Solid forms of compounds for modulating Cot

Abstract

Disclosed herein is a solid form of a compound useful for regulating Cot.Disclosure also relates to pharmaceutical compositions containing one or more of the solid forms disclosed herein, as well as the method of using the solid forms in the treatment of conditions mediated by Cot.Disclosure also relates to the method of obtaining such solid forms.Cot is known to be upstream in the MEK-ERK pathway, and is essential for the LPS-induced production of tumor necrosis factor-α (TNF-α).

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 341,289, filed May 12, 2022, which is incorporated herein in its entirety for all purposes.

[0002] FIELD OF THEINVENTION The present disclosure relates to solid forms of compounds useful for modulating Cot (cancer Osaka thyroid), as well as pharmaceutical formulations and therapeutic uses thereof. [Background technology]

[0003] The Cot (Osaka-type thyroid cancer) protein is a serine / threonine kinase that is 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 tumorigenic transforming activity in cells and has been shown to regulate tumorigenic and inflammatory pathways.

[0004] Cot is known to be upstream in the MEK-ERK pathway and is essential for the LPS-induced production of tumor necrosis factor-α (TNF-α). Cot has already been shown to be involved in both the production and signaling of TNFα. TNFα is a pro-inflammatory cytokine and plays an important role in inflammatory diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), inflammatory bowel disease (IBD), diabetes, sepsis, psoriasis, dysregulation of TNFα expression, and transplant rejection.

[0005] Compounds that bind to the Osaka-type thyroid cancer (Cot) protein can act as regulators of Cot. Cot regulators are useful for the treatment and / or prevention of diseases and conditions through the binding of Cot. One compound useful for modulating Cot is a compound of formula I.

Chemical formula

[0006] Although numerous compounds are known to be useful for modulating Cot, what is desired in the art is a physically stable form of a compound of formula I or a pharmaceutically acceptable salt thereof that has desired properties such as good physical and chemical stability, good water solubility, and good bioavailability. For example, pharmaceutical compositions are desired that address issues of stability, variable pharmacodynamic responses, drug-drug interactions, pH effects, food effects, and / or oral bioavailability.

[0007] Therefore, there is a need for a stable form of the compound of formula I that has suitable chemical and physical stability for formulation, therapeutic use, manufacture, and storage.

[0008] A solid form may have properties such as bioavailability, stability, purity, and / or manufacturability in certain conditions that may be suitable for medical or pharmaceutical use. Summary of the Invention [Means for solving the problem]

[0009] In some embodiments, the present disclosure provides a solid form of formula I: [ka] and pharma- ceutically acceptable salts, solvates, and hydrates thereof.

[0010] These forms are useful for treating human patients suffering from inflammatory diseases or conditions, such as, for example, rheumatoid arthritis (RA), lupus, osteoarthritis (OA), or inflammatory bowel disease (IBD), 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 kidney disease (DKD), or chronic kidney disease (CKD). The solid forms of the present disclosure may be useful for preparing medicaments for treating inflammatory diseases. The solid forms of the present disclosure may be used to regulate Cot.

[0011] In some embodiments, the present disclosure is directed to Formula I that is amorphous.

[0012] In some embodiments, the present disclosure is directed to Formula I Form I.

[0013] In some embodiments, the present disclosure is directed to Formula I Form II.

[0014] In some embodiments, the present disclosure is directed to Formula I Form III.

[0015] In some embodiments, the present disclosure is directed to Formula I Form IV.

[0016] In some embodiments, the present disclosure is directed to Formula I Form V.

[0017] In some embodiments, the present disclosure is directed to Formula I Form VI.

[0018] In some embodiments, the present disclosure is directed to Formula I Form VII.

[0019] In some embodiments, the present disclosure is directed to Formula I Form VIII.

[0020] In some embodiments, the present disclosure is directed to Formula I Form IX.

[0021] In some embodiments, the present disclosure is directed to Formula I Form X.

[0022] In some embodiments, the present disclosure is directed to Formula I form XI.

[0023] In some embodiments, the present disclosure is directed to Formula I Form XII.

[0024] In some embodiments, the present disclosure is directed to Formula I Form XIII.

[0025] In some embodiments, the present disclosure is directed to Formula I Form XIV.

[0026] In some embodiments, the present disclosure is directed to Formula I Form XV.

[0027] In some embodiments, the present disclosure is directed to Formula I 2-(4-hydroxybenzoyl)benzoate.

[0028] In some embodiments, the present disclosure is directed to a vanillic acid salt of formula I.

[0029] In some embodiments, the present disclosure is directed to a hippurate salt of formula I.

[0030] In some embodiments, the present disclosure is directed to Formula I maleate salts.

[0031] In some embodiments, the present disclosure is directed to a glyoxylate salt of formula I.

[0032] In some embodiments, the present disclosure is directed to L-pyroglutamate salts of formula I.

[0033] In some embodiments, the present disclosure is directed to Formula I 2-naphthalenesulfonate salts.

[0034] In some embodiments, the present disclosure is directed to Formula I 1-naphthalenesulfonate salts.

[0035] In some embodiments, the present disclosure is directed to Formula I 1-hydroxy-2-naphthoic acid salts.

[0036] In some embodiments, the disclosure is directed to formula I S-mandelate salts.

[0037] In some embodiments, the present disclosure is directed to formula I gentisate salt.

[0038] In some embodiments, the present disclosure is directed to Formula I citrate salts.

[0039] In some embodiments, the disclosure is directed to formula I R-mandelate salts.

[0040] In some embodiments, the present disclosure is directed to a benzoate salt of Formula I.

[0041] In some embodiments, the present disclosure is directed to Formula I Methylparabenate.

[0042] In some embodiments, the present disclosure is directed to a caffeate salt of formula I.

[0043] In some embodiments, the present disclosure is directed to a glycolic acid salt of formula I.

[0044] In some embodiments, the present disclosure is directed to Formula I α-Ketobutyrate:

[0045] In some embodiments, the present disclosure is directed to a pyruvate salt of formula I.

[0046] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a solid form of formula I. [Brief description of the drawings]

[0047] [Figure 1] 1 shows the XRPD pattern of amorphous Formula I.

[0048] [Diagram 2] 1 shows a DSC thermogram of amorphous Formula I.

[0049] [Diagram 3] 1 shows a TGA thermogram of amorphous Formula I.

[0050] [Figure 4] 1 shows the DVS isotherm of amorphous Formula I.

[0051] [Diagram 5] 1 shows the XRPD pattern of Formula I Form I.

[0052] [Figure 6] 1 shows a DSC thermogram of Formula I Form I.

[0053] [Figure 7] 1 shows the XRPD pattern of Formula I Form II.

[0054] [Figure 8] 1 shows the Whole Pattern Pawley Refinement of Formula I Form II (85% RH).

[0055] [Figure 9] 1 shows the DVS isotherm of Formula I Form II.

[0056] [Figure 10] 4 shows VH-XRD data showing RH vs. scan.

[0057] [Figure 11] 1 shows the XRPD pattern of Formula I Form III (RH 36%, KF 2.3% water).

[0058] [Figure 12] 1 shows VH-XRD data of Form III of Formula I showing XRPD acquired at 40% RH.

[0059] [Figure 13] 1 shows the full pattern Pauly refinement for Formula I Form III at 40% RH.

[0060] [Figure 14] 1 shows the DVS isotherm of Formula I Form III.

[0061] [Figure 15] 1 shows the full pattern Pauli refinement for Formula I Form IV at 0% RH.

[0062] [Figure 16] 1 shows the XRPD pattern of Form IV of Formula I at 5% RH.

[0063] [Figure 17] 1 shows the XRPD pattern of Form V of Formula I.

[0064] [Figure 18] 1 shows a DSC thermogram of Formula I Form V.

[0065] [Figure 19] 1 shows the XRPD pattern of Formula I Form VI.

[0066] [Figure 20] 1 shows a magnified view of the XRPD pattern of Formula I Form VI.

[0067] [Figure 21] 1 shows a DSC thermogram of Formula I Form VI.

[0068] [Figure 22] 1 shows the XRPD pattern of Formula I Form VII.

[0069] [Diagram 23] 1 shows the XRPD pattern of Formula I Form VIII.

[0070] [Figure 24] 1 shows the XRPD pattern of Formula I Form IX.

[0071] [Figure 25] 1 shows the XRPD pattern of Form X of Formula I.

[0072] [Figure 26] 1 shows the XRPD pattern of Formula I Form XI.

[0073] [Figure 27] 1 shows the XRPD pattern of Formula I Form XII.

[0074] [Figure 28]1 shows the XRPD pattern of Formula I Form XIII.

[0075] [Figure 29] 1 shows the XRPD pattern of Formula I Form XIV.

[0076] [Diagram 30] 1 shows the XRPD pattern of Formula I Form XV.

[0077] [Diagram 31] 1 shows the XRPD pattern of 2-(4-hydroxybenzoyl)benzoate Form A of Formula I.

[0078] [Diagram 32] 1 shows the XRPD pattern of 2-(4-hydroxybenzoyl)benzoate Form B of Formula I.

[0079] [Diagram 33] 1 shows a DSC thermogram of Formula I 2-(4-hydroxybenzoyl)benzoate Form B.

[0080] [Diagram 34] 1 shows a TGA thermogram of Formula I 2-(4-hydroxybenzoyl)benzoate Form B.

[0081] [Diagram 35] 1 shows the XRPD pattern of vanillic acid salt Form A of formula I.

[0082] [Diagram 36] 1 shows the XRPD pattern of vanillic acid salt form B of formula I.

[0083] [Figure 37] FIG. 2 shows a DSC thermogram of vanillic acid salt Form B of Formula I.

[0084] [Figure 38] 1 shows a TGA thermogram of Formula I vanillate salt Form B.

[0085] [Figure 39] 1 shows the XRPD pattern of Formula I hippurate salt Form A.

[0086] [Diagram 40] 1 shows the XRPD pattern of Formula I hippurate salt form B.

[0087] [Diagram 41] 1 shows a DSC thermogram of Formula I hippurate salt form B.

[0088] [Diagram 42] 1 shows a TGA thermogram of Formula I hippurate salt Form B.

[0089] [Diagram 43] 1 shows the XRPD pattern of Formula I maleate salt Form A.

[0090] [Diagram 44] 1 shows the XRPD pattern of Formula I maleate salt form B.

[0091] [Diagram 45] 1 shows a DSC thermogram of Formula I maleate salt Form B.

[0092] [Diagram 46] 1 shows a TGA thermogram of Formula I maleate salt Form B.

[0093] [Figure 47] 1 shows the XRPD pattern of glyoxylate salt Form A of Formula I.

[0094] [Figure 48] 1 shows the XRPD pattern of glyoxylate salt Form B of Formula I.

[0095] [Figure 49] 1 shows a DSC thermogram of glyoxylate salt Form B of Formula I.

[0096] [Figure 50] 1 shows a TGA thermogram of glyoxylate salt Form B of Formula I.

[0097] [Figure 51] FIG. 1 shows the XRPD pattern of Formula I L-pyroglutamic acid salt (wet cake).

[0098] [Figure 52] 1 shows a DSC thermogram of Formula I L-pyroglutamic acid salt (air dried).

[0099] [Figure 53] 1 shows the XRPD pattern of Formula I 2-naphthalenesulfonate salt (wet cake).

[0100] [Figure 54] 1 shows the XRPD pattern of Formula I 2-naphthalenesulfonate salt (air dried).

[0101] [Figure 55] 1 shows a DSC thermogram of Formula I 2-naphthalenesulfonate salt (air dried).

[0102] [Figure 56] 1 shows a TGA thermogram of Formula I 2-naphthalenesulfonate salt (air dried).

[0103] [Figure 57] 1 shows the XRPD pattern of Formula I 1-naphthalenesulfonate salt (wet cake).

[0104] [Figure 58] 1 shows the XRPD pattern of Formula I 1-naphthalenesulfonate salt (air dried).

[0105] [Figure 59] 1 shows a DSC thermogram of Formula I 1-naphthalenesulfonate salt (air dried).

[0106] [Figure 60] 1 shows the XRPD pattern of Formula I 1-hydroxy-2-naphthoic acid salt (wet cake).

[0107] [Figure 61] 1 shows the XRPD pattern of Formula I 1-hydroxy-2-naphthoic acid salt (air dried).

[0108] [Figure 62] 1 shows a DSC thermogram of Formula I 1-hydroxy-2-naphthoic acid salt (air dried).

[0109] [Figure 63] 1 shows a TGA thermogram of Formula I 1-hydroxy-2-naphthoic acid salt (air dried).

[0110] [Figure 64] 1 shows the XRPD pattern of Formula I S-mandelate salt form A.

[0111] [Figure 65] 1 shows the XRPD pattern of Formula I S-mandelate salt form B.

[0112] [Figure 66] 1 shows a DSC thermogram of Formula I S-mandelate salt form B.

[0113] [Figure 67] 1 shows a TGA thermogram of Formula I S-mandelate salt form B.

[0114] [Figure 68] 1 shows the XRPD pattern of Formula I gentisate salt (wet cake).

[0115] [Figure 69] 1 shows the XRPD pattern of formula I gentisate salt (air dried).

[0116] [Figure 70]1 shows a DSC thermogram of Formula I gentisate salt (air dried).

[0117] [Figure 71] 1 shows a TGA thermogram of Formula I gentisate salt (air dried).

[0118] [Figure 72] 1 shows the XRPD pattern of Formula I citrate salt (wet cake).

[0119] [Figure 73] 1 shows the XRPD pattern of Formula I citrate salt (air dried).

[0120] [Figure 74] 1 shows a DSC thermogram of Formula I citrate salt (air dried).

[0121] [Figure 75] 1 shows the TGA thermogram of Formula I citrate salt (air dried).

[0122] [Figure 76] 1 shows the XRPD pattern of Formula I R-mandelate salt form A.

[0123] [Figure 77] 1 shows the XRPD pattern of Formula I R-mandelate salt form B.

[0124] [Figure 78] 1 shows a DSC thermogram of Formula I R-mandelate salt form B.

[0125] [Figure 79] 1 shows a TGA thermogram of Formula I R-mandelate salt form B.

[0126] [Figure 80] 1 shows the XRPD pattern of Formula I benzoate Form A.

[0127] [Figure 81]1 shows the XRPD pattern of Formula I benzoate Form B.

[0128] [Figure 82] 1 shows a DSC thermogram of Formula I benzoate Form B.

[0129] [Figure 83] 1 shows a TGA thermogram of Formula I benzoate Form B.

[0130] [Figure 84] 1 shows the XRPD pattern of methyl parabenate form A of formula I.

[0131] [Figure 85] 1 shows the XRPD pattern of methyl parabenate form B of formula I.

[0132] [Figure 86] 1 shows a DSC thermogram of methyl parabenate form B of formula I.

[0133] [Figure 87] 1 shows a TGA thermogram of methyl parabenate form B of formula I.

[0134] [Figure 88] 1 shows the XRPD pattern of Formula I caffeate salt (wet cake).

[0135] [Figure 89] 1 shows the XRPD pattern of Formula I caffeate salt (air dried).

[0136] [Figure 90] 1 shows a DSC thermogram of Formula I caffeate salt (air dried).

[0137] [Figure 91] 1 shows the TGA thermogram of Formula I caffeate salt (air dried).

[0138] [Figure 92]1 shows the XRPD pattern of Formula I glycolate wet cake.

[0139] [Figure 93] 1 shows the XRPD pattern of dried glycolic acid salt of Formula I.

[0140] [Figure 94] 1 shows the XRPD pattern of Formula I α-ketobutyrate salt wet cake.

[0141] [Figure 95] 1 shows the XRPD pattern of dried Formula I α-ketobutyrate salt.

[0142] [Figure 96] 1 shows the XRPD pattern of Formula I pyruvate wet cake.

[0143] [Figure 97] 1 shows the XRPD pattern of dried pyruvate salt of Formula I. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0144] In the following description, certain specific details are described to provide a thorough understanding of various embodiments of the present disclosure. However, those skilled in the art will understand that the present disclosure can be practiced without these details. The following description of some embodiments is made with the understanding that the present disclosure should be considered as an illustration of the claimed subject matter, and is not intended to limit the scope of the appended claims to the specific embodiments illustrated. Headings used throughout this disclosure are provided for convenience only, and should not be construed as limiting the scope of the claims in any way. An embodiment illustrated under any heading may be combined with an embodiment illustrated under any other heading. definition

[0145] Unless otherwise required by context, throughout this specification and claims, the word "comprise" and variations thereof, such as "comprises" or "comprising", are to be interpreted in an open and inclusive sense, i.e., "including but not limited to."

[0146] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment of the present disclosure. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0147] Embodiments referring to "compounds" throughout this specification include crystal, salts, co-crystals, hydrates, solvates, and / or amorphous forms of the formulas and / or compounds disclosed herein. Thus, the appearance or phrase "compound of formula I" includes amorphous formula I, formula I Form I, formula I Form II, formula I Form III, formula I Form IV, formula I Form V, formula I Form VI, formula I Form VII, formula I Form VIII, formula I Form IX, formula I Form X, formula I Form XI, formula I Form XII, formula I Form XIII, formula I Form XIV, formula I Form XV, formula I 2-(4-hydroxybenzoyl)benzoate, formula I vanillate, formula I hippurate, formula I maleate, formula I glyoxylate, formula I L-pyroglutamate, formula I 2-naphthalenesulfonate, formula I 1-naphthalenesulfonate, formula I 1-hydroxy-2-naphthoate, formula I S-mandelate, formula I gentisate, formula I citrate, formula I It may include R-mandelate, benzoate of formula I, methyl parabenate of formula I, caffeate of formula I, glycolate of formula I, α-ketobutyrate of formula I, and / or pyruvate of formula I.

[0148] The disclosure disclosed herein is also meant to encompass all pharma- ceutically acceptable compounds of formula I that are isotopically labeled by replacing one or more atoms with atoms 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, e.g., 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 These radiolabeled compounds can be useful, for example, to determine or measure the effectiveness of a compound by characterizing the site or mode of action, or binding affinity to a pharmacologically important site of action. Certain isotopically labeled compounds of formula I, for example those incorporating a radioisotope, are useful in drug research and / or substrate tissue distribution studies. The radioisotope tritium, i.e. 3 H, and carbon-14, i.e. 14 C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[0149] Deuterium, i.e. 2 Substitution with heavier isotopes, such as H, may confer certain therapeutic advantages due to greater metabolic stability. For example, the in vivo half-life may be increased or the required dosage may be reduced. Thus, in some situations, heavier isotopes may be preferred.

[0150] 11 C. 18 F, 15 O, and 13Substitution with positron emitting isotopes, such as N, can be useful in Positron Emission Topography (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 processes analogous to those described in the Examples below, using the appropriate isotopically labeled reagents in place of conventionally used non-labeled reagents.

[0151] "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.

[0152] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes cases where that event or circumstance occurs as well as cases where that 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 both substituted and unsubstituted aryl groups.

[0153] A "pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, filler, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, and / or emulsifying agent, or a combination of one or more of the above, that is recognized by the United States Food and Drug Administration as acceptable for use in humans or veterinary medicine.

[0154] "Pharmaceutical composition" refers to a formulation of a compound of the present disclosure (e.g., a compound of Formula I) with a vehicle generally accepted in the art for delivering a biologically active compound to a mammal, e.g., a human. Such vehicles include all pharma- ceutically acceptable excipients therefor.

[0155] An "effective amount" or "therapeutically effective amount" refers to an amount of a compound according to the present disclosure that is sufficient to provide treatment of a disease state, condition, or disorder for which the compound is useful when administered to a patient in need thereof. Such an amount will be sufficient to elicit a biological or medical response in a tissue system or patient that is desired by a 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 used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of treatment, the type and severity of the disease state or disorder being treated, drugs used in combination with or concurrently with the compound of the present disclosure, and the patient's age, weight, general health, sex, and diet. Such a therapeutically effective amount can usually be determined by one skilled in the art having regard to his or her knowledge, the state of the art, and this disclosure.

[0156] "Prevention" or "preventing" or "prophylaxis" refers to any treatment of a disease or condition that does not cause the clinical symptoms of the disease or condition to develop. In some embodiments, the compounds may be administered to subjects (including humans) at risk for or who have a family history of the disease or condition.

[0157] "Treating" a disease and "treatment" of a disease include: (1) preventing or reducing the risk of developing a disease, i.e., preventing the development of clinical symptoms of a disease in a subject who may be exposed to or susceptible to a disease but who has not yet experienced or exhibited symptoms of the disease; (2) inhibiting the disease, i.e., preventing or reducing the onset of the disease or its clinical symptoms; and (3) Relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

[0158] The term "subject" or "patient" refers to an animal, such as a mammal (including a human), that has been or is the object of treatment, observation, or experiment. The methods described herein may be useful in 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, a pet (e.g., dog and cat), a livestock animal (e.g., cow, horse, sheep, goat, and pig), and / or a laboratory animal (e.g., mouse, rat, hamster, guinea pig, pig, rabbit, dog, and monkey). In some embodiments, the subject (or patient) is a human. A "human (or patient) in need thereof" refers to a human who may have or is suspected of having a disease or condition that would benefit from a particular treatment, for example, a human who is being treated with a compound disclosed herein in accordance with the present application.

[0159] Reference herein to "about" a value or parameter includes (and describes) embodiments directed to that value or parameter per se. For example, a reference to "about X" includes a reference to "X." Also, the singular forms "a" and "the" include plural references unless the context clearly dictates otherwise. 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 of skill in the art.

[0160] "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other substances that are useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0161] A "unit dosage form" is a physically discrete unit suitable as a unitary dosage 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.

[0162] The term "substantially as shown in," 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 spectra that are not necessarily identical to those shown herein, but that fall within the limits of experimental error or deviation as would be considered by one of ordinary skill in the art.

[0163] In some embodiments, the term "substantially pure" or "substantially free" with respect to a particular crystalline form of a compound means that a composition comprising a crystalline form contains less than 99% by weight, less than 95% by weight, less than 90% by weight, less than 85% by weight, less than 80% by weight, less than 75% by weight, less than 70% by weight, less than 65% by weight, less than 60% by weight, less than 55% by weight, less than 50% by weight, less than 40% by weight, less than 30% by weight, less than 20% by weight, less than 15% by weight, less than 10% by weight, less than 5% by weight, or less than 1% by weight of other materials, including other crystalline forms and / or impurities. In certain embodiments, "substantially pure" or "substantially free" refers to a material that is free of other materials, including other crystalline forms and / or impurities. Impurities may include, for example, by-products or residual reagents from chemical reactions, contaminants, decomposition products, other crystalline forms, water, and solvents.

