Solid forms of compounds for modulating cot

Abstract

Disclosed herein are solid forms of compounds useful for modulating Cot. The disclosure also relates to pharmaceutical compositions comprising one or more of the solid forms disclosed herein, and methods of using the solid forms to treat conditions mediated by Cot. The present disclosure also relates to processes for obtaining such solid forms.

Description

[0001] Cross-references

[0002] This application claims priority to U.S. Provisional Application No. 63 / 341,289, filed on May 12, 2022, which is incorporated herein by reference in its entirety for all purposes. Technical Field

[0003] The present disclosure relates to solid forms of compounds useful for modulating Cot (Osaka thyroid), as well as their pharmaceutical formulations and therapeutic uses. Background Art

[0004] The Cot (Osaka thyroid carcinoma) protein is a serine / threonine kinase and a member of the MAP kinase kinase kinase (MAP3K) family. It is also known as "Tpl2" (tumor progression locus), "MAP3K8" (mitogen-activated protein kinase kinase kinase 8) or "EST" (Ewing sarcoma transformant). Cot was identified by its oncogenic transforming activity in cells and has been shown to regulate oncogenic and inflammatory pathways.

[0005] Cot is known to be upstream in the MEK-ERK pathway and is essential for LPS-induced tumor necrosis factor-α (TNF-α) production. Cot has been shown to be involved in the production and signaling of TNFα. TNFα is a proinflammatory cytokine and plays an important role in inflammatory diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), inflammatory bowel disease (IBD), diabetes, sepsis, psoriasis, misregulated TNFα expression, and transplant rejection.

[0006] Compounds that bind to the Osaka thyroid carcinoma (Cot) protein can act as modulators of Cot. Cot modulators can be used to treat and / or prevent diseases and conditions by binding to Cot. One compound that can be used to modulate Cot is a compound of Formula I:

[0007]

[0008] (I)

[0009] Although many compounds are known that can be used to modulate Cot, what is desired in the art is a physically stable form of a compound of Formula I or a pharmaceutically acceptable salt thereof having desirable properties such as good physical and chemical stability, good aqueous solubility, and good bioavailability. For example, pharmaceutical compositions that address the challenges of stability, variable pharmacodynamic responses, drug-drug interactions, pH effects, food effects, and / or oral bioavailability are needed.

[0010] Therefore, there is a need for stable forms of compounds of Formula I having suitable chemical and physical stability for formulation, therapeutic use, manufacture and storage of the compounds.

[0011] Solid forms may possess properties such as bioavailability, stability, purity, and / or manufacturability under certain conditions that may be suitable for medical or pharmaceutical use. Summary of the invention

[0012] In some embodiments, the present disclosure relates to solid forms of Formula I:

[0013]

[0014] Formula I

[0015] and pharmaceutically acceptable salts, solvates and hydrates thereof.

[0016] These forms can be used, for example, to treat human patients with inflammatory diseases or conditions, such as rheumatoid arthritis (RA), lupus, osteoarthritis (OA) or inflammatory bowel disease (IBD) such as ulcerative colitis (UC) or Crohn's disease (CD), non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), idiopathic pulmonary fibrosis (IPF), interstitial lung disease (ILD), diabetic nephropathy (DKD) or chronic kidney disease (CKD). The solid forms of the present disclosure can be used to prepare drugs for the treatment of inflammatory diseases. The solid forms of the present disclosure can be used to regulate Cot.

[0017] In some embodiments, the present disclosure relates to Amorphous Form I.

[0018] In some embodiments, the disclosure relates to Form I of Formula I.

[0019] In some embodiments, the disclosure relates to Form II of Formula I.

[0020] In some embodiments, the disclosure relates to Formula I Form III.

[0021] In some embodiments, the disclosure relates to Formula I Form IV.

[0022] In some embodiments, the disclosure relates to Formula I Form V.

[0023] In some embodiments, the disclosure relates to Formula I Form VI.

[0024] In some embodiments, the disclosure relates to Formula I Form VII.

[0025] In some embodiments, the disclosure relates to Formula I Form VIII.

[0026] In some embodiments, the disclosure relates to Formula I Form IX.

[0027] In some embodiments, the disclosure relates to Form X of Formula I.

[0028] In some embodiments, the disclosure relates to Formula I Form XI.

[0029] In some embodiments, the disclosure relates to Formula I Form XII.

[0030] In some embodiments, the disclosure relates to Formula I Form XIII.

[0031] In some embodiments, the disclosure relates to Formula I Form XIV.

[0032] In some embodiments, the disclosure relates to Formula I Form XV.

[0033] In some embodiments, the present disclosure relates to 2-(4-hydroxybenzoyl)benzoate salts of Formula I.

[0034] In some embodiments, the present disclosure relates to the vanillic acid salt of Formula I.

[0035] In some embodiments, the disclosure relates to the hippurate salt of Formula I.

[0036] In some embodiments, the disclosure relates to the maleate salt of Formula I.

[0037] In some embodiments, the disclosure relates to glyoxylate salts of Formula I.

[0038] In some embodiments, the present disclosure relates to L-pyroglutamate of Formula 1.

[0039] In some embodiments, the present disclosure relates to the 2-naphthalenesulfonate salt of Formula I.

[0040] In some embodiments, the present disclosure relates to 1-naphthalenesulfonate salts of Formula I.

[0041] In some embodiments, the present disclosure relates to 1-hydroxy-2-naphthoic acid salts of Formula I.

[0042] In some embodiments, the disclosure relates to Formula I S-mandelate salt.

[0043] In some embodiments, the disclosure relates to Formula I gentisate salts.

[0044] In some embodiments, the disclosure relates to Formula I citrate salts.

[0045] In some embodiments, the disclosure relates to Formula 1 R-mandelate salt.

[0046] In some embodiments, the disclosure relates to Formula I benzoate salts.

[0047] In some embodiments, the present disclosure relates to methylparabenate of Formula I.

[0048] In some embodiments, the present disclosure relates to the caffeic acid salt of Formula I.

[0049] In some embodiments, the disclosure relates to the glycolic acid salt of Formula I.

[0050] In some embodiments, the disclosure relates to α-ketobutyrate salts of Formula I.

[0051] In some embodiments, the disclosure relates to Formula I pyruvate salts.

[0052] In some embodiments, a pharmaceutical composition comprises a therapeutically effective amount of a solid form of Formula I. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] FIG1 shows the XRPD pattern of Amorphous Form I.

[0054] FIG2 shows the DSC thermogram of Amorphous Form I.

[0055] FIG3 shows the TGA thermogram of Amorphous Form I.

[0056] FIG4 shows the DVS isotherm of Amorphous Form I.

[0057] FIG5 shows the XRPD pattern of Form I of Formula I.

[0058] FIG6 shows the DSC thermogram of Form I of Formula I.

[0059] FIG. 7 shows the XRPD pattern of Form II of Formula I.

[0060] FIG. 8 shows the Whole Pattern Pawley Refinement of Form II of Formula I (85% RH).

[0061] FIG. 9 shows the DVS isotherm of Form II of Formula I.

[0062] FIG. 10 shows VH-XRD data plotting RH vs. scan.

[0063] Figure 11 shows the XRPD pattern of Form III of Formula I (RH 36%; KF 2.3% water).

[0064] Figure 12 shows VH-XRD data for Form III of Formula I depicting XRPD taken at 40% RH.

[0065] Figure 13 shows the full pattern Poly refinement of Formula I Form III at 40% RH.

[0066] FIG. 14 shows the DVS isotherm of Formula I Form III.

[0067] Figure 15 shows the full pattern Poly refinement of Formula I Form IV at 0% RH.

[0068] Figure 16 shows the XRPD pattern of Form IV of Formula I at 5% RH.

[0069] Figure 17 shows the XRPD pattern of Form V of Formula I.

[0070] Figure 18 shows the DSC thermogram of Form V of Formula I.

[0071] Figure 19 shows the XRPD pattern of Formula I Form VI.

[0072] Figure 20 shows an enlarged view of the XRPD pattern of Formula I Form VI.

[0073] Figure 21 shows the DSC thermogram of Formula I Form VI.

[0074] Figure 22 shows the XRPD pattern of Formula I Form VII.

[0075] Figure 23 shows the XRPD pattern of Formula I Form VIII.

[0076] Figure 24 shows the XRPD pattern of Formula I Form IX.

[0077] FIG. 25 shows an XRPD pattern of Form X of Formula I.

[0078] Figure 26 shows the XRPD pattern of Formula I Form XI.

[0079] Figure 27 shows the XRPD pattern of Formula I Form XII.

[0080] Figure 28 shows the XRPD pattern of Formula I Form XIII.

[0081] Figure 29 shows the XRPD pattern of Formula I Form XIV.

[0082] Figure 30 shows the XRPD pattern of Formula I Form XV.

[0083] FIG31 shows the XRPD pattern of Form A of 2-(4-hydroxybenzoyl)benzoate salt of Formula I.

[0084] FIG32 shows the XRPD pattern of Form B of 2-(4-hydroxybenzoyl)benzoate of Formula I.

[0085] FIG33 shows the DSC thermogram of Form B of 2-(4-hydroxybenzoyl)benzoate of Formula I.

[0086] FIG34 shows the TGA thermogram of Form B of 2-(4-hydroxybenzoyl)benzoate salt of Formula I.

[0087] Figure 35 shows the XRPD pattern of the vanillic acid salt Form A of Formula I.

[0088] FIG36 shows the XRPD pattern of Form B of the vanillic acid salt of Formula I.

[0089] FIG37 shows the DSC thermogram of the vanillic acid salt Form B of Formula I.

[0090] FIG38 shows the TGA thermogram of the vanillic acid salt Form B of Formula I.

[0091] FIG39 shows an XRPD pattern of Form A hippurate salt of Formula I.

[0092] FIG40 shows an XRPD pattern of Form B hippurate salt of Formula I.

[0093] FIG. 41 shows the DSC thermogram of Form B hippurate salt of Formula I.

[0094] FIG42 shows the TGA thermogram of Form B hippurate salt of Formula I.

[0095] Figure 43 shows the XRPD pattern of Formula I maleate salt Form A.

[0096] Figure 44 shows the XRPD pattern of Formula I maleate salt Form B.

[0097] FIG. 45 shows the DSC thermogram of Formula I maleate salt Form B.

[0098] Figure 46 shows the TGA thermogram of Formula I maleate salt Form B.

[0099] Figure 47 shows the XRPD pattern of glyoxylate salt Form A of Formula I.

[0100] Figure 48 shows the XRPD pattern of glyoxylate salt Form B of Formula I.

[0101] FIG. 49 shows the DSC thermogram of glyoxylate salt Form B of Formula I.

[0102] Figure 50 shows the TGA thermogram of glyoxylate salt Form B of Formula I.

[0103] Figure 51 shows the XRPD pattern of L-pyroglutamate salt of Formula I (wet cake).

[0104] Figure 52 shows the DSC thermogram of Formula I L-pyroglutamate salt (air dried).

[0105] Figure 53 shows the XRPD pattern of Formula I 2-naphthalenesulfonate salt (wet cake).

[0106] Figure 54 shows the XRPD pattern of Formula I 2-naphthalenesulfonate salt (air dried).

[0107] Figure 55 shows the DSC thermogram of Formula I 2-naphthalenesulfonate salt (air dried).

[0108] Figure 56 shows the TGA thermogram of Formula I 2-naphthalenesulfonate salt (air dried).

[0109] Figure 57 shows the XRPD pattern of Formula I 1-naphthalenesulfonate salt (wet cake).

[0110] Figure 58 shows the XRPD pattern of Formula I 1-naphthalenesulfonate salt (air dried).

[0111] Figure 59 shows the DSC thermogram of the 1-naphthalenesulfonate salt of Formula I (air dried).

[0112] Figure 60 shows the XRPD pattern of Formula I 1-hydroxy-2-naphthoate salt (wet cake).

[0113] Figure 61 shows the XRPD pattern of Formula I 1-hydroxy-2-naphthoate salt (air dried).

[0114] Figure 62 shows the DSC thermogram of Formula I 1-hydroxy-2-naphthoate salt (air dried).

[0115] Figure 63 shows the TGA thermogram of Formula I 1-hydroxy-2-naphthoate salt (air dried).

[0116] Figure 64 shows the XRPD pattern of Formula I S-mandelate Salt Form A.

[0117] Figure 65 shows the XRPD pattern of Formula I S-mandelate Salt Form B.

[0118] Figure 66 shows the DSC thermogram of Formula I S-mandelate Salt Form B.

[0119] Figure 67 shows the TGA thermogram of Formula I S-mandelate Salt Form B.

[0120] Figure 68 shows the XRPD pattern of the gentisate salt of Formula I (wet cake).

[0121] Figure 69 shows the XRPD pattern of the gentisate salt of Formula I (air-dried).

[0122] Figure 70 shows the DSC thermogram of the gentisate salt of Formula I (air dried).

[0123] Figure 71 shows the TGA thermogram of the gentisate salt of Formula I (air dried).

[0124] Figure 72 shows the XRPD pattern of the citrate salt of Formula I (wet cake).

[0125] Figure 73 shows the XRPD pattern of the citrate salt of Formula I (air dried).

[0126] Figure 74 shows the DSC thermogram of the citrate salt of Formula I (air dried).

[0127] Figure 75 shows the TGA thermogram of the citrate salt of Formula I (air dried).

[0128] Figure 76 shows the XRPD pattern of Formula I R-mandelate Salt Form A.

[0129] Figure 77 shows the XRPD pattern of Formula I R-mandelate Salt Form B.

[0130] FIG. 78 shows the DSC thermogram of Formula I R-mandelate Salt Form B.

[0131] Figure 79 shows the TGA thermogram of Formula I R-mandelate Salt Form B.

[0132] Figure 80 shows the XRPD pattern of Formula I benzoate salt Form A.

[0133] Figure 81 shows the XRPD pattern of Form B benzoate salt of Formula I.

[0134] Figure 82 shows the DSC thermogram of Formula I benzoate salt Form B.

[0135] Figure 83 shows the TGA thermogram of Form B benzoate salt of Formula I.

[0136] Figure 84 shows the XRPD pattern of methyl paraben, Form A of Formula I.

[0137] Figure 85 shows the XRPD pattern of methyl paraben, Form B of Formula I.

[0138] Figure 86 shows the DSC thermogram of methyl paraben Form B of Formula I.

[0139] Figure 87 shows the TGA thermogram of methyl paraben, Form B of Formula I.

[0140] Figure 88 shows the XRPD pattern of the caffeic acid salt of Formula I (wet cake).

[0141] Figure 89 shows the XRPD pattern of the caffeic acid salt of Formula I (air dried).

[0142] Figure 90 shows the DSC thermogram of the caffeic acid salt of Formula I (air dried).

[0143] Figure 91 shows the TGA thermogram of the caffeic acid salt of Formula I (air dried).

[0144] Figure 92 shows the XRPD pattern of the wet cake of the glycolic acid salt of Formula I.

[0145] Figure 93 shows the XRPD pattern of the dried glycolic acid salt of Formula I.

[0146] Figure 94 shows the XRPD pattern of the wet cake of the α-ketobutyrate salt of Formula I.

[0147] Figure 95 shows the XRPD pattern of the dried α-ketobutyrate salt of Formula I.

[0148] Figure 96 shows the XRPD pattern of the Formula I pyruvate salt wet cake.

[0149] Figure 97 shows the XRPD pattern of the dried pyruvate salt of Formula I. DETAILED DESCRIPTION

[0150] In the following description, certain specific details are set forth in order to provide a thorough understanding of the various embodiments of the present disclosure. However, it will be appreciated by those skilled in the art that the present disclosure may be practiced without these details. Under the understanding that the present disclosure is considered to be an illustration of the claimed subject matter rather than intended to limit the appended claims to the specific embodiments shown, several embodiments are described below. The titles used throughout the present disclosure are provided only for convenience and should not be construed as limiting the claims in any way. The embodiments illustrated under any title may be combined with the embodiments illustrated under any other title.

[0151] definition

[0152] Unless the context requires otherwise, throughout this specification and claims, the word "comprise" and variations such as "include" and "comprising" are to be interpreted in an open, inclusive sense, ie, to mean "including, but not limited to."

[0153] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in conjunction with the embodiment is included in at least one embodiment of the present disclosure. Thus, the phrases "in one embodiment" or "in an embodiment" appearing in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, in one or more embodiments, the particular features, structures, or characteristics may be combined in any suitable manner.

[0154] Reference throughout this specification to "compound" embodiments includes crystalline, salt, co-crystal, hydrate, solvate and / or amorphous forms of the formulae and / or compounds disclosed herein. Thus, the phrase "a compound of Formula I" may include occurrences of Amorphous Form I; Form I of Formula I; Form II of Formula I; Form III of Formula I; Form IV of Formula I; Form V of Formula I; Form VI of Formula I; Form VII of Formula I; Form VIII of Formula I; Form IX of Formula I; Form X of Formula I; Form XI of Formula I; Form XII of Formula I; Form XIII of Formula I; Form XIV of Formula I; Form XV of Formula I; 2-(4-hydroxybenzoyl)benzoate of Formula I; vanillate of Formula I; hippurate of Formula I; maleate of Formula I; glyoxylate of Formula I; L-pyroglutamate of Formula I; 2-naphthalenesulfonate of Formula I; 1-naphthalenesulfonate of Formula I; 1-hydroxy-2-naphthalenesulfonate of Formula I; S-mandelate of Formula I; gentisate of Formula I; citrate of Formula I; R-mandelate of Formula I; benzoate of Formula I; methylparaben of Formula I; caffeate of Formula I; glycolate of Formula I; α-ketobutyrate; and / or pyruvate of formula I.

[0155] The disclosure disclosed herein is also intended to encompass all pharmaceutically acceptable compounds of Formula I that are isotopically labeled by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 Cl, 123 I and 125 I. These radiolabeled compounds can be used to help determine or measure the effectiveness of a compound by characterizing, for example, the site or mode of action or the binding affinity for a pharmacologically important site of action. Certain isotopically labeled compounds of Formula I, such as those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose due to their ease of incorporation and readily available means of detection.

[0156] Using heavier isotopes such as deuterium (i.e.2 H) substitution may offer certain therapeutic advantages resulting from greater metabolic stability. For example, in vivo half-life may be increased or dosage requirements may be reduced. Thus, in some circumstances, heavier isotopes may be preferred.

[0157] Using positron emitting isotopes such as 11 C. 18 F. 15 O and 13 Substitution of N can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of Formula I can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the Examples listed below, using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.

[0158] "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0159] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and that the description includes substituted aryl groups and aryl groups that are not substituted.

[0160] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent and / or emulsifier, or a combination of one or more of the foregoing, which have been approved by the U.S. Food and Drug Administration as acceptable for use in humans or livestock.

[0161] "Pharmaceutical composition" refers to a formulation of a compound of the present disclosure and a medium generally accepted in the art for delivering the biologically active compound to a mammal (e.g., a human). Such a medium therefore includes all pharmaceutically acceptable excipients.

[0162] "Effective amount" or "therapeutically effective amount" refers to the amount of a compound according to the present disclosure that, when administered to a patient in need thereof, is sufficient to achieve treatment of the disease state, condition, or disorder for which the compound has utility. Such an amount will be sufficient to elicit the biological or medical response of the tissue system or patient sought by the researcher or clinician. The amount of a compound according to the present disclosure that constitutes a therapeutically effective amount will vary depending on factors such as the compound and its biological activity, the composition for administration, the time of administration, the route of administration, the excretion rate of the compound, the duration of treatment, the type of disease state or disorder treated and its severity, the drugs combined with or used concurrently with the compounds of the present disclosure, and the age, weight, general health, sex, and diet of the patient. Such a therapeutically effective amount can be routinely determined by those of ordinary skill in the art, taking into account their own knowledge, the prior art, and the present disclosure.

[0163] "Preventing" or "prevention" means any treatment of a disease or condition that results in clinical symptoms of the disease or condition not developing. In some embodiments, the compound may be administered to a subject (including humans) who is at risk or has a family history of the disease or condition.

[0164] "Treatment" and "management" of disease include the following:

[0165] (1) preventing or reducing the risk of developing the disease, that is, causing clinical symptoms of the disease to not develop in a subject who may be exposed to or susceptible to the disease but who does not yet experience or display symptoms of the disease,

[0166] (2) inhibiting the disease, i.e., preventing or reducing the development of the disease or its clinical symptoms, and

[0167] (3) Remission of disease, i.e., regression of the disease or its clinical symptoms.

[0168] The term "subject" or "patient" refers to an animal, such as a mammal (including a human), that has been or will be the subject of treatment, observation, or experiment. The methods described herein can be used for human therapy and / or veterinary applications. In some embodiments, the subject is a mammal (or patient). In some embodiments, the subject (or patient) is a human, livestock (e.g., dogs and cats), farm animals (e.g., cattle, horses, sheep, goats, and pigs), and / or laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs, rabbits, dogs, and monkeys). In some embodiments, the subject (or patient) is a human. "A person (or patient) in need thereof" refers to a person who may have or is suspected of having a disease or condition that would benefit from certain treatments; for example, treatment with a compound disclosed herein according to the present application.

[0169] Reference herein to "about" a value or parameter includes (and describes) embodiments involving the value or parameter itself. For example, reference to "about X" includes description of "X". In addition, unless the context clearly dictates otherwise, the singular forms "a", "an", and "the" include plural references. Thus, for example, reference to "a compound" includes a plurality of such compounds, and reference to "an assay" includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0170] "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0171] "Unit dosage forms" are physically discrete units suitable as unitary dosages for subjects (e.g., 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.

[0172] The term "substantially as shown" when referring to, for example, an XRPD pattern, a DSC thermogram, a DVS isotherm, a TGA-MS thermogram, or a TGA thermogram includes patterns, thermograms, or graphs that are not necessarily the same as those depicted herein, but that fall within the limits of experimental error or deviation when considered by one of ordinary skill in the art.

[0173] In some embodiments, the term "substantially pure" or "substantially free" with respect to a particular crystalline form of a compound means that the composition comprising the crystalline form contains less than 99%, less than 95%, less than 90%, less than 85%, less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, less than 50%, less than 40%, less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, or less than 1% by weight of other substances, including other crystalline forms and / or impurities. In certain embodiments, "substantially pure" or "substantially free" refers to a substance that is free of other substances, including other crystalline forms and / or impurities. Impurities may, for example, include byproducts or residual reagents from chemical reactions, contaminants, degradation products, other crystalline forms, water, and solvents.

[0174] In addition, the compounds of the present disclosure can exist in the form of solvates, such as those including as solvate water, or pharmaceutically acceptable solvates, such as alcohol, particularly ethanol. "Solvate" is formed by the interaction of a solvent and a compound. When the solvent is water, a "solvate" is a "hydrate". "Solvate" can also be formed by interacting with the surrounding environment and the starting material. Solvents are generally known to those skilled in the art, and can include, for example, methanol, ethanol, ethanol / water, acetone, tetrahydrofuran, dichloromethane, methyl tert-butyl ether, 2-propanol, 1-propanol and cyclopentyl methyl ether.

[0175] In certain embodiments, optical isomers, racemates or other mixtures thereof of a compound described herein or a pharmaceutically acceptable salt thereof or a mixture thereof are provided. In some embodiments, isomers can be separated by methods well known in the art, such as by liquid chromatography. In these cases, a single enantiomer or diastereomer, i.e., an optically active form, can be obtained by asymmetric synthesis or by resolution. For example, resolution can be achieved by conventional methods, such as crystallization in the presence of a resolving agent, or chromatography using, for example, a chiral high pressure liquid chromatography (HPLC) column.

[0176] "Stereoisomers" refer to compounds composed of the same atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. The present invention encompasses various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another. "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of one another.

[0177] The compounds disclosed herein and their pharmaceutically acceptable salts may include asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined by absolute stereochemistry as (R) or (S) or, for amino acids, as (D) or (L). The present invention is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (), (R) and (S), or (D) and (L) isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, it is intended that the compounds include both E and Z geometric isomers.

[0178] Compositions provided herein including compounds described herein or pharmaceutically acceptable salts, isomers or mixtures thereof may include racemic mixtures or mixtures containing an enantiomeric excess of one enantiomer or a single diastereomer or a mixture of diastereomers. All such isomeric forms of these compounds are expressly included herein, as if each and every isomeric form were specifically and individually listed.

[0179] Solid form of Formula I

[0180] Solid forms of Formula I (including crystalline forms and substantially pure forms) can provide advantages of bioavailability and stability suitable for use as active ingredients in pharmaceutical compositions. The development of suitable solid forms for pharmaceutical compositions requires consideration of stability and bioavailability in different environments. For example, in the case of a pharmaceutical product or active ingredient, it may be desirable to exhibit stability at a pH below 5. For example, Formula I Forms II, III, and IV exhibit favorable physical properties, such as good physical and chemical stability (e.g., at pH 5 and below), good water solubility, good pharmacokinetic properties, and / or good bioavailability. In addition, conversions between solid forms under different conditions should be considered. For example, humidity changes may result in conversion from one form to another. Care should be taken to ensure that the desired form exhibits the desired properties under the conditions of interest. At different humidities, conversions between Forms II, III, and IV may occur. Ideally, Formula I exhibits desirable stability under different humidity conditions. In some cases, changes in the crystal structure of a drug substance or active ingredient may affect the dissolution rate, bioavailability, manufacturability (including, for example, ease of handling, the ability to consistently prepare doses of known strength), and stability (e.g., thermal stability, shelf life, etc.) of the drug product or active ingredient. Such changes can affect the preparation or formulation of pharmaceutical compositions of different dosages or delivery forms, such as solutions or solid oral dosage forms, including tablets and capsules. Compared with other forms such as non-crystalline forms or amorphous forms, crystalline forms can provide required or suitable hygroscopicity, particle size control, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield and / or process control. Therefore, the solid form of the compound of Formula I can provide advantages, such as improving: the stability or storability of the manufacturing method of the compound, the drug product form of the compound, the stability or storability of the drug substance of the compound and / or the bioavailability and / or stability of the compound as an active agent.

[0181] It has been discovered that the use of certain solvents and / or processes produces different solid forms of the compounds of Formula I described herein that may exhibit one or more of the above-described advantageous characteristics. The preparation of the solid forms described herein and the characterization of these solid forms are described in detail below.

[0182] In specific embodiments, solid forms of Formula I are disclosed, such as crystalline forms. In some embodiments, solid forms of amorphous Form I are disclosed. In some embodiments, solid forms of Form I of Formula I are disclosed. In some embodiments, solid forms of Form II of Formula I are disclosed. In some embodiments, solid forms of Form III of Formula I are disclosed. In some embodiments, solid forms of Form IV of Formula I are disclosed. In some embodiments, solid forms of Form V of Formula I are disclosed. In some embodiments, solid forms of Form VI of Formula I are disclosed. In some embodiments, solid forms of Form VII of Formula I are disclosed. In some embodiments, solid forms of Form VIII of Formula I are disclosed. In some embodiments, solid forms of Form IX of Formula I are disclosed. In some embodiments, solid forms of Form X of Formula I are disclosed. In some embodiments, solid forms of Form XI of Formula I are disclosed. In some embodiments, solid forms of Form XII of Formula I are disclosed. In some embodiments, solid forms of Form XIII of Formula I are disclosed. In some embodiments, solid forms of Form XIV of Formula I are disclosed. In some embodiments, solid forms of Form XV of Formula I are disclosed. In some embodiments, solid forms of Formula I 2-(4-hydroxybenzoyl)benzoate Form A are disclosed. In some embodiments, solid forms of Formula I 2-(4-hydroxybenzoyl)benzoate Form B are disclosed. In some embodiments, solid forms of Formula I vanillate Form A are disclosed. In some embodiments, solid forms of Formula I vanillate Form B are disclosed. In some embodiments, solid forms of Formula I hippurate Form A are disclosed. In some embodiments, solid forms of Formula I hippurate Form B are disclosed. In some embodiments, solid forms of Formula I maleate Form A are disclosed. In some embodiments, solid forms of Formula I maleate Form B are disclosed. In some embodiments, solid forms of Formula I glyoxylate Form A are disclosed. In some embodiments, solid forms of Formula I glyoxylate Form B are disclosed. In some embodiments, solid forms of Formula I L-pyroglutamate are disclosed. In some embodiments, solid forms of Formula I 2-naphthalenesulfonate are disclosed. In some embodiments, solid forms of Formula I 1-naphthalenesulfonate are disclosed. In some embodiments, solid forms of the 1-hydroxy-2-naphthoate salt of Formula I are disclosed. In some embodiments, solid forms of the S-mandelate salt Form A of Formula I are disclosed. In some embodiments, solid forms of the S-mandelate salt Form B of Formula I are disclosed. In some embodiments, solid forms of the gentisate salt of Formula I are disclosed. In some embodiments, solid forms of the citrate salt of Formula I are disclosed. In some embodiments, solid forms of the R-mandelate salt Form A of Formula I are disclosed. In some embodiments, solid forms of the R-mandelate salt Form B of Formula I are disclosed.In some embodiments, solid forms of the benzoate salt Form A of Formula I are disclosed. In some embodiments, solid forms of the benzoate salt Form B of Formula I are disclosed. In some embodiments, solid forms of the methyl paraben Form A of Formula I are disclosed. In some embodiments, solid forms of the methyl paraben Form B of Formula I are disclosed. In some embodiments, solid forms of the caffeate salt of Formula I are disclosed. In some embodiments, solid forms of the glycolate salt of Formula I are disclosed. In some embodiments, solid forms of the α-ketobutyrate salt of Formula I are disclosed. In some embodiments, solid forms of the pyruvate salt of Formula I are disclosed.

