mg / kg / day or about 20 mg / kg / day.

[0424] In certain embodiments, the ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid pharmaceutically acceptable salt (for example, ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid ethanolamine salt) or a solid or crystalline form thereof, or a pharmaceutical composition provided herein at a dosage of between about 10 mg / kg / day and about 400 mg / kg / day, or between about 50 mg / kg / day and about 300 mg / kg / day, or 100 mg / kg / day to 250 mg / kg / day ( In some embodiments, the ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid pharmaceutically acceptable salt (for example, ( )-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 as provided herein at about 100 mg / kg / day, about 110 mg / kg / day, about 120 mg / kg / day, about 130 mg / kg / day, about 140 mg / kg / day, about 150 mg / kg / day, about 160 mg / kg / day, about 170 mg / kg / day, about 180 mg / kg / day, about 190 mg / kg / day, about 200 mg / kg / day, about 210 mg / kg / day, about 220 mg / kg / day, about 230 mg / kg / day, about 240 mg / kg / day, about 250 mg / kg / day, about 260 mg / kg / day, about 270 mg / kg / day, about 280 mg / kg / day, about 290 mg / kg / day, or about 300 mg / kg / day ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid compound is administered at a dosage.

[0425] For oral administration, the pharmaceutical compositions provided herein can be in the form of a mixture containing 10 mg to 10,000 mg of the ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid pharmaceutically acceptable salt (for example, ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid) or a solid or crystalline form thereof, in particular about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg and about 1500 mg of ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid pharmaceutically acceptable salt (for example, ( The composition may be administered on a schedule of 1 to 4 times per day, including once, twice, three times, and four times per day.

[0426] In certain embodiments, for oral administration, the pharmaceutical compositions provided herein can be administered as a mixture containing 1 mg to 100 mg of the ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid pharmaceutically acceptable salt (for example, ( The invention also provides a pharmaceutical composition comprising the ...

[0427] However, it will be understood that the specific dosage level and dosage frequency for any particular patient may vary and will depend on a variety of factors, including the activity of the specific compound used, the metabolic stability and length of action of the 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.

[0428] In certain embodiments, kits are also provided herein that, when used by a practitioner, can simplify the administration of an appropriate amount of a solid form, a pharmaceutically acceptable salt, or a crystalline form thereof, or a pharmaceutical composition thereof, such as a pharmaceutical composition provided herein, to a subject. )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid pharmaceutically acceptable salt (for example, ( ) or a solid form or crystalline form thereof. In certain embodiments, the kits provided herein include a container and a dosage form of a solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, e.g., a dosage form of a solid form provided herein ) or a solid form or crystalline form thereof. In certain embodiments, the kits provided herein include a container and a dosage form of a solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, e.g., a dosage form of a solid form provided herein ) or a solid form or crystalline form thereof. In certain embodiments, the kits provided herein include a container and a dosage form of a solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, e.g., a dosage form of a solid form provided herein

[0429] The kits provided herein can further include a device for administering a solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, e.g., a dosage form of a solid form provided herein ) or a solid form or crystalline form thereof. In certain embodiments, the kits provided herein include a container and a dosage form of a solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, e.g., a dosage form of a solid form provided herein ) or a solid form or crystalline form thereof. In certain embodiments, the kits provided herein include a container and a dosage form of a solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, e.g., a dosage form of a solid form provided herein

[0430] The kits provided herein can further include a pharmaceutically acceptable vehicle that can be used to administer a solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, e.g., a dosage form of a solid form provided herein ) or a solid form or crystalline form thereof. In certain embodiments, the kits provided herein include a container and a dosage form of a solid form, pharmaceutically acceptable salt, or crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein, e.g., a dosage form of a solid form provided herein ) or a solid form or crystalline form thereof. For example, if a solid form provided herein, a pharmaceutically acceptable salt or a crystalline form thereof provided herein, or a pharmaceutical composition thereof provided herein is provided as 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 particulate-free sterile solution suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to: 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, ethanol, 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.

[0431] Those skilled in the art will appreciate that numerous changes and / or modifications can be made to the above-described embodiments without departing from the general scope of the present disclosure. Accordingly, the embodiments are to be considered in all respects as illustrative and not restrictive.

[0432] Disclosed herein are the following numbered embodiments:

[0433] Embodiment 1 : A solid form of (R)-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. Embodiment 2: A solid form of (R)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1- oxo-2-propenyl]amino]benzoic acid or a salt thereof having an endothermic onset temperature of 29°C to 187°C as measured by differential scanning calorimetry.

[0434] Embodiment 3: A solid form of (R)-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.

[0435] Embodiment 4: A solid form of (R)-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 and an endothermic onset temperature of 29°C to 187°C as measured by differential scanning calorimetry. Embodiment 5: A solid form of (R)-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, a melting point of 57°C to 199°C as measured by differential scanning calorimetry, and an endothermic onset temperature of 29°C to 187°C as measured by differential scanning calorimetry.

[0436] Embodiment 6: A solid form of (R)-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, a melting point of 57°C to 199°C as measured by differential scanning calorimetry, and an endothermic onset temperature of 29°C to 187°C as measured by differential scanning calorimetry.​) a solid form of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2- propenyl]amino]benzoic acid or a salt thereof having an onset temperature of an endotherm of 29 °C to 187 °C and a melting point of 57 °C to 199 °C as measured by differential scanning calorimetry.