[0164] Furthermore, the compounds of the present disclosure may exist in the form of solvates, such as solvates that include as pharma- ceutically acceptable solvates such as water of solvation or alcohol, especially ethanol. A "solvate" is formed by the interaction of a solvent with a compound. When the solvent is water, the "solvate" is a "hydrate". A "solvate" may also be formed through interaction with the surrounding environment and the starting material. Solvents are commonly known to those skilled in the art and may include, for example, methanol, ethanol, ethanol / water, acetone, tetrahydrofuran, dichloromethane, methyl t-butyl ether, 2-propanol, 1-propanol, and cyclopentyl methyl ether.

[0165] In certain embodiments, the optical isomers, racemates, or other mixtures thereof or mixtures thereof of the compounds described herein or their pharma- ceutically acceptable salts are provided. In some embodiments, isomers can be separated by methods well known in the art, for example, by liquid chromatography. In these situations, single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution. Resolution can be achieved by conventional methods, such as, for example, crystallization in the presence of a resolving agent, or chromatography, for example, using a chiral high-pressure liquid chromatography (HPLC) column.

[0166] "Stereoisomers" refer to compounds that are composed of the same atoms bonded by the same bonds, but have different three-dimensional structures that are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof, and includes "enantiomers" which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other. "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but are not mirror images of each other.

[0167] The compounds disclosed herein and their pharma- ceutically acceptable salts may contain asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined in terms of 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, e.g., chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemates (or racemates of salts or derivatives) using, e.g., 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, these compounds are intended to include both E and Z geometric isomers.

[0168] Compositions provided herein that contain the compounds described herein, or pharma- ceutically acceptable salts, isomers, or mixtures thereof, may include racemic mixtures, or mixtures containing an enantiomeric excess of one enantiomer or a single diastereomer, or diastereomeric mixtures. All such isomeric forms of these compounds are expressly included herein as if each and every isomeric form were specifically and individually listed. Solid Forms of Formula I

[0169] Solid forms of formula I, including crystalline forms and substantially pure forms, may provide bioavailability and stability advantages suitable for use as an active ingredient in a pharmaceutical composition. The development of a solid form suitable for use in a pharmaceutical composition requires consideration of stability and bioavailability in various environments. For example, for a pharmaceutical drug product or active ingredient, it may be desirable to exhibit stability at a pH of less than 5. For example, formula I forms II, III and IV exhibit advantageous physical properties, such as good physical and chemical stability at pH 5 or less, good water solubility, good pharmacokinetic properties and / or good bioavailability. In addition, conversion between solid forms under various conditions should be considered. For example, humidity shifts 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. Under different humidity, conversion between forms II, III and IV may occur. Desirably, formula I exhibits the desired stability under different humidity conditions. Variations in the crystal structure of a pharmaceutical drug substance or active ingredient may, in some cases, affect the dissolution rate, bioavailability, manufacturability (e.g., ease of handling, ability to consistently prepare doses of known strength), and stability (e.g., thermal stability, shelf life, etc.) of the pharmaceutical drug product or active ingredient. Such variations may affect the preparation or formulation of pharmaceutical compositions in different dosage or delivery forms, such as solutions or solid oral dosage forms, including tablets and capsules. Compared to other forms, such as non-crystalline or amorphous forms, crystalline forms may provide desired or suitable hygroscopicity, particle size control, dissolution rate, solubility, purity, physical and chemical stability, manufacturability, yield, and / or process control. Thus, solid forms of the compound of formula I may provide advantages such as improving the manufacturing process of the compound, the stability or storage of the drug product form of the compound, the stability or storage of the drug substance of the compound, and / or the bioavailability and / or stability of the compound as an active agent.

[0170] It has been found that the use of certain solvents and / or processes produces different solid forms of the compound of formula I described herein, which may exhibit one or more of the preferred characteristics described above. The processes for the preparation of the solid forms described herein and the characterization of these solid forms are described in detail below.

[0171] In certain embodiments, solid forms such as crystalline forms of Formula I are disclosed. In some embodiments, amorphous solid forms of Formula I are disclosed. In some embodiments, solid forms of Formula I Form I are disclosed. In some embodiments, solid forms of Formula I Form II are disclosed. In some embodiments, solid forms of Formula I Form III are disclosed. In some embodiments, solid forms of Formula I Form IV are disclosed. In some embodiments, solid forms of Formula I Form V are disclosed. In some embodiments, solid forms of Formula I Form VI are disclosed. In some embodiments, solid forms of Formula I Form VII are disclosed. In some embodiments, solid forms of Formula I Form VIII are disclosed. In some embodiments, solid forms of Formula I Form IX are disclosed. In some embodiments, solid forms of Formula I Form X are disclosed. In some embodiments, solid forms of Formula I Form XI are disclosed. In some embodiments, solid forms of Formula I Form XII are disclosed. In some embodiments, solid forms of Formula I Form XIII are disclosed. In some embodiments, solid forms of Formula I Form XIV are disclosed. In some embodiments, a solid form of Formula I Form XV is disclosed. In some embodiments, a solid form of Formula I 2-(4-hydroxybenzoyl)benzoic acid Form A is disclosed. In some embodiments, a solid form of Formula I 2-(4-hydroxybenzoyl)benzoic acid Form B is disclosed. In some embodiments, a solid form of Formula I vanillate Form A is disclosed. In some embodiments, a solid form of Formula I vanillate Form B is disclosed. In some embodiments, a solid form of Formula I hippurate Form A is disclosed. In some embodiments, a solid form of Formula I hippurate Form B is disclosed. In some embodiments, a solid form of Formula I maleate Form A is disclosed. In some embodiments, a solid form of Formula I maleate Form B is disclosed. In some embodiments, a solid form of Formula I glyoxylate Form A is disclosed. In some embodiments, a solid form of Formula I glyoxylate Form B is disclosed. In some embodiments, a solid form of Formula I L-pyroglutamate is disclosed. In some embodiments, a solid form of Formula I 2-naphthalenesulfonate salt is disclosed.In some embodiments, a solid form of Formula I 1-naphthalenesulfonate is disclosed. In some embodiments, a solid form of Formula I 1-hydroxy-2-naphthoate is disclosed. In some embodiments, a solid form of Formula I S-mandelate Form A is disclosed. In some embodiments, a solid form of Formula I S-mandelate Form B is disclosed. In some embodiments, a solid form of Formula I gentisate is disclosed. In some embodiments, a solid form of Formula I citrate is disclosed. In some embodiments, a solid form of Formula I R-mandelate Form A is disclosed. In some embodiments, a solid form of Formula I R-mandelate Form B is disclosed. In some embodiments, a solid form of Formula I benzoate Form A is disclosed. In some embodiments, a solid form of Formula I benzoate Form B is disclosed. In some embodiments, a solid form of Formula I methyl parabenate Form A is disclosed. In some embodiments, a solid form of Formula I methyl parabenate Form B is disclosed. In some embodiments, a solid form of Formula I caffeate is disclosed. In some embodiments, a solid form of Formula I glycolate is disclosed. In some embodiments, a solid form of Formula I α-ketobutyrate is disclosed. In some embodiments, a solid form of Formula I pyruvate is disclosed.

[0172] In some embodiments, there is provided a crystalline salt and / or co-crystal comprising Formula I. In some embodiments, the crystalline salt and / or co-crystal comprising Formula I is derived from hydroxybenzoylbenzoic acid, vanillic acid, gentisic acid, hippuric acid, maleic acid, glyoxylic acid, 2-naphthalenesulfonic acid, 1-naphthalenesulfonic acid, 1-hydroxy-2-naphthoic acid, S-mandelic acid, citric acid, R-mandelic acid, benzoic acid, methylparaben, caffeic acid, glycolic acid, α-ketobutyrate, and pyruvic acid. Amorphous Formula I

[0173] In some embodiments, provided herein is an amorphous solid compound of formula I (amorphous formula I). ​​In further embodiments, amorphous formula I exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 1. Amorphous formula I may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 2. Amorphous formula I may exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 3. Amorphous formula I may exhibit a dynamic vapor sorption (DVS) isotherm substantially as shown in Figure 4.

[0174] In some embodiments of amorphous Formula I, at least one, at least two, at least three, or all of the following (a)-(d) apply: (a) amorphous Formula I has an XRPD pattern substantially as shown in FIG. 1; (b) amorphous Formula I has a DSC thermogram substantially as shown in FIG. 2; (c) amorphous Formula I has a TGA thermogram substantially as shown in FIG. 3; and (d) amorphous Formula I has a DVS isotherm substantially as shown in FIG. 4. Formula I Form I

[0175] In some embodiments, provided herein is a solid form of Formula I Form I. In further embodiments, Formula I Form I exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 5. Formula I Form I may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 6.

[0176] In some embodiments, Formula I Form I has one or both of the following properties: (a) An XRPD pattern substantially as shown in FIG. 5; (b) DSC thermogram substantially as shown in FIG.

[0177] In some embodiments, Formula I Form 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 degrees 2θ-reflection whose intensities are maximal substantially as in the XRPD pattern as shown in FIG.

[0178] In certain embodiments, Formula I Form I has an XRPD pattern that includes 6.2, 8.3, and 11.6 degrees 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form I has an XRPD pattern that includes one, two, or three of 6.2, 8.3, and 11.6 degrees 2θ reflection angles (±0.2 degrees 2θ), and 10.9, 14.5, and 22.4 degrees 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form I has an XRPD pattern that includes one, two, or three of 6.2, 8.3, and 11.6 degrees 2θ reflection angles (±0.2 degrees 2θ), and 17.4, 18.7, and 22.6 degrees 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form I has an XRPD pattern comprising the following reflection angles 2θ of 6.2, 8.3, 11.6, 10.9, 14.5, 22.4, 17.4, 18.7, and 22.6 degrees 2θ (±0.2 degrees 2θ).

[0179] In some embodiments, Formula I Form I has a differential scanning calorimetry thermogram with an endotherm with an onset at about 25° C. In some embodiments, Formula I Form I has a differential scanning calorimetry thermogram with an exotherm with an onset at about 175° C. Formula I Form II

[0180] In some embodiments, provided herein is a solid form of Formula I Form II, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 7. Formula I Form II may exhibit a dynamic vapor sorption (DVS) isotherm substantially as shown in Figure 9.

[0181] In some embodiments of Formula I Form II, one or both of the following apply: (a) Formula I Form II has an XRPD pattern substantially as shown in FIG. 7; (b) Formula I Form II has a DVS isotherm substantially as shown in FIG. 9.

[0182] In some embodiments, Formula I Form II 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 of the 2θ reflection angles having maximal intensities substantially as shown in the XRPD pattern in FIG.

[0183] In certain embodiments, Formula I Form II has an XRPD pattern that includes 7.4, 9.4, and 10.6 degrees 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form II has an XRPD pattern that includes one, two, or three of 7.4, 9.4, and 10.6 degrees 2θ reflection angles (±0.2 degrees 2θ), and 8.8, 12.3, and 26.1 degrees 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form II has an XRPD pattern that includes one, two, or three of 7.4, 9.4, and 10.6 degrees 2θ reflection angles (±0.2 degrees 2θ), and 14.7, 18.1, and 22.4 degrees 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form I has an XRPD pattern comprising the following reflection angles 2θ of 7.4, 9.4, 10.6, 8.8, 12.3, 26.1, 14.7, 18.1, and 22.4 degrees 2θ (±0.2 degrees 2θ). Formula I Form III

[0184] In some embodiments, provided herein is Formula I Form III, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 11. Formula I Form III may exhibit a VH-XRD pattern substantially as shown in Figure 12. Formula I Form III may exhibit a Pauly refinement pattern substantially as shown in Figure 13. Formula I Form III may exhibit a dynamic vapor sorption (DVS) isotherm substantially as shown in Figure 14.

[0185] In some embodiments, Formula I Form III has at least one, at least two, at least three, or at least four of the following characteristics: (a) An XRPD pattern substantially as shown in FIG. 11; (b) VH-XRD pattern substantially as shown in FIG. 12; (c) Pauly refinement pattern XRPD substantially as shown in FIG. 13; (d) DVS isotherm substantially as shown in FIG.

[0186] In some embodiments, Formula I Form III 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 of the 2θ reflection angles with maximum intensities substantially as shown in the XRPD pattern in FIG.

[0187] In certain embodiments, Formula I Form III has an XRPD pattern that includes 7.8, 9.8, and 10.7 degrees 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form III has an XRPD pattern that includes one, two, or three of 7.8, 9.8, and 10.7 degrees 2θ reflection angles (±0.2 degrees 2θ), and 8.9, 12.5, and 20.1 degrees 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form III has an XRPD pattern that includes one, two, or three of 7.8, 9.8, and 10.7 degrees 2θ reflection angles (±0.2 degrees 2θ), and 15.5, 18.2, and 22.9 degrees 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form III has an XRPD pattern comprising the following reflection angles 2θ of 7.8, 9.8, 10.7, 8.9, 12.5, 20.1, 15.5, 18.2, and 22.9 degrees 2θ (±0.2 degrees 2θ). Formula I Form IV

[0188] In some embodiments, provided herein is Formula I Form IV, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 16. Formula I Form IV may exhibit a Pauly refined XRPD pattern substantially as shown in Figure 15.

[0189] In some embodiments, Formula I Form IV 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 of the 2θ reflection angles with maximum intensities substantially as shown in the XRPD pattern in FIG.

[0190] In certain embodiments, Formula I Form IV has an XRPD pattern that includes 8.0, 18.1, and 20.0 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form IV has an XRPD pattern that includes one, two, or three of 8.0, 18.1, and 20.0 degree 2θ reflection angles (±0.2 degrees 2θ), and 9.0, 9.9, and 10.8 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form IV has an XRPD pattern that includes one, two, or three of 8.0, 18.1, and 20.0 degree 2θ reflection angles (±0.2 degrees 2θ), and 15.6, 22.8, and 24.9 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form IV has an XRPD pattern comprising the following reflection angles 2θ of 8.0, 18.1, 20.0, 9.0, 9.9, 10.8, 15.6, 22.8, and 24.9 degrees 2θ (±0.2 degrees 2θ). Formula I Form V

[0191] In some embodiments, provided herein is Formula I Form V, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 17. Formula I Form V may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 18.

[0192] In some embodiments of Form V of Formula I, one or both of the following apply: (a) Form V of Formula I has an XRPD pattern substantially as shown in FIG. 17; (b) Form V of Formula I has a DSC thermogram substantially as shown in FIG. 18.

[0193] 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in FIG.

[0194] In certain embodiments, Formula I Form V has an XRPD pattern that includes 6.2, 22.6, and 20.4 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form V has an XRPD pattern that includes one, two, or three of 6.2, 22.6, and 20.4 degree 2θ reflection angles (±0.2 degrees 2θ), and 16.3, 16.5, and 17.4 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form V has an XRPD pattern that includes one, two, or three of 6.2, 22.6, and 20.4 degree 2θ reflection angles (±0.2 degrees 2θ), and 22.4, 23.5, and 25.1 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Form V of Formula I has an XRPD pattern comprising the following reflection angles 2θ of 6.2, 22.6, 20.4, 16.3, 16.5, 17.4, 22.4, 23.5, and 25.1 degrees 2θ (±0.2 degrees 2θ). Formula I Form VI

[0195] In some embodiments, provided herein is Formula I Form VI, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 19. Formula I Form VI may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 21.

[0196] In some embodiments of Formula I Form VI, one or both of the following 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.

[0197] In some embodiments, Formula I Form VI 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in FIG.

[0198] In certain embodiments, Formula I Form VI has an XRPD pattern that includes 7.2, 14.4, and 21.7 degrees 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form VI has an XRPD pattern that includes one, two, or three of 7.2, 14.4, and 21.7 degrees 2θ reflection angles (±0.2 degrees 2θ), and 29.1, 25.3, and 25.0 degrees 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form VI has an XRPD pattern that includes one, two, or three of 7.2, 14.4, and 21.7 degrees 2θ reflection angles (±0.2 degrees 2θ), and 16.6, 26.7, and 30.2 degrees 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form VI has an XRPD pattern comprising the following reflection angles 2θ of 7.2, 14.4, 21.7, 29.1, 25.3, 25.0, 16.6, 26.7, and 30.2 degrees 2θ (±0.2 degrees 2θ). Formula I Form VII

[0199] In some embodiments, provided herein is Formula I Form VII, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG.

[0200] In some embodiments, Formula I Form VII 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in FIG.

[0201] In certain embodiments, Formula I Form VII has an XRPD pattern that includes 6.2, 8.4, and 22.6 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form VII has an XRPD pattern that includes one, two, or three of 6.2, 8.4, and 22.6 degree 2θ reflection angles (±0.2 degrees 2θ), and 10.3, 10.9, and 11.7 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form VII has an XRPD pattern that includes one, two, or three of 6.2, 8.4, and 22.6 degree 2θ reflection angles (±0.2 degrees 2θ), and 16.1, 16.4, and 17.3 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form VII has an XRPD pattern comprising the following reflection angles of 6.2, 8.4, 22.6, 10.3, 10.9, 11.7, 16.1, 16.4, and 17.3 degrees 2θ (±0.2 degrees 2θ). Formula I Form VIII

[0202] In some embodiments, provided herein is Formula I Form VIII, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG.

[0203] 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 of the 2θ reflection angles with maximum intensities substantially as shown in the XRPD pattern in FIG.

[0204] In certain embodiments, Formula I Form VIII has an XRPD pattern that includes 6.2, 8.3, and 22.3 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form VIII has an XRPD pattern that includes one, two, or three of 6.2, 8.3, and 22.3 degree 2θ reflection angles (±0.2 degrees 2θ), and 11.6, 10.8, and 14.5 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form VIII has an XRPD pattern that includes one, two, or three of 6.2, 8.3, and 22.3 degree 2θ reflection angles (±0.2 degrees 2θ), and 16.5, 18.7, and 20.5 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form VIII has an XRPD pattern comprising the following reflection angles 2θ of 6.2, 8.3, 22.3, 11.6, 10.8, 14.5, 16.5, 18.7, and 20.5 degrees 2θ (±0.2 degrees 2θ). Formula I Form IX

[0205] In some embodiments, provided herein is Formula I Form IX, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG.

[0206] In some embodiments, Formula I Form IX 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in FIG.

[0207] In certain embodiments, Formula I Form IX has an XRPD pattern that includes 7.2, 5.8, and 5.7 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form IX has an XRPD pattern that includes one, two, or three of 7.2, 5.8, and 5.7 degree 2θ reflection angles (±0.2 degrees 2θ), and 10.7, 15.3, and 17.1 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form IX has an XRPD pattern that includes one, two, or three of 7.2, 5.8, and 5.7 degree 2θ reflection angles (±0.2 degrees 2θ), and 7.4, 10.0, and 8.9 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form IX has an XRPD pattern comprising the following reflection angles 2θ of 7.2, 5.8, 5.7, 10.7, 15.3, 17.1, 7.4, 10.0, and 8.9 degrees 2θ (±0.2 degrees 2θ). Formula I Form X

[0208] In some embodiments, provided herein is Formula I Form X, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG.

[0209] 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in FIG.

[0210] In certain embodiments, Formula I Form X has an XRPD pattern that includes 16.3, 7.2, and 5.7 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form X has an XRPD pattern that includes one, two, or three of 16.3, 7.2, and 5.7 degree 2θ reflection angles (±0.2 degrees 2θ), and 10.8, 13.7, and 18.3 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form X has an XRPD pattern that includes one, two, or three of 16.3, 7.2, and 5.7 degree 2θ reflection angles (±0.2 degrees 2θ), and 19.1, 22.4, and 26.5 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Form X of Formula I has an XRPD pattern comprising the following reflection angles 2θ of 16.3, 7.2, 5.7, 10.8, 13.7, 18.3, 19.1, 22.4, and 26.5 degrees 2θ (±0.2 degrees 2θ). Formula I Form XI

[0211] In some embodiments, provided herein is Formula I Form XI, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG.

[0212] In some embodiments, Formula I Form XI 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in FIG.

[0213] In certain embodiments, Formula I Form XI has an XRPD pattern that includes 7.8, 5.5, and 6.8 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form XI has an XRPD pattern that includes one, two, or three of 7.8, 5.5, and 6.8 degree 2θ reflection angles (±0.2 degrees 2θ), and 8.6, 9.5, and 10.3 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form XI has an XRPD pattern that includes one, two, or three of 7.8, 5.5, and 6.8 degree 2θ reflection angles (±0.2 degrees 2θ), and 15.4, 17.8, and 19.4 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form XI has an XRPD pattern comprising the following reflection angles 2θ of 7.8, 5.5, 6.8, 8.6, 9.5, 10.3, 15.4, 17.8, and 19.4 degrees 2θ (±0.2 degrees 2θ). Formula I Form XII

[0214] In some embodiments, provided herein is Formula I Form XII, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG.

[0215] In some embodiments, Formula I Form XII 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in FIG.

[0216] In certain embodiments, Formula I Form XII has an XRPD pattern that includes 6.2, 5.4, and 11.5 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form XII has an XRPD pattern that includes one, two, or three of 6.2, 5.4, and 11.5 degree 2θ reflection angles (±0.2 degrees 2θ), and 14.5, 16.4, and 22.3 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form XII has an XRPD pattern that includes one, two, or three of 6.2, 5.4, and 11.5 degree 2θ reflection angles (±0.2 degrees 2θ), and 12.5, 9.7, and 19.2 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form XII has an XRPD pattern comprising the following reflection angles 2θ of 6.2, 5.4, 11.5, 14.5, 16.4, 22.3, 12.5, 9.7, and 19.2 degrees 2θ (±0.2 degrees 2θ). Formula I Form XIII

[0217] In some embodiments, provided herein is Formula I Form XIII, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG.

[0218] In some embodiments, Formula I Form XIII 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in FIG.

[0219] In certain embodiments, Formula I Form XIII has an XRPD pattern that includes 5.8, 6.2, and 8.1 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form XIII has an XRPD pattern that includes one, two, or three of 5.8, 6.2, and 8.1 degree 2θ reflection angles (±0.2 degrees 2θ), and 11.6, 16.6, and 20.0 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form XIII has an XRPD pattern that includes one, two, or three of 5.8, 6.2, and 8.1 degree 2θ reflection angles (±0.2 degrees 2θ), and 13.0, 22.0, and 22.8 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form XIII has an XRPD pattern comprising the following reflection angles 2θ of 5.8, 6.2, 8.1, 11.6, 16.6, 20.0, 13.0, 22.0, and 22.8 degrees 2θ (±0.2 degrees 2θ). Formula I Form XIV

[0220] In some embodiments, provided herein is Formula I Form XIV, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG.

[0221] In some embodiments, Formula I Form XIV 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in FIG.