[0183] In some embodiments, crystalline salts and / or co-crystals comprising Formula I are provided. In some embodiments, crystalline salts and / or co-crystals comprising Formula I are derived from hydroxybenzoylbenzoic acid, vanillic acid, gentisic acid, hippuric acid, maleic acid, glyoxylic acid, 2-naphthalenesulfonic acid, 1-naphthalenesulfonic acid, 1-hydroxy-2-naphthalenecarboxylic acid, S-mandelic acid, citric acid, R-mandelic acid, benzoic acid, methylparaben, caffeic acid, glycolic acid, α-ketobutyric acid, and pyruvic acid.

[0184] Amorphous Form I

[0185] In some embodiments, provided herein is an amorphous solid compound of Formula I (Amorphous Form I). In another embodiment, Amorphous Form I exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 1. Amorphous Form I may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 2. Amorphous Form I may exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 3. Amorphous Form I may exhibit a dynamic vapor sorption (DVS) isotherm substantially as shown in Figure 4.

[0186] In some embodiments of Amorphous Form I, at least one, at least two, at least three, or all of the following (a)-(d) apply: (a) Amorphous Form I has an XRPD pattern substantially as shown in Figure 1; (b) Amorphous Form I has a DSC thermogram substantially as shown in Figure 2; (c) Amorphous Form I has a TGA thermogram substantially as shown in Figure 3; (d) Amorphous Form I has a DVS isotherm substantially as shown in Figure 4.

[0187] Formula I Form I

[0188] In some embodiments, provided herein is a solid form of Form I of Formula I. In another embodiment, Form I of Formula I exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 5. Form I of Formula I may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 6.

[0189] In some embodiments, Form I of Formula I has one or both of the following properties:

[0190] (a) XRPD pattern substantially as shown in FIG5

[0191] (b) DSC thermogram substantially as shown in Figure 6.

[0192] In some embodiments, Form I of Formula I has an XRPD pattern exhibiting at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in Figure 5.

[0193] In certain embodiments, Formula I Form I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.3°, and 11.6°. In some embodiments, Formula I Form I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.3°, and 11.6°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 10.9°, 14.5°, and 22.4°. In some embodiments, Formula I Form I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.3°, and 11.6°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 17.4°, 18.7°, and 22.6°. In some embodiments, Formula I Form I has an XRPD pattern comprising 2θ-reflections at 6.2°, 8.3°, 11.6°, 10.9°, 14.5°, 22.4°, 17.4°, 18.7°, and 22.6° (±0.2 degrees 2θ).

[0194] In some embodiments, Form I of Formula I has a differential scanning calorimetry thermogram with an endotherm onset at about 25° C. In some embodiments, Form I of Formula I has a differential scanning calorimetry thermogram with an exotherm onset at about 175° C.

[0195] Formula I Form II

[0196] In some embodiments, provided herein is a solid form of Form II of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 7. Form II of Formula I may exhibit a dynamic vapor sorption (DVS) isotherm substantially as shown in Figure 9.

[0197] In some embodiments of Formula I Form II, one or both of the following (a)-(b) apply: (a) Formula I Form II has an XRPD pattern substantially as shown in Figure 7; (b) Formula I Form II has a DVS isotherm substantially as shown in Figure 9.

[0198] In some embodiments, Formula I Form II has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in Figure 7.

[0199] In certain embodiments, Formula I Form II has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.4°, 9.4°, and 10.6°. In some embodiments, Formula I Form II has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.4°, 9.4°, and 10.6°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 8.8°, 12.3°, and 26.1°. In some embodiments, Formula I Form II has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.4°, 9.4°, and 10.6°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 14.7°, 18.1°, and 22.4°. In some embodiments, Formula I Form I has an XRPD pattern comprising 2θ-reflections at 7.4°, 9.4°, 10.6°, 8.8°, 12.3°, 26.1°, 14.7°, 18.1°, and 22.4° (±0.2 degrees 2θ).

[0200] Formula I Form III

[0201] In some embodiments, provided herein is a Form III of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 11. Form III of Formula I may exhibit a VH-XRD pattern substantially as shown in Figure 12. Form III of Formula I may exhibit a Poly refinement pattern substantially as shown in Figure 13. Form III of Formula I may exhibit a dynamic vapor sorption (DVS) isotherm substantially as shown in Figure 14.

[0202] In some embodiments, Formula I Form III has at least one, at least two, at least three, or at least four of the following properties:

[0203] (a) An XRPD pattern substantially as shown in FIG. 11

[0204] (b) VH-XRD pattern substantially as shown in FIG. 12

[0205] (c) A Poly refinement pattern XRPD substantially as shown in FIG. 13

[0206] (d) DVS isotherm substantially as shown in FIG. 14 .

[0207] In some embodiments, Formula I Form III has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in Figure 11.

[0208] In certain embodiments, Formula I Form III has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.8°, 9.8°, and 10.7°. In some embodiments, Formula I Form III has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.8°, 9.8°, and 10.7°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 8.9°, 12.5°, and 20.1°. In some embodiments, Formula I Form III has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.8°, 9.8°, and 10.7°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 15.5°, 18.2°, and 22.9°. In some embodiments, Formula I Form III has an XRPD pattern comprising 2θ-reflections at 7.8°, 9.8°, 10.7°, 8.9°, 12.5°, 20.1°, 15.5°, 18.2°, and 22.9° (±0.2 degrees 2θ).

[0209] Formula I Form IV

[0210] In some embodiments, provided herein is a Form IV of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 16. Form IV of Formula I may exhibit a Poly refined XRPD pattern substantially as shown in Figure 15.

[0211] In some embodiments, Formula I Form IV has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in Figure 16.

[0212] In certain embodiments, Formula I Form IV has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 8.0°, 18.1°, and 20.0°. In some embodiments, Formula I Form IV has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 8.0°, 18.1°, and 20.0°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 9.0°, 9.9°, and 10.8°. In some embodiments, Formula I Form IV has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 8.0°, 18.1°, and 20.0°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 15.6°, 22.8°, and 24.9°. In some embodiments, Formula I Form IV has an XRPD pattern comprising 2θ-reflections at 8.0°, 18.1°, 20.0°, 9.0°, 9.9°, 10.8°, 15.6°, 22.8°, and 24.9° (±0.2 degrees 2θ).

[0213] Formula I Form V

[0214] In some embodiments, provided herein is Form V of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 17. Form V of Formula I may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 18.

[0215] In some embodiments of Formula I Form V, one or both of the following (a)-(b) apply: (a) Formula I Form V has an XRPD pattern substantially as shown in Figure 17; (b) Formula I Form V has a DSC thermogram substantially as shown in Figure 18.

[0216] In some embodiments, Formula I Form V has an XRPD pattern exhibiting at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in Figure 17.

[0217] In certain embodiments, Formula I Form V has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 22.6°, and 20.4°. In some embodiments, Formula I Form V has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 22.6°, and 20.4°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 16.3°, 16.5°, and 17.4°. In some embodiments, Formula I Form V has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 22.6°, and 20.4°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 22.4°, 23.5°, and 25.1°. In some embodiments, Formula I Form V has an XRPD pattern comprising 2θ-reflections at 6.2°, 22.6°, 20.4°, 16.3°, 16.5°, 17.4°, 22.4°, 23.5°, and 25.1° (±0.2 degrees 2θ).

[0218] Formula I Form VI

[0219] In some embodiments, provided herein is Form VI of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 19. Form VI of Formula I may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 21.

[0220] In some embodiments of Formula I Form VI, one or both of the following (a)-(b) apply: (a) Formula I Form VI has an XRPD pattern substantially as shown in Figures 19 and 20 (enlarged images); (b) Formula I Form VI has a DSC thermogram substantially as shown in Figure 21.

[0221] In some embodiments, Formula I Form VI has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in Figure 19.

[0222] In certain embodiments, Formula I Form VI has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.2°, 14.4°, and 21.7°. In some embodiments, Formula I Form VI has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.2°, 14.4°, and 21.7°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 29.1°, 25.3°, and 25.0°. In some embodiments, Formula I Form VI has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.2°, 14.4°, and 21.7°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 16.6°, 26.7°, and 30.2°. In some embodiments, Formula I Form VI has an XRPD pattern comprising 2θ-reflections at 7.2°, 14.4°, 21.7°, 29.1°, 25.3°, 25.0°, 16.6°, 26.7°, and 30.2° (±0.2 degrees 2θ).

[0223] Formula I form VII

[0224] In some embodiments, provided herein is Form VII of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 22 .

[0225] In some embodiments, Formula I Form VII has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in Figure 22.

[0226] In certain embodiments, Formula I Form VII has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.4°, and 22.6°. In some embodiments, Formula I Form VII has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.4°, and 22.6°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 10.3°, 10.9°, and 11.7°. In some embodiments, Formula I Form VII has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.4°, and 22.6°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 16.1°, 16.4°, and 17.3°. In some embodiments, Formula I Form VII has an XRPD pattern comprising 2θ-reflections at 6.2°, 8.4°, 22.6°, 10.3°, 10.9°, 11.7°, 16.1°, 16.4°, and 17.3° (±0.2 degrees 2θ).

[0227] Formula I Form VIII

[0228] In some embodiments, provided herein is Form VIII of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 23 .

[0229] In some embodiments, Formula I Form VIII has an XRPD pattern exhibiting at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in Figure 23.

[0230] In certain embodiments, Formula I Form VIII has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.3°, and 22.3°. In some embodiments, Formula I Form VIII has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.3°, and 22.3°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 11.6°, 10.8°, and 14.5°. In some embodiments, Formula I Form VIII has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.3°, and 22.3°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 16.5°, 18.7°, and 20.5°. In some embodiments, Formula I Form VIII has an XRPD pattern comprising 2θ-reflections at 6.2°, 8.3°, 22.3°, 11.6°, 10.8°, 14.5°, 16.5°, 18.7°, and 20.5° (±0.2 degrees 2θ).

[0231] Formula I Form IX

[0232] In some embodiments, provided herein is Form IX of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 24 .

[0233] In some embodiments, Formula I Form IX has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in Figure 24.

[0234] In certain embodiments, Formula I Form IX has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.2°, 5.8°, and 5.7°. In some embodiments, Formula I Form IX has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.2°, 5.8°, and 5.7°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 10.7°, 15.3°, and 17.1°. In some embodiments, Formula I Form IX has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.2°, 5.8°, and 5.7°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 7.4°, 10.0°, and 8.9°. In some embodiments, Formula I Form IX has an XRPD pattern comprising 2θ-reflections at 7.2°, 5.8°, 5.7°, 10.7°, 15.3°, 17.1°, 7.4°, 10.0°, and 8.9° (±0.2 degrees 2θ).

[0235] Formula I Form X

[0236] In some embodiments, provided herein is Form X of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 25 .

[0237] In some embodiments, Form X of Formula I has an XRPD pattern exhibiting at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in Figure 25.

[0238] In certain embodiments, Formula I Form X has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 16.3°, 7.2°, and 5.7°. In some embodiments, Formula I Form X has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 16.3°, 7.2°, and 5.7°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 10.8°, 13.7°, and 18.3°. In some embodiments, Formula I Form X has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 16.3°, 7.2°, and 5.7°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 19.1°, 22.4°, and 26.5°. In some embodiments, Formula I Form X has an XRPD pattern including 2θ-reflections at 16.3°, 7.2°, 5.7°, 10.8°, 13.7°, 18.3°, 19.1°, 22.4°, and 26.5° (±0.2 degrees 2θ).

[0239] Formula I Form XI

[0240] In some embodiments, provided herein is Form XI of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 26 .

[0241] In some embodiments, Form XI of Formula I has an XRPD pattern exhibiting at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in Figure 26.

[0242] In certain embodiments, Formula I Form XI has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.8°, 5.5°, and 6.8°. In some embodiments, Formula I Form XI has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.8°, 5.5°, and 6.8°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 8.6°, 9.5°, and 10.3°. In some embodiments, Formula I Form XI has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.8°, 5.5°, and 6.8°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 15.4°, 17.8°, and 19.4°. In some embodiments, Formula I Form XI has an XRPD pattern comprising 2θ-reflections at 7.8°, 5.5°, 6.8°, 8.6°, 9.5°, 10.3°, 15.4°, 17.8°, and 19.4° (±0.2 degrees 2θ).

[0243] Formula I Form XII

[0244] In some embodiments, provided herein is Form XII of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 27 .

[0245] In some embodiments, Form XII of Formula I has an XRPD pattern exhibiting at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in Figure 27.

[0246] In certain embodiments, Formula I Form XII has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 5.4°, and 11.5°. In some embodiments, Formula I Form XII has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 5.4°, and 11.5°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 14.5°, 16.4°, and 22.3°. In some embodiments, Formula I Form XII has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 5.4°, and 11.5°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 12.5°, 9.7°, and 19.2°. In some embodiments, Formula I Form XII has an XRPD pattern comprising 2θ-reflections at 6.2°, 5.4°, 11.5°, 14.5°, 16.4°, 22.3°, 12.5°, 9.7°, and 19.2° (±0.2 degrees 2θ).

[0247] Formula I Form XIII

[0248] In some embodiments, provided herein is Form XIII of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 28.

[0249] In some embodiments, Formula I Form XIII has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in Figure 28.

[0250] In certain embodiments, Formula I Form XIII has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 5.8°, 6.2°, and 8.1°. In some embodiments, Formula I Form XIII has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 5.8°, 6.2°, and 8.1°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 11.6°, 16.6°, and 20.0°. In some embodiments, Formula I Form XIII has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 5.8°, 6.2°, and 8.1°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 13.0°, 22.0°, and 22.8°. In some embodiments, Formula I Form XIII has an XRPD pattern comprising 2θ-reflections at 5.8°, 6.2°, 8.1°, 11.6°, 16.6°, 20.0°, 13.0°, 22.0°, and 22.8° (±0.2 degrees 2θ).

[0251] Formula I Form XIV

[0252] In some embodiments, provided herein is Form XIV of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 29 .

[0253] In some embodiments, Form XIV of Formula I has an XRPD pattern exhibiting at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in Figure 29.

[0254] In certain embodiments, Formula I Form XIV has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 5.8°, 8.2°, and 18.5°. In some embodiments, Formula I Form XIV has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 5.8°, 8.2°, and 18.5°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 11.7°, 16.6°, and 22.0°. In some embodiments, Formula I Form XIV has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 5.8°, 8.2°, and 18.5°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 22.8°, 10.0°, and 10.5°. In some embodiments, Formula I Form XIV has an XRPD pattern comprising 2θ-reflections at 5.8°, 8.2°, 18.5°, 11.7°, 16.6°, 22.0°, 22.8°, 10.0°, and 10.5° (±0.2 degrees 2θ).

[0255] Formula I Form XV

[0256] In some embodiments, provided herein is Form XV of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 30 .

[0257] In some embodiments, Formula I Form XV has an XRPD pattern exhibiting at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in Figure 30.

[0258] In certain embodiments, Formula I Form XV has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 5.4°, and 8.3°. In some embodiments, Formula I Form XV has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 5.4°, and 8.3°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 11.6°, 16.4°, and 19.3°. In some embodiments, Formula I Form XV has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 5.4°, and 8.3°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 12.4°, 20.3°, and 22.4°. In some embodiments, Formula I Form XV has an XRPD pattern comprising 2θ-reflections at 6.2°, 5.4°, 8.3°, 11.6°, 16.4°, 19.3°, 12.4°, 20.3°, and 22.4° (±0.2 degrees 2θ).

[0259] Formula I 2-(4-hydroxybenzoyl)benzoate

[0260] In some embodiments, provided herein is a 2-(4-hydroxybenzoyl)benzoate salt of Formula I, Form A, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 31 .

[0261] In some embodiments, Formula I 2-(4-hydroxybenzoyl)benzoate Form A has an XRPD pattern exhibiting at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in Figure 31.

[0262] In certain embodiments, Formula I 2-(4-hydroxybenzoyl)benzoate Form A has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 11.0°, and 13.7°. In some embodiments, Formula I 2-(4-hydroxybenzoyl)benzoate Form A has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 11.0°, and 13.7°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 15.2°, 17.4°, and 18.3°. In some embodiments, Formula I 2-(4-hydroxybenzoyl)benzoate Form A has an XRPD pattern comprising 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 11.0°, and 13.7° and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 20.8°, 7.6°, and 8.5°. In some embodiments, Formula I 2-(4-hydroxybenzoyl)benzoate Form A has an XRPD pattern comprising 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 11.0°, 13.7°, 15.2°, 17.4°, 18.3°, 20.8°, 7.6°, and 8.5°.

[0263] In some embodiments, provided herein is a 2-(4-hydroxybenzoyl)benzoate salt of Formula I, Form B, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 32. The 2-(4-hydroxybenzoyl)benzoate salt of Formula I, Form B, may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 33. The 2-(4-hydroxybenzoyl)benzoate salt of Formula I, Form B, may exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 34.

[0264] In some embodiments, Form B of Formula I 2-(4-hydroxybenzoyl)benzoate has at least one, at least two, or at least three of the following properties:

[0265] (a) An XRPD pattern substantially as shown in FIG. 32

[0266] (b) DSC thermogram substantially as shown in FIG. 33

[0267] (c) TGA thermogram substantially as shown in Figure 34.

[0268] Vanillate of Formula I

[0269] In some embodiments, provided herein is a vanillic acid salt Form A of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 35 .

[0270] In some embodiments, the vanillic acid salt Form A of Formula I has an XRPD pattern exhibiting at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in Figure 35.

[0271] In certain embodiments, Formula I Vanillate Salt Form A has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 7.3°, and 16.4°. In some embodiments, Formula I Vanillate Salt Form A has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 7.3°, and 16.4°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 17.5°, 24.7°, and 30.6°. In some embodiments, Formula I Vanillate Salt Form A has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 7.3°, and 16.4°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 12.4°, 13.4°, and 20.2°. In some embodiments, the vanillic acid salt Form A of Formula I has an XRPD pattern comprising 2θ-reflections at 6.2°, 7.3°, 16.4°, 17.5°, 24.7°, 30.6°, 12.4°, 13.4°, and 20.2° (±0.2 degrees 2θ).

[0272] In some embodiments, provided herein is a vanillic acid salt Form B of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 36. The vanillic acid salt Form B of Formula I may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 37. The vanillic acid salt Form B of Formula I may exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 38.

[0273] In some embodiments, the vanillic acid salt Form B of Formula I has at least one, at least two, or at least three of the following properties:

[0274] (a) An XRPD pattern substantially as shown in FIG. 36

[0275] (b) DSC thermogram substantially as shown in FIG. 37

[0276] (c) TGA thermogram substantially as shown in Figure 38.

[0277] Formula I hippurate

[0278] In some embodiments, provided herein is a hippurate salt of Formula I, Form A, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 39 .

[0279] In some embodiments, the hippurate salt of Formula I, Form A, has an XRPD pattern exhibiting at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in Figure 39.

[0280] In certain embodiments, the hippurate salt Form A of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.5°, 8.2°, and 9.3°. In some embodiments, the hippurate salt Form A of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.5°, 8.2°, and 9.3°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 7.0°, 13.1°, and 21.8°. In some embodiments, the hippurate salt Form A of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.5°, 8.2°, and 9.3°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 14.7°, 18.0°, and 25.7°. In some embodiments, the hippurate salt Form A of Formula I has an XRPD pattern comprising 2θ-reflections at 6.5°, 8.2°, 9.3°, 7.0°, 13.1°, 21.8°, 14.7°, 18.0°, and 25.7° (±0.2 degrees 2θ).

[0281] In some embodiments, provided herein is a hippurate salt of Formula I, Form B, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 40. The hippurate salt of Formula I, Form B, may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 41. The hippurate salt of Formula I, Form B, may exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 42.

[0282] In some embodiments, the hippurate salt Form B of Formula I has at least one, at least two, or at least three of the following properties:

[0283] (a) An XRPD pattern substantially as shown in FIG. 40

[0284] (b) DSC thermogram substantially as shown in FIG. 41

[0285] (c) TGA thermogram substantially as shown in Figure 42.

[0286] Formula I maleate

[0287] In some embodiments, provided herein is a maleate salt Form A of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 43 .

[0288] In some embodiments, Formula I maleate salt Form A has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensity with an XRPD pattern substantially as shown in Figure 43.

[0289] In certain embodiments, Formula I maleate salt Form A has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 5.8°, 8.2°, and 11.7°. In some embodiments, Formula I maleate salt Form A has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 5.8°, 8.2°, and 11.7°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 10.0°, 10.4°, and 14.9°. In some embodiments, Formula I maleate salt Form A has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 5.8°, 8.2°, and 11.7°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 6.4°, 20.0°, and 25.7°. In some embodiments, Formula I maleate salt Form A has an XRPD pattern comprising 2θ-reflections at 5.8°, 8.2°, 11.7°, 10.0°, 10.4°, 14.9°, 6.4°, 20.0°, and 25.7° (±0.2 degrees 2θ).

[0290] In some embodiments, provided herein is a maleate salt Form B of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 44. The maleate salt Form B of Formula I may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 45. The maleate salt Form B of Formula I may exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 46.

[0291] In some embodiments, Formula I maleate salt Form B has at least one, at least two, or at least three of the following properties:

[0292] (a) An XRPD pattern substantially as shown in FIG. 44

[0293] (b) DSC thermogram substantially as shown in FIG. 45

[0294] (c) TGA thermogram substantially as shown in Figure 46.

[0295] In some embodiments, Formula I maleate salt Form B has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in Figure 44.

[0296] In certain embodiments, Formula I maleate salt Form B has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.1°, 8.3°, and 10.7°. In some embodiments, Formula I maleate salt Form B has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.1°, 8.3°, and 10.7°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 14.4°, 16.4°, and 20.1°. In some embodiments, Formula I maleate salt Form B has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.1°, 8.3°, and 10.7°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 21.4°, 22.7°, and 28.4°. In some embodiments, Formula I maleate salt Form B has an XRPD pattern comprising 2θ-reflections at 6.1°, 8.3° 10.7°, 14.4°, 16.4°, 20.1°, 21.4°, 22.7°, and 28.4° (±0.2 degrees 2θ).

[0297] Glyoxylate of Formula I

[0298] In some embodiments, provided herein is a glyoxylate salt of Formula I, Form A, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 47 .

[0299] In some embodiments, Formula I glyoxylate salt Form A has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in Figure 47.

[0300] In certain embodiments, Formula I glyoxylate Form A has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 5.9°, 22.5°, and 8.1°. In some embodiments, Formula I glyoxylate Form A has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 5.9°, 22.5°, and 8.1°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 12.4°, 16.4°, and 19.1°. In some embodiments, Formula I glyoxylate Form A has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 5.9°, 22.5°, and 8.1°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 15.0°, 20.0°, and 28.1°. In some embodiments, Formula I glyoxylate salt Form A has an XRPD pattern comprising 2θ-reflections at 5.9°, 22.5°, 8.1°, 12.4°, 16.4°, 19.1°, 15.0°, 20.0°, and 28.1° (±0.2 degrees 2θ).

[0301] In some embodiments, provided herein is a glyoxylate salt of Formula I, Form B, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 48. Form B of Formula I glyoxylate salt may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 49. Form B of Formula I glyoxylate salt may exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 50.

[0302] In some embodiments, glyoxylate Form B of Formula I has at least one, at least two, or at least three of the following properties:

[0303] (a) An XRPD pattern substantially as shown in FIG. 48

[0304] (b) DSC thermogram substantially as shown in FIG. 49

[0305] (c) TGA thermogram substantially as shown in Figure 50.

[0306] In some embodiments, Form B of the glyoxylate salt of Formula I has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in Figure 48.

[0307] In certain embodiments, Formula I glyoxylate Form B has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.3°, and 12.6°. In some embodiments, Formula I glyoxylate Form B has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.3°, and 12.6°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 10.8°, 16.1°, and 16.4°. In some embodiments, Formula I glyoxylate Form B has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.3°, and 12.6°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 18.6°, 19.4°, and 20.3°. In some embodiments, Formula I glyoxylate salt Form B has an XRPD pattern comprising 2θ-reflections at 6.2°, 8.3° 12.6°, 10.8°, 16.1°, 16.4°, 18.6°, 19.4°, and 20.3° (±0.2 degrees 2θ).

[0308] Formula I L-pyroglutamate

[0309] In some embodiments, provided herein is a solid form of the L-pyroglutamate salt of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 51 .

[0310] In some embodiments, the L-pyroglutamate salt of Formula I has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensity with an XRPD pattern substantially as shown in Figure 51.

[0311] In certain embodiments, the L-pyroglutamate salt of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.1°, 16.5°, and 19.8°. In some embodiments, the L-pyroglutamate salt of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.1°, 16.5°, and 19.8°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 11.6°, 12.4°, and 17.3°. In some embodiments, the L-pyroglutamate salt of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.1°, 16.5°, and 19.8°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 22.8°, 23.0°, and 28.4°. In some embodiments, the L-pyroglutamate salt of Formula I has an XRPD pattern including 2θ-reflections at 6.1°, 16.5°, 19.8°, 11.6°, 12.4°, 17.3°, 22.8°, 23.0°, and 28.4° (±0.2 degrees 2θ).

[0312] In some embodiments, provided herein is a solid form of the L-pyroglutamate salt of Formula I, wherein the solid form exhibits a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 52 .

[0313] Formula I 2-naphthalenesulfonate

[0314] In some embodiments, provided herein is a 2-naphthalenesulfonate salt of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 53.

[0315] In some embodiments, the 2-naphthalenesulfonate salt of Formula I has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensity with an XRPD pattern substantially as shown in FIG. 53 .

[0316] In certain embodiments, the 2-naphthalenesulfonate salt of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 5.9°, 8.1°, and 16.3°. In some embodiments, the 2-naphthalenesulfonate salt of Formula I, Form A, has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 5.9°, 8.1°, and 16.3°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 18.6°, 19.1°, and 20.0°. In some embodiments, the 2-naphthalenesulfonate salt of Formula I, Form A, has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 5.9°, 8.1°, and 16.3°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 10.1°, 12.6°, and 13.1°. In some embodiments, Formula I 2-naphthalenesulfonate salt Form A has an XRPD pattern comprising 2θ-reflections at 5.9°, 8.1°, 16.3°, 18.6°, 19.1°, 20.0°, 10.1°, 12.6°, and 13.1° (±0.2 degrees 2θ).

[0317] In some embodiments, provided herein is an air-dried 2-naphthalenesulfonate salt of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 54. The 2-naphthalenesulfonate salt of Formula I may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 55. The 2-naphthalenesulfonate salt of Formula I may exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 56.

