2-oxoquinazoline crystalline form

Abstract

The present disclosure provides crystalline forms of the compound having formula (I), which are crystalline forms A-U. Crystalline forms A-U are characterized by X-ray powder diffraction (XRPD) patterns. Selected crystalline forms are further characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and / or polarized light microscopy (PLM) profiles. The present disclosure also provides a substantially amorphous form of the compound having formula (I) prepared by milling any one of crystalline forms A-U, particularly crystalline form T. The present disclosure also provides methods for preparing crystalline forms, particularly crystalline forms A, C, D, E, and I. The present disclosure also provides solid-state forms of the compound of formula (I) and methods for their manufacture. The present disclosure further provides methods for treating diseases mediated by MAT2A, such as cancer, using the crystalline forms of the present disclosure or pharmaceutical compositions thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS Not applicable

[0002] STATEMENT REGARDING RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT Not applicable

[0003] Reference to a "Sequence Listing," table, or computer program listing appendix submitted on a compact disc Not applicable [Background technology]

[0004] Cancer is a leading cause of death worldwide. A limitation of commonly used therapeutic approaches, such as chemotherapy and immunotherapy, is that their cytotoxic effects are not restricted to cancer cells and can cause harmful side effects in normal tissues. Therefore, new strategies are needed to better target cancer cells.

[0005] Synthetic lethality occurs when cell death is caused by the combined loss of expression of two or more genes, but not by a loss in only one of these genes. The concept of synthetic lethality originates from studies of the Drosophila model system, in which the combination of mutations in two or more distinct genes causes cell death (as opposed to viability, which occurs when only one of the genes is mutated or deleted). Recently, numerous studies have explored maladaptive genetic changes in cancer cells that make them susceptible to synthetic lethal approaches. These tumor-specific genetic defects have led to the use of targeted drugs to induce tumor cell death without affecting normal cells.

[0006] Methionine adenosyltransferase 2A (MAT2A) is an enzyme that utilizes methionine (Met) and adenosine triphosphate (ATP) to generate s-adenosylmethionine (SAM). SAM is the primary methyl donor in cells, used to methylate several substrates, including DNA, RNA, and proteins. One methylase that utilizes SAM as a methyl donor is the protein arginine N-methyltransferase 5 (PRMT5). While SAM is required for PRMT5 activity, PRMT5 is competitively inhibited by 5'-methylthioadenosine (MTA). Because MTA is part of the methionine salvage pathway, intracellular MTA levels remain low in a process initiated by methylthioadenosine phosphorylase (MTAP).

[0007] MTAP is located at a locus on chromosome 9 that is frequently deleted in cells from patients with cancers originating from several tissues of origin, including the central nervous system, pancreas, esophagus, bladder, and lung (cBioPortal database). Loss of MTAP leads to the accumulation of MTA, which makes MTAP-deficient cells more dependent on SAM production and, therefore, MAT2A activity, compared with MTAP-expressing cells. In an shRNA cell line screen of approximately 400 cancer cell lines, knockdown of MAT2A reduced viability in a high proportion of MTAP-deficient cells compared with MTAP wild-type cells (see McDonald et al., 2017 Cell 170, 577-592). Furthermore, inducible knockdown of MAT2A protein reduced tumor growth in vivo (see Marjon et al., 2016 Cell Reports 15(3), 574-587). These results indicate that MAT2A inhibitors and their polymorphic forms may provide useful treatments for cancer patients, including those with MTAP-deficient tumors. Summary of the Invention

[0008] In a first aspect, the present disclosure provides a compound having formula (I): [ka] The present invention provides a crystalline form of the compound represented by the formula (I), wherein the crystalline form is any one of crystalline forms A to U, each of which is characterized by an X-ray powder diffraction (XRPD) pattern described herein.

[0009] In a second aspect, the present disclosure provides a compound having formula (I): [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the solid form of Formula (I) is Solid Form V. In some embodiments, Solid Form V of Formula (I) is substantially crystalline.

[0010] In a third aspect, the present disclosure provides a method for preparing crystalline form A of a compound having formula (I), the method comprising: a) forming a first mixture comprising a crude compound of formula (I), ACN, and water; b) solvent exchange with water at a temperature of about 65°C or less to form a second mixture; c) cooling and stirring the second mixture to form a third precipitate; d) isolating the third precipitate; and e) forming a slurry comprising the third precipitate, methyl ethyl ketone (MEK), and water; i) isolating the fourth precipitate of step e); g) drying the fourth precipitate to obtain crystalline Form A of Formula (I); Includes:

[0011] In a fourth aspect, the present disclosure provides a method for preparing a crystalline form of a compound having formula (I), comprising: a) forming a slurry comprising Solid Form V of Formula (I) and a solvent; b) stirring the slurry for at least 1 day; c) isolating the precipitate; d) drying the precipitate to obtain the crystalline form of formula (I); Including, wherein the crystalline form is crystalline form C and the solvent is methanol, or wherein the crystalline form is crystalline form D and the solvent is water, or wherein the crystalline form is crystalline form E and the solvent is methanol / water (optionally in a 1:1 ratio), or wherein the crystalline form is crystalline form I and the solvent is acetone / water (optionally in a 1:1 ratio), or wherein the crystalline form is crystalline form A and the solvent is acetonitrile / water (optionally in a 1:1 ratio).

[0012] In a fifth aspect, the present disclosure provides a method for treating a disease mediated by MAT2A in a patient, the method comprising administering to the patient a therapeutically effective amount of a crystalline form of a compound of formula (I) described herein or a pharmaceutical composition thereof.

[0013] In a sixth aspect, the present disclosure provides a method of treating an MTAP-null cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of a crystalline form of a compound of formula (I) described herein or a pharmaceutical composition thereof.

[0014] In a seventh aspect, the present disclosure provides a method for treating cancer in a patient, wherein the cancer is characterized by reduced or absent MTAP gene expression, absent MTAP gene, reduced levels of MTAP protein, reduced function of MTAP protein, absent MTAP protein, or a combination thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline form of compound of formula (I) described herein or a pharmaceutical composition thereof. [Brief explanation of the drawings]

[0015] [Figure 1] FIG. 1 shows the X-ray powder diffraction pattern of solid form V.

[0016] [Figure 2] FIG. 2 shows the differential scanning calorimetry (DSC) thermogram of solid form V.

[0017] [Figure 3]FIG. 3 shows the thermogravimetric analysis (TGA) thermogram of solid form V.

[0018] [Figure 4] FIG. 4 shows the polarized light microscope (PLM) profile of solid form V.

[0019] [Figure 5] FIG. 5 shows the 1H NMR spectrum of solid form V.

[0020] [Figure 6] FIG. 6 shows the X-ray powder diffraction pattern of crystalline form A.

[0021] [Figure 7] FIG. 7 shows the differential scanning calorimetry (DSC) thermogram of crystalline form A.

[0022] [Figure 8] FIG. 8 shows the thermogravimetric analysis (TGA) thermogram of crystalline form A.

[0023] [Figure 9] FIG. 9 shows the polarized light microscope (PLM) profile of crystalline form A.

[0024] [Figure 10] 10A and B show the dynamic vapor sorption (DVS) profile of crystalline form A.

[0025] [Figure 11] FIG. 11 shows the 1H NMR spectrum of crystalline form A.

[0026] [Figure 12] FIG. 12 shows the X-ray powder diffraction pattern of crystalline form B.

[0027] [Figure 13] FIG. 13 shows the X-ray powder diffraction pattern of crystalline form C.

[0028] [Figure 14] FIG. 14 shows a differential scanning calorimetry (DSC) thermogram of crystalline form C.

[0029] [Figure 15] FIG. 15 shows the thermogravimetric analysis (TGA) thermogram of crystalline form C.

[0030] [Figure 16] FIG. 16 shows the polarized light microscope (PLM) profile of crystalline form C.

[0031] [Figure 17] FIG. 17 shows the 1H NMR spectrum of crystalline form C.

[0032] [Figure 18] 18A and B show the dynamic vapor sorption (DVS) profile of crystalline form C.

[0033] [Figure 19] FIG. 19 shows the X-ray powder diffraction pattern of crystalline form D.

[0034] [Figure 20] FIG. 20 shows the differential scanning calorimetry (DSC) thermogram of crystalline form D.

[0035] [Figure 21] FIG. 21 shows the thermogravimetric analysis (TGA) thermogram of crystalline form D.

[0036] [Figure 22] FIG. 22 shows the polarized light microscope (PLM) profile of crystalline form D.

[0037] [Figure 23] FIG. 23 shows the 1H NMR spectrum of crystalline form D.

[0038] [Figure 24]24A and B show the dynamic vapor sorption (DVS) profile of crystalline form D.

[0039] [Figure 25] FIG. 25 shows the X-ray powder diffraction pattern of crystalline form E.

[0040] [Figure 26] FIG. 26 shows the differential scanning calorimetry (DSC) thermogram of crystalline form E.