[0437] Embodiment 5: A solid form of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-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. Embodiment 5: A solid form of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-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.

[0438] Embodiment 6: A solid form of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2- propenyl]amino]benzoic acid or a salt thereof having a solubility of 2.4 mg / ml to 5.14 mg / ml at 24 hours in FaSSIF media (pH 7.5).

[0439] Embodiment 7: A solid form of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-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 at 24 hours in FaSSIF media (pH 7.5). Embodiment 8: A solid form of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2- propenyl]amino]benzoic acid or a salt thereof having a solubility of 1.2 mg / ml to 5.14 mg / ml at 24 hours in FeSSIF media (pH 7.8).

[0440] Embodiment 9: A solid form of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2- propenyl]amino]benzoic acid or a salt thereof having a solubility of 1.2 mg / ml to greater than 5.14 mg / ml at 24 hours in FeSSIF media (pH 7.8).

[0441] Embodiment 10: A solid form of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2- propenyl]amino]benzoic acid or a salt thereof having a solubility of 1.2 mg / ml to 5.14 mg / ml at 24 hours in FaSSIF media (pH 7.5) and a solubility of 1.2 mg / ml to greater than 5.14 mg / ml at 24 hours in FeSSIF media (pH 7.8). Embodiment 10: A solid form of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2- propenyl]amino]benzoic acid or a salt thereof having a solubility of 1.2 mg / ml to 5.14 mg / ml at 24 hours in FaSSIF media (pH 7.5) and a solubility of 1.2 mg / ml to greater than 5.14 mg / ml at 24 hours in FeSSIF media (pH 7.8).

[0442] ​​​)-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid, or a salt thereof, having a solubility of 2.4 mg / ml to 5.14 mg / ml in FaSSIF medium (pH 7.5) at 24 hours and a solubility of 1.2 mg / ml to 5.14 mg / ml in FeSSIF medium (pH 7.8) at 24 hours.

[0443] Example 11: A solid form of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-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 FaSSIF medium (pH 7.5) at 24 hours and a solubility of 1.2 mg / ml to greater than 5.14 mg / ml in FeSSIF medium (pH 7.8) at 24 hours.

[0444] Example 12: A solid form of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid, or a salt thereof, having a bioavailability of 39 F% to 82 F%.

[0445] Example 13: The solid form according to Example 12, having a bioavailability of at least 50 F%, at least 55 F%, at least 60 F%, at least 65 F%, at least 70 F%, at least 75 F%, or at least 80 F%.

[0446] Example 14: The solid form according to any one of Examples 1 to 13, wherein the solid form has any two or more of the following properties:

[0447] a water sorption at 80% relative humidity of 0.49% to 1.61%, as determined by dynamic vapor sorption;

[0448] an endothermic onset temperature of 29 °C to 187 °C, as measured by differential scanning calorimetry;

[0449] a melting point of 57 °C to 199 °C, as measured by differential scanning calorimetry;

[0450] 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;

[0451] solubility at 24 hours in FaSSIF medium (pH 7.5) is 2.4 mg / ml to 5.14 mg / ml;

[0452] solubility at 24 hours in FaSSIF medium (pH 7.5) is 2.4 mg / ml to greater than 5.14 mg / ml;

[0453] solubility at 24 hours in FeSSIF medium (pH 7.8) is 1.2 mg / ml to 5.14 mg / ml;

[0454] solubility at 24 hours in FeSSIF medium (pH 7.8) is 1.2 mg / ml to greater than 5.14 mg / ml;

[0455] bioavailability is 39 F% to 82 F%.

[0456] Example 15: The solid form of any one of Examples 1-14, wherein the solid form is a crystalline form of a salt of (-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2- propenyl]amino]benzoic acid.

[0457] Example 16: The solid form of any one of Examples 1-15, wherein the solid form is a crystalline form of a salt of (-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2- propenyl]amino]benzoic acid.

[0458] Example 17: The solid form of any one of Examples 1-16, wherein the solid form is a crystalline form of a pharmaceutically acceptable salt of (-2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid.

[0459] Example 18: A solid form of a salt of (-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l- oxo-2-propenyl]amino]benzoic acid having a water sorption at 80% relative humidity of 0.49% to 8.82%, as determined by dynamic vapor sorption. Example 19: A solid form of a salt of (-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l- oxo-2-propenyl]amino]benzoic acid having an endothermic onset temperature of 29 °C to 203 °C, as measured by differential scanning calorimetry.

[0460] Example 19: A solid form of a salt of (-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l- oxo-2-propenyl]amino]benzoic acid having an endothermic onset temperature of 29 °C to 203 °C, as measured by differential scanning calorimetry. ​​​​

[0461] Example 20: A solid form of a salt of (E)-2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid having a melting point of 57 °C to 204 °C as measured by differential scanning calorimetry.

[0462] Example 21 : A solid form of a salt of (E)-2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid having an endothermic onset temperature of 29 °C to 203 °C and a melting point of 57 °C to 204 °C as measured by differential scanning calorimetry.

[0463] Example 22: A solid form of a salt of (E)-2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-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.

[0464] Example 23: A solid form of a salt of (E)-2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid having a solubility of 2.4 mg / ml to 5.14 mg / ml in FaSSIF media (pH 7.5) at 24 hours.