[0318] In some embodiments, the 2-naphthalenesulfonate salt of Formula I has at least one, at least two, or at least three of the following properties:

[0319] (a) An XRPD pattern substantially as shown in FIG. 54

[0320] (b) DSC thermogram substantially as shown in FIG. 55

[0321] (c) TGA thermogram substantially as shown in Figure 56.

[0322] In some embodiments, the 2-naphthalenesulfonate salt of Formula I has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensity with an XRPD pattern substantially as shown in FIG. 54 .

[0323] In certain embodiments, the 2-naphthalenesulfonate salt of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.4°, and 16.5°. In some embodiments, the 2-naphthalenesulfonate salt of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.4°, and 16.5°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 10.8°, 11.7°, and 19.1°. In some embodiments, the 2-naphthalenesulfonate salt of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.4°, and 16.5°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 12.6°, 14.6°, and 22.6°. In some embodiments, the 2-naphthalenesulfonate salt of Formula I has an XRPD pattern including 2θ-reflections at 6.2°, 8.4°, 16.5°, 10.8°, 11.7°, 19.1°, 12.6°, 14.6°, and 22.6° (±0.2 degrees 2θ).

[0324] Formula I 1-naphthalenesulfonate

[0325] In some embodiments, provided herein is a 1-naphthalenesulfonate salt of Formula I wet cake, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 58 .

[0326] In some embodiments, the 1-naphthalenesulfonate salt of Formula I wet cake has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensity with an XRPD pattern substantially as shown in FIG. 58 .

[0327] In certain embodiments, the 1-naphthalenesulfonate salt of Formula I wet cake has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 5.9°, 8.1°, and 16.3°. In some embodiments, the 1-naphthalenesulfonate salt of Formula I wet cake has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 5.9°, 8.1°, and 16.3°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 10.0°, 10.5°, and 20.0°. In some embodiments, the 1-naphthalenesulfonate salt of Formula I wet cake has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 5.9°, 8.1°, and 16.3°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 18.6°, 19.0°, and 22.6°. In some embodiments, the 1-naphthalenesulfonate salt of Formula I wet cake has an XRPD pattern including 2θ-reflections at 5.9°, 8.1°, 16.3°, 10.0°, 10.5°, 20.0°, 18.6°, 19.0°, and 22.6° (±0.2 degrees 2θ).

[0328] In some embodiments, provided herein is a solid form of a 1-naphthalenesulfonate salt of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 58. The solid form of the 1-naphthalenesulfonate salt of Formula I may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 58.

[0329] In some embodiments, the solid form of the 1-naphthalenesulfonate salt of Formula I has one or both of the following properties:

[0330] (a) An XRPD pattern substantially as shown in FIG. 58

[0331] (b) DSC thermogram substantially as shown in Figure 59.

[0332] In some embodiments, the 1-naphthalenesulfonate salt of Formula I has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensity with an XRPD pattern substantially as shown in FIG. 58 .

[0333] In certain embodiments, the 1-naphthalenesulfonate salt of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.4°, and 16.5°. In some embodiments, the 1-naphthalenesulfonate salt of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.4°, and 16.5°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 10.9°, 11.7°, and 20.5°. In some embodiments, the 1-naphthalenesulfonate salt of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.4°, and 16.5°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 14.6°, 15.3°, and 17.3°. In some embodiments, the 1-naphthalenesulfonate salt of Formula I has an XRPD pattern including 2θ-reflections at 6.2°, 8.4°, 16.5°, 10.9°, 11.7°, 20.5°, 14.6°, 15.3°, and 17.3° (±0.2 degrees 2θ).

[0334] Formula I 1-hydroxy-2-naphthoate

[0335] In some embodiments, provided herein is a 1-hydroxy-2-naphthoate salt of Formula I wet cake, wherein the 1-hydroxy-2-naphthoate salt of Formula I wet cake exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 60 .

[0336] In some embodiments, the 1-hydroxy-2-naphthoate salt of Formula I has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensity with an XRPD pattern substantially as shown in FIG. 60 .

[0337] In certain embodiments, the wet cake of the 1-hydroxy-2-naphthoate salt of Formula I has an XRPD pattern comprising 2θ-reflections at 5.3°, 5.6°, and 7.4° (±0.2 degrees 2θ). In some embodiments, the wet cake of the 1-hydroxy-2-naphthoate salt of Formula I has an XRPD pattern comprising 2θ-reflections at 5.3°, 5.6°, and 7.4° (±0.2 degrees 2θ) and one, two, or three of 2θ-reflections at 6.7°, 9.3°, and 21.0° (±0.2 degrees 2θ). In some embodiments, the wet cake of the 1-hydroxy-2-naphthoate salt of Formula I has an XRPD pattern comprising 2θ-reflections (±0.2 degrees 2θ) at 5.3°, 5.6°, and 7.4° and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 17.5°, 18.5°, and 23.6°. In some embodiments, the wet cake of the 1-hydroxy-2-naphthoate salt of Formula I has an XRPD pattern comprising 2θ-reflections (±0.2 degrees 2θ) at 5.3°, 5.6°, 7.4°, 6.7°, 9.3°, 21.0°, 17.5°, 18.5°, and 23.6°.

[0338] In some embodiments, provided herein is a solid form of a 1-hydroxy-2-naphthoate salt of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 61. The 1-hydroxy-2-naphthoate salt of Formula I may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 62. The 1-hydroxy-2-naphthoate salt of Formula I may exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 63.

[0339] In some embodiments, the solid form of the 1-hydroxy-2-naphthoate salt of Formula I has at least one, at least two, or at least three of the following properties:

[0340] (a) An XRPD pattern substantially as shown in FIG. 61

[0341] (b) DSC thermogram substantially as shown in FIG. 62

[0342] (c) TGA thermogram substantially as shown in Figure 63.

[0343] In some embodiments, the solid form of the 1-hydroxy-2-naphthoate salt of Formula I has an XRPD pattern showing at least two or at least three 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in FIG. 61 .

[0344] In certain embodiments, the solid form of the 1-hydroxy-2-naphthoate salt of Formula I has an XRPD pattern that includes 2θ-reflections at 6.1°, 7.3°, and 15.9° (±0.2 degrees 2θ).

[0345] Formula I S-mandelate

[0346] In some embodiments, provided herein is a Formula I S-mandelate salt Form A, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 64.

[0347] In some embodiments, Formula I S-mandelate salt Form A has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in Figure 64.

[0348] In certain embodiments, Formula 1 S-mandelate salt Form A has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 5.5°, 5.7°, and 6.3°. In some embodiments, Formula 1 S-mandelate salt Form A has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 5.5°, 5.7°, and 6.3°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 11.4°, 16.6°, and 20.8°. In some embodiments, Formula 1 S-mandelate salt Form A has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 5.5°, 5.7°, and 6.3°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 10.0°, 10.4°, and 19.0°. In some embodiments, Formula I S-mandelate Salt Form A has an XRPD pattern comprising 2θ-reflections at 5.5°, 5.7°, 6.3°, 11.4°, 16.6°, 20.8°, 10.0°, 10.4°, and 19.0° (±0.2 degrees 2θ).

[0349] In some embodiments, provided herein is a Formula 1 S-mandelate salt Form B, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 65. Formula 1 S-mandelate salt Form B may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 66. Formula 1 S-mandelate salt Form B may exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 67.

[0350] In some embodiments, Formula 1 S-mandelate salt Form B has at least one, at least two, or at least three of the following properties:

[0351] (a) An XRPD pattern substantially as shown in FIG. 65

[0352] (b) DSC thermogram substantially as shown in FIG. 66

[0353] (c) TGA thermogram substantially as shown in Figure 67.

[0354] In some embodiments, Formula I S-mandelate salt Form B has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in Figure 65.

[0355] In certain embodiments, Formula 1 S-mandelate salt Form B has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 5.7°, 6.2°, and 22.6°. In some embodiments, Formula 1 S-mandelate salt Form B has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 5.7°, 6.2°, and 22.6°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 8.0°, 8.4°, and 11.7°. In some embodiments, Formula 1 S-mandelate salt Form B has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 5.7°, 6.2°, and 22.6°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 13.5°, 16.0°, and 16.6°. In some embodiments, Formula I S-mandelate salt Form B has an XRPD pattern including 2θ-reflections at 5.7°, 6.2°, 22.6°, 8.0°, 8.4°, 11.7°, 13.5°, 16.0°, and 16.6° (±0.2 degrees 2θ).

[0356] In some embodiments, Formula I S-mandelate salt Form B has a differential scanning calorimetry thermogram comprising an endotherm with an onset temperature of about 50°C.

[0357] Gentisate of Formula I

[0358] In some embodiments, provided herein is a Formula I gentisate wet cake, wherein the Formula I gentisate wet cake exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 68 .

[0359] In some embodiments, the Formula I gentisate salt wet cake has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensity with an XRPD pattern substantially as shown in Figure 68.

[0360] In certain embodiments, Formula I gentisate salt Form A has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.4°, 6.5°, and 8.0°. In some embodiments, the Formula I gentisate salt wet cake has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.4°, 6.5°, and 8.0°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 13.5°, 16.9°, and 12.0°. In some embodiments, the Formula I gentisate salt wet cake has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.4°, 6.5°, and 8.0°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 25.1°, 22.4°, and 19.3°. In some embodiments, the Formula I gentisate salt wet cake has an XRPD pattern comprising 2θ-reflections at 7.4°, 6.5°, 8.0°, 13.5°, 16.9°, 12.0°, 25.1°, 22.4°, and 19.3° (±0.2 degrees 2θ).

[0361] In some embodiments, provided herein is a solid form of a gentisate salt of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 69. The gentisate salt of Formula I may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 70. The gentisate salt of Formula I may exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 71.

[0362] In some embodiments, the solid form of the gentisate salt of Formula I has at least one, at least two, or at least three of the following properties:

[0363] (a) An XRPD pattern substantially as shown in FIG. 69

[0364] (b) DSC thermogram substantially as shown in FIG. 70

[0365] (c) TGA thermogram substantially as shown in Figure 71.

[0366] In some embodiments, the solid form of the gentisate salt of Formula I has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensity with an XRPD pattern substantially as shown in Figure 69.

[0367] In certain embodiments, the solid form of the Formula I gentisate has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.4°, 6.1°, and 8.4°. In some embodiments, the Formula I gentisate has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.4°, 6.1°, and 8.4°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 16.7°, 17.9°, and 9.1°. In some embodiments, the Formula I gentisate has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.4°, 6.1°, and 8.4°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 24.9°, 22.8°, and 12.3°. In some embodiments, the gentisate salt of Formula I has an XRPD pattern comprising 2θ-reflections at 7.4°, 6.1°, 8.4°, 16.7°, 17.9°, 9.1°, 24.9°, 22.8°, and 12.3° (±0.2 degrees 2θ).

[0368] Formula I Citrate

[0369] In some embodiments, provided herein is a Formula I citrate salt wet cake, wherein the Formula I citrate salt wet cake exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 72 .

[0370] In some embodiments, the citrate salt of Formula I wet cake has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ reflections having maximum intensity with an XRPD pattern substantially as shown in FIG. 72 .

[0371] In certain embodiments, the wet cake of the citrate salt of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.4°, 7.9°, and 16.7°. In some embodiments, the wet cake of the citrate salt of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.4°, 7.9°, and 16.7°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 15.1°, 17.7°, and 20.4°. In some embodiments, the wet cake of the citrate salt of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.4°, 7.9°, and 16.7°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 11.4°, 18.9°, and 22.1°. In some embodiments, the citrate salt wet cake of Formula I has an XRPD pattern comprising 2θ-reflections at 7.4°, 7.9°, 16.7°, 15.1°, 17.7°, 20.4°, 11.4°, 18.9°, and 22.1° (±0.2 degrees 2θ).

[0372] In some embodiments, provided herein is a solid form of a citrate salt of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 89. The citrate salt of Formula I may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 73. The citrate salt of Formula I may exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 75.

[0373] In some embodiments, Form B of the citrate salt of Formula I has at least one, at least two, or all of the following properties:

[0374] (a) An XRPD pattern substantially as shown in FIG. 73

[0375] (b) DSC thermogram substantially as shown in FIG. 74

[0376] (c) TGA thermogram substantially as shown in Figure 75.

[0377] In some embodiments, the citrate salt of Formula I has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in FIG. 73 .

[0378] In certain embodiments, the citrate salt of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.1°, 7.4°, and 18.2°. In some embodiments, the citrate salt of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.1°, 7.4°, and 18.2°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 8.3°, 16.4°, and 36.7°. In some embodiments, the citrate salt of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.1°, 7.4°, and 18.2°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 20.7°, 24.5°, and 26.0°. In some embodiments, the citrate salt of Formula I has an XRPD pattern including 2θ-reflections at 6.1°, 7.4°, 18.2°, 8.3°, 16.4°, 36.7°, 20.7°, 24.5°, and 26.0° (±0.2 degrees 2θ).

[0379] Formula I R-mandelate

[0380] In some embodiments, provided herein is a Formula I R-mandelate salt Form A, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 76 .

[0381] In some embodiments, Formula I R-mandelate salt Form A has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in Figure 76.

[0382] In certain embodiments, Formula 1 R-mandelate salt Form A has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 5.7°, 5.4°, and 16.5°. In some embodiments, Formula 1 R-mandelate salt Form A has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 5.7°, 5.4°, and 16.5°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 7.8°, and 11.5°. In some embodiments, Formula 1 R-mandelate salt Form A has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 5.7°, 5.4°, and 16.5°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 10.5°, 13.4°, and 18.5°. In some embodiments, Formula I R-mandelate Salt Form A has an XRPD pattern including 2θ-reflections at 5.7°, 5.4°, 16.5°, 6.2°, 7.8°, 11.5°, 10.5°, 13.4°, and 18.5° (±0.2 degrees 2θ).

[0383] In some embodiments, provided herein is a Formula 1 R-mandelate salt Form B, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 77. Formula 1 R-mandelate salt Form B may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 78. Formula 1 R-mandelate salt Form B may exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 79.

[0384] In some embodiments, Formula I R-mandelate salt Form B has at least one, at least two, or all of the following properties:

[0385] (a) An XRPD pattern substantially as shown in FIG. 77

[0386] (b) DSC thermogram substantially as shown in FIG. 78

[0387] (c) TGA thermogram substantially as shown in Figure 79.

[0388] In some embodiments, Formula I R-mandelate salt Form B exhibits an XRPD pattern of at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensity with an XRPD pattern substantially as shown in Figure 77.

[0389] In certain embodiments, Formula 1 R-mandelate salt Form B has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.3°, and 22.4°. In some embodiments, Formula 1 R-mandelate salt Form B has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.3°, and 22.4°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 15.9°, 16.3°, and 17.0°. In some embodiments, Formula 1 R-mandelate salt Form B has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.3°, and 22.4°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 10.0°, 10.8°, and 11.6°. In some embodiments, Formula I R-mandelate salt Form B has an XRPD pattern comprising 2θ-reflections at 6.2°, 8.3°, 22.4°, 15.9°, 16.3°, 17.0°, 10.0°, 10.8°, and 11.6° (±0.2 degrees 2θ).

[0390] Formula I Benzoate

[0391] In some embodiments, provided herein is a benzoate salt Form A of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 80.

[0392] In some embodiments, the benzoate salt of Formula I, Form A, has an XRPD pattern exhibiting at least two, at least three, at least four, at least five, at least six, or at least seven 2θ-reflections having maximum intensity with an XRPD pattern substantially as shown in FIG. 80 .

[0393] In certain embodiments, Formula I benzoate salt Form A has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.44°, 18.97°, and 16.70°. In some embodiments, Formula I benzoate salt Form A has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.44°, 18.97°, and 16.70°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 21.14°, 22.45°, 25.07°, and 6.09°. In some embodiments, Formula I benzoate salt Form A has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.44°, 18.97°, 16.70°, 21.14°, 22.45°, 25.07°, and 6.09°.

[0394] In some embodiments, provided herein is a benzoate salt of Formula I, Form B, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 81. The benzoate salt of Formula I, Form B, may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 82. The benzoate salt of Formula I, Form B, may exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 83.

[0395] In some embodiments, Form B of the benzoate salt of Formula I has at least one, at least two, or at least three of the following properties:

[0396] (a) An XRPD pattern substantially as shown in FIG. 81

[0397] (b) DSC thermogram substantially as shown in FIG. 82

[0398] (c) TGA thermogram substantially as shown in Figure 83.

[0399] In some embodiments, Formula I benzoate salt Form B exhibits an XRPD pattern of at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensity with an XRPD pattern substantially as shown in Figure 81.

[0400] In certain embodiments, Formula I benzoate salt Form B has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 14.9°, 6.7°, and 7.4°. In some embodiments, Formula I benzoate salt Form B has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 14.9°, 6.7°, and 7.4°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 20.6°, 22.5°, and 8.1°. In some embodiments, Formula I benzoate salt Form B has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 14.9°, 6.7°, and 7.4°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 6.7°, 14.9°, and 21.5°. In some embodiments, Formula I benzoate salt Form B has an XRPD pattern comprising 2θ-reflections at 14.9°, 6.7°, 7.4°, 20.6°, 22.5°, 8.1°, 6.7°, 14.9°, and 21.5° (±0.2 degrees 2θ).

[0401] Formula I Methyl p-hydroxybenzoate

[0402] In some embodiments, provided herein is methyl paraben Form A of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 84.

[0403] In some embodiments, methyl paraben, Form A of Formula I has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in Figure 84.

[0404] In certain embodiments, Formula I methyl paraben Form A has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.4°, 8.0°, and 6.3°. In some embodiments, Formula I methyl paraben Form A has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.4°, 8.0°, and 6.3°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 20.5°, 19.2°, and 12.1°. In some embodiments, Formula I methyl paraben Form A has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.4°, 8.0°, and 6.3°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 31.6°, 22.8°, and 14.0°. In some embodiments, Formula I methyl paraben Form A has an XRPD pattern including 2θ-reflections at 7.4°, 8.0°, 6.3°, 20.5°, 19.2°, 12.1°, 31.6°, 22.8°, and 14.0° (±0.2 degrees 2θ).

[0405] In some embodiments, provided herein is a methyl paraben of Formula I, Form B, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 85. Methyl paraben of Formula I, Form B may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 86. Methyl paraben of Formula I, Form B may exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 87.

[0406] In some embodiments, methyl paraben, Form B of Formula I has at least one, at least two, or at least three of the following properties:

[0407] (a) An XRPD pattern substantially as shown in FIG. 85

[0408] (b) DSC thermogram substantially as shown in FIG. 86

[0409] (c) TGA thermogram substantially as shown in Figure 87.

[0410] In some embodiments, methyl paraben, Form B of Formula I has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in Figure 85.

[0411] In certain embodiments, Formula I methyl paraben Form B has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.4°, 8.3°, and 6.5°. In some embodiments, Formula I methyl paraben Form B has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.4°, 8.3°, and 6.5°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 19.3°, 20.6°, and 21.6°. In some embodiments, Formula I methyl paraben Form B has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 7.4°, 8.3°, and 6.5°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 12.2°, 13.0°, and 31.8°. In some embodiments, Formula I methyl paraben Form B has an XRPD pattern including 2θ-reflections at 7.4°, 8.3°, 6.5°, 19.3°, 20.6°, 21.6°, 12.2°, 13.0°, and 31.8° (±0.2 degrees 2θ).

[0412] Formula I Caffeic acid salt

[0413] In some embodiments, provided herein is a wet cake of a caffeic acid salt of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 88 .

[0414] In some embodiments, the wet cake of the caffeic acid salt of Formula I has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ reflections having maximum intensity with an XRPD pattern substantially as shown in Figure 88.

[0415] In certain embodiments, the wet cake of the coffee acid salt of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 5.3°, 7.4°, and 9.1°. In some embodiments, the wet cake of the coffee acid salt of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 5.3°, 7.4°, and 9.1°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 6.5°, 7.0°, and 15.9°. In some embodiments, the wet cake of the coffee acid salt of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 5.3°, 7.4°, and 9.1°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 27.1°, 22.5°, and 10.6°. In some embodiments, the caffeic acid salt of Formula I wet cake has an XRPD pattern comprising 2θ-reflections at 5.3°, 7.4°, 9.1°, 6.5°, 7.0°, 15.9°, 27.1°, 22.5°, and 10.6° (±0.2 degrees 2θ).

[0416] In some embodiments, provided herein is a solid form of a caffeic acid salt of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 89. The caffeic acid salt of Formula I may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 90. The caffeic acid salt of Formula I may exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 91.

[0417] In some embodiments, the solid form of the caffeic acid salt of Formula I has at least one, at least two, or at least three of the following properties:

[0418] (a) An XRPD pattern substantially as shown in FIG. 89

[0419] (b) DSC thermogram substantially as shown in FIG. 90

[0420] (c) TGA thermogram substantially as shown in Figure 91.

[0421] Formula I glycolate

[0422] In some embodiments, provided herein is a wet cake of a glycolic acid salt of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 92 .

[0423] In some embodiments, the wet cake of the glycolic acid salt of Formula I has an XRPD pattern exhibiting at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensity with an XRPD pattern substantially as shown in Figure 92.

[0424] In certain embodiments, the wet cake of the glycolate salt of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.4°, and 11.5°. In some embodiments, the wet cake of the glycolate salt of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.4°, and 11.5°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 10.9°, 16.4°, and 22.3°. In some embodiments, the wet cake of the glycolate salt of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.4°, and 11.5°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 13.6°, 14.0°, and 15.3°. In some embodiments, the Formula I glycolate wet cake has an XRPD pattern comprising 2θ-reflections at 6.2°, 8.4°, 11.5°, 10.9°, 16.4°, 22.3°, 13.6°, 14.0°, and 15.3° (±0.2 degrees 2θ).

[0425] In some embodiments, provided herein is a solid form of a glycolic acid salt of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 93 .

[0426] In some embodiments, the glycolic acid salt of Formula I has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in FIG. 93 .

[0427] In certain embodiments, the glycolate salt of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.3°, and 11.5°. In some embodiments, the glycolate salt of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.3°, and 11.5°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 10.8°, 16.4°, and 22.2°. In some embodiments, the glycolate salt of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.3°, and 11.5°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 13.6°, 14.9°, and 15.3°. In some embodiments, the glycolic acid salt of Formula I has an XRPD pattern comprising 2θ-reflections at 6.2°, 8.3°, 11.5°, 10.8°, 16.4°, 22.2°, 13.6°, 14.9°, and 15.3° (±0.2 degrees 2θ).

[0428] Formula I α-ketobutyrate

[0429] In some embodiments, provided herein is a Formula I α-ketobutyrate salt wet cake, wherein the Formula I α-ketobutyrate salt wet cake exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 94 .

[0430] In some embodiments, the α-ketobutyrate salt of Formula I wet cake has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ reflections having maximum intensity with an XRPD pattern substantially as shown in Figure 94.

[0431] In certain embodiments, the α-ketobutyrate salt of Formula I wet cake has an XRPD pattern comprising 2θ-reflections at 6.2°, 8.3°, and 10.8° (±0.2 degrees 2θ). In some embodiments, the α-ketobutyrate salt of Formula I wet cake has an XRPD pattern comprising 2θ-reflections at 6.2°, 8.3°, and 10.8° (±0.2 degrees 2θ) and one, two, or three of 2θ-reflections at 12.3°, 12.5°, and 12.7° (±0.2 degrees 2θ). In some embodiments, the α-ketobutyrate salt of Formula I wet cake has an XRPD pattern comprising 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.3°, and 10.8° and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 16.4°, 19.0°, and 21.6°. In some embodiments, the α-ketobutyrate salt of Formula I wet cake has an XRPD pattern comprising 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.3°, 10.8°, 12.3°, 12.5°, 12.7°, 16.4°, 19.0°, and 21.6°.

[0432] In some embodiments, provided herein is a solid form of an α-ketobutyrate salt of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 95 .

[0433] In some embodiments, the α-ketobutyrate salt of Formula I has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensity with an XRPD pattern substantially as shown in Figure 95.

[0434] In certain embodiments, the α-ketobutyrate salt of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 16.4°, and 8.3°. In some embodiments, the α-ketobutyrate salt of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 16.4°, and 8.3°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 10.8°, 11.5°, and 20.3°. In some embodiments, the α-ketobutyrate salt of Formula I has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 16.4°, and 8.3°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 18.5°, 19.0°, and 21.6°. In some embodiments, the α-ketobutyrate salt of Formula I has an XRPD pattern including 2θ-reflections at 6.2°, 16.4°, 8.3°, 10.8°, 11.5°, 20.3°, 18.5°, 19.0°, and 21.6° (±0.2 degrees 2θ).

[0435] Formula I pyruvate

[0436] In some embodiments, provided herein is a Formula I pyruvate salt wet cake, wherein the Formula I pyruvate salt wet cake exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 96 .

[0437] In some embodiments, the Formula I pyruvate salt wet cake has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in FIG. 96 .

[0438] In certain embodiments, the Formula I pyruvate salt wet cake has an XRPD pattern comprising 2θ-reflections at 6.21°, 8.34°, and 10.85° (±0.2 degrees 2θ). In some embodiments, the Formula I pyruvate salt wet cake has an XRPD pattern comprising 2θ-reflections at 6.21°, 8.34°, and 10.85° (±0.2 degrees 2θ) and one, two, or three of 2θ-reflections at 11.56°, 13.60°, and 14.51° (±0.2 degrees 2θ). In some embodiments, the Formula I pyruvate salt wet cake has an XRPD pattern comprising 2θ-reflections (±0.2 degrees 2θ) at 6.21°, 8.34°, and 10.85° and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 20.34°, 21.73°, and 22.59°. In some embodiments, the Formula I pyruvate salt wet cake has an XRPD pattern comprising 2θ-reflections (±0.2 degrees 2θ) at 6.21°, 8.34°, 10.85°, 11.56°, 13.60°, 14.51°, 20.34°, 21.73°, and 22.59°.

[0439] In some embodiments, provided herein is a solid form of a pyruvate salt of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 97 .

[0440] In some embodiments, the pyruvate salt of Formula I has an XRPD pattern showing at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine 2θ-reflections having maximum intensities with an XRPD pattern substantially as shown in FIG. 97 .

[0441] In certain embodiments, the Formula I pyruvate salt has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.3°, and 10.8°. In some embodiments, the Formula I pyruvate salt has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.3°, and 10.8°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 11.5°, 16.3°, and 19.1°. In some embodiments, the Formula I pyruvate salt has an XRPD pattern including 2θ-reflections (±0.2 degrees 2θ) at 6.2°, 8.3°, and 10.8°, and one, two, or three of 2θ-reflections (±0.2 degrees 2θ) at 20.3°, 21.7°, and 22.1°. In some embodiments, Formula I has an XRPD pattern that includes 2θ-reflections at 6.2°, 8.3°, 10.8°, 11.5°, 16.3°, 19.1°, 20.3°, 21.7°, and 22.1° (±0.2 degrees 2θ).

[0442] Pharmaceutical composition

[0443] For the purpose of administration, in certain embodiments, the compounds described herein are administered as chemical raw materials or formulated into pharmaceutical compositions. The pharmaceutical compositions of the present disclosure may include a therapeutically effective amount of a compound of formula I and at least one pharmaceutically acceptable carrier and / or excipient. The compound of formula I is present in the composition in an amount effective to treat a particular disease or condition of interest. The pharmaceutical compositions of the present disclosure may additionally include one or more other compounds as active ingredients, including, for example, prodrugs, other nuclear receptor modulators or other active pharmaceutical ingredients, such as active pharmaceutical ingredients for the treatment of liver diseases, such as ACC inhibitors or ASK1 inhibitors. In some embodiments, the pharmaceutical compositions of the present disclosure additionally include ACC inhibitors and ASK1 inhibitors.