[0041] [Figure 27] FIG. 27 shows the thermogravimetric analysis (TGA) thermogram of crystalline form E.

[0042] [Figure 28] FIG. 28 shows the polarized light microscope (PLM) profile of crystalline form E.

[0043] [Figure 29] FIG. 29 shows the 1H NMR spectrum of crystalline form E.

[0044] [Figure 30] FIG. 30 shows the X-ray powder diffraction pattern of crystalline form F.

[0045] [Figure 31] FIG. 31 shows the differential scanning calorimetry (DSC) thermogram of crystalline form F.

[0046] [Figure 32] FIG. 32 shows the thermogravimetric analysis (TGA) thermogram of crystalline form F.

[0047] [Figure 33] FIG. 33 shows the X-ray powder diffraction pattern of crystalline form G.

[0048] [Figure 34] FIG. 34 shows the differential scanning calorimetry (DSC) thermogram of crystalline form G.

[0049] [Figure 35] FIG. 35 shows the thermogravimetric analysis (TGA) thermogram of crystalline form G.

[0050] [Figure 36] FIG. 36 shows the 1H NMR spectrum of crystalline form G.

[0051] [Figure 37] FIG. 37 shows the X-ray powder diffraction pattern of crystalline form H.

[0052] [Figure 38] FIG. 38 shows the differential scanning calorimetry (DSC) thermogram of crystalline form H.

[0053] [Figure 39] FIG. 39 shows the thermogravimetric analysis (TGA) thermogram of crystalline form H.

[0054] [Figure 40] FIG. 40 shows the 1H NMR spectrum of crystalline form H.

[0055] [Figure 41] FIG. 41 shows the X-ray powder diffraction pattern of crystalline Form I.

[0056] [Figure 42] FIG. 42 shows the differential scanning calorimetry (DSC) thermogram of crystalline Form I.

[0057] [Figure 43] FIG. 43 shows the thermogravimetric analysis (TGA) thermogram of crystalline Form I.

[0058] [Figure 44] FIG. 44 shows the polarized light microscope (PLM) profile of crystalline Form I.

[0059] [Figure 45]FIG. 45 shows the 1H NMR spectrum of crystalline form I.

[0060] [Figure 46] FIG. 46 shows the X-ray powder diffraction pattern of crystalline form J.

[0061] [Figure 47] FIG. 47 shows the differential scanning calorimetry (DSC) thermogram of crystalline form J.

[0062] [Figure 48] FIG. 48 shows the thermogravimetric analysis (TGA) thermogram of crystalline form J.

[0063] [Figure 49] FIG. 49 shows the H NMR spectrum of crystalline form J.

[0064] [Figure 50] FIG. 50 shows the X-ray powder diffraction pattern of crystalline form K.

[0065] [Figure 51] FIG. 51 shows the X-ray powder diffraction pattern of crystalline form L.

[0066] [Figure 52] FIG. 52 shows the differential scanning calorimetry (DSC) thermogram of crystalline form L.

[0067] [Figure 53] FIG. 53 shows the thermogravimetric analysis (TGA) thermogram of crystalline form L.

[0068] [Figure 54] FIG. 54 shows the X-ray powder diffraction pattern of crystalline form M.

[0069] [Figure 55] FIG. 55 shows the X-ray powder diffraction pattern of crystalline form N.

[0070] [Figure 56] FIG. 56 shows the X-ray powder diffraction pattern of crystalline form O.

[0071] [Figure 57] FIG. 57 shows the X-ray powder diffraction pattern of crystalline form P.

[0072] [Figure 58] FIG. 58 shows the X-ray powder diffraction pattern of crystalline form Q.

[0073] [Figure 59] FIG. 59 shows the X-ray powder diffraction pattern of crystalline form R.

[0074] [Figure 60] FIG. 60 shows the X-ray powder diffraction pattern of crystalline form S.

[0075] [Figure 61] FIG. 61 shows the X-ray powder diffraction pattern of crystalline form T.

[0076] [Figure 62] FIG. 62 shows the differential scanning calorimetry (DSC) thermogram of crystalline form T.

[0077] [Figure 63] FIG. 63 shows the thermogravimetric analysis (TGA) thermogram of crystalline form T.

[0078] [Figure 64] FIG. 64 shows the polarized light microscope (PLM) profile of crystalline form T.

[0079] [Figure 65] FIG. 65 shows the 1H NMR spectrum of crystalline form T.

[0080] [Figure 66] 66A and B show the dynamic vapor sorption (DVS) profile of crystalline form T.

[0081] [Figure 67] FIG. 67 shows the X-ray powder diffraction pattern of crystalline form U.

[0082] [Figure 68] FIG. 68 shows the X-ray powder diffraction pattern of the substantially amorphous form obtained by dry-milling Form T. Form for carrying out the invention

[0083] I. General The present disclosure provides crystalline forms of a compound having formula (I), which are crystalline forms A-U. Crystalline forms A-U are characterized by X-ray powder diffraction (XRPD) patterns. Selected crystalline forms are further characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and / or polarized light microscopy (PLM) profiles. The present disclosure also provides methods for preparing crystalline forms, particularly forms A, C, D, E, and I. Also disclosed herein are solid-state forms of the compound of formula (I) and methods for their manufacture. In some embodiments, the solid-state form is solid-state form V. The present disclosure further provides methods for treating diseases mediated by MAT2A, particularly cancer, using the crystalline forms of the present disclosure or pharmaceutical compositions thereof. The present disclosure is useful for treating various cancers, including solid tumors. The present disclosure is useful for treating various diseases or disorders treatable by inhibiting MAT2A. The present disclosure is also useful for treating MTAP-deficient tumors.

[0084] II. Definition "Substantially free" refers to the presence of 10% or less of another form in a particular desired form, preferably 9%, 8.5%, 8%, 7.55, 7%, 6.5%, 6%, 5.5%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.5% or less of another form.

[0085] "Crude" refers to a mixture containing the desired compound (e.g., a compound of Formula (I)) and at least one other species (e.g., a solvent, a reagent such as an acid or base, a starting material, or a by-product of the reaction to give the desired compound).

[0086] "Alkyl alcohol" refers to an alkyl group having a hydroxy group attached to a carbon atom of the alkyl group, where the alkyl group is defined as a straight-chain or branched saturated aliphatic group having the indicated number of carbon atoms (i.e., C1-4 means 1 to 4 carbons). For example, C1-4 alkyl alcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, and tert-butanol. The alkyl alcohols useful in the present invention are fully saturated. One of ordinary skill in the art will understand that other alcohols are useful in the present invention.

[0087] "Solvate" refers to a compound provided herein or a salt thereof bound to a stoichiometric or non-stoichiometric amount of solvent by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0088] "Hydrate" refers to a compound complexed with stoichiometric or non-stoichiometric amounts of water. The compounds of the present invention can be complexed with 1 / 2 or 1 to 10 water molecules. For example, the compounds of the present invention can be complexed with 1 / 2 water molecule. The compounds of the present invention can be complexed with 1 water molecule, or the compounds of the present invention can be complexed with 2 water molecules.

[0089] "Crystalline form" refers to a solid form of a compound in which the constituent molecules are packed in a regularly arranged, repeating pattern. Crystalline forms can include triclinic, monoclinic, orthorhombic, tetragonal, trigonal, hexagonal, and cubic crystal geometries. Crystalline forms can contain one or more regions with distinct crystal boundaries, i.e., grains. A crystalline solid can contain more than one crystal geometry.

[0090] "Amorphous form" refers to a solid form of a compound that does not have a definite crystalline structure, i.e., does not have a regular repeating pattern of arranged constituent molecules.

[0091] "FeSSIF" stands for fed simulated intestinal fluid. "FaSSIF" stands for fasted simulated intestinal fluid. "SGF" stands for simulated gastric fluid.

[0092] "About" means a range of values ​​that one of ordinary skill in the art would consider reasonably similar to the specified value, including the specified value. In some embodiments, the term "about" means within a standard deviation using generally accepted measurements in the art. In some embodiments, "about" means within ±10% of the specified value.

[0093] As used herein, "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared using relatively non-toxic acids or bases, depending on the particular substituents found on the compounds described herein. When a compound disclosed herein contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, etc. (e.g., arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.) When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like.Also included are salts of amino acids, such as arginic acid, and salts of organic acids, such as glucuronic acid or galacturonic acid (see, e.g., Berge, SM, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds of the present invention contain both basic and acidic functional groups that allow the compounds to be converted into either base or acid addition salts.

[0094] "Solid state form" refers to any crystalline and / or amorphous solid phase of a compound having Formula (I) or a pharmaceutically acceptable salt thereof. This includes mixtures of crystalline or amorphous solid phases. Solid state forms include anhydrate, hydrate, and solvate solid forms of a compound having Formula (I) or a pharmaceutically acceptable salt thereof. The solid state forms described herein can comprise at least 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% by weight of a particular crystalline form. In some embodiments, the particular crystalline form is Form A.