[0222] In certain embodiments, Formula I Form XIV has an XRPD pattern that includes 5.8, 8.2, and 18.5 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form XIV has an XRPD pattern that includes one, two, or three of 5.8, 8.2, and 18.5 degree 2θ reflection angles (±0.2 degrees 2θ), and 11.7, 16.6, and 22.0 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form XIV has an XRPD pattern that includes one, two, or three of 5.8, 8.2, and 18.5 degree 2θ reflection angles (±0.2 degrees 2θ), and 22.8, 10.0, and 10.5 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form XIV has an XRPD pattern comprising the following reflection angles of 5.8, 8.2, 18.5, 11.7, 16.6, 22.0, 22.8, 10.0, and 10.5 degrees 2θ (±0.2 degrees 2θ). Formula I Form XV

[0223] In some embodiments, provided herein is Formula I Form XV, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG.

[0224] 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in FIG.

[0225] In certain embodiments, Formula I Form XV has an XRPD pattern that includes 6.2, 5.4, and 8.3 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form XV has an XRPD pattern that includes one, two, or three of 6.2, 5.4, and 8.3 degree 2θ reflection angles (±0.2 degrees 2θ), and 11.6, 16.4, and 19.3 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form XV has an XRPD pattern that includes one, two, or three of 6.2, 5.4, and 8.3 degree 2θ reflection angles (±0.2 degrees 2θ), and 12.4, 20.3, and 22.4 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I Form XV has an XRPD pattern comprising the following reflection angles 2θ of 6.2, 5.4, 8.3, 11.6, 16.4, 19.3, 12.4, 20.3, and 22.4 degrees 2θ (±0.2 degrees 2θ). Formula I 2-(4-hydroxybenzoyl)benzoate

[0226] In some embodiments, provided herein is 2-(4-hydroxybenzoyl)benzoate Form A of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 31.

[0227] 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in FIG.

[0228] In certain embodiments, Formula I 2-(4-hydroxybenzoyl)benzoate Form A has an XRPD pattern that includes 6.2, 11.0, and 13.7 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I 2-(4-hydroxybenzoyl)benzoate Form A has an XRPD pattern that includes one, two, or three of 6.2, 11.0, and 13.7 degree 2θ reflection angles (±0.2 degrees 2θ) and 15.2, 17.4, and 18.3 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I 2-(4-hydroxybenzoyl)benzoate Form A has an XRPD pattern that includes one, two, or three of 6.2, 11.0, and 13.7 degree 2θ reflection angles (±0.2 degrees 2θ), and 20.8, 7.6, and 8.5 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I 2-(4-hydroxybenzoyl)benzoate Form A has an XRPD pattern that includes 6.2, 11.0, 13.7, 15.2, 17.4, 18.3, 20.8, 7.6, and 8.5 degree 2θ reflection angles (±0.2 degrees 2θ).

[0229] In some embodiments, provided herein is 2-(4-hydroxybenzoyl)benzoate Form B of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 32. 2-(4-hydroxybenzoyl)benzoate Form B of Formula I may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 33. 2-(4-hydroxybenzoyl)benzoate Form B of Formula I may exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 34.

[0230] In some embodiments, Formula I 2-(4-hydroxybenzoyl)benzoate Form B has at least one, at least two, or at least three of the following characteristics: (a) An XRPD pattern substantially as shown in FIG. 32. (b) A DSC thermogram substantially as shown in FIG. 33. (c) TGA thermogram substantially as shown in FIG. Formula I Vanillic Acid Salt

[0231] In some embodiments, provided herein is vanillic acid salt of formula I, Form A, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 35.

[0232] In some embodiments, Formula I vanillate 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in FIG.

[0233] In certain embodiments, vanillic acid salt Form A of Formula I has an XRPD pattern that includes 6.2, 7.3, and 16.4 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, vanillic acid salt Form A of Formula I has an XRPD pattern that includes one, two, or three of 6.2, 7.3, and 16.4 degree 2θ reflection angles (±0.2 degrees 2θ), and 17.5, 24.7, and 30.6 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, vanillic acid salt Form A of Formula I has an XRPD pattern that includes one, two, or three of 6.2, 7.3, and 16.4 degree 2θ reflection angles (±0.2 degrees 2θ), and 12.4, 13.4, and 20.2 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, formula I vanillate Form A has an XRPD pattern comprising the following reflection angles 2θ of 6.2, 7.3, 16.4, 17.5, 24.7, 30.6, 12.4, 13.4, and 20.2 degrees 2θ (±0.2 degrees 2θ).

[0234] In some embodiments, provided herein is vanillic acid salt of Formula I, Form B, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 36. Vanillic acid salt of Formula I, Form B, can exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 37. Vanillic acid salt of Formula I, Form B, can exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 38.

[0235] In some embodiments, vanillate Form B of Formula I has at least one, at least two, or at least three of the following characteristics: (a) an XRPD pattern substantially as shown in FIG. 36; (b) A DSC thermogram substantially as shown in FIG. 37; (c) TGA thermogram substantially as shown in FIG. Formula I Hippurate

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

[0237] In some embodiments, the hippurate 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in FIG.

[0238] In certain embodiments, Formula I hippurate Form A has an XRPD pattern that includes 6.5, 8.2, and 9.3 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I hippurate Form A has an XRPD pattern that includes one, two, or three of 6.5, 8.2, and 9.3 degree 2θ reflection angles (±0.2 degrees 2θ) and 7.0, 13.1, and 21.8 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I hippurate Form A has an XRPD pattern that includes 6.5, 8.2, and 9.3 degree 2θ reflection angles (±0.2 degrees 2θ) and one, two, or three of 14.7, 18.0, and 25.7 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, formula I hippurate Form A has an XRPD pattern comprising the following reflection angles 2θ of 6.5, 8.2, 9.3, 7.0, 13.1, 21.8, 14.7, 18.0, and 25.7 degrees 2θ (±0.2 degrees 2θ).

[0239] In some embodiments, provided herein is a hippuric acid salt of formula I, Form B, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 40. Hippuric acid salt of formula I, Form B, may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 41. Hippuric acid salt of formula I, Form B, may exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 42.

[0240] In some embodiments, Formula I hippurate Form B has at least one, at least two, or at least three of the following characteristics: (a) An XRPD pattern substantially as shown in FIG. (b) A DSC thermogram substantially as shown in FIG. (c) TGA thermogram substantially as shown in FIG. Formula I Maleate Salt

[0241] In some embodiments, provided herein is a maleate salt of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG.

[0242] In some embodiments, Formula I maleate 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 of the 2θ reflection angles having maximal intensities substantially as shown in the XRPD pattern in FIG.

[0243] In certain embodiments, Formula I maleate Form A has an XRPD pattern that includes 5.8, 8.2, and 11.7 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I maleate Form A has an XRPD pattern that includes one, two, or three of 5.8, 8.2, and 11.7 degree 2θ reflection angles (±0.2 degrees 2θ), and 10.0, 10.4, and 14.9 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I maleate Form A has an XRPD pattern that includes one, two, or three of 5.8, 8.2, and 11.7 degree 2θ reflection angles (±0.2 degrees 2θ), and 6.4, 20.0, and 25.7 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I maleate salt Form A has an XRPD pattern comprising the following reflection angles 2θ of 5.8, 8.2, 11.7, 10.0, 10.4, 14.9, 6.4, 20.0, and 25.7 degrees 2θ (±0.2 degrees 2θ).

[0244] In some embodiments, provided herein is maleate salt Form I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 44. Maleate salt Form B of Formula I may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 45. Maleate salt Form B of Formula I may exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 46.

[0245] In some embodiments, Formula I maleate Form B has at least one, at least two, or at least three of the following characteristics: (a) An XRPD pattern substantially as shown in FIG. (b) A DSC thermogram substantially as shown in FIG. (c) TGA thermogram substantially as shown in FIG.

[0246] In some embodiments, Formula I maleate Form B 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 of the 2θ reflection angles having maximal intensities substantially as shown in the XRPD pattern in FIG.

[0247] In certain embodiments, Formula I maleate Form B has an XRPD pattern that includes 6.1, 8.3, and 10.7 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I maleate Form B has an XRPD pattern that includes one, two, or three of 6.1, 8.3, and 10.7 degree 2θ reflection angles (±0.2 degrees 2θ), and 14.4, 16.4, and 20.1 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I maleate Form B has an XRPD pattern that includes one, two, or three of 6.1, 8.3, and 10.7 degree 2θ reflection angles (±0.2 degrees 2θ), and 21.4, 22.7, and 28.4 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I maleate salt Form B has an XRPD pattern comprising the following reflection angles 2θ of 6.1, 8.3, 10.7, 14.4, 16.4, 20.1, 21.4, 22.7, and 28.4 degrees 2θ (±0.2 degrees 2θ). Formula I Glyoxylate

[0248] In some embodiments, provided herein is glyoxylate salt Form A of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 47.

[0249] In some embodiments, the glyoxylate 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in FIG.

[0250] In certain embodiments, glyoxylate salt Form A of Formula I has an XRPD pattern that includes 5.9, 22.5, and 8.1 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, glyoxylate salt Form A of Formula I has an XRPD pattern that includes one, two, or three of 5.9, 22.5, and 8.1 degree 2θ reflection angles (±0.2 degrees 2θ), and 12.4, 16.4, and 19.1 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, glyoxylate salt Form A of Formula I has an XRPD pattern that includes one, two, or three of 5.9, 22.5, and 8.1 degree 2θ reflection angles (±0.2 degrees 2θ), and 15.0, 20.0, and 28.1 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the glyoxylate salt Form A of formula I has an XRPD pattern comprising the following reflection angles 2θ of 5.9, 22.5, 8.1, 12.4, 16.4, 19.1, 15.0, 20.0, and 28.1 degrees 2θ (±0.2 degrees 2θ).

[0251] In some embodiments, provided herein is glyoxylate salt Form B of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 48. Glyoxylate salt Form B of Formula I may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 49. Glyoxylate salt Form B of Formula I may exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 50.

[0252] In some embodiments, the glyoxylate salt Form B of Formula I has at least one, at least two, or at least three of the following characteristics: (a) An XRPD pattern substantially as shown in FIG. (b) A DSC thermogram substantially as shown in FIG. (c) TGA thermogram substantially as shown in FIG.

[0253] In some embodiments, the glyoxylate salt Form B 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in FIG.

[0254] In certain embodiments, glyoxylate salt Form B of Formula I has an XRPD pattern that includes 6.2, 8.3, and 12.6 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, glyoxylate salt Form B of Formula I has an XRPD pattern that includes one, two, or three of 6.2, 8.3, and 12.6 degree 2θ reflection angles (±0.2 degrees 2θ), and 10.8, 16.1, and 16.4 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, glyoxylate salt Form B of Formula I has an XRPD pattern that includes one, two, or three of 6.2, 8.3, and 12.6 degree 2θ reflection angles (±0.2 degrees 2θ), and 18.6, 19.4, and 20.3 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the glyoxylate salt Form B of Formula I has an XRPD pattern comprising the following reflection angles 2θ of 6.2, 8.3, 12.6, 10.8, 16.1, 16.4, 18.6, 19.4, and 20.3 degrees 2θ (±0.2 degrees 2θ). Formula I L-pyroglutamate

[0255] In some embodiments, provided herein is a solid form of formula I L-pyroglutamic acid salt, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG.

[0256] In some embodiments, the L-pyroglutamate 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 of the 2θ reflection angles with maximum intensities substantially as shown in the XRPD pattern in FIG.

[0257] In certain embodiments, the formula I L-pyroglutamate has an XRPD pattern that includes 6.1, 16.5, and 19.8 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the formula I L-pyroglutamate has an XRPD pattern that includes one, two, or three of 6.1, 16.5, and 19.8 degree 2θ reflection angles (±0.2 degrees 2θ), and 11.6, 12.4, and 17.3 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the formula I L-pyroglutamate has an XRPD pattern that includes one, two, or three of 6.1, 16.5, and 19.8 degree 2θ reflection angles (±0.2 degrees 2θ), and 22.8, 23.0, and 28.4 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the Formula I L-pyroglutamate has an XRPD pattern comprising the following reflection angles 2θ of 6.1, 16.5, 19.8, 11.6, 12.4, 17.3, 22.8, 23.0, and 28.4 degrees 2θ (±0.2 degrees 2θ).

[0258] In some embodiments, provided herein is a solid form of Formula I L-pyroglutamic acid salt, wherein the solid form exhibits a differential scanning calorimetry (DSC) thermogram substantially as shown in FIG. 52. Formula I 2-Naphthalenesulfonate

[0259] 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 FIG.

[0260] In some embodiments, the 2-naphthalenesulfonate 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 of the 2θ reflection angles having maximal intensities substantially as shown in the XRPD pattern in FIG.

[0261] In certain embodiments, Formula I 2-naphthalenesulfonate has an XRPD pattern that includes 5.9, 8.1, and 16.3 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I 2-naphthalenesulfonate Form A has an XRPD pattern that includes one, two, or three of 5.9, 8.1, and 16.3 degree 2θ reflection angles (±0.2 degrees 2θ), and 18.6, 19.1, and 20.0 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I 2-naphthalenesulfonate Form A has an XRPD pattern that includes one, two, or three of 5.9, 8.1, and 16.3 degree 2θ reflection angles (±0.2 degrees 2θ), and 10.1, 12.6, and 13.1 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I 2-naphthalenesulfonate Form A has an XRPD pattern including 5.9, 8.1, 16.3, 18.6, 19.1, 20.0, 10.1, 12.6, and 13.1 degree 2θ reflection angles (±0.2 degrees 2θ).

[0262] 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.

[0263] In some embodiments, the 2-naphthalenesulfonate salt of Formula I has at least one, at least two, or at least three of the following characteristics: (a) An XRPD pattern substantially as shown in FIG. (b) A DSC thermogram substantially as shown in FIG. (c) TGA thermogram substantially as shown in FIG. 56.

[0264] In some embodiments, the 2-naphthalenesulfonate 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 of the 2θ reflection angles having maximal intensities substantially as shown in the XRPD pattern in FIG.

[0265] In certain embodiments, the 2-naphthalenesulfonate salt of Formula I has an XRPD pattern that includes 6.2, 8.4, and 16.5 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the 2-naphthalenesulfonate salt of Formula I has an XRPD pattern that includes one, two, or three of 6.2, 8.4, and 16.5 degree 2θ reflection angles (±0.2 degrees 2θ), and 10.8, 11.7, and 19.1 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the 2-naphthalenesulfonate salt of Formula I has an XRPD pattern that includes one, two, or three of 6.2, 8.4, and 16.5 degree 2θ reflection angles (±0.2 degrees 2θ), and 12.6, 14.6, and 22.6 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I 2-naphthalenesulfonate salt has an XRPD pattern comprising reflection angles of 6.2, 8.4, 16.5, 10.8, 11.7, 19.1, 12.6, 14.6, and 22.6 degrees 2θ (±0.2 degrees 2θ). Formula I 1-Naphthalenesulfonate

[0266] In some embodiments, provided herein is a 1-naphthalenesulfonate wetcake of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 58.

[0267] In some embodiments, the Formula I 1-naphthalenesulfonate wet cake 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in FIG.

[0268] In certain embodiments, the Formula I 1-naphthalenesulfonate wet cake has an XRPD pattern that includes 5.9, 8.1, and 16.3 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the Formula I 1-naphthalenesulfonate wet cake has an XRPD pattern that includes one, two, or three of 5.9, 8.1, and 16.3 degree 2θ reflection angles (±0.2 degrees 2θ), and 10.0, 10.5, and 20.0 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the Formula I 1-naphthalenesulfonate wet cake has an XRPD pattern that includes one, two, or three of 5.9, 8.1, and 16.3 degree 2θ reflection angles (±0.2 degrees 2θ), and 18.6, 19.0, and 22.6 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the 1-naphthalenesulfonate wet cake of Formula I has an XRPD pattern comprising the following reflection angles 2θ of 5.9, 8.1, 16.3, 10.0, 10.5, 20.0, 18.6, 19.0, and 22.6 degrees 2θ (±0.2 degrees 2θ).

[0269] In some embodiments, provided herein is a solid form of Formula I 1-naphthalenesulfonate, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 58. The solid form of Formula I 1-naphthalenesulfonate may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 58.

[0270] In some embodiments, the solid form of the 1-naphthalenesulfonate salt of Formula I has one or both of the following properties: (a) An XRPD pattern substantially as shown in FIG. 58. (b) DSC thermogram substantially as shown in FIG. 59.

[0271] In some embodiments, the 1-naphthalenesulfonate 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 of the 2θ reflection angles having maximal intensities substantially as shown in the XRPD pattern in FIG.

[0272] In certain embodiments, the Formula I 1-naphthalenesulfonate salt has an XRPD pattern that includes 6.2, 8.4, and 16.5 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the Formula I 1-naphthalenesulfonate salt has an XRPD pattern that includes one, two, or three of 6.2, 8.4, and 16.5 degree 2θ reflection angles (±0.2 degrees 2θ), and 10.9, 11.7, and 20.5 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the Formula I 1-naphthalenesulfonate salt has an XRPD pattern that includes one, two, or three of 6.2, 8.4, and 16.5 degree 2θ reflection angles (±0.2 degrees 2θ), and 14.6, 15.3, and 17.3 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the 1-naphthalenesulfonate salt of Formula I has an XRPD pattern comprising reflection angles of 6.2, 8.4, 16.5, 10.9, 11.7, 20.5, 14.6, 15.3, and 17.3 degrees 2θ (±0.2 degrees 2θ). Formula I 1-Hydroxy-2-naphthoic acid salt

[0273] In some embodiments, provided herein is a 1-hydroxy-2-naphthoate wetcake of Formula I, wherein the 1-hydroxy-2-naphthoate wetcake of Formula I exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 60.

[0274] In some embodiments, the 1-hydroxy-2-naphthoic 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in FIG.

[0275] In certain embodiments, the Formula I 1-hydroxy-2-naphthoate wet cake has an XRPD pattern that includes 5.3, 5.6, and 7.4 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the Formula I 1-hydroxy-2-naphthoate wet cake has an XRPD pattern that includes one, two, or three of 5.3, 5.6, and 7.4 degree 2θ reflection angles (±0.2 degrees 2θ), and 6.7, 9.3, and 21.0 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the Formula I 1-hydroxy-2-naphthoate wet cake has an XRPD pattern that includes 5.3, 5.6, and 7.4 degree 2θ reflection angles (±0.2 degrees 2θ), and one, two, or three of 17.5, 18.5, and 23.6 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the Formula I 1-hydroxy-2-naphthoic acid salt wetcake has an XRPD pattern comprising the following reflection angles 2θ of 5.3, 5.6, 7.4, 6.7, 9.3, 21.0, 17.5, 18.5, and 23.6 degrees 2θ (±0.2 degrees 2θ).

[0276] In some embodiments, provided herein is a solid form of Formula I 1-hydroxy-2-naphthoic acid salt, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 61. Formula I 1-hydroxy-2-naphthoic acid salt can exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 62. Formula I 1-hydroxy-2-naphthoic acid salt can exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 63.

[0277] In some embodiments, a solid form of the 1-hydroxy-2-naphthoic acid salt of Formula I has at least one, at least two, or at least three of the following characteristics: (a) An XRPD pattern substantially as shown in FIG. (b) A DSC thermogram substantially as shown in FIG. (c) TGA thermogram substantially as shown in FIG.

[0278] In some embodiments, the solid form of 1-hydroxy-2-naphthoic acid of formula I has an XRPD pattern exhibiting at least two or at least three of the 2θ reflection angles with maximum intensities substantially as shown in the XRPD pattern in FIG.

[0279] In certain embodiments, a solid form of the 1-hydroxy-2-naphthoic acid salt of Formula I has an XRPD pattern comprising reflection angles of 6.1, 7.3, and 15.9 degrees 2θ (±0.2 degrees 2θ). Formula I S-Mandelate

[0280] In some embodiments, provided herein is 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.

[0281] In some embodiments, Formula IS-mandelate 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in FIG.

[0282] In certain embodiments, Formula I S-mandelate Form A has an XRPD pattern that includes 5.5, 5.7, and 6.3 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I S-mandelate Form A has an XRPD pattern that includes one, two, or three of 5.5, 5.7, and 6.3 degree 2θ reflection angles (±0.2 degrees 2θ), and 11.4, 16.6, and 20.8 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I S-mandelate Form A has an XRPD pattern that includes 5.5, 5.7, and 6.3 degree 2θ reflection angles (±0.2 degrees 2θ), and one, two, or three of 10.0, 10.4, and 19.0 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I S-mandelate Form A has an XRPD pattern comprising the following reflection angles of 5.5, 5.7, 6.3, 11.4, 16.6, 20.8, 10.0, 10.4, and 19.0 degrees 2θ (±0.2 degrees 2θ).

[0283] In some embodiments, provided herein is Formula I S-mandelate Form B, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 65. Formula I S-mandelate Form B can exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 66. Formula I S-mandelate Form B can exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 67.

[0284] In some embodiments, Formula I S-mandelate Form B has at least one, at least two, or at least three of the following characteristics: (a) An XRPD pattern substantially as shown in FIG. (b) A DSC thermogram substantially as shown in FIG. (c) TGA thermogram substantially as shown in FIG.

[0285] In some embodiments, Formula IS-mandelate Form B 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in FIG.

[0286] In certain embodiments, Formula I S-mandelate Form B has an XRPD pattern that includes 5.7, 6.2, and 22.6 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I S-mandelate Form B has an XRPD pattern that includes one, two, or three of 5.7, 6.2, and 22.6 degree 2θ reflection angles (±0.2 degrees 2θ), and 8.0, 8.4, and 11.7 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I S-mandelate Form B has an XRPD pattern that includes one, two, or three of 5.7, 6.2, and 22.6 degree 2θ reflection angles (±0.2 degrees 2θ), and 13.5, 16.0, and 16.6 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I S-mandelate Form B has an XRPD pattern including the following reflection angles 2θ (±0.2 degrees 2θ): 5.7, 6.2, 22.6, 8.0, 8.4, 11.7, 13.5, 16.0, and 16.6 degrees 2θ.

[0287] In some embodiments, Formula I S-mandelate Form B has a differential scanning calorimetry thermogram that includes an endotherm with an onset at about 50°C. Formula I gentisate

[0288] In some embodiments, provided herein is a gentisic acid salt wet cake of Formula I, wherein the gentisic acid salt wet cake of Formula I exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 68.

[0289] In some embodiments, the Formula I gentisate wet cake 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in Figure 68.

[0290] In certain embodiments, gentisic acid salt Form A of Formula I has an XRPD pattern that includes 7.4, 6.5, and 8.0 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, gentisic acid salt wet cake of Formula I has an XRPD pattern that includes one, two, or three of 7.4, 6.5, and 8.0 degree 2θ reflection angles (±0.2 degrees 2θ), and 13.5, 16.9, and 12.0 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, gentisic acid salt wet cake of Formula I has an XRPD pattern that includes one, two, or three of 7.4, 6.5, and 8.0 degree 2θ reflection angles (±0.2 degrees 2θ), and 25.1, 22.4, and 19.3 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the gentisate wet cake of Formula I has an XRPD pattern comprising the following reflection angles 2θ of 7.4, 6.5, 8.0, 13.5, 16.9, 12.0, 25.1, 22.4, and 19.3 degrees 2θ (±0.2 degrees 2θ).

