Solid forms of n-1-(2-chloro-3-fluorophenyl)-1-hydroxypentan-2-yl)-7-fluoro-2-oxoindoline-4-carboxamide and methods of their preparation

Abstract

The present disclosure provides solid forms of N-(1-(2-chloro-3- fluorophenyl)-1-hydroxypentan-2-yl)-7-fluoro-2-oxoindoline-4- carboxamide of formula (1) and methods for the preparation thereof. Solid forms of N-(1-(2-chloro-3 -fluorophenyl)- 1 -hydroxypentan-2-yl) -7-fluoro-2-oxoindoline-4-carboxamide may be useful in the treatment of alpha-1-antitrypsin mediated diseases.

Description

SOLID FORMS OF N-l-(2-CHLORO-3-FLUOROPHENYL)-l-HYDROXYPENTAN-2- YL)-7-FLUORO-2-OXOINDOLINE-4-CARBOXAMIDE AND METHODS OF THEIR PREPARATION1. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of Indian Provisional Patent Application No.202341058423 filed August 31, 2023, the disclosure of which is incorporated by reference herein in its entirety.2. FIELD

[0002] The present disclosure relates generally to solid forms of N-(l-(2-chloro-3- fluorophenyl)-l-hydroxypentan-2-yl)-7-fluoro-2-oxoindoline-4-carboxamide and methods of its preparation. Such compounds may be useful in treating diseases, disorders, and conditions associated with alpha- 1 -antitrypsin.3. BACKGROUND

[0003] Alpha- 1 -antitrypsin or alantitrypsin (A1AT, sometimes referred to as AAT) is a protease inhibitor belonging to the serpin superfamily. It is a protein made in hepatocytes (as well as in other cells) and secreted into the blood where it functions to limit enzymatic activity of key proteases, in particular, neutrophil elastase. In its absence, the activity of key proteases including neutrophil elastase is unchecked resulting in excessive breakdown of elastin and connective tissues.

[0004] Alpha- 1 -antitrypsin or alantitrypsin deficiency (A1ATD, also referred to as AATD or AATLD) is an autosomal co-dominant genetic disorder usually caused by mutations in the SERPINA1 gene. Most severe cases of AATD are caused by homozygosity for the mutant Z allele (protease inhibitor [Pi] ZZ), in which a single amino acid substitution (E342K) produces a thermodynamically unstable protein. This unstable protein readily forms an unstable intermediate which in turn accepts the reactive center loop (RCL) of other Al AT proteins, forming large intracellular polymers. As a result, the mutated Z form of the Al AT protein (Z Al AT) is poorly secreted and a substantial reduction in the median plasma concentration of Al AT is observed . The organ most commonly affected by accumulation of Z-Al AT is the liver, where polymer accumulation can lead to fibrosis and other forms of liver damage. Polymers of Z-A1AT are also found in other tissues including blood, lungs, and skin. Polymers have been1SUBSTITUTE SHEET (RULE 26)shown to be pro-inflammatory and may contribute to pathology in tissues where they are found, particularly the lung and the skin.

[0005] Although N-(l-(2-chloro-3-fluorophenyl)-l-hydroxypentan-2-yl)-7-fluoro-2- oxoindoline-4-carboxamide (herein “Compound 1”) has been identified as potentially therapeutic in treating AlAT-associated liver disease (see, e.g., US20220340525A1), which is incorporated herein by reference in its entirety, pharmaceutical compositions of Compound 1 having satisfactory stability, bioavailability, workability, etc. are not available. The variety of possible solid forms creates potential diversity in physical and chemical properties for a given pharmaceutical compound. The discovery and selection of solid forms are of great importance in the development of an effective, stable, and marketable pharmaceutical product.4. SUMMARY

[0006] In one aspect, the present disclosure provides a solid form comprising Compound 1 or a pharmaceutically acceptable solvate thereof:

[0007] In one embodiment, the solid form is of Compound 1-A or its enantiomer (Compound 1-D), or a pharmaceutically acceptable solvate thereof:(1-D)

[0008] In one embodiment, the solid form is of Compound 1-A, or a pharmaceutically acceptable solvate thereof.

[0009] In one embodiment, the solid form of Compound 1-A or Compound 1-D is crystalline.

[0010] In one embodiment, the present disclosure provides Form A of Compound 1 -A, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least three peaks selected from the group consisting of approximately 9.2, 9.8, 10.2,16.4, 19.6, and 23.3 °20. In one embodiment, Form A is characterized by an XRPD pattern comprising at least four peaks selected from the group consisting of approximately 9.2, 9.8, 10.2,16.4, 19.6, and 23.3 °29. In one embodiment, Form A is characterized by an XRPD pattern comprising at least five peaks selected from the group consisting of approximately 9.2, 9.8, 10.2,16.4, 19.6, and 23.3 °29. In one embodiment, Form A is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises peaks at approximately 9.8 and 23.3 °29. In one embodiment, Form A is further characterized by an XRPD pattern comprising peaks at approximately 9.2 and 10.2 °29. In one embodiment, Form A of Compound 1-A is characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG. 1.

[0011] In one embodiment, the present disclosure provides Form B of Compound 1-A, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least three peaks selected from the group consisting of approximately 9.5, 12.0, 12.3, 14.6, 24.0, and 29.4 °29. In one embodiment, Form B is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least four peaks selected from the group consisting of approximately 9.5, 12.0, 12.3, 14.6, 24.0, and 29.4 °29. In one embodiment, Form B is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least five peaks selected from the group consisting of approximately 9.5, 12.0, 12.3, 14.6,24.0, and 29.4 °20. In one embodiment, Form B is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises peaks at approximately 9.5, 12.0, and 29.4 °20. In one embodiment, Form B is further characterized by an XRPD pattern comprising peaks at approximately 12.3 and 14.6 °29. In one embodiment, Form B is characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG. 2.

[0012] In one embodiment, the present disclosure provides Form C of Compound 1-A, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least three peaks selected from the group consisting of approximately 11.7, 12.5, 14.0, 22.2, 23.1,23.5, and 28.2 °20. In one embodiment, Form C is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at four peaks selected from the group consisting of approximately 11.7, 12.5, 14.0, 22.2, 23.1, 23.5, and 28.2 °20. In one embodiment, Form C is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least five peaks selected from the group consisting of approximately 11.7, 12.5, 14.0, 22.2, 23.1, 23.5, and 28.2 °20. In one embodiment, Form C is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises peaks at approximately 14.0,23.1, and 28.2 °20. In one embodiment, Form C is further characterized by an XRPD pattern comprising peaks at approximately 11.7 and 12.5 °20. In one embodiment, Form C exhibits, as characterized by DSC, a thermal event with an onset temperature of about 151 °C to about 156 °C. In one embodiment, Form C exhibits a weight loss of about 1.9% to about 2.7% upon heating from about 30°C to about 144 °C. In one embodiment, Form C is characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG. 3.

[0013] In one embodiment, the present disclosure provides Form D of Compound 1-A, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least three peaks selected from the group consisting of approximately 9.4, 10.4,16.2, 19.6, 22.2, and 24.5 °20. In one embodiment, Form D is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least four peaks selected from the group consisting of approximately 9.4, 10.4, 16.2, 19.6, 22.2, and 24.5 °20. In one embodiment, Form D is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least five peaks selected from the group consisting of approximately 9.4, 10.4, 16.2,19.6, 22.2, and 24.5 °20. In one embodiment, Form D is characterized by an XRPD pattern,which when measured using Cu Ko, radiation, comprises peaks at approximately 10.4, 19.6, and 22.2 °20. In one embodiment, Form D is further characterized by an XRPD pattern comprising peaks at approximately 9.4 and 24.5 °29. In one embodiment, Form D exhibits, as characterized by DSC, a thermal event with an onset temperature of about 182.5 °C. In one embodiment, Form D exhibits a weight loss of about 0.29% upon heating from about 30 °C to about 122 °C. In one embodiment, Form D is characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG. 6.

[0014] In one embodiment, the present disclosure provides Form I of Compound 1-A, which is amorphous. In one embodiment, Form J is characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG. 19.

[0015] In one embodiment, the present disclosure provides Form L of Compound 1-A, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least three peaks selected from the group consisting of approximately 8.7, 10.5, 16.5, 18.0, 19.1, and 22.9 °29. In one embodiment, Form L is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least four peaks selected from the group consisting of approximately 8.7, 10.5, 16.5, 18.0, 19.1, and 22.9 °20. In one embodiment, Form L is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least five peaks selected from the group consisting of approximately 8.7, 10.5, 16.5, 18.0, 19.1, and 22.9 °29. In one embodiment, Form L is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises peaks at approximately 8.7, 19.5, and 18.0 °29. In one embodiment, Form L is further characterized by an XRPD pattern comprising peaks at approximately 19.1 and 22.9 °29.

[0016] In one embodiment, the present disclosure provides Form M of Compound 1-A, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least three peaks selected from the group consisting of approximately 8.7, 9.4, 16.0, 18.0, 22.9, 23.0, and 26.3 °29. In one embodiment, Form M is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least four peaks selected from the group consisting of approximately 8.7, 9.4, 16.0, 18.0, 22.9, 23.0, and 26.3 °29. In one embodiment, Form M is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least five peaks selected from the group consisting of approximately 8.7,9.4, 16.0, 18.0, 22.9, 23.0, and 26.3 °20. In one embodiment, Form M is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises peaks at approximately8.7, 9.4, and 16.0 °29. In one embodiment, Form M is further characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises peaks at approximately 18.0 and23.0 °29.

[0017] In one embodiment, the present disclosure provides Form N of Compound 1-A, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least three peaks selected from the group consisting of approximately 11.2, 12.9,13.7, 22.2, 23.7, and 27.8 °29. In one embodiment, Form N is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least four peaks selected from the group consisting of approximately 11.2, 12.9, 13.7, 22.2, 23.7, and 27.8 °29. In one embodiment, Form N is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least five peaks selected from the group consisting of approximately 11.2, 12.9,13.7, 22.2, 23.7, and 27.8 °29. In one embodiment, Form N is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises peaks at approximately 11.2, 12.9, and 13.7 °29. In one embodiment, Form N is further characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprising peaks at approximately 7.2 and 23.7 °29.

[0018] In another aspect, the present disclosure provides a pharmaceutical composition comprising one or more of solid forms A, B, C, D, J, L, M, or N of Compound 1-A and a pharmaceutically acceptable excipient. In one embodiment, the pharmaceutical composition is formulated as a solid formulation. In one embodiment, the formulation is suitable for oral administration. In one embodiment, the formulation is a tablet or a capsule.

[0019] In another aspect, the present disclosure provides a method of treating a patient having a disease or disorder related to the polymerization of alpha- 1 antitrypsin comprising administering to the patient one or more of solid forms A, B, C, D, J, L, M, or N of Compound 1- A, a pharmaceutical composition comprising one or more of solid forms A, B, C, D, J, L, M, or N of Compound 1-A and a pharmaceutically acceptable excipient. In one embodiment, the pharmaceutical composition is in the form or a tablet or a capsule comprising one or more of solid forms A, B, C, D, J, L, M, or N of Compound 1-A and a pharmaceutically acceptable excipient. In one embodiment, the disease or disorder related to the polymerization of alpha- 1antitrypsin is a serpinopathy. In one embodiment, the disease or disorder related to the polymerization of alpha-1 antitrypsin is associated with a Z-AT mutation of alpha-1 antitrypsin. In one embodiment, the disease or disorder related to the polymerization of alpha- 1 antitrypsin is selected from the group consisting of alpha-1 antitrypsin deficiency, liver dysfunction, fibrosis, cirrhosis, liver failure, hepatocellular carcinoma, liver cirrhosis, autoimmune hepatitis, jaundice, inflammatory conditions of the skin, dermatitis, and pruritus.

[0020] In another aspect, the present disclosure provides a method of making Form A comprising heating solid Form N to a temperature of about 165 °C.

[0021] In another aspect, the present disclosure provides a method of making Form A, comprising drying solid Form M under ambient conditions.

[0022] In another aspect, the present disclosure provides a method of making Form B comprising contacting solid Form D with di chloromethane to make a mixture and evaporating the dichloromethane from the mixture.

[0023] In another aspect, the present disclosure provides a method of making Form C comprising contacting solid Form D with a mixture of 80:20 ethanol in water at room temperature.

[0024] In another aspect, the present disclosure provides a method of making Form C comprising subjecting solid Form N to ambient conditions.

[0025] In another aspect, the present disclosure provides a method of making Form C comprising contacting amorphous Compound 1-A to a mixture of acetone in water, wherein the mixture has an Awof about 0.26, at a temperature of about 5 °C to about 50 °C.

[0026] In another aspect, the present disclosure provides a method of making Form D comprising contacting solid Form B with isopropyl alcohol at a temperature of about 20 °C to about 50 °C.

[0027] In another aspect, the present disclosure provides a method of making Form D comprising drying solid Form M at a temperature of at least 60 °C under vacuum.

[0028] In another aspect, the present disclosure provides a method of making Form D comprising drying solid Form L at room temperature.

[0029] In another aspect, the present disclosure provides a method of making Form D comprising contacting amorphous Compound 1-A with acetone at a temperature of about 50 °C.

[0030] In another aspect, the present disclosure provides a method of making amorphous Compound 1-A comprising lyophilizing a slurry of the solid Form D in t-butyl alcohol.

[0031] In another aspect, the present disclosure provides a method of making Form L comprising contacting solid Form D with a mixture of methanol in water, wherein the mixture has a water activity Awof about 0.64, and wherein the ratio of methanol to water is about 69:31.

[0032] In another aspect, the present disclosure provides a method of making Form M comprising contacting solid Form C with a mixture of ethanol in water, wherein the mixture has a water activity Aw of about 0.65, and wherein the ratio of ethanol to water is about 80:20.

[0033] In another aspect, the present disclosure provides a method of making Form N comprising heating the solid Form C to a temperature of about 120 °C to about 140 °C under vacuum.

[0034] In another aspect, the present disclosure provides a method of making a pharmaceutical composition comprising combining one or more of solid forms A, B, C, D, J, L, M, or N with a pharmaceutically acceptable excipient.5. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] FIG. 1 is a representative X-ray powder diffraction (XRPD) pattern of Form A of Compound 1-A.

[0036] FIG. 2 is a representative XRPD pattern of Form B of Compound 1-A.

[0037] FIG. 3 is a representative XRPD pattern of Form C of Compound 1-A.

[0038] FIG. 4 is a representative thermogravimetric analysis (TGA) thermogram for Form C of Compound 1-A.

[0039] FIG. 5 is a representative differential scanning calorimetry (DSC) thermogram for Form C of Compound 1-A.

[0040] FIG. 6 is a representative XRPD pattern of Form D of Compound 1-A.

[0041] FIG. 7 is a representative TGA thermogram for Form D of Compound 1-A.

[0042] FIG. 8 is a representative DSC thermogram for Form D of Compound 1-A.

[0043] FIG. 9 is a representative XRPD pattern of Form E of Compound 1-A.

[0044] FIG. 10 is a representative TGA thermogram for Form E of Compound 1-A.