[0095] III.Crystal form In a first aspect, the present disclosure provides a compound having formula (I): [ka] The present disclosure provides a crystalline form of the compound having formula (I), wherein the crystalline form is any one of crystalline forms A-U, each of which is characterized by an X-ray powder diffraction (XRPD) pattern described herein. Particular crystalline forms may include pharmaceutically acceptable salts of the compound of formula (I). Particular crystalline forms may be hydrates, solvates, or anhydrous forms of the compound of formula (I). The present disclosure also provides solid forms of the compound having formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the solid form of formula (I) is solid form V. In some embodiments, solid form V of formula (I) is substantially crystalline.

[0096] The compound of formula (I) exhibits complex polymorphic behavior. Three anhydrous forms, Form A, Form I, and Form T, and three hydrate forms, Form C, Form D, and Form E, have been identified. In addition, other crystalline forms and a substantially amorphous form have been identified.

[0097] Methods for collecting XRPD data are known in the art, and any such method can be used to characterize the crystalline forms of the compounds of formula (I). For example, Cu-Kα1 radiation can be used to generate the X-ray powder diffraction patterns described herein.

[0098] In some embodiments, the crystalline forms described herein are further characterized by differential scanning calorimetry (DSC) thermograms. In some embodiments, DSC thermograms are recorded using a sample weight of about 1-2 mg, exposed to temperatures ranging from 30° C. to 350° C. using a ramp of 10° C. / min.

[0099] In some embodiments, the crystalline forms described herein are further characterized by thermogravimetric analysis (TGA). In some embodiments, TGA thermograms are recorded using a sample weight of about 2-10 mg, exposed to temperatures ranging from 30°C to 300°C using a ramp of 10°C / min.

[0100] In some embodiments, the crystalline forms described herein are further characterized by polarized light microscopy (PLM) profiles, which in some embodiments are recorded using crossed polarizers.

[0101] In some embodiments, the crystalline forms described herein are further characterized by a dynamic vapor sorption (DVS) profile. In some embodiments, the DVS is recorded at 25° C. under a cycle of 40-0-95-0-40% RH according to the methods described herein.

[0102] III-1.Crystal form A In one embodiment, the disclosure provides crystalline Form A of the compound having Formula (I). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 6.1, 11.1, and 16.6 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 6.1, 11.1, 12.1, and 16.6 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 6.1, 6.6, 11.1, 12.1, and 16.6 degrees 2θ (±0.2 degrees 2θ).

[0103] In one embodiment, the present disclosure provides crystalline Form A of the compound having Formula (I), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.1, 11.1, 12.1, 16.6, and 27.7 °2θ (±0.2 °2θ). In some embodiments, crystalline Form A of the compound having Formula (I) is further characterized by an X-ray powder diffraction pattern comprising peaks at 6.6, 15.6, 22.4, 27.4, and 28.4 °2θ (±0.2 °2θ). In some embodiments, crystalline Form A of the compound having Formula (I) is characterized by an X-ray powder diffraction pattern further comprising peaks at 10.0, 18.5, 20.8, 25.3, and 25.7 °2θ (±0.2 °2θ). In some embodiments, crystalline Form A of the compound of Formula (I) is characterized by an X-ray powder diffraction pattern further comprising peaks at 6.1, 6.6, 11.1, 12.1, 15.6, 16.6, 22.4, 27.4, 27.7, and 28.4 °2θ (±0.2 °2θ) (i.e., the first 10 peaks ranked according to % relative peak intensities). In some embodiments, crystalline Form A of the compound of Formula (I) is characterized by an X-ray powder diffraction pattern further comprising peaks at 6.1, 6.6, 10.0, 11.1, 12.1, 15.6, and 16.6 °2θ (±0.2 °2θ). In some embodiments, crystalline form A of the compound of formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks selected from 6.1, 6.6, 10.0, 11.1, 12.1, 15.6, and 16.6 degrees two-theta (±0.2 degrees two-theta). In some embodiments, crystalline form A of the compound of formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks selected from 6.1, 6.6, 10.0, 11.1, 12.1, 15.6, and 16.6 degrees two-theta (±0.2 degrees two-theta). In some embodiments, crystalline Form A of the compound of Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least any of four peaks selected from 6.1, 6.6, 10.0, 11.1, 12.1, 15.6, and 16.6 degrees 2θ (±0.2 degrees 2θ).In some embodiments, crystalline Form A of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least any of five peaks selected from 6.1, 6.6, 10.0, 11.1, 12.1, 15.6, and 16.6 °2θ (±0.2 °2θ). In some embodiments, Form A is characterized by an X-ray powder diffraction (XRPD) pattern comprising one, two, three, four, five, or more peaks listed in Table 4. In some embodiments, Form A is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks listed in Table 4. In some embodiments, Form A is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks listed in Table 4. In some embodiments, Form A is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks listed in Table 4.

[0104] In some embodiments, crystalline Form A of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG.

[0105] In some embodiments, crystalline Form A is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0106] In some embodiments, crystalline form A is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 323.5° C. In some embodiments, crystalline form A is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an onset temperature at about 318.2° C. and an endothermic peak at about 323.5° C.

[0107] In some embodiments, crystalline Form A is further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with FIG.

[0108] In some embodiments, crystalline Form A is further characterized by a weight percent loss of about 1.0% when heated to about 220° C. as measured by thermogravimetric analysis (TGA).

[0109] In some embodiments, crystalline Form A is further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with FIG.

[0110] In some embodiments, crystalline Form A is further characterized by a polarized light microscopy (PLM) profile substantially as shown in FIG.

[0111] In some embodiments, crystalline Form A is further characterized by a dynamic vapor sorption (DVS) profile substantially as shown in FIG.

[0112] Crystalline form A is an anhydrous form.

[0113] In some embodiments, crystalline form A is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 6, and further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 7. In some embodiments, crystalline form A is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 6, and further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 7, and further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 8.

[0114] III-2.Crystal form B In one embodiment, the disclosure provides crystalline Form B of the compound having Formula (I). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 10.6, 16.6, and 18.1 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 10.6, 11.8, 16.6, and 18.1 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 10.6, 11.5, 11.8, 16.6, and 18.1 degrees 2θ (±0.2 degrees 2θ).

[0115] In one embodiment, the present disclosure provides crystalline Form B of the compound having Formula (I), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 10.6, 16.6, 18.1, 26.6, and 27.3 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 11.5, 11.8, 12.0, 19.7, and 28.3 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 17.3, 20.3, 22.1, 24.2, and 29.6 °2θ (±0.2 °2θ). In some embodiments, crystalline Form B of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 10.6, 11.5, 11.8, 12.0, 16.6, 18.1, 19.7, 26.6, 27.3, and 28.3 °2θ (±0.2 °2θ) (i.e., the first 10 peaks ranked according to relative peak intensities). In some embodiments, Form B is characterized by an X-ray powder diffraction (XRPD) pattern comprising one, two, three, four, five, or more peaks listed in Table 5. In some embodiments, Form B is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks listed in Table 5. In some embodiments, Form B is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks listed in Table 5.

[0116] In some embodiments, crystalline form B of the compound having formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG.

[0117] In some embodiments, crystalline form B is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0118] III-3.Crystal form C In one embodiment, the disclosure provides crystalline Form C of the compound having Formula (I). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 11.8, 16.6, and 17.5 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 10.9, 11.8, 16.6, and 17.5 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 10.9, 11.8, 16.6, 17.5, and 17.8 °2θ (±0.2 °2θ).

[0119] In one embodiment, the present disclosure provides crystalline Form C of the compound having Formula (I), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 11.8, 16.6, 17.5, 27.2, and 28.2 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 19.7, 20.3, 23.7, 24.5, and 29.8 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 10.9, 17.8, 21.8, 26.0, and 26.6 °2θ (±0.2 °2θ). In some embodiments, crystalline form C of the compound of Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 1.8, 16.6, 17.5, 19.7, 20.3, 23.7, 24.5, 27.2, 28.2, and 29.8 °2θ (±0.2 °2θ) (i.e., the first 10 peaks ranked according to % relative peak intensity). In some embodiments, crystalline form C of the compound of Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 10.9, 11.8, 16.6, 17.5, and 17.8 °2θ (±0.2 °2θ). In some embodiments, crystalline form C of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern including at least two peaks selected from 10.9, 11.8, 16.6, 17.5, and 17.8 °2θ (±0.2 °2θ). In some embodiments, crystalline form C of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern including at least three peaks selected from 10.9, 11.8, 16.6, 17.5, and 17.8 °2θ (±0.2 °2θ). In some embodiments, crystalline form C of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern including at least four peaks selected from 10.9, 11.8, 16.6, 17.5, and 17.8 °2θ (±0.2 °2θ). In some embodiments, Form C is characterized by an X-ray powder diffraction (XRPD) pattern comprising one, two, three, four, five, or more peaks listed in Table 7.In some embodiments, Form C is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks listed in Table 7. In some embodiments, Form C is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks listed in Table 7.