[0465] Example 24: A solid form of a salt of (E)-2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid having a solubility of 2.4 mg / ml to greater than 5.14 mg / ml in FaSSIF media (pH 7.5) at 24 hours.

[0466] Example 25: A solid form of a salt of (E)-2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid having a solubility of 1.2 mg / ml to 5.14 mg / ml in FeSSIF media (pH 7.8) at 24 hours.

[0467] Example 26: A solid form of a salt of (E)-2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid having a solubility of 1.2 mg / ml to greater than 5.14 mg / ml in FeSSIF media (pH 7.8) at 24 hours. ​​​​​​The invention relates to a solid form of a salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid, wherein the solubility in FeSSIF medium (pH 7.8) is 1.2 mg / ml to greater than 5.14 mg / ml at 24 hours.

[0468] Example 27: A ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid in a solid form, with a solubility of 2.4 mg / ml to 5.14 mg / ml in FaSSIF medium (pH 7.5) at 24 hours and a solubility of 1.2 mg / ml to 5.14 mg / ml in FeSSIF medium (pH 7.8) at 24 hours.

[0469] Example 28: A ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid in a solid form, having a solubility of 2.4 mg / ml to greater than 5.14 mg / ml in FaSSIF medium (pH 7.5) at 24 hours and a solubility of 1.2 mg / ml to greater than 5.14 mg / ml in FeSSIF medium (pH 7.8) at 24 hours.

[0470] Example 29: A ( The solid form of a salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has a solubility of 0.048 mg / ml to 0.090 mg / ml in a medium at pH 6.8 after 24 hours.

[0471] Example 30: A ( The solid form of a salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid has a bioavailability of 39 F% to 82 F%.

[0472] Embodiment 31: The solid form of embodiment 30, having a bioavailability of at least 50 F%, at least 55 F%, at least 60 F%, at least 65 F%, at least 70 F%, at least 75 F%, or at least 80 F%.

[0473] Embodiment 32: The solid form of any one of embodiments 18 to 31, wherein the solid form has any two or more of the following properties:

[0474] a water uptake of 0.49% to 8.82% at 80% relative humidity, as determined by dynamic vapor sorption;

[0475] an endothermic onset temperature of 29 °C to 203 °C, as measured by differential scanning calorimetry;

[0476] a melting point of 57 °C to 204 °C, as measured by differential scanning calorimetry;

[0477] a weight loss of 0.07% to 5.24% when heated from 25 °C to 120 °C, as determined by thermogravimetric analysis;

[0478] a solubility of 2.4 mg / ml to 5.14 mg / ml at 24 hours in FaSSIF media (pH 7.5);

[0479] a solubility of 2.4 mg / ml to greater than 5.14 mg / ml at 24 hours in FaSSIF media (pH 7.5);

[0480] a solubility of 1.2 mg / ml to 5.14 mg / ml at 24 hours in FeSSIF media (pH 7.8);

[0481] a solubility of 1.2 mg / ml to greater than 5.14 mg / ml at 24 hours in FeSSIF media (pH 7.8);

[0482] a solubility of 0.048 mg / ml to 0.090 mg / ml at 24 hours in media at pH 6.8;

[0483] a bioavailability of 39 F% to 82 F%.

[0484] Example 33: The solid form of any one of Examples 18-32, wherein the solid form is a crystalline form of a salt of )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid.

[0485] Example 34: The solid form of any one of Examples 18-33, 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.

[0486] Example 35: The solid form of any one of Examples 18-34, wherein the solid form is a crystalline form of a salt of ) a crystalline form of a pharmaceutically acceptable salt of 2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid: ) a potassium salt, a meglumine salt, a tris(hydroxymethyl)aminomethane salt, an ethanolamine salt, a tert-butylamine salt, an ammonium salt, and a lysine salt of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid.

[0487] Embodiment 36: The solid form of any one of embodiments 18-35, wherein the solid form is selected from the group consisting of: ) a crystalline form of a pharmaceutically acceptable salt of 2-[[3-(3-methoxy-4- propargyloxy)phenyl)-l-oxo-2-propenyl]amino]benzoic acid: ) a meglumine salt, a tris(hydroxymethyl)aminomethane salt, an ethanolamine salt, and a tert-butylamine salt of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)-l-oxo-2- propenyl]amino]benzoic acid.

[0488] Embodiment 37: The solid form of any one of embodiments 18-36, wherein the solid form is: ) a crystalline form of an ethanolamine salt of 2-[[3-(3-methoxy-4-propargyloxy)phenyl)- l-oxo-2-propenyl]amino]benzoic acid.

[0489] Embodiment 38: A crystalline form of a pharmaceutically acceptable salt of a compound of Formula (I):

[0490]

[0491] Formula (I),

[0492] wherein the crystalline form has a water uptake of less than 1.7% at 25 °C and 80% relative humidity, as determined by dynamic vapor sorption.

[0493] 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.

[0494] 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 at 24 hours in FaSSIF media (pH 7.5).

[0495] Example 41: The crystalline form of Example 38, wherein the solubility of the crystalline form in FeSSIF media (pH 7.8) at 24 hours is 3.4 mg / ml to greater than 5.0 mg / ml.

[0496] Example 42: The crystalline form of Example 38, wherein the solubility of the crystalline form in media at pH 6.8 at 24 hours is 0.07 mg / ml to 0.090 mg / ml.