[0291] In some embodiments, provided herein is a solid form of gentisic acid salt of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 69. The gentisic acid salt of Formula I may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 70. The gentisic acid salt of Formula I may exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 71.

[0292] In some embodiments, a solid form of the gentisate salt of Formula I has at least one, at least two, or at least three of the following characteristics: (a) An XRPD pattern substantially as shown in FIG. (b) A DSC thermogram substantially as shown in FIG. (c) TGA thermogram substantially as shown in FIG.

[0293] In some embodiments, the solid form of gentisate 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 of the 2θ reflection angles whose maximum intensities are substantially as shown in the XRPD pattern in FIG.

[0294] In certain embodiments, the solid form of gentisic acid salt of formula I has an XRPD pattern that includes 7.4, 6.1, and 8.4 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, gentisic acid salt of formula I has an XRPD pattern that includes one, two, or three of 7.4, 6.1, and 8.4 degree 2θ reflection angles (±0.2 degrees 2θ), and 16.7, 17.9, and 9.1 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, gentisic acid salt of formula I has an XRPD pattern that includes one, two, or three of 7.4, 6.1, and 8.4 degree 2θ reflection angles (±0.2 degrees 2θ), and 24.9, 22.8, and 12.3 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the gentisate salt of Formula I has an XRPD pattern comprising reflection angles of 7.4, 6.1, 8.4, 16.7, 17.9, 9.1, 24.9, 22.8, and 12.3 degrees 2θ (±0.2 degrees 2θ). Formula I Citrate Salt

[0295] In some embodiments, provided herein is a citrate wetcake of Formula I, wherein the citrate wetcake of Formula I exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 72.

[0296] In some embodiments, Formula I citrate wet cake 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in FIG.

[0297] In certain embodiments, the Formula I citrate wet cake has an XRPD pattern that includes 7.4, 7.9, and 16.7 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the Formula I citrate wet cake has an XRPD pattern that includes one, two, or three of 7.4, 7.9, and 16.7 degree 2θ reflection angles (±0.2 degrees 2θ), and 15.1, 17.7, and 20.4 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the Formula I citrate wet cake has an XRPD pattern that includes one, two, or three of 7.4, 7.9, and 16.7 degree 2θ reflection angles (±0.2 degrees 2θ), and 11.4, 18.9, and 22.1 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I citrate wet cake has an XRPD pattern comprising the following reflection angles 2θ (±0.2 degrees 2θ): 7.4, 7.9, 16.7, 15.1, 17.7, 20.4, 11.4, 18.9, and 22.1 degrees 2θ.

[0298] In some embodiments, provided herein is a solid form of Formula I citrate salt, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 89. Formula I citrate salt may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 73. Formula I citrate salt may exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 75.

[0299] In some embodiments, Formula I Citrate Salt Form B has at least one, at least two, or all of the following characteristics: (a) An XRPD pattern substantially as shown in FIG. 73. (b) A DSC thermogram substantially as shown in FIG. (c) TGA thermogram substantially as shown in FIG.

[0300] In some embodiments, the citrate 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 of the 2θ reflection angles having maximal intensities substantially as shown in the XRPD pattern in FIG.

[0301] In certain embodiments, the citrate salt of formula I has an XRPD pattern that includes 6.1, 7.4, and 18.2 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the citrate salt of formula I has an XRPD pattern that includes one, two, or three of 6.1, 7.4, and 18.2 degree 2θ reflection angles (±0.2 degrees 2θ), and 8.3, 16.4, and 36.7 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the citrate salt of formula I has an XRPD pattern that includes one, two, or three of 6.1, 7.4, and 18.2 degree 2θ reflection angles (±0.2 degrees 2θ), and 20.7, 24.5, and 26.0 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the citrate salt of Formula I has an XRPD pattern comprising the following reflection angles of 6.1, 7.4, 18.2, 8.3, 16.4, 36.7, 20.7, 24.5, and 26.0 degrees 2θ (±0.2 degrees 2θ). Formula I R-Mandelate

[0302] In some embodiments, provided herein is 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.

[0303] In some embodiments, Formula I R-mandelate 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in FIG.

[0304] In certain embodiments, Formula I R-mandelate Form A has an XRPD pattern that includes 5.7, 5.4, and 16.5 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I R-mandelate Form A has an XRPD pattern that includes one, two, or three of 5.7, 5.4, and 16.5 degree 2θ reflection angles (±0.2 degrees 2θ), and 6.2, 7.8, and 11.5 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I R-mandelate Form A has an XRPD pattern that includes one, two, or three of 5.7, 5.4, and 16.5 degree 2θ reflection angles (±0.2 degrees 2θ), and 10.5, 13.4, and 18.5 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I R-mandelate Form A has an XRPD pattern including the following reflection angles 2θ of 5.7, 5.4, 16.5, 6.2, 7.8, 11.5, 10.5, 13.4, and 18.5 degrees 2θ (±0.2 degrees 2θ).

[0305] In some embodiments, provided herein is Formula I R-mandelate Form B, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 77. Formula I R-mandelate Form B can exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 78. Formula I R-mandelate Form B can exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 79.

[0306] In some embodiments, Formula I R-mandelate Form B has at least one, at least two, or all of the following characteristics: (a) An XRPD pattern substantially as shown in FIG. 77. (b) A DSC thermogram substantially as shown in FIG. (c) TGA thermogram substantially as shown in FIG.

[0307] In some embodiments, Formula I R-mandelate Form B 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in FIG.

[0308] In certain embodiments, Formula I R-mandelate Form B has an XRPD pattern that includes 6.2, 8.3, and 22.4 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I R-mandelate Form B has an XRPD pattern that includes one, two, or three of 6.2, 8.3, and 22.4 degree 2θ reflection angles (±0.2 degrees 2θ), and 15.9, 16.3, and 17.0 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I R-mandelate Form B has an XRPD pattern that includes one, two, or three of 6.2, 8.3, and 22.4 degree 2θ reflection angles (±0.2 degrees 2θ), and 10.0, 10.8, and 11.6 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I R-mandelate Form B has an XRPD pattern including the following reflection angles 2θ of 6.2, 8.3, 22.4, 15.9, 16.3, 17.0, 10.0, 10.8, and 11.6 degrees 2θ (±0.2 degrees 2θ). Formula I Benzoate

[0309] In some embodiments, provided herein is a benzoate salt of formula I, Form A, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 80.

[0310] In some embodiments, Formula I benzoate 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in Figure 80.

[0311] In certain embodiments, Formula I benzoate Form A has an XRPD pattern that includes 7.44, 18.97, and 16.70 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I benzoate Form A has an XRPD pattern that includes one, two, or three of 7.44, 18.97, and 16.70 degree 2θ reflection angles (±0.2 degrees 2θ) and 21.14, 22.45, 25.07, and 6.09 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I benzoate Form A has an XRPD pattern that includes 7.44, 18.97, 16.70, 21.14, 22.45, 25.07, and 6.09 degree 2θ reflection angles (±0.2 degrees 2θ).

[0312] In some embodiments, provided herein is benzoate salt Form B of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 81. Benzoate salt Form B of Formula I may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 82. Benzoate salt Form B of Formula I may exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 83.

[0313] In some embodiments, Formula I Benzoate Form B has at least one, at least two, or at least three of the following characteristics: (a) an XRPD pattern substantially as shown in FIG. (b) A DSC thermogram substantially as shown in FIG. 82. (c) TGA thermogram substantially as shown in FIG.

[0314] In some embodiments, Formula I benzoate Form B 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in FIG.

[0315] In certain embodiments, Formula I benzoate Form B has an XRPD pattern that includes 14.9, 6.7, and 7.4 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I benzoate Form B has an XRPD pattern that includes one, two, or three of 14.9, 6.7, and 7.4 degree 2θ reflection angles (±0.2 degrees 2θ), and 20.6, 22.5, and 8.1 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I benzoate Form B has an XRPD pattern that includes one, two, or three of 14.9, 6.7, and 7.4 degree 2θ reflection angles (±0.2 degrees 2θ), and 6.7, 14.9, and 21.5 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I benzoate Form B has an XRPD pattern comprising the following reflection angles of 14.9, 6.7, 7.4, 20.6, 22.5, 8.1, 6.7, 14.9, and 21.5 degrees 2θ (±0.2 degrees 2θ). Formula I Methylparabenate

[0316] In some embodiments, provided herein is methyl parabenate Form A of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 84.

[0317] In some embodiments, methyl parabenate 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in Figure 84.

[0318] In certain embodiments, methyl parabenate Form A of formula I has an XRPD pattern that includes 7.4, 8.0, and 6.3 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, methyl parabenate Form A of formula I has an XRPD pattern that includes one, two, or three of 7.4, 8.0, and 6.3 degree 2θ reflection angles (±0.2 degrees 2θ), and 20.5, 19.2, and 12.1 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, methyl parabenate Form A of formula I has an XRPD pattern that includes one, two, or three of 7.4, 8.0, and 6.3 degree 2θ reflection angles (±0.2 degrees 2θ), and 31.6, 22.8, and 14.0 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, methyl parabenate Form A of formula I has an XRPD pattern comprising the following reflection angles 2θ of 7.4, 8.0, 6.3, 20.5, 19.2, 12.1, 31.6, 22.8, and 14.0 degrees 2θ (±0.2 degrees 2θ).

[0319] In some embodiments, provided herein is methyl parabenate Form B of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 85. Methyl parabenate Form B of Formula I may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 86. Methyl parabenate Form B of Formula I may exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 87.

[0320] In some embodiments, methyl parabenate Form B of Formula I has at least one, at least two, or at least three of the following properties: (a) an XRPD pattern substantially as shown in FIG. (b) A DSC thermogram substantially as shown in FIG. (c) TGA thermogram substantially as shown in FIG.

[0321] In some embodiments, methyl parabenate Form B 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in Figure 85.

[0322] In certain embodiments, methyl parabenate Form B of formula I has an XRPD pattern that includes 7.4, 8.3, and 6.5 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, methyl parabenate Form B of formula I has an XRPD pattern that includes one, two, or three of 7.4, 8.3, and 6.5 degree 2θ reflection angles (±0.2 degrees 2θ), and 19.3, 20.6, and 21.6 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, methyl parabenate Form B of formula I has an XRPD pattern that includes one, two, or three of 7.4, 8.3, and 6.5 degree 2θ reflection angles (±0.2 degrees 2θ), and 12.2, 13.0, and 31.8 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, methyl parabenate Form B of Formula I has an XRPD pattern comprising the following reflection angles 2θ (±0.2 degrees 2θ): 7.4, 8.3, 6.5, 19.3, 20.6, 21.6, 12.2, 13.0, and 31.8 degrees 2θ. Formula I Caffeate

[0323] In some embodiments, provided herein is a caffeate salt of Formula I wetcake, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 88.

[0324] In some embodiments, Formula I caffeate wet cake 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in Figure 88.

[0325] In certain embodiments, the caffeate wet cake of Formula I has an XRPD pattern that includes 5.3, 7.4, and 9.1 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the caffeate wet cake of Formula I has an XRPD pattern that includes one, two, or three of 5.3, 7.4, and 9.1 degree 2θ reflection angles (±0.2 degrees 2θ), and 6.5, 7.0, and 15.9 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the caffeate wet cake of Formula I has an XRPD pattern that includes one, two, or three of 5.3, 7.4, and 9.1 degree 2θ reflection angles (±0.2 degrees 2θ), and 27.1, 22.5, and 10.6 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I caffeate wet cake has an XRPD pattern comprising the following reflection angles: 5.3, 7.4, 9.1, 6.5, 7.0, 15.9, 27.1, 22.5, and 10.6 degrees 2θ (±0.2 degrees 2θ).

[0326] In some embodiments, provided herein is a solid form of caffeine salt of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 89. The caffeine salt of Formula I may exhibit a differential scanning calorimetry (DSC) thermogram substantially as shown in Figure 90. The caffeine salt of Formula I may exhibit a thermogravimetric analysis (TGA) thermogram substantially as shown in Figure 91.

[0327] In some embodiments, a solid form of the caffeate salt of Formula I has at least one, at least two, or at least three of the following characteristics: (a) an XRPD pattern substantially as shown in FIG. (b) A DSC thermogram substantially as shown in FIG. (c) TGA thermogram substantially as shown in FIG. Formula I Glycolic Acid Salt

[0328] In some embodiments, provided herein is a glycolic acid salt wetcake of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 92.

[0329] In some embodiments, the Formula I glycolate wet cake 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in FIG.

[0330] In certain embodiments, the glycolate wet cake of Formula I has an XRPD pattern that includes 6.2, 8.4, and 11.5 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the glycolate wet cake of Formula I has an XRPD pattern that includes one, two, or three of 6.2, 8.4, and 11.5 degree 2θ reflection angles (±0.2 degrees 2θ), and 10.9, 16.4, and 22.3 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the glycolate wet cake of Formula I has an XRPD pattern that includes one, two, or three of 6.2, 8.4, and 11.5 degree 2θ reflection angles (±0.2 degrees 2θ), and 13.6, 14.0, and 15.3 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the Formula I glycolate wet cake has an XRPD pattern comprising the following reflection angles 2θ (±0.2 degrees 2θ): 6.2, 8.4, 11.5, 10.9, 16.4, 22.3, 13.6, 14.0, and 15.3 degrees 2θ.

[0331] In some embodiments, provided herein is a solid form of formula I glycolate salt, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in FIG. 93.

[0332] In some embodiments, 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in FIG.

[0333] In certain embodiments, the glycolate salt of Formula I has an XRPD pattern that includes 6.2, 8.3, and 11.5 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the glycolate salt of Formula I has an XRPD pattern that includes one, two, or three of 6.2, 8.3, and 11.5 degree 2θ reflection angles (±0.2 degrees 2θ), and 10.8, 16.4, and 22.2 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the glycolate salt of Formula I has an XRPD pattern that includes one, two, or three of 6.2, 8.3, and 11.5 degree 2θ reflection angles (±0.2 degrees 2θ), and 13.6, 14.9, and 15.3 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the glycolate salt of Formula I has an XRPD pattern comprising reflection angles of 6.2, 8.3, 11.5, 10.8, 16.4, 22.2, 13.6, 14.9, and 15.3 degrees 2θ (±0.2 degrees 2θ). Formula I α-ketobutyrate

[0334] In some embodiments, provided herein is a Formula I α-ketobutyric acid salt wetcake, wherein the Formula I α-ketobutyric acid salt wetcake exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 94.

[0335] In some embodiments, Formula I α-ketobutyrate wetcake 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in FIG.

[0336] In certain embodiments, the Formula I α-ketobutyric acid salt wet cake has an XRPD pattern that includes 6.2, 8.3, and 10.8 degrees 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the Formula I α-ketobutyric acid salt wet cake has an XRPD pattern that includes one, two, or three of 6.2, 8.3, and 10.8 degrees 2θ reflection angles (±0.2 degrees 2θ), and 12.3, 12.5, and 12.7 degrees 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the Formula I α-ketobutyric acid salt wet cake has an XRPD pattern that includes one, two, or three of 6.2, 8.3, and 10.8 degrees 2θ reflection angles (±0.2 degrees 2θ), and 16.4, 19.0, and 21.6 degrees 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I α-ketobutyrate wetcake has an XRPD pattern comprising the following reflection angles: 6.2, 8.3, 10.8, 12.3, 12.5, 12.7, 16.4, 19.0, and 21.6 degrees 2θ (±0.2 degrees 2θ).

[0337] In some embodiments, provided herein is a solid form of formula I α-ketobutyric acid salt, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 95.

[0338] In some embodiments, the α-ketobutyrate 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in FIG.

[0339] In certain embodiments, the α-ketobutyrate salt of formula I has an XRPD pattern that includes 6.2, 16.4, and 8.3 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the α-ketobutyrate salt of formula I has an XRPD pattern that includes one, two, or three of 6.2, 16.4, and 8.3 degree 2θ reflection angles (±0.2 degrees 2θ), and 10.8, 11.5, and 20.3 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the α-ketobutyrate salt of formula I has an XRPD pattern that includes one, two, or three of 6.2, 16.4, and 8.3 degree 2θ reflection angles (±0.2 degrees 2θ), and 18.5, 19.0, and 21.6 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, Formula I α-ketobutyrate has an XRPD pattern comprising the following reflection angles of 6.2, 16.4, 8.3, 10.8, 11.5, 20.3, 18.5, 19.0, and 21.6 degrees 2θ (±0.2 degrees 2θ). Formula I Pyruvate

[0340] In some embodiments, provided herein is a pyruvate wetcake of Formula I, wherein the pyruvate wetcake of Formula I exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 96.

[0341] In some embodiments, the Formula I pyruvate wet cake 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in FIG.

[0342] In certain embodiments, the Formula I pyruvate wet cake has an XRPD pattern that includes 6.21, 8.34, and 10.85 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the Formula I pyruvate wet cake has an XRPD pattern that includes one, two, or three of 6.21, 8.34, and 10.85 degree 2θ reflection angles (±0.2 degrees 2θ), and 11.56, 13.60, and 14.51 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the Formula I pyruvate wet cake has an XRPD pattern that includes one, two, or three of 6.21, 8.34, and 10.85 degree 2θ reflection angles (±0.2 degrees 2θ), and 20.34, 21.73, and 22.59 degree 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the Formula I pyruvate wet cake has an XRPD pattern comprising the following reflection angles 6.21, 8.34, 10.85, 11.56, 13.60, 14.51, 20.34, 21.73, and 22.59 degrees 2θ (±0.2 degrees 2θ).

[0343] In some embodiments, provided herein is a solid form of pyruvate of Formula I, wherein the solid form exhibits an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 97.

[0344] In some embodiments, the pyruvate 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 of the 2θ reflection angles having maximum intensities substantially as shown in the XRPD pattern in FIG.

[0345] In certain embodiments, the pyruvate of formula I has an XRPD pattern that includes 6.2, 8.3, and 10.8 degrees 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the pyruvate of formula I has an XRPD pattern that includes one, two, or three of 6.2, 8.3, and 10.8 degrees 2θ reflection angles (±0.2 degrees 2θ), and 11.5, 16.3, and 19.1 degrees 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the pyruvate of formula I has an XRPD pattern that includes one, two, or three of 6.2, 8.3, and 10.8 degrees 2θ reflection angles (±0.2 degrees 2θ), and 20.3, 21.7, and 22.1 degrees 2θ reflection angles (±0.2 degrees 2θ). In some embodiments, the pyruvate salt of Formula I has an XRPD pattern comprising the following reflection angles 2θ of 6.2, 8.3, 10.8, 11.5, 16.3, 19.1, 20.3, 21.7, and 22.1 degrees 2θ (±0.2 degrees 2θ). Pharmaceutical Compositions

[0346] For the purpose of administration, in certain embodiments, the compounds described herein are administered as raw chemicals or formulated as pharmaceutical compositions. The pharmaceutical compositions of the present disclosure can include a therapeutically effective amount of a compound of formula I and at least one pharma- ceutically 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 can further include one or more other compounds as active ingredients, including, for example, other active pharmaceutical ingredients such as prodrugs, other nuclear receptor modulators, or active pharmaceutical ingredients for use in treating liver disease, such as ACC inhibitors or ASK1 inhibitors. In some embodiments, the pharmaceutical compositions of the present disclosure further include an ACC inhibitor and an ASK1 inhibitor.

[0347] In some embodiments, the pharmaceutical composition comprises an amorphous form of Formula I, Formula I Form I, Formula I Form II, Formula I Form III, Formula I Form IV, Formula I Form V, Formula I Form VI, Formula I Form VII, Formula I Form VIII, Formula I Form IX, Formula I Form X, Formula I Form XI, Formula I Form XII, Formula I Form XIII, Formula I Form XIV, Formula I Form XV, Formula I 2-(4-hydroxybenzoyl)benzoate Form A, Formula I 2-(4-hydroxybenzoyl)benzoate Form B, Formula I vanillate Form A, Formula I vanillate Form B, Formula I hippurate Form A, Formula I hippurate Form B, Formula I maleate Form A, Formula I maleate Form B, Formula I glyoxylate Form A, Formula I glyoxylate Form B, Formula I L-pyroglutamate, Formula I 2-naphthalenesulfonate Form A, Formula I 2-naphthalenesulfonate Form B, Formula I 1-Naphthalenesulfonate Form A, Formula I 1-Naphthalenesulfonate Form B, Formula I 1-Hydroxy-2-naphthoate Form A, Formula I 1-Hydroxy-2-naphthoate Form B, Formula I S-Mandelate Form A, Formula I S-Mandelate Form B, Formula I Gentisic Acid Salt Form A, Formula I Gentisic Acid Salt Form B, Formula I Citrate Form A, Formula I Citrate Form B, Formula I R-Mandelate Form A, Formula I R-Mandelate Form B, Formula I Benzoate Form A, Formula I Benzoate Form B, Formula I Methyl Parabenate Form A, Formula I Methyl Parabenate Form B, Formula I Caffeate Form A, Formula I Caffeate Form B, Formula I Glycolate Form A, Formula I Glycolate Form B, Formula I α-Ketobutyrate Form A, Formula I α-ketobutyrate Form B, pyruvate Form A of Formula I, and / or pyruvate Form B of Formula I, and a pharma- ceutically acceptable carrier.

[0348] The activity of a compound of formula I can be determined by one of ordinary skill in the art, for example, as described herein. Appropriate therapeutically effective concentrations and dosages can be readily determined by one of ordinary skill in the art.

[0349] In certain embodiments, the crystal, salt, and / or solvate forms described herein may exhibit improved properties. For example, in certain embodiments, the crystal and / or salt forms described herein may exhibit improved stability. Such improved stability may have beneficial effects on the manufacture of the compound of formula I, for example, providing the ability to store process intermediates for extended periods of time. Improved stability may also be beneficial to the composition or pharmaceutical composition of the compound of formula I. In certain embodiments, the crystal salt and / or solvate forms described herein may also provide improved yields of the compound of formula I, or improved quality of the compound of formula I. In certain embodiments, the crystal, salt, and / or solvate forms described herein may also exhibit improved pharmacokinetic properties and / or improved bioavailability.

[0350] The compositions are suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (intranasal 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 being treated and on the nature of the active ingredient. The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art.