[0045] FIG. 11 is a representative DSC thermogram for Form E of Compound 1-A.

[0046] FIG. 12 is a representative XRPD pattern of Form G of Compound 1-A.

[0047] FIG. 13 is a representative TGA thermogram for Form G of Compound 1-A.

[0048] FIG. 14 is a representative DSC thermogram for Form G of Compound 1-A.

[0049] FIG. 15 is a representative XRPD pattern of Form H of Compound 1-A.

[0050] FIG. 16 is a representative TGA thermogram for Form H of Compound 1-A.

[0051] FIG. 17 is a representative DSC thermogram for Form H of Compound 1-A.

[0052] FIG. 18 is a representative XRPD pattern of Form I of Compound 1-A.

[0053] FIG. 19 is a representative XRPD pattern of Form J of Compound 1-A.

[0054] FIG. 20 is a representative TGA thermogram for Form J of Compound 1-A.

[0055] FIG. 21 is a representative DSC thermogram (top trace) for Form J of Compound 1 -A.

[0056] FIG. 22 is a representative XRPD pattern of Form L of Compound 1-A.

[0057] FIG. 23 is a representative XRPD pattern of Form M of Compound 1-A.

[0058] FIG. 24 is a representative XRPD pattern of Form N of Compound 1-A.

[0059] FIG. 25 is a diagram depicting the relationship between the various solid forms ofCompound 1-A.

[0060] FIG. 26 depicts representative XRPD patterns of (top) Form C of Compound 1-A, (middle) a mixture of Form C and Form N of Compound 1-A, and (bottom) Form N of Compound 1-A.

[0061] FIG. 27 depicts representative XRPD patterns of (top) Form K of Compound 1-A and (bottom) Form G of Compound 1-A.

[0062] FIG. 28 depicts representative XRPD patterns for each of (A) starting material Form C of Compound 1-A, (B) starting material Form D of Compound 1-A, a mixture of Form C and Form O of Compound 1-A in acetone, (D) 98.7:1.3 acetone / water (F), or 94.2:5.8 acetone / water (H), and Form C of Compound 1-A formed in 80:20 acetone / water (C) or upon drying (E, G, I, J).

[0063] FIG. 29 depicts representative XRPD patterns for each of (A) Form D of Compound 1-A, (B) Form A of Compound 1-A, (C) Form P of Compound 1-A, and (D) a mixture of Form P and Form A of Compound 1-A.

[0064] FIG. 30 depicts representative XRPD patterns of (A) Form A of Compound 1-A, (B) Form D of Compound 1-A, (C) a mixture of Forms Q, A, and D of Compound 1-A generatedafter drying at 40 °C under vacuum, (D-F) a mixture of Forms Q, A, and D of Compound 1 -A generated after drying under ambient conditions, (G) a mixture of Forms Q, A, and D of Compound 1-A generated under wet conditions.

[0065] FIG. 31 depicts representative XRPD patterns for (A) Form D of Compound 1-A, (B) Form R of Compound 1-A after 20 hours (C) Form R of Compound 1-A after 88 hours, (D) a mixture of Forms T and D of Compound 1-A after slurrying for 88 hours then drying under vacuum, and (E) a mixture of Forms S and D of Compound 1-A after slurrying for 116 hours.

[0066] FIG. 32 depicts representative XRPD patterns for (A) Form D of Compound 1-A, (B) Form S of Compound 1-A slurrying in isopropanol (IPA) / heptane for 20 hours and (C) Form S of Compound 1-A slurrying in IPA / heptane for 88 hours, (D) a mixture of Forms T and D of Compound 1-A after slurrying for 88 hours then drying under vacuum, and (E) a mixture of Forms S and D of Compound 1-A after slurrying for 116 hours.6. DETAILED DESCRIPTION6.1 Definitions

[0067] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art of the present disclosure. As used herein, the following terms have the meanings ascribed to them below, unless specified otherwise.

[0068] In some embodiments, chemical structures are disclosed with a corresponding chemical name. In case of conflict, the chemical structure controls the meaning, rather than the name.

[0069] Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive. Unless specifically stated or obvious from context otherwise, as used herein, the terms “a”, “an”, and “the” are understood to be singular or plural.

[0070] “Crystalline,” as used herein, refers to a homogeneous solid formed by a repeating, three-dimensional pattern of atoms, ions or molecules having fixed distances between constituent parts. The unit cell is the simplest repeating unit in this pattern. Notwithstanding the homogenous nature of an ideal crystal, a perfect crystal rarely, if ever, exists. “Crystalline,” as used herein, encompasses crystalline forms that include crystalline defects, for example, crystalline defects commonly formed by manipulating (e.g., preparing, purifying) the crystalline forms describedherein. A person skilled in the art is capable of determining whether a sample of a compound is crystalline notwithstanding the presence of such defects. Crystalline forms can be characterized by analytical methods such as x-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance spectroscopy (NMR), single crystal x-ray diffraction, Raman spectroscopy, Fourier transform infrared spectroscopy (FTIR) and / or any other suitable analytical techniques. In particular, crystalline forms of a solid can be distinguished from non-crystalline forms by the presence of sharp, distinct peaks in the XRPD patterns of crystalline forms.

[0071] As used herein, the term “substantially pure” with respect to any solid form, e.g., a single crystalline form as disclosed herein e.g., Form A, B, C, D, G, H, I, K, L, M, orN), means no detectable amount of another crystalline form as determined by observing no detectable significant differences in an XRPD and / or DSC pattern between the single crystalline form and a crystalline composition of Compound 1. However, a “substantially pure” solid form can include impurities, such as, but not limited to, synthetic reactants or by-products generated during the chemical synthesis.

[0072] As used herein “solvate” refers to a crystalline form of a molecule, atom, and / or ions that further comprises molecules of a solvent or solvents incorporated into the crystalline lattice structure. The solvent molecules in the solvate may be present in a regular arrangement and / or a non-ordered arrangement. The solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules. For example, a solvate with a nonstoichiometric number of solvent molecules may result from partial loss of solvent from the solvate. Solvates may occur as dimers or oligomers comprising more than one molecule or compound within the crystalline lattice structure.

[0073] As used herein “amorphous” refers to a solid form of a molecule, atom, and / or ions that is not crystalline. In particular, the term “amorphous form” describes a disordered solid form, i.e., a solid form lacking long range crystalline order. An amorphous solid does not display distinctive sharp peaks in its XRPD pattern.

[0074] As used herein and unless otherwise specified, the term “solid form” and related terms refer to a physical form, which includes crystalline forms, amorphous forms, and mixtures thereof. As used herein and unless otherwise specified, the term “crystal forms” and relatedterms refer to solid forms that are crystalline. Crystal forms include, but are not limited to, nonsolvates, non-hydrates, solvates, hydrates, and other molecular complexes, as well as salts, solvates of salts, hydrates of salts, and other molecular complexes of salts thereof. In certain embodiments, a solid form or crystal form of a substance may be substantially free of amorphous forms and / or other solid forms and / or crystal forms.

[0075] Solid forms may exhibit distinct physical characterization data that are unique to a particular solid form, such as the crystal forms described herein. These characterization data may be obtained by various techniques known to those skilled in the art. The data provided by these techniques may be used to identify a particular solid form. For example, an XRPD pattern, DSC thermogram or TGA thermal curve that “matches” or, interchangeably, is “substantially in accordance” with one or more figures herein showing an XRPD pattern or DSC thermogram or TGA thermal curve, respectively, is one that would be considered by one skilled in the art to represent the same single crystalline form of the compound as the sample of the compound that provided the pattern or thermogram or thermal curve of one or more figures provided herein. Thus, an XRPD pattern or DSC thermogram or TGA thermal curve that matches or is substantially in accordance may be identical to that of one of the figures or, more likely, may be somewhat different from one or more of the figures. For example, an XRPD pattern that is somewhat different from one or more of the figures may not necessarily show each of the lines of the diffraction pattern presented herein and / or may show a slight change in appearance or intensity of the lines or a shift in the position of the lines. These differences typically result from differences in the conditions involved in obtaining the data or differences in the purity of the sample used to obtain the data. A person skilled in the art is capable of determining if a sample of a crystalline compound is of the same form as or a different form from a form disclosed herein by comparison of the XRPD pattern or DSC thermogram or TGA thermal curve of the sample and the corresponding XRPD pattern or DSC thermogram or TGA thermal curve disclosed herein.

[0076] The term “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commerciallyrelevant mammals such as cattle, pigs, horses, sheep, goats, cats, rats, mice, and / or dogs; and / or birds, including commercially relevant birds such as chickens, ducks, geese, quails, and / or turkeys. In certain embodiments, the subject is a human. As used herein and unless otherwise specified, a human subject to which administration of a therapeutic (e.g, a compound as described herein) is contemplated in order to treat, prevent, or manage a disease, disorder, or condition, or symptoms thereof, is also called a “patient.”

[0077] As used herein and unless otherwise specified, the terms “treatment” and “treating” refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease, disorder, or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. In one embodiment, “treatment” comprises administration of a therapeutic after manifestation of the unwanted condition (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof). In some particular embodiments, “treatment” can mean reducing rate at which Al AT polymers accumulate in the liver, or preferably halting the accumulation of A1AT polymers in the liver, or more preferably reducing the amount of A1AT polymers in the liver (“amount” in this context is usually measured as a concentration but might also refer to weight.) In some particular embodiments, “treatment” can mean increasing the secretion of Al AT from the liver, usually as measured by an increase in the concentration of A1AT outside of the liver.

[0078] An “effective amount,” as used herein, refers to an amount that is sufficient to achieve a desired biological effect. A “therapeutically effective amount,” as used herein, refers to an amount that is sufficient to achieve a desired therapeutic effect. In some particular embodiments, “effective amount” can mean an amount effective for reducing rate at which A1AT polymers accumulate in the liver, or preferably effective for halting the accumulation of A1AT polymers in the liver, or more preferably effective for reducing the amount of Al AT polymers in the liver (“amount” in this context is usually measured as a concentration but might also refer to weight.) In some particular embodiments, “effective amount” can mean an amounteffective for increasing the secretion of Al AT from the liver, usually as measured by an increase in the concentration of A1AT outside of the liver, and particularly in the plasma.

[0079] As used herein, and unless otherwise specified, the terms “about” and “approximately,” when used in connection with doses, amounts, or weight percent of ingredients of a composition or a dosage form, mean a dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent. In certain embodiments, the terms “about” and “approximately,” when used in this context, contemplate a dose, amount, or weight percent within 30%, within 20%, within 15%, within 10%, or within 5%, of the specified dose, amount, or weight percent.

[0080] As used herein and unless otherwise specified, the terms “about” and “approximately,” when used in connection with a numeric value or a range of values which is provided to characterize a particular solid form, e.g., a specific temperature or temperature range, such as, for example, that describing a melting, dehydration, desolvation or glass transition temperature; a mass change, such as, for example, a mass change as a function of temperature or humidity; a solvent or water content, in terms of, for example, mass or a percentage; indicate that the value or range of values may deviate to an extent deemed reasonable to one of ordinary skill in the art while still describing the particular solid form. For example, in particular embodiments, the terms “about” and “approximately,” when used in this context, indicate that the numeric value or range of values may vary within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the recited value or range of values.

[0081] Analytical Methods

[0082] Solid forms may exhibit distinct physical characterization data that are unique to a particular solid form, such as the crystal and amorphous forms described herein. These characterization data may be obtained by various techniques known to those skilled in the art, including for example, X-Ray Powder Diffraction (XRPD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). The data obtained by analyzing a sample of a solid via these techniques may be used to identify a particular solid form, because different solid forms, such as different crystal forms, will provide different diffraction patterns when analyzed by XRPD, and in many cases will also provide different results when analyzed by DSC or TGA.One skilled in the art appreciates that these analyses are subject to experimental error, and that, when comparing, for example, two XRPD patterns, the patterns can be assigned to the same solid form even if one or more, and in some cases all, of the peaks in the pattern vary within the experimental error. Thus, as an example, values of degrees 20 derived from XRPD, even when presented as exact numbers, should therefore be understood as encompassing those deviations from the presented values that would be considered to be within experimental error. In some embodiments, the value of XRPD peak position may vary by up to ± 0.5 degrees 20 while still describing the particular XRPD peak, due to, for example, experimental error. In some embodiments, the value of XRPD peak position may vary by up to ± 0.2 degrees 20 while still describing the particular XRPD peak due to, for example, experimental error. In some embodiments, the value of XRPD peak position may vary by up to ± 0.1 degrees 20 due to, for example, experimental error. In some embodiment, the value of XRPD peak position may vary by up to ± 0.05 degrees 20 due to, for example, experimental error.

[0083] Unless otherwise indicated the following methods were used to characterize the various solid forms disclosed herein.

[0084] X-Ray Powder Diffraction (XRPD) analyses were performed by two different methods as follows:(1) Using a Panalytical Empyrean diffractometer equipped with a Cu X-ray tube and a PIXcel 1D-Medipix3 detector system. The samples were analyzed at ambient temperature in transmission mode and held between low density PVC films. Samples were analyzed at a scan range of 4-40 °20, step size 0.01313°, counting time 23 sec, about 5 min run time. Samples were spun at 60 rpm during data collection. XRPD patterns were sorted and manipulated using HighScore Plus v4.9 software. Unless otherwise indicated, this method (1) was used to obtain XRPD diffractograms.(2) Using a Rigaku MiniFlex X-Ray diffractometer equipped with Cu X-ray tube and a HyPix-400 MF 2D hybrid pixel array detector. Enough de-lump sample powder (for slurry samples few drops of semi-solid) was taken in a standard sample holder and made surface smooth using glass slide. The sample holder was placed in holder cabin on the goniometer and analyzed in the scan range of 3-40 °20 in continuous scan mode. X-ray diffraction patterns were processed and marked the peak positions.

[0085] Variable Temperature X-Ray Powder Diffraction (VT-XRPD) analyses, unless indicated otherwise, were performed using Panalytical Aeris benchtop XRPD using an Anton Paar BTS 500 hot stage. The sample was analyzed in reflection mode. Diffractograms of the samples were typically collected at a set temperature selected from DSC or TG / DTA thermograms (scan range 3-40 °29, step size 0.011°, counting time 19 sec, about 5 min run time). XRPD diffractograms were processed using HighScore Plus v4.9 software.

[0086] Differential Scanning Calorimetry (DSC) analyses, unless indicated otherwise, were carried out on a Perkin Elmer Jade Differential Scanning Calorimeter. Accurately weighed samples were placed in crimped aluminum pans (i.e., closed but not gas tight). Each sample was heated under nitrogen at a rate of 10 °C / minute to a maximum of 200 °C. Indium metal was used as the calibration standard. Temperatures were reported at the transition onset to the nearest 0.01 degree.

[0087] Thermogravimetric Analyses (TGA), unless indicated otherwise, were carried out on a Mettler Toledo TGA / DSC1 STARe. The calibration standards were indium and tin.Samples were placed in an aluminum sample pan, accurately weighed, and inserted into the TG furnace. Under a stream of nitrogen at a rate of 10 °C / minute, the heat flow signal was stabilized for one minute at 30 °C, prior to heating to 300 °C.