[0497] Example 43: The crystalline form of Example 38, wherein the bioavailability of the crystalline form is 39 F% to 82 F%.

[0498] Example 44: The crystalline form of Example 38, wherein the pharmaceutically acceptable salt is selected from the group consisting of a meglumine salt, an ethanolamine salt, a tris(hydroxymethyl)aminomethane salt, and a t-butylamine salt.

[0499] Example 45: A pharmaceutical composition comprising the crystalline form of Example 38 and at least one pharmaceutically acceptable excipient.

[0500] Example 46: A crystalline form of a pharmaceutically acceptable salt of a compound of Formula (I):

[0501]

[0502] Formula (I),

[0503] wherein the bioavailability of the crystalline form is 39 F% to 82 F%.

[0504] Example 47: The crystalline form of Example 46, wherein the pharmaceutically acceptable salt is selected from the group consisting of a potassium salt, a meglumine salt, an ethanolamine salt, a tris(hydroxymethyl)aminomethane salt, a t-butylamine salt, an ammonium salt, and a lysine salt.

[0505] Example 48: The crystalline form of Example 46, wherein the bioavailability of the crystalline form is 50 F% to 82 F%.

[0506] Example 49: The crystalline form of Example 46, wherein the bioavailability of the crystalline form is 64 F% to 82 F%.

[0507] Example 50: A pharmaceutical composition comprising the crystalline form of Example 46 and at least one pharmaceutically acceptable excipient.

[0508] Example 51: A crystalline form of an ethanolamine salt of a compound of Formula (I):

[0509]

[0510] Formula (I),

[0511] wherein the bioavailability of the crystalline form is at least about 1.5x compared to the bioavailability of the free form of the compound of Formula (I).

[0512] Example 52: The crystalline form of Example 51, wherein the bioavailability of the crystalline form is at least about 2x compared to the bioavailability of the free form of the compound of Formula (I).

[0513] Example 53: The crystalline form of Example 51, wherein the bioavailability of the crystalline form is 82F%.

[0514] Example 54: The crystalline form of Example 51, wherein the water uptake of the crystalline form at 25 °C and 80% relative humidity is 0.49%, as determined by dynamic vapor sorption.

[0515] Example 55: The crystalline form of Example 51, wherein the crystalline form has an endothermic onset temperature of 176 °C, as measured by differential scanning calorimetry.

[0516] Example 56: The crystalline form of Example 51, wherein the crystalline form has a melting point of 178 °C, as measured by differential scanning calorimetry.

[0517] Example 57: The crystalline form of Example 51, wherein the weight loss of the crystalline form when heated from 25 °C to 120 °C is 0.10%, as determined by thermogravimetric analysis.

[0518] Example 58: The crystalline form of Example 51, wherein the solubility of the crystalline form in FaSSIF media (pH 7.5) at 24 hours is greater than 7.99 mg / ml.

[0519] Example 59: The crystalline form of Example 51, wherein the solubility of the crystalline form in FeSSIF media (pH 7.8) at 24 hours is greater than 8.02 mg / ml.

[0520] Example 60: The crystalline form of Example 51, wherein the solubility of the crystalline form in media at pH 6.8 at 24 hours is 0.088 mg / ml.

[0521] Example 61: A pharmaceutical composition comprising the crystalline form of Example 51 and at least one pharmaceutically acceptable excipient.

[0522] Example 62: A crystalline form of the ethanolamine salt of the compound of formula (I):

[0523]

[0524] Formula (I),

[0525] wherein the crystalline form exhibits an X-ray powder diffraction pattern having at least one peak selected from the group consisting of 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° 2θ.

[0526] Embodiment 63. The crystalline form of Embodiment 62, wherein the crystalline form exhibits an X-ray powder diffraction pattern having at least two peaks selected from the group consisting of: 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° 2θ.

[0527] Embodiment 64. The crystalline form of Embodiment 62, wherein the crystalline form exhibits an X-ray powder diffraction pattern having at least three peaks selected from the group consisting of: 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° 2θ.

[0528] Embodiment 65. The crystalline form of Embodiment 62, wherein the crystalline form exhibits an X-ray powder diffraction pattern having at least four peaks selected from the group consisting of: 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° 2θ.

[0529] Embodiment 66. The crystalline form of Embodiment 62, wherein the crystalline form exhibits an X-ray powder diffraction pattern having at least five peaks selected from the group consisting of: 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° 2θ.

[0530] Example 67: A crystalline form of the ethanolamine salt of the compound of Formula (I) according to Example 62, wherein the crystalline form exhibits an X-ray powder diffraction pattern having at least one peak, in degrees 2-theta, 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° 2Theta.

[0531] Example 68: A crystalline form of the ethanolamine salt of the compound of Formula (I) according to Example 62, wherein the crystalline form exhibits an X-ray powder diffraction pattern having at least two peaks, in degrees 2-theta, 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° 2Theta.

[0532] Example 69: A crystalline form of the ethanolamine salt of the compound of Formula (I) according to Example 62, wherein the crystalline form exhibits an X-ray powder diffraction pattern having at least three peaks, in degrees 2-theta, 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° 2Theta.

[0533] Example 70: A crystalline form of the ethanolamine salt of the compound of Formula (I):

[0534]

[0535] Formula (I),

[0536] 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° 2Theta.