[0120] In some embodiments, crystalline form C of the compound having formula (I) is characterized by an X-ray powder diffraction pattern substantially in accordance with FIG.

[0121] In some embodiments, crystalline form C is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0122] In some embodiments, crystalline form C is further characterized by a differential scanning calorimetry (DSC) thermogram comprising one or more endothermic peaks at about 69.5°C, about 197.5°C, and about 326.6°C. In some embodiments, crystalline form C is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 69.5°C. In some embodiments, crystalline form C is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 197.5°C. In some embodiments, crystalline form C is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 326.6°C. In some embodiments, crystalline form C is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an onset temperature at about 43.8°C and an endothermic peak at about 69.5°C. In some embodiments, crystalline form C is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an onset temperature at about 184.5° C. and an endothermic peak at about 197.5° C. In some embodiments, crystalline form C is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an onset temperature at about 321.3° C. and an endothermic peak at about 326.6° C.

[0123] In some embodiments, crystalline form C is further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with FIG.

[0124] In some embodiments, crystalline form C is further characterized by a weight percent loss of about 3.9% when heated to about 220° C. as measured by thermogravimetric analysis (TGA).

[0125] In some embodiments, crystalline form C is further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with FIG.

[0126] In some embodiments, crystalline form C is further characterized by a polarized light microscopy (PLM) profile substantially as shown in Figure 16. In some embodiments, crystalline form C is an irregular particle characterized by a polarized light microscopy (PLM) profile substantially as shown in Figure 16.

[0127] In some embodiments, crystalline form C is further characterized by a dynamic vapor sorption (DVS) profile substantially as shown in FIG.

[0128] Crystalline form C is a hydrate form.

[0129] In some embodiments, crystalline form C is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 13, and further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 14. In some embodiments, crystalline form C is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 13, and further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 14, and further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 15.

[0130] III-4.Crystal form D In one embodiment, the disclosure provides crystalline Form D of the compound having Formula (I). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 6.1, 12.4, and 16.5 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 6.1, 12.4, 13.7, and 16.5 (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 6.1, 10.9, 12.4, 13.7, and 16.5 °2θ (±0.2 °2θ).

[0131] In one embodiment, the present disclosure provides crystalline Form D of the compound having Formula (I), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.1, 12.4, 13.7, 16.5, and 27.6 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 10.9, 14.8, 25.2, 26.7, and 27.9 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 10.3, 19.3, 21.2, 24.1, and 29.9 °2θ (±0.2 °2θ). In some embodiments, crystalline form D of the compound of formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.1, 10.9, 12.4, 13.7, 14.8, 16.5, 25.2, 26.7, 27.6, and 27.9 °2θ (±0.2 °2θ) (i.e., the first 10 peaks ranked according to relative peak intensities). In some embodiments, crystalline form D of the compound of formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.1, 10.9, 12.4, 13.7, 14.8, and 16.5 °2θ (±0.2 °2θ). In some embodiments, crystalline form D of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks selected from 6.1, 10.9, 12.4, 13.7, 14.8, and 16.5 °2θ (±0.2 °2θ). In some embodiments, crystalline form D of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks selected from 6.1, 10.9, 12.4, 13.7, 14.8, and 16.5 °2θ (±0.2 °2θ). In some embodiments, crystalline form D of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks selected from 6.1, 10.9, 12.4, 13.7, 14.8, and 16.5 °2θ (±0.2 °2θ).In some embodiments, crystalline Form D of the compound of Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least any of five peaks selected from 6.1, 10.9, 12.4, 13.7, 14.8, and 16.5 °2θ (±0.2 °2θ). In some embodiments, Form D is characterized by an X-ray powder diffraction (XRPD) pattern comprising one, two, three, four, five, or more peaks listed in Table 8. In some embodiments, Form D is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks listed in Table 8. In some embodiments, Form D is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks listed in Table 8.

[0132] In some embodiments, crystalline form D of the compound having formula (I) is characterized by an X-ray powder diffraction pattern substantially in accordance with FIG.

[0133] In some embodiments, crystalline form D is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0134] In some embodiments, crystalline form D is further characterized by a differential scanning calorimetry (DSC) thermogram comprising one or more endothermic peaks at about 66.8°C and about 322.0°C. In some embodiments, crystalline form D is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 66.8°C. In some embodiments, crystalline form D is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 322.0°C. In some embodiments, crystalline form D is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an onset temperature at about 45.8°C and an endothermic peak at about 66.8°C. In some embodiments, crystalline form D is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an onset temperature at about 317.1°C and an endothermic peak at about 322.0°C.

[0135] In some embodiments, crystalline form D is further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with FIG.

[0136] In some embodiments, crystalline form D is further characterized by a weight percent loss of about 2.1% when heated to about 220° C. as measured by thermogravimetric analysis (TGA).

[0137] In some embodiments, crystalline form D is further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with FIG. 21.

[0138] In some embodiments, crystalline Form D is further characterized by a polarized light microscopy (PLM) profile substantially as shown in Figure 22. In some embodiments, crystalline Form D is an irregular particle characterized by a polarized light microscopy (PLM) profile substantially as shown in Figure 22.

[0139] In some embodiments, crystalline form C is further characterized by a dynamic vapor sorption (DVS) profile substantially as shown in FIG.

[0140] Crystalline form D is a hydrate form.

[0141] In some embodiments, crystalline form D is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 19, and further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 20. In some embodiments, crystalline form D is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 19, and further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 20, and further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 21.

[0142] III-5.Crystal form E In one embodiment, the disclosure provides crystalline Form E of the compound having Formula (I). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 12.3, 13.7, and 19.4 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 12.3, 13.7, 15.0, and 19.4 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 12.3, 13.7, 14.6, 15.0, and 19.4 degrees 2θ (±0.2 degrees 2θ).

[0143] In one embodiment, the present disclosure provides crystalline Form E of the compound having Formula (I), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 12.3, 13.7, 19.4, 26.7, and 27.6 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 20.8, 24.5, 25.3, 28.1, and 30.0 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 7.2, 14.6, 14.9, 18.2, and 22.5 °2θ (±0.2 °2θ). In some embodiments, crystalline form E of the compound of formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 12.3, 13.7, 19.4, 20.8, 24.5, 25.3, 26.7, 27.6, 28.1, and 30.0 °2θ (±0.2 °2θ) (i.e., the first 10 peaks ranked according to % relative peak intensity). In some embodiments, crystalline form E of the compound of formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 7.2, 12.3, 13.7, 14.6, 14.9, 18.2, and 19.4 °2θ (±0.2 °2θ). In some embodiments, crystalline form E of the compound of formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks selected from 7.2, 12.3, 13.7, 14.6, 14.9, 18.2, and 19.4 degrees 2θ (±0.2 degrees 2θ). In some embodiments, crystalline form E of the compound of formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks selected from 7.2, 12.3, 13.7, 14.6, 14.9, 18.2, and 19.4 degrees 2θ (±0.2 degrees 2θ). In some embodiments, crystalline form E of the compound of formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least any of four peaks selected from 7.2, 12.3, 13.7, 14.6, 14.9, 18.2, and 19.4 degrees 2θ (±0.2 degrees 2θ).In some embodiments, crystalline Form E of the compound of Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks selected from 7.2, 12.3, 13.7, 14.6, 14.9, 18.2, and 19.4 °2θ (±0.2 °2θ). In some embodiments, crystalline Form E of the compound of Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks selected from 7.2, 12.3, 13.7, 14.6, 14.9, 18.2, and 19.4 °2θ (±0.2 °2θ). In some embodiments, Form E is characterized by an X-ray powder diffraction (XRPD) pattern containing one, two, three, four, five, or more peaks listed in Table 10. In some embodiments, Form E is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks listed in Table 10. In some embodiments, Form E is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks listed in Table 10.

[0144] In some embodiments, crystalline form E of the compound having formula (I) is characterized by an X-ray powder diffraction pattern substantially in accordance with FIG.

[0145] In some embodiments, crystalline form E is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0146] In some embodiments, crystalline form E is further characterized by a differential scanning calorimetry (DSC) thermogram comprising one or more endothermic peaks at about 85.9°C and about 325.0°C. In some embodiments, the differential scanning calorimetry (DSC) thermogram further comprises an exothermic peak at 199.6°C. In some embodiments, crystalline form E is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 85.9°C. In some embodiments, crystalline form E is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 325.0°C. In some embodiments, crystalline form E is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an onset temperature at about 58.9°C and an endothermic peak at about 85.9°C. In some embodiments, crystalline form E is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an onset temperature at about 195.4° C. and an exothermic peak at about 199.6° C. In some embodiments, crystalline form E is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an onset temperature at about 318.3° C. and an endothermic peak at about 325.0° C.