[0444] In some embodiments, the pharmaceutical composition comprises amorphous Form I; Form I of Formula I; Form II of Formula I; Form III of Formula I; Form IV of Formula I; Form V of Formula I; Form VI of Formula I; Form VII of Formula I; Form VIII of Formula I; Form IX of Formula I; Form X of Formula I; Form XI of Formula I; Form XII of Formula I; Form XIII of Formula I; Form XIV of Formula I; Form XV of Formula I; 2-(4-hydroxybenzoyl)benzoate Form A of Formula I; 2-(4-hydroxybenzoyl)benzoate Form B of Formula I; Vanillate Form A of Formula I; Vanillate Form B of Formula I; Hippurate Form A of Formula I; Hippurate Form B of Formula I; Maleate Form A of Formula I; Maleate Form B of Formula I; Glyoxylate Form A of Formula I; Glyoxylate Form B of Formula I; L-pyroglutamate of Formula I; 2-naphthalenesulfonate Form A of Formula I; 2-naphthalenesulfonate Form B of Formula I; 1-naphthalenesulfonate Form A of Formula I; 1-naphthalenesulfonate form B; 1-hydroxy-2-naphthalenesulfonate form A of formula I; 1-hydroxy-2-naphthalenesulfonate form B of formula I; 1-hydroxy-2-naphthalenesulfonate form A of formula I; 1-hydroxy-2-naphthalenesulfonate form B of formula I; S-mandelate form A of formula I; S-mandelate form B of formula I; gentisate form A of formula I; gentisate form B of formula I; citrate form A of formula I; citrate form B of formula I; R-mandelate form A of formula I; R-mandelate form B of formula I; benzoate form A of formula I; benzoate form B of formula I; methyl parahydroxybenzoate form A of formula I; methyl parahydroxybenzoate form B of formula I; caffeate form A of formula I; caffeate form B of formula I; glycolate form A of formula I; glycolate form B of formula I; α-ketobutyrate form A of formula I; α-ketobutyrate form B of formula I; pyruvate form A of formula I; and / or pyruvate form B of formula I and a pharmaceutically acceptable carrier.

[0445] The activity of the compounds of Formula I can be determined by one skilled in the art, for example, as described herein. Appropriate therapeutically effective concentrations and dosages can be readily determined by one skilled in the art.

[0446] In certain embodiments, the crystallization, salt and / or solvate forms described herein may potentially exhibit improved properties. For example, in certain embodiments, the crystallization and / or salt forms described herein may potentially exhibit improved stability. This improved stability may have a potential beneficial effect on the preparation of the compound of Formula I, such as providing the ability to store the processing intermediate for an extended period of time. The improved stability may also potentially benefit the composition or pharmaceutical composition of the compound of Formula I. In certain embodiments, the crystallization salt and / or solvate forms described herein may also potentially lead to an increase in the yield of the compound of Formula I or an increase in the quality of the compound of Formula I. In certain embodiments, the crystallization, salt and / or solvate forms described herein may also exhibit improved pharmacokinetic properties and / or potentially improved bioavailability.

[0447] The compositions are suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation) or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the condition to be treated and the nature of the active ingredient. They may conveniently be presented in unit dosage form and prepared by any of the methods well known in the pharmaceutical art.

[0448] In actual use, the compounds of the present disclosure can be closely blended and combined with pharmaceutical carriers as active ingredients according to conventional pharmaceutical compounding techniques. Depending on the form of the preparation required for administration, such as oral or parenteral (including intravenous), the carrier can take a variety of forms. When preparing a composition for oral dosage forms, any commonly used pharmaceutical medium can be used, such as water, glycols, oils, alcohols, flavoring agents, preservatives, colorants, etc. in the case of oral liquid preparations (such as suspensions, elixirs and solutions); or in the case of oral solid preparations (such as powders, hard and soft capsules and tablets), carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, etc., wherein solid oral preparations are preferred over liquid preparations.

[0449] Tablets and capsules represent the most advantageous oral dosage unit forms due to their ease of administration, in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1% of the active compound. Of course, the percentage of the active compound in these compositions may vary, and may conveniently be between about 2% and about 60% of the unit weight. The amount of the active compound in such therapeutically useful compositions is such that an effective dose will be obtained. The active compound may also be administered intranasally, for example, as drops or sprays.

[0450] Tablets, pills, capsules, etc. may also contain a binder such as gum tragacanth, gum arabic, corn starch or gelatin; an excipient such as dicalcium phosphate, microcrystalline cellulose, lactose monohydrate, mannitol or colloidal silicon dioxide; a disintegrant such as corn starch, potato starch, alginic acid, cross-linked carboxymethylcellulose sodium or cross-linked polyvinylpyrrolidone; a lubricant such as magnesium stearate; and a sweetener such as sucrose, lactose or saccharin. When the dosage unit form is a capsule, it may contain, in addition to the above-mentioned types of materials, a liquid carrier such as a fatty oil or a pharmaceutical medium, for example, water, a glycol (e.g., polyethylene glycol 400) or an alcohol.

[0451] Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar, polyvinyl alcohol, polyethylene glycol 3350, titanium dioxide, talc, coloring agents, or combinations thereof. In addition to the active ingredient, a syrup or elixir may contain sucrose as a sweetener, methyl and propylparabens as preservatives, dyes, and flavorings (such as cherry or orange flavoring).

[0452] Compounds of the present disclosure may also be administered parenterally. Solutions or suspensions of these active compounds may be prepared in water appropriately mixed with organic matter, additives or combinations thereof. Examples of organic matter include, but are not limited to, N-methylpyrrolidone, dimethyl sulfoxide, polyethylene glycol and combinations thereof. Examples of additives include, but are not limited to, hydroxypropylcellulose, polyvinylpyrrolidone, poloxamer, poly(lactic acid-co-glycolic acid), polysorbate, povidone, carboxymethylcellulose and combinations thereof. Dispersions may also be prepared in glycerol, liquid polyethylene glycol and mixtures thereof in oil. Under general storage and use conditions, these preparations may contain preservatives, for example, to prevent the growth of microorganisms. In some embodiments, parenteral administration includes intravenous administration of a preparation comprising a solution of a mixture of an organic matter and an aqueous medium. In some embodiments, intravenous administration is administered with 100% organic solution.

[0453] The pharmaceutical form that is suitable for injectable purposes comprises sterile aqueous solution or dispersion and is used for the extemporaneous preparation of sterile injectable solution or the sterile powder of dispersion.In all cases, this form must be sterile, and must be the fluid that reaches the degree of easy injection.For example, these forms can be stable under manufacturing and storage conditions.These forms can be preserved with the contamination effect (for example, via the use of preservative) of resisting microorganism such as bacterium and fungus.Carrier can be the solvent or the dispersion medium containing for example water, ethanol, polyol (for example glycerine, propylene glycol and liquid polyethylene glycol), their suitable mixture and vegetable oil.

[0454] Any suitable route of administration can be used to provide an effective dose of the compounds of the present disclosure to mammals, especially humans. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, etc. can be used. Dosage forms include tablets, lozenges, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, etc. In some embodiments, the compounds of the present disclosure are administered orally.

[0455] In specific embodiments of compositions comprising a crystalline form of Formula I, or a pharmaceutically acceptable salt thereof, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the Formula I present in the composition is one of the crystalline forms disclosed herein. In certain embodiments, the composition comprises at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of one of the crystalline forms of Formula I.

[0456] In other embodiments of the compositions comprising a crystalline form disclosed herein, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% of Formula I present in the composition is other amorphous or crystalline forms of Formula I and / or impurities.

[0457] In other embodiments of the compositions comprising the crystalline forms disclosed herein, the impurities account for less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% of the total mass relative to the mass of the crystalline forms present. Impurities may, for example, include by-products of the synthesis of formula I, pollutants, degradation products, other crystalline forms, amorphous forms, water and solvents. In certain embodiments, impurities include by-products from the process of synthesizing formula I. In certain embodiments, impurities include pollutants from the process of synthesizing formula I. In certain embodiments, impurities include degradation products of formula I. In certain embodiments, impurities include other crystalline forms of formula I. In certain embodiments, impurities include other crystalline forms of formula I and / or amorphous forms of formula I. In certain embodiments, impurities include water or solvents. In certain embodiments of the compositions comprising the crystalline forms disclosed herein, impurities are selected from the group consisting of by-products of the synthesis of formula I, pollutants, degradation products, other crystalline forms, amorphous forms, water, solvents and combinations thereof.

[0458] dose

[0459] The effective dosage of active ingredient employed may vary depending on the specific compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosages can be readily determined by those skilled in the art.

[0460] When treating or preventing Cot-mediated diseases to which the compounds of the present invention are applicable, when the compounds of the present invention are administered at a daily dose of about 0.1 mg to about 100 mg per kg of animal body weight, satisfactory results are generally obtained. In some embodiments, the compounds of the present invention are administered in a single daily dose or in divided doses twice to six times a day or in a sustained release form. For most large mammals, the total daily dose may be about 1 mg to about 1000 mg. In the case of a 70 kg adult, the total daily dose will generally be about 7 mg to about 350 mg. The dosage regimen may be adjusted to provide the best therapeutic response. In some embodiments, the total daily dose is about 1 mg to about 900 mg, about 10 mg to about 800 mg, about 20 mg to about 700 mg, about 30 mg to about 600 mg, about 40 mg to about 550 mg, or about 50 mg to about 400 mg. In some embodiments, the total daily dose is from about 10 mg to about 50 mg, from about 20 mg to about 40 mg, from about 25 mg to about 35 mg, from about 50 mg to about 150 mg, from about 70 mg to about 130 mg, from about 80 mg to about 120 mg, from about 90 mg to about 100 mg, from about 1 mg to about 150 mg, from about 1 mg to about 75 mg, from about 1 mg to about 50 mg, from about 25 mg to about 125 mg, from about 125 mg to about 275 mg, from about 275 mg to about 425 mg, from about 425 mg to about 575 mg, from about 575 mg to about 725 mg, from about 725 mg to about 875 mg, or from about 875 mg to about 1000 mg.

[0461] The compounds of the present application or compositions thereof can be administered once, twice, three times or four times a day using any suitable mode described above. Moreover, administration or treatment with the compound can continue for several days or months; for example, treatment will generally continue for at least 7 days, 14 days or 28 days, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months.

[0462] In a specific embodiment, the methods provided herein include administering to a subject an initial daily dose of about 1 mg to about 1500 mg, such as 150 mg to 600 mg, for example 150 mg, 300 mg, 600 mg of a compound described herein. In another embodiment, the method includes gradually increasing the dose until clinical efficacy is achieved. Increments of about 5 mg, 10 mg, 25 mg, 30 mg, 40 mg, 50 mg, or 100 mg can be used to increase the dose. The dose can be increased every day, every other day, twice a week, once a week, or once every 4 weeks.

[0463] Treatments and uses

[0464] "Treatment" is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results may include one or more of the following: (a) inhibiting a disease or condition (e.g., reducing one or more symptoms caused by the disease or condition, and / or reducing the extent of the disease or condition); (b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread (e.g., metastasis of the disease or condition); and / or (c) relieving the disease, i.e., causing regression of clinical symptoms (e.g., improving the disease state, providing partial or total remission of the disease or condition, enhancing the effect of another drug, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival).

[0465] The present disclosure also relates to the use of the compound for treating and / or preventing diseases and / or conditions by binding the compound to the nuclear receptor. The present disclosure also relates to the use of the compound for preparing a medicament for treating and / or preventing diseases and / or conditions by binding the compound to the nuclear receptor.

[0466] Also provided herein are methods of treating a patient suffering from a Cot-mediated disorder. In some embodiments, the method comprises administering a compound or composition disclosed herein. In some embodiments, the method of treating a patient suffering from a Cot-mediated disorder comprises administering a therapeutically effective amount of amorphous Form I; Form I of Formula I; Form II of Formula I; Form III of Formula I; Form IV of Formula I; Form V of Formula I; Form VI of Formula I; Form VII of Formula I; Form VIII of Formula I; Form IX of Formula I; Form X of Formula I; Form XI of Formula I; Form XII of Formula I; Form XIII of Formula I; Form XIV of Formula I; Form XV of Formula I; 2-(4-hydroxybenzoyl)benzoate of Formula I; vanillate of Formula I; hippurate of Formula I; maleate of Formula I; glyoxylate of Formula I; L-pyroglutamate of Formula I; 2-naphthalenesulfonate of Formula I; 1-naphthalenesulfonate of Formula I; 1-hydroxy-2-naphthalenesulfonate of Formula I; S-mandelate of Formula I; gentisate of Formula I; citrate of Formula I; R-mandelate of Formula I; benzoate of Formula I; methylparaben of Formula I; caffeate of Formula I; glycolate of Formula I; α-ketobutyrate; and / or pyruvate of formula I.

[0467] Also provided herein is a method of treating or preventing a disease or condition in a patient in need thereof, the method comprising administering a therapeutically effective amount of a compound useful for modulating Cot, wherein the disease or condition is an inflammatory disease, and wherein the compound useful for modulating Cot is a compound of Formula I

[0468]

[0469] (I).

[0470] Reagent test kit

[0471] Also provided herein are kits comprising a compound or composition described herein and suitable packaging. In one embodiment, the kit further comprises instructions for use. In one aspect, the kit comprises a crystalline form of the disclosure, or a composition comprising a crystalline form of the disclosure, and a label and / or instructions for use of the compound in a treatment indication, including a disease or condition described herein.

[0472] Also provided herein are articles of manufacture comprising a compound or composition described herein in a suitable container. The container may be a vial, a jar, an ampoule, a preloaded syringe, and an intravenous bag.