[0537] Example 71: A crystalline form of the ethanolamine salt of the compound of Formula (I):

[0538]

[0539] Formula (I),

[0540] 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° 2Theta.

[0541] Example 72: Form I crystalline ) -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid ethanolum.

[0542] Example 73: A pharmaceutical composition comprising the crystalline form of any one of Examples 62-72 and a pharmaceutically acceptable carrier.

[0543] Example 74: A pharmaceutical composition comprising the solid form or crystalline form of any one of Examples 1-72 and a pharmaceutically acceptable excipient.

[0544] Example 75: The pharmaceutical composition of Example 73 or Example 74, wherein the pharmaceutical composition is formulated for single dose administration.

[0545] Example 76: The pharmaceutical composition of any one of Examples 73-75, wherein the pharmaceutical composition is formulated as an oral dosage form, a parenteral dosage form, or an intravenous dosage form.

[0546] Example 77: The pharmaceutical composition of any one of Examples 73-76, wherein the pharmaceutical composition is formulated as an oral dosage form.

[0547] Example 78: The pharmaceutical composition of Example 77, wherein the oral dosage form is a tablet or a capsule.

[0548] Example 79: The pharmaceutical composition of any one of Examples 73-78, wherein the pharmaceutical composition comprises about 1 mg to about 2000 mg of the solid form or crystalline form of any one of Examples 1-72.

[0549] Example 80: The pharmaceutical composition of any one of Examples 73-79, wherein the pharmaceutical composition comprises about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, or about 1500 mg of the solid form or crystalline form of any one of Examples 1-72.

[0550] Example 81: The pharmaceutical composition of any one of Examples 73-79, wherein the pharmaceutical composition comprises about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or about 400 mg of the solid form or crystalline form of any one of Examples 1-72.

[0551] Example 82: The pharmaceutical composition of any one of Examples 73-79, wherein the pharmaceutical composition comprises about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg of the solid form or crystalline form of any one of Examples 1-72.

[0552] Example 83: The pharmaceutical composition of any one of Examples 73-78, wherein the pharmaceutical composition comprises an amount of the solid form or crystalline form of any one of Examples 1-72 effective to provide a dose of about 1 mg / kg to about 500 mg / kg of the compound of Formula (I).

[0553] mg / kg, about 160 mg / kg, about 170 mg / kg, about 180 mg / kg, about 190 mg / kg, about 200 mg / kg, about 210 mg / kg, about 220 mg / kg, about 230 mg / kg, about 240 mg / kg, about 250 mg / kg, about 260 mg / kg, about 270 mg / kg, about 280 mg / kg, about 290 mg / kg, about 300 mg / kg, about 310 mg / kg, about 320 mg / kg, about 330 mg / kg, about 340 mg / kg, about 350 mg / kg, about 360 mg / kg, about 370 mg / kg, about 380 mg / kg, about 390 mg / kg, or about 400 mg / kg of the compound of Formula (I).

[0554] mg / kg, about 160 mg / kg, about 170 mg / kg, about 180 mg / kg, about 190 mg / kg, about 200 mg / kg, about 210 mg / kg, about 220 mg / kg, about 230 mg / kg, about 240 mg / kg, about 250 mg / kg, about 260 mg / kg, about 270 mg / kg, about 280 mg / kg, about 290 mg / kg, about 300 mg / kg, about 310 mg / kg, about 320 mg / kg, about 330 mg / kg, about 340 mg / kg, about 350 mg / kg, about 360 mg / kg, about 370 mg / kg, about 380 mg / kg, about 390 mg / kg, or about 400 mg / kg of the compound of Formula (I).

[0555] mg / kg, about 160 mg / kg, about 170 mg / kg, about 180 mg / kg, about 190 mg / kg, about 200 mg / kg, about 210 mg / kg, about 220 mg / kg, about 230 mg / kg, about 240 mg / kg, about 250 mg / kg, about 260 mg / kg, about 270 mg / kg, about 280 mg / kg, about 290 mg / kg, about 300 mg / kg, about 310 mg / kg, about 320 mg / kg, about 330 mg / kg, about 340 mg / kg, about 350 mg / kg, about 360 mg / kg, about 370 mg / kg, about 380 mg / kg, about 390 mg / kg, or about 400 mg / kg of the compound of Formula (I).

[0556] mg / kg, about 160 mg / kg, about 170 mg / kg, about 180 mg / kg, about 190 mg / kg, about 200 mg / kg, about 210 mg / kg, about 220 mg / kg, about 230 mg / kg, about 240 mg / kg, about 250 mg / kg, about 260 mg / kg, about 270 mg / kg, about 280 mg / kg, about 290 mg / kg, about 300 mg / kg, about 310 mg / kg, about 320 mg / kg, about 330 mg / kg, about 340 mg / kg, about 350 mg / kg, about 360 mg / kg, about 370 mg / kg, about 380 mg / kg, about 390 mg / kg, or about 400 mg / kg of the compound of Formula (I).

[0557] pharmaceutical composition according to any one of embodiments 73-78, wherein the pharmaceutical composition comprises the solid or crystalline form according to any one of embodiments 1-72 in an amount effective to provide a concentration of the compound of Formula (I) at its site of action of about 20 µM to about 40 µM, about 25 µM to about 35 µM, or about 30 µM.