[0088] The disclosure can be understood more fully by reference to the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments.6.2 Solid Forms of Compound 1

[0089] Solids forms of N-[(lR)-l-[(S)-(2-chloro-3-fluorophenyl)hydroxymethyl]butyl]-7- fluoro-2,3-dihydro-2-oxo-lH-indole-4-carboxamide disclosed herein include crystalline solids and amorphous solids. Solid forms may be crystalline, amorphous, or mixtures of crystalline and amorphous forms. The crystal forms described herein, therefore, may have varying degrees of crystallinity or lattice order. The solid forms described herein are not limited to any particular degree of crystallinity or lattice order and may be 0 - 100% crystalline. Methods of determining the degree of crystallinity are known to those of ordinary skill in the art, such as those described in Suryanarayanan, R., X-Ray Powder Diffractometry, Physical Characterization of Pharmaceutical Solids, H.G. Brittain, Editor, Marcel Dekker, Murray Hill, NJ., 1995, pp. 187 -199, which is incorporated herein by reference in its entirety. In some embodiments, the solid forms described herein are about 0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% crystalline.

[0090] The solid forms provided herein may be used as active pharmaceutical ingredients in the preparation of formulations for use in animals or humans. Thus, embodiments herein encompass the use of these solid forms as a final drug product.

[0091] In one aspect, the present disclosure provides a solid form of N-(l-(2-chloro-3- fIuorophenyl)-l-hydroxypentan-2-yl)-7-fluoro-2-oxoindoline-4-carboxamide (Compound 1) or a pharmaceutically acceptable solvate thereof:

[0092] It is contemplated that Compound 1, or a stereoisomer, or a mixture of stereoisomers thereof can exist in a variety of solid forms. In one embodiment, the solid form comprising Compound 1 can be a crystalline form, a partially crystalline form, or a mixture of crystalline form(s), or amorphous form(s). In one embodiment, provided herein is a solid form comprising a crystalline form of Compound 1.

[0093] In one embodiment, the solid form comprises a solvate of Compound 1. In some embodiments, the molar ratio of Compound 1 to the solvent in the solid form ranges from about 20: 1 to about 1 :20. In some embodiments, the molar ratio of Compound 1 to the solvent in the solid form ranges from about 10: 1 to about 1 : 10. In some embodiments, the molar ratio of Compound 1 to the solvent in the solid form ranges from about 5: 1 to about 1 :5. In some embodiments, the molar ratio of Compound 1 to the solvent in the solid form ranges from about 3: 1 to about 1 :3. In some embodiments, the molar ratio of Compound 1 to the solvent in the solid form ranges from about 2: 1 to about 1 :2. In one embodiment, the molar ratio is about 1 :2 (i.e., bis-solvate). In another embodiment, the molar ratio is about 1 : 1 (i.e., mono-solvate). In yet another embodiment, the molar ratio is about 2:1 i.e., hemi-solvate).

[0094] In another embodiment, the solid form is an amorphous form.

[0095] In one embodiment, the solid form is substantially pure.

[0096] Compound 1 is described in international patent application No.PCT / GB2019 / 051761, the entirety of which is incorporated herein by reference.

[0097] Compound 1 has two chiral centers. Therefore, in one embodiment, Compound 1 is Compound 1-A, 1-B, 1-C, or 1-D:1-C 1-D

[0098] As will be discussed herein, the various solid forms of Compound 1 may be characterized by, inter alia, x-ray powder diffraction (XRPD). XRPD is an achiral technique and as such, a compound and its enantiomer will display the same XRPD pattern. Though XRPD patterns are described with respect to Compound 1-A (the S,R enantiomer) herein, the same XRPD peaks may also be used to describe Compound 1-D (the R,S enantiomer) or a mixture of Compound 1-A and Compound 1-D. This is the case because XRPD is not a chiral method, and is therefore incapable of differentiating between enantiomers such as Compound 1-A and Compound 1-D. Furthermore, in most cases XRPD cannot differentiate between diastereomers of the same compound. Thus, the XRPD peaks described below with respect to Compound 1-A may also be used to describe Compound 1 generally.6.3.1 Solid forms of Compound 1-A

[0099] In one aspect, provided herein is a solid form comprising N-[(lR)-l-[(S)-(2-chloro-3- fluorophenyl)hydroxymethyl]butyl]-7-fluoro-2,3-dihydro-2-oxo-lH-indole-4-carboxamide(Compound 1-A), which is the 1S,2R stereoisomer of Compound 1 :(1-A)

[0100] In one embodiment, provided herein is a solid form comprising an anhydrous Compound 1-A. In one embodiment, provided herein is a solid form comprising a solvate of Compound 1-A. In one embodiment, provided herein is a solid form comprising a methanol, ethanol, acetonitrile, MTBE, 2-MeTHF, or acetone solvate of Compound 1-A. In one embodiment, provided herein is a solid form comprising a hydrate or a hemihydrate of Compound 1-A.6.2.1.1 Form A of Compound 1-A

[0101] In one embodiment, provided herein is Form A of Compound 1-A.

[0102] A representative XRPD pattern of Form A of Compound 1-A is provided in FIG. 1.

[0103] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or all of the XRPD peaks located at approximately the following positions (e.g, degrees(°) 20 ± 0.2) when measured using Cu Ka radiation: 6.3, 9.2, 9.8, 10.2, 13.8, 14.5, 16.0, 16.4, 17.4, 18.3, 19.0, 19.6, 20.4, 20.9, 22.1, 22.7, 23.3, 23.6, 24.4, 25.0, 26.1, 26.7, 27.9, 29.2, 30.9, 31.5, 32.0, 33.1, 33.9, 37.9, and 38.6 °20. In one embodiment, the solid form is characterized by at least 3 of the peaks. In one embodiment, the solid form is characterized by at least 5 of the peaks. In one embodiment, the solid form is characterized by at least 7 of the peaks. In one embodiment, the solid form is characterized by at least 9 of the peaks. In one embodiment, the solid form is characterized by at least 11 of the peaks. In one embodiment, the solid form is characterized by at least 13 of the peaks. In one embodiment, the solid form ischaracterized by at least 15 of the peaks. Tn one embodiment, the solid form is characterized by at least 20 of the peaks. In one embodiment, the solid form is characterized by all of the peaks.

[0104] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least three peaks selected from the group consisting of approximately (e.g., ± 0.2 °) 9.2, 9.8, 10.2, 16.4, 19.6, and 23.3 °29. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least four peaks selected from the group consisting of approximately (e.g., ± 0.2 °) 9.2, 9.8, 10.2, 16.4, 19.6, and 23.3 °20. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least five peaks selected from the group consisting of approximately (e.g., ± 0.2 °) 9.2, 9.8, 10.2, 16.4, 19.6, and 23.3 °20.

[0105] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern comprising peaks at approximately (e.g., ± 0.2 °) 9.8, 19.6, and 23.6 °20. In one embodiment, the XRPD pattern further comprises peaks at approximately (e.g., ± 0.2 °) 9.2 and 10.2 °20. In one embodiment, the XRPD pattern comprises peaks at approximately (e.g., ± 0.2 °) 9.2, 9.8, 10.2, 16.4, 19.6, and 23.3 °20.

[0106] In one embodiment, provided herein is a solid form comprising Compound 1, characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG. 1.

[0107] It is believed that Form A of Compound 1-A is anhydrous or substantially anhydrous. As used herein, “substantially anhydrous” refers to less than 0.6% water content.

[0108] In one embodiment, the solid form comprising Compound 1-A is a crystalline anhydrate (Form A) of Compound 1-A. In some embodiments, the solid form is substantially free of amorphous Compound 1-A. In some embodiments, the solid form is substantially free of other solid forms (e.g., another crystalline form) of Compound 1-A. In some embodiments, the solid form is provided as substantially pure.

[0109] In one embodiment, provided herein is a solid form comprising Form A of Compound 1-A and amorphous Compound 1-A. In one embodiment, provided herein is a solid form comprising Form A of Compound 1-A and one or more other crystalline forms of Compound 1- A provided herein.

[0110] All of the combinations of the above embodiments are encompassed by this application.6.2.1.2 Form B of Compound 1-A

[0111] In one embodiment, provided herein is Form B of Compound 1-A.

[0112] A representative XRPD pattern of Form B of Compound 1-A is provided in FIG. 2.

[0113] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or all of the XRPD peaks located at approximately the following positions (e.g, degrees(°) 20 ± 0.2) when measured using Cu Ka radiation: 9.5, 9.7, 11.8, 12.0, 12.3, 14.0, 14.3, 14.4, 14.6, 15.0, 16.1, 16.3, 17.4, 17.6, 19.1, 20.5, 21.2, 21.6, 22.8, 23.1, 23.5, 23.7, 24.0,24.2, 24.5, 24.8, 25.3, 29.4, 30.3, and 31.0 °29. In one embodiment, the solid form is characterized by at least 3 of the peaks. In one embodiment, the solid form is characterized by at least 5 of the peaks. In one embodiment, the solid form is characterized by at least 7 of the peaks. In one embodiment, the solid form is characterized by at least 9 of the peaks. In one embodiment, the solid form is characterized by at least 11 of the peaks. In one embodiment, the solid form is characterized by at least 13 of the peaks. In one embodiment, the solid form is characterized by at least 15 of the peaks. In one embodiment, the solid form is characterized by at least 20 of the peaks. In one embodiment, the solid form is characterized by all of the peaks.

[0114] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least three peaks selected from the group consisting of approximately (e.g., ± 0.2 °) 9.5, 12.0,12.3, 14.6, 24.0, and 29.4 °20. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least four peaks selected from the group consisting of approximately (e.g., ± 0.2 °) 9.5, 12.0, 12.3, 14.6, 24.0, and 29.4 °29. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least five peaks selected from the group consisting of approximately (e.g., ± 0.2 °) 9.5, 12.0, 12.3, 14.6, 24.0, and 29.4 °20.

[0115] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern comprising peaks at approximately (e.g., ± 0.2 °) 9.5, 12.0, and 29.4 °29. In one embodiment, the XRPD pattern further comprises peaks at approximately (e.g., ± 0.2 °) 12.3 and 14.6 °20. In one embodiment, the XRPD pattern comprises peaks at approximately (e.g., ± 0.2 °) 9.5, 12.0, 12.3, 14.6, 24.0, and 29.4 °20.

[0116] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG. 2.

[0117] It is believed that Form B of Compound 1-A is anhydrous or substantially anhydrous.

[0118] In one embodiment, the solid form comprising Compound 1-A is a crystalline anhydrate (Form B) of Compound 1-A. In some embodiments, the solid form is substantially free of amorphous Compound 1-A. In some embodiments, the solid form is substantially free of other solid forms (e.g., another crystalline form) of Compound 1-A. In some embodiments, the solid form is provided as substantially pure. In one embodiment, provided herein is a solid form comprising Form B of Compound 1-A and amorphous Compound 1-A. In one embodiment, provided herein is a solid form comprising Form B Compound 1-A and one or more other crystalline forms of Compound 1-A provided herein.

[0119] All of the combinations of the above embodiments are encompassed by this application.6.2.1.3 Form C of Compound 1-A

[0120] In one embodiment, provided herein is Form C of Compound 1-A.

[0121] A representative XRPD pattern of Form C of Compound 1-A is provided in FIG. 3.

[0122] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 228, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 or all of the XRPD peaks located at approximately the following positions e.g., degrees(°) 20 ± 0.2) when measured using Cu Ka radiation: 9.9, 11.7, 12.5, 14.0, 15.6, 16.3, 16.6, 17.7, 19.8, 20.8, 21.5, 22.2, 22.7, 23.1, 23.5, 23.9, 24.2, 24.5, 25.2, 25.4, 26.7, 27.5, 28.2, 29.1, 29.3, 29.8, 30.0, 30.3, 31.3, 31.6, 32.1, 32.8, 33.0, 33.6, 34.1, 35.6, 36.0, 36.3, 36.8, 37.2, and 37.6 °20. In one embodiment, the solid form is characterized by at least 3 of the peaks. In one embodiment, the solid form is characterized by at least 5 of the peaks. In one embodiment, the solid form is characterized by at least 7 of the peaks. In one embodiment, the solid form is characterized by at least 9 of the peaks. In one embodiment, the solid form is characterized by at least 11 of the peaks. In one embodiment, the solid form is characterized by at least 13 of the peaks. In one embodiment, the solid form is characterized by at least 15 of the peaks. In one embodiment, the solid form is characterized by at least 20 of the peaks. In one embodiment, the solid form is characterized by all of the peaks.

[0123] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least three peaks selected from the group consisting of approximately (e.g., ± 0.2 °) 11.7, 12.5, 14.0, 22.2, 23.1, 23.5, and 28.2 °20. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least four peaks selected from the group consisting of approximately (e.g., ± 0.2 °) 11.7, 12.5, 14.0, 22.2, 23.1, 23.5, and 28.2 °20. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least five peaks selected from the group consisting of approximately (e.g., ± 0.2 °) 11.7, 12.5, 14.0, 22.2, 23.1, 23.5, and 28.2 °20.

[0124] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern comprising peaks at approximately (e.g., ± 0.2 °) 14.0, 23.1, and 28.2 °20. In one embodiment, the XRPD pattern further comprises peaks at approximately (e.g., ± 0.2 °) 11.7 and 12.5 °20. In one embodiment, the XRPD pattern comprises peaks at approximately (e.g., ± 0.2 °) 11.7, 12.5, 14.0, 22.2, 23.1, 23.5, and 28.2 °20.

[0125] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG. 3.

[0126] In some embodiments, Form C of Compound 1-A is partially hydrated. In some embodiments, Form C of Compound 1-A is a hemihydrate.

[0127] A representative TGA thermogram of Form C is provided in FIG. 4. In one embodiment, provided herein is a solid form comprising Compound 1-A, which exhibits a weight loss of about 2.2% to about 2.7% upon heating from about 30 °C to about 144 °C. In one embodiment, the solid form is characterized by a TGA thermogram that matches the TGA thermogram depicted in FIG. 4. In one embodiment, the TGA thermogram is as measured using a heating rate of about 10 °C / minute.

[0128] A representative DSC thermogram of Form C is provided in FIG. 5. In one embodiment, provided herein is a solid form comprising Compound 1-A, which exhibits, as characterized by DSC, a thermal (endo) event with an onset temperature of about 151 °C (e.g., ± 2 °) to about 156 °C (e.g., ± 2 °). In one embodiment, the solid form is characterized by a DSC thermogram that matches the DSC thermogram depicted in FIG. 5. In one embodiment, the DSC thermogram is as measured by DSC using a scanning rate of about 10 °C / minute.

[0129] In one embodiment, the solid form comprising Compound 1 -A is a crystalline hemihydrate (Form C) of Compound 1-A. In some embodiments, the solid form is substantially free of amorphous Compound 1-A. In some embodiments, the solid form is substantially free of other solid forms (e.g., another crystalline form) of Compound 1-A. In some embodiments, the solid form is provided as substantially pure.