[0473] Additional therapeutic agents

[0474] In some embodiments, the compounds of the present disclosure are co-administered with one or more (e.g., one, two, three, or four) additional therapeutic agents. In some embodiments, additional therapeutic agents include agents useful for regulating, treating, or preventing inflammation, such as 5-HT 1a receptor partial agonists and antagonists, 5-HT 2a receptor partial agonists and antagonists, 5-HT 2b receptor antagonists, 5-HT 6 receptor antagonists, 5-HT 7 receptor antagonists, Abl tyrosine kinase inhibitors, ACE inhibitors, acid mammalian chitinase inhibitors, actin antagonists, acetaldehyde dehydrogenase inhibitors, acetyl-CoA carboxylase (ACC) inhibitors, ACC-1 inhibitors, ACC-2 inhibitors, 2-acylglycerol O-acyltransferase 2 (DGAT2) inhibitors, ACTH receptor agonists, activin receptor antagonists, adenosine homocysteinease inhibitors, adenosine receptor antagonists and agonists, adenosine deaminase inhibitors, adenylate cyclase-related protein 1 inhibitors, lipotrophin inhibitors, adiponectin receptor agonists, ADP-ribose cyclase-1 inhibitors, ADP-ribose cyclase-1 modulators , ADP ribosylation factor 6 inhibitors, adrenocorticotropic hormone ligands, adrenomedullin ligands, adrenaline receptor antagonists and agonists, Adropin stimulators, proteoglycanase-2 inhibitors, AIMP multisynthase complex protein 1 stimulators, AKT1 gene inhibitors, AKT protein kinase inhibitors, albumin antagonists, albumin modulators, acetaldehyde dehydrogenase 2 stimulators, aldosterone antagonists, aldosterone synthase inhibitors Alk-5 protein kinase inhibitors, α2 adrenergic receptor agonists, α2 adrenergic receptor modulators, α1 antitrypsin stimulators, alpha-fetoprotein modulators, Alstrom syndrome protein 1 (ALMS1) / PKC α protein interaction inhibitors, 1-aminocyclopropane carboxyl synthase inhibitors, amylin receptor agonists, AMP-activated protein kinase (AMPK), AMP-activated protein kinase inhibitors, activators or stimulators, AMP-activated protein kinase α2 stimulators, androgen receptor agonists and antagonists, angiopoietin-related protein-3 inhibitors, angiotensin II receptor antagonists, angiotensin II AT-1 receptor antagonists, angiotensin II AT-2 receptor agonists, angiotensinogen ligand inhibitors, annexin A1 modulators, antibiotics, antifungal drugs, anti-IL6 antibodies, anti-TNF steroid conjugates, activator protein 1 (AP1) transcription factor inhibitors, AP1 transcription factor regulators, Apelin receptor agonists, APOA1 gene stimulators, apolipoprotein A antagonists, apolipoprotein B regulators, apolipoprotein L1 regulators, apoptosis regulators Bcl w inhibitors, aryl hydrocarbon receptor (AHR) agonists and modulators, AHR agonists plus autoantigens, ASK1 inhibitors, ATPase inhibitors, ATP-binding cassette transporter C2 inhibitors, ATP citrate lyase inhibitors,Autophagy protein regulators and stimulators, autotaxin inhibitors, Axl tyrosine kinase receptor inhibitors, BAFF / APRIL inhibitors, Basigin inhibitors, B and T lymphocyte attenuation stimulators, Bax protein stimulators, Bcl-2 protein inhibitors, Bcl-xLBcl-2 associated death promoter inhibitors, Bcl-xL Bcl-2 associated death promoter modulators, Bcr protein inhibitors, benzodiazepine receptor agonists, beta adrenergic receptor antagonists, BET inhibitors, beta2 adrenergic receptor agonists, beta amyloid antagonists, beta-catenin inhibitors, beta-catenin modulators, beta-catenin stimulators, beta-galactosidase inhibitors, beta lactamase modulators, 17beta hydroxysteroid dehydrogenase 13 inhibitors, bifunctional aminoacyl tRNA synthetase inhibitors, B-lymphocyte antigen CD19 inhibitors, B-lymphocyte antigen CD20 inhibitors, B-lymphocyte antigen CD20 modulators, B-lymphocyte adhesion molecule inhibitors, B-lymphocyte stimulator ligand inhibitors, B-lymphocyte stimulator ligand modulators, bioactive lipids, bone morphogenetic protein-7 ligands, bone morphogenetic protein-7 ligand modulators agents, bradykinin receptor modulators, BRAF gene inhibitors, branched-chain amino acid aminotransferase 1 inhibitors, bromodomain-containing protein (BRD) inhibitors, BRD1, BRD2 and BRD4 inhibitors, BTK inhibitors, B7 homolog inhibitors, cadherin-11 antagonists, Cak tyrosine kinase receptor inhibitors, calcineurin inhibitors, calcium channel inhibitors, Ca2+ release-activated Ca2+ channel 1 inhibitors, calcitonin agonists, calpain-IX inhibitors, calpain-I inhibitors, calpain-II inhibitors, calreticulin inhibitors, caveolin-1 stimulators, cannabinoid CB1 receptor antagonists and inverse agonists, cannabinoid CB2 receptor agonists, cannabinoid receptor antagonists and agonists, cannabinoid CB1 receptor inverse agonists, carbohydrate metabolism modulators, carbonic anhydrase inhibitors, casein kinase-I Delta and / or epsilon inhibitors, CASP9 gene stimulators, caspase inhibitors, caspase-3 stimulators, catalase stimulators, cathepsin inhibitors, cathepsin K inhibitors, cathepsin S inhibitors, caveolin 1 inhibitors, CCK receptor antagonists, CCAAT enhancer binding protein beta modulators, CC motif ligand 26 (CCL26) gene inhibitors, chemokine receptor antagonists, CC motif chemokine receptor (CCR) 1 antagonists, CCR2 antagonists, CCR3 antagonists and modulators, CCR4 antagonists, CCR5 antagonists, CCR6 antagonists, CCR7 modulators, CCR9 chemokine antagonists, CCR3 gene modulators, CD3 modulators or antagonists, CD4 agonists or antagonists, CD7 inhibitors, CD11b agonists, CD29 modulators, CD39 agonists,CD40 ligand receptor modulators or antagonists, CD47 antagonists, CD52 antagonists, CD73 agonists and antagonists, CD79b modulators, CD80 modulators or antagonists, CD86 modulators or antagonists, CD95 antagonists, CD126 antagonists, CD223 modulators, CDGSH iron-sulfur domain protein modulators, CDw123 antagonists, cell adhesion molecule inhibitors, cell surface glycoprotein CD200R agonists, cell surface glycoprotein MUC18 inhibitors, chemokine CXC ligand inhibitors, chaperone protein inhibitors and modulators, chitinase inhibitors, chitotriosidase 1 inhibitors, chloride channel stimulators, cholera enterotoxin B subunit inhibitors, choline kinase inhibitors, CHST15 gene inhibitors, chymotrypsin inhibitors, Claudin 1 inhibitors, clusterin stimulators, CNR1 inhibitors, collagen I antagonists, collagen VII antagonists, collagen gene inhibitors, collagenase inhibitors, collagen regulators, complement C1q subcomponent inhibitors, complement C1s subcomponent inhibitors, complement C3 inhibitors, complement C5 factor inhibitors, complement C5a receptor antagonists, complement cascade inhibitors, complement factor stimulators, complement factor B inhibitors, complement factor D inhibitors, connective tissue growth factor ligand inhibitors, corticosteroid hormone receptor agonists, COT protein kinase inhibitors, CREB binding protein inhibitors, C-reactive protein (CRP) inhibitors, cerebrospinal fluid (CSF)-1 stimulators agonists and antagonists, C-type lectin domain protein 4C inhibitors, CTGF gene inhibitors, CX3CR1 antagonists and modulators, CXCR2 antagonists, CXCR3 antagonists, CXCR4 antagonists and modulators, CXCR5 antagonists and modulators, CXC5 ligand inhibitors, CXC6 chemokine ligand inhibitors, CXC10 ligand inhibitors, CXC11 ligand modulators, cyclin-dependent kinase (CDK) 1, 2, 5, 7 and / or 9 inhibitors, cyclooxygenase (COX) inhibitors, COX-1 inhibitors, COX-2 inhibitors and modulators, cysteine ​​palmitoyltransferase porcupine inhibitors, cytochrome P450 7A1 inhibitors, cytochrome P450 11B2 inhibitors, cytochrome P450 2E1 inhibitors (CYP2E1), cytochrome P450 reductase inhibitors, cytokine receptor agonists and antagonists, cytosolic phospholipase A2 (cPLA2) inhibitors, cytotoxic T-lymphocyte protein-4 (CTLA4) modulators and stimulators, deoxyribonuclease (DNase) modulators, DNase γ stimulators, DNase I stimulators, DGAT2 gene inhibitors, DHFR inhibitors, diacylglycerol O acyltransferase (DGAT) 1 inhibitors, DGAT2 inhibitors, diamine acetyltransferase inhibitors, dihydroceramide δ4 desaturase inhibitors, dihydroorotate dehydrogenase inhibitors, dipeptidyl peptidase (DPP) I inhibitors, DPP IV inhibitors,DNA binding protein Ikaros inhibitor, DNA methyltransferase inhibitor, DNA polymerase inhibitor, dopamine D2 receptor partial agonist, dopamine D3 receptor partial agonist, dopamine D4 receptor partial agonist, dopamine D2 receptor agonist, DYRK-1 α-protein kinase inhibitors, ectonucleotide pyrophosphatase-PDE-2 inhibitors, EGFR tyrosine kinase receptor inhibitors, EGR1 gene inhibitors, elongation factor 2 inhibitors, endoglin inhibitors, endoplasmic reticulum inhibitors, endosialin modulators, endostatin modulators, endothelin ET-A receptor antagonists, endothelin ET-B receptor antagonists, endothelial nitric oxide synthase stimulators, enolase 1 inhibitors, enteropeptidase inhibitors, eotaxin 2 ligand inhibitors, eotaxin ligand inhibitors, EP4 prostaglandin receptor antagonists or agonists, EP4 prostaglandin receptor antagonists, epidermal growth factor (EGF) receptor antagonists, EGF modulators, epoxide hydrolase inhibitors, erythropoietin receptor antagonists or agonists, exportin 1 inhibitors, extracellular matrix protein modulators, F1F0 ATP synthase modulators, facilitating glucose transporter-1 modulators, factor IIa antagonists, factor XIIa antagonists, farnesoid X receptor (FXR) agonists and modulators, fatty acid synthase inhibitors, fecal microbiota transplantation (FMT), fibroblast activation protein (FAP) inhibitors, fibroblast growth factor (FGF) receptor agonists and antagonists, FGF-2 ligand inhibitors, FGF1 receptor agonists and antagonists, FGF2 receptor antagonists, FGF3 receptor antagonists, FGF19 gene stimulators, FGF-15 ligands or modulators, FGF-19 ligands or modulators, FGF-21 ligands or modulators, FK506 binding protein inhibitors, FK506 binding Protein-10 inhibitors, FK506 binding protein-12 modulators, Flt3 tyrosine kinase inhibitors, focal adhesion kinase inhibitors, folate antagonists or agonists, folate receptor beta antagonists, FP prostaglandin receptor antagonists, fractal chemokine ligand inhibitors, free fatty acid receptor 1, 2 and / or 3 agonists, free fatty acid receptor 2 antagonists, Frizzled-5 receptor agonists, Frizzled-8 receptor agonists, Fyn tyrosine kinase inhibitors, G-protein coupled bile acid receptor 1 agonists, G protein coupled receptor 15 antagonists, G-protein beta subunit inhibitors, G-protein coupled receptor (GPCR) 35, 44, 84, 119, 120 modulators, GPCR 44, 87 antagonists, GABA A receptor modulators, GABA A receptor α-2 subunit modulators, GABA A receptor α-3 subunit modulators, galanin GAL2 receptor agonists, galectin-3 inhibitors, gastric inhibitory polypeptide receptor (GIP-R) agonists and modulators, GATA3 transcription factor inhibitors, GDNF family receptor α-like agonists,GHR gene inhibitor, glucagon-like peptide (GLP) 1 agonist, GLP 2 agonist, GLP 1 receptor modulator, glucocorticoid agonist or antagonist, glucocorticoid-induced leucine zipper stimulator, glucokinase stimulator, glucose 6-phosphate 1-dehydrogenase inhibitor, glutaminyl peptide cyclotransferase inhibitor, glutaredoxin 1 modulator, glutathione-dependent PGD synthase inhibitor, glycoprotein Ib (GPIb) antagonist, GM-CSF receptor antagonist or modulator, GMP synthase inhibitor, GNRH receptor modulator, GP IIb IIIa antagonist, GPCR modulator, GPR40 agonist, GPR84 antagonist, GroEL protein 2 inhibitor, GroEL protein 2 inhibitor, growth hormone ligand, growth hormone receptor agonist, growth regulatory protein α ligand inhibitor, guanylate cyclase receptor agonist, guanylate cyclase stimulator, heat shock protein inhibitor, H+ K+ ATPase inhibitors, Hedgehog (Hh) modulators, Hh protein inhibitors, heme oxygenase 1 modulators, hepatitis B structural protein inhibitors, hepatitis C virus NS3 protease inhibitors, hepatitis C virus protein NS5A inhibitors, hepatocyte nuclear factor 4 alpha regulator (HNF4A), hepatocyte growth factor regulators and antagonists, hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors, HIF prolyl hydroxylase-2 inhibitors, high mobility group protein B1 inhibitors, histamine H1 receptor antagonists, histamine H4 receptor agonists, histamine H4 receptor antagonists, histone deacetylase (HDAC) inhibitors, HDAC -1 inhibitors, HDAC -2 inhibitors, HDAC -3 inhibitors, HDAC -6 inhibitors, H+ K+ ATPase inhibitors, HIV-1 gp120 protein inhibitors, HLA antigen modulators, HLA class II antigen DQ-2 alpha modulators, HLA class II antigen DR-1 β inhibitors, HLA Class II antigen inhibitors, HLA class II antigen modulators, HMGCoA reductase inhibitors, homeodomain interacting kinase 2 (HIPK2) inhibitors, hormone-sensitive lipase stimulators, HSD17B3 gene modulators, HSD17B13 gene inhibitors, Hsp 70 family inhibitors and stimulators, Hsp 90 inhibitors, hyaluronidase stimulators, hydrolase inhibitors, hypoxia-inducible factor (HIF) regulators, HIF-1 inhibitors, HIF-1 α regulators and stimulators, HIF-2 α inhibitors, ICAM1 gene inhibitors, ICE inhibitors, interferon β (IFNB) gene stimulators, insulin-like growth factor 1 (IGF1) gene inhibitors, IgG receptor FcRn large subunit p51 antagonists, IgG receptor FcRn large subunit p51 modulators, I-κ B kinase inhibitors, I-κ B kinase β inhibitors, IK potassium channel inhibitors, interleukin (IL)-1 antagonists,IL-2 agonists or antagonists, IL-3 antagonists, IL-4 agonists or antagonists, IL-5 antagonists, IL-6 agonists or antagonists, IL-7 receptor antagonists, IL-8 antagonists, IL-10 antagonists or agonists, IL-11 agonists, IL-12 antagonists, IL-13 antagonists, IL-15 antagonists, IL-17, IL17A and IL17B agonists or antagonists, IL-18 antagonists, IL-21 antagonists, IL-22 agonists or antagonists, IL-23 antagonists, IL-1β ligand modulators, IL-23A inhibitors, IL-31 receptor IL-36 inhibitors, IL-6 neutralizing human antibodies, IL-1 receptor accessory protein inhibitors, IL-18 receptor accessory protein antagonists, IL-2 receptor alpha subunit inhibitors, IL-2 receptor alpha subunit stimulators, interleukin ligands, IL-1α ligand inhibitors, IL-1 ligand inhibitors, IL-1β ligand inhibitors and modulators, IL-1β ligands, interleukin ligand inhibitors, IL-2 ligands, IL-4 ligands, IL-4 ligand inhibitors, IL-6 ligand inhibitors, IL-8 ligand inhibitors, IL-10 ligands, IL-13 ligand inhibitors, IL 17 ligand inhibitors, IL 17A ligand inhibitors and modulators, IL-17F ligand inhibitors, IL 18 ligand inhibitors, interleukin-22 ligands, IL -29 ligand, IL-33 ligand inhibitor, IL-1-like receptor inhibitor, ileal bile acid sodium transporter inhibitor, immunoglobulin (Ig) agonists or antagonists, IgE antagonists and modulators, immunoglobulin Fc receptor modulators, IgG agonists, IgG1 agonists and antagonists, IgG2 antagonists and modulators, immunoglobulin gamma Fc receptor antagonists, immunoglobulin gamma Fc receptor II modulators, immunoglobulin gamma Fc receptor IIB antagonists, immunoglobulin kappa modulators, immunoglobulin-like domain receptor 2 antagonists, IgM antagonists, inducible nitric oxide synthase inhibitors (iNO S inhibitors), inducible T-cell co-stimulation inhibitors, inosine monophosphate dehydrogenase inhibitors, insulin ligands, insulin ligand agonists, insulin receptor agonists, insulin receptor substrate-1 inhibitors, insulin sensitizers, integrin antagonists and modulators, integrin α-1 / β-1 antagonists, integrin α-4 / β-1 antagonists, integrin α-V / β-1 antagonists, integrin α-V / β-3 antagonists, integrin α-V / β-6 antagonists, integrin α-V / β-8 modulators, integrin α-4 / β-7 antagonists, integrin α-9 antagonists, interferon (IFN) α ligands, IFN α ligand inhibitors and modulators, IFN Ω ligand inhibitors, IFN β ligands, IFN β ligand inhibitors, IFN γ ligands, IFN γ receptor 1 agonists, IFN γ receptor antagonists, interferon type I receptor antagonists,Interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors, IRE1 protein kinase inhibitors, Itk tyrosine kinase inhibitors, Janus kinase (JAK) inhibitors and modulators, JAK3 gene inhibitors, JAK1 inhibitors, JAK2 inhibitors, JAK3 inhibitors, Jun N-terminal kinase inhibitors, Jun N-terminal kinase-1 inhibitors, kallikrein inhibitors, kallikrein 2 inhibitors, kallikrein 7 inhibitors, KCNA voltage-gated potassium channel-3 inhibitors, KCNA voltage-gated potassium channel-3 modulators, KCNN potassium channel-4 inhibitors, KCNN4 gene inhibitors, Kelch-like ECH-associated protein 1 modulators, ketohexokinase (KHK) inhibitors, Kit tyrosine kinase inhibitors, Klotho β stimulants, lactoferrin stimulators, LanC-like protein 2 stimulators, LanC-like protein 2 modulators, Lck tyrosine kinase inhibitors, LDHA gene inhibitors, LDL receptor-associated protein-1 stimulators, LDL receptor-associated protein-6 inhibitors, LDL receptor-associated protein-6 stimulators, lectin mannose binding protein inhibitors, leukocyte elastase inhibitors, leukocyte Ig-like receptor A4 modulators, leukocyte proteinase-3 inhibitors, leukotriene receptor antagonists, leukotriene A4 hydrolase inhibitors, leukotriene BLT receptor antagonists, leukotriene D4 antagonists, 5-lipoxygenase activating protein inhibitors, 5-lipoxygenase inhibitors, lipoxygenase modulators, lipoprotein lipase inhibitors, LITAF gene inhibitors, liver X receptor agonists and antagonists, liver X receptor alpha inverse agonists, liver X receptor beta inverse agonists, LPL gene stimulators, lymphocyte function antigen-3 receptor antagonists, Lyn tyrosine kinase inhibitors, Lyn tyrosine kinase stimulators, lysophosphatidic acid-1 receptor antagonists, lysyl oxidase homolog (LOXL) 2 inhibitors, LXR inverse agonists, macrophage-drug conjugates (MDC), macrophage inflammatory protein (MIP) 2α inhibitors, MIP 2 β inhibitors, MIP 3 α ligand inhibitors, macrophage mannose receptor 1 modulators, macrophage migration inhibitory factor inhibitors, MAdCAM inhibitors, MAdCAM modulators, MALT protein 1 inhibitors, mannan-binding lectin serine protease-2 inhibitors, MAP kinase inhibitors, MAP kinase kinase 4 inhibitors, MAP kinase modulators, MAP3K2 gene inhibitors, MAPKAPK2 inhibitors, MAPKAPK5 inhibitors, matrix extracellular phosphoglycoprotein modulators, matrix metalloproteinase inhibitors, MCH receptor 1 antagonists, MCL1 gene inhibitors, MEK protein kinase inhibitors, MEK-1 protein kinase inhibitors, MEK-2 protein kinase inhibitors, MEKK-5 protein kinase inhibitors, melanin-concentrating hormone (MCH-1) antagonists, melanocortin agonists, melanocortin MC1 receptor agonists, melanocortin MC3 receptor agonists,Melanocortin receptor agonists, membrane copper amine oxidase inhibitors, metalloproteinase-1 inhibitors, metalloproteinase-2 inhibitors, metalloproteinase-9 inhibitors, metalloproteinase-9 stimulators, methylprednisolone, methionine aminopeptidase-2 inhibitors, methyl CpG binding protein 2 modulators, microbiome targeted therapy, microRNA-132 (miR-132) antagonists, microRNA-21 (miR-21) inhibitors, midkine ligand inhibitors, mineralocorticoid receptor antagonists and modulators, mitochondrial uncouplers, mitochondrial 10kDa thermophiles Shock protein stimulator, mitochondrial pyruvate carrier 2 inhibitor, mitochondrial pyruvate carrier inhibitor, mixed lineage kinase-3 inhibitor, MKL myocardin-like protein inhibitor, MNK protein kinase inhibitor, monocarboxylate transporter inhibitor, monocyte macrophage differentiation inhibitor, motile sperm domain protein 2 inhibitor, MST-1 protein kinase inhibitor, mTOR complex 1 inhibitor, mTOR complex 2 inhibitor, mTOR inhibitor, myelin basic protein stimulator, myeloperoxidase inhibitor, myosin 2 inhibitor, N-formyl peptide receptor antagonist, NACHT LRR PYD domain protein 3 (NLRP3) inhibitors, NAD ADP ribosyltransferase stimulators, NAD-dependent deacetylase sirtuin stimulators, NAD-dependent deacetylase sirtuin-1 stimulators, NADPH oxidase inhibitors, NADPH oxidase 1 inhibitors, NADPH oxidase 4 inhibitors, NAMPT gene inhibitors, natriuretic peptide receptor C agonists, neuregulin-4 ligands, neuropilin 2 modulators, neutral endopeptidase inhibitors, NFκB inhibitor stimulators, NFAT gene inhibitors, NFE2L2 gene inhibitors, NFE2L2 gene stimulators, nicotinic acetylcholine receptor antagonists, nicotinic acid receptor 1 agonists, nicotinamide phosphoribosyltransferase inhibitors, NK cell receptor modulators, NK1 receptor antagonists, NKG2 AB activated NK receptor antagonists, NKG2 D activated NK receptor antagonists, NLR family member X1 stimulators, NLRP3 inhibitors, NMDA receptor ε2 subunit inhibitors, NOD2 gene modulators, non-receptor tyrosine kinase TYK2 antagonists, NOX4 gene inhibitors, NUAK SNF1-like protein kinase 1 inhibitors, nuclear erythroid 2-related factor 2 stimulators, nuclear factor κ (NFK) B inhibitors and modulators, nuclear factor κB p105 inhibitors, nuclear hormone receptor modulators, nuclear pore complex protein modulators, nuclear receptor modulators, nuclease stimulators, nucleoside reverse transcriptase inhibitors, nucleosome assembly protein 1-like-4 inhibitors, oncostatin M receptor modulators, oncostatin M receptor subunit β inhibitors, opioid receptor antagonists, opioid growth factor receptor agonists, opioid receptor δ, κ and µ antagonists, opioid receptor σ antagonists 1, orphan nuclear receptor antagonists, osteoclast differentiation factor antagonists,Osteoclast differentiation factor ligand inhibitors, oxidoreductase inhibitors, OX40 ligand inhibitors, OX-40 receptor antagonists and modulators, oxyntomodulin ligands, PGE1 agonists, P-glycoprotein inhibitors, P-selectin glycoprotein ligand-1, 14-3-3 protein eta inhibitors, P2X3 purinergic receptor antagonists, P2X7 purinergic receptor agonists and modulators, P2Y6 purinergic receptor modulators, P2Y13 purinergic receptor agonists, p38 MAP kinase alpha inhibitors, p38 MAP kinase inhibitors, p53 tumor suppressor protein stimulators, PACAP type I receptor agonists, pan-cathepsin inhibitors, parathyroid hormone ligand inhibitors, PARP modulators, PDE 1 inhibitors, PDE 3 inhibitors, PDE 4 inhibitors, PDE 4b inhibitors, PDE 5 inhibitors, PDGF-B ligand inhibitors, PDGF receptor agonists, PDGF receptor α antagonists, PDGF receptor β antagonists and modulators, PEGylated long-acting glucagon-like peptide-1 / glucagon (GLP-1R / GCGR) receptor dual agonists, Pellino homolog 1 inhibitors, peptidyl-prolyl cis-trans isomerase A inhibitors, peptidyl-prolyl cis-trans isomerase D inhibitors, PERK gene inhibitors, PGI2 agonists, PGD2 antagonists, phenylalanine hydroxylase stimulators, phosphatidylinositol 3 kinase subunit 3 inhibitors, phosphoinositide 3-kinase inhibitors, phosphoinositide-3 kinase alpha, delta and gamma inhibitors, phospholipase A2 inhibitors, phospholipase C inhibitors, phosphodiesterase inhibitors, phosphorylase inhibitors, plasma retinol binding protein inhibitors, plasminogen activator inhibitor 1 inhibitors, plasmin stimulators, platelet activating factor receptor antagonists, plexin domain-containing protein stimulators, PNPLA3 gene inhibitors and modulators, potassium channel inhibitors PPAR agonists, PPAR α / δ agonists, PPAR δ agonists, PPAR γ agonists and modulators, PRKAA2 gene stimulators, programmed cell death ligand (PDL) 1 modulators, programmed cell death protein 1 modulators, programmed cell death protein 1 stimulators, proprotein convertase PC9 inhibitors, prostacyclin (PGI2) agonists, prostaglandin D synthase stimulators, prostaglandin receptor antagonists, protease-activated receptor-2 antagonists, proteasome beta-8 subunit modulators, proteasome inhibitors, protein arginine deiminase inhibitors, protein arginine deiminase IV inhibitors, protein C activators, cerebellum protein modulators, protein fimH inhibitors, protein kinase C theta inhibitors, protein kinase inhibitors and modulators, protein kinase C theta inhibitors, protein MB21D1 inhibitors and modulators, protein NOV homolog modulators, P-selectin glycoprotein ligand-1 inhibitors, protein tyrosine kinase inhibitors, protein tyrosine phosphatase beta inhibitors, protein tyrosine phosphatase-1B inhibitors,Protein tyrosine phosphatase-2C inhibitors, protein tyrosine phosphatase 1E inhibitors, P-selectin glycoprotein ligand-1 stimulators, PTGS2 gene inhibitors, PurH purine biosynthesis protein inhibitors, QSK serine threonine protein kinase inhibitors, Ras gene inhibitors, reactive oxygen species regulator inhibitors, relaxin receptor modulators, relaxin receptor 2 modulators, renin inhibitors, resistin ligand inhibitors, resistin / CAP1 (adenylate cyclase-associated protein 1) interaction inhibitors, retinoic acid receptor agonists, retinoic acid receptor gamma antagonists and inverse agonists, retinoic acid receptor agonists, retinoid X receptor agonists and modulators, retinoid Z receptor gamma agonists and antagonists, Ret tyrosine kinase receptor inhibitors agents, Rev protein modulators, Rho-associated protein kinase inhibitors, Rho-associated protein kinase 1 inhibitors, Rho-associated protein kinase 2 inhibitors, rhomboid family member 2 inhibitors, ribonuclease P inhibitors, RIP-1 kinase inhibitors, RIP-2 kinase inhibitors, RNA polymerase inhibitors, Seprase inhibitors, serine threonine protein kinase TBK1 inhibitors, serine threonine protein kinase TBK1 modulators, serine threonine SNF1-like kinase 2 inhibitors, SERPINH1 gene inhibitors, serum amyloid A protein modulators, serum amyloid P stimulators, signal transduction protein CD24 modulators, signal transduction inhibitors, SLC22A12 inhibitors, SMAD inhibitors preparations, SMAD-3 inhibitors, smoothened receptor antagonists, S-nitrosoglutathione reductase (GSNOR) enzyme inhibitors, sodium channel inhibitors, sodium glucose transporter-1 inhibitors, sodium glucose transporter-2 inhibitors, solute carrier family inhibitors, somatostatin receptor agonists, sphingolipid delta 4 desaturase DES1 inhibitors, sphingosine kinase 1 inhibitors, sphingosine kinase 2 inhibitors, sphingosine 1 phosphate phosphatase modulators, sphingosine 1 phosphate phosphatase 1 stimulators, sphingosine-1-phosphate receptor-1 agonists, sphingosine-1-phosphate receptor-5 agonists, sphingosine-1-phosphate receptor-1 antagonists, sphingosine-1-phosphate receptor-1 modulators, sphingosine-1-phosphate receptor-3 modulators, sphingosine-1- Phosphate receptor-4 modulators, sphingosine-1-phosphate receptor-5 modulators, Src tyrosine kinase inhibitors, SREBP transcription factor inhibitors, SREBP transcription factor 1 inhibitors, SREBP transcription factor 2 inhibitors, STAT inhibitors, STAT3 gene inhibitors, STAT-1 inhibitors and modulators, STAT-3 inhibitors and modulators, STAT-5 inhibitors, STAT-6 inhibitors, stearoyl-CoA desaturase-1 inhibitors, stem cell antigen-1 inhibitors, interferon gene stimulators, STK25 inhibitors, stress-inducible secretory protein 1 stimulators, superoxide dismutase modulators, superoxide dismutase stimulators, cytokine signaling inhibitor-1 stimulators,Cytokine signaling inhibitor-3 stimulator, SYK inhibitor, syndecan-1 inhibitor, TACE inhibitor, TAK1 binding protein modulator, human talin modulator, type 2 taste receptor agonist, T-box transcription factor TBX21 modulator, T-cell differentiation antigen CD6 inhibitor, T cell receptor modulator, T cell receptor antagonist, T-cell surface glycoprotein CD1a inhibitor, T-cell surface glycoprotein CD8 inhibitor, T-cell surface glycoprotein CD28 inhibitor, T-cell surface glycoprotein CD8 modulator, T-cell surface glycoprotein CD28 stimulator, T-cell transcription factor NFAT modulator, Tec tyrosine kinase inhibitor, telomerase stimulator, tenascin modulator, TERT gene modulator, TGF-β activated kinase 1 inhibitor, TGF-β activated modulator, TGF β agonist, TGF β ligand inhibitor, TGF β1 ligand inhibitor, TGF β3 ligand inhibitor, TGF β1 gene inhibitor, TGF β1 ligand modulator, TGF β receptor antagonists, TGF β receptor antagonists, TGF-β type II receptor antagonists, TGFB1 gene inhibitors, thromboxane A2 antagonists, thromboxane A2 receptor antagonists, thromboxane synthesis inhibitors, thymic stromal lymphopoietin ligand inhibitors, thymic stromal lymphopoietin ligand modulators, thymic stromal lymphopoietin receptor modulators, thymosin agonists, thyroid hormone receptor agonists, thyroid hormone receptor β agonists, tissue transglutaminase inhibitors, Toll-like receptor (TLR)-2 antagonists, TLR-3 antagonists, TLR-4 antagonists, TLR-7 antagonists and modulators, TLR-8 antagonists, TLR-9 antagonists and agonists, TLR modulators, TNF Alpha ligand agonists and antagonists, TNF ligand agonists and antagonists, TNF binders, TNF gene inhibitors, TNFSF11 gene inhibitors, topoisomerase II inhibitors, TPL-2 inhibitors, transaminase stimulators, transcription factor regulators, transcription factor p65 inhibitors, transcription factor RelB inhibitors, transferrin regulators, transforming growth factor beta (TGF-β), transforming growth factor beta activated kinase 1 (TAK1), transglutaminase inhibitors, transthyretin regulators, TrkA receptor antagonists, Trk tyrosine Kinase receptor inhibitors, TRP cation channel A1 inhibitors, TRP cation channel C5 inhibitors, TRP cation channel C6 inhibitors, tryptophan 5-hydroxylase-1 inhibitors, tryptophanase inhibitors, tubulin binding agents, tumor necrosis factor ligand inhibitors, tumor necrosis factor ligand 13 inhibitors, tumor necrosis factor 15 ligand inhibitors, tumor necrosis factor 14 ligand modulators, tumor necrosis factor 13C receptor antagonists, tumor necrosis factor 14 ligand inhibitors, Tyk2 tyrosine kinase inhibitors, type I IL-1 receptor antagonists,Type I TNF receptor antagonist, Type II TNF receptor antagonist, Type II TNF receptor modulator, Tyrosine kinase receptor inhibitor, Tyrosine kinase receptor modulator, Ubiquitin ligase modulators and stimulators, Ubiquitin thioesterase-30 inhibitor, Uncoupling protein modulator, Unspecified cell adhesion molecule inhibitor, Unspecified GPCR agonist, Unspecified GPCR modulator, Unspecified growth factor receptor antagonist, Uric acid anion exchanger 1 inhibitor, Vanilloid VR1 agonist, Vanilloid VR1 receptor antagonist, Vasopressin V1a receptor antagonist, VDR agonist, VEGF receptor antagonist, VEGF receptor modulator, VEGF-1 receptor antagonist, VEGF-2 receptor antagonist, VEGF-3 receptor antagonist, VEGF-2 receptor modulator, VEGF-B ligand inhibitor, Vimentin inhibitor, VIP 1 receptor agonist, VIP2 receptor agonist, Vitamin D3 receptor agonist, Vitamin D3 receptor modulator, Vitamin K-dependent protein C stimulator, WNT modulator, Wnt ligand inhibitor, Wnt 5A ligand inhibitors, xanthine oxidase inhibitors, X-linked inhibitor of apoptosis protein inhibitors, XPO1 gene regulators, YAP / TAZ regulators, YSK-4 protein kinase inhibitors, Zap70 tyrosine kinase inhibitors, zinc finger binding protein Aiolos inhibitors, zonulin inhibitors.

[0475] Rheumatoid arthritis

[0476] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with one or more agents useful for treating and / or preventing rheumatic disorders.

[0477] In some embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are co-administered with one or more agents useful for treating and / or preventing rheumatoid arthritis. Non-limiting examples of such agents include disease-modifying antirheumatic drugs (DMARDS), such as hydroxychloroquine, sulfasalazine, methotrexate, and leflunomide; TNF inhibitors (e.g., etanercept, adalimumab, infliximab, golimumab, certolizumab pegol), T cell co-stimulation inhibitors (e.g., abatacept), IL-6 receptor inhibitors (e.g., tocilizumab, salizumab), anti-CD20 antibodies (e.g., rituximab); and JAK inhibitors (e.g., tofacitinib, baricitinib, upadacitinib); NSAIDs, such as ibuprofen, naproxen, and diclofenac; COX-2 inhibitors Preparations, such as celecoxib and etoricoxib; steroids and corticosteroids, such as prednisolone and cortisone; and biological agents known to be used to treat and / or prevent such conditions, including, for example, etanercept (e.g., ENBREL), infliximab (e.g., REMICADE), adalimumab (e.g., HUMIRA), anakinra (e.g., KINARET), abatacept (ORENCIA), rituximab (e.g., RITUXAN), certolizumab (e.g., CIMZIA), golimumab (e.g., SIMPONI) and tocilizumab (e.g., ACTEMRA). In some embodiments, the compounds of the present disclosure are administered with two additional therapeutic agents useful for treating and / or preventing rheumatic conditions. In some embodiments, agents useful for treating and / or preventing rheumatic disorders include a compound of the present disclosure and two additional therapeutic agents, such as methotrexate + leflunomide, methotrexate + sulfasalazine, methotrexate + cyclosporine, methotrexate + hydroxychloroquine, and triple therapy treatment hydroxychloroquine + sulfasalazine + methotrexate, hydroxychloroquine + sulfasalazine + leflunomide.

[0478] lupus

[0479] In some embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are co-administered with one or more agents useful for treating and / or preventing systemic lupus erythematosus (SLE) or lupus nephritis (LN). Non-limiting examples of such agents include immunosuppressive drugs that suppress immune system activity and agents approved for the treatment of SLE, such as hydroxychloroquine, steroids and corticosteroids (e.g., prednisone, methylprednisolone), belimumab, azathioprine, methotrexate, cyclophosphamide, mycophenolate and mycophenolate mofetil, cyclosporine, leflunomide, cyclosporine, abatacept, aniluomab, rituximab, NSAIDS such as naproxen sodium and ibuprofen, antimalarials such as hydroxychloroquine, calcineurin inhibitors, and tacrolimus.

[0480] In some embodiments, a compound of the present disclosure or a pharmaceutically acceptable salt thereof is co-administered with two or more agents useful for treating LN, such as prednisone + mycophenolic acid analogs, prednisone + mycophenolate sodium, prednisone + cyclophosphamide, prednisone + tacrolimus, prednisone + cyclosporine, prednisone + belimumab + mycophenolic acid analogs, prednisone + belimumab + cyclophosphamide, prednisone + rituximab.

[0481] In other embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with two or more agents useful for treating LN, such as prednisone + mycophenolic acid analogs, prednisone + mycophenolate sodium, prednisone + azathioprine, prednisone + tacrolimus, prednisone + cyclosporine, prednisone + mizoribine.

[0482] Osteoarthritis

[0483] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, are co-administered with one or more agents useful for treating and / or preventing osteoarthritis (OA). Non-limiting examples of such agents include nonsteroidal anti-inflammatory drugs (NSAIDs), topical capsaicin, intra-articular glucocorticoid injections, acetaminophen, duloxetine, tramadol, and injectable corticosteroids such as methylprednisolone acetate, triamcinolone acetonide acetate, betamethasone acetate and betamethasone sodium phosphate, triamcinolone acetonide hexane, and dexamethasone.

[0484] Ulcerative colitis

[0485] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, are co-administered with one or more agents useful for treating and / or preventing gastrointestinal disorders such as ulcerative colitis (UC) or Crohn's disease (CD). Non-limiting examples of such agents include infliximab, adalimumab, golimumab, vedolizumab, tofacitinib, ustekinumab, natalizumab, aminosalicylic acid, azo-bonded 5-ASA, sulfasalazine, balsalazide, olsalazine, corticosteroids such as budesonide, hydrocortisone, methylprednisolone, and prednisone; immunosuppressants or immunomodulators such as azathioprine and 6-mercaptopurine, cyclosporine, and methotrexate.

[0486] Pulmonology

[0487] In some embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are co-administered with one or more agents useful for treating and / or preventing lung diseases such as idiopathic pulmonary fibrosis (IPF) or interstitial lung disease (ILD). Non-limiting examples of such agents include nitendanib, pirfenidone, corticosteroids such as prednisone), other rheumatic drugs including mycophenolate mofetil (e.g., CellCept ® ), azathioprine (eg, Imuran ® ), leflunomide (eg, ARAVA ® ), rituximab (eg, RITUXAN ® ), cyclophosphamide (eg, CYTOXAN ® ), tacrolimus (eg, PROGRAF ® ), drugs that reduce stomach acid such as H-2-receptor antagonists or proton pump inhibitors such as lansoprazole (e.g., PREVACID ® 24HR), omeprazole (eg, Prilosec OTC), and pantoprazole (eg, PROTONIX ® ).

[0488] Hepatology and Nephrology

[0489] In some embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts thereof are co-administered with one or more agents useful for treating and / or preventing liver or kidney diseases such as NAFLD, NASH, DKD, or CKD. Non-limiting examples of such agents include metformin, sodium-glucose cotransporter-2 inhibitors (SGLT2i), drug therapy for glycemic control, DPP-4 inhibitors, insulin, sulfonylureas, TZDs (thiazolidinediones), alpha-glucosidase inhibitors, SGLT2 inhibitors (e.g., empagliflozin, canagliflozin, dapagliflozin), glucagon-like peptide-1 receptor agonists (GLP-1 RA) (e.g., lixisenatide, liraglutide, semaglutide, exenatide, albiglutide, dulaglutide), DPP-4 inhibitors (e.g., saxagliptin, alogliptin, sitagliptin, linagliptin), one or more agents for treating high blood pressure (such as angiotensin converting enzyme (ACE) inhibitors and angiotensin 2 receptor blockers (ARBs)), agents to support weight loss or for controlling blood sugar, cholesterol-lowering drugs (e.g., statins), finerenone, and agents for treating diabetes, such as alpha-glucosidase inhibitors (e.g., acarbose, miglitol, voglibose).

[0490] Dermatology

[0491] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with one or more agents useful for treating and / or preventing a skin disorder such as atopic dermatitis (AD). Non-limiting examples of such agents include topical corticosteroids (TCS) (e.g., desonide, hydrocortisone, fluocinolone, triamcinolone, betamethasone dipropionate), topical calcineurin inhibitors (TCI) (e.g., tacrolimus, pimecrolimus), topical antimicrobials and antiseptics, cyclosporine, methotrexate, mycophenolate mofetil, interferon gamma, phosphodiesterase 4 (PDE4) inhibitors such as crisaborole, JAK inhibitors (e.g., ruxolitinib, upadacitinib, abrocitinib), systemic glucocorticoids (e.g., prednisone), dupilumab, and anti-IL-13 antibodies (e.g., tralokinumab).

[0492] synthesis

[0493] In some embodiments, a method for synthesizing formula (I) and / or formula (II) is provided. In some embodiments, intermediate (I-2) and a compound of formula (II) are formed according to the following synthesis scheme:

[0494] .

[0495] In some embodiments, the method of preparing a compound of formula (I-2):

[0496]

[0497] The compound comprising the intermediate (I-1):

[0498]

[0499] Or its salt and alkali and chloromethyl chloroformate reaction. In some embodiments, the base includes carbonate, metal hydride or organic base. In some embodiments, the base is an aromatic base. In some embodiments, the base is pyridine. In some embodiments, the compound of intermediate (I-2) is reacted in a solvent. In some embodiments, the solvent includes a halogenated solvent. In some embodiments, the solvent includes dichloromethane.