[0351] In practical use, the compounds of the present disclosure can be combined as active ingredients in homogeneous admixture with pharmaceutical carriers according to conventional pharmaceutical compounding techniques. Carriers can take a wide variety of forms, depending on the form of preparation desired for administration (e.g., oral or parenteral (including intravenous)). When preparing compositions for oral dosage forms, any of the usual pharmaceutical media can be used, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., for oral liquid preparations such as suspensions, elixirs and solutions, or carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, etc., for oral solid preparations such as powders, hard and soft capsules and tablets, and solid oral preparations are preferred over liquid preparations.

[0352] Due to their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are used. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of the active compound. The percentage of the active compound in these compositions can, of course, vary and can conveniently be about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage is obtained. The active compound can also be administered intranasally, for example, as drops or spray.

[0353] Tablets, pills, capsules, etc. may also contain binders such as gum tragacanth, acacia, corn starch, or gelatin, excipients such as dicalcium phosphate, microcrystalline cellulose, lactose monohydrate, mannitol, or colloidal silicon dioxide, disintegrants such as corn starch, potato starch, alginic acid, croscarmellose sodium, or crospovidone, lubricants such as magnesium stearate, and sweeteners such as sucrose, lactose, or saccharin. When the dosage unit form is a capsule, it may contain, in addition to materials of the above types, a liquid carrier (e.g., fatty oils) or a pharmaceutical medium (e.g., water, glycols (e.g., polyethylene glycol 400), or alcohol).

[0354] Various other materials may be present as coatings or to improve the physical form of the unit dosage form. For example, tablets may be coated with shellac, sugar, polyvinyl alcohol, polyethylene glycol 3350, titanium dioxide, talc, coloring agents, or combinations thereof. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and a flavoring such as cherry or orange flavor.

[0355] The compounds of the present disclosure may also be administered parenterally. Solutions or suspensions of these active compounds may be prepared in water suitably mixed with organics, additives, or combinations thereof. Examples of organics include, but are not limited to, N-methylpyrrolidone, dimethylsulfoxide, polyethylene glycol, and combinations thereof. Examples of additives include, but are not limited to, hydroxypropylcellulose, polyvinylpyrrolidone, poloxamer, poly(lactic-co-glycolic acid), polysorbate, povidone, carboxymethylcellulose, and combinations thereof. Dispersions may be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under normal conditions of storage and use, these preparations may contain preservatives, for example, to prevent the growth of microorganisms. In some embodiments, parenteral administration includes intravenous administration by formulations that include solutions that include a mixture of organics and aqueous media. In some embodiments, intravenous administration is administered as a 100% organic solution.

[0356] Pharmaceutical forms suitable for injection use include sterile aqueous solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. For example, the form can be stable under the conditions of manufacture and storage. The form can be preserved against the contaminating action of microorganisms such as bacteria and fungi (for example, by the use of a preservative). The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0357] Any suitable route of administration can be used to provide an effective dose of the disclosed compound to a mammal, particularly a human. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, etc. can be used. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, etc. In some embodiments, the disclosed compound is administered orally.

[0358] In certain embodiments of a composition comprising a crystalline form of Formula I or a pharma- ceutically 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 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.

[0359] In other embodiments of the compositions comprising the crystalline forms 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.

[0360] In yet other embodiments of the compositions comprising the crystalline forms disclosed herein, the impurities comprise 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, based on the mass of the crystalline form present. The impurities may include, for example, by-products from synthesizing Formula I, contaminants, decomposition products, other crystalline forms, amorphous forms, water, and solvents. In certain embodiments, the impurities include by-products from the process of synthesizing Formula I. In certain embodiments, the impurities include contaminants from the process of synthesizing Formula I. In certain embodiments, the impurities include decomposition products of Formula I. In certain embodiments, the impurities include other crystalline forms of Formula I. In certain embodiments, the impurities include other crystalline forms of Formula I and / or amorphous forms of Formula I. In certain embodiments, the impurities include water or solvents. In certain embodiments of the compositions comprising the crystalline forms disclosed herein, the impurities are selected from the group consisting of by-products from the synthesis of Formula I, contaminants, decomposition products, other crystalline forms, amorphous forms, water, solvents, and combinations thereof. Dosage

[0361] The effective dosage of the active ingredient used may vary depending on the particular compound used, the mode of administration, the condition being treated, and the severity of the condition being treated. Such dosages may be readily ascertained by one skilled in the art.

[0362] When treating or preventing a Cot-mediated condition for which a compound of the present disclosure is required, generally satisfactory results are obtained when the compound of the present disclosure is administered at a daily dosage of about 0.1 milligrams to about 100 milligrams per kilogram of animal body weight. In some embodiments, the compound of the present disclosure is given as a single daily dose or divided doses 2-6 times daily, or in sustained release form. For most large mammals, the total daily dosage can be from about 1 milligram to about 1000 milligrams. For a 70 kg adult human, the total daily dosage will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen can be adjusted to provide the optimal therapeutic response. In some embodiments, the total daily dosage is from about 1 milligram to about 900 milligrams, from about 10 milligrams to about 800 milligrams, from about 20 milligrams to about 700 milligrams, from about 30 milligrams to about 600 milligrams, from about 40 milligrams to about 550 milligrams, or from about 50 milligrams to about 400 milligrams. In some embodiments, the total daily dosage is about 10 milligrams to about 50 milligrams, about 20 milligrams to about 40 milligrams, about 25 milligrams to about 35 milligrams, about 50 milligrams to about 150 milligrams, about 70 milligrams to about 130 milligrams, about 80 milligrams to about 120 milligrams, about 90 milligrams to about 100 milligrams, about 1 milligrams to about 150 milligrams, about 1 milligrams to about 75 milligrams, about 1 milligrams to about 50 milligrams, about 25 milligrams to about 125 milligrams, about 125 milligrams to about 275 milligrams, about 275 milligrams to about 425 milligrams, about 425 milligrams to about 575 milligrams, about 575 milligrams to about 725 milligrams, about 725 milligrams to about 875 milligrams, or about 875 milligrams to about 1000 milligrams.

[0363] 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 as described above, and administration or treatment with the compound can continue for days or months, for example, treatment generally continues for at least 7, 14, or 28 days, or for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.

[0364] In certain embodiments, the methods provided herein include administering to the subject an initial daily dose of a compound described herein of about 1 mg to about 1500 mg, e.g., 150 to 600 mg, e.g., 150 mg, 300 mg, 600 mg. In further embodiments, the methods include increasing the dose in increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 30, 40, 50, or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice a week, once a week, or once every four weeks. Treatment Methods and Uses

[0365] "Treatment" or "treating" is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include one or more of the following: (a) inhibiting a disease or condition (e.g., reducing one or more symptoms resulting from a disease or condition and / or attenuating the severity of a disease or condition), (b) slowing or arresting the onset of one or more clinical symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, preventing or slowing the worsening or progression of a disease or condition, and / or preventing or slowing the spread (e.g., metastasis) of a disease or condition), and / or (c) palliating the disease, i.e., causing regression of clinical symptoms (e.g., improving the disease state, providing partial or complete remission of a disease or condition, enhancing the effect of another drug, slowing the progression of a disease, improving quality of life, and / or prolonging survival).

[0366] The present disclosure further relates to the use of said compounds for the treatment and / or prevention of diseases and / or conditions due to binding of said nuclear receptors by said compounds.The present disclosure further relates to the use of said compounds for the preparation of a medicament for the treatment and / or prevention of diseases and / or conditions due to binding of said nuclear receptors by said compounds.

[0367] Also provided herein are methods of treating a patient having a Cot-mediated condition. In some embodiments, the methods include administering a compound or composition disclosed herein. In some embodiments, the methods of treating a patient having a Cot-mediated condition include administering a therapeutically effective amount of amorphous Formula I, Formula I Form I, Formula I Form II, Formula I Form III, Formula I Form IV, Formula I Form V, Formula I Form VI, Formula I Form VII, Formula I Form VIII, Formula I Form IX, Formula I Form X, Formula I Form XI, Formula I Form XII, Formula I Form XIII, Formula I Form XIV, Formula I Form XV, Formula I 2-(4-hydroxybenzoyl)benzoate, Formula I vanillate, Formula I hippurate, Formula I maleate, Formula I glyoxylate, Formula I L-pyroglutamate, Formula I 2-naphthalenesulfonate, Formula I 1-naphthalenesulfonate, Formula I 1-hydroxy-2-naphthoate, Formula I This includes administering S-mandelate, gentisate of formula I, citrate of formula I, IR-mandelate, benzoate of formula I, methyl parabenate of formula I, caffeate of formula I, glycolate of formula I, α-ketobutyrate of formula I, and / or pyruvate of formula I.

[0368] Also provided herein is 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 an inflammatory disease and the compound useful for modulating Cot is a compound of Formula I. [ka] kit

[0369] Also provided herein is a kit 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 present disclosure or a composition comprising a crystalline form of the present disclosure, and a label and / or instructions for use of the compound in treating an indication, including a disease or condition described herein.

[0370] Also provided herein is an article of manufacture comprising a compound or composition described herein in a suitable container, which may be a vial, a jar, an ampoule, a pre-filled syringe, and an infusion bag. Additional Therapeutic Agents

[0371] 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, the additional therapeutic agents include 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, acidic mammalian chitinase inhibitors, actin antagonists, acetaldehyde dehydrogenase inhibitors, acetyl CoA carboxylase (ACC) inhibitors, ACC-1 inhibitors, ACC-2 inhibitors, 2-Acylglycerol O-acyltransferase 2 ( ... 2, DGAT2) inhibitors, ACTH receptor agonists, activin receptor antagonists, adenosylhomocysteinase inhibitors, adenosine receptor antagonists and agonists, adenosine deaminase inhibitors, adenylyl cyclase-related protein 1 inhibitors, adiponutrin inhibitors, adiponectin receptor agonists, ADP-ribosyl cyclase-1 inhibitors, ADP-ribosyl cyclase-1 regulators, ADP-ribosylation factor 6 inhibitors, adrenocorticotropic hormone ligands, adrenomedullin ligands, adrenoceptor antagonists and agonists, adropin stimulators, aggrecanase-2 inhibitors, AIMP multisynthetase complex protein 1 stimulators, AKT1 gene inhibitors, AKT protein kinase inhibitors, albumin antagonists, albumin regulators, aldehyde dehydrogenase 2 stimulators, aldosterone antagonists, aldosterone synthase inhibitors, Alk-5 protein kinase inhibitors, alpha 2 adrenergic receptor agonists, alpha 2 adrenergic receptor regulators, alpha 1 antitrypsin stimulators, alpha-fetoprotein regulators, Alstrom syndrome protein 11, ALMS1) / PKC alpha 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 alpha 2 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, antifungals, anti-IL6 antibodies, anti-TNF steroid conjugates, activator protein 1 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 regulator Bcl w inhibitors, aryl hydrocarbon receptor (AHR) agonists and regulators, AHR agonists + 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 attenuator stimulators, Bax protein stimulators, Bcl-2 protein inhibitors, Bcl-xL Bcl-2-associated death promoter inhibitors, Bcl-xLBcl-2 associated death promoter modulators, Bcr protein inhibitors, benzodiazepine receptor agonists, beta adrenergic receptor antagonists, BET inhibitors, beta 2 adrenergic receptor agonists, beta amyloid antagonists, beta-catenin inhibitors, beta-catenin modulators, beta-catenin stimulators, beta-galactosidase inhibitors, beta-lactamase modulators, beta 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 cell 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, bradykinin receptor modulators, BRAF gene inhibitors, branched amino acid aminotransferase 1 inhibitors, bromodomain containing proteins BRD (brancheskin protein) 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 cannabinoid CB2 receptor agonists, cannabinoid receptor antagonists and agonists, cannabinoid CB1 receptor inverse agonists, carbohydrate metabolism regulators, 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 regulators, CC motif ligand 26 (CCL26) gene inhibitors, chemokine receptor antagonists, CC motif chemokine receptor (CC motifchemokine receptor, CCR1 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 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 glycotan Protein MUC18 inhibitors, chemokine CXC ligand inhibitors, chaperonin inhibitors and regulators, chitinase inhibitors, chitotriosidase 1 inhibitors, chloride channel stimulators, cholera toxin subunit B inhibitors, choline kinase inhibitors, CHST15 gene inhibitors, chymase 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 factor C5 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 (cerebrospinal fluid)CSF-1 agonists and antagonists, C-type lectin domain protein 4C inhibitors, CTGF gene inhibitors, CX3CR1 antagonists and regulators, CXCR2 antagonists, CXCR3 antagonists, CXCR4 antagonists and regulators, CXCR5 antagonists and regulators, CXC5 ligand inhibitors, CXC6 chemokine ligand inhibitors, CXC10 ligand inhibitors, CXC11 ligand regulators, cyclin-dependent kinase (CDK) 1, 2, 5, 7, and / or 9 inhibitors, cyclooxygenase (COX) inhibitors, COX-1 inhibitors, COX-2 inhibitors and regulators, cysteine ​​palmitoyltransferase porcupine inhibitors, cytochrome P450 7A1 inhibitors, cytochrome P450 11B2 inhibitors, cytochrome P450 2E1 inhibitors 2E1 inhibitor, CYP2E1), cytochrome P450 reductase inhibitors, cytokine receptor agonists and antagonists, cytosolic phospholipase A2 (cPLA2) inhibitors, cytotoxic T-lymphocyte protein-4 (CTLA4) regulators and stimulators, deoxyribonuclease (DNase) regulators, DNase gamma stimulators, DNase I stimulators, DGAT2 gene inhibitors, DHFR inhibitors, diacylglycerol O acyltransferase (DGAT) 1 inhibitors, DGAT2 inhibitors, diamine acetyltransferase inhibitors, dihydroceramide delta 4 desaturase inhibitors, dihydroorotic acid dehydrogenase inhibitors, dipeptidyl peptidase (DPP) I inhibitors, DPPIV inhibitors, DNA binding protein Ikaros inhibitors, DNA methyltransferase inhibitors, DNA polymerase inhibitors, dopamine D2 receptor partial agonists, dopamine D3 receptor partial agonists, dopamine D4 receptor partial agonists, dopamine D2 receptor agonists, DYRK-1 alpha protein kinase inhibitors, ectonucleotide pyrophosphatase-PDE-2 inhibitors, EGFR tyrosine kinase receptor inhibitors, EGR1 gene inhibitors, elongation factor 2 inhibitors, endoglin inhibitors, endoplasmin 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 prostanoid receptor antagonists or agonists, EP4 prostanoid receptor antagonists, epidermal growth factor EGF receptor antagonists, EGF regulators, epoxide hydrolase inhibitors, erythropoietin receptor antagonists or agonists, exportin 1 inhibitors, extracellular matrix protein regulators, F1F0 ATP synthase regulators, enhanced glucose transporter-1 regulators, factor IIa antagonists, factor XIIa antagonists, farnesoid X receptor (FXR) agonists and regulators, fatty acid synthase inhibitors, fecal microbiota transplantation (FMT), fibroblast activation protein (FAP) inhibitors, fibroblast growth factor (fibroblast growth factor) inhibitors, 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 regulators, FGF-19 ligands or regulators, FGF-21 ligands or regulators, FK506 binding protein inhibitors, FK506 binding protein-10 inhibitors, FK506 binding Protein-12 regulators, Flt3 tyrosine kinase inhibitors, focal adhesion kinase inhibitors, folate antagonists or agonists, folate receptor beta antagonists, FP prostanoid receptor antagonists, fractalkine 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 regulators, GPCR 44, 87 antagonists, GABA A receptor regulators, GABA A receptor alpha-2 subunit regulators, GABA A receptor alpha-3 subunit modulators, galanin GAL2 receptor agonists, galectin-3 inhibitors, gastric inhibitory polypeptide receptor (GIP-R) agonists and modulators, GATA 3 transcription factor inhibitors, GDNF family receptor alpha-like agonists, GHR gene inhibitors, glucagon-like peptide (GLP) 1 agonists, GLP 2 agonists, GLP 1 receptor modulators, glucocorticoid agonists or antagonists, glucocorticoid-induced leucine zipper stimulators, glucokinase stimulators, glucose 6-phosphate 1-dehydrogenase inhibitors, glutaminyl peptide cyclotransferase inhibitors, glutaredoxin 1 modulators, glutathione-dependent PGD synthase inhibitors, glycoprotein Ib Ib, GPIb) antagonists, GM-CSF receptor antagonists or modulators, GMP synthetase inhibitors, GNRH receptor modulators, GP IIb IIIa antagonists, GPCR modulators, GPR40 agonists, GPR84 antagonists, GroEL protein 2 inhibitors, GroEL protein 2 inhibitors, growth hormone ligands, growth hormone receptor agonists, growth regulatory protein alpha ligand inhibitors, guanylate cyclase receptor agonists,Guanylate cyclase stimulators, heat shock protein inhibitors, H+K+ATPase inhibitors, Hedgehog (Hh) regulators, Hh protein inhibitors, heme oxygenase 1 regulators, Hepatitis B structural protein inhibitors, Hepatitis C virus NS3 protease inhibitors, Hepatitis C virus protein NS5A inhibitors, Hepatocyte nuclear factor 4 alpha modulators (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, Histamine H4 receptor regulators, Histone deacetylase 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 beta inhibitors, HLA class II antigen inhibitors, HLA class II antigen modulators, HMG CoA 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) modulators, HIF-1 inhibitors, HIF-1 alpha modulators and stimulators, HIF-2 alpha inhibitors, ICAM1 gene inhibitors, ICE inhibitors, interferon beta beta, IFNB) gene stimulators, insulin-like growth factor 1 (IGF1) gene inhibitors, IgG receptor FcRn large subunit p51 antagonists, IgG receptor FcRn large subunit p51 regulators, I-kappa B kinase inhibitors,I-kappa B kinase beta 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, I L-17, IL17A, and IL17B agonists or antagonists, IL-18 antagonists, IL-21 antagonists, IL-22 agonists or antagonists, IL-23 antagonists, IL-1 beta ligand modulators, IL-23A inhibitors, IL-31 receptor modulators and antagonists, 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-1 (IL-1) receptors, leukin ligand, IL-1 alpha ligand inhibitor, IL-1 ligand inhibitor, IL-1 beta ligand inhibitor and regulator, IL-1 beta ligand, interleukin ligand inhibitor, IL-2 ligand, IL-4 ligand, IL-4 ligand inhibitor, IL-6 ligand inhibitor, IL-8 ligand inhibitor, IL-10 ligand, IL-13 ligand inhibitor, IL17 ligand inhibitor, IL17A ligand inhibitor and regulator, IL-17F ligand inhibitor, IL18 ligand inhibitor, interleukin-22 ligand, IL-29 ligand, IL-33 ligand inhibitors, IL-1-like receptor inhibitors, ileal sodium bile acid cotransporter inhibitors, immunoglobulin (Ig) agonists or antagonists, IgE antagonists and regulators, immunoglobulin Fc receptor regulators, IgG agonists, IgG1 agonists and antagonists, IgG2 antagonists and regulators, immunoglobulin gamma Fc receptor antagonists, immunoglobulin gamma Fc receptor II regulators, immunoglobulin gamma Fc receptor IIB antagonists, immunoglobulin kappa regulators,Immunoglobulin-like domain receptor 2 antagonists, IgM antagonists, inducible nitric oxide synthase inhibitors (iNOS inhibitors), inducible T cell costimulatory molecule 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 alpha-1 / beta-1 antagonists, integrin alpha-4 / beta-1 antagonists, integrin alpha-V / beta-1 antagonists, integrin alpha-V / beta-3 antagonists agonists, integrin alpha-V / beta-6 antagonists, integrin alpha-V / beta-8 modulators, integrin alpha-4 / beta-7 antagonists, integrin alpha-9 antagonists, interferon (IFN) alpha ligands, IFN alpha ligand inhibitors and modulators, IFN omega ligand inhibitors, IFN beta ligands, IFN beta ligand inhibitors, IFN gamma ligands, IFN gamma receptor 1 agonists, IFN gamma receptor antagonists, IFN I type receptor antagonists, interleukin-1 receptor associated kinase 4 (interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors, IRE1 protein kinase inhibitors, Itk tyrosine kinase inhibitors, Janus kinase (JAK) inhibitors and regulators, 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 regulators, KCNN potassium channel-4 inhibitors, KCNN4 gene inhibitors, Kelch-like ECH-associated protein 1 regulators, ketohexokinase (KHK) inhibitors, Kit tyrosine kinase inhibitors, Klotho beta stimulators, lactoferrin stimulators, LanC-like protein 2 stimulators, LanC-like protein 2 regulators, 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 protease-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, Lysophosphatidate-1 receptor antagonists, Lysyl oxidase homologs (Lysyl oxidase homolog (LOXL) 2 inhibitors, LXR inverse agonists, macrophage-drug conjugates (MDC), macrophage inflammatory protein (MIP) 2 alpha inhibitors, MIP2 beta inhibitors, MIP3 alpha 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 (MEK-1) inhibitors, hormone, MCH-1) antagonist, melanocortin agonist, melanocortin MC1 receptor agonist, melanocortin MC3 receptor agonist,Melanocortin receptor agonists, membrane copper amine oxidase inhibitors, metalloprotease-1 inhibitors, metalloprotease-2 inhibitors, metalloprotease-9 inhibitors, metalloprotease-9 stimulators, methylprednisolone, methionine aminopeptidase-2 inhibitors, methyl-CpG binding protein 2 modulators, microbiome targeted therapeutics, microRNA-132 (MicroRNA-132, miR-132) antagonists, microRNA-21 (MicroRNA-21, miR-21) inhibitors, midkine ligand inhibitors, mineralocorticoid receptor antagonists and modulators, mitochondrial uncouplers, mitochondrial 10 kDa heat shock protein stimulators, mitochondrial pyruvate transporter 2 inhibitors, mitochondrial pyruvate transporter inhibitors, mixed lineage kinase-3 inhibitors, MKL myocardin-like protein inhibitors, MNK protein kinase inhibitors, , monocarboxylate transporter inhibitors, monocyte-macrophage differentiation inhibitors, motile sperm domain protein 2 inhibitors, MST-1 protein kinase inhibitors, mTOR complex 1 inhibitors, mTOR complex 2 inhibitors, mTOR inhibitors, myelin basic protein inhibitors, myeloperoxidase inhibitors, myosin 2 inhibitors, N-formyl peptide receptor antagonists, 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, NF-kappa B 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, NKG2A B activating NK receptor antagonists, NKG2 D-activated NK receptor antagonists, NLR family member X1 stimulators, NLRP3 inhibitors, NMDA receptor epsilon 2 subunit inhibitors, NOD2 gene regulators, 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 kappa (NFK) B inhibitors and regulators, nuclear factor kappa B 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 beta inhibitors, opioid receptor antagonists, opioid growth factor receptor agonists, opioid receptor delta, kappa, mu antagonists, opioid receptor sigma 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 stimulators, p38 MAP kinase alpha inhibitors, p38 MAP kinase inhibitors, p53 tumor suppressor protein stimulators, PACAPI 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 alpha antagonists, PDGF receptor beta antagonists and modulators, PEGylated long-acting glucagon-like peptide-1 / glucagon (GLP-1R / GCGR) receptor dual agonists, perino 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, phosphatonin receptor agonists, phosphoinositide 3-kinase inhibitors, phosphoinositide 3-kinase alpha inhibitors, alpha, delta, and gamma inhibitors, phospholipase A2 inhibitors, phospholipase C inhibitors, phosphodiester hydrolase 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 alpha / delta agonists, PPAR delta agonists, PPAR gamma agonists and modulators,PRKAA2 gene stimulator, programmed cell death ligand ligand, PDL)1 regulators, programmed cell death protein 1 regulators, programmed cell death protein 1 stimulators, proprotein convertase PC9 inhibitors, prostacyclin (PGI2) agonists, prostaglandin D synthase stimulators, prostanoid receptor antagonists, protease-activated receptor-2 antagonists, proteasome beta-8 subunit regulators, proteasome inhibitors, protein arginine deiminase inhibitors, protein arginine deiminase IV inhibitors, protein C activators, protein cereblon regulators, protein fimH inhibitors, protein kinase C theta inhibitors, protein kinase inhibitors and regulators, protein kinase C theta inhibitors, protein MB21D1 inhibitors and regulators, protein NOV homolog regulators, 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 agonists, retinoid receptor agonists, retinoid X receptor agonists and modulators, retinoid Z receptor gamma agonists and antagonists, Ret tyrosine kinase receptor inhibitors, 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 regulators, Serine-threonine SNF1-like kinase 2 inhibitors, SERPINH1 gene inhibitors, Serum amyloid A protein regulators, Serum amyloid P stimulators, Signal transduction CD24 regulators, Signal transduction inhibitors, SLC22A12 inhibitors, SMAD inhibitors, SMAD-3 inhibitors, Smoothened receptor antagonists, S-nitrosoglutathione reductase reductase, GSNOR) enzyme inhibitors, sodium channel inhibitors, sodium glucose transporter-1 inhibitors, sodium glucose transporter-2 inhibitors, solute transporter 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 agents, SREBP transcription factor inhibitors, SREBP transcription factor 1 inhibitors, SREBP transcription factor 2 inhibitors, STAT inhibitors, STAT3 gene inhibitors, STAT-1 inhibitors and regulators, STAT-3 inhibitors and regulators, STAT-5 inhibitors, STAT-6 inhibitors, stearoyl CoA desaturase-1 inhibitors, stem cell antigen-1 inhibitors, interferon gene stimulator protein inhibitors, STK25 inhibitors, stress-induced secretory protein 1 stimulators, superoxide dismutase regulators, superoxide dismutase stimulators, suppressor of cytokine signaling-1 stimulators, suppressor of cytokine signaling-3 stimulators, SYK inhibitors, syndecan-1 inhibitors, TACE inhibitors, TAK1 binding protein regulators, talin regulators, taste receptor type 2 agonists, T box transcription factor TBX21 regulators, T cell differentiation antigen CD6 inhibitors, T cell receptor regulators,T cell receptor antagonists, T cell surface glycoprotein CD1a inhibitors, T cell surface glycoprotein CD8 inhibitors, T cell surface glycoprotein CD28 inhibitors, T cell surface glycoprotein CD8 modulators, T cell surface glycoprotein CD28 stimulators, T cell transcription factor NFAT modulators, Tec tyrosine kinase inhibitors, telomerase stimulators, tenascin modulators, TERT gene modulators, TGF-beta activated kinase-1 inhibitors, TGF-beta activation modulators, TGF beta agonists, TGF beta ligand inhibitors, TGF beta 1 ligand inhibitors, TGF beta 3 ligand inhibitors, TGF beta 1 gene inhibitors, TGF beta 1 ligand modulators agonists, TGF beta receptor antagonists, TGF beta receptor antagonists, TGF-beta type II receptor antagonists, TGFB1 gene inhibitors, thioredoxin reductase inhibitors, thrombomodulin stimulators, thromboxane A2 antagonists, thromboxane A2 receptor antagonists, thromboxane synthesis inhibitors, thymic stromal lymphopoietin ligand inhibitors, thymic stromal lymphopoietin ligand regulators, thymic stromal lymphopoietin receptor regulators, thymulin agonists, thyroid hormone receptor agonists, thyroid hormone receptor beta agonists, tissue transglutaminase inhibitors, Toll-like receptors 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 modulators, transcription factor p65 inhibitors, transcription factor RelB inhibitors, transferrin modulators, transforming growth factor β (TGF-β), transforming growth factor β activated Kinase 1 (TAK1), transglutaminase inhibitors, transthyretin modulators, 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 antagonists, , type II TNF receptor antagonists, type II TNF receptor modulators, tyrosine kinase receptor inhibitors, tyrosine kinase receptor modulators, ubiquitin ligase modulators and stimulators, ubiquitin thioesterase-30 inhibitors, uncoupling protein modulators, unspecified cell adhesion molecule inhibitors, unspecified GPCR agonists, unspecified GPCR modulators, unspecified growth factor receptor antagonists, urate anion exchanger 1 inhibitors, vanilloid VR1 agonists, vanilloid VR1 antagonists, vasopressin V1a and the like. Examples of agents useful for regulating, treating, or preventing inflammation include receptor antagonists, VDR agonists, VEGF receptor antagonists, VEGF receptor modulators, VEGF-1 receptor antagonists, VEGF-2 receptor antagonists, VEGF-3 receptor antagonists, VEGF-2 receptor modulators, VEGF-B ligand inhibitors, vimentin inhibitors, VIP1 receptor agonists, VIP2 receptor agonists, vitamin D3 receptor agonists, vitamin D3 receptor modulators, vitamin K-dependent protein C stimulators, WNT modulators, Wnt ligand inhibitors, Wnt 5A ligand inhibitors, xanthine oxidase inhibitors, X-linked inhibitor of apoptosis protein inhibitors, XPO1 gene modulators, YAP / TAZ modulators, YSK-4 protein kinase inhibitors, Zap70 tyrosine kinase inhibitors, zinc finger binding protein Aiolos inhibitors, and zonulin inhibitors. Rheumatoid arthritis