[0558] embodiments 1-72 in an amount effective to provide a concentration of the compound of Formula (I) at its site of action of about 20 µM to about 40 µM, about 25 µM to about 35 µM, or about 30 µM. embodiments 1-72 in an amount effective to provide a concentration of the compound of Formula (I) at its site of action of about 20 µM to about 40 µM, about 25 µM to about 35 µM, or about 30 µM. embodiments 1-72 in an amount effective to provide a concentration of the compound of Formula (I) at its site of action of about 20 µM to about 40 µM, about 25 µM to about 35 µM, or about 30 µM. embodiments 1-72 in an amount effective to provide a concentration of the compound of Formula (I) at its site of action of about 20 µM to about 40 µM, about 25 µM to about 35 µM, or about 30 µM.

[0559] embodiments 1-72 in an amount effective to provide a concentration of the compound of Formula (I) at its site of action of about 20 µM to about 40 µM, about 25 µM to about 35 µM, or about 30 µM. embodiments 1-72 in an amount effective to provide a concentration of the compound of Formula (I) at its site of action of about 20 µM to about 40 µM, about 25 µM to about 35 µM, or about 30 µM. embodiments 1-72 in an amount effective to provide a concentration of the compound of Formula (I) at its site of action of about 20 µM to about 40 µM, about 25 µM to about 35 µM, or about 30 µM.

[0560] embodiments 1-72 in an amount effective to provide a concentration of the compound of Formula (I) at its site of action of about 20 µM to about 40 µM, about 25 µM to about 35 µM, or about 30 µM. embodiments 1-72 in an amount effective to provide a concentration of the compound of Formula (I) at its site of action of about 20 µM to about 40 µM, about 25 µM to about 35 µM, or about 30 µM. embodiments 1-72 in an amount effective to provide a concentration of the compound of Formula (I) at its site of action of about 20 µM to about 40 µM, about 25 µM to about 35 µM, or about 30 µM.

[0561] embodiments 1-72 in an amount effective to provide a concentration of the compound of Formula (I) at its site of action of about 20 µM to about 40 µM, about 25 µM to about 35 µM, or about 30 µM. embodiments 1-72 in an amount effective to provide a concentration of the compound of Formula (I) at its site of action of about 20 µM to about 40 µM, about 25 µM to about 35 µM, or about 30 µM. ) -2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid ethanamine salt in crystalline Form I.

[0562] Example 93: A method of treating, preventing, or ameliorating 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 or crystalline form according to any one of Examples 1-72 or a pharmaceutical composition according to any one of Examples 73-92.

[0563] Example 94: The method of Example 93, wherein the fibrotic, inflammatory, or proliferative disease or condition is selected from fibrosis of the skin, lung, heart, kidney, pancreas, eye, and liver.

[0564] Example 95: The method of Example 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, nephropathy, systemic sclerosis (scleroderma), hypertrophic scarring, keloids, pulmonary fibrosis, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC).

[0565] Example 96: The method of Example 93, wherein the fibrotic, inflammatory, or proliferative disease or condition is nephropathy.

[0566] Example 97: The method of Example 93, wherein 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, membranous proliferative glomerulonephritis, diffuse proliferative glomerulonephritis, membranous focal segmental glomerulosclerosis, secondary glomerulonephritis, membranous nephropathy, IgA nephropathy, or ischemic nephropathy.

[0567] Example 98: The method of Example 93, wherein the fibrotic, inflammatory, or proliferative disease or condition is chronic kidney disease.

[0568] Example 99: The method of Example 93, wherein the fibrotic, inflammatory, or proliferative disease or condition is diabetic kidney disease.

[0569] Example 100: The method of Example 93, wherein the fibrotic, inflammatory, or proliferative disease or condition is focal segmental glomerulosclerosis.

[0570] 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.

[0571] Embodiment 102: The method of embodiment 93, wherein the fibrotic, inflammatory, or proliferative disease or condition is systemic sclerosis or scleroderma.

[0572] Embodiment 103: The method of embodiment 93, wherein the fibrotic, inflammatory, or proliferative disease or condition is pulmonary fibrosis.

[0573] Embodiment 104: The method of embodiment 103, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF).

[0574] Embodiment 105: The method of embodiment 93, wherein the fibrotic, inflammatory, or proliferative disease or condition is selected from the group consisting of chronic obstructive pulmonary disorder (COPD), asthma, and cystic fibrosis.

[0575] Embodiment 106: The method of embodiment 93, wherein the fibrotic, inflammatory, or proliferative disease or condition is a fibrotic eye disease.

[0576] Embodiment 107: The method of embodiment 106, wherein the fibrotic eye disease is selected from the group consisting of diabetic retinopathy, wet age-related macular degeneration, and diabetic macular edema.

[0577] Embodiment 108: The method of embodiment 93, wherein the fibrotic, inflammatory, or proliferative disease or condition is a cancer.

[0578] Embodiment 109: The method of embodiment 108, wherein the cancer is selected from the group consisting of 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.

[0579] Embodiment 110: The method of embodiment 93, wherein the fibrotic, inflammatory, or proliferative disease or condition is selected from the group consisting of diabetic retinopathy, diabetic macular edema, macular degeneration, retinopathy of prematurity (ROP), and proliferative vitreoretinopathy (PVR).