[0130] In one embodiment, provided herein is a solid form comprising Form C of Compound 1-A and amorphous Compound 1-A. In one embodiment, provided herein is a solid form comprising Form C Compound 1-A and one or more other crystalline forms of Compound 1-A provided herein.

[0131] All of the combinations of the above embodiments are encompassed by this application.6.2.1.4 Form D of Compound 1-A

[0132] In one embodiment, provided herein is Form D of Compound 1-A.

[0133] A representative XRPD pattern of Form D of Compound 1-A is provided in FIG. 6.

[0134] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 228, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or all of the XRPD peaks located at approximately the following positions (e.g., degrees(°) 20 ± 0.2) when measured using Cu Ka radiation: 8.1, 9.4, 9.6, 10.4, 12.6, 13.0, 15.5, 16.2, 16.6, 16.9, 18.3, 18.5, 18.9, 19.6, 20.3, 20.9, 21.6, 21.9, 22.2, 22.5, 23.4, 23.7, 24.4, 24.7, 26.1, 26.4, 26.8, 27.1, 27.7, 28.3, 28.8, 30.3, 30.4, 31.0, 31.8, 34.7, 35.3, 37.4, 38.3, and 38.9 °20. In one embodiment, the solid form is characterized by at least 3 of the peaks. In one embodiment, the solid form is characterized by at least 5 of the peaks. In one embodiment, the solid form is characterized by at least 7 of the peaks. In one embodiment, the solid form is characterized by at least 9 of the peaks. In one embodiment, the solid form is characterized by at least 11 of the peaks. In one embodiment, the solid form is characterized by at least 13 of the peaks. In one embodiment, the solid form is characterized by at least 15 of the peaks. In one embodiment, the solid form is characterized by at least 20 of the peaks. In one embodiment, the solid form is characterized by all of the peaks.

[0135] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises atleast three peaks selected from the group consisting of approximately (e.g., ± 0.2 °) 9.4, 10.4, 16.2, 19.6, 22.2, and 24.5 °20. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least four peaks selected from the group consisting of approximately (e.g., ± 0.2 °) 9.4, 10.4, 16.2, 19.6, 22.2, and 24.5 °20. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least five peaks selected from the group consisting of approximately (e.g., ± 0.2 °) 9.4, 10.4, 16.2, 19.6, 22.2, and 24.5 °20.

[0136] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern comprising peaks at approximately (e.g., ± 0.2 °) 10.4, 19.6, and 22.2 °20. In one embodiment, the XRPD pattern further comprises peaks at approximately (e.g., ± 0.2 °) 9.4 and 24.5 °20. In one embodiment, the XRPD pattern comprises peaks at approximately (e.g., ± 0.2 °) 9.4, 10.4, 16.2, 19.6, 22.2, and 24.5 °20.

[0137] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG. 6.

[0138] It is believed that Form D of Compound 1-A is anhydrous or substantially anhydrous.

[0139] A representative TGA thermogram of Form D is provided in FIG. 7. In one embodiment, provided herein is a solid form comprising Compound 1-A, which exhibits a weight loss of about 0.29% upon heating from about 33 °C to about 122 °C. In one embodiment, the solid form is characterized by a TGA thermogram that matches the TGA thermogram depicted in FIG. 7. In one embodiment, the TGA thermogram is as measured using a heating rate of about 10 °C / minute.

[0140] A representative DSC thermogram of Form D is provided in FIG. 8. In one embodiment, provided herein is a solid form comprising Compound 1-A, which exhibits, as characterized by DSC, a thermal (endo) event with an onset temperature of about 182.5 °C (e.g., ± 2 °). In one embodiment, the solid form is characterized by a DSC thermogram that matches the DSC thermogram depicted in FIG. 8. In one embodiment, the DSC thermogram is as measured by DSC using a scanning rate of about 10 °C / minute.

[0141] In one embodiment, the solid form comprising Compound 1-A is a crystalline anhydrate (Form D) of Compound 1-A. In some embodiments, the solid form is substantially free of amorphous Compound 1-A. In some embodiments, the solid form is substantially free ofother solid forms (e.g, another crystalline form) of Compound 1-A. Tn some embodiments, the solid form is provided as substantially pure.[001421 In one embodiment, provided herein is a solid form comprising Form D of Compound 1-A and amorphous Compound 1-A. In one embodiment, provided herein is a solid form comprising Form D Compound 1-A and one or more other crystalline forms of Compound 1-A provided herein.

[0143] All of the combinations of the above embodiments are encompassed by this application.6.2.1.5 Form E of Compound 1-A

[0144] In one embodiment, provided herein is Form E of Compound 1-A.

[0145] A representative XRPD pattern of Form E of Compound 1-A is provided in FIG. 9.

[0146] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or all of the XRPD peaks located at approximately the following positions (e.g., degrees (°) 20 ± 0.2) when measured using Cu Ka radiation: 7.2, 8.2, 11.9, 13.2, 13.7, 14.5, 16.7, 17.7, 18.9, 19.7, 20.5, 21.6, 22.9, 24.0, 25.5, and 26.8 °20. In one embodiment, the solid form is characterized by at least 3 of the peaks. In one embodiment, the solid form is characterized by at least 5 of the peaks. In one embodiment, the solid form is characterized by at least 7 of the peaks. In one embodiment, the solid form is characterized by at least 9 of the peaks. In one embodiment, the solid form is characterized by at least 12 of the peaks. In one embodiment, the solid form is characterized by at least 9 of the peaks. In one embodiment, the solid form is characterized by all of the peaks.

[0147] In one embodiment, provided herein is a solid form comprising Compound 1-A characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, or all of the XRPD peaks located at approximately the following positions (e.g, degrees (°) 29 ± 0.2) when measured using Cu Ka radiation: 7.2, 8.2, 11.9, 13.2, 13.7, 14.5, 17.7, 18.9, 22.9, and 26.8 °29. In one embodiment, the solid form is characterized by at least 3 of the peaks. In one embodiment, the solid form is characterized by at least 5 of the peaks. In one embodiment, the solid form is characterized by at least 7 of the peaks. In one embodiment, the solid form is characterized by at least 9 of the peaks. In one embodiment, the solid form is characterized by all of the peaks.

[0148] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least three peaks selected from the group consisting of approximately (e.g., ± 0.2 °) 7.2, 8.2, 13.7, 14.5, 17.7, and 22.9 °20. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least four peaks selected from the group consisting of approximately (e.g., ± 0.2 °) 7.2, 8.2, 13.7, 14.5, 17.7, and 22.9 °20. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least five peaks selected from the group consisting of approximately (e.g., ± 0.2 °) 7.2, 8.2, 13.7, 14.5, 17.7, and 22.9 °29.

[0149] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern comprising peaks at approximately (e.g., ± 0.2 °) 7.2, 8.2, and 14.5 °20. In one embodiment, the XRPD pattern further comprises peaks at approximately (e.g, ± 0.2 °) 13.7 and 22.9 °20. In one embodiment, the XRPD pattern comprises peaks at approximately (e.g., ± 0.2 °) 7.2, 8.2, 13.7, 14.5, 17.7, and 22.9 °20.

[0150] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG. 9.

[0151] A representative TGA thermogram of Form E is provided in FIG. 10. In one embodiment, provided herein is a solid form comprising Compound 1-A, which exhibits a weight loss of about 9.7% upon heating from about 90 °C to about 130 °C. In one embodiment, the solid form is characterized by a TGA thermogram that matches the TGA thermogram depicted in FIG. 10. In one embodiment, the TGA thermogram is as measured using a heating rate of about 10 °C / minute.

[0152] A representative DSC thermogram of Form E is provided in FIG. 11. In one embodiment, provided herein is a solid form comprising Compound 1-A, which exhibits, as characterized by DSC, a thermal (endo) event with an onset temperature of about 115.5 °C (e.g., ± 2 °). In one embodiment, the solid form is characterized by a DSC thermogram that matches the DSC thermogram depicted in FIG. 11. In one embodiment, the DSC thermogram is as measured by DSC using a scanning rate of about 10 °C / minute.

[0153] In one embodiment, the solid form comprising Compound 1-A is a crystalline dioxane solvate (Form E) of Compound 1-A. In some embodiments, the solid form is substantially free of amorphous Compound 1-A. In some embodiments, the solid form issubstantially free of other solid forms (e.g., another crystalline form) of Compound 1-A. In some embodiments, the solid form is provided as substantially pure.[001541 In one embodiment, provided herein is a solid form comprising Form E of Compound 1-A and amorphous Compound 1-A. In one embodiment, provided herein is a solid form comprising Form E Compound 1-A and one or more other crystalline forms of Compound 1-A provided herein.

[0155] All of the combinations of the above embodiments are encompassed by this application.6.2.1.6 Form G of Compound 1-A

[0156] In one embodiment, provided herein is Form G of Compound 1-A.

[0157] A representative XRPD pattern of Form G of Compound 1-A is provided in FIG. 12. XRPD analyses of Form G of Compound 1-A were performed by X-Ray Powder Diffraction (XRPD) analysis method (2).

[0158] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by 1, 2, 3, 4, 5, or all of the XRPD peaks located at approximately the following positions (e.g., degrees (°) 20 ± 0.2) when measured using Cu Ka radiation: 13.4, 13.6, 24.1, 24.6, 29.1, and 37.5 °20. In one embodiment, the solid form is characterized by at least 3 of the peaks. In one embodiment, the solid form is characterized by all of the peaks.

[0159] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least three peaks selected from the group consisting of approximately (e.g., ± 0.2 °) 11.8, 14.2, 14.8, 23.0, 24.2, and 29.5 °20. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least four peaks selected from the group consisting of approximately (e.g., ± 0.2 °) 13.4, 13.6, 24.1, 24.6, 29.1, and 37.5 °20. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least five peaks selected from the group consisting of approximately (e.g., ± 0.2 °) 13.4, 13.6, 24.1, 24.6, 29.1, and 37.5 °20.

[0160] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern comprising peaks at approximately (e.g., ± 0.2 °) 13.6, 24.1, and 24.6 °20. In one embodiment, the XRPD pattern further comprises peaks at approximately(e.g., ± 0.2 °) 13.4 and 29.1 °20. In one embodiment, the XRPD pattern comprises peaks at approximately (e.g., ± 0.2 °) 13.4, 13.6, 24.1, 24.6, 29.1, and 37.5 °20.

[0161] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG. 12.

[0162] A representative TGA thermogram of Form G is provided in FIG. 13. In one embodiment, provided herein is a solid form comprising Compound 1-A, which exhibits a weight loss of about 11.1% upon heating from about 45 °C to about 145 °C. In one embodiment, the solid form is characterized by a TGA thermogram that matches the TGA thermogram depicted in FIG. 13. In one embodiment, the TGA thermogram is as measured using a heating rate of about 10 °C / minute. TGA analyses for Form G of Compound 1-A were performed on a TGA 550 TGA by TA Instruments.

[0163] A representative DSC thermogram of Form G is provided in FIG. 14. In one embodiment, provided herein is a solid form comprising Compound 1-A, which exhibits, as characterized by DSC, a thermal (endo) event with an onset temperature of about 136.7 °C (e.g., ± 2 °). In one embodiment, the solid form is characterized by a DSC thermogram that matches the DSC thermogram depicted in FIG. 14. In one embodiment, the DSC thermogram is as measured by DSC using a scanning rate of about 10 °C / minute. DSC analyses for Form G of Compound 1-A were performed on a Q200 DSC by TA Instruments.

[0164] In one embodiment, the solid form comprising Compound 1-A is a crystalline nitromethane solvate (Form G) of Compound 1-A. In some embodiments, the solid form is substantially free of amorphous Compound 1-A. In some embodiments, the solid form is substantially free of other solid forms (e.g., another crystalline form) of Compound 1-A. In some embodiments, the solid form is provided as substantially pure.

[0165] In one embodiment, provided herein is a solid form comprising Form G of Compound 1-A and amorphous Compound 1-A. In one embodiment, provided herein is a solid form comprising Form G Compound 1-A and one or more other crystalline forms of Compound 1-A provided herein.

[0166] All of the combinations of the above embodiments are encompassed by this application.6.2.1.7 Form H of Compound 1 -A

[0167] In one embodiment, provided herein is Form H of Compound 1 -A.

[0168] A representative XRPD pattern of Form H of Compound 1-A is provided in FIG. 15. XRPD analyses of Form H of Compound 1-A were performed by X-Ray Powder Diffraction (XRPD) analysis method (2).

[0169] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9 , 10, 11, 12,13, 14, 15 or all of the XRPD peaks located at approximately the following positions (e.g., degrees (°) 20 ± 0.2) when measured using Cu Ka radiation: 9.0, 9.7, 11.8, 12.3, 13.5, 14.1, 14.7, 16.0, 17.8, 18.2, 19.8, 21.3, 23.0, 23.6, 27.7, and 37.0 °20. In one embodiment, the solid form is characterized by at least 3 of the peaks. In one embodiment, the solid form is characterized by at least 5 of the peaks. In one embodiment, the solid form is characterized by at least 7 of the peaks. In one embodiment, the solid form is characterized by at least 9 of the peaks. In one embodiment, the solid form is characterized by at least 12 of the peaks. In one embodiment, the solid form is characterized by all of the peaks.

[0170] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by 1, 2, 3, 4, 5, 6, 7, or all of the XRPD peaks located at approximately the following positions (e.g., degrees (°) 29 ± 0.2) when measured using Cu Ka radiation: 9.0, 11.8, 12.3, 14.1, 18.2, 23.6, 27.7, and 37.0 °2Q. In one embodiment, the solid form is characterized by at least 3 of the peaks. In one embodiment, the solid form is characterized by at least 5 of the peaks. In one embodiment, the solid form is characterized by at least 7 of the peaks. In one embodiment, the solid form is characterized by all of the peaks.

[0171] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least three peaks selected from the group consisting of approximately (e.g., ± 0.2 °) 11.8, 12.3, 14.1, 21.2, and 23.6 °20. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least four peaks selected from the group consisting of approximately (e.g., ± 0.2 °) 11.8, 12.3, 14.1, 21.2, and 23.6 °20. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least five peaks selected from the group consisting of approximately (e.g, ± 0.2 °) 11.8, 12.3, 14.1, 21.2, and 23.6 °29.

[0172] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern comprising peaks at approximately (e.g., ± 0.2 °) 11.8, 14.1,and 23.6 °20. In one embodiment, the XRPD pattern further comprises peaks at approximately (e.g., ± 0.2 °) 9.0 and 12.3 °20. In one embodiment, the XRPD pattern comprises peaks at approximately (e.g., ± 0.2 °) 11.8, 12.3, 14.1, 18.2, and 23.6 °20.

[0173] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG. 15.

[0174] A representative TGA thermogram of Form H is provided in FIG. 16. In one embodiment, provided herein is a solid form comprising Compound 1-A, which exhibits a weight loss of about 8.8% upon heating from about 25 °C to about 150 °C. In one embodiment, the solid form is characterized by a TGA thermogram that matches the TGA thermogram depicted in FIG. 16. In one embodiment, the TGA thermogram is as measured using a heating rate of about 10 °C / minute.