[0372] In some embodiments, a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, is co-administered with one or more agents useful for the treatment and / or prevention of a rheumatic condition.

[0373] In some embodiments, the compounds of the present disclosure, or pharma- ceutically acceptable salts thereof, are co-administered with one or more agents useful in the treatment and / or prevention of rheumatoid arthritis. Non-limiting examples of such agents include disease-modifying antirheumatic drugs, such as hydroxychloroquine, sulfasalazine, methotrexate, and leflunomide. drug, DMARDS); TNF inhibitors (e.g., etanercept, adalimumab, infliximab, golimumab, certolizumab pegol), T cell costimulation inhibitors, (e.g., abatacept), IL-6 receptor inhibitors (e.g., tocilizumab, sarilumab), anti-CD20 antibodies (e.g., rituximab); and JAK inhibitors (e.g., tofacitinib, baricitinib, upadacitinib); NSAIDs, such as ibuprofen, naproxen, and diclofenac; COX-2 inhibitors, such as celecoxib and etoricoxib; steroids and corticosteroids, such as prednisolone and cortisone; and biologic agents known for the treatment and / or prevention of such conditions, such as 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 the treatment and / or prevention of a rheumatic condition. In some embodiments, agents useful for the treatment and / or prevention of rheumatic conditions include a compound of the present disclosure and two additional therapeutic agents, for example, methotrexate + leflunomide, methotrexate + sulfasalazine, methotrexate + cyclosporine, methotrexate + hydroxychloroquine, and the triple therapy treatments hydroxychloroquine + sulfasalazine + methotrexate, hydroxychloroquine + sulfasalazine + leflunomide. lupus

[0374] In some embodiments, the compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, is co-administered with one or more agents useful for the treatment and / or prevention of systemic lupus erythematosus (SLE) or lupus nephritis (LN).Non-limiting examples of such agents include immunosuppressants that inhibit the activity of the immune system 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, voclosporin, abatacept, anifrolumab, rituximab, NSAIDs, such as naproxen sodium and ibuprofen, antimalarials, such as hydroxychloroquine, calcineurin inhibitors and tacrolimus.

[0375] In some embodiments, a compound of the disclosure, or a pharma- ceutically acceptable salt thereof, is co-administered with two or more agents useful in the treatment of LN, e.g., prednisone + mycophenolic acid analog, prednisone + sodium mycophenolate prednisone + cyclophosphamide, prednisone + tacrolimus, prednisone + voclosporin, prednisone + belimumab + mycophenolic acid analog, prednisone + belimumab + cyclophosphamide, prednisone + rituximab.

[0376] In a further embodiment, a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, is co-administered with two or more agents useful in the treatment of LN, such as prednisone plus a mycophenolic acid analog, prednisone plus sodium mycophenolate, prednisone plus azathioprine, prednisone plus tacrolimus, prednisone plus cyclosporine, prednisone plus mizoribine. Osteoarthritis

[0377] In some embodiments, the compounds of the present disclosure, or pharma- ceutically acceptable salts thereof, are co-administered with one or more agents useful for the treatment and / or prevention of 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 acetate, betamethasone acetate and betamethasone phosphate sodium acetate, triamcinolone hexacetonide, and dexamethasone. ulcerative colitis

[0378] In some embodiments, the compounds of the present disclosure, or pharma- ceutically acceptable salts thereof, are co-administered with one or more agents useful for the treatment and / or prevention of gastrointestinal conditions, such as ulcerative colitis (UC) or Crohn's disease (CD). Non-limiting examples of such agents include corticosteroids, such as infliximab, adalimumab, golimumab, vedolizumab, tofacitinib, ustekinumab, natalizumab, mesalamine, diazo-conjugated 5-ASA, sulfasalazine, balsalazide, olsalazine, budesonide, hydrocortisone, methylprednisolone and prednisone; immunosuppressants or immunomodulators, such as azathioprine and 6-mercaptopurine, cyclosporine, and methotrexate. pulmonology

[0379] In some embodiments, a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, is co-administered with one or more agents useful for the treatment and / or prevention of a pulmonary condition, such as idiopathic pulmonary fibrosis (IPF) or interstitial lung disease (ILD). Non-limiting examples of such agents include corticosteroids such as nitendanib, pirfenidone, prednisone, mycophenolates (e.g., CellCept®), azathioprine (e.g., Imuran®), leflunomide (e.g., ARAVA®), rituximab (e.g., RITUXAN®), cyclophosphamide (e.g., CYTOXAN®), tacrolimus (e.g., PROGRAF®), other rheumatology drugs including, agents that reduce stomach acid such as H-2 receptor antagonists or proton pump inhibitors such as lansoprazole (e.g., PREVACID® 24HR), omeprazole (e.g., Prilosec OTC), and pantoprazole (e.g., PROTONIX®). Hepatology and Nephrology

[0380] In some embodiments, a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, is co-administered with one or more agents useful for the treatment and / or prevention of a hepatic or renal condition, such as NAFLD, NASH, DKD, or CKD. Non-limiting examples of such agents include metformin, sodium-glucose cotransporter-2 inhibitors (SGLT2i), medications for glycemic control, DPP-4 inhibitors, insulin, sulfonylureas, thiazolidinedione (TZD), α-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), angiotensin-converting enzyme (ACE) inhibitors (e.g., saxagliptin, alogliptin, sitagliptin, linagliptin), and the like. These include one or more drugs used to treat high blood pressure, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin 2 receptor blockers (ARBs), drugs to aid in weight loss or for the control of blood sugar, cholesterol-lowering drugs (e.g., statins), fine lenone, and drugs for the treatment of diabetes mellitus, such as alpha-glucosidase inhibitors (e.g., acarbose, miglitol, voglibose). dermatology

[0381] In some embodiments, a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, is co-administered with one or more agents useful in the treatment and / or prevention of skin disorders, 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 antibacterial agents 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). synthesis

[0382] In some embodiments, methods of synthesizing compounds of Formula (I) and / or Formula (II) are provided. In some embodiments, intermediate (I-2) and compounds of Formula (II) are formed according to the following synthetic scheme: [ka]

[0383] In some embodiments, the process for preparing the compound of intermediate (I-2) comprises: [ka] Intermediate (I-1) compound: [ka] or a salt thereof with a base and chloromethyl chloroformate. In some embodiments, the base comprises a carbonate, a metal hydride, or an organic base. In some embodiments, the base is an aromatic base. In some embodiments, the base is pyridine. In some embodiments, reacting the compound of intermediate (I-2) is carried out in a solvent. In some embodiments, the solvent comprises a halogenated solvent. In some embodiments, the solvent comprises dichloromethane.

[0384] Intermediate (I-1) can be combined with a solvent such as dichloromethane, a base such as pyridine, and chloromethyl chloroformate to give intermediate (I-2). Other exemplary solvents that can be used include, but are not limited to, ethers (such as tetrahydrofuran, 2-methyltetrahydrofuran, tert-butylmethylether, etc.), polar aprotic solvents (such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, etc.), halogenated solvents (such as dichloromethane, 1,2-dichloroethane, chlorobenzene, etc.), and hydrocarbons (such as toluene, n-heptane, etc.). Other exemplary bases that can be used include, but are not limited to, carbonates (lithium, sodium, potassium, cesium carbonate, etc.), metal hydrides (sodium hydride, potassium hydride, etc.), hindered alkoxides (sodium tert-butoxide, lithium tert-butoxide, etc.), and organic bases (1,8-diazabicyclo(5.4.0)undec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene, 2,6-lutidine, etc.). Temperatures suitable for the reaction can range from -30 to 60°C.

[0385] In some embodiments, the process for preparing a compound of formula (II) comprises: [ka] The method includes reacting a compound of intermediate (I-2) or a salt thereof 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 potassium di-tert-butyl 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, reacting the compound of intermediate (I-2) is carried out in a solvent. In some embodiments, the solvent includes a halogenated solvent. In some embodiments, the solvent includes dichloromethane.

[0386] Formula (II) can be formed by combining intermediate (I-2) in a solvent with a phosphate source in the presence of a catalyst. The phosphate source can 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., tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, etc.), sodium iodide, and other promoters known in the art for promoting Finkelstein-like reactions. Exemplary solvents that can be used include ethers (tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, etc.), polar aprotic solvents (N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, etc.), halogenated solvents (dichloromethane, 1,2-dichloroethane, chlorobenzene, etc.), hydrocarbons (toluene, n-heptane, etc.), esters (ethyl acetate, isopropyl acetate, etc.), or combinations of the foregoing, optionally with water. Temperatures suitable for the reaction can range from 0 to 60°C.

[0387] In some embodiments, the process 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, para-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 an acetyl halide. In some embodiments, the acid source comprises acetyl chloride. In some embodiments, deprotecting a compound of formula (II) is carried out in a solvent. In some embodiments, the solvent comprises an alcoholic solvent. In some embodiments, the solvent comprises methanol.

[0388] In some embodiments, a compound of formula (I) is formed by deprotecting formula (II), for example, according to the following scheme: [ka]

[0389] Formula (II) can be combined with a solvent and an acid source. Examples of acids that can be used as an acid source include acetyl chloride, concentrated hydrogen chloride, concentrated sulfuric acid, phosphoric acid, trifluoroacetic acid, para-toluenesulfonic acid, hydrogen chloride gas, and anhydrous hydrogen chloride sources (i.e., acid chlorides and alcohol solvents). Solvents that can be used include alcohols (methanol, ethanol, 2-propanol, etc.), ethers (tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, etc.), polar aprotic solvents (N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, etc.), acids (acetic acid, etc.), halogenated solvents (dichloromethane, 1,2-dichloroethane, chlorobenzene, etc.), hydrocarbons (toluene, n-heptane, etc.), and / or combinations of the foregoing with water. Temperatures suitable for the reaction can range from 0 to 50°C.

[0390] In some embodiments, the process for preparing a compound of formula I comprises: (a) 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); (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 (c) deprotecting the compound of formula (II) or a salt thereof with an acid source to prepare a compound of formula I.

[0391] In some embodiments, the process for preparing a compound of formula I comprises: (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 (b) deprotecting the compound of formula (II) or a salt thereof with an acid source to prepare a compound of formula I.

[0392] In some embodiments, the process 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 process 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).

[0393] In some embodiments, the process for preparing a compound of formula (II) comprises: (a) 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); and (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).

[0394] In some embodiments, the process for 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). EXAMPLES

[0395] method Compounds of formula I were synthesized according to known methods, such as those disclosed in US Pat. No. 10,947,259. X-ray powder diffraction (XRPD)

[0396] XRPD patterns were collected on a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu Kα radiation generated using a long fine focus source and a nickel filter. The diffractometer was configured using a symmetric Bragg-Brentano geometry. Prior to analysis, a silicon specimen (NIST SRM 640e) was analyzed to confirm that the observed position of the Si111 peak matched the NIST certified position. Sample specimens were prepared as thin circular layers centered on silicon zero background substrates. An antiscatter slit (SS) was used to minimize background generated by air. Soller slits for the incident and diffracted beams were used to minimize spread from axial divergence. Diffraction patterns were collected using a scanning position sensitive detector (X'Celerator) positioned 240 mm from the sample and Data Collector software v.2.2b. Differential Scanning Calorimetry (DSC)

[0397] Differential scanning calorimetry (DSC) data was collected using a TA Instruments Q2000 Differential Scanning Calorimeter. Temperature calibration was performed using NIST traceable indium metal. Samples were placed in TO aluminum DSC pans covered with lids that were pierced using a needle. The weight was then accurately recorded. A weighed aluminum pan configured as the sample pan was placed on the reference side of the cell. Samples were heated from 0°C to 300°C at 10°C / min. Thermogravimetric analysis (TGA)

[0398] Thermogravimetric analysis (TGA) data was collected using a TA Instruments Discovery Thermogravimetric Analyzer. Temperature calibration was performed using nickel and Alumel™. Each sample was placed in an aluminum pan and inserted into the TG furnace. The furnace was heated under a nitrogen purge. Samples were heated from ambient to 300° C. at 10° C. / min. Thermogravimetric-Mass Spectrometer analysis (TG-MS)

[0399] Thermogravimetric-mass spectrometer analysis (TG-MS) was used to identify volatile outgassing and to evaluate sample weight loss as a function of temperature on a Discovery TGA (TA Instruments, New Castle, DE) by loading 1-10 mg of material onto a weighing pan and heating the sample to completely desolvate the material at a rate of 20 °C / min. Sample and reference pans were placed under a nitrogen purge of 60 mL / min and 40 mL / min, respectively. Data analysis was completed using a TRIOS (TA Instruments, New Castle, DE). The mass spectrometer was a Discovery MS (TA Instruments, New Castle, DE) benchtop quadrupole instrument. Dynamic Vapor Sorption (DVS)

[0400] 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 (2–20 mg) were placed in aluminum DVS pans and loaded on the sample side of a twin-pan balance. Water sorption 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 to 5% in 10% RH increments (occasionally increased from 0 to 90% RH and then decreased to 0%). Each relative humidity increment had an equilibration time of 120 min unless the % weight change was less than 0.01% in 20 min. 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. Proton nuclear magnetic resonance ( 1 H NMR)

[0401] Proton nuclear magnetic resonance ( 1 H NMR spectra were collected on a Bruker Avance III-HD 400 equipped with SampleXpress. Default proton parameters were: spectral width: 16.19 to -3.84 ppm (8012.8 Hz), relaxation delay: 1 s, pulse: 90 degrees, acquisition time: 4.0894 s, number of scans or repeats: 16, temperature: 25 °C. Amorphous Formula I

[0402] Amorphous Formula I was prepared by ball milling. Approximately 5 grams of Formula I Form III was loaded into a cylindrical stainless steel cell containing stainless steel balls. The cell was capped and the solid was milled in a Retsch Model MM200 ball mill at an oscillation frequency of 30 / sec for a total time of approximately 24 minutes. During this period, milling was stopped three times to check the progress by (polarized light microscopy) PLM (Polarized Light Microscopy), and at the end of milling, PLM showed no signs of birefringence. The material was stored in the cell at approximately 10° C. The next day, the solid was collected and weighed.

[0403] Amorphous Formula I was characterized by XRPD, DSC, TGA, and DVS. XRPD was performed and the diffractogram is shown in Figure 1. A DSC thermogram was obtained and is shown in Figure 2, which shows a broad endotherm (28-120°C, 135 J / g, due to loss of water), and an exotherm above about 150°C. TGA was run and the resulting thermogram is shown in Figure 3. DVS was performed and the resulting isotherm is shown in Figure 4. Formula I

[0404] Compounds of Formula I were prepared by methods known to those skilled in the art and / or according to the following reaction schemes. [ka] Introduction of carbamate and di-tert-butyl phosphate onto (I-1) to form formula (II): [ka]

[0405] Intermediate (I-1) (1.00 equiv., conversion 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 provide a dichloromethane solution of intermediate (I-2).

[0406] The reactor containing the intermediate (I-2)-dichloromethane solution was charged with tetra-n-butylammonium hydrogen sulfate (0.10 eq.) and potassium di-tert-butyl phosphate (1.24 eq.). The mixture was stirred at about 40° C. until the reaction was deemed complete. The mixture was then cooled to about 22° C. and the mixture was washed with water (5.0 vol.). The organic layer was concentrated under vacuum to about 3 vol. and N,N-dimethylacetamide (3.0 vol.) was charged. The mixture was concentrated to about 4 vol. and the temperature was adjusted to about 40° C. Formula (II) seed crystals (0.001 wt. equivalents) were charged, the mixture was stirred at about 40° C. for about 1 hour, and 2-propanol (12.0 vol.) was charged. The mixture was adjusted to about 10° C. and stirred at about 10° C., and the slurry was filtered. The filter cake was washed with 2-propanol (3.0 vol.) and then dried to obtain Formula (II). 1 H NMR (400 MHz, CDCl 3):δ8.54(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,6 H),1.43(s,9H),1.34(s,9 H0,1.03(s,9H). 13 C NMR (100 MHz, CDCl 3 ): δ162.21, 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. Deprotection of Formula (II) to Form Formula (I) [ka]

[0407] Formula (II) (1.00 equivalents, conversion factor) and methanol (3.00 volumes) were charged to a reactor. Acetyl chloride (2.97 equivalents) was charged while maintaining the temperature below about 30° C., and the mixture was stirred at about 22° C. until the reaction was deemed complete. The mixture was diluted with dichloromethane (5.0 volumes) and charged with 5 wt % aqueous sodium chloride solution (3.2 volumes). The layers were separated, and the organic layer was then concentrated under vacuum to about 4 volumes. 2-propanol (5.1 volumes) was charged, and the mixture was concentrated under vacuum to about 4.0 volumes. Water (3.0 volumes) was charged, and the mixture was stirred at about 22° C. for about 1 hour. Formula (I) seed crystals (0.002 weight equivalents) were charged, and the mixture was stirred at about 22° C. The slurry was filtered, and the filter cake was rinsed with a mixture of water (1.3 volumes) and 2-propanol (1.3 volumes), then dried to provide Formula (I). 1 H NMR (400MHz, DMSO-d 6 ):δ8.47(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,1 H),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 C NMR (100 MHz, DMSO-d 6 ):δ161.1,154.5,152.9,152.7,144.8,142.7,135.5,135.0,134.7,133.4,132.7,131.7,131.6,127.5 ,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. Formula I Form I

[0408] The reactor was charged with 1 equivalent of Formula II and the contents were flushed with nitrogen. [ka]

[0409] Methanol (3V) was added, stirring was set to 250 rpm, and the internal reactor temperature was adjusted to about 15° C. The reactor was charged with 2.3 equivalents of acetyl chloride, and the internal temperature was maintained below about 30° C. Once the addition of acetyl chloride was complete, 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 % aqueous NaCl (about 3 volumes) were added, the mixture was stirred for about 15 minutes, and allowed to stand overnight. The phases were separated. The organic stream was concentrated to about 3 volumes, 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 solids were washed with about 1 volume of pre-chilled 9:1 ethanol:water (v:v). The solid was dried under vacuum with moist nitrogen at about 20° C. and about 25% RH.