[0580] Embodiment 111 : The method of embodiment 93, wherein the fibrotic, inflammatory, or proliferative disease or condition is an autoimmune disease or condition.

[0581] 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.

[0582] Embodiment 113: The method of any one of embodiments 93-112, wherein the solid form or crystalline form or the pharmaceutical composition is administered orally.

[0583] Embodiment 114: The method of any one of embodiments 93-113, wherein the solid form or crystalline form or the pharmaceutical composition is administered daily.

[0584] Embodiment 115: The method of any one of embodiments 93-114, wherein the solid form or crystalline form or the pharmaceutical composition is administered at a dose of about 10 mg / kg / day to about 400 mg / kg / day, or about 50 mg / kg / day to about 300 mg / kg / day, or 100 mg / kg / day to 250 mg / kg / day of the compound of Formula (I).

[0585] Embodiment 116: The method of any one of embodiments 93-115, wherein the solid form or crystalline form or the pharmaceutical composition is administered at a dose of about 200 mg / kg / day of the compound of Formula (I).

[0586] Embodiment 117: The method of any one of embodiments 93-116, wherein the subject is a human.

[0587] Example

[0588] The present disclosure is further described by the following examples, which are not intended to limit the scope of the claims.

[0589] Dynamic vapor sorption (DVS)

[0590] Polarized light microscopy (PLM)

[0591] All inorganic reagents, organic solvents and water were at least of the standard of analytical laboratory reagent grade.

[0592] Solubility measurements

[0593]

[0594] Example 2. Preparation of salts of (R)-2-[[3-(3-methoxy-4- propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid

[0595] Figure 1

[0596] X-ray powder diffraction (XRPD) patterns were obtained on a Shimadzu XRD-6000 instrument. XRPD bulk patterns were measured at room temperature. XRPD samples were run using the following method:

[0597]

[0598] Figure 8

[0599] Approximately 1 mg of sample was tested in a pinhole aluminum pan under a nitrogen purge using a temperature ramp of 20 °C / min in the range of 30 °C to 300 °C (adjust the test range depending on the decomposition temperature of the sample).

[0600]

[0601] Figure 9

[0602] A compound sample (4-6 mg) was weighed into a pan and heated under a nitrogen purge using a temperature ramp of 20 °C / min in the range of 30 °C to 350 °C, and then held at 350 °C for an additional 1 minute.

[0603]

[0604] Figure 10

[0605] Approximately 10 mg of sample was used to test moisture sorption / desorption curves during a 0% to 95% to 0% relative humidity (RH) cycle at 25 °C, with the following parameters:

[0606]

[0607] During DVS analysis, the humidity was held at each value during the 0% to 95% to 0% Rh cycle, varying in increments of 5% RH, and the change in mass was measured at each such value. For example, the sample was subjected to an increase in relative humidity from 25% RH to 30% RH, and any consequent change in mass was measured. The humidity was held constant at 30% RH until the mass change of the sample reached equilibrium, as determined by a weight change rate of 0.01% per minute or less. The humidity was then changed to the next step value, and the consequent change in mass was measured, and so on. Thus, the moisture response curve was observed over the range of conditions of the 0% to 95% to 0% RH cycle, but a standard comparison can be provided by the moisture content values at set conditions, such as at 80% RH. Table 11 lists the hygroscopicity values of the relevant samples in the sorption cycle by reciting the moisture content at the time of mass equilibrium measured at 80% RH during the ramp from 0 to 95% RH.

[0608] Therefore, when hygroscopicity values ​​at a specific humidity are reported herein, the hygroscopicity values ​​refer to the values ​​obtained at the stated humidity level, measured during an adsorption cycle where the humidity is increased from 0% RH to 95% RH, before returning to 0% RH. The hygroscopicity values ​​recited herein refer only to the total water content since the start of the experiment and therefore do not necessarily equal the actual total water content of the sample.

[0609] The hygroscopicity of the samples was classified as follows:

[0610]

[0611] *At 25 ± 1°C and 80 ± 2% relative humidity (RH) (Ph. Eur. 10.0);

[0612] W: Amount of water adsorbed from 0% RH to 80% RH.

[0613] Figure 11

[0614] The samples dispersed in silicone oil were observed under crossed polarizers using an eyepiece (10×) and an objective lens (40×) and recorded by a camera / computer system with a magnification scale.

[0615] 1 H nuclear magnetic resonance (NMR)

[0616] Weigh approximately 3 mg of sample into an NMR tube and add 0.5 mL of deuterated dimethyl sulfoxide or deuterated methanol to completely dissolve the sample.

[0617] Figure 12

[0618] Accurately weigh approximately 8-12 mg ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid salt (with 8 mg ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (equimolar, free form) was placed into each glass vial, and then 4 ml of the indicated culture medium was added. The samples were stirred at 37°C using a magnetic stirrer. After stirring for 1 or 24 hours, 1 ml of each sample was collected and the final pH was recorded. The samples were filtered by centrifugation (12,000 rpm, 5 minutes). The supernatant was diluted (2x) with HPLC-grade solvent and analyzed by HPLC.

[0619] 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 / H2O; mobile phase B (MPB): ACN.