[0500] Intermediate (I-1) can be combined with a solvent (such as dichloromethane), a base (such as pyridine) and chloromethyl chloroformate to obtain intermediate (I-2). Other exemplary solvents that can be used include, but are not limited to, ethers (such as tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether), polar aprotic solvents (such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone), halogenated solvents (such as dichloromethane, 1,2-dichloroethane, chlorobenzene) and hydrocarbons (such as toluene, n-heptane). Other exemplary bases that may be used include, but are not limited to, carbonates (such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate), metal hydrides (such as sodium hydride, potassium hydride), hindered alkoxides (such as sodium tert-butoxide, lithium tert-butoxide), and organic bases (such as 1,8-diazabicyclo (5.4.0) undec-7-ene, 1,5-diazabicyclo (4.3.0) non-5-ene, 2,6-lutidine). Suitable temperature ranges for the reaction may be in the range of 30° C. to 60° C.

[0501] In some embodiments, the method of preparing a compound of formula (II):

[0502]

[0503] Including reacting the compound of intermediate (I-2) or its salt with a phosphate source in the presence of a catalyst. In some embodiments, the phosphate source includes di-tert-butyl phosphate. In some embodiments, the phosphate source includes di-tert-butyl potassium phosphate. In some embodiments, the catalyst includes a quaternary ammonium salt. In some embodiments, the catalyst includes tetra-n-butylammonium hydrogen sulfate. In some embodiments, the compound of intermediate (I-2) is reacted in a solvent. In some embodiments, the solvent includes a halogenated solvent. In some embodiments, the solvent includes dichloromethane.

[0504] Formula (II) can be formed by mixing the intermediate (I-2) with a phosphate source in a solvent in the presence of a catalyst. The phosphate source may include potassium di-tert-butyl phosphate, or, for example, sodium di-tert-butyl phosphate or cesium di-tert-butyl phosphate. Exemplary catalysts that can be used include, but are not limited to, tetra-n-butylammonium hydrogen sulfate or quaternary ammonium salts (i.e., tetrabutylammonium chloride, tetra-n-butylammonium bromide, etc.), sodium iodide, and other promoters known in the art that promote Finkelstein-like reactions. Exemplary solvents that can be used include ethers (such as tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether), polar aprotic solvents (such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone), halogenated solvents (such as dichloromethane, 1,2-dichloroethane, chlorobenzene), hydrocarbons (such as toluene, n-heptane), esters (such as ethyl acetate, isopropyl acetate) or the aforementioned optionally in combination with water. A suitable temperature range for the reaction may be in the range of 0°C to 60°C.

[0505] In some embodiments, the method for preparing a compound of formula I comprises deprotecting a compound of formula (II) or a salt thereof with an acid source. In some embodiments, the acid source comprises acetyl chloride, acetic acid, hydrogen chloride, sulfuric acid, phosphoric acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrogen chloride gas or anhydrous hydrogen chloride source. In some embodiments, the acid source comprises an acyl halide. In some embodiments, the acid source comprises acetyl halide. In some embodiments, the acid source comprises acetyl chloride. In some embodiments, the deprotection of the compound of formula (II) is carried out in a solvent. In some embodiments, the solvent comprises an alcohol solvent. In some embodiments, the solvent comprises methanol.

[0506] In some embodiments, compounds of Formula (I) are formed by deprotecting compounds of Formula (II), for example according to the following schemes.

[0507]

[0508] Formula (II) can be mixed with a solvent and an acid source. Examples of acids that can be used as acid sources include acetylchloroacetic acid, concentrated hydrogen chloride, concentrated sulfuric acid, phosphoric acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrogen chloride gas, and anhydrous hydrogen chloride sources (i.e., acyl chlorides and alcohol solvents). Available solvents include alcohols (such as methanol, ethanol, 2-propanol), ethers (such as tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether), polar aprotic solvents (such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone), acids (such as acetic acid), halogenated solvents (such as dichloromethane, 1,2-dichloroethane, chlorobenzene), hydrocarbons (such as toluene, n-heptane) and / or combinations of the above solvents and water. The suitable temperature range for the reaction can be in the range of 0°C to 50°C.

[0509] In some embodiments, the method of preparing a compound of Formula I comprises:

[0510] (a) reacting the compound of intermediate (I-1) or a salt thereof with a base and chloromethyl chloroformate to produce a compound of intermediate (I-2);

[0511] (b) reacting the compound of intermediate (I-2) or a salt thereof with a phosphate source in the presence of a catalyst to prepare a compound of formula (II); and

[0512] (c) deprotecting the compound of formula (II) or a salt thereof with an acid source to prepare a compound of formula I.

[0513] In some embodiments, the method of preparing a compound of Formula I comprises:

[0514] (a) reacting a compound of intermediate (I-2) or a salt thereof with a phosphate source in the presence of a catalyst to prepare a compound of formula (II); and

[0515] (b) deprotecting the compound of formula (II) or a salt thereof with an acid source to prepare a compound of formula I.

[0516] In some embodiments, the method for preparing a compound of formula I comprises reacting a compound of intermediate (I-1) or a salt thereof with a base and chloromethyl chloroformate to prepare a compound of intermediate (I-2). In some embodiments, the method for preparing a compound of formula I comprises reacting a compound of intermediate (I-2) or a salt thereof with a phosphate source in the presence of a catalyst to prepare a compound of formula (II).

[0517] In some embodiments, the method of preparing a compound of formula (II) comprises:

[0518] (a) reacting the compound of intermediate (I-1) or a salt thereof with a base and chloromethyl chloroformate to produce a compound of intermediate (I-2); and

[0519] (b) reacting the compound of the intermediate (I-2) or a salt thereof with a phosphate source in the presence of a catalyst to prepare a compound of formula (II).

[0520] In some embodiments, the method of preparing a compound of formula II comprises reacting a compound of formula (I-1) or a salt thereof with a base and chloromethyl chloroformate to prepare a compound of intermediate (I-2).

[0521] Example

[0522] method

[0523] Compounds of formula I are synthesized according to known methods, such as those disclosed in US Pat. No. 10,947,259.

[0524] X-ray powder diffraction (XRPD)

[0525] XRPD patterns were collected with a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu Kα radiation, which was produced using a long fine focus source and a nickel filter. The diffractometer was constructed using a symmetrical Bragg-Brentano geometry. Prior to analysis, a silicon specimen (NIST SRM 640e) was analyzed to verify that the observed position of the Si 111 peak was consistent with the NIST certified position. Specimens of the sample were prepared as a circular thin layer centered on a silicon zero background substrate. The background generated by air was minimized using an anti-scatter slit (SS). Soller slits for the incident and diffracted beams were used to minimize broadening from axial divergence. Diffraction patterns were collected using a scanning position sensitive detector (X'Celerator) located 240 mm from the sample and data collector software v. 2.2b.

[0526] Differential Scanning Calorimetry (DSC)

[0527] Differential Scanning Calorimetry (DSC) data were collected using a TA Instruments Q2000 Differential Scanning Calorimeter. Temperature calibration was performed using NIST traceable indium metal. The sample was placed in a T zero aluminum DSC pan and covered with a lid with a hole pierced with a needle. The weight was then accurately recorded. A weighed aluminum pan configured as a sample pan was placed on the reference side of the unit. The sample was heated from 0°C to 300°C at a rate of 10°C / min.

[0528] Thermogravimetric analysis (TGA)

[0529] Thermogravimetric analysis (TGA) data were collected using a TA Instruments Discovery Thermogravimetric Analyzer. Nickel and Alumel ™ Temperature correction was performed. Each sample was placed in an aluminum pan and inserted into a TG furnace. The furnace was heated under a nitrogen purge. The samples were heated from ambient temperature to 300°C at a rate of 10°C / min.

[0530] Thermogravimetric-mass spectrometry analysis (TG-MS)

[0531] Thermogravimetric-mass spectrometry analysis (TG-MS) was used to identify volatile off-gassing and evaluate sample weight loss as a function of temperature on a Discovery TGA (TA Instruments, New Castle, DE) by loading 1 mg to 10 mg of material onto a weighing pan and heating the sample at a rate of 20 °C / min to completely desolvate the material. The sample and reference pans were placed under a nitrogen purge of 60 mL / min and 40 mL / min, respectively. Data analysis was completed using TRIOS (TA Instruments, New Castle, DE). The mass spectrometer was a Discovery MS (TA Instruments, New Castle, DE) benchtop quadrupole instrument.

[0532] Dynamic Vapor Sorption (DVS)

[0533] Hygroscopicity was studied using dynamic vapor sorption (DVS, TA Q5000 SA, TA Instruments, New Castle, DE or DVS, DVS Intrinsic, Surface Measurement Systems, London, UK). Samples (2 mg-20 mg) were placed in aluminum DVS pans and loaded on the sample side of a double pan balance. Water adsorption and desorption were studied as a function of relative humidity (RH) at 25 °C. Relative humidity was increased from 5% RH to 95% RH and then decreased back to 5% (in some cases from 0 to 90% RH and then back to 0%) in 10% RH increments. Each relative humidity increment had an equilibrium time of 120 minutes unless the % weight change was less than 0.01% within 20 minutes. Data analysis was performed using Universal Analysis 2000 Version 4.7A (TA Instruments, New Castle, DE) for TA DVS runs and Microsoft Excel for SMS DVS runs.

[0534] Proton NMR ( 1 H NMR)

[0535] Proton NMR was collected on a Bruker Avance III-HD 400 with SampleXpress ( 1 HNMR) spectrum. The default proton parameters are spectral width: 16.19 ppm to -3.84 ppm (8012.8 Hz); relaxation delay: 1 sec; pulse: 90 degrees; acquisition time: 4.0894 sec; number of scans or repetitions: 16; temperature: 25 °C.

[0536] Amorphous Form I

[0537] Amorphous Form I was prepared via ball milling. A cylindrical stainless steel cell containing stainless steel balls was charged with about 5 grams of Form III of Formula I. The cell was capped and the solid was milled in a Retsch Model MM200 ball mill at a vibration frequency of 30 / second for a total time of about 24 minutes. The milling was stopped 3 times during this period to check the progress via (polarized light microscopy) PLM, and at the end of the milling, the PLM showed no signs of birefringence. The material was stored in the cell at about 10°C. The solid was collected and weighed the next day.

[0538] Amorphous Form I was characterized by XRPD, DSC, TGA and DVS. XRPD was performed and the diffraction pattern is depicted in Figure 1. A DSC thermogram was obtained and depicted in Figure 2, which shows a broad endotherm (28°C-120°C; 135 J / g; this is attributed to the loss of water)) and an exothermic event above about 150°C. TGA was performed and the resulting thermogram is depicted in Figure 3. DVS was performed and the resulting isotherm is shown in Figure 4.

[0539] Formula I

[0540] Formula I is prepared by methods known to those skilled in the art and / or according to the following reaction schemes.

[0541]

[0542] Add carbamate and di-tert-butyl phosphate to (I-1) to form formula (II):

[0543]

[0544] Intermediate (I-1) (1.00 equiv., scale factor) and dichloromethane (9.8 vol.) were charged to a reactor and the mixture was stirred at about 5°C. Pyridine (1.80 equiv.) was charged followed by chloromethyl chloroformate (1.38 equiv.). The mixture was stirred at about 5°C until the reaction was deemed complete. 9 wt.% aqueous sulfuric acid (5.0 vol.) was charged and the mixture was stirred at about 22°C. The layers were separated and the organic layer was washed with 9 wt.% aqueous sulfuric acid (5.0 vol.) followed by 5 wt.% aqueous potassium bicarbonate (5.0 vol.) to give a solution of intermediate (I-2) in dichloromethane.

[0545] A reactor containing the intermediate (I-2)-dichloromethane solution is charged with tetra-n-butylammonium hydrogen sulfate (0.10 equivalents) and di-tert-butyl potassium phosphate (1.24 equivalents). The mixture is stirred at about 40°C until the reaction is considered complete. The mixture is then cooled to about 22°C and the mixture is washed with water (5.0 volumes). The organic layer is concentrated to about 3 volumes under vacuum and N,N-dimethylacetamide (3.0 volumes) is charged. The mixture is concentrated to about 4 volumes and the temperature is adjusted to about 40°C. Seed crystals of formula (II) (0.001 weight equivalents) are charged, the mixture is stirred at about 40°C for about 1 hour, and 2-propanol (12.0 volumes) is charged. The mixture is adjusted to about 10°C, stirred at about 10°C, and the slurry is filtered. The filter cake is washed with 2-propanol (3.0 volumes) and then dried to obtain formula (II). 1 H NMR (400MHz, CDCl3): δ 8.54 (s, 1H), 8.29 (d,J = 7.9Hz, 1H), 8.20 (br s, 1H), 7.75 (br s, 1H), 7.54 (s, 1H), 7.51 (d, J =7.3Hz, 1H), 7.33 (s, 1H), 7.19 (d, J = 7.9Hz, 1H), 7.16 (dd, J = 7.6Hz,4.6Hz, 1H), 6.85 (br s, 1H), 6.74 (d, J = 7.7Hz, 1H), 5.65 (dd, J = 16.3Hz,5.3Hz, 1H), 5.42 (br d, J = 9.2Hz, 1H), 3.85 (m, 1H), 3.62 (m, 1H), 3.59 (s,3H), 2.73 (s, 1H), 2.41 (s, 6H), 1.43 (s, 9H), 1.34 (s, 9H0, 1.03 (s, 9H). 13C NMR (100MHz, CDCl3): δ 162.21, 154.70, 153.18 153.05, 144.88, 143.73,135.64, 135.04, 133.75, 133.64, 133.43, 132.48, 131.04, 128.59, 126.62,125.96, 122.02, 119.63, 119.01, 101.21, 84.59, 84.16, 84.09, 83.82, 83.74,83.62, 83.54, 55.00, 54.77, 53.23, 51.99, 37.14, 33.12, 29.76, 29.72, 29.65,29.61, 27.21, 23.46.

[0546] Deprotecting the compound of formula (II) to form the compound of formula (I)

[0547]

[0548] Formula (II) (1.00 equivalents, scale factor) and methanol (3.00 volumes) are charged to a reactor. Acetyl chloride (2.97 equivalents) is charged while maintaining below about 30°C and the mixture is stirred at about 22°C until the reaction is considered complete. The mixture is diluted with dichloromethane (5.0 volumes) and a 5 wt% aqueous sodium chloride solution (3.2 volumes) is charged. The layers are separated and the organic layer is then concentrated to about 4 volumes under vacuum. 2-Propanol (5.1 volumes) is charged and the mixture is concentrated to about 4.0 volumes under vacuum. Water (3.0 volumes) is charged and the mixture is stirred at about 22°C for about 1 hour. Seed crystals of formula (I) are charged (0.002 weight equivalents) and the mixture is stirred at about 22°C. The slurry is filtered and the filter cake is rinsed with a mixture of water (1.3 volumes) and 2-propanol (1.3 volumes) and then dried to obtain formula (I). 1H NMR (400MHz, DMSO-d6): δ 8.47 (s, 1H), 8.30 (s, 1H), 8.04 (d, J = 7.2Hz, 1H), 7.99 (br s, 1H), 7.96 (s, 1H), 7.92 (br s,1H), 7.58 (d, J = 8.0Hz, 1H), 7.33 (s, 1H), 7.26 (d, J = 6.8Hz, 1H), 7.19 (t,J = 7.6Hz, 1H), 6.72 (d, J = 6.4Hz, 1H), 3.91 (m, 1H), 5.56 (m, 1H), 5.38 (m,1H), 3.49 (s, 3H), 3.35 (m, 1H), 2.71 (s, 1H), 2.35 (s, 6H), 0.87 (s, 9H). 13 CNMR (100MHz, DMSO-d6): δ 161.1, 154.5, 152.9, 152.7, 144.8, 142.7, 135.5,135.0, 134.7, 133.4, 132.7, 131.7, 131.6, 127.5, 125.6, 125.5, 123.4, 119.7,118.8, 100.1, 83.6, 83.4, 54.3, 53.2, 52.6, 51.5, 36.5, 33.3, 26.8, 22.9.

[0549] Formula I Form I

[0550] The reactor was charged with 1 equivalent of Formula II and the contents were flushed with nitrogen.

[0551]

[0552] (II)

[0553] Methanol (3V) was added, stirring was set to 250 rpm and the internal temperature of the reactor was adjusted to about 15°C. 2.3 equivalents of acetyl chloride were charged to the reactor and the internal temperature was maintained below about 30°C. When the addition of acetyl chloride was completed, the internal temperature was maintained at about 20°C. The mixture was stirred for about 2 hours. Dichloromethane (DCM) (about 5 volumes) and 5 wt% NaCl aqueous solution (about 3 volumes) were added, the mixture was stirred for about 15 minutes, and left to stand overnight. The phases were separated. The organic stream was concentrated to about 3 volumes and diluted with about 5.4 volumes of ethanol, and then concentrated again to about 3 volumes. Additional ethanol (about 5.4 volumes) was charged, and the mixture was concentrated again to about 5.4 volumes and diluted with about 0.6 volumes of water. The internal temperature was adjusted to about 15°C and the mixture was stirred overnight. The slurry was filtered and the solid was washed with about 1 volume of pre-cooled 9:1 ethanol: water (v:v). The solid was dried under reduced pressure with wet nitrogen at about 25% RH and about 20°C.

[0554] Formula I Form I was characterized by XRPD and the resulting diffraction pattern is shown in Figure 5. The XRPD peak list is reported in Table 1.

[0555] Table 1.

[0556] serial number Position °2-θ Relative strength (%) 1 6.2 100.0 2 8.3 6.5 3 11.6 10.3 4 10.9 6.7 5 14.5 6.0 6 22.4 8.1 7 17.4 5.9 8 18.7 8.4 9 22.6 8.7

[0557] A DSC thermogram was obtained and showed a broad endothermic event from about 25°C-100°C and an exothermic event from about 175°C-225°C (Figure 6). TGA-MS analysis was performed and showed mass loss due to loss of hydration water, as well as release of carbon dioxide and formaldehyde due to decomposition. DVS was performed and the resulting isotherm showed a weight change of about 9.5 wt% from RH 5%-95% and moderate hysteresis.

[0558] Formula I Form II

[0559] Method 1: A 4 mL threaded glass vial with a stir bar was charged with approximately 100 mg of Form I of Formula I and approximately 2 mL of 1:1 2-propanol / water. The mixture was capped and stirred at room temperature for about one day, yielding Form II of Formula I as crystals suspended in solution.

[0560] Method 2: Charge 1 equivalent of Formula II to the reactor and flush the contents with nitrogen. Charge methanol (about 3 volumes), set stirring to about 250 rpm and adjust the internal temperature of the reactor to about 15°C. Charge 3 equivalents of acetyl chloride to the reactor and maintain the internal temperature below about 30°C. When the addition of acetyl chloride is complete, maintain the internal temperature at about 20°C. Stir the mixture for about 4 hours. Add DCM (about 5 volumes) and 5 wt% NaCl aqueous solution (about 3 volumes), stir for about 15 minutes, and let stand overnight. Separate the phases. Concentrate the organic stream to about 4 volumes and dilute with about 5 volumes of 2-propanol, then concentrate to about 4 volumes and dilute with about 3 volumes of water. Adjust the internal temperature to about 20°C, add about 0.005 wt% of Formula I Form I seeds after about 1 hour, and stir the mixture overnight. Filter the slurry and wash the solid (Formula I Form II) with about 2.5 volumes of 1:1 (v:v) 2-propanol:water. The solid was dried under reduced pressure at about 20°C.

[0561] Formula I Form II was characterized by XRPD, VH-XRD, single crystal X-ray crystallography and DVS. The resulting XRPD diffraction pattern is depicted in Figure 7. The XRPD peak list is shown in Table 2.

[0562] Table 2.

[0563] serial number Position °2-θ Relative strength (%) 1 7.4 100.0 2 9.4 31.5 3 10.6 25.9 4 8.8 8.8 5 12.3 34.6 6 26.1 22.1 7 14.7 23.2 8 18.1 23.0 9 22.4 21.1

[0564] The diffraction patterns obtained when equilibrated at 85% RH in the VH-XRD measurement were indexed using the Pauli method, and the unit cell dimensions were determined and reported in Table 3.

[0565] Table 3.

[0566] Space group <![CDATA[P212121]]> <![CDATA[Volume (Å 3 ).]]> 4008.4 a（Å） 11.042 α（°） 90 b（Å） 15.045 β（°） 90 c（Å） 24.130 γ (°) 90 <![CDATA[τ G (nm)]]> 149.4 <![CDATA[ε L ]]> 0.186 SAM (mm) 13.3 <![CDATA[R wp ]]> 2.9%

[0567] Single crystal X-ray crystallography of Form II was performed and the data showed that Form II is a tetrahydrate.

[0568] Figure 8 shows the full pattern Poly refinement of Form II of Formula I at 85% RH.

[0569] DVS showed multiple mass changes with RH, with low hysteresis (Figure 9). In the DVS experiment, Form II was present at the highest RH point.

[0570] Formula I Form III

[0571] Method 1: Form I Form III was prepared from Form I and Form II and mixtures thereof by prolonged exposure to 40% RH. A relative humidity controller was used for the following analysis. The controller was programmed and the following target RH values ​​were maintained for 1 hour, each of which was 40%, 50%, 60%, 80%, 85%, 80%, 60%, 50% and 40%. Figure 10 depicts the measured RH values ​​and the corresponding 5-minute XRPD repeat scans performed during the RH program. The total run time was approximately 14 hours, during which XRPD patterns (5-minute repeats) were collected.

[0572] Method 2: Charge 1 equivalent of Formula II to the reactor and flush the contents with nitrogen. Charge methanol (about 3 volumes), set stirring to about 250 rpm and adjust the internal temperature of the reactor to about 15°C. Charge about 3 equivalents of acetyl chloride to the reactor and maintain the internal temperature below about 30°C. After the addition of acetyl chloride, maintain the internal temperature at about 20°C. Stir the mixture for about 4 hours. Add DCM (about 5 volumes) and 5 wt% aqueous NaCl solution (about 3 volumes), stir the mixture for about 15 minutes, and let stand overnight. Separate the phases. Concentrate the organic stream to about 4 volumes and dilute with about 5 volumes of 2-propanol, then concentrate again to about 4 volumes and dilute with about 3 volumes of water. Adjust the internal temperature to about 20°C, add about 0.002 wt% of Form II seeds after about 1 hour, and stir the mixture overnight. Filter the slurry, and wash the solid with about 2.5 volumes of 1:1 (v:v) 2-propanol:water. Dry the solid under reduced pressure at about 20°C.

[0573] Method 3: About 1 gram of Formula I Form II was charged into a 20 mL glass vial. The vial was covered with a Kimwipe and left to stand exposed to ambient atmosphere and temperature (about 47% RH and about 22° C.). After about 46 hours, the temperature and RH were recorded and samples were taken for XRPD and KF, as reported below.

[0574] Method 4: About 40 mg of Formula I S-mandelate salt was charged into a 4 mL glass vial equipped with a cap and a stir bar. About 0.5 mL of ethanol / water (35:65 v:v) was added, the vial was capped, and the mixture was stirred at room temperature overnight. After stirring overnight, the solid was separated and air-dried at room temperature overnight and then oven-dried at about 40°C for about 3 hours. An XRPD pattern of the oven-dried solid was obtained and the solid form was identified as Form III, as reported below.

[0575] The samples prepared as described above (Method 1, Method 2, Method 3 and Method 4) were characterized by XRPD, VH-XRD and DVS. The resulting XRPD is depicted in FIG11 , which shows the XRPD taken at about 36% RH for the sample prepared by Method 3. The water content was assessed by KF measurement and found to be 2.3% water (1 mole, monohydrate form). The 40% RH XRPD from the VH-XRD experiment (Method 1) is depicted in FIG12 .

[0576] The 40% RH diffraction pattern was indexed using the Pauli method and the unit cell dimensions were determined. The results can be seen in Figure 13 and reported in Table 4.

[0577] Table 4.

[0578] Space group <![CDATA[P212121]]> <![CDATA[Volume (Å 3 ).]]> 3715.2 a（Å） 10.993 α（°） 90 b（Å） 14.976 β（°） 90 c（Å） 22.566 γ (°) 90 <![CDATA[τ G (nm)]]> 152.4 <![CDATA[ε L ]]> 0.183 SAM (mm) 14.0 <![CDATA[R wp ]]> 2.7%

[0579] The XRPD peak list for Form III is reported in Table 5.

[0580] Table 5.

[0581] serial number Position °2-θ Relative strength (%) 1 9.8 100.0 2 7.8 83.8 3 10.7 52.3 4 12.5 41.0 5 8.9 29.2 6 20.1 95.7 7 15.5 68.2 8 18.2 56.0 9 22.9 48.3

[0582] DVS was performed and the resulting isotherms are depicted in FIG14 .

[0583] Formula I Form IV

[0584] Form IV of Formula I was prepared from Form III and Form II, and mixtures thereof, by exposure to dry nitrogen (0% to 5% RH).

[0585] The samples prepared as described above were characterized by VH-XRD and DVS.

[0586] The diffraction pattern of Form IV of Formula I was indexed using the Pauli method (Figure 15). The unit cell dimensions were determined and reported in Table 6.

[0587] Table 6.

[0588] Space group <![CDATA[P212121]]> <![CDATA[Volume (Å 3 ).]]> 3718.3 a（Å） 11.034 α（°） 90 b（Å） 15.157 β（°） 90 c（Å） 22.232 γ (°) 90 <![CDATA[τ G (nm)]]> 167.9 <![CDATA[ε L ]]> 0.264 SAM (mm) 13.9 <![CDATA[R wp ]]> 2.5%

[0589] XRPDs were collected and the resulting diffraction pattern is depicted in Figure 16, which was obtained at equilibration at 5% RH as described. The XRPD peak list for the 5% RH XRPD is reported in Table 7.

[0590] Table 7.

[0591] serial number Position °2-θ Relative strength (%) 1 20.0 100.0 2 8.0 19.0 3 18.1 76.6 4 9.0 33.2 5 9.9 65.8 6 10.8 47.7 7 15.6 57.3 8 22.8 47.3 9 24.9 34.1

[0592] Formula I Form V

[0593] About 1.4 g of Formula I Form I and about 10 mL of ethanol / water solution (9:1 v:v) were charged to a 20 mL screw-thread glass container. The mixture formed a suspension, the vial was capped, and the suspension was stirred on a nutating mixer at room temperature. After 12 days, a sample for testing was obtained via centrifugal filtration.

[0594] Formula I Form V was characterized by XRPD, DSC and TGA-MS. The resulting XRPD is shown in Figure 17. The XRPD peak list is reported in Table 8.

[0595] Table 8.

[0596] serial number Position °2-θ Relative strength (%) 1 6.23 100.0 2 22.6 45.9 3 20.4 36.6 4 16.3 16.9 5 16.5 21.3 6 17.4 21.2 7 22.4 30.8 8 23.5 25.1 9 25.1 22.0

[0597] A DSC thermogram was obtained and is depicted in Figure 18. TGA-MS was performed and the data obtained showed a combined loss of 7.3 wt% water and ethanol from about 50°C to 150°C, and loss of formaldehyde and carbon dioxide due to decomposition above 150°C.

[0598] Formula I Form VI

[0599] About 1.4 g of Form I of Formula I and about 10 mL of ethanol / water solution (7.4:2.6) were charged to a 20 mL screw-thread glass container. The mixture formed a suspension, the vial was capped, and the suspension was stirred on a nutating mixer at room temperature. After 12 days, a sample for testing was obtained via centrifugal filtration.

[0600] Formula I Form VI was characterized by XRPD, DSC and TGA-MS. The resulting XRPD diffraction pattern is depicted in Figure 19. A second image (Figure 20) with the vertical axis limit set to 2000 counts is included. The XRPD peak list is reported in Table 9.

[0601] Table 9.

[0602] serial number Position °2-θ Relative strength (%) 1 7.2 100.0 2 14.4 9.6 3 21.7 4.2 4 29.1 2.9 5 25.3 1.3 6 25.0 0.7 7 16.6 0.23 8 26.7 0.28 9 30.2 0.13

[0603] A DSC thermogram was obtained and is depicted in Figure 21. TGA-MS was performed and showed a loss of about 3.8 wt% water at 30°C during 15 minutes of drying, and a combined mass loss of about 7.4 wt% water and ethanol from about 30°C-200°C. This second mass loss showed that ions of water and ethanol were detected at different times. Additional mass loss detected above about 150°C was attributed to decomposition due to loss of carbon dioxide, water, and formaldehyde.