[0410] Form I of Formula I was characterized by XRPD and the resulting diffractogram is shown in Figure 5. The XRPD peak list is reported in Table 1. [Table 1]

[0411] A DSC thermogram was obtained, showing a broad endothermic event from about 25 to 100 °C and an exothermic event from about 175 to 225 °C (Figure 6). TGA-MS analysis was performed, showing mass loss due to loss of water of hydration, and evolution of carbon dioxide and formaldehyde due to decomposition. DVS was performed, and the resulting isotherm shows a weight change of about 9.5 weight percent from RH 5 to 95%, and moderate hysteresis. Formula I Form II

[0412] Method 1: A 4 mL screw-top glass vial equipped with a stir bar was charged with about 100 mg of Formula I Form I and about 2 mL of 2-propanol / water 1:1. The mixture was capped and stirred at room temperature for about 1 day to produce Formula I Form II as crystals suspended in the solution.

[0413] Method 2: A reactor was charged with 1 equivalent of Formula II and the contents were flushed with nitrogen. Methanol (about 3 volumes) was added, the agitation was set to about 250 rpm, and the internal reactor temperature was adjusted to about 15° C. The reactor was charged with 3 equivalents of acetyl chloride and the internal temperature was maintained below about 30° C. Once the addition of acetyl chloride was complete, the internal temperature was maintained at about 20° C. The mixture was stirred for about 4 hours. DCM (about 5 volumes) and 5 wt % aqueous NaCl (about 3 volumes) were added, stirred for about 15 minutes, and allowed to stand overnight. The phases were separated. The organic stream was concentrated to about 4 volumes, diluted with about 5 volumes of 2-propanol, then concentrated to about 4 volumes and diluted with about 3 volumes of water. The internal temperature was adjusted to about 20° C. and after about 1 hour about 0.005 wt % seed crystals of Formula I Form I were added and the mixture was stirred overnight. The slurry was filtered and the solid (Formula I Form II) was washed with about 2.5 volumes of 1:1 (v:v) 2-propanol:water. The solid was dried under reduced pressure at about 20° C.

[0414] Formula I Form II was characterized by XRPD, VH-XRD, single crystal X-ray crystallography, and DVS. The resulting XRPD diffractogram is shown in Figure 7. The XRPD peak list is shown in Table 2. [Table 2]

[0415] Diffractograms obtained at equilibrium at 85% RH in the VH-XRD assay were indexed using the Pauly method to determine the unit cell dimensions, reported in Table 3. [Table 3]

[0416] Single crystal X-ray crystallography of Form II was performed and the data indicated that Form II is a tetrahydrate.

[0417] FIG. 8 shows the full pattern Pauly refinement of Formula I Form II at 85% RH.

[0418] DVS showed multiple mass changes as a function of RH with low hysteresis (Figure 9). Form II was present at the highest RH points in the DVS experiments. Formula I Form III

[0419] Method 1: Formula I Form III was prepared from Form I and Form II and their mixtures by prolonged exposure to 40% RH. A relative humidity controller was used for the following analyses. The controller was programmed to maintain each target RH value of 40%, 50%, 60%, 80%, 85%, 80%, 60%, 50%, and 40% for 1 hour. Figure 10 shows the measured RH values ​​and the corresponding 5 minute XRPD repeat scans taken during the RH program. The total run time was about 14 hours, during which XRPD patterns (5 minute repeats) were collected.

[0420] Method 2: A reactor was charged with 1 equivalent of Formula II and the contents were flushed with nitrogen. Methanol (about 3 volumes) was added, the agitation was set to about 250 rpm, and the internal reactor temperature was adjusted to about 15° C. The reactor was charged with about 3 equivalents of acetyl chloride and the internal temperature was maintained below about 30° C. After the acetyl chloride addition, the internal temperature was maintained at about 20° C. The mixture was stirred for about 4 hours. DCM (about 5 volumes) and 5 wt % aqueous NaCl (about 3 volumes) were added, the mixture was stirred for about 15 minutes, and allowed to stand overnight. The phases were separated. The organic stream was concentrated to about 4 volumes, diluted with about 5 volumes of 2-propanol, then concentrated again to about 4 volumes and diluted with about 3 volumes of water. The internal temperature was adjusted to about 20° C., and after about 1 hour, about 0.002 wt % seed crystals of Form II were added, and the mixture was stirred overnight. The slurry was filtered and the solids were washed with about 2.5 volumes of 1:1 (v:v) 2-propanol:water. The solids were dried under vacuum at about 20° C.

[0421] Method 3: Approximately 1 gram of Formula I Form II was loaded into a 20 mL glass vial. The vial was covered with a Kimwipe cloth and allowed to sit 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.

[0422] Method 4: Approximately 40 mg of Formula I S-mandelate salt was loaded into a 4 mL glass vial equipped with a cap and stir bar. Approximately 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 isolated and air-dried at room temperature overnight, 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.

[0423] The samples prepared as above (Method 1, Method 2, Method 3, and Method 4) were characterized by XRPD, VH-XRD, and DVS. The resulting XRPD is shown in Figure 11, which shows the XRPD obtained at about 36% RH prepared by Method 3. The water content was assessed by KF measurement and found to be 2.3% water (1 mole, monohydrate form). The XRPD at 40% RH from the VH-XRD experiment (Method 1) is shown in Figure 12.

[0424] The 40% RH diffractograms were indexed using the Pauly method to determine the unit cell dimensions, and the results can be seen in Figure 13 and are reported in Table 4. [Table 4]

[0425] The XRPD peak list for Form III is reported in Table 5. [Table 5]

[0426] DVS was performed and the resulting isotherms are shown in FIG. Formula I Form IV

[0427] Formula I Form IV was prepared from Form III and Form II and mixtures thereof by exposure to dry nitrogen (0%-5% RH).

[0428] The samples prepared as above were characterized by VH-XRD and DVS.

[0429] The diffractogram of Formula I Form IV was indexed using the Pauly method (Figure 15). The unit cell dimensions were determined and are reported in Table 6. [Table 6]

[0430] An XRPD was collected and the resulting diffractogram is shown in Figure 16, which was obtained at equilibrium at 5% RH as indicated. The XRPD peak list for the 5% RH XRPD is reported in Table 7. [Table 7] Formula I Form V

[0431] A 20 mL screw-top glass vial was charged with about 1.4 g of Formula I Form I and about 10 mL of an ethanol / water solution (9:1 v:v). The mixture formed a suspension, the vial was capped, and the suspension was stirred with a nutating mixer at room temperature. After 12 days, a sample was taken for testing by centrifugal filtration.

[0432] Form V of Formula I 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. [Table 8]

[0433] A DSC thermogram was obtained and is shown in Figure 18. A TGA-MS was performed and the data obtained showed a combined loss of 7.3 weight percent water and ethanol from about 50 to 150°C, as well as loss of formaldehyde and carbon dioxide due to decomposition above 150°C. Formula I Form VI

[0434] A 20 mL screw-top glass vial was charged with about 1.4 g of Formula I Form I and about 10 mL of an ethanol / water solution (7.4:2.6). The mixture formed a suspension, the vial was capped, and the suspension was stirred with a nutating mixer at room temperature. After 12 days, a sample was taken for testing by centrifugal filtration.

[0435] Formula I Form VI was characterized by XRPD, DSC, and TGA-MS. The resulting XRPD diffractogram is shown in Figure 19. A second image is included with the vertical limit set to 2000 counts (Figure 20). The XRPD peak list is reported in Table 9. [Table 9]

[0436] DSC thermograms were obtained and are shown in Figure 21. TGA-MS was performed and showed a water loss of about 3.8 wt% at 30°C during the 15 minute drying period, and a combined mass loss of water and ethanol of about 7.4 wt% from about 30 to 200°C. This second mass loss indicated that ions of water and ethanol were detected at different times. Further mass loss detected above about 150°C was attributed to decomposition with loss of carbon dioxide, water, and formaldehyde. Formula I Form VII

[0437] 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.

[0438] Formula I Form VII was characterized by XRPD and TGA-MS. The resulting XRPD diffractogram is shown in Figure 22. The XRPD peak list is reported in Table 10. [Table 10]

[0439] TGA-MS was performed and the resulting thermogram showed a mass loss of about 2.9 wt.%, identified as methanol and water, from about 50 to 125° C. The mass loss above about 150° C. was attributed to carbon dioxide, water, and formaldehyde from decomposition. Formula I Form VIII

[0440] Formula I Form VIII was prepared by stirring a mixture of about 0.2-0.4 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.

[0441] Formula I Form VIII was characterized by XRPD and TGA-MS. The resulting XRPD diffractogram is shown in Figure 23. The XRPD peak list is reported in Table 11. [Table 11]

[0442] TGA-MS was run and the resulting thermogram showed a total mass loss of about 5.9 wt.%, identified as ethanol and water, from about 50 to 125 °C. The ethanol and water peaks overlapped. The mass loss above 156 °C was attributed to the decomposition products carbon dioxide, water, and formaldehyde. Formula I Form IX

[0443] Formula I Form IX was prepared by stirring a mixture of about 0.2-0.4 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.

[0444] Formula I Form IX was characterized by XRPD and TGA-MS. The resulting XRPD diffractogram is shown in Figure 33. The XRPD peak list is reported in Table 12. [Table 12]

[0445] TGA-MS was performed, which showed an overlapping mass loss of about 6.3% of surface water and acetone during the drying step at 30° C., and an overlapping mass loss of about 1.8% (also due to water and acetone) from about 30 to 150° C. Mass loss above 150° C. was observed and was attributed to the decomposition products carbon dioxide, water, and formaldehyde. Formula I Form X

[0446] Formula I Form X was prepared by stirring a mixture of about 0.2-0.4 grams of Formula I Form I in about 3 mL of THF at room temperature for several days. The solid was isolated by centrifugal filtration and characterized.

[0447] Form X of Formula I was characterized by XRPD and TGA-MS. The resulting XRPD diffractogram is shown in Figure 25. The XRPD peak list is reported in Table 13. [Table 13]

[0448] TGA-MS was performed and the resulting thermograms showed an overlapping mass loss of about 8.5% of surface water and THF during the drying step at 30° C., and an overlapping mass loss of about 8.5% (also due to water and THF) from about 30 to 150° C. The mass loss above 150° C. was due to the decomposition products carbon dioxide, water, and formaldehyde. Formula I Form XI

[0449] Formula I Form XI was prepared by stirring a mixture of about 0.2-0.4 grams 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.

[0450] Form XI of Formula I was characterized by XRPD and TGA-MS. The resulting XRPD diffractogram is shown in Figure 26. The XRPD peak list is reported in Table 14. [Table 14]

[0451] TGA-MS was performed and showed a mass loss of about 2.6% from surface water during the drying step at 30 °C, with an overlapping mass loss of about 3.8% from about 30 to 150 °C attributed to water and DCM. Mass loss above 150 °C was observed and was attributed to the decomposition products carbon dioxide, water, and formaldehyde. Formula I Form XII

[0452] Formula I Form XII was prepared by stirring a mixture of about 0.2-0.4 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.

[0453] Form XII of Formula I was characterized by XRPD and TGA-MS. The resulting XRPD diffractogram is shown in Figure 27. The XRPD peak list is reported in Table 15. [Table 15]

[0454] TGA-MS was performed, which showed a mass loss of about 4.2% from surface water during the drying step at 30 °C, and an overlapping mass loss of about 1.2% from about 30 to 150 °C due to water. A loss of MTBE was observed from about 100 to 200 °C, with the overlapping mass loss due to the decomposition products carbon dioxide, water, and formaldehyde. Formula I Form XIII

[0455] Formula I Form XIII was prepared by stirring a mixture of about 0.2-0.4 grams of Formula I Form I in about 3 mL of IPA at room temperature for several days. The solid was isolated by centrifugal filtration and characterized.

[0456] Formula I Form XIII was characterized by XRPD and TGA-MS. The resulting XRPD diffractogram is shown in Figure 28. The XRPD peak list is reported in Table 16. [Table 16]

[0457] TGA-MS was performed and showed a mass loss of about 3.7% of the surface water and IPA during the drying process at 30 °C, with an overlapping mass loss of about 10.7% due to water and IPA from about 30 to 150 °C. The mass loss above 150 °C was due to the decomposition products carbon dioxide, water, and formaldehyde. Formula I Form XIV

[0458] Formula I Form XIV was prepared by stirring a mixture of about 0.2-0.4 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.

[0459] Formula I Form XIX was characterized by XRPD and TGA-MS. The resulting XRPD diffractogram is shown in Figure 29. The XRPD peak list is reported in Table 17. [Table 17]

[0460] TGA-MS was performed, which showed a mass loss of about 1.6% of surface water and 1-propanol during the drying step at 30° C., and an overlapping mass loss of about 11.6% from about 30 to 150° C. due to water and 1-propanol. Mass loss above 150° C. was observed and was attributed to the decomposition products carbon dioxide, water, and formaldehyde. Formula I Form XV

[0461] Formula I Form XV was prepared by stirring a mixture of about 0.2-0.4 grams 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.

[0462] Form XV of formula I was characterized by XRPD and TGA-MS. The resulting XRPD diffractogram is shown in Figure 30. The XRPD peak list is reported in Table 18. [Table 18]

[0463] TGA-MS was performed and showed a mass loss of about 8.3% of surface water and CPME during the drying process at 30 °C, with an overlapping mass loss of about 3.2% from about 30 to 150 °C due to water and CPME. CPME was seen from about 5 to 200 °C, with the overlapping mass loss due to the decomposition products carbon dioxide, water, and formaldehyde. Formula I 2-(4-hydroxybenzoyl)benzoate

[0464] A 4 mL screw-top 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.

[0465] 2-(4-hydroxybenzoyl)benzoate of formula I was analyzed by XRPD, DSC, TGA, and 1 The solid was characterized by H NMR. The resulting XRPD diffractogram of the freshly isolated solid (Formula I 2-(4-hydroxybenzoyl)benzoate Form A) as a wet cake is shown in Figure 31. The XRPD peak list is reported in Table 19. [Table 19]

[0466] The above 2-(4-hydroxybenzoyl)benzoate Form A of Formula I was allowed to air dry. The resulting solid form, 2-(4-hydroxybenzoyl)benzoate Form B of Formula I, was characterized. The XRPD diffractogram of Formula I 2-(4-hydroxybenzoyl)benzoate Form B is shown in FIG. 32. A DSC thermogram of Formula I 2-(4-hydroxybenzoyl)benzoate Form B was performed and the resulting thermogram is shown in FIG. 33, which shows a broad endothermic event from about 30 to 100° C., as well as 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 FIG. 34. 1 H NMR indicated about 0.63 wt % IPAc (about 0.07 moles) and a ratio of Formula I:2-(4-hydroxybenzoyl)benzoate of 1.0:0.96. Formula I Vanillic Acid Salt

[0467] A 4 mL screw-top glass vial was charged with about 0.2 g of Formula I, about 2 equivalents of vanillic 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 for testing.

[0468] The vanillic acid salt of formula I was analyzed by XRPD, DSC, TGA, and 1 The solid was characterized by H NMR. The resulting XRPD diffractogram of the newly isolated solid (Formula I vanillate salt Form A) is shown in Figure 35. The XRPD peak list of Formula I vanillate salt Form A is reported in Table 20. [Table 20]

[0469] Vanillate Formula I Form A, as described above, was allowed to air dry. The resulting solid form, vanillate Formula I Form B, was characterized. The XRPD diffractogram of vanillate Formula I Form B is shown in FIG. 36. A DSC thermogram of vanillate Formula I Form B was performed and the resulting thermogram is shown in FIG. 37, which shows a broad endothermic event from about 30-100° C., as well as broad endothermic and exothermic events above about 150° C. A TGA of vanillate Formula I Form B was performed and the resulting thermogram is shown in FIG. 38. 1 1 H NMR indicated approximately 1.5% by weight IPAc and a Formula I:vanillic acid ratio of 1:0.44. Formula I Hippurate

[0470] A 4 mL screw-top glass vial was charged with about 0.2 g of Formula I, about 2 equivalents of hippuric 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 for testing.

[0471] The hippuric acid salt of formula I was analyzed by XRPD, DSC, TGA, and 1 The solid was characterized by H NMR. The resulting XRPD diffractogram of the newly isolated solid (Formula I hippuric acid salt Form A) is shown in Figure 39. The XRPD peak list of Formula I hippuric acid salt Form A is reported in Table 21. [Table 21]

[0472] The above Hippuric acid salt Form A of Formula I was allowed to air dry. The resulting solid form, Hippuric acid salt Form B of Formula I, was characterized. An XRPD diffractogram of Hippuric acid salt Form B of Formula I is shown in FIG. 40. A DSC thermogram of Hippuric acid salt Form B of Formula I was performed and the resulting thermogram is shown in FIG. 41, which shows a broad endothermic event from about 30-100° C., as well as broad endothermic and exothermic events above about 150° C. A TGA of Hippuric acid salt Form B of Formula I was performed and the resulting thermogram is shown in FIG. 42. 1 1 H NMR indicated approximately 0.45% by weight IPAc and a Formula I:hippuric acid ratio of 1:0.49. Formula I Maleate Salt

[0473] A 4 mL screw-top glass vial was charged with about 0.2 g of Formula I, about 2 equivalents of maleic acid, and about 2 mL of isopropyl acetate. The vial was capped and stirred at room temperature for about 12 days. The solid was isolated by centrifugation for testing.

[0474] The maleate salt of formula I was analyzed by XRPD, DSC, TGA, and 1 The solid was characterized by H NMR. The resulting XRPD diffractogram of the newly isolated solid (Formula I Maleate Salt Form A) is shown in Figure 43. The XRPD peak list is reported in Table 22. [Table 22]

[0475] The above maleate salt Form A of Formula I was allowed to air dry. The resulting solid form, maleate salt Form B of Formula I, was characterized. The XRPD diffractogram of maleate salt Form B of Formula I is shown in Figure 44. The XRPD peak list is included in Table 23. [Table 23]

[0476] A DSC thermogram of Formula I maleate salt form B was run and the resulting thermogram is shown in Figure 45, which shows a broad endothermic event from about 30 to 100° C., as well as broad endothermic and exothermic events above about 150° C. A TGA thermogram of Formula I maleate salt form B was run and the resulting thermogram is shown in Figure 46. 1 1 H NMR indicated a Formula I:maleic acid ratio of about 1:0.4 and about 0.05 wt % IPAc. Formula I Glyoxylate

[0477] A 4 mL screw-top glass vial was charged with about 0.1 g of Formula I, about 2 equivalents of glyoxylic acid, and about 2 mL of isopropyl acetate. The vial was capped and stirred at room temperature for about 12 days. The solid was isolated by centrifugation for testing.

[0478] The glyoxylate salt of formula I was analyzed by XRPD, DSC, TGA, and 1 The solid was characterized by H NMR. The resulting XRPD diffractogram of the newly isolated solid (Formula I glyoxylate salt Form A) is shown in Figure 47. The XRPD peak list is reported in Table 24. [Table 24]

[0479] The glyoxylate salt Form A of Formula I above was allowed to air dry. The resulting solid form, glyoxylate salt Form B of Formula I, was characterized. The XRPD diffractogram of glyoxylate salt Form B of Formula I is shown in Figure 48. The XRPD peak list is reported in Table 25. [Table 25]

[0480] A DSC thermogram of glyoxylate salt Form B of Formula I was performed and the resulting thermogram is shown in Figure 49. A TGA of glyoxylate salt Form B of Formula I was run and the resulting thermogram is shown in Figure 50. 1 Solid state H NMR showed the Formula I:glyoxyl ratio to be about 1.0:0.77, with about 3.0 wt % IPAc present. Formula I L-pyroglutamate

[0481] A 4 mL screw-top glass vial was charged with about 0.1 g of Formula I, about 2 equivalents of L-pyroglutamic acid, and about 2 mL of isopropyl acetate. The vial was capped and stirred at room temperature for about 12 days. The solid was isolated by centrifugation for testing.

[0482] The L-pyroglutamate salt of formula I was analyzed by XRPD, DSC, and 1 Characterized by H NMR. The resulting XRPD diffractogram of (wet cake) is shown in Figure 67. The XRPD peak list is reported in Table 26. [Table 26]

[0483] The L-pyroglutamate salt of formula I was air-dried and characterized by DSC (Figure 52). 1 1 H NMR showed that the ratio of Formula I:L-pyroglutamine was about 1.0:0.63, with about 0.8% by weight IPAc present. Formula I 2-Naphthalenesulfonate

[0484] A 4 mL screw-top 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.

[0485] The 2-naphthalenesulfonate salt of formula I was analyzed by XRPD, DSC, TGA, and 1 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. [Table 27]

[0486] 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. [Table 28]

[0487] A DSC thermogram of the air-dried 2-naphthalenesulfonate salt of Formula I was performed and the resulting thermogram is shown in Figure 55. A TGA was performed on the air-dried solid and the thermogram of the 2-naphthalenesulfonate salt of Formula I is shown in Figure 56. 1 1 H NMR showed a Formula I:2-naphthalenesulfonate ratio of 1.0:0.99 with 3.1 wt % IPAc present. Formula I 1-Naphthalenesulfonate

[0488] A 4 mL screw-top glass vial was charged with about 0.1 g of Formula I, about 1 equivalent of 1-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 for testing.