[0175] A representative DSC thermogram of Form H is provided in FIG. 17. In one embodiment, provided herein is a solid form comprising Compound 1-A, which exhibits, as characterized by DSC, a thermal (endo) event with an onset temperature of about 137.5 °C (e. , ± 2 °). In one embodiment, the solid form is characterized by a DSC thermogram that matches the DSC thermogram depicted in FIG. 17. In one embodiment, the DSC thermogram is as measured by DSC using a scanning rate of about 10 °C / minute.

[0176] It is believed that Form H of Compound 1-A is an acetonitrile solvate.

[0177] In one embodiment, the solid form comprising Compound 1-A is a crystalline acetonitrile solvate (Form H) of Compound 1-A. In some embodiments, the solid form is substantially free of amorphous Compound 1-A. In some embodiments, the solid form is substantially free of other solid forms (e.g., another crystalline form) of Compound 1-A. In some embodiments, the solid form is provided as substantially pure.

[0178] In one embodiment, provided herein is a solid form comprising Form H of Compound 1-A and amorphous Compound 1-A. In one embodiment, provided herein is a solid form comprising Form H Compound 1-A and one or more other crystalline forms of Compound 1-A provided herein.

[0179] All of the combinations of the above embodiments are encompassed by this application.6.2.1.8 Form 1 of Compound 1-A

[0180] In one embodiment, provided herein is Form I of Compound 1-A.

[0181] A representative XRPD pattern of Form I of Compound 1-A is provided in FIG. 18.XRPD analyses of Form I of Compound 1-A were performed by X-Ray Powder Diffraction (XRPD) analysis method (2).

[0182] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by 1, 2, 3, 4, 5, 6, or all of the XRPD peaks located at approximately the following positions (e.g., degrees (°) 29 ± 0.2) when measured using Cu Kot radiation: 7.9, 9.5, 13.8, 20.9, 23.8, 26.1, and 28.0. In one embodiment, the solid form is characterized by at least 3 of the peaks. In one embodiment, the solid form is characterized by at least 5 of the peaks. In one embodiment, the solid form is characterized by at least 7 of the peaks. In one embodiment, the solid form is characterized by at least 9 of the peaks. In one embodiment, the solid form is characterized by at least 11 of the peaks. In one embodiment, the solid form is characterized by all of the peaks.

[0183] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG. 18.

[0184] In one embodiment, the solid form comprising Compound 1-A is a methyl acetate / n- heptane solvate (Form I) of Compound 1-A. In some embodiments, the solid form is substantially free of amorphous Compound 1-A. In some embodiments, the solid form is substantially free of other solid forms (e.g, another crystalline form) of Compound 1-A. In some embodiments, the solid form is provided as substantially pure.

[0185] In one embodiment, provided herein is a solid form comprising Form I of Compound 1-A and amorphous Compound 1-A. In one embodiment, provided herein is a solid form comprising Form I Compound 1-A and one or more other crystalline forms of Compound 1-A provided herein.6.2.1.9 Form J o f Compound 1-A

[0186] In one embodiment, provided herein is Form J of Compound 1-A.

[0187] A representative XRPD pattern of Form J of Compound 1-A is provided in FIG. 19.

[0188] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG. 19.

[0189] A representative TGA thermogram of Form J is provided in FIG. 20. In one embodiment, provided herein is a solid form comprising Compound 1-A, which exhibits a weight loss of about 2.6% upon heating from about 25 °C to about 110 °C. In one embodiment, the solid form is characterized by a TGA thermogram that matches the TGA thermogram depicted in FIG. 20. In one embodiment, the TGA thermogram is as measured using a heating rate of about 10 °C / minute.

[0190] A representative DSC thermogram of Form J is provided in FIG. 21 as the top trace. In one embodiment, provided herein is a solid form comprising Compound 1-A, which exhibits, as characterized by DSC, a glass transition event with a Tgmid-point at about 66 °C. In one embodiment, the solid form is characterized by a DSC thermogram that matches the DSC thermogram depicted in the top trace of in FIG. 21. In one embodiment, the DSC thermogram is as measured by DSC using a scanning rate of about 10 °C / minute.

[0191] In some embodiments, Form J of Compound 1-A is substantially amorphous. In one embodiment, the solid form comprising Compound 1-A is an amorphous (Form J) of Compound 1-A. In some embodiments, the solid form is substantially free of crystalline Compound 1-A.

[0192] All of the combinations of the above embodiments are encompassed by this application.6.2.1.10 Form L of Compound 1 -A

[0193] In one embodiment, provided herein is Form L of Compound 1-A.

[0194] A representative XRPD pattern of Form L of Compound 1-A is provided in FIG. 22.

[0195] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38 or all of the XRPD peaks located at approximately the following positions (e.g., degrees(°) 20 ± 0.2) when measured using Cu Ka radiation: 8.7, 9.9, 10.5, 14.4, 14.7, 16.5, 18.0, 18.4, 18.7, 19.1, 19.7, 20.3, 20.7, 21.5, 22.3, 22.9, 23.0, 23.4, 24.3, 25.0, 25.9, 26.7, 27.0, 27.3, 27.7, 28.2, 28.6, 29.1, 29.6, 29.9, 30.2, 30.7, 31.0, 32.5, 32.8, 33.3, 36.9, 37.5, and 37.9 °20. In one embodiment, the solid form is characterized by at least 3 of the peaks. In one embodiment, the solid form is characterized by at least 5 of the peaks. In one embodiment, the solid form is characterized by at least 7 of the peaks. In one embodiment, the solid form is characterized by at least 9 of the peaks. In one embodiment, thesolid form is characterized by at least 11 of the peaks. In one embodiment, the solid form is characterized by at least 13 of the peaks. In one embodiment, the solid form is characterized by at least 15 of the peaks. In one embodiment, the solid form is characterized by at least 20 of the peaks. In one embodiment, the solid form is characterized by all of the peaks.

[0196] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least three peaks selected from the group consisting of approximately (e.g., ± 0.2 °) 8.7, 10.5,16.5, 18.0, 19.1, and 22.9 °29. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least four peaks selected from the group consisting of approximately (e.g., ± 0.2 °) 8.7, 10.5, 16.5, 18.0, 19.1, and 22.9 °20. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least five peaks selected from the group consisting of approximately (e.g., ± 0.2 °) 8.7, 10.5, 16.5, 18.0, 19.1, and 22.9 °20.

[0197] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern comprising peaks at approximately (e.g., ± 0.2 °) 8.7, 10.5, and 18.0 °20. In one embodiment, the XRPD pattern further comprises peaks at approximately (e.g., ± 0.2 °) 19.1 and 22.9 °29. In one embodiment, the XRPD pattern comprises peaks at approximately (e.g., ± 0.2 °) 8.7, 10.5, 16.5, 18.0, 19.1, and 22.9 °29.

[0198] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG. 22.

[0199] It is believed that Form L of Compound 1-A is a methanol solvate.6.2.1.11 Form M of Compound 1-A

[0200] In one embodiment, provided herein is Form M of Compound 1-A.

[0201] A representative XRPD pattern of Form M of Compound 1-A is provided in FIG. 23.

[0202] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or all of the XRPD peaks located at approximately the following positions e.g., degrees(°) 29 ± 0.2) when measured using Cu Ka radiation: 7.3, 8.7, 9.4, 11.9,14.6, 15.4, 16.0, 17.4, 18.0, 18.7, 19.0, 20.3, 20.8, 21.3, 22.6, 22.9, 23.0, 24.0, 25.3, 25.6, 26.0, 26.3, 27.3, 28.1, 28.3, 28.6, 29.3, 29.6, 30.0, 34, 38.5, and 39.2 °29. In one embodiment, the solid form is characterized by at least 3 of the peaks. In one embodiment, the solid form ischaracterized by at least 5 of the peaks. In one embodiment, the solid form is characterized by at least 7 of the peaks. In one embodiment, the solid form is characterized by at least 9 of the peaks. In one embodiment, the solid form is characterized by at least 11 of the peaks. In one embodiment, the solid form is characterized by at least 13 of the peaks. In one embodiment, the solid form is characterized by at least 15 of the peaks. In one embodiment, the solid form is characterized by at least 20 of the peaks. In one embodiment, the solid form is characterized by all of the peaks.

[0203] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least three peaks selected from the group consisting of approximately (e.g., ± 0.2 °) 8.7, 9.4, 16.0, 18.0, 22.9, and 23.0 °29. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least four peaks selected from the group consisting of approximately (e.g., ± 0.2 °) 8.7, 9.4, 16.0, 18.0, 22.9, and 23.0 °20. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least five peaks selected from the group consisting of approximately (e.g., ± 0.2 °) 8.7, 9.4, 16.0, 18.0, 22.9, and 23.0 °20.

[0204] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern comprising peaks at approximately (e.g, ± 0.2 °) 8.7, 9.4, and 16.0 °20. In one embodiment, the XRPD pattern further comprises peaks at approximately (e.g., ± 0.2 °) 18.0 and 23.0 °29. In one embodiment, the XRPD pattern comprises peaks at approximately (e.g., ± 0.2 °) 8.7, 9.4, 16.0, 18.0, 22.9, 23.0, and 26.3 °20.

[0205] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG. 23.

[0206] It is believed that Form M of Compound 1-A is an ethanol solvate.6.2.1.12 Form N of Compound 1-A

[0207] In one embodiment, provided herein is Form N of Compound 1-A.

[0208] A representative XRPD pattern of Form N of Compound 1-A is provided in FIG. 24.

[0209] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or all of the XRPD peaks located at approximately the following positions (e.g., degrees(°) 20 ± 0.2) when measured using Cu Ka radiation: 6.7, 7.2,7.3, 9.6, 11.2, 12.9, 13.0, 13.7, 15.6, 16.4, 16.9, 18.9, 19.5, 19.8, 21.8, 22.2, 22.6, 22.7, 23.7, 24.5, 25.7, 26.3, 27.8, 27.9, 28.9, 29.4, 30.3, 31.2, 31.6, 33.0, 33.6, 34.6, 36.1, 37.0, and 37.5 °29. In one embodiment, the solid form is characterized by at least 3 of the peaks. In one embodiment, the solid form is characterized by at least 5 of the peaks. In one embodiment, the solid form is characterized by at least 7 of the peaks. In one embodiment, the solid form is characterized by at least 9 of the peaks. In one embodiment, the solid form is characterized by at least 11 of the peaks. In one embodiment, the solid form is characterized by at least 13 of the peaks. In one embodiment, the solid form is characterized by at least 15 of the peaks. In one embodiment, the solid form is characterized by at least 20 of the peaks. In one embodiment, the solid form is characterized by all of the peaks.

[0210] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern, which when measured using Cu Kot radiation, comprises at least three peaks selected from the group consisting of approximately (e.g., ± 0.2 °) 7.2, 11.2, 12.9, 13.7, 22.2, 23.7, and 27.8 °20. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least four peaks selected from the group consisting of approximately (e.g., ± 0.2 °) 7.2, 11.2, 12.9, 13.7, 22.2, 23.7, and 27.8 °20. In one embodiment, the solid form is characterized by an XRPD pattern comprising at least five peaks selected from the group consisting of approximately (e.g., ± 0.2 °) 7.2, 11.2, 12.9, 13.7, 22.2, 23.7, and 27.8 °20.

[0211] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern comprising peaks at approximately (e.g., ± 0.2 °) 11.2, 12.9, and 13.7 °29. In one embodiment, the XRPD pattern further comprises peaks at approximately (e.g., ± 0.2 °) 7.2 and 23.7 °20. In one embodiment, the XRPD pattern comprises peaks at approximately (e.g., ± 0.2 °) 7.2, 11.2, 12.9, 13.7, and 23.7 °20.

[0212] It is believed that Form N of Compound 1-A is a desolvated hydrate.

[0213] In one embodiment, provided herein is a solid form comprising Compound 1-A, characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG. 24.6.3 Method of Preparing Solid Forms of Compound 1-A

[0214] As used herein and unless otherwise specified, all solvents ratios are meant for volume ratios.6.3.1 Method of Preparing Form A

[0215] In one embodiment, provided herein is a method for preparing Form A, comprising heating solid Form N, as described herein, to a temperature of about 165 °C.

[0216] In another embodiment, provided herein is a method for preparing Form A, comprising drying solid Form M, as described herein, under ambient conditions. As used here, ambient conditions comprise a temperature of about 25 °C and about 40% relative humidity. In one embodiment, this method provides a mixture of Forms A and M.6.3.2 Method of Preparing Form B

[0217] In one embodiment, provided herein is a method for preparing Form B, comprising recovering Form B, as described herein, from a solution of solid Form D in dichloromethane. In one embodiment, Form A is recovered by evaporating the dichloromethane from the solution.6.3.3 Method of Preparing Form C

[0218] In one embodiment, provided herein is a method for preparing Form C, comprising recovering Form C, as described herein, from a solution of Form D in a mixture of ethanol and water. In one embodiment, the mixture of ethanol and water is about 80% ethanol in water. In one embodiment, the recovering is carried out at room temperature.

[0219] In one embodiment, provided herein is a method for preparing Form C, comprising subjecting solid Form N, as described herein, to ambient conditions.

[0220] In one embodiment, provided herein is a method for preparing Form C, comprising recovering Form C, as described herein, from a solution of amorphous Compound 1-A in a mixture of acetone and water. In one embodiment, the mixture of acetone and has a water activity (Aw) of about 0.26. In one embodiment, the recovering is carried out at a temperature of about 5 °C to about 50 °C.6.3.4 Method of Preparing Form D

[0221] In one embodiment, provided herein is a method for preparing Form D, comprising recovering Form D, as described herein, from a solution of Form B in isopropyl alcohol. In one embodiment, the recovering is carried out at a temperature of about 20 °C to about 50 °C.

[0222] In one embodiment, provided herein is a method for preparing Form D, comprising drying solid Form M, as described herein, at a temperature of at least about 60 °C under vacuum.

[0223] In one embodiment, provided herein is a method for preparing Form D, comprising drying solid Form L, as described herein, at room temperature.

[0224] In one embodiment, provided herein is a method for preparing Form D, comprising recovering Form D, as described herein, from a solution of amorphous Compound 1-A in acetone. In one embodiment, the recovering is carried out at a temperature of about 50 °C.6.3.5 Method of Preparing Amorphous (Form J)

[0225] In one embodiment, provided herein is a method for preparing Form D, comprising lyophilizing a slurry of solid Form D, as described herein, in t-butyl alcohol.6.3.6 Method of Preparing Form L Compound 1-A

[0226] In one embodiment, provided herein is a method for preparing Form L, comprising recovering Form L, as described herein, from a solution of Form D, as described herein, from a mixture of methanol in water. In one embodiment, the mixture of methanol in water has an Aw of about 0.64. In one embodiment, the mixture of methanol and water is about 69% methanol in water.6.3.7 Method of Preparing Form M

[0227] In one embodiment, provided herein is a method for preparing Form M, comprising recovering Form M, as described herein, from a solution of Form C from a mixture of ethanol in water. In one embodiment, the mixture of ethanol in water has an Aw of about 0.65. In one embodiment, the mixture of ethanol and water is about 80% ethanol in water.6.3.8 Method of Preparing Form N

[0228] In one embodiment, provided herein is a method for preparing Form M, comprising heating solid Form C, as described herein, to a temperature of about 120 °C to about 140 °C under vacuum.6.4 Pharmaceutical Compositions

[0229] In another aspect, the present disclosure provides a pharmaceutical composition comprising one or more solid forms of Compound 1-A and / or Compound 1-D (e. ., one or more of solid Forms A, B, C, D, E, J, L, M, and N) and a pharmaceutically acceptable excipient.