[0147] In some embodiments, crystalline form E is further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with FIG.

[0148] In some embodiments, crystalline form E is further characterized by a weight percent loss of about 4.3% when heated to about 195° C. as measured by thermogravimetric analysis (TGA).

[0149] In some embodiments, crystalline form E is further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with FIG.

[0150] In some embodiments, crystalline form E is further characterized by a polarized light microscopy (PLM) profile substantially as shown in Figure 28. In some embodiments, crystalline form E is irregular particles characterized by a polarized light microscopy (PLM) profile substantially as shown in Figure 28.

[0151] Crystalline form E is a hydrate form.

[0152] In some embodiments, crystalline form E is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 25, and further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 26. In some embodiments, crystalline form E is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 25, and further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 26, and further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 27.

[0153] III-6. Crystal form F In one embodiment, the disclosure provides crystalline Form F of the compound having Formula (I). In some embodiments, the X-ray powder diffraction pattern includes peaks at 7.8 and 18.2 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern includes peaks at 7.8, 17.8, and 18.2 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern includes peaks at 7.8, 14.7, 17.8, and 18.2 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern includes peaks at 7.8, 14.7, 15.7, 17.8, and 18.2 degrees 2θ (±0.2 degrees 2θ).

[0154] In one embodiment, the present disclosure provides crystalline Form F of the compound having Formula (I), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 7.8, 18.2, 23.8, 27.5, and 27.8 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 14.7, 15.7, 17.8, 24.9, and 25.4 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 12.4, 13.1, 17.3, 19.7, and 21.3 °2θ (±0.2 °2θ). In some embodiments, crystalline Form F of the compound of Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 7.8, 14.7, 15.7, 17.8, 18.2, 23.8, 24.9, 25.4, 27.5, and 27.8 °2θ (±0.2 °2θ) (i.e., the first 10 peaks ranked according to relative peak intensities). In some embodiments, Form F is characterized by an X-ray powder diffraction (XRPD) pattern comprising one, two, three, four, five, or more peaks listed in Table 11. In some embodiments, Form F is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks listed in Table 11. In some embodiments, Form F is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks listed in Table 11.

[0155] In some embodiments, crystalline form F of the compound having formula (I) is characterized by an X-ray powder diffraction pattern substantially in accordance with FIG.

[0156] In some embodiments, crystalline form F is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0157] In some embodiments, crystalline form F is further characterized by a differential scanning calorimetry (DSC) thermogram comprising one or more endothermic peaks at about 74.9°C, 212.0°C, and about 325.8°C. In some embodiments, crystalline form F is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 74.9°C. In some embodiments, crystalline form F is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 212.0°C. In some embodiments, crystalline form F is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 325.0°C. In some embodiments, crystalline form F is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an onset temperature at about 45.2°C and an endothermic peak at about 74.9°C. In some embodiments, crystalline form F is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an onset temperature at about 205.2° C. and an endothermic peak at about 212.0° C. In some embodiments, crystalline form F is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an onset temperature at about 319.7° C. and an endothermic peak at about 325.8° C.

[0158] In some embodiments, crystalline form F is further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with FIG.

[0159] In some embodiments, crystalline form F is further characterized by a weight percent loss of about 3.2% when heated to about 200° C. as measured by thermogravimetric analysis (TGA).

[0160] In some embodiments, crystalline form F is further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with FIG.

[0161] Crystalline form F is a hydrate form.

[0162] In some embodiments, crystalline form F is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 30, and further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 31. In some embodiments, crystalline form F is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 30, and further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 31, and further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 32.

[0163] III-7. Crystalline Form G In one embodiment, the disclosure provides crystalline Form G of the compound having Formula (I). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 5.5, 15.6, and 17.2 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 5.5, 10.0, 15.6, and 17.2 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 5.5, 7.4, 10.0, 15.6, and 17.2 degrees 2θ (±0.2 degrees 2θ).

[0164] In one embodiment, the present disclosure provides crystalline form G of the compound having formula (I), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.5, 10.0, 15.6, 17.2, and 23.4 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 7.4, 7.8, 20.9, 24.5, and 27.7 °2θ (±0.2 °2θ). In some embodiments, crystalline form G of the compound having formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.5, 7.4, 7.8, 10.0, 15.6, 17.2, 20.9, 23.4, 24.5, and 27.7 °2θ (±0.2 °2θ) (i.e., the first 10 peaks ranked according to % relative peak intensity). In some embodiments, Form G is characterized by an X-ray powder diffraction (XRPD) pattern comprising one, two, three, four, five, or more peaks listed in Table 12. In some embodiments, Form G is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks listed in Table 12. In some embodiments, Form G is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks listed in Table 12.

[0165] In some embodiments, crystalline form G of the compound having formula (I) is characterized by an X-ray powder diffraction pattern substantially in accordance with FIG.

[0166] In some embodiments, crystalline form G is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0167] In some embodiments, crystalline form G is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 322.3° C. In some embodiments, crystalline form G is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an onset temperature at about 317.7° C. and an endothermic peak at about 322.8° C.

[0168] In some embodiments, crystalline form G is further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with FIG.

[0169] In some embodiments, crystalline form G is further characterized by a first weight percent loss of 2.5% when heated to about 160°C and a second weight percent loss of about 0.9% when heated to about 233°C, as measured by thermogravimetric analysis (TGA).

[0170] In some embodiments, crystalline form G is further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with FIG.

[0171] In some embodiments, crystalline form G is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 33, and further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 34. In some embodiments, crystalline form G is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 33, and further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 34, and further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 35.

[0172] III-8.Crystal form H In one embodiment, the disclosure provides crystalline form H of the compound having formula (I). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 5.1, 5.8, and 15.6 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 5.1, 5.8, 8.8, and 15.6 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 5.1, 5.8, 7.8, 8.8, and 15.6 °2θ (±0.2 °2θ).

[0173] In one embodiment, the present disclosure provides crystalline form H of the compound having formula (I), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.1, 5.8, 8.8, 15.6, and 23.4 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 7.8, 11.9, 17.3, and 28.3 °2θ (±0.2 °2θ). In some embodiments, crystalline form H of the compound having formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.1, 5.8, 7.8, 8.8, 11.9, 15.6, 17.3, 23.4, and 28.3 °2θ (±0.2 °2θ) (i.e., the first 9 peaks ranked according to % relative peak intensity). In some embodiments, Form H is characterized by an X-ray powder diffraction (XRPD) pattern comprising one, two, three, four, five, or more peaks listed in Table 13. In some embodiments, Form H is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks listed in Table 13. In some embodiments, Form H is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks listed in Table 13.

[0174] In some embodiments, crystalline form H of the compound having formula (I) is characterized by an X-ray powder diffraction pattern substantially in accordance with FIG.

[0175] In some embodiments, crystalline form H is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0176] In some embodiments, crystalline form H is further characterized by a differential scanning calorimetry (DSC) thermogram comprising one or more endothermic peaks at about 226.3°C and about 322.6°C. In some embodiments, crystalline form H is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 226.3°C. In some embodiments, crystalline form H is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 322.6°C. In some embodiments, crystalline form H is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an onset temperature at about 210.5°C and an endothermic peak at about 226.3°C. In some embodiments, crystalline form H is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an onset temperature at about 315.5°C and an endothermic peak at about 322.6°C.

[0177] In some embodiments, crystalline form H is further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with FIG.

[0178] In some embodiments, crystalline form H is further characterized by a weight percent loss of about 8.7% when heated to about 238° C. as measured by thermogravimetric analysis (TGA).

[0179] In some embodiments, crystalline form H is further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with FIG.

[0180] Crystalline form H is a methyl t-butyl ether solvate form.

[0181] In some embodiments, crystalline form H is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 37, and further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 38. In some embodiments, crystalline form H is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 37, and further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 38, and further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 39.

[0182] III-9.Crystal form I In one embodiment, the disclosure provides crystalline Form I of a compound having Formula (I). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 5.8, 6.4, and 16.1 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 5.8, 6.4, 16.1, and 16.5 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 5.8, 6.4, 13.1, 16.1, and 16.5 degrees 2θ (±0.2 degrees 2θ).