[0604] Formula I Form VII

[0605] Formula I Form VII was prepared by stirring a mixture of about 0.3 grams of Formula I Form I in about 3 mL of methanol at room temperature for several days. The solid was isolated by centrifugal filtration and characterized.

[0606] Formula I Form VII was characterized by XRPD and TGA-MS. The resulting XRPD diffraction pattern is depicted in Figure 22. The XRPD peak list is reported in Table 10.

[0607] Table 10.

[0608] serial number Position °2-θ Relative strength (%) 1 6.2 100.0 2 8.4 10.4 3 22.6 31.5 4 10.3 8.7 5 10.9 9.3 6 11.7 11.0 7 16.1 12.4 8 16.4 15.6 9 17.3 13.7

[0609] TGA-MS was performed and the resulting thermogram showed a mass loss of about 2.9 wt% mass from about 50° C. to 125° C., identified as methanol and water. Mass loss above about 150° C. was attributed to carbon dioxide, water, and formaldehyde produced by decomposition.

[0610] Formula I Form VIII

[0611] Formula I Form VIII was prepared by stirring a mixture of about 0.2 grams to 0.4 grams of Formula I Form I in about 3 mL of ethanol at room temperature for several days. The solid was isolated by centrifugal filtration and characterized.

[0612] Formula I Form VIII was characterized by XRPD and TGA-MS. The resulting XRPD diffraction pattern is shown in Figure 23. The XRPD peak list is reported in Table 11.

[0613] Table 11.

[0614] serial number Position °2-θ Relative strength (%) 1 6.2 100.0 2 8.3 8.3 3 22.3 20.3 4 11.6 9.56 5 10.8 8.0 6 14.5 10.9 7 16.5 8.0 8 18.7 8.4 9 20.5 8.7

[0615] TGA-MS was performed and the resulting thermogram showed a combined mass loss of about 5.9 wt % from about 50°C to 125°C, identified as ethanol and water. The peaks for ethanol and water overlapped. The mass loss above 156°C was attributed to the decomposition products carbon dioxide, water, and formaldehyde.

[0616] Formula I Form IX

[0617] Formula I Form IX was prepared by stirring a mixture of about 0.2 grams to 0.4 grams of Formula I Form I in about 3 mL of acetone at room temperature for several days. The solid was isolated by centrifugal filtration and characterized.

[0618] Formula I Form IX was characterized by XRPD and TGA-MS. The resulting XRPD diffraction pattern is depicted in Figure 33. The XRPD peak list is reported in Table 12.

[0619] Table 12.

[0620] serial number Position °2-θ Relative strength (%) 1 7.2 100.0 2 5.8 69.4 3 5.7 28.5 4 10.7 8.8 5 15.3 3.9 6 17.1 6.0 7 7.4 8.8 8 10.0 4.1 9 8.9 3.6

[0621] TGA-MS was performed and showed an overlapping mass loss of about 6.3% of surface water and acetone during the 30°C drying step and about 1.8% of overlapping mass loss from about 30°C to 150°C, which was also attributed to water and acetone. Mass loss was observed above 150°C and was attributed to the decomposition products carbon dioxide, water and formaldehyde.

[0622] Formula I Form X

[0623] Formula I Form X was prepared by stirring a mixture of about 0.2 g to 0.4 g of Formula I Form I in about 3 mL THF at room temperature for several days. The solid was isolated by centrifugal filtration and characterized.

[0624] Formula I Form X was characterized by XRPD and TGA-MS. The resulting XRPD diffraction pattern is shown in Figure 25. The XRPD peak list is reported in Table 13.

[0625] Table 13.

[0626] serial number Position °2-θ Relative strength (%) 1 16.3 100 2 7.2 94.7 3 5.7 85.6 4 10.8 36.6 5 13.7 17.6 6 18.3 24.0 7 19.1 24.0 8 22.4 19.6 9 26.5 10.3

[0627] TGA-MS was performed and the resulting thermogram showed overlapping mass losses of about 8.5% of surface water and THF during the 30° C. drying step and about 8.5% of overlapping mass losses from about 30° C. to 150° C., also attributed to water and THF. Mass losses above 150° C. were attributed to the decomposition products carbon dioxide, water, and formaldehyde.

[0628] Formula I Form XI

[0629] Formula I Form XI was prepared by stirring a mixture of about 0.2 g to 0.4 g of Formula I Form I in about 3 mL of DCM at room temperature for several days. The solid was isolated by centrifugal filtration and characterized.

[0630] Formula I Form XI was characterized by XRPD and TGA-MS. The resulting XRPD diffraction pattern is shown in Figure 26. The XRPD peak list is reported in Table 14.

[0631] Table 14.

[0632] serial number Position °2-θ Relative strength (%) 1 7.8 100.0 2 5.5 41.5 3 6.8 27.4 4 8.6 51.0 5 9.5 16.2 6 10.3 28.3 7 15.4 13.2 8 17.8 30.5 9 19.4 22.0

[0633] TGA-MS was performed and showed a mass loss of about 2.6% of surface water during the 30°C drying step and an overlapping mass loss of about 3.8% from about 30°C to 150°C, which was attributed to water and DCM. Mass loss was observed above 150°C and was attributed to the decomposition products carbon dioxide, water and formaldehyde.

[0634] Formula I Form XII

[0635] Formula I Form XII was prepared by stirring a mixture of about 0.2 grams to 0.4 grams of Formula I Form I in about 3 mL of MTBE at room temperature for several days. The solid was isolated by centrifugal filtration and characterized.

[0636] Formula I Form XII was characterized by XRPD and TGA-MS. The resulting XRPD diffraction pattern is shown in Figure 27. The XRPD peak list is reported in Table 15.

[0637] Table 15.

[0638] serial number Position °2-θ Relative strength (%) 1 6.2 100.0 2 5.4 14.3 3 11.5 9.6 4 14.5 7.5 5 16.4 10.6 6 22.3 9.0 7 12.5 4.6 8 9.7 2.4 9 19.2 4.2

[0639] TGA-MS was performed and showed a mass loss of about 4.2% of surface water during the 30°C drying step and an overlapping mass loss of about 1.2% from about 30°C to 150°C, which was attributed to water. Loss of MTBE was observed from about 100°C-200°C, and the overlapping mass loss was attributed to the decomposition products carbon dioxide, water, and formaldehyde.

[0640] Formula I Form XIII

[0641] Formula I Form XIII was prepared by stirring a mixture of about 0.2 grams to 0.4 grams of Formula I Form I in about 3 mL IPA at room temperature for several days. The solid was isolated by centrifugal filtration and characterized.

[0642] Formula I Form XIII was characterized by XRPD and TGA-MS. The resulting XRPD diffraction pattern is shown in Figure 28. The XRPD peak list is reported in Table 16.

[0643] surface 16 .

[0644] serial number Position °2-θ Relative strength (%) 1 5.8 100 2 6.2 32.8 3 8.1 9.4 4 11.6 5.7 5 16.6 9.9 6 20.0 8.8 7 13.0 5.0 8 22.0 5.9 9 22.8 13.2

[0645] TGA-MS was performed and showed a mass loss of about 3.7% of surface water and IPA during the 30°C drying step and an overlap mass loss of about 10.7% from about 30°C to 150°C, which was attributed to water and IPA. The mass loss above 150°C was attributed to the decomposition products carbon dioxide, water, and formaldehyde.

[0646] Formula I Form XIV

[0647] Formula I Form XIV was prepared by stirring a mixture of about 0.2 grams to 0.4 grams of Formula I Form I in about 3 mL of 1-propanol at room temperature for several days. The solid was isolated by centrifugal filtration and characterized.

[0648] Formula I Form XIX was characterized by XRPD and TGA-MS. The resulting XRPD diffraction pattern is shown in Figure 29. The XRPD peak list is reported in Table 17.

[0649] Table 17.

[0650] serial number Position °2-θ Relative strength (%) 1 5.8 100 2 8.2 12.0 3 18.5 23.0 4 11.7 7.7 5 16.6 10.9 6 22.0 13.7 7 22.8 23.9 8 10.0 4.9 9 10.5 4.1

[0651] TGA-MS was performed and showed a mass loss of about 1.6% of surface water and 1-propanol during the 30°C drying step and an overlapping mass loss of about 11.6% from about 30°C to 150°C, which was attributed to water and 1-propanol. Mass loss was observed above 150°C and was attributed to the decomposition products carbon dioxide, water, and formaldehyde.

[0652] Formula I Form XV

[0653] Formula I Form XV was prepared by stirring a mixture of about 0.2 g to 0.4 g of Formula I Form I in about 3 mL of CPME at room temperature for several days. The solid was isolated by centrifugal filtration and characterized.

[0654] Formula I Form XV was characterized by XRPD and TGA-MS. The resulting XRPD diffraction pattern is shown in Figure 30. The XRPD peak list is reported in Table 18.

[0655] Table 18.

[0656] serial number Position °2-θ Relative strength (%) 1 6.2 100 2 5.4 7.8 3 8.3 8.2 4 11.6 19.4 5 16.4 22.1 6 19.3 20.2 7 12.4 15.5 8 20.3 18.2 9 22.4 17.8

[0657] TGA-MS was performed and showed a mass loss of about 8.3% of surface water and CPME during the 30°C drying step and an overlapping mass loss of about 3.2% from about 30°C to 150°C, which was attributed to water and CPME. CPME was observed from about 5°C-200°C, and the overlapping mass loss was attributed to the decomposition products carbon dioxide, water, and formaldehyde.

[0658] Formula I 2-(4-hydroxybenzoyl)benzoate

[0659] A 4 mL threaded glass vial was charged with about 0.2 g of Formula I, about 2 equivalents of 2-(4-hydroxybenzoyl)benzoic acid, and about 3 mL of isopropyl acetate. The vial was capped and stirred at room temperature for about 19 days. The solid was isolated by centrifugation.

[0660] By XRPD, DSC, TGA and 1 H NMR was used to characterize the 2-(4-hydroxybenzoyl)benzoate salt of Formula I. The resulting XRPD diffractogram of the freshly isolated solid in the form of a wet cake (Formula I 2-(4-hydroxybenzoyl)benzoate salt Form A) is shown in Figure 31. The XRPD peak list is reported in Table 19.

[0661] Table 19.

[0662] serial number Position °2-θ Relative strength (%) 1 6.2 100 2 11.0 7.5 3 13.7 7.6 4 15.2 6.6 5 17.4 5.3 6 18.3 9.6 7 20.8 6.5 8 7.6 3.9 9 8.5 4.4

[0663] The above-mentioned Formula I 2-(4-hydroxybenzoyl)benzoate Form A was air dried. The resulting solid form, Formula I 2-(4-hydroxybenzoyl)benzoate Form B was characterized. The XRPD diffraction pattern of Formula I 2-(4-hydroxybenzoyl)benzoate Form B is depicted in Figure 32. A DSC thermogram of Formula I 2-(4-hydroxybenzoyl)benzoate Form B was performed, and the resulting thermogram is shown in Figure 33, which shows a broad endothermic event from about 30°C-100°C and broad endothermic and exothermic events above about 150°C. A TGA of Formula I 2-(4-hydroxybenzoyl)benzoate Form A was performed, and the resulting thermogram is shown in Figure 34. 1 H NMR showed about 0.63 wt % IPAc (about 0.07 mole) and a 1.0:0.96 ratio of Formula I: 2-(4-hydroxybenzoyl)benzoate.

[0664] Vanillate of Formula I

[0665] About 0.2 g of Formula I, about 2 equivalents of vanillic acid and about 3 mL of isopropyl acetate were charged into a 4 mL threaded glass vial. The vial was capped and stirred at room temperature for about 19 days. The solid was isolated by centrifugation for testing.

[0666] By XRPD, DSC, TGA and 1 The vanillic acid salt of Formula I was characterized by H NMR. The resulting XRPD diffractogram of the freshly isolated solid (Formula I Vanillic Acid Salt Form A) is shown in Figure 35. The XRPD peak list of Formula I Vanillic Acid Salt Form A is reported in Table 20.

[0667] Table 20.

[0668] serial number Position °2-θ Relative strength (%) 1 6.2 7.8 2 7.3 100.0 3 16.4 13.8 4 17.5 6.3 5 24.7 6.2 6 30.6 6.7 7 12.4 4.8 8 13.4 3.9 9 20.2 4.3

[0669] The above-described vanillic acid salt Form A of Formula I was air dried. The resulting solid form, Vanillic acid salt Form B of Formula I was characterized. The XRPD diffraction pattern of Vanillic acid salt Form B of Formula I is shown in FIG36. A DSC thermogram of Vanillic acid salt Form B of Formula I was performed, and the resulting thermogram is shown in FIG37, which shows a broad endothermic event from about 30°C-100°C and broad endothermic and exothermic events above about 150°C. A TGA of Vanillic acid salt Form B of Formula I was performed, and the resulting thermogram is depicted in FIG38. 1 H NMR showed approximately 1.5 wt % IPAc and a 1:0.44 ratio of Formula I:vanillic acid.

[0670] Formula I hippurate

[0671] About 0.2 g of Formula I, about 2 equivalents of hippuric acid, and about 3 mL of isopropyl acetate were charged into a 4 mL threaded glass vial. The vial was capped and stirred at room temperature for about 19 days. The solid was isolated by centrifugation for testing.

[0672] By XRPD, DSC, TGA and 1 The hippurate salt of Formula I was characterized by H NMR. The resulting XRPD diffractogram of the freshly isolated solid (Hippurate Salt of Formula I, Form A) is shown in Figure 39. The XRPD peak list of the hippurate salt of Formula I, Form A, is reported in Table 21.

[0673] Table 21.

[0674] serial number Position °2-θ Relative strength (%) 1 6.5 100.0 2 8.2 48.1 3 9.3 41.5 4 7.0 35.9 5 13.1 63.6 6 21.8 89.9 7 14.7 15.4 8 18.0 28.6 9 25.7 23.6

[0675] The hippurate salt Form A of Formula I as described above was air dried. The resulting solid form, hippurate salt Form B of Formula I was characterized. The XRPD diffraction pattern of hippurate salt Form B of Formula I is shown in Figure 40. A DSC thermogram of hippurate salt Form B of Formula I was performed, and the resulting thermogram is shown in Figure 41, which shows a broad endothermic event from about 30°C-100°C and broad endothermic and exothermic events above about 150°C. A TGA of hippurate salt Form B of Formula I was performed, and the resulting thermogram is depicted in Figure 42. 1 H NMR showed approximately 0.45 wt % IPAc and a 1:0.49 ratio of Formula I:hippuric acid.

[0676] Formula I maleate

[0677] About 0.2 g of Formula I, about 2 equivalents of maleic acid and about 2 mL of isopropyl acetate were charged into a 4 mL threaded glass vial. The vial was capped and stirred at room temperature for about 12 days. The solid was isolated by centrifugation for testing.

[0678] By XRPD, DSC, TGA and 1The maleate salt of Formula I was characterized by H NMR. The resulting XRPD diffractogram of the freshly isolated solid (Formula I Maleate Salt Form A) is shown in Figure 43. The XRPD peak list is reported in Table 22.

[0679] Table 22.

[0680] serial number Position °2-θ Relative strength (%) 1 5.8 100.0 2 8.2 10.0 3 11.7 11.3 4 10.0 8.5 5 10.4 10.3 6 14.9 9.8 7 6.4 5.9 8 20.0 9.9 9 25.7 6.7

[0681] The above Formula I maleate salt Form A was air dried. The resulting solid form, Formula I maleate salt Form B was characterized. The XRPD diffraction pattern of Formula I maleate salt Form B is shown in Figure 44. The XRPD peak list is included in Table 23.

[0682] Table 23.

[0683] serial number Position °2-θ Relative strength (%) 1 6.1 100.0 2 8.3 8.6 3 10.7 11.6 4 14.4 19.4 5 16.4 31.6 6 20.1 22.1 7 21.4 14.9 8 22.7 29.0 9 28.4 15.6

[0684] A DSC thermogram of the maleate salt Form B of Formula I was performed and the resulting thermogram is depicted in Figure 45, which shows a broad endothermic event from about 30°C-100°C and broad endothermic and exothermic events above about 150°C. A TGA thermogram of the maleate salt Form B of Formula I was performed and the resulting thermogram is shown in Figure 46. 1 H NMR showed a Formula I:maleic acid ratio of about 1:0.4 and about 0.05 wt % IPAc.

[0685] Glyoxylate of Formula I

[0686] About 0.1 g of Formula I, about 2 equivalents of glyoxylic acid, and about 2 mL of isopropyl acetate were charged into a 4 mL threaded glass vial. The vial was capped and stirred at room temperature for about 12 days. The solid was isolated by centrifugation for testing.

[0687] By XRPD, DSC, TGA and 1 The glyoxylate salt of Formula I was characterized by H NMR. The resulting XRPD diffractogram of the freshly isolated solid (Formula I glyoxylate salt Form A) is shown in Figure 47. The XRPD peak list is reported in Table 24.

[0688] Table 24.

[0689] serial number Position °2-θ Relative strength (%) 1 5.9 100.0 2 22.5 58.1 3 8.1 13.2 4 12.4 19.0 5 16.4 37.2 6 19.1 37.3 7 15.0 18.0 8 20.0 32.4 9 28.1 24.8

[0690] The above-described glyoxylate salt Form A of Formula I was air dried. The resulting solid form, glyoxylate salt Form B of Formula I was characterized. The XRPD diffraction pattern of glyoxylate salt Form B of Formula I is shown in Figure 48. The XRPD peak list is reported in Table 25.

[0691] Table 25.

[0692] serial number Position °2-θ Relative strength (%) 1 6.2 100 2 8.3 14.4 3 12.6 13.9 4 10.8 9.0 5 16.1 12.9 6 16.4 16.4 7 18.6 19.4 8 19.4 19.3 9 20.3 22.9

[0693] A DSC thermogram of Form B of the glyoxylate salt of Formula I was performed and the resulting thermogram is depicted in Figure 49. A TGA of Form B of the glyoxylate salt of Formula I was performed and the resulting thermogram is depicted in Figure 50. 1 H NMR showed a ratio of Formula I:glyoxylic acid of about 1.0:0.77, and about 3.0 wt % IPAc was present.

[0694] Formula I L-pyroglutamate

[0695] About 0.1 g of Formula I, about 2 equivalents of L-pyroglutamic acid and about 2 mL of isopropyl acetate were charged into a 4 mL threaded glass vial. The vial was capped and stirred at room temperature for about 12 days. The solid was isolated by centrifugation for testing.

[0696] By XRPD, DSC and 1 The L-pyroglutamate salt of Formula 1 was characterized by H NMR. The resulting XRPD diffraction pattern of (wet cake) is shown in Figure 67. The XRPD peak list is reported in Table 26.

[0697] Table 26.

[0698] serial number Position °2-θ Relative strength (%) 1 6.1 88.4 2 16.5 24.6 3 19.8 100.0 4 11.6 13.3 5 12.4 13.8 6 17.3 13.8 7 22.8 34.4 8 23.0 39.8 9 28.4 11.5

[0699] The L-pyroglutamate salt of Formula I was air dried and characterized by DSC (Figure 52). 1 H NMR showed a Formula I:L-pyroglutamic acid ratio of about 1.0:0.63, and the presence of about 0.8 wt % IPAc.

[0700] Formula I 2-naphthalenesulfonate

[0701] A 4 mL threaded glass vial was charged with about 0.1 g of Formula I, about 1 equivalent of 2-naphthalenesulfonic acid, and about 3 mL of isopropyl acetate. The vial was capped and stirred at room temperature for about 12 days. The solid was isolated by centrifugation.

[0702] By XRPD, DSC, TGA and 1 The 2-naphthalenesulfonate salt of Formula I was characterized by H NMR. The resulting XRPD diffractogram of the freshly prepared solid (wet cake) is shown in Figure 53. The XRPD peak list is reported in Table 27.

[0703] Table 27.

[0704] serial number Position °2-θ Relative strength (%) 1 5.9 100.0 2 8.1 15.9 3 16.3 38.5 4 18.6 23.8 5 19.1 28.2 6 20.0 26.1 7 10.1 9.1 8 12.6 10.6 9 13.1 8.4

[0705] The 2-naphthalenesulfonate salt of Formula I was air dried and subjected to XRPD. The resulting XRPD diffractogram of the 2-naphthalenesulfonate salt of Formula I is shown in Figure 54. The XRPD peak list is reported in Table 28.

[0706] Table 28.

[0707] serial number Position °2-θ Relative strength (%) 1 6.2 100.0 2 8.4 8.6 3 16.5 17.5 4 10.8 7.3 5 11.7 13.4 6 19.1 14.9 7 12.6 4.7 8 14.6 6.1 9 22.6 13.8

[0708] A DSC thermogram of the air-dried 2-naphthalenesulfonate salt of Formula I was performed, and the resulting thermogram is depicted in Figure 55. A TGA was performed on the air-dried solid, and the thermogram of the 2-naphthalenesulfonate salt of Formula I is depicted in Figure 56. 1 H NMR showed a Formula I:2-naphthalenesulfonate ratio of 1.0:0.99 and the presence of 3.1 wt % IPAc.

[0709] Formula I 1-naphthalenesulfonate

[0710] About 0.1 g of Formula I, about 1 equivalent of 1-naphthalenesulfonic acid, and about 3 mL of isopropyl acetate were charged into a 4 mL threaded glass vial. The vial was capped and stirred at room temperature for about 12 days. The solid was isolated by centrifugation for testing.

[0711] By XRPD, DSC and 1 The resulting 1-naphthalenesulfonate of Formula I was characterized by H NMR. The resulting XRPD diffractogram of the freshly prepared solid (Formula I1-naphthalene wet cake) is shown in Figure 57. The XRPD peak list is reported in Table 29.

[0712] Table 29.

[0713] serial number Position °2-θ Relative strength (%) 1 5.9 100.0 2 8.1 11.7 3 16.3 21.0 4 10.0 7.6 5 10.5 6.1 6 20.0 17.9 7 18.6 13.2 8 19.0 9.3 9 22.6 17.9

[0714] The wet cake of the 1-naphthalenesulfonate salt of Formula I as described above was air dried and subjected to XRPD analysis. The XRPD diffraction pattern of the air dried 1-naphthalenesulfonate salt of Formula I is depicted in Figure 58. The XRPD peak list is reported in Table 30.

[0715] Table 30.

[0716] serial number Position °2-θ Relative strength (%) 1 6.2 100.0 2 8.4 8.8 3 16.5 18.0 4 10.9 8.9 5 11.7 14.3 6 20.5 12.5 7 14.6 7.8 8 15.3 8.3 9 17.3 9.5

[0717] DSC of the air-dried 1-naphthalenesulfonate salt of Formula I was performed and the resulting thermogram is shown in Figure 59. 1 H NMR showed a Formula I:1-NSA ratio of 1.0:0.60 and the presence of 4.0 wt % IPAc.

[0718] Formula I 1-hydroxy-2-naphthoate

[0719] About 0.1 g of Formula I, about 2 equivalents of 1-hydroxy-2-naphthoic acid, and about 3 mL of isopropyl acetate were charged into a 4 mL threaded glass vial. The vial was capped and stirred at room temperature for about 12 days. The solid was isolated by centrifugation for testing.

[0720] By XRPD, DSC, TGA and 1 The 1-hydroxy-2-naphthoate salt of Formula I was characterized by H NMR. The resulting XRPD diffractogram of the freshly prepared solid (1-hydroxy-2-naphthoate salt of Formula I wet cake) is shown in Figure 60. The XRPD peak list is reported in Table 31.

[0721] Table 31.

[0722] serial number Position °2-θ Relative strength (%) 1 5.3 75.0 2 5.6 100.0 3 7.4 62.1 4 6.7 57.3 5 9.3 46.8 6 21.0 35.8 7 17.5 21.3 8 18.5 27.1 9 23.6 30.6

[0723] The 1-hydroxy-2-naphthoic acid salt of Formula I was air dried and subjected to XRPD. The XRPD diffractogram of the air dried 1-hydroxy-2-naphthoic acid salt of Formula I is shown in Figure 61. The XRPD peak list is reported in Table 32.

[0724] Table 32.

[0725] serial number Position °2-θ Relative strength (%) 1 6.1 100.0 2 7.3 47.0 3 15.9 18.0

[0726] DSC of the air-dried 1-hydroxy-2-naphthoate salt of Formula I was performed and the resulting thermogram is depicted in Figure 62. The TGA thermogram of the 1-hydroxy-2-naphthoate salt of Formula I is shown in Figure 63. 1 H NMR showed a Formula I: 1-hydroxy-2-naphthoic acid ratio of about 1.0:0.43, and the presence of about 1.4 wt % IPAc.

[0727] Formula I S-mandelate

[0728] About 0.2 g of Formula I, about 2 equivalents of S-mandelic acid, and about 3 mL of isopropyl acetate were charged into a 4 mL threaded glass vial. The vial was capped and stirred at room temperature for about 30 days. The solid was isolated by centrifugation.

[0729] By XRPD, DSC, TGA and 1 The Formula I S-mandelate salt was characterized by H NMR. The resulting XRPD diffraction pattern of the freshly prepared solid (wet cake) (Formula I S-mandelate salt Form A) is depicted in Figure 64. The XRPD peak list is reported in Table 33.

[0730] Table 33.

[0731] serial number Position °2-θ Relative strength (%) 1 5.5 100.0 2 5.7 97.0 3 6.3 26.0 4 11.4 30.4 5 16.6 36.5 6 20.8 24.9 7 10.0 10.7 8 10.4 10.5 9 19.0 22.6

[0732] The above Formula 1 S-mandelate salt Form A was air dried. The resulting solid form, Formula 1 S-mandelate salt Form B, was subjected to XRPD analysis. The XRPD diffraction pattern of Formula 1 S-mandelate salt Form B is shown in Figure 65. The XRPD peak list of Formula 1 S-mandelate salt Form B is reported in Table 34.

[0733] Table 34.

[0734] serial number Position °2-θ Relative strength (%) 1 5.7 100.0 2 6.2 76.5 3 22.6 90.2 4 8.0 15.8 5 8.4 8.9 6 11.7 58.7 7 13.5 24.4 8 16.0 39.3 9 16.6 56.6

[0735] A DSC thermogram of Formula I S-mandelate salt Form B was performed and the resulting thermogram is shown in Figure 66 and shows a broad endothermic event from about 50°C to 75°C, a sharp endothermic event at about 150°C. The endothermic and exothermic events at higher temperatures are attributed to decomposition. The TGA thermogram of Formula I S-mandelate salt Form B is depicted in Figure 67 and shows a mass loss of about 3.0 wt % up to about 100°C and a larger mass loss above 150°C, which may be attributed to decomposition. 1 H NMR showed a Formula I:S-mandelic acid ratio of 1.0:0.6 and an IPAc content of 2.2 wt%.

[0736] Gentisate of Formula I

[0737] About 0.2 g of Formula I, about 2 equivalents of gentisic acid, and about 3 mL of isopropyl acetate were charged into a 4 mL threaded glass vial. The vial was capped and stirred at room temperature for about 30 days. The solid was isolated by centrifugation.

[0738] By XRPD, DSC, TGA and 1 H NMR was used to characterize the gentisate salt of Formula I. The resulting XRPD diffractogram of the freshly prepared solid (gentisate salt of Formula I wet cake) is shown in Figure 68. The XRPD peak list is reported in Table 35.

[0739] Table 35.

[0740] serial number Position °2-θ Relative strength (%) 1 7.4 100.0 2 6.5 96.4 3 8.0 45.7 4 13.5 16.4 5 16.9 36.0 6 12.0 26.9 7 25.1 13.1 8 22.4 14.5 9 19.3 19.8

[0741] The wet cake of the gentisate of Formula I was air dried. The resulting solid form was characterized by XRPD. The resulting XRPD diffraction pattern is shown in Figure 69. The XRPD peak list is reported in Table 36.

[0742] Table 36.