[0230] In one embodiment, the present disclosure provides a pharmaceutical formulation comprising a solid form comprising Compound 1-A and / or Compound 1-D (e.g., one or more ofsolid Forms A, B, C, D, E, J, L, M, and N) and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical preparations may be for use in treating or preventing a condition or disease as described herein. Any of the disclosed solid forms of any of the compounds may be used in the manufacture of medicaments for the treatment of any diseases or conditions where they provide an ameliorative, curative, or prophylactic benefit, such as those diseases or conditions disclosed herein.

[0231] Pharmaceutical compositions may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, inhaled, intranasal, topical (including buccal, sublingual, or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) route. Such compositions may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the pharmaceutically acceptable excipient(s).

[0232] Pharmaceutical compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.

[0233] For instance, for oral administration in the form of a tablet or capsule, an active ingredient (e.g., Compound 1 or a stereoisomer thereof) can be combined with an oral, non-toxic pharmaceutically acceptable inert excipient such as ethanol, glycerol, water, and the like. Flavoring, preservative, dispersing and coloring agent can also be present.

[0234] Pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, vehicle or carrier. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules, or the like in the case of solid compositions.

[0235] In one embodiment, a unit dosage composition contains a daily dose or sub-dose, or an appropriate fraction thereof, of an active ingredient. Such unit doses may therefore beadministered once or more than once a day. Such pharmaceutical compositions may be prepared by any of the methods well known in the pharmacy art.

[0236] It should be understood that in addition to the ingredients particularly mentioned above, the compositions may include other agents conventional in the art having regard to the type of formulation in question.6.5 Therapeutic Methods[00237J In another aspect, the present disclosure a method of treating a subject in need thereof with a solid form of Compound 1-A (e.g., one or more of solid Forms A, B, C, D, E, J, L, M, and N). Such a compound may be administered in a pharmaceutical composition as described in Section 6.4 in an effective amount, which will be readily determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0238] In one embodiment, the present disclosure provides a method of treating a disease, condition, or disorder related to the polymerization of alpha- 1 -antitrypsin in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a solid form of Compound 1-A (e. ., one or more of solid Forms A, B, C, D, E, J, L, M, and N). In one embodiment, the present disclosure provides use of a solid form of Compound 1-A (e.g., one or more of solid Forms A, B, C, D, E, J, L, M, and N), in the manufacture of a medicament for use treating a disease, condition, or disorder related to the polymerization of alpha- 1 -antitrypsin in a subject in need thereof. In one embodiment, the disease, disorder, or condition related to the polymerization of alpha- 1 -antitrypsin is liver disease.

[0239] For the treatment of liver disease, the compounds or pharmaceutical compositions of the invention may be administered with other therapeutic agents useful in treating these diseases. Therefore, in another aspect, the present disclosure provides a method of treating a disease, disorder, or condition related to the polymerization of alpha- 1 -antitrypsin (e.g., liver disease), comprising administering a therapeutically effective amount of a solid form of Compound 1-A (e.g., one or more of solid Forms A, B, C, D, E, J, L, M, and N), together with a second therapeutically active agent. In one embodiment, the present disclosure provides use of a solid form of Compound 1-A (e.g., one or more of solid Forms A, B, C, D, E, J, L, M, and N) in themanufacture of a medicament for use treating a disease, condition, or disorder related to the polymerization of alpha- 1 -antitrypsin (e.g., liver disease) in a subject in need thereof, wherein the medicament is intended to be administered to the subject together with a second therapeutic agent effective to treat liver disease.7. EXAMPLESPreparation of Solid Forms of Compound 1[00240J FIG. 25 is a diagram depicting the relationship between the various solid forms of Compound 1-A disclosed herein, including conditions for interconversion therebetween.Example 1: Preparation of Form A of Compound 1-A

[0241] 1 .7 g of Compound 1-A was taken in 50 mL of ethyl acetate and heated at 40 °C for15 minutes. Then 187 mL of heptane was added into it. The resultant solution was then kept at room temperature overnight. The reaction mixture was further cooled to 20 °C for 2 hours. Solid was separated by filtering and dried under vacuum for 2 hours at room temperature. The obtained solid was further dried at 50 °C for 2-4 hours.

[0242] Form A was also observed / isolated during (at 165 °C and 170 °C) and after variable temperature XRPD analysis of Form C of Compound 1-A. The material remained as Form A when the VT-XRPD sample returned to room temperature.

[0243] Disordered Form A was observed from slow evaporation of solvent from a mixture of Compound 1-A in a mixture of methyl ethyl ketone and water (49: 1, Aw~0.4).

[0244] A mixture of Form A and Form C and a disordered Form A was also observed after slow evaporation of solvent from a mixture of Compound 1-A in a mixture of acetone and water (20:1, Aw~0.6).Example 2: Preparation of Form B of Compound 1-A

[0245] Form A (0.7 g) was taken in 16 mL of MeOH and heated at 40 °C for 15 minutes.Then 20 mL of water was added. The reaction mixture was then kept at room temperature overnight. It was then further cooled to -20 °C for 5 hours. Solid was filtered and dried under vacuum for 2 hours at room temperature. The obtained solid was further dried at 50 °C for 5 hours and identified as Form B by XRPD.

[0246] Form B may also have been isolated from slow evaporation of solvent from a mixture of Compound 1-A in dichloromethane.Example 3: Preparation of Form C of Compound 1-A

[0247] Form A (0.7 g) was taken in 10 mL of DMSO and heated at 40 °C for 15 minutes.Then 10 mL of water was added into it. The reaction mixture was then kept at room temperature overnight. It was then further cooled to -20 °C for 5 hours. Solid was filtered and dried under vacuum for 2 hours at room temperature. The obtained solid was further dried at 50 °C for 5 hours.Example 4: Preparation of Form C of Compound 1-A

[0248] Form C was generated by charging Form D of Compound 1-A (about 0.2 g) to a vial. EtOH / water (80:20 v / v, Aw ~ 0.65, 3 vols) was charged to the solids and stirred for about 5 days at about 20 °C. An aliquot was taken and analyzed by XRPD to confirm composition. When Form C conversion was confirmed by XRPD, the bulk was isolated by vacuum filtration and dried for about 3-4 hours on the sinter. A yield of about 89% was recorded.

[0249] XRPD analysis confirmed the material was composed of Form C and proton NMR analysis conformed to the expected structure of the compound with negligible ethanol detected. TGA analysis showed a weight loss of about 2.7% observed during heating from 30 °C to 204 °C.

[0250] Form C remained physically stable to humidity stressing (23, 59, 75, 98% relative humidity (RH), 40 °C / 75% RH) for up to 1 week.

[0251] The crystal structure of Form C was determined with monoclinic crystal system and C2 space group. The structure of Form C is hydrated and contains one symmetry independent molecule of Compound 1-A per asymmetric unit and one water molecule which sits in a crystallographically significant interstitial site. Unit cell dimensions were determined to be a = 12.5812(3 )A; a = 90°; b =12.3282(3) A; c = 12.5581(4) A; = 95.9185(10)°; y = 90°.

[0252] Form C was also generated by preparing a slurry of amorphous Compound 1-A material in acetone and in acetone / water (80:20 v / v, Aw~0.81) at 50 °C.Example 5: Preparation of Form D of Compound 1-A

[0253] Form A (5 g) was taken in 100 mL of methanol (MeOH) and heated at 40 °C for 30 minutes. Then 100 mL of heptane was added. The resultant solution was then kept at room temperature overnight. Then the solution was further cooled to -20 °C for 2 hours. Solid werefiltered and dried under vacuum for 2 hours at room temperature. The obtained solid was further dried at 50 °C for 2-4 hours.

[0254] Form D was also generated by preparing a slurry of about 100 mg Form C in 1 : 1 methanol :heptane (375 pL; 3.75 vols) at ambient temperature. The slurry was seeded (about 0.75 mg) with Form D and the mixture was left to stir overnight. The mixture was then subjected to centrifuge filtration and dried in a vacuum oven at 60 °C overnight. The undried solid corresponded to Form L upon analysis by XRPD. Complete desolvation to Form D occurred following overnight drying in a vacuum oven at 60 °C.

[0255] Form D was physically stable to slurrying in water (5, 20 and 50 °C) for 6 days and relative humidity stressing (23, 59, 75, 98% RH, 40 °C / 75% RH) for up to 1 week.

[0256] The hygroscopicity and the sorption properties of Form D were determined using Dynamic Vapor Sorption (DVS). The isotherm showed the material exhibits slow uptake of moisture, generating an increase in weight from 40-80% RH followed by an increase in weight at a higher rate, in the range of 80-90% RH. The isotherm showed the total weight gain observed between ambient (z.e., 40% RH) to 80% RH to be 0.63% w / w which indicates that the sample is slightly hygroscopic. Post DVS XRPD analysis was carried out and the resulting XRPD pattern matched that of the input material, indicating that no physical changes had occurred.Example 6: Preparation of Form E of Compound 1-A

[0257] Compound 1-A (about 10-15 mg) was charged to a vial and dissolved in dioxane (1.5 mL). The solution was filtered. The sample was dried overnight on a freeze drier to afford white solids which were analyzed by XRPD and were consistent with Form E.

[0258] Form E was also generated by adding aliquots of dioxane (20-100 pL) to a sample (about 20 mg) of Compound 1-A at ambient temperature until dissolved. The solution was diluted until the sample contained 1 mL of solvent (49:1 dioxane:water; Aw~0.2), then the solution was filtered into a vial, covered with perforated aluminum foil, and evaporated for several days until solids were isolated.Example 7: Preparation of Form H of Compound 1-A

[0259] Aliquots (20-100 pL) of ACN / water (92:8 v / v) were added to an accurately weighed sample (about 20 mg) of Compound 1-A at ambient temperature. Complete dissolution of the test material was determined by visual inspection. The solution was diluted until the samplecontained 1 mL of solvent, then the solution was filtered (0.2 m, PTFE) into a vial, covered with perforated aluminum foil and evaporated for several days until solids were isolated.

[0260] Form H was also generated by temperature cycling. Aliquots (20-100 pL) of acetonitrile (ACN) / water (92:8 v / v) were added to a weighed sample (about 20 mg) of Compound 1-A at ambient temperature. The mixture was heated to within 3 °C of the lower of the solvent boiling point or 100 °C at 0.5 °C / minute. The mixture was then cooled to 20 °C at 0.2 °C / minute. The process is repeated once more for a total of two cycles. During the heat / cooling, the mixture was s stirred.Example 8: Preparation of Amorphous (Form J) of Compound 1-A

[0261] Amorphous Compound 1-A was isolated from fdtered Compound 1-A in tert-BuOH (about 6 mg / mL) with about 0.26 mol eq. of solvent remaining. Lyophilization was performed at a concentration of about 5 mg / mL to provide amorphous Compound 1-A.Example 9: Preparation of Form L of Compound 1-A

[0262] Form D of Compound 1-A (about 200 mg) was charged to a vial. MeOH / water (69:31% v / v, Aw~ 0.64, 5 vols) was charged to the solids and stirred overnight at room temperature. A further 3 vols of solvent was added to aid stirring. An aliquot was isolated by filtration and analyzed by XRPD. From the methanol mixture, Form L was observed, and the sample was then stirred overnight. After stirring overnight, another aliquot was isolated by centrifugal filtration and analyzed by XRPD confirming Form L remained. XRPD re-analysis of this material after storage under ambient conditions for approximately three hours showed the material converted to Form D, followed by further reanalysis after 3 days which confirmed Form D material remained. Continued slurrying of Form L material in MeOH / water (69:31 v / v, Aw~ 0.64, 8 vols) for a further 3 days resulted in no change in form with Form L still being isolated.Example 10: Preparation of Form M of Compound 1-A

[0263] Form D of Compound 1-A (about 200 mg) was charged to a vial. EtOH / water (80:20%v / v, Aw ~ 0.65, 5 vols) was charged to the solids and stirred overnight at room temperature. An aliquot was isolated by centrifugal filtration and analyzed by XRPD. From the ethanol mixture, the desired form was observed (Form C) and the sample was then cooled to 5 °C to help improve yield and stirred overnight. After stirring overnight at 5 °C, another aliquot was isolated by centrifugal filtration and analyzed by XRPD confirming Form M. XRPD re-analysis of this material after approximately three hours showed the material remained as Form M, followed by re-analysis after 3 days which showed some conversion to Form A. The batch was then split into two portions, one held at room temperature and the other remained at 5 °C. Analysis of these solids showed they both remained Form M.Example 11: Preparation of Form N of Compound 1-A

[0264] Form N of Compound 1-A is a suspected desolvated hydrate Form N material was observed at 120 °C and 140 °C by heating form C of Compound 1-A during variable temperature XRPD analysis. FIG. 26 depicts representative XRPD patterns of (top) Form C of Compound 1- A, (middle) a mixture of Form C and Form N of Compound 1-A, and (bottom) Form N of Compound 1-A.Example 11: Preparation of Other Solid Forms of Compound 1-A

[0265] Additional solid forms of Compound 1-A were also prepared:

[0266] Form K of Compound 1-A was prepared by conversion of Form G of Compound 1-A to Form K of Compound 1-A under ambient conditions. FIG. 27 depicts the XRPD patterns of (top) Form K and (bottom) Reference Form G. XRPD analyses of Forms K and G of Compound 1-A were performed by X-Ray Powder Diffraction (XRPD) analysis method (2).

[0267] Form O of Compound 1-A was prepared by charging 15 mg of each of Form C of Compound 1-A and Form D of Compound 1-A to a vial. Saturated solutions (3-5 vols) of Compound 1-A in acetone, a 98.7: 1.3 %v / v acetone / water mixture, or 94.2:5.8%v / v acetone / water mixture were charged to the solids and stirred at the desired temperature for several days. Solids were isolated and then dried. On review of the wet XRPD data, a new form, Form O, a suspected acetone solvate was observed by XRPD. On reanalysis of the XRPD foils(after drying under ambient conditions), only Form C was observed, indicating the propensity of the acetone solvate to desolvate to Form C material. FIG. 28 shows representative XRPD patterns of (A) starting material Form C of Compound 1-A, (B) starting material Form D of Compound 1-A, a mixture of Form C and Form O of Compound 1-A in acetone, (D) 98.7: 1.3 acetone / water (F), or 94.2:5.8 acetone / water (H), and Form C of Compound 1-A formed in 80:20 acetone / water (C) or upon drying (E, G, I, J).