[0489] The resulting 1-naphthalenesulfonate salt of formula I was analyzed by XRPD, DSC, and 1 The solid was characterized by H NMR. The resulting XRPD diffractogram of the freshly prepared solid (Formula I 1-naphthalene wetcake) is shown in Figure 57. The XRPD peak list is reported in Table 29. [Table 29]

[0490] The above wet cake of 1-naphthalenesulfonate salt of Formula I was air-dried and subjected to XRPD analysis. The XRPD diffractogram of the air-dried 1-naphthalenesulfonate salt of Formula I is shown in Figure 58. The XRPD peak list is reported in Table 30. [Table 30]

[0491] DSC was performed on the air-dried 1-naphthalenesulfonate salt of Formula I, and the resulting thermogram is shown in Figure 59. 1 H NMR showed the Formula I:1-NSA ratio was 1.0:0.60 with 4.0 wt % IPAc present. Formula I 1-Hydroxy-2-naphthoic acid salt

[0492] A 4 mL screw-top glass vial was charged with about 0.1 g of Formula I, about 2 equivalents of 1-hydroxy-2-naphthoic 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 for testing.

[0493] The 1-hydroxy-2-naphthoic acid salt of formula I was analyzed by XRPD, DSC, TGA, and 1 The solid was characterized by H NMR. The resulting XRPD diffractogram of the freshly prepared solid (Formula I 1-hydroxy-2-naphthoic acid salt wetcake) is shown in Figure 60. The XRPD peak list is reported in Table 31. [Table 31]

[0494] 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. [Table 32]

[0495] DSC was performed on the air-dried 1-hydroxy-2-naphthoic acid salt of Formula I and the resulting thermogram is shown in Figure 62. The TGA thermogram of 1-hydroxy-2-naphthoic acid salt of Formula I is shown in Figure 63. 1 1 H NMR showed the ratio of Formula I:1-hydroxy-2-naphthoic acid to be about 1.0:0.43 with about 1.4 wt % IPAc present. Formula I S-Mandelate

[0496] A 4 mL screw-top glass vial was charged with about 0.2 g of Formula I, about 2 equivalents of S-mandelic acid, and about 3 mL of isopropyl acetate. The vial was capped and stirred at room temperature for about 30 days. The solid was isolated by centrifugation.

[0497] The S-mandelate salt of formula I was analyzed by XRPD, DSC, TGA, and 1 The compound was characterized by H NMR. The resulting XRPD diffractogram of the freshly prepared solid (wet cake) (Formula IS-Mandelate Salt Form A) is shown in Figure 64. The XRPD peak list is reported in Table 33. [Table 33]

[0498] The above Formula I S-mandelate Form A was allowed to air dry. The resulting solid form, Formula I S-mandelate Form B, was subjected to XRPD analysis. The XRPD diffractogram of Formula I S-mandelate Form B is shown in Figure 65. The XRPD peak list for Formula I S-mandelate Form B is reported in Table 34. [Table 34]

[0499] A DSC thermogram of Formula I S-mandelate Form B was performed and the resulting thermogram is shown in Figure 66, which shows a broad endothermic event from about 50 to 75°C, a sharp endothermic event at about 150°C. The endothermic and exothermic events at higher temperatures were attributed to decomposition. A TGA thermogram of Formula I S-mandelate Form B is shown in Figure 67, which shows a mass loss of about 3.0 weight percent up to about 100°C and a larger mass loss above 150°C, which may be attributed to decomposition. 1 H NMR showed that the formula I:S-mandelic acid ratio was 1.0:0.6 and the IPAc content was 2.2 wt%. Formula I gentisate

[0500] A 4 mL screw-top glass vial was charged with about 0.2 g of Formula I, about 2 equivalents of gentisic acid, and about 3 mL of isopropyl acetate. The vial was capped and stirred at room temperature for about 30 days. The solid was isolated by centrifugation.

[0501] The gentisate salt of formula I was analyzed by XRPD, DSC, TGA, and 1 Characterized by H NMR. The resulting XRPD diffractogram of the freshly prepared solid (Formula I gentisate wetcake) is shown in Figure 68. The XRPD peak list is reported in Table 35. [Table 35]

[0502] The above Formula I gentisate wet cake was allowed to air dry. The resulting solid form was characterized by XRPD. The resulting XRPD diffractogram is shown in Figure 69. The XRPD peak list is reported in Table 36. [Table 36]

[0503] A DSC thermogram was taken of the air-dried gentisate salt of Formula I and the resulting thermogram is shown in Figure 70. A TGA was run of the air-dried gentisate salt of Formula I and the resulting thermogram is shown in Figure 71. The TGA showed a mass loss of about 1.5 weight percent up to about 100°C and a larger mass loss above 150°C, which may be due to decomposition. 1 1 H NMR showed that the ratio of Formula I:gentisic acid was 1.0:0.8 and the IPAc content was 2.6 wt %. Formula I Citrate Salt

[0504] A 4 mL screw-top glass vial was charged with about 0.2 g of Formula I, about 2 equivalents of citric acid, and about 3 mL of isopropyl acetate. The vial was capped and stirred at room temperature for about 30 days. The solid was isolated by centrifugation for testing.

[0505] The citrate salt of formula I was analyzed by XRPD, DSC, TGA, and 1 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. [Table 37]

[0506] The above citrate salt of Formula I was allowed to air dry. The resulting solid form was characterized by XRPD (Figure 73). The XRPD peak list is reported in Table 38. [Table 38]

[0507] DSC was performed on the air-dried Formula I citrate salt and the resulting thermogram is shown in Figure 74. TGA was run on Formula I citrate salt Form B and the resulting thermogram is shown in Figure 75, which showed a mass loss of about 2.3 weight percent up to about 100°C and a larger mass loss above 150°C, which may be due to decomposition. 1 H NMR showed that the Formula I:citric acid ratio was 1.0:0.8 and the IPAc content was 0.3 wt%. Formula I R-Mandelate

[0508] A 4 mL screw-top glass vial was charged with about 0.2 g of Formula I, about 2 equivalents of R-mandelic acid, and about 3 mL of isopropyl acetate. The vial was capped and stirred at room temperature for about 30 days. The solid was isolated by centrifugation for testing.

[0509] The R-mandelate salt of formula I was analyzed by XRPD, DSC, TGA, and 1 The solid was characterized by H NMR. The resulting XRPD diffractogram of the freshly prepared solid (Formula I R-mandelate salt Form A) is shown in Figure 76. The XRPD peak list is reported in Table 39. [Table 39]

[0510] The above Formula I R-mandelate salt Form A was allowed to air dry. The resulting solid form, Formula I R-mandelate salt Form B, was characterized by XRPD. The XRPD diffractogram of Formula I R-mandelate salt Form B is shown in Figure 77. The XRPD peak list is reported in Table 40. [Table 40]

[0511] DSC of Formula I R-mandelate Form B was performed and the resulting thermogram is shown in Figure 78, which shows a broad endothermic event between about 50-75°C, a sharp endothermic event at about 150°C, and endothermic and exothermic events at higher temperatures, which may be due to decomposition. TGA of Formula I R-mandelate Form B was performed and the resulting thermogram is shown in Figure 79. The TGA showed a mass loss of about 3.3 weight percent up to about 100°C, and a larger mass loss above 150°C, which may be due to decomposition. 1 1 H NMR showed the formula I:R mandelic acid ratio to be about 1:0.5, with IPAc being about 0.7 wt %. Formula I Benzoate

[0512] A 4 mL screw-top glass vial was charged with about 0.2 g of Formula I, about 2 equivalents of benzoic acid, and about 3 mL of isopropyl acetate. The vial was capped and stirred at room temperature for about 30 days. The solid was isolated by centrifugation for testing.

[0513] The benzoate salt of formula I was analyzed by XRPD, DSC, TGA, and 1 The compound was characterized by H NMR. The resulting XRPD diffractogram of the freshly prepared solid (wet cake) (Formula I Benzoate Form A) is shown in Figure 80. The XRPD peak list is reported in Table 41. [Table 41]

[0514] The above benzoate salt form A of formula I was allowed to air dry. The resulting solid form, benzoate salt form B of formula I, was characterized. The XRPD diffractogram of benzoate salt form B of formula I is shown in Figure 81. The XRPD peak list is reported in Table 42. [Table 42]

[0515] A DSC thermogram of Formula I benzoate Form B was performed and the resulting thermogram is shown in Figure 82. A TGA of Formula I benzoate Form B was run and the resulting thermogram is shown in Figure 83. 1 1 H NMR showed that the Formula I:benzoic acid ratio was about 1.0:0.5 and the IPAc content was about 1.9 wt %. Formula I Methylparabenate

[0516] A 4 mL screw-top glass vial was charged with about 0.2 g of Formula I, about 2 equivalents of methyl parabenate, and about 3 mL of isopropyl acetate. The vial was capped and stirred at room temperature for about 30 days. The solid was isolated by centrifugation.

[0517] Methyl parabenate of formula I was analyzed by XRPD, DSC, TGA, and 1 Characterized by H NMR. The resulting XRPD diffractogram of the freshly prepared solid (wet cake) (Formula I methyl parabenate Form A) is shown in Figure 85. The XRPD peak list is reported in Table 43. [Table 43]

[0518] The above methyl parabenate form A of formula I was allowed to air dry. The resulting solid form, methyl parabenate form B of formula I, was characterized by XRPD (Figure 85). The XRPD peak list is reported in Table 44. [Table 44]

[0519] A DSC thermogram of methyl parabenate Form B of Formula I was performed and the thermogram is shown in Figure 86. A TGA of methyl parabenate Form B of Formula I was run and the resulting thermogram is shown in Figure 87. 1 1 H NMR showed the Formula I:methylparaben ratio to be about 1.0:0.7 and the IPAc content to be about 0% by weight. Formula I Caffeate

[0520] A 4 mL screw-top glass vial was charged with about 0.2 g of Formula I, about 2 equivalents of caffeic acid, and about 3 mL of isopropyl acetate. The vial was capped and stirred at room temperature for about 30 days. The solid was isolated by centrifugation.

[0521] The caffeate salt of formula I was analyzed by XRPD, DSC, TGA, and 1 The solid was characterized by H NMR. The resulting XRPD diffractogram of the freshly prepared solid (Formula I caffeate wetcake) is shown in Figure 88. The XRPD peak list is reported in Table 45. [Table 45]

[0522] The above caffeate Formula I wet cake was air dried and characterized by XRPD. The resulting XRPD diffractogram is shown in Figure 89. DSC of the air dried caffeate Formula I was performed and the resulting thermogram is shown in Figure 90. TGA was run and the resulting thermogram is shown in Figure 91. 1 1 H NMR showed the ratio of Formula I:caffeic acid to be about 1.0:1.3. Formula I Glycolic Acid Salt

[0523] A 4 mL screw-top glass vial was charged with a stir bar, about 0.9 g of Formula I Form II, 1.0 equivalent 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 isolated by centrifugation for XRPD characterization.

[0524] The glycolate salt of formula I was analyzed by XRPD, 1 It was characterized by H NMR, and DVS. 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. [Table 46]

[0525] The above glycolic acid salt wet cake of Formula I was vacuum dried. The resulting solid form was characterized by XRPD and the resulting diffractogram is shown in Figure 93. The XRPD peak list is reported in Table 47. [Table 47]

[0526] DVS was performed on the dried Formula I glycolate salt and showed a weight change of approximately 7.5% from 0 to 90% RH. Weak hysteresis was observed and the behavior was nearly linear. The weight change from 50 to 90% RH was approximately 2%. 1 1 H NMR showed the ratio of Formula I:glycolic acid to be 1.0:0.8. Formula I α-ketobutyrate

[0527] A flask was charged with a stir bar, about 5.0 g of Formula I 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 sampled for testing. The suspension was filtered, washed with about 2 mL of ethyl acetate the next day, air dried for about 1 day, and then vacuum dried at about 40° C. for about 7 days.

[0528] The α-ketobutyrate salt of formula I was analyzed by XRPD, 1 Characterized by H NMR, and DVS. The resulting XRPD diffractogram of Formula I α-ketobutyrate wet cake is shown in Figure 94. The XRPD peak list is reported in Table 48. [Table 48]

[0529] The above formula I α-ketobutyrate salt was characterized by air- and XRPD (Figure 95). The XRPD peak list of the dry material is reported in Table 49. [Table 49]

[0530] A DVS isotherm of Formula I α-ketobutyrate salt form B was performed and the resulting isotherm showed a weight change of about 5.5% from 0-90% RH. Hysteresis was small from 10-90% RH, but a slope change was observed from 0-10% RH. The weight change from 50-90% RH was about 2%. 1 1 H NMR showed the ratio of Formula I:glycolic acid to be 1.0:0.8. Formula I Pyruvate

[0531] A screw-top glass vial was charged with about 5 grams of Formula I Form I, about 1.0 equivalent of pyruvic acid, and about 10 mL of ethyl acetate. The vial was capped and the suspension was magnetically stirred at room temperature for about 5 days. The suspension was filtered and the cake was washed with about 2 mL of ethyl acetate. The cake was dried under vacuum at room temperature to isolate the product.

[0532] The pyruvate salt of formula I was analyzed by XRPD, 1 It was characterized by H NMR, and DVS. 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. [Table 50]

[0533] The pyruvate salt of Formula I above was dried under vacuum and subjected to XRPD. The XRPD thermogram is shown in Figure 97. The XRPD peak list is reported in Table 51. [Table 51]

[0534] DVS of pyruvate form B 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 50-90% RH is about 2.5%. 1 1 H NMR indicated a Formula I:pyruvic acid ratio of 1.0:0.90. stability studies

[0535] Amorphous material of Formula I and Forms I, II, III, and IV were tested for loss of purity over time as determined by liquid chromatography. As seen by the data presented in Table 57, Formula I Forms II, III, and IV exhibit reduced loss of purity over time when compared to Formula I Form I or amorphous material of Formula I.

[0536] Sample preparation for the stability study is described below. Amorphous Form I: A sample of the amorphous solid was placed open to air at about 22° C. and the purity was monitored by liquid chromatography over a period of 3 days. 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. Formula I Form II: A sample of Formula I Form II was placed in an open vial. The vial was placed in a container with a saturated salt solution 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 periodically monitored by liquid chromatography. Formula I Form III: A sample of Formula I Form II was placed in an open vial. The vial was placed in a container with a saturated salt solution 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 periodically monitored by liquid chromatography. Formula I Form IV: A sample of Formula I Form IV was packaged in a PE bag at about 0% RH and heat sealed in a foil pouch. The pouch was then placed in a chamber at about 40° C. and the purity was monitored periodically by liquid chromatography.

[0537] The results are reported in Table 52. [Table 52] * * *

[0538] Unless otherwise defined, 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 pertains.

[0539] Thus, while the present disclosure has been specifically disclosed in terms of preferred embodiments, it is to be understood that any features, modifications, improvements, and variations of the disclosure embodied herein disclosed herein may be utilized by one of ordinary skill in the art, and such modifications, improvements, and variations are deemed to be within the scope of the present disclosure. The materials, methods, and examples provided herein are representative of preferred embodiments, are illustrative, and are not intended as limitations on the scope of the present disclosure.

[0540] The present disclosure has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the present disclosure. This includes the general description of the present disclosure with any conditional or negative limitation removing any subject matter from the genus, regardless of whether the excised material is specifically set forth herein.

[0541] In addition, when features or aspects of the disclosure are described in terms of a Markush group, those skilled in the art will recognize that the disclosure is also described in terms of any individual members or subgroups of members of the Markush group.

[0542] While the present disclosure has been described in conjunction with the above embodiments, it should be understood that the foregoing description and examples are intended to be illustrative and not limiting of 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 this disclosure pertains.

Claims

1. A solid form of Formula I Form II, wherein said Formula I has the following structure: 【Chemistry 13】

2. 10. The solid form of claim 1, characterized by an X-ray diffraction pattern having 2θ reflections at 7.4, 9.4, and 10.6 degrees 2θ, plus or minus 0.2 degrees 2θ.

3. 3. The solid form of claim 1 or 2, characterized by an X-ray diffraction pattern further comprising 2-theta reflections at 8.8, 12.3, and 26.1 degrees 2-theta, plus or minus 0.2 degrees 2-theta.

4. 4. The solid form of any one of claims 1 to 3, characterized by an X-ray diffraction pattern further comprising 2θ reflections at 14.7, 18.1, and 22.4 degrees 2θ, plus or minus 0.2 degrees 2θ.

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

6. 6. The solid form of any one of claims 1 to 5, having a full-pattern Pauly refined diffractogram substantially as shown in Figure 8.

7. A solid form of Formula I Form III, wherein said Formula I has the following structure: 【Chemistry 14】

8. 8. The solid form of claim 7, characterized by an X-ray diffraction pattern having 2θ reflections at 7.8, 9.8, and 10.7 degrees 2θ, plus or minus 0.2 degrees 2θ.

9. 9. The solid form of claim 7 or 8, characterized by an X-ray diffraction pattern further comprising 2-theta reflections at 8.9, 12.5, and 20.1 degrees 2-theta, plus or minus 0.2 degrees 2-theta.

10. 10. The solid form of any one of claims 7 to 9, characterized by an X-ray diffraction pattern further comprising 2θ reflections at 15.5, 18.2, and 22.9 degrees 2θ, plus or minus 0.2 degrees 2θ.

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

12. 12. The solid form of any one of claims 7 to 11, having a dynamic vapor sorption isotherm substantially as shown in Figure 14.

13. A solid form of formula I Form IV, wherein said formula I has the following structure: 【Chemistry 15】

14. 14. The solid form of claim 13, characterized by an X-ray diffraction pattern having 2θ reflections at 8.0, 18.1, and 20.0 degrees 2θ, plus or minus 0.2 degrees 2θ.

15. 15. The solid form of claim 13 or 14, characterized by an X-ray diffraction pattern further comprising 2θ reflections at 9.0, 9.9, and 10.8 degrees 2θ, plus or minus 0.2 degrees 2θ.

16. 16. The solid form of any one of claims 13 to 15, characterized by an X-ray diffraction pattern further comprising 2θ reflections at 15.6, 22.8, and 24.9 degrees 2θ, plus or minus 0.2 degrees 2θ.

17. 17. The solid form of 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 said formula I has the following structure: 【Chemistry 16】

19. 20. The solid form of claim 18, characterized by an X-ray diffraction pattern having 2θ reflections at 6.2, 8.4, and 22.6 degrees 2θ, plus or minus 0.2 degrees 2θ.

20. 20. The solid form of claim 18 or 19, characterized by an X-ray diffraction pattern further comprising 2θ reflections at 10.3, 10.9, and 11.7 degrees 2θ, plus or minus 0.2 degrees 2θ.

21. 21. The solid form of any one of claims 18 to 20, characterized by an X-ray diffraction pattern further comprising 2θ reflections at 16.1, 16.4, and 17.3 degrees 2θ, plus or minus 0.2 degrees 2θ.

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

23. 23. The solid form of any one of claims 18 to 22, having a mass loss of about 2.9% by weight at temperatures between about 50 and 125°C when subjected to thermogravimetry-mass spectrometry.

24. A solid form of Formula I Form IX, wherein said Formula I has the structure: 【Chemistry 17】

25. 25. The solid form of claim 24, characterized by an X-ray diffraction pattern having 2θ reflections at 7.2, 5.8, and 5.7 degrees 2θ, plus or minus 0.2 degrees 2θ.

26. 26. The solid form of claim 24 or 25, characterized by an X-ray diffraction pattern further comprising 2θ reflections at 10.7, 15.3, and 17.1 degrees 2θ, plus or minus 0.2 degrees 2θ.

27. 27. The solid form of any one of claims 24 to 26, characterized by an X-ray diffraction pattern further comprising 2θ reflections at 7.4, 10.0, and 8.9 degrees 2θ, plus or minus 0.2 degrees 2θ.

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

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

30. A solid form of S-mandelate salt Form A of Formula I, wherein said Formula I has the following structure: 【Chemistry 18】

31. 31. The solid form of claim 30, characterized by an X-ray diffraction pattern having 2θ reflections at 5.5, 5.7, and 6.3 degrees 2θ, plus or minus 0.2 degrees 2θ.

32. 32. The solid form of claim 30 or 31, characterized by an X-ray diffraction pattern further comprising 2-theta reflections at 11.4, 16.6, and 20.8 degrees 2-theta, plus or minus 0.2 degrees 2-theta.

33. 33. The solid form of any one of claims 30-32, characterized by an X-ray diffraction pattern further comprising 2θ reflections at 10.0, 10.4, and 19.0 degrees 2θ, plus or minus 0.2 degrees 2θ.

34. 34. The solid form of 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 said Formula I has the following structure: 【Chemistry 19】

36. 36. The solid form of claim 35, characterized by an X-ray diffraction pattern having 2θ reflections at 5.7, 6.2, and 22.6 degrees 2θ, plus or minus 0.2 degrees 2θ.

37. 37. The solid form of claim 35 or 36, characterized by an X-ray diffraction pattern further comprising 2-theta reflections at 8.0, 8.4, and 11.7 degrees 2-theta, plus or minus 0.2 degrees 2-theta.

38. 38. The solid form of any one of claims 35-37, characterized by an X-ray diffraction pattern further comprising 2θ reflections at 13.5, 16.0, and 16.6 degrees 2θ, plus or minus 0.2 degrees 2θ.

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

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

42. 67. The solid form of 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 said Formula I has the following structure: 【Chemistry 20】

44. 44. The solid form of claim 43, characterized by an X-ray diffraction pattern having 2θ reflections at 5.7, 5.4, and 16.5 degrees 2θ, plus or minus 0.2 degrees 2θ.

45. 45. The solid form of claim 43 or 44, characterized by an X-ray diffraction pattern further comprising 2θ reflections at 6.2, 7.8, and 11.5 degrees 2θ, plus or minus 0.2 degrees 2θ.

46. 46. ​​The solid form of any one of claims 43-45, characterized by an X-ray diffraction pattern further comprising 2θ reflections at 10.5, 13.4, and 18.5 degrees 2θ, plus or minus 0.2 degrees 2θ.

47. 92. The solid form of 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 said Formula I has the following structure: 【Chemistry 21】

49. 49. The solid form of claim 48, characterized by an X-ray diffraction pattern having 2θ reflections at 6.2, 8.3, and 22.4 degrees 2θ, plus or minus 0.2 degrees 2θ.

50. 50. The solid form of claim 48 or 49, characterized by an X-ray diffraction pattern further comprising 2θ reflections at 15.9, 16.3, and 17.0 degrees 2θ, plus or minus 0.2 degrees 2θ.

51. 51. The solid form of any one of claims 48-50, characterized by an X-ray diffraction pattern further comprising 2θ reflections at 10.0, 10.8, and 11.6 degrees 2θ, plus or minus 0.2 degrees 2θ.

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

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

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

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

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

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

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

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

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

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

62. 56. 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 a liver disease, and the compound useful for modulating Cot is a solid form according to any one of claims 1 to 55.

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