[0743] serial number Position °2-θ Relative strength (%) 1 7.4 100.0 2 6.1 71.5 3 8.4 71.4 4 16.7 59.8 5 17.9 41.5 6 9.1 38.4 7 24.9 30.5 8 22.8 19.4 9 12.3 16.3

[0744] A DSC thermogram of the air-dried gentisate salt of Formula I was performed and the resulting thermogram is shown in Figure 70. A TGA of the air-dried gentisate salt of Formula I was performed and the resulting thermogram is depicted in Figure 71. The TGA showed a mass loss of about 1.5 wt % up to about 100°C and a greater mass loss above 150°C, which may be due to decomposition. 1 H NMR showed a Formula I:gentisic acid ratio of 1.0:0.8 and an IPAc content of 2.6 wt %.

[0745] Formula I Citrate

[0746] About 0.2 g of Formula I, about 2 equivalents of citric acid, and about 3 mL of isopropyl acetate were charged into a 4 mL threaded glass vial. The vial was capped and stirred at room temperature for about 30 days. The solid was isolated by centrifugation for testing.

[0747] By XRPD, DSC, TGA and 1 The citrate salt of Formula I was characterized by H NMR. The resulting XRPD diffractogram of the freshly prepared solid (wet cake) is shown in Figure 72. The XRPD peak list is reported in Table 37.

[0748] Table 37.

[0749] serial number Position °2-θ Relative strength (%) 1 7.4 100.0 2 7.9 26.4 3 16.7 33.0 4 15.1 7.4 5 17.7 13.8 6 20.4 17.6 7 11.4 4.1 8 18.9 14.5 9 22.1 15.2

[0750] The above formula I citrate salt was air dried. The resulting solid form was characterized by XRPD (Figure 73). The XRPD peak list is reported in Table 38.

[0751] Table 38.

[0752] serial number Position °2-θ Relative strength (%) 1 6.1 58.5 2 7.4 92.1 3 18.2 100.0 4 8.3 44.2 5 16.4 60.1 6 36.7 48.4 7 20.7 36.4 8 24.5 18.8 9 26.0 22.7

[0753] DSC was performed on the air-dried Formula I citrate salt and the resulting thermogram is depicted in Figure 74. TGA of the Formula I citrate salt Form B was performed and the resulting thermogram is depicted in Figure 75, which shows a mass loss of about 2.3 wt % up to about 100°C and a larger mass loss above 150°C, which may be due to decomposition. 1 H NMR showed a Formula I:citric acid ratio of 1.0:0.8 and an IPAc content of 0.3 wt %.

[0754] Formula I R-mandelate

[0755] About 0.2 g of Formula I, about 2 equivalents of R-mandelic acid, and about 3 mL of isopropyl acetate were charged into a 4 mL threaded glass vial. The vial was capped and stirred at room temperature for about 30 days. The solid was isolated by centrifugation for testing.

[0756] By XRPD, DSC, TGA and 1 The Formula 1 R-mandelate salt was characterized by H NMR. The resulting XRPD diffraction pattern of the freshly prepared solid (Formula 1R-mandelate salt Form A) is shown in Figure 76. The XRPD peak list is reported in Table 39.

[0757] Table 39.

[0758] serial number Position °2-θ Relative strength (%) 1 5.7 100.0 2 5.4 83.3 3 16.5 37.0 4 6.2 22.0 5 7.8 9.2 6 11.5 19.1 7 10.5 12.8 8 13.4 17.0 9 18.5 14.1

[0759] The above Formula 1 R-mandelate Salt Form A was air dried. The resulting solid form, Formula 1 R-mandelate Salt Form B, was characterized by XRPD. The XRPD diffraction pattern of Formula 1 R-mandelate Salt Form B is shown in Figure 77. The XRPD peak list is reported in Table 40.

[0760] Table 40.

[0761] serial number Position °2-θ Relative strength (%) 1 6.2 100.0 2 8.3 8.9 3 22.4 19.7 4 15.9 10.3 5 16.3 8.7 6 17.0 11.4 7 10.0 5.8 8 10.8 8.3 9 11.6 12.3

[0762] DSC of Formula 1 R-mandelate Salt Form B was performed and the resulting thermogram is depicted in Figure 78 and shows a broad endothermic event from about 50°C to 75°C, a sharp endothermic event at about 150°C, and endothermic and exothermic events at higher temperatures, which may be attributed to decomposition. TGA of Formula 1 R-mandelate Salt Form B was performed and the resulting thermogram is shown in Figure 79. The TGA shows a mass loss of about 3.3 wt % up to about 100°C and a larger mass loss above 150°C, which may be attributed to decomposition. 1 H NMR showed a Formula I:R-mandelic acid ratio of about 1:0.5 and about 0.7 wt % IPAc.

[0763] Formula I Benzoate

[0764] About 0.2 g of Formula I, about 2 equivalents of benzoic acid and about 3 mL of isopropyl acetate were charged into a 4 mL threaded glass vial. The vial was capped and stirred at room temperature for about 30 days. The solid was isolated by centrifugation for testing.

[0765] By XRPD, DSC, TGA and 1 The benzoate salt of Formula I was characterized by H NMR. The resulting XRPD diffractogram of the freshly prepared solid (wet cake) (Formula I benzoate salt Form A) is shown in Figure 80. The XRPD peak list is reported in Table 41.

[0766] Table 41.

[0767] serial number Position °2-θ Relative strength (%) 1 7.44 100.00 2 18.97 33.75 3 16.70 41.50 4 21.14 26.17 5 22.45 23.59 6 25.07 23.94 7 6.09 20.93

[0768] The above Formula I benzoate Form A was air dried. The resulting solid form, Formula I benzoate Form B was characterized. The XRPD diffraction pattern of Formula I benzoate Form B is shown in Figure 81. The XRPD peak list is reported in Table 42.

[0769] Table 42.

[0770] serial number Position °2-θ Relative strength (%) 1 14.9 34.0 2 6.7 29.0 3 7.4 100.0 4 20.6 40.3 5 22.5 43.1 6 8.1 43.3 7 6.7 29.0 8 14.9 34.0 9 21.5 34.8

[0771] A DSC thermogram of the benzoate salt Form B of Formula I was performed and the resulting thermogram is depicted in Figure 82. A TGA of the benzoate salt Form B of Formula I was performed and the resulting thermogram is shown in Figure 83. 1 H NMR showed a Formula I:benzoic acid ratio of about 1.0:0.5, and an IPAc content of about 1.9 wt %.

[0772] Formula I Methyl p-hydroxybenzoate

[0773] About 0.2 g of Formula I, about 2 equivalents of methyl paraben and about 3 mL of isopropyl acetate were charged into a 4 mL threaded glass vial. The vial was capped and stirred at room temperature for about 30 days. The solid was isolated by centrifugation.

[0774] By XRPD, DSC, TGA and 1 H NMR was used to characterize the methyl paraben of Formula I. The resulting XRPD diffractogram of the freshly prepared solid (wet cake) (methyl paraben of Formula I, Form A) is shown in Figure 85. The XRPD peak list is reported in Table 43.

[0775] Table 43.

[0776] serial number Position °2-θ Relative strength (%) 1 7.4 100 2 8.0 82.5 3 6.3 45.7 4 20.5 36.8 5 19.2 19.2 6 12.1 20.0 7 31.6 10.6 8 22.8 27.6 9 14.0 19.4

[0777] The above-described methyl paraben, Form A of Formula I, was air dried. The resulting solid form, methyl paraben, Form B of Formula I ( FIG. 85 ), was characterized by XRPD. The XRPD peak list is reported in Table 44.

[0778] Table 44.

[0779] serial number Position °2-θ Relative strength (%) 1 7.4 100.0 2 8.3 71.0 3 6.5 33.1 4 19.3 51.1 5 20.6 64.4 6 21.6 69.7 7 12.2 27.4 8 13.0 18.3 9 31.8 26.6

[0780] A DSC thermogram of methyl paraben, Form B of Formula I was performed and the thermogram is depicted in Figure 86. A TGA of methyl paraben, Form B of Formula I was performed and the resulting thermogram is shown in Figure 87. 1 H NMR showed a Formula I: methyl paraben ratio of about 1.0:0.7, and an IPAc content of about 0 wt %.

[0781] Formula I Caffeic acid salt

[0782] About 0.2 g of Formula I, about 2 equivalents of caffeic acid, and about 3 mL of isopropyl acetate were charged into a 4 mL threaded glass vial. The vial was capped and stirred at room temperature for about 30 days. The solid was isolated by centrifugation.

[0783] By XRPD, DSC, TGA and 1 The caffeic acid salt of Formula I was characterized by H NMR. The resulting XRPD diffractogram of the freshly prepared solid (caffeic acid salt of Formula I wet cake) is shown in Figure 88. The XRPD peak list is reported in Table 45.

[0784] Table 45.

[0785] serial number Position °2-θ Relative strength (%) 1 5.3 100 2 7.4 20.6 3 9.1 21.7 4 6.5 12.4 5 7.0 10.2 6 15.9 19.0 7 27.1 19.0 8 22.5 16.1 9 10.6 7.7

[0786] The wet cake of the coffee acid salt of formula I was air dried and characterized by XRPD. The resulting XRPD diffractogram is shown in Figure 89. DSC of the air-dried coffee acid salt of formula I was performed, and the resulting thermogram is shown in Figure 90. TGA was performed, and the resulting thermogram is depicted in Figure 91. 1 H NMR showed a Formula I:caffeic acid ratio of about 1.0:1.3.

[0787] Formula I glycolate

[0788] A 4 mL threaded glass vial was charged with a stirring bar, about 0.9 g of Form II of Formula I, 1.0 equivalents of glycolic acid, and 2 mL of ethyl acetate. The suspension was stirred at room temperature for about 6 days and sampled for further analysis. The solid was separated by centrifugation for XRPD characterization.

[0789] Through XRPD, 1 H NMR and DVS were used to characterize the glycolic acid salt of Formula I. The resulting XRPD diffractogram of the freshly prepared solid (wet cake) is shown in Figure 92. The XRPD peak list is reported in Table 46.

[0790] Table 46.

[0791] serial number Position °2-θ Relative strength (%) 1 6.2 100.0 2 8.4 13.7 3 11.5 16.6 4 10.9 10.8 5 16.4 33.2 6 22.3 14.5 7 13.6 11.3 8 14.0 6.7 9 15.3 9.2

[0792] The wet cake of the glycolate salt of Formula I was dried under vacuum. The resulting solid form was characterized by XRPD and the resulting diffraction pattern is shown in Figure 93. The XRPD peak list is reported in Table 47.

[0793] Table 47.

[0794] serial number Position °2-θ Relative strength (%) 1 6.2 100.0 2 8.3 12.5 3 11.5 12.2 4 10.8 9.5 5 16.4 33.2 6 22.2 13.2 7 13.6 6.5 8 14.9 6.3 9 15.3 7.7

[0795] DVS of the dried glycolate salt of Formula I was performed and showed a weight change of about 7.5% from 0%-90% RH. Weak hysteresis was observed and the behavior was roughly linear. The weight change from 50%-90% RH was about 2%. 1 H NMR showed a Formula I:glycolic acid ratio of 1.0:0.8.

[0796] Formula I α-ketobutyrate

[0797] A flask was charged with a stirring bar, about 5.0 g of Form I, 1.0 equivalent of α-ketobutyric acid, and 10 mL of ethyl acetate. The suspension was stirred at room temperature for about 3 days and samples were taken for testing. The next day, the suspension was filtered and washed with about 2 mL of ethyl acetate, air-dried for about 1 day, and then vacuum-dried at about 40° C. for about 7 days.

[0798] Through XRPD, 1 H NMR and DVS were used to characterize the α-ketobutyrate salt of Formula I. The resulting XRPD diffraction pattern of the wet cake α-ketobutyrate salt of Formula I is shown in Figure 94. The XRPD peak list is reported in Table 48.

[0799] Table 48.

[0800] serial number Position °2-θ Relative strength (%) 1 6.2 100.0 2 8.3 11.3 3 10.8 10.1 4 12.3 1.6 5 12.5 1.5 6 12.7 1.9 7 16.4 6.9 8 19.0 6.3 9 21.6 5.0

[0801] The above Formula I α-ketobutyrate salt was air dried and characterized by XRPD (Figure 95). The XRPD peak list of the dry material is reported in Table 49.

[0802] Table 49.

[0803] serial number Position °2-θ Relative strength (%) 1 6.2 100.0 2 16.4 15.8 3 8.3 15.1 4 10.8 11.8 5 11.5 12.6 6 20.3 12.4 7 18.5 5.9 8 19.0 5.7 9 21.6 7.1

[0804] A DVS isotherm of Formula I α-ketobutyrate Form B was performed and the resulting isotherm showed a weight change of about 5.5% from 0%-90% RH. The hysteresis from 10%-90% RH was smaller, but a slope change was observed between 0% and 10% RH. The weight change from 50%-90% RH was about 2%. 1 H NMR showed a Formula I:glycolic acid ratio of 1.0:0.8.

[0805] Formula I pyruvate

[0806] About 5 grams of Formula I Form I, about 1.0 equivalents of pyruvic acid and about 10 mL of ethyl acetate were loaded into a threaded glass vial. The vial was capped and the suspension was stirred magnetically at room temperature for about 5 days. The suspension was filtered and the filter cake was washed with about 2 mL of ethyl acetate. The filter cake was vacuum dried at room temperature and the product was isolated.

[0807] Through XRPD, 1 H NMR and DVS were used to characterize the pyruvate salt of Formula I. The resulting XRPD diffractogram of the freshly prepared solid (wet cake) is shown in Figure 96. The XRPD peak list is reported in Table 50.

[0808] Table 50.

[0809] serial number Position °2-θ Relative strength (%) 1 6.21 100.00 2 8.34 13.30 3 10.85 11.29 4 11.56 8.27 5 13.60 6.37 6 14.51 5.59 7 20.32 10.59 8 21.73 7.08 9 22.59 5.13

[0810] The above Formula I pyruvate salt was vacuum dried and subjected to XRPD. The XRPD diffraction pattern is shown in Figure 97. The XRPD peak list is reported in Table 51.

[0811] Table 51.

[0812] serial number Position °2-θ Relative strength (%) 1 6.2 100.0 2 8.3 15.0 3 10.8 10.8 4 11.5 16.1 5 16.3 20.1 6 19.1 9.1 7 20.3 17.9 8 21.7 11.4 9 22.1 10.8

[0813] DVS of Form B pyruvate salt of Formula I was performed and the resulting isotherm showed a weight change of about 4.3% from 10%-90% RH with weak hysteresis and linear behavior. The weight change from 50% to 90% RH was about 2.5%. 1 H NMR showed a 1.0:0.90 ratio of Formula I:pyruvate.

[0814] Stability studies

[0815] The amorphous material and Forms I, II, III and IV of Formula I were tested for purity loss over time as determined by liquid chromatography. As observed from the data presented in Table 57, Forms II, III and IV of Formula I had reduced purity loss over time when compared to Form I of Formula I or amorphous material of Formula I.

[0816] The sample preparation for stability studies is described below:

[0817] Formula I Amorphous: A sample of the amorphous solid was placed at about 22°C, open to air, and monitored for purity by liquid chromatography for 3 days.

[0818] Formula I Form I: A sample of Formula I Form I was placed in a sealed glass vial and placed in a chamber at about 40°C and about 75% RH and the purity was monitored periodically by liquid chromatography.

[0819] Formula I Form II: A sample of Formula I Form II was placed in an open vial. The vial was placed side by side with a saturated saline solution in a container to provide a humidity of about 88% RH and sealed. The sealed container was then placed in a chamber at about 40°C and the purity was monitored regularly by liquid chromatography.

[0820] Formula I Form III: A sample of Formula I Form II was placed in an open vial. The vial was placed side by side with a saturated saline solution in a container to provide a humidity of about 27% RH and sealed. The sealed container was then placed in a chamber at about 40°C and the purity was monitored regularly by liquid chromatography.

[0821] Formula I Form IV: Samples of Formula I Form IV were packaged in PE bags at about 0% RH and heat sealed in foil bags. The pouches were then placed in a chamber at about 40°C and purity was monitored regularly by liquid chromatography.

[0822] The results are recorded in Table 52.

[0823] Table 52.

[0824]

[0825] ***

[0826] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0827] Therefore, it should be understood that although the present disclosure has been specifically disclosed by preferred embodiments and optional features, modifications, improvements and variations of the disclosure implemented therein disclosed herein may be adopted by those skilled in the art, and such modifications, improvements and variations are considered to be within the scope of the present disclosure. The materials, methods and examples provided herein represent preferred embodiments, are exemplary, and are not intended to limit the scope of the present disclosure.

[0828] The present disclosure has been described broadly and generically herein. Each narrower genus and subgeneric grouping falling within the generic disclosure also forms a part of the present disclosure. This includes the generic description of the present disclosure with a proviso or negative limitation removing any subject matter from the genus, regardless of whether the excised material is specifically recited herein.

[0829] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0830] It should be understood that although the present disclosure has been described in conjunction with the above embodiments, the foregoing description and examples are intended to illustrate rather than limit the scope of the present disclosure. Other aspects, advantages and modifications within the scope of the present disclosure will be apparent to those skilled in the art to which the present disclosure belongs.

Claims

1. A solid form of Formula I Form II, wherein Formula I has the following structure: (I)。 2. The solid form according to claim 1, characterized in that The X-ray diffraction pattern has 2θ-reflections at 7.4 degrees 2θ, 9.4 degrees 2θ, and 10.6 degrees 2θ plus or minus 0.2 degrees 2θ.

3. The solid form according to claim 1 or 2, characterized in that The X-ray diffraction pattern also includes 2θ-reflections at 8.8 degrees 2θ, 12.3 degrees 2θ, and 26.1 degrees 2θ plus or minus 0.2 degrees 2θ.

4. The solid form according to any one of claims 1 to 3, characterized in that The X-ray diffraction pattern also includes 2θ-reflections at 14.7 degrees 2θ, 18.1 degrees 2θ, and 22.4 degrees 2θ plus or minus 0.2 degrees 2θ.

5. A solid form according to any one of claims 1 to 4 having an X-ray diffraction pattern substantially as shown in Figure 7.

6. A solid form according to any one of claims 1 to 5, having a full pattern Polyhedral refined diffraction pattern substantially as shown in Figure 8.

7. A solid form of Formula I Form III, wherein Formula I has the following structure: (I)。 8. The solid form according to claim 7, characterized in that The X-ray diffraction pattern has 2θ-reflections at 7.8 degrees 2θ, 9.8 degrees 2θ, and 10.7 degrees 2θ plus or minus 0.2 degrees 2θ.

9. The solid form according to claim 7 or 8, characterized in that The X-ray diffraction pattern also includes 2θ-reflections at 8.9 degrees 2θ, 12.5 degrees 2θ, and 20.1 degrees 2θ plus or minus 0.2 degrees 2θ.

10. The solid form according to any one of claims 7 to 9, characterized in that The X-ray diffraction pattern also includes 2θ-reflections at 15.5 degrees 2θ, 18.2 degrees 2θ, and 22.9 degrees 2θ plus or minus 0.2 degrees 2θ.

11. A solid form according to any one of claims 7 to 10 having an X-ray diffraction pattern substantially as shown in Figure 11.

12. A solid form according to any one of claims 7 to 11 having a dynamic vapour sorption isotherm substantially as shown in Figure 14.

13. A solid form of Form IV of Formula I, wherein Formula I has the structure: (I)。 14. The solid form according to claim 13, characterized in that The X-ray diffraction pattern has 2θ-reflections at 8.0 degrees 2θ, 18.1 degrees 2θ, and 20.0 degrees 2θ plus or minus 0.2 degrees 2θ.

15. The solid form according to claim 13 or 14, characterized in that The X-ray diffraction pattern also includes 2θ-reflections at 9.0 degrees 2θ, 9.9 degrees 2θ, and 10.8 degrees 2θ plus or minus 0.2 degrees 2θ.

16. The solid form according to any one of claims 13 to 15, characterized in that The X-ray diffraction pattern also includes 2θ-reflections at 15.6 degrees 2θ, 22.8 degrees 2θ, and 24.9 degrees 2θ plus or minus 0.2 degrees 2θ.

17. A solid form according to any one of claims 13 to 16 having an X-ray diffraction pattern substantially as shown in Figure 16.

18. A solid form of Formula I Form VII, wherein Formula I has the structure: (I)。 19. The solid form according to claim 18, characterized in that The X-ray diffraction pattern has 2θ-reflections at 6.2 degrees 2θ, 8.4 degrees 2θ, and 22.6 degrees 2θ plus or minus 0.2 degrees 2θ.

20. The solid form according to claim 18 or 19, characterized in that The X-ray diffraction pattern also includes 2θ-reflections at 10.3 degrees 2θ, 10.9 degrees 2θ, and 11.7 degrees 2θ plus or minus 0.2 degrees 2θ.

21. The solid form according to any one of claims 18 to 20, characterized in that The X-ray diffraction pattern also includes 2θ-reflections at 16.1 degrees 2θ, 16.4 degrees 2θ, and 17.3 degrees 2θ plus or minus 0.2 degrees 2θ.

22. A solid form according to any one of claims 18 to 21 having an X-ray diffraction pattern substantially as shown in Figure 22.

23. The solid form of any one of claims 18 to 22, having a mass loss of about 2.9 wt% at a temperature of about 50°C to 125°C when subjected to thermogravimetric analysis-mass spectrometry.

24. A solid form of Formula I Form IX, wherein Formula I has the structure: (I)。 25. The solid form according to claim 24, characterized in that The X-ray diffraction pattern has 2θ-reflections at 7.2 degrees 2θ, 5.8 degrees 2θ, and 5.7 degrees 2θ plus or minus 0.2 degrees 2θ.

26. The solid form according to claim 24 or 25, characterized in that The X-ray diffraction pattern also includes 2θ-reflections at 10.7 degrees 2θ, 15.3 degrees 2θ, and 17.1 degrees 2θ plus or minus 0.2 degrees 2θ.

27. The solid form according to any one of claims 24 to 26, characterized in that The X-ray diffraction pattern also includes 2θ-reflections at 7.4 degrees 2θ, 10.0 degrees 2θ, and 8.9 degrees 2θ plus or minus 0.2 degrees 2θ.

28. A solid form according to any one of claims 24 to 27 having an X-ray diffraction pattern substantially as shown in Figure 24.

29. The Formula I Form IX according to any one of claims 24 to 28, having a mass loss of about 6.3% at 30°C when subjected to thermogravimetric analysis-mass spectrometry.

30. A solid form of Formula I S-mandelate salt Form A, wherein Formula I has the following structure: (I)。 31. The solid form of claim 30, characterized in that The X-ray diffraction pattern has 2θ-reflections at 5.5 degrees 2θ, 5.7 degrees 2θ, and 6.3 degrees 2θ plus or minus 0.2 degrees 2θ.

32. The solid form according to claim 30 or 31, characterized in that The X-ray diffraction pattern also includes 2θ-reflections at 11.4 degrees 2θ, 16.6 degrees 2θ, and 20.8 degrees 2θ plus or minus 0.2 degrees 2θ.

33. The solid form according to any one of claims 30 to 32, characterized in that The X-ray diffraction pattern also includes 2θ-reflections at 10.0 degrees 2θ, 10.4 degrees 2θ, and 19.0 degrees 2θ plus or minus 0.2 degrees 2θ.

34. A solid form according to any one of claims 30 to 33 having an X-ray diffraction pattern substantially as shown in Figure 64.

35. A solid form of Formula I S-mandelate salt Form B, wherein Formula I has the structure: (I)。 36. The solid form of claim 35, characterized in that The X-ray diffraction pattern has 2θ-reflections at 5.7 degrees 2θ, 6.2 degrees 2θ, and 22.6 degrees 2θ plus or minus 0.2 degrees 2θ.

37. The solid form according to claim 35 or 36, characterized in that The X-ray diffraction pattern also includes 2θ-reflections at 8.0 degrees 2θ, 8.4 degrees 2θ, and 11.7 degrees 2θ plus or minus 0.2 degrees 2θ.

38. A solid form according to any one of claims 35 to 37, characterised in that The X-ray diffraction pattern also includes 2θ-reflections at 13.5 degrees 2θ, 16.0 degrees 2θ, and 16.6 degrees 2θ plus or minus 0.2 degrees 2θ.

39. A solid form according to any one of claims 35 to 38 having an X-ray diffraction pattern substantially as shown in Figure 65.

40. The solid form of any one of claims 35 to 39, having a differential scanning calorimetry thermogram comprising a first endothermic event at about 50°C to about 75°C and a second endothermic event at about 150°C.

41. The solid form of any one of claims 35 to 40 having a differential scanning calorimetry thermogram substantially as shown in Figure 66.

42. A solid form according to any one of claims 35 to 41 having a thermogravimetric analysis substantially as shown in Figure 67.

43. A solid form of Formula I R-mandelate salt Form A, wherein Formula I has the structure: (I)。 44. The solid form of claim 43, characterized in that The X-ray diffraction pattern has 2θ-reflections at 5.7 degrees 2θ, 5.4 degrees 2θ, and 16.5 degrees 2θ plus or minus 0.2 degrees 2θ.

45. The solid form according to claim 43 or 44, characterized in that The X-ray diffraction pattern also includes 2θ-reflections at 6.2 degrees 2θ, 7.8 degrees 2θ, and 11.5 degrees 2θ plus or minus 0.2 degrees 2θ.

46. ​​A solid form according to any one of claims 43 to 45, characterised in that The X-ray diffraction pattern also includes 2θ-reflections at 10.5 degrees 2θ, 13.4 degrees 2θ, and 18.5 degrees 2θ plus or minus 0.2 degrees 2θ.

47. A solid form according to any one of claims 43 to 46 having an X-ray diffraction pattern substantially as shown in Figure 92.

48. A solid form of Formula I R-mandelate salt Form B, wherein Formula I has the structure: (I)。 49. The solid form of claim 48, characterized in that The X-ray diffraction pattern has 2θ-reflections at 6.2 degrees 2θ, 8.3 degrees 2θ, and 22.4 degrees 2θ plus or minus 0.2 degrees 2θ.

50. The solid form according to claim 48 or 49, characterized in that The X-ray diffraction pattern also includes 2θ-reflections at 15.9 degrees 2θ, 16.3 degrees 2θ, and 17.0 degrees 2θ plus or minus 0.2 degrees 2θ.

51. The solid form according to any one of claims 48 to 50, characterized in that The X-ray diffraction pattern also includes 2θ-reflections at 10.0 degrees 2θ, 10.8 degrees 2θ, and 11.6 degrees 2θ plus or minus 0.2 degrees 2θ.

52. A solid form according to any one of claims 48 to 51 having an X-ray diffraction pattern substantially as shown in Figure 77.

53. The solid form of any one of claims 48 to 52, having a differential scanning calorimetry thermogram comprising a first endotherm with an onset temperature of about 50°C and a second endotherm with an onset temperature of about 150°C.

54. A solid form according to any one of claims 48 to 53 having a differential scanning calorimetry thermogram substantially as shown in Figure 78.

55. A solid form according to any one of claims 48 to 54 having a thermogravimetric analysis substantially as shown in Figure 79.

56. A pharmaceutical composition comprising a therapeutically effective amount of a solid form according to any one of claims 1 to 55 and a pharmaceutically acceptable carrier.

57. The pharmaceutical composition of claim 56, further comprising one to three additional therapeutic agents.

58. The pharmaceutical composition of claim 57, wherein at least one of the additional therapeutic agents is active against an inflammatory disease.

59. A pharmaceutical composition according to any one of claims 56 to 58, wherein the pharmaceutical composition is in unit dosage form.

60. The pharmaceutical composition of claim 59, wherein the unit dosage form is a tablet.

61. Use of a solid form or pharmaceutical composition according to any one of claims 1 to 60 for the treatment of liver disease.

62. A method of treating or preventing a disease or condition in a patient in need thereof, comprising administering a therapeutically effective amount of a compound useful for modulating Cot, wherein the disease or condition is cancer, diabetes, an inflammatory disease, or liver disease, and wherein the compound useful for modulating Cot is in a solid form according to any one of claims 1 to 55.

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