[0268] Form P of Compound 1-A was prepared by generating a saturated suspension of Form D of Compound 1-A in 2-MeTHF (dried over molecular sieves) and subjected to temperature cycling from 20 °C to 80 °C, held for 15 minutes cooled to 0 °C, held for 15 minutes and the cycle was then repeated heating from 0 °C to 80 °C. After holding overnight, the resulting suspension was centrifuged and the solids obtained were initially analyzed wet by XRPD before drying in a vacuum oven at 60 °C. Analyzed wet sample from 2-MeTHF displayed a novel XRPD pattern, Form P. Following drying, the Form P sample showed only slight conversion to Form A, indicating that Form P is likely a 2-MeTHF solvate which was not easily desolvated under the drying conditions employed. FIG. 29 depicts representative XRPD patterns for each of (A) input Form D of Compound 1-A, (B) example Form A of Compound 1-A, (C) Form P of Compound 1-A as obtained as above, and (D) a mixture of Form P and Form A of Compound 1-A.

[0269] Form Q of Compound 1-A was prepared by charging a mixture of Form B + D (minor), (about 30 mg) to a vial. MTBE (200 pL) was charged to the solids and the mixture stirred overnight at the desired temperature. The mixture was seeded with Forms A and D of Compound 1-A and stirred for several days. Solids were isolated by centrifugation, and then dried at ambient prior to analysis by XRPD, with further drying of solids in a vacuum oven (40 °C). XRPD foils were analyzed after storage under ambient conditions. XRPD analysis showed the formation of new material, Form Q, which was a suspected MTBE solvate. FIG. 30 depicts representative XRPD patterns of (A) seed Form A, (B) Seed Form D, (C) a mixture of Form Q, A, and D generated after drying at 40 °C under vacuum, (D-F) a mixture of Form Q, A, and D generated after drying under ambient conditions, (G) a mixture of Form Q, A, and D generated under wet conditions.

[0270] Forms R and T of Compound 1 -A were obtained during interconversion slurries.75 mg of Form B of Compound 1-A and 1.5 mL of IPA / heptane (40:60 % v / v) were stirred and seeded with Form D of Compound 1-A. Samples were removed from the mixture and isolated at selected intervals. Solids analyzed after 20 hours and 88 hours consisted of a novel form designated Form R. Sample removed after 88 hours was also subjected to drying under vacuum at 60 °C for 20 h and these solids converted to another novel Form T as a mixture with Form D of Compound 1-A. FIG. 31 depicts representative XRPD patterns for each of (A) Forms D, (B) Form R after 20 hours (C) Form R after 88 hours, (D) the mixture of Forms T and D after slurrying for 88 hours then drying under vacuum, and (E) the mixture of Forms S and D after slurrying for 116 hours.

[0271] Form R of Compound 1-A was also obtained during a crystallization experiment in isopropyl alcohol (3.5 volumes), using heptane as an anti-solvent. Form S was initially formed, but after prolonged slurrying (66 hours), Form R was generated. The mixture was seeded with Form D, causing a thickening of turbidity. A 0.5 mL aliquot was then removed, and 0.5 mL heptane added over 2 hours via syringe pump. This resulted in generation of a mobile slurry. XRPD analysis of sample displayed presence of Form S, which had previously been obtained by IPA / heptane slurry indicating a solvent related dependency for formation of this form. Further aging for 66 hours generated Form R solid.

[0272] Form S of Compound 1-A was obtained during interconversion slurries 75 mg of Form B of Compound 1-A and 1.5 mL of IPA / heptane (20:80 %v / v) (50 mg / mL) were stirred and seeded with Form D. Samples were removed and isolated at selected intervals via centrifuge filtration. Sample removed after 88 hours was also subjected to drying under vacuum at 60 °C for 20 hours. Form S of Compound 1-A was isolated after 20 hours and 88 hours slurrying of Form B in IPA / heptane (20:80 %v / v). After slurrying for 116 hours a mixture of Form S and Form D were observed. FIG. 32 depicts representative XRPD patterns for each of (A) Forms D, (B) Form S slurrying in IPA / heptane for 20 hours and (C) Form S slurrying in IPA / heptane for 88 hours, (D) the mixture of Forms T and D after slurrying for 88 hours then drying under vacuum, and (E) the mixture of Forms S and D after slurrying for 116 hours. DSC analysis of the dried mixture of Form S and Form D generated a thermogram with a first endothermic event atan onset temperature of about 11 1 °C and a second endothermic event at an onset temperature of about 181 °C.

[0273] Form S of Compound 1-A was also obtained during a crystallization experiment in isopropyl alcohol (3.5 volumes), using heptane as an anti-solvent.

[0274] Form T of Compound 1-A was formed during interconversion of Form B of Compound 1-A. 75 mg of Form B of Compound 1-A and 1.5 mb of IPA / heptane (20:80 %v / v) (50 mg / mL) were stirred and seeded with Form D. Samples were removed and isolated at selected intervals via centrifuge fdtration. Samples removed after 88 hours were also subjected to drying under vacuum at 60 °C for 20 hours. Solids that were dried consisted of a mixture of Form D and Form T. DSC analysis of the dried mixture of Form D and Form T generated a thermogram with a first endothermic event at an onset temperature of about 113 °C and a second endothermic event at an onset temperature of about 181 °C.Example 12: Equilibrium Solubility

[0275] The equilibrium solubility (~24 hours) of Form C and Form D of Compound 1-A was assessed by UPLC. Form C or Form D (~25 mg) were charged to a vial. Water (0.5 m ) was charged to the solids and stirred at the ambient temperature for 24 hours. Solids were isolated by centrifugation and solids dried at ambient prior to analysis by XRPD. Solutions were recovered and analyzed by HPLC (UPLC) according to Table 1 below:Table 1: UPLC Analysis Parameters

[0276] Form D had solubility of about 0.029 mg / mL and XRPD analysis of the solids showed the material remained physically stable, while Form C material had lower solubility of about 0.016 mg / mL and remained physically stable by XRPD.Example 13: Synthesis of Compound 1-A (N-[(lR)-l-[(S)-(2-chloro-3- fluorophenyl)hydroxymethyl]butyl]-7-fluoro-2,3-dihydro-2-oxo-lH-indole-4-carboxamide)Step 1: Preparation of tert-butyl (R)-(l-(methoxy(methyl)amino)-l-oxopentan-2- yl)carbamate (Compound 2-A)Part A

[0277] (R)-2-((tert-butoxycarbonyl)amino)pentanoic acid di cyclohexylamine (1 eq), was added to a reactor followed by 2-MeTHF (10 vol) and agitated. The slurry was cooled to -10 °C to -5 °C after which 10% aqueous sulfuric acid (5 vol) was added slowly over a period of 15 minutes maintaining the temperature at or below 20 °C. The mixture was then warmed to room temperature and stirred for at least 30 minutes. The mixture was allowed to settle, and the aqueous (bottom) layer was discharged. The remaining organic layer was washed with 10% aqueous sulfuric acid, a mixture of water and brine, and brine. Azeodistillation followed by filtration provided a solution of (R)-2-((tert-butoxycarbonyl)amino)pentanoic acid in 2-MeTHF.Part B

[0278] In a separate reactor, DMF (2 vol), A(O-dimethylhydroxylamine hydrochloride (1.2 eq), and 2-MeTHF (4 vol) were combined and agitated. Triethylamine (1.2 eq) was slowly added over a period of 30 minutes at a temperature of 30 °C or less. The reaction mixture was stirred at room temperature for at least one hour then cooled to -2 °C to 2 °C.Part C

[0279] In a separate reactor CDI (1.1 eq) was combined with 2-MeTHF (4 vol) and agitated under nitrogen atmosphere. The slurry was cooled to -2 to 2 °C after which the (R)-2-((tert- butoxycarbonyl)amino)pentanoic acid solution in 2-MeTHF was added slowly while maintaining a temperature of no more than 2 °C, and the reaction mixture was stirred for at least 1 hour.

[0280] The reaction mixture was then slowly added to the Part B reactor while maintaining the temperature of the reaction mixture at or below 2 °C. The reaction mixture was then warmed to room temperature and stirred for at least 3 hours. The reaction mixture was then slowly quenched with HC1 (IN) at a temperature of 25 °C or less, followed by washing with HC1 (1 N), with potassium phosphate dibasic (5% aqueous), with water, and with brine. The product wasazeotropically distilled, cooled to room temperature, and fdtered to yield a solution of tert-butyl (R)-(l-(methoxy(methyl)amino)-l-oxopentan-2-yl)carbamate (2-A) in 2-MeTHF.Step 2: Preparation of tert-butyl (R)-(l-(2-chloro-3-fluorophenyl)-l-oxopentan-2- yl)carbamate (Compound 4-A)Part A

[0281] A solution of isopropylmagnesium chloride (2 M in THF, 1.87 eq) was added to 1- bromo-2-chl oro-3 -fluorobenzene (1.7 eq) in 2-MeTHF (3.8 vol) maintaining the temperature of the reaction mixture at or below 5 °C. The reaction mixture was stirred for at least 2.5 hours.Part B

[0282] In a second reactor, 2-MeTHF (7 vol) was added to tert-butyl (R)-(l- (methoxy(methyl)amino)-l-oxopentan-2-yl)carbamate (Compound 2-A) and the reaction mixture was cooled to -10 to -5 °C. A solution of isopropylmagnesium chloride (2 M in THF, 1.0 eq) was then added over a period of 1 hour, maintaining the temperature at or below 5 °C.Part C

[0283] The product of Part A was slowly added to the reactor from Part B while maintaining a temperature at or below 15 °C. The reaction mixture was then warmed to 46 °C to 48 °C over a period of 2 hours then stirred at that temperature for 7 hours. The reaction mixture was cooled to -5 °C - 0 °C, then slowly quenched with acetic acid (6 eq) at room temperature, followed by washing with acetic acid, with water and brine, with aqueous potassium phosphate dibasic (15%), with water and brine, and with brine. The reaction mixture was then distilled to change solvents to 2-propanol. Following cooling to -5 °C to 0 °C over 2 hours, water (8 vol) was charged to crystallize the product, which was then isolated by filtration and dried to yield tert-butyl (R)-(l-(2-chloro-3 -fluorophenyl)- l-oxopentan-2-yl)carbamate (Compound 4-A).Step 1-3: Preparation of Compound 6-A

[0284] Toluene (6 vol) and isopropyl alcohol (11 eq) were added to tert-butyl (R)-(l-(2- chloro-3-fluorophenyl)-l-oxopentan-2-yl)carbamate (Compound 4-A, 1 eq) and aluminum isopropoxide (0.2 eq) at room temperature. The reaction mixture was heated to 50 °C over 2 hours and agitated at the same temperature for at least 10 hours. The reaction mixture was then cooled to room temperature and quenched with HC1 (IN), followed by washing with HC1 (1 N), with potassium phosphate dibasic (5% aqueous), with water, and with brine.

[0285] The reaction mixture was then distilled to switch solvents to toluene, filtered, and cyclopentyl methyl ether (CMPE, 4 vol) was added. HC1 (3 M) in CPME (7 eq) was then added slowly over a period of 1 hour while maintaining the temperature below 30 °C. The mixture was then stirred at room temperature for at least 24 hours. (lS,2R)-2-amino-l-(2-chloro-3- fluorophenyl)pentan-l-ol hydrochloride (Compound 6-A) was isolated by filtration, and dried.

[0286] The foregoing synthetic conditions, i.e., as specified in Step 1-3 above, provided a high yield of the R,S enantiomer product. If instead a mixture of S,R and R,S enantiomers is desired, a non-stereoselective reducing agent, such as sodium borohydride, may be used under the same conditions.6-A 1-A

[0287] 7 -Fluoro-2-oxoindoline-4-carboxylic acid (Compound 7, 1.2 eq), DMAP (2.5 eq) andEDC (1.5 eq) were charged to a pre-cooled reactor at 0 °C under nitrogen. DMF (5.5 vol) was added followed by (l S,2R)-2-amino-l -(2-chloro-3-fluorophenyl)pentan-l-ol hydrochloride (Compound 6-A). The reaction mixture was warmed to room temperature and stirred for at least 4 hours. Ethyl acetate (8 vol) was added, and the reaction mixture cooled to 13 - 17 °C. I N HC1 (5 vol) was then charged to the reactor and the reaction mixture was agitated. The reaction mixture was then filtered, and the filtrate allowed to settle, after which the lower aqueous phase was removed from the upper organic phase. The organic phase was then washed with 1 N HC1 and brine, potassium phosphate dibasic (5%) and brine, and then with water and brine, followed by brine. The reaction mixture was then distilled with ethyl acetate. The temperature was adjusted to 50-55 °C, and SilaMet S thiol resin (10 wt. %) was added and the resulting mixture stirred at the same temperature for at least 3 hours. The reaction mixture was then filtered, and the solvent was switched to ethanol. The reaction mixture was cooled to 15-20 °C over at least 1.5 h and stirred. Heptane (27 vol) was then added to obtain a slurry. Compound 1-A was isolated by filtration, washed with 4: 1 heptane / ethanol, dried, and analyzed by chiral HPLC, which revealed no detectable amount of Compound 1-B, 1-C, or 1-D. Due to instrument error of ± 0.2%, the stereochemical purity of the obtained compound was determined to be 99.8% or greater.[00288J First Exemplary Synthesis of Compound 7: 4-bromo-7-fluoroindoline-2,3-diketone (50 g, 205 mmol) and hydrazine hydrate (15.4 g (250 mmol, 80%) was added to ethylene glycol (250 mL) in a 500 mL three-necked flask and the reaction mixture was stirred for 30 minutes maintaining the temperature at 55-65 °C. The reaction was allowed to occur for 2-6 hours. Thetemperature was lowered to room temperature, and filtration was carried out to obtain 60 g of a crude product. In a separate three-neck flask, ethylene glycol (500 mb) and sodium acetate (1.7 g, 20.5 mmol) were added to the crude product (60 g) and the reaction temperature was raised to 145 °C after which the contents of the flask were concentrated under reduced pressure to a third of the original volume, cooled to 0-10 °C, filtered, leached with 100 mL of water, and dried in vacuum to obtain 40 g of 4-bromo-7-fluoroindolin-2-one. Methanol (300 mL), 4-bromo- 7-fluoroindolin-2-one (30 g), TEA (27 mL), and (dppf)PdCh (21.55 g) were charged to a 500 mL pressure reactor, which was purged with CO three times, maintaining the pressure of CO in the reaction kettle at 0.5 mPa and the temperature at 115-125 °C. The reaction was carried out for 10 h after which the reaction mixture was cooled to room temperature and concentrated. DMF and DCM were added, and the mixture was stirred for 30 minutes then filtered to obtain 23 g of 4-(but-l-en-2-yl)-7-fluoroindolin-2-one. Methanol (100 mL) and 4-(but-l-en-2-yl)-7- fluoroindolin-2-one (20 g, 95.7 mmol) were charged to a 250 mL three-neck flask and sodium hydroxide (7.7 g, 191 mmol) and water (100 mL) were added. The reaction mixture was stirred for 30 minutes at a temperature of 40 to 60 °C for 5 hours. The reaction mixture was then concentrated, and the pH adjusted to 1-2 with 1 M hydrochloric acid. The mixture was filtering to obtain 17.7 g of Compound 7.