[0183] In one embodiment, the present disclosure provides crystalline Form I of the compound having Formula (I), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.8, 6.4, 16.1, 16.5, and 27.7 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 10.0, 10.8, 13.1, 25.5, and 29.0 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 8.4, 11.9, 17.7, 19.6, and 23.3 °2θ (±0.2 °2θ). In some embodiments, crystalline Form I of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.8, 6.4, 10.0, 10.8, 13.1, 16.1, 16.5, 25.5, 27.7, and 29.0 °2θ (±0.2 °2θ) (i.e., the first 10 peaks ranked according to relative peak intensities %). In some embodiments, crystalline Form I of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.8, 6.4, 10.0, 10.8, 13.1, 16.1, and 16.5 °2θ (±0.2 °2θ). In some embodiments, crystalline Form I of the compound of Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern containing at least two peaks selected from 5.8, 6.4, 10.0, 10.8, 13.1, 16.1, and 16.5 °2θ (±0.2 °2θ). In some embodiments, crystalline Form I of the compound of Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern containing at least three peaks selected from 5.8, 6.4, 10.0, 10.8, 13.1, 16.1, and 16.5 °2θ (±0.2 °2θ). In some embodiments, crystalline Form I of the compound of Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least any of four peaks selected from 5.8, 6.4, 10.0, 10.8, 13.1, 16.1, and 16.5 degrees 2θ (±0.2 degrees 2θ).In some embodiments, crystalline Form I of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks selected from 5.8, 6.4, 10.0, 10.8, 13.1, 16.1, and 16.5 °2θ (±0.2 °2θ). In some embodiments, crystalline Form I of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern containing at least six peaks selected from 5.8, 6.4, 10.0, 10.8, 13.1, 16.1, and 16.5 °2θ (±0.2 °2θ). In some embodiments, Form I is characterized by an X-ray powder diffraction (XRPD) pattern containing one, two, three, four, five, or more peaks listed in Table 15. In some embodiments, Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks listed in Table 15. In some embodiments, Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks listed in Table 15.

[0184] In some embodiments, crystalline Form I of the compound having Formula (I) is characterized by an X-ray powder diffraction pattern substantially in accordance with FIG.

[0185] In some embodiments, crystalline Form I is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0186] In some embodiments, crystalline form I is further characterized by a differential scanning calorimetry (DSC) thermogram comprising one or more endothermic peaks at about 267.05°C and about 323.7°C. In some embodiments, crystalline form I is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 267.05°C. In some embodiments, crystalline form I is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 323.7°C. In some embodiments, crystalline form I is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an onset temperature at about 261.6°C and an endothermic peak at about 267.05°C. In some embodiments, crystalline form I is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an onset temperature at about 319.6°C and an endothermic peak at about 323.7°C.

[0187] In some embodiments, crystalline Form I is further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with FIG.

[0188] In some embodiments, crystalline Form I is further characterized by a weight percent loss of about 1.1% when heated to about 220° C. as measured by thermogravimetric analysis (TGA).

[0189] In some embodiments, crystalline Form I is further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with FIG.

[0190] In some embodiments, crystalline Form I is further characterized by a polarized light microscopy (PLM) profile substantially as shown in Figure 44. In some embodiments, crystalline Form I is irregular particles characterized by a polarized light microscopy (PLM) profile substantially as shown in Figure 44.

[0191] Crystalline Form I is an anhydrous form.

[0192] In some embodiments, crystalline Form I is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 41, and further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 42. In some embodiments, crystalline Form I is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 41, and further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 42, and further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 43.

[0193] III-10.Crystal form J In one embodiment, the disclosure provides crystalline Form J of the compound having Formula (I). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 7.7, 12.9, and 14.6 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 7.7, 12.9, 14.6, and 18.1 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 7.7, 12.9, 14.6, 17.4, and 18.1 degrees 2θ (±0.2 degrees 2θ).

[0194] In one embodiment, the present disclosure provides crystalline Form J of the compound having Formula (I), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 7.7, 12.9, 14.6, 26.9, and 27.6 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 18.1, 22.2, 23.2, 25.3, and 27.4 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 17.4, 21.3, 23.8, 26.0, and 26.8 °2θ (±0.2 °2θ). In some embodiments, crystalline Form J of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 7.7, 12.9, 14.6, 18.1, 22.2, 23.2, 25.3, 26.9, 27.4, and 27.6 °2θ (±0.2 °2θ) (i.e., the first 10 peaks ranked according to relative peak intensities). In some embodiments, Form J is characterized by an X-ray powder diffraction (XRPD) pattern containing one, two, three, four, five, or more peaks listed in Table 16. In some embodiments, Form J is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks set forth in Table 16. In some embodiments, Form J is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks listed in Table 16.

[0195] In some embodiments, crystalline form J of the compound having formula (I) is characterized by an X-ray powder diffraction pattern substantially in accordance with FIG.

[0196] In some embodiments, crystalline form J is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0197] In some embodiments, crystalline form J is further characterized by a differential scanning calorimetry (DSC) thermogram comprising one or more endothermic peaks at about 131.9°C, 212.0°C, and about 324.0°C. In some embodiments, crystalline form J is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 131.9°C. In some embodiments, crystalline form J is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 212.0°C. In some embodiments, crystalline form J is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 324.0°C. In some embodiments, crystalline form J is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an onset temperature at about 84.2°C and an endothermic peak at about 131.9°C. In some embodiments, crystalline form J is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an onset temperature at about 204.0° C. and an endothermic peak at about 212.0° C. In some embodiments, crystalline form J is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an onset temperature at about 319.4° C. and an endothermic peak at about 324.0° C.

[0198] In some embodiments, crystalline form J is further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with FIG.

[0199] In some embodiments, crystalline form J is further characterized by a weight percent loss of about 9.9% when heated to about 200° C. as measured by thermogravimetric analysis (TGA).

[0200] In some embodiments, crystalline form J is further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with FIG.

[0201] Crystalline form J is an isopropyl solvate form.

[0202] In some embodiments, crystalline form J is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 46, and further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 47. In some embodiments, crystalline form J is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 46, and further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 47, and further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 48.

[0203] III-11.Crystal form K In one embodiment, the disclosure provides crystalline form K of the compound having formula (I). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 5.5, 11.1, and 16.5 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 5.5, 11.1, 13.8, and 16.5 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 5.5, 11.1, 13.8, 16.5, and 17.5 degrees 2θ (±0.2 degrees 2θ).

[0204] In one embodiment, the present disclosure provides crystalline form K of the compound having formula (I), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.5, 11.1, 16.5, 27.1, and 27.7 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 13.8, 17.5, 22.2, 25.2, and 28.9 °2θ (±0.2 °2θ). In some embodiments, crystalline form K of the compound having formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.5, 11.1, 13.8, 16.5, 17.5, 22.2, 25.2, 27.1, 27.7, and 28.9 °2θ (±0.2 °2θ) (i.e., the first 10 peaks ranked according to % relative peak intensity). In some embodiments, Form K is characterized by an X-ray powder diffraction (XRPD) pattern comprising one, two, three, four, five, or more peaks listed in Table 17. In some embodiments, Form K is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks listed in Table 17. In some embodiments, Form K is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks listed in Table 17.

[0205] In some embodiments, crystalline form K of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG.

[0206] In some embodiments, crystalline form K is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0207] III-12.Crystal form L In one embodiment, the disclosure provides crystalline form L of the compound having formula (I). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 11.7, 17.9, and 18.4 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 11.7, 12.3, 17.9, and 18.4 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 11.7, 12.3, 16.6, 17.9, and 18.4 degrees 2θ (±0.2 degrees 2θ).

[0208] In one embodiment, the present disclosure provides crystalline form L of the compound having Formula (I), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 11.7, 17.9, 18.4, 26.3, and 27.0 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 10.8, 12.3, 16.3, 16.6, and 22.2 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 17.0, 19.7, 20.3, 23.3, and 28.1 °2θ (±0.2 °2θ). In some embodiments, crystalline Form L of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 10.8, 11.7, 12.3, 16.3, 16.6, 17.9, 18.4, 22.2, 26.3, and 27.0 °2θ (±0.2 °2θ) (i.e., the first 10 peaks ranked according to relative peak intensities %). In some embodiments, Form L is characterized by an X-ray powder diffraction (XRPD) pattern comprising one, two, three, four, five, or more peaks listed in Table 18. In some embodiments, Form L is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks listed in Table 18. In some embodiments, Form L is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks listed in Table 18.

[0209] In some embodiments, crystalline form L of the compound having formula (I) is characterized by an X-ray powder diffraction pattern substantially in accordance with FIG.

[0210] In some embodiments, crystalline form L is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0211] In some embodiments, crystalline form L is further characterized by a differential scanning calorimetry (DSC) thermogram comprising one or more endothermic peaks at about 202.5°C and about 326.6.0°C. In some embodiments, crystalline form L is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 202.5°C. In some embodiments, crystalline form L is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 326.6.0°C. In some embodiments, crystalline form L is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an onset temperature at about 195.6°C and an endothermic peak at about 202.5°C. In some embodiments, crystalline form L is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an onset temperature at about 322.6°C and an endothermic peak at about 326.6.0°C.

[0212] In some embodiments, crystalline form L is further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with FIG.

[0213] In some embodiments, crystalline form L is further characterized by a weight percent loss of about 2.0% when heated to about 220° C. as measured by thermogravimetric analysis (TGA).

[0214] In some embodiments, crystalline form L is further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with FIG.