[0620] The HPLC gradient was as follows:

[0621]

[0622] Figure 13 Figure 24 Figure 25

[0623] Accurately weigh approximately 100 mg ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid ('FT011 free form'; hereinafter also referred to as 'API') is placed in each glass vial, and then an appropriate amount of a solvent selected from ethyl acetate (EA) and 90% isopropyl alcohol (90% IPA) is added to the glass vial, and the mixture is 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 is added to each vial in an appropriate molar ratio (e.g., 5% molar excess). In the case of meglumine and Tris base, they are accurately weighed and mixed with the FT011 free form, and then the solvent is added to the mixture. The corresponding mixture is stirred at 50 ° C for 1 hour, then allowed to cool to room temperature (20-25 ° C) and kept stirring for 24-48 hours, after which the solid precipitate is separated by centrifugation. If there is no precipitation in the system, the clear solution is evaporated by blowing compressed air or nitrogen at room temperature. The obtained sample is dried under vacuum at 40 ° C overnight. 1 The dried samples were analyzed by H NMR, TGA, DSC and PLM. The detailed procedure of salt formation and its physical properties are summarized in Table 1.

[0624] Table 1: Experimental details of salt formation.

[0625]

[0626] Based on the experimental results, potassium hydroxide, meglumine, ethanolamine (MEA), tris(hydroxymethyl)aminomethane (Tris base), t-butylamine (TBA), ammonia, and lysine form crystalline solid salt forms of ( )-2-[[3-(3-methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid. Sodium hydroxide forms a solid salt form with low crystallinity, while L-arginine and choline do not form solid salt forms but rather oils.

[0627] A crystalline solid salt form of ( )-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). Example 3. Physico-chemical characterization of solid forms of (R)-2-[[3-(3- methoxy-4-propargyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid An X-ray powder diffraction pattern of a sample of crystalline Form I of the ethanolamine salt o...

Claims

1. A pharmaceutically acceptable salt of a compound of formula (I), Formula (I), or a solvate thereof, The pharmaceutically acceptable salt is selected from the group consisting of ethanolamine salt, tert-butylamine salt, potassium salt, meglumine salt, tris(hydroxymethyl)aminomethane salt, lysine salt and ammonium salt. 2 . The pharmaceutically acceptable salt or a 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 claim 2, wherein the pharmaceutically acceptable salt is an ethanolamine salt.

4. 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 solid form.

5. 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. The pharmaceutically acceptable salt or solvate thereof according to any one of the preceding claims, wherein the bioavailability of the pharmaceutically acceptable salt or solvate thereof is at least 39 F%, or 39 F% to 82 F%, or 50 F% to 82 F%, or 64 F% to 82 F%.

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

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

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

10. The pharmaceutically acceptable salt or solvate thereof according to any one of the preceding claims, which has one or more of the following properties: - Solubility in FaSSIF medium (pH 7.5) at 24 hours: 2.5 mg / ml to greater than 5.0 mg / ml; - Solubility in FeSSIF medium (pH 7.8) at 24 hours: 3.4 mg / ml to greater than 5.0 mg / ml; - Solubility in pH 6.8 medium at 24 hours ranges from 0.07 mg / ml to 0.090 mg / ml.

11. The 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 pharmaceutically acceptable salt or solvate thereof according to claim 11, wherein the pharmaceutically acceptable salt or solvate thereof has one or more of the following properties: - Bioavailability is 82 F; - water absorption of 0.49% at 25°C and 80% relative humidity, as determined by dynamic vapor sorption; - an endothermic onset temperature of 176°C as measured by differential scanning calorimetry; - a melting point of 178°C as measured by differential scanning calorimetry; - a weight loss of 0.10% 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 greater than 8.02 mg / ml in FeSSIF medium (pH 7.8) at 24 hours; - Solubility in pH 6.8 medium at 24 hours is 0.088 mg / ml.

13. The pharmaceutically acceptable salt or solvate thereof according to claim 11, wherein the crystalline form exhibits an X-ray powder diffraction pattern having at least one peak selected from the group consisting of 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° 2θ.

14. The pharmaceutically acceptable salt or solvate thereof according to claim 13, wherein the crystalline form exhibits an X-ray powder diffraction pattern having at least two, at least three, at least four, or at least five peaks selected from the group consisting of: 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° 2θ.

15. The pharmaceutically acceptable salt or solvate thereof according to claim 11, wherein the crystalline form is an ethanolamine salt of the compound of formula (I), and the crystalline form exhibits a single X-ray crystallography analysis having the following parameters: 16 . A pharmaceutical composition comprising the pharmaceutically acceptable salt or solvate thereof according to claim 1 and a pharmaceutically acceptable excipient.

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. A method for treating, preventing or ameliorating a fibrotic, inflammatory or proliferative disease or condition in a subject, the method 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 claim 17.

19. 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 claim 17, for preparing a medicament for treating, preventing or ameliorating a fibrotic, inflammatory or proliferative disease or condition in a subject.

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

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

24. The method of claim 18, the use of claim 19, or the pharmaceutically acceptable salt thereof or solvate or pharmaceutical composition for 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 kidney disease, glomerulonephritis, focal segmental glomerulosclerosis, systemic lupus, lupus nephritis, primary glomerulonephritis, membranous nephropathy, membranous proliferative glomerulonephritis, diffuse proliferative glomerulonephritis, membranous focal segmental glomerulosclerosis, secondary glomerulonephritis, membranous nephropathy, IgA nephropathy or ischemic nephropathy.

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

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

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

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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