[0289] Second Exemplary Synthesis of Compound 7:

[0290] A solution of 4-bromo-7-fluoro-indolin-2-one (1.0 eq) in THF (7.0 vols) was charged to a mixture of sodium hydride in mineral oil (60% w / w, 2.76 eq) and THF (3.0 vols) at 5 ± 5 °C in a first vessel. The mixture was stirred for 10 mins at 5 ± 5 °C and a solution of tertbutyldimethylsilyl chloride (TBDMS-C1, 2.56 eq) in THF (2.5 vols) was charged at 5 ± 5 °C. The mixture was warmed to 20 to 25 °C and stirred for 2 hours until reaction completion. The reaction mixture was cooled to -10 °C. A biphasic mixture of 1 M potassium phosphate buffer (10.0 vols) and n-heptane (12.0 vols) was cooled to 15 ± 5 °C in a second vessel. The contents ofthe first vessel were added to the second vessel over approximately 1 hour, during which time off-gassing was controlled by the rate of addition and a temperature of 15 ± 5 °C was maintained. The residue in the first vessel was rinsed into the second vessel with THF (1.0 vols). The biphasic mixture was warmed to 25 ± 5 °C and the two phases were separated. The organic layer was washed with water (10.0 vols) at 25 ± 5 °C and distilled in vacuo to 8 volumes at approximately 50 °C. n-Heptane (3.0 vols) was added, and the mixture was distilled in vacuo to 8 volumes at approximately 50 °C. The mixture was cooled to 25 ± 5 °C and analyzed for THF content by GC-HS. Basic aluminum oxide (0.1% w / w) was added, followed by rinsing with n- heptane (1.0 vols) and the mixture was stirred at 25 ± 5 °C for about 1 hour. The slurry was filtered into a third vessel, followed by a line rinse with n-heptane (2.0 vols). The following procedure was repeated three times: isopropanol (9.0 vols) was added, and the solution was distilled to 7 to 8 volumes at NMT 60 °C. The mixture was heated at 75 to 80 °C until dissolution was confirmed. The solution was cooled to 17 ± 3 °C at 0.2 °C / min and held at this temperature for approximately 22 hours. The solid was filtered off, washed with isopropanol (4.0 vols) at 17 ± 3 °C, and dried in vacuo at 50 ± 5 °C. This resulted in 4-bromo-l-(tert- butyldimethylsilyl)-2-((tert-butyldimethylsilyl)oxy)-7-fluoro-lH-indole as Compound 8:

[0291] A solution of the bis-silyl-bromo-oxindole intermediate (Compound 8, 1 .00 eq) in THF (6.8 vols) was cooled to 4°C in a vessel. Isopropyl magnesium chloride in THF (2 M, 0.47 eq) was added to the vessel over 8 minutes, followed by the addition of n-butyl lithium in hexanes (2.5 M, 0.93 eq) over 10 minutes at 0-5 °C. The mixture was stirred for 15 minutes. Gaseous carbon dioxide (1.5 eq) was added by sparging, with the gas addition rate adjusted as needed to maintain the reaction temperature <10 °C, after which time the mixture was stirred at 0 °C for 70 minutes. The mixture was diluted with methanol (1.4 vol) then 85% w / w H3PO4 (2.5 eq) was added. The mixture was warmed to 25°C over 3 hours and stirred for at least 16 hours. Water (6 vols) was added and the mixture was agitated for 30 minutes. The pH of the mixture was adjusted to pH < 2 by addition of 85% w / w aqueous H3PO4 and stirred for another 30 minutes. The solids were isolated by fdtration, washed with water (2 x 1.4 vols) THF:MeOH (85: 15 v / v, 1.4 vol), then MeOH (1.4 vol) and dried at 50 °C under vacuum to give Compound 7.* * * * *

[0292] Throughout this application, various publications, patents, patent applications and other documents have been referenced. The disclosures of these publications, patents, patent applications and other documents in their entireties are hereby incorporated by reference in this application for all purposes, including in order to more fully describe the state of the art to which this the subject matter disclosed herein pertains. Although the disclosed subject matter has been described with reference to the examples provided above, it should be understood that various modifications could be made without departing from the spirit of the disclosed subject matter. Many variations will become apparent to those skilled in the art upon review of this specification.

Claims

CLAIMSWhat is claimed is:

1. A solid form of Compound 1 or a pharmaceutically acceptable solvate thereof:

2. The solid form of claim 1, wherein Compound 1 is Compound 1-A, Compound 1-D, or a mixture thereof:(1-D)3. The solid form of claim 1, wherein Compound 1 is Compound 1-A.

4. The solid form of any one of claims 1-3, which is crystalline.

5. The solid form of claim 4, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least three peaks selected from the group consisting of approximately 9.2, 9.8, 10.2, 16.4, 19.6, and 23.3 °20.

6. The solid form of claim 4, which is characterized by an XRPD pattern comprising at least four peaks selected from the group consisting of approximately 9.2, 9.8, 10.2, 16.4, 19.6, and 23.3 °20.

7. The solid form of claim 4, which is characterized by an XRPD pattern comprising at least five peaks selected from the group consisting of approximately 9.2, 9.8, 10.2, 16.4, 19.6, and 23.3 °20.

8. The solid form of claim 4, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises peaks at approximately 9.8 and 23.3 °20.

9. The solid form of claim 8, which is further characterized by an XRPD pattern comprising peaks at approximately 9.2 and 10.2 °29.

10. The solid form of claim 4, which is characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG. 1.

11. The solid form of claim 4, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least three peaks selected from the group consisting of approximately 9.5, 12.0, 12.3, 14.6, 24.0, and 29.4 °20.

12. The solid form of claim 4, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least four peaks selected from the group consisting of approximately 9.5, 12.0, 12.3, 14.6, 24.0, and 29.4 °20.

13. The solid form of claim 4, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least five peaks selected from the group consisting of approximately 9.5, 12.0, 12.3, 14.6, 24.0, and 29.4 °20.

14. The solid form of claim 4, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises peaks at approximately 9.5, 12.0, and 29.4 °29.

15. The solid form of claim 14, which is further characterized by an XRPD pattern comprising peaks at approximately 12.3 and 14.6 °20.

16. The solid form of claim 4, which is characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG. 2.

17. The solid form of any one of claims 11-16, which is anhydrous.

18. The solid form of claim 4, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least three peaks selected from the group consisting of approximately 11.7, 12.5, 14.0, 22.2, 23.1, 23.5, and 28.2 °20.

19. The solid form of claim 4, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at four three peaks selected from the group consisting of approximately 11.7, 12.5, 14.0, 22.2, 23.1, 23.5, and 28.2 °29.

20. The solid form of claim 4, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least five peaks selected from the group consisting of approximately 11.7, 12.5, 14.0, 22.2, 23.1, 23.5, and 28.2 °29.

21. The solid form of claim 4, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises peaks at approximately 14.0, 23.1, and 28.2 °29.

22. The solid form of claim 21, which is further characterized by an XRPD pattern comprising peaks at approximately 11.7 and 12.5 °29.

23. The solid form of any one of claims 18 to 22, which exhibits, as characterized by DSC, a thermal event with an onset temperature of about 151°C to about 156°C.

24. The solid form of any one of claims 18 to 23, which exhibits a weight loss of about 2.2% to about 2.7% upon heating from about 30 °C to about 144 °C.

25. The solid form of claim 4, which is characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG. 3.

26. The solid form of any one of claims 18-25, which is a hydrate of Compound 1-A.

27. The solid form of claim 26, which is a hemihydrate of Compound 1-A.

28. The solid form of claim 4, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least three peaks selected from the group consisting of approximately 9.4, 10.4, 16.2, 19.6, 22.2, and 24.5 °20.

29. The solid form of claim 4, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at four three peaks selected from the group consisting of approximately 9.4, 10.4, 16.2, 19.6, 22.2, and 24.5 °29.

30. The solid form of claim 4, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least five peaks selected from the group consisting of approximately 99.4, 10.4, 16.2, 19.6, 22.2, and 24.5 °29.

31. The solid form of claim 4, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises peaks at approximately 10.4, 19.6, and 22.2 °29.

32. The solid form of claim 31, which is further characterized by an XRPD pattern comprising peaks at approximately 9.4 and 24.5 °29.

33. The solid form of any one of claims 28 to 31, which exhibits, as characterized by DSC, a thermal event with an onset temperature of about 182.5°C.

34. The solid form of any one of claims 28 to 33, which exhibits a weight loss of about 0.29% upon heating from about 30 °C to about 122 °C.

35. The solid form of claim 4, which is characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG. 6.

36. The solid form of any one of claims 28-35, which is anhydrous.

37. The solid form of claim 1, which is amorphous.

38. The solid form of claim 4, which is characterized by an XRPD pattern that matches the XRPD pattern depicted in FIG. 19.

39. The solid form of claim 4, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least three peaks selected from the group consisting of approximately 8.7, 10.5, 16.5, 18.0, 19.1, and 22.9 °20.

40. The solid form of claim 4, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least four peaks selected from the group consisting of approximately 8.7, 10.5, 16.5, 18.0, 19.1, and 22.9 °20.

41. The solid form of claim 4, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least five peaks selected from the group consisting of approximately 8.7, 10.5, 16.5, 18.0, 19.1, and 22.9 °20.

42. The solid form of claim 4, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises peaks at approximately 8.7, 10.5, and 18.0 °29.

43. The solid form of claim 42, which is further characterized by an XRPD pattern comprising peaks at approximately 19.1 and 22.9 °20.

44. The solid form of any one of claims 39-43, which is a methanol solvate of Compound 1-A.

45. The solid form of claim 4, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least three peaks selected from the group consisting of approximately 8.68, 8.7, 9.4, 16.0, 18.0, 22.9, 23.0, and 26.3 °20.

46. The solid form of claim 4, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least four peaks selected from the group consisting of approximately 8.7, 9.4, 16.0, 18.0, 22.9, 23.0, and 26.3 °20.

47. The solid form of claim 4, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least five peaks selected from the group consisting of approximately 8.7, 9.4, 16.0, 18.0, 22.9, 23.0, and 26.3 °20.

48. The solid form of claim 4, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises peaks at approximately 8.7, 9.4, and 16.0 °20.

49. The solid form of claim 48, which is further characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises peaks at approximately 18.0 and 23.0 °20.

50. The solid form of any one of claims 45-49, which is an ethanol solvate of Compound 1-A.51 . The solid form of claim 4, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least three peaks selected from the group consisting of approximately 11.2, 12.9, 13.7, 22.2, 23.7, and 27.8 °20.

52. The solid form of claim 4, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least four peaks selected from the group consisting of approximately 11.2, 12.9, 13.7, 22.2, 23.7, and 27.8 °20.

53. The solid form of claim 4, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises at least five peaks selected from the group consisting of approximately 11.2, 12.9, 13.7, 22.2, 23.7, and 27.8 °20.

54. The solid form of claim 4, which is characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises peaks at approximately 11.2, 12.9, and 13.7 °20.

55. The solid form of claim 54, which is further characterized by an XRPD pattern, which when measured using Cu Ka radiation, comprises peaks at approximately 7.2 and 23.7 °29.

56. A pharmaceutical composition comprising the solid form of any one of claims 1 to 55, and a pharmaceutically acceptable excipient.

57. The pharmaceutical composition of claim 56, wherein the pharmaceutical composition is formulated as a solid formulation.

58. The pharmaceutical composition of claim 56 or 57, wherein the formulation is suitable for oral administration.

59. The formulation of any one of claims 56-58, wherein the formulation is a tablet or a capsule.

60. A method of treating a patient having a disease or disorder related to the polymerization of alpha-1 antitrypsin comprising administering to the patient the solid form of any one of claims 1-55.

61. A method of treating a patient having a disease or disorder related to polymerization of alpha- 1 antitrypsin comprising administering the pharmaceutical composition of any one of claims 56-59.

62. The method of claim 60 or 61, wherein the disease or disorder related to the polymerization of alpha- 1 antitrypsin is a serpinopathy.

63. The method of any one of claims 60-62, wherein the disease or disorder related to the polymerization of alpha-1 antitrypsin is associated with a Z-AT mutation of alpha-1 antitrypsin.

64. The method of any one of claims 60-63, wherein the disease or disorder related to the polymerization of alpha-1 antitrypsin is selected from the group consisting of alpha-1 antitrypsin deficiency, liver dysfunction, fibrosis, cirrhosis, liver failure,hepatocellular carcinoma, liver cirrhosis, autoimmune hepatitisjaundice, inflammatory conditions of the skin, dermatitis, and pruritus.

65. A method of making the solid form of any one of claims 5-10, comprising heating the solid form of any one of claims 51-55 to a temperature of about 165°C.

66. A method of making the solid form of any one of claims 5-10, comprising drying the solid form of any one of claims 45-49 under ambient conditions.

67. A method of making the solid form of any one of claims 18-25, comprising contacting the solid form of any one of claims 28-35 with a mixture of 80:20 ethanol in water at room temperature.

68. A method of making the solid form of any one of claims 18-25, comprising subjecting the solid form of any one of claims 51-55 to ambient conditions.

69. A method of making the solid form of any one of claims 18-25, comprising contacting the solid form of claim 37 or 38 to a mixture of acetone in water, wherein the mixture has an Awof about 0.26, at a temperature of about 5°C to about 50 °C.

70. A method of making the solid form of any one of claims 28-36, comprising contacting the solid form of any one of claims 11-17 with isopropyl alcohol at a temperature of about 25 °C to about 50 °C.

71. A method of making the solid form of any one of claims 28-36, comprising drying the solid form of any one of claims 45-49 at a temperature of at least 60 °C under vacuum.

72. A method of making the solid form of claim 28-36, comprising drying the solid form of any one of claims 39-44 at room temperature.

73. A method of making the solid form of claim 28-36, comprising contacting the solid form of claim 37 or 38 with acetone at a temperature of about 50 °C.

74. A method of making the solid form of claim 37 or 38, comprising lyophilizing a slurry of the solid form of any one of claims 28-36 in t-butyl alcohol.

75. A method of making the solid form of any one of claims 39-44, comprising contacting the solid form of any one of claims 28-36 with a mixture of methanol in water, wherein the mixture has a water activity Awof about 0.64, and wherein the ratio of methanol to water is about 69:31.

76. A method of making the solid form of any one of claims 45-50, comprising contacting the solid form of any one of claims 18-25 with a mixture of ethanol in water, wherein the mixture has a water activity Awof about 0.65, and wherein the ratio of ethanol to water is about 80:20.

77. A method of making the solid form of any one of claims 51-55, comprising heating the solid form of any one of claims 18-25 to a temperature of about 120 °C to about 140 °C under vacuum.

78. A method of making a pharmaceutical composition comprising combining a solid form of any one of claims 1-55 with a pharmaceutically acceptable excipient.

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