[0215] Crystalline form L is the anhydrous form.

[0216] In some embodiments, crystalline form L is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 51, and further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 52. In some embodiments, crystalline form L is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 51, and further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 52, and further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 53.

[0217] III-13.Crystal form M In one embodiment, the disclosure provides crystalline form M of the compound having formula (I). In some embodiments, the disclosure provides crystalline form M of the compound having formula (I), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.2, 12.4, and 13.4 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the disclosure provides crystalline form M of the compound having formula (I), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.2, 10.5, 12.4, and 13.4 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the disclosure provides crystalline form M of the compound having formula (I), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.2, 6.7, 10.5, 12.4, and 13.4 degrees 2θ (±0.2 degrees 2θ).

[0218] In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 16.1, 17.6, 24.2, 27.1, and 28.3 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 17.0, 20.2, 22.7, 23.1, and 26.5 °2θ (±0.2 °2θ). In some embodiments, crystalline Form M of the compound of Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.2, 6.7, 10.5, 12.4, 13.4, 16.1, 17.6, 24.2, 27.1, and 28.3 °2θ (±0.2 °2θ) (i.e., the first 10 peaks ranked according to % relative peak intensity). In some embodiments, Form M is characterized by an X-ray powder diffraction (XRPD) pattern comprising one, two, three, four, five, or more peaks listed in Table 19. In some embodiments, Form M is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks listed in Table 19. In some embodiments, Form M is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks listed in Table 19.

[0219] In some embodiments, crystalline form M of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG.

[0220] In some embodiments, crystalline form M is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0221] III-14.Crystal form N In one embodiment, the disclosure provides crystalline Form N of the compound having Formula (I). In some embodiments, the X-ray powder diffraction pattern includes peaks at 5.4, 10.7, and 16.1 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern includes peaks at 5.4, 10.7, 14.6, and 16.1 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern includes peaks at 5.4, 10.7, 12.4, 14.6, and 16.1 degrees 2θ (±0.2 degrees 2θ).

[0222] In some embodiments, Form N is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.4, 10.7, 16.1, 27.0, and 28.0 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 14.6, 21.6, 24.9, 25.4, and 28.4 °2θ (±0.2 °2θ). In some embodiments, crystalline Form N of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.4, 10.7, 16.1, 14.6, 21.6, 24.9, 25.4, 27.0, 28.0, and 28.4 °2θ (±0.2 °2θ) (i.e., the first 10 peaks ranked according to % relative peak intensity). In some embodiments, Form N is characterized by an X-ray powder diffraction (XRPD) pattern comprising one, two, three, four, five, or more peaks listed in Table 20. In some embodiments, Form N is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks listed in Table 20. In some embodiments, Form N is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks listed in Table 20.

[0223] In some embodiments, crystalline form N of the compound having formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG.

[0224] In some embodiments, crystalline form N is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0225] III-15.Crystal form O In one embodiment, the disclosure provides crystalline form O of the compound having formula (I). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 5.0, 5.9, and 13.4 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 5.0, 5.9, 13.4, and 17.8 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 5.0, 5.9, 13.4, 15.3, and 17.8 degrees 2θ (±0.2 degrees 2θ).

[0226] In some embodiments, Form O is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.0, 5.9, 13.4, 17.8, and 25.7 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 12.8, 15.3, 26.9, 27.9, and 29.0 °2θ (±0.2 °2θ). In some embodiments, crystalline Form O of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.0, 5.9, 12.8, 13.4, 15.3, 17.8, 25.7, 26.9, 27.9, and 29.0 °2θ (±0.2 °2θ) (i.e., the first 10 peaks ranked according to relative peak intensities %). In some embodiments, Form O is characterized by an X-ray powder diffraction (XRPD) pattern comprising one, two, three, four, or five or more peaks listed in Table 21. In some embodiments, Form O is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks listed in Table 21. In some embodiments, Form O is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks listed in Table 21.

[0227] In some embodiments, crystalline form O of the compound having formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG.

[0228] In some embodiments, crystalline form O is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0229] III-16.Crystal form P In one embodiment, the disclosure provides crystalline form P of the compound having formula (I). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 5.6, 6.0, and 17.1 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 5.6, 6.0, 10.8, and 17.1 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 5.6, 6.0, 10.8, 12.0, and 17.1 degrees 2θ (±0.2 degrees 2θ).

[0230] In some embodiments, Form P is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.6, 6.0, 17.1, 26.6, and 27.9 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 10.8, 12.0, 14.3, 14.8, and 18.1 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 6.7, 9.5, 15.8, 16.8, and 30.3 degrees 2θ (±0.2 degrees 2θ). In some embodiments, crystalline form P of the compound of Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.6, 6.0, 10.8, 12.0, 14.3, 14.8, 17.1, 18.1, 26.6, and 27.9 °2θ (±0.2 °2θ) (i.e., the first 10 peaks ranked according to relative peak intensities %). In some embodiments, crystalline form P of the compound of Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.6, 6.0, 10.8, 12.0, 14.3, 14.8, 17.1, and 18.1 °2θ (±0.2 °2θ). In some embodiments, form P is characterized by an X-ray powder diffraction (XRPD) pattern comprising one, two, three, four, five, or more peaks listed in Table 22. In some embodiments, Form P is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks listed in Table 22. In some embodiments, Form P is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks listed in Table 22.

[0231] In some embodiments, crystalline form P of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG.

[0232] In some embodiments, crystalline form P is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0233] III-17.Crystal form Q In one embodiment, the disclosure provides crystalline form Q of the compound having formula (I). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 3.3, 5.4, and 16.1 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 3.3, 5.4, 10.7, and 16.1 degrees 2θ (±0.2 degrees 2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 3.3, 4.0, 5.4, 10.7, and 16.1 degrees 2θ (±0.2 degrees 2θ).

[0234] In some embodiments, Form Q is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 3.3, 5.4, 16.1, 27.0, and 31.7 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 3.3, 5.4, and 16.1 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 4.0, 10.7, 25.0, 27.9, and 28.0 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 8.2, 14.5, 19.5, 22.6, and 24.9 °2θ (±0.2 °2θ). In some embodiments, crystalline form Q of the compound of Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern containing peaks at 3.3, 4.0, 5.4, 10.7, 16.1, 25.0, 27.0, 27.9, 28.0, and 31.7 °2θ (±0.2 °2θ) (i.e., the first 10 peaks ranked according to relative peak intensities). In some embodiments, form Q is characterized by an X-ray powder diffraction (XRPD) pattern containing one, two, three, four, five, or more peaks listed in Table 23. In some embodiments, form Q is characterized by an X-ray powder diffraction (XRPD) pattern containing at least five peaks listed in Table 23. In some embodiments, form Q is characterized by an X-ray powder diffraction (XRPD) pattern containing at least four peaks listed in Table 23.

[0235] In some embodiments, crystalline form Q of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG.

[0236] In some embodiments, crystalline form Q is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0237] III-18.Crystal form R In one embodiment, the disclosure provides crystalline form R of the compound having formula (I). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 3.2, 7.0, and 13.9 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 3.2, 7.0, 13.9, and 18.9 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern comprises peaks at 3.2, 7.0, 13.9, 18.5, and 18.9 °2θ (±0.2 °2θ).

[0238] In one embodiment, the disclosure provides crystalline form R of the compound having formula (I). In some embodiments, form R is characterized by an X-ray powder diffraction (XRPD) pattern comprising one, two, three, four, or five or more peaks listed in Table 24. In some embodiments, form R is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks listed in Table 24. In some embodiments, form R is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks listed in Table 24.

[0239] In some embodiments, crystalline form R of the compound having formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG.

[0240] In some embodiments, crystalline form R is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0241] III-19.Crystal form S In one embodiment, the disclosure provides crystalline Form S of the compound having Formula (I). In some embodiments, Form S is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.1, 13.5, and 16.5 °2θ (±0.2 °2θ). In some embodiments, Form S is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.1, 10.8, 13.5, and 16.5 °2θ (±0.2 °2θ). In some embodiments, Form S is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.1, 10.4, 10.8, 13.5, and 16.5 °2θ (±0.2 °2θ).

[0242] In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 12.3, 12.4, 14.0, 17.4, and 28.6 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 12.0, 16.0, 19.0, 26.8, and 29.3 °2θ (±0.2 °2θ). In some embodiments, crystalline Form S of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.1, 10.4, 10.8, 12.3, 12.4, 13.5, 14.0, 16.5, 17.4, and 28.6 °2θ (±0.2 °2θ) (i.e., the first 10 peaks ranked according to % relative peak intensity). In some embodiments, crystalline Form S of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.1, 10.4, 10.8, 13.5, and 16.5 degrees two-theta (±0.2 degrees two-theta). In some embodiments, Form S is characterized by an X-ray powder diffraction (XRPD) pattern comprising one, two, three, four, five, or more peaks listed in Table 25. In some embodiments, Form S is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks listed in Table 25. In some embodiments, Form S is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks listed in Table 25.

[0243] In some embodiments, crystalline form S of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG.

[0244] In some embodiments, crystalline form S is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0245] Crystalline form S is the anhydrous form.

[0246] III-20.Crystal form T In one embodiment, the disclosure provides crystalline Form T of the compound having Formula (I). In some embodiments, Form T is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.5, 10.9, and 16.9 °2θ (±0.2 °2θ). In some embodiments, Form T is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.5, 10.9, 13.0, and 16.9 °2θ (±0.2 °2θ). In some embodiments, Form T is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.5, 10.9, 12.4, 13.0, and 16.9 °2θ (±0.2 °2θ).

[0247] In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 10.5, 16.6, 22.2, 27.5, and 27.9 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 17.6, 23.2, 24.0, 25.3, and 25.4 °2θ (±0.2 °2θ). In some embodiments, crystalline Form T of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.5, 10.5, 10.9, 12.4, 13.0, 16.6, 16.9, 22.2, 27.5, and 27.9 °2θ (±0.2 °2θ) (i.e., the first 10 peaks ranked according to % relative peak intensity). In some embodiments, crystalline form T of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.5, 10.9, 12.4, 13.0, and 16.9 °2θ (±0.2 °2θ). In some embodiments, crystalline form T of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks selected from 6.5, 10.9, 12.4, 13.0, and 16.9 °2θ (±0.2 °2θ). In some embodiments, crystalline form T of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks selected from 6.5, 10.9, 12.4, 13.0, and 16.9 °2θ (±0.2 °2θ). In some embodiments, crystalline Form T of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least any of four peaks selected from 6.5, 10.9, 12.4, 13.0, and 16.9 °2θ (±0.2 °2θ). In some embodiments, Form T is characterized by an X-ray powder diffraction (XRPD) pattern comprising one, two, three, four, five, or more peaks listed in Table 26. In some embodiments, Form T is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks listed in Table 26.In some embodiments, Form T is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks listed in Table 26.

[0248] In some embodiments, crystalline form T of the compound having formula (I) is characterized by an X-ray powder diffraction pattern substantially in accordance with FIG.

[0249] In some embodiments, crystalline form T is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0250] In some embodiments, crystalline form T is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 319.4° C. In some embodiments, crystalline form T is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an onset temperature at about 307.6° C. and an endothermic peak at about 319.4° C.

[0251] In some embodiments, crystalline form T is further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with FIG.

[0252] In some embodiments, crystalline form T is further characterized by a weight percent loss of about 0.8% when heated to about 220° C. as measured by thermogravimetric analysis (TGA).

[0253] In some embodiments, crystalline form T is further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with FIG.

[0254] In some embodiments, crystalline form T is further characterized by a polarized light microscopy (PLM) profile substantially as shown in Figure 64. In some embodiments, crystalline form T is an irregular particle characterized by a polarized light microscopy (PLM) profile substantially as shown in Figure 64.

[0255] In some embodiments, crystalline form T is further characterized by a dynamic vapor sorption (DVS) profile substantially as shown in FIG.

[0256] Crystalline form T is an anhydrous form.

[0257] In some embodiments, crystalline form T is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 61, and further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 62. In some embodiments, crystalline form T is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 61, and further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 62, and further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 63.

[0258] III-21.Crystal form U In one embodiment, the disclosure provides crystalline Form U of the compound having Formula (I). In some embodiments, Form U is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.2, 12.4, and 16.4 degrees 2θ (±0.2 degrees 2θ). In some embodiments, Form U is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.2, 10.3, 12.4, and 16.4 degrees 2θ (±0.2 degrees 2θ). In some embodiments, Form U is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.2, 10.3, 10.8, 12.4, and 16.4 degrees 2θ (±0.2 degrees 2θ).

[0259] In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 17.6, 21.3, 22.4, 27.2, and 28.5 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 8.8, 13.8, 18.3, 19.8, and 23.2 °2θ (±0.2 °2θ). In some embodiments, crystalline form U of the compound of Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.2, 10.3, 10.8, 12.4, 16.4, 17.6, 21.3, 22.4, 27.2, and 28.5 °2θ (±0.2 °2θ) (i.e., the first 10 peaks ranked according to % relative peak intensity). In some embodiments, Form U is characterized by an X-ray powder diffraction (XRPD) pattern comprising one, two, three, four, five, or more peaks listed in Table 28. In some embodiments, Form U is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks listed in Table 28. In some embodiments, Form U is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks listed in Table 28.

[0260] In some embodiments, crystalline form U of the compound having formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG.

[0261] In some embodiments, crystalline form U is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0262] III-22. Solid Forms and Form V In some embodiments, the present disclosure provides a solid state form of a compound having Formula (I). The solid state form of a compound having Formula (I) includes embodiments in which the solid state form is not an isolated single crystalline form. In some embodiments, the solid state form of a compound having Formula (I) is substantially crystalline. In some embodiments, the solid state form of a compound having Formula (I) comprises at least 30% by weight of a particular crystalline form. In some embodiments, the solid state form of a compound having Formula (I) comprises at least 35% by weight of a particular crystalline form. In some embodiments, the solid state form of a compound having Formula (I) comprises at least 40% by weight of a particular crystalline form. In some embodiments, the solid state form of a compound having Formula (I) comprises at least 45% by weight of a particular crystalline form. In some embodiments, the solid state form of a compound having Formula (I) comprises at least 50% by weight of a particular crystalline form. In some embodiments, the solid state form of a compound having Formula (I) comprises at least 55% by weight of a particular crystalline form. In some embodiments, the solid state form of a compound having Formula (I) comprises at least 60% by weight of a particular crystalline form. In some embodiments, the solid form of the compound having Formula (I) comprises at least 65% by weight of a particular crystalline form. In some embodiments, the solid form of the compound having Formula (I) comprises at least 70% by weight of a particular crystalline form. In some embodiments, the solid form of the compound having Formula (I) comprises at least 75% by weight of a particular crystalline form. In some embodiments, the solid form of the compound having Formula (I) comprises at least 80% by weight of a particular crystalline form. In some embodiments, the solid form of the compound having Formula (I) comprises at least 85% by weight of a particular crystalline form. In some embodiments, the solid form of the compound having Formula (I) comprises at least 90% by weight of a particular crystalline form. In some embodiments, the solid form of the compound having Formula (I) comprises at least 95% by weight of a particular crystalline form. In some embodiments, the solid form of the compound having Formula (I) comprises at least 99% by weight of a particular crystalline form.

[0263] In some embodiments, the specific crystalline form in the solid state forms described herein is Form A. In some embodiments, the specific crystalline form in the solid state forms described herein is Form B. In some embodiments, the specific crystalline form in the solid state forms described herein is Form C. In some embodiments, the specific crystalline form in the solid state forms described herein is Form D. In some embodiments, the specific crystalline form in the solid state forms described herein is Form E. In some embodiments, the specific crystalline form in the solid state forms described herein is Form F. In some embodiments, the specific crystalline form in the solid state forms described herein is Form G. In some embodiments, the specific crystalline form in the solid state forms described herein is Form H. In some embodiments, the specific crystalline form in the solid state forms described herein is Form I. In some embodiments, the specific crystalline form in the solid state forms described herein is Form J. In some embodiments, the specific crystalline form in the solid state forms described herein is Form K. In some embodiments, the specific crystalline form in the solid state forms described herein is Form L. In some embodiments, the specific crystalline form in the solid state forms described herein is Form M. In some embodiments, the specific crystalline form in the solid state forms described herein is Form N. In some embodiments, the specific crystalline form in the solid state forms described herein is Form O. In some embodiments, the specific crystalline form in the solid state forms described herein is Form P. In some embodiments, the specific crystalline form in the solid state forms described herein is Form Q. In some embodiments, the specific crystalline form in the solid state forms described herein is Form R. In some embodiments, the specific crystalline form in the solid state forms described herein is Form S. In some embodiments, the specific crystalline form in the solid state forms described herein is Form T. In some embodiments, the specific crystalline form in the solid state forms described herein is Form U.

[0264] In some embodiments, the particular crystalline form is the solid state form described herein that is Form A.

[0265] In some embodiments, the solid state form of the compound having Formula (I) comprises at least 30% by weight of crystalline form A. In some embodiments, the solid state form of the compound having Formula (I) comprises at least 35% by weight of crystalline form A. In some embodiments, the solid state form of the compound having Formula (I) comprises at least 40% by weight of crystalline form A. In some embodiments, the solid state form of the compound having Formula (I) comprises at least 45% by weight of crystalline form A. In some embodiments, the solid state form of the compound having Formula (I) comprises at least 50% by weight of crystalline form A. In some embodiments, the solid state form of the compound having Formula (I) comprises at least 55% by weight of crystalline form A. In some embodiments, the solid state form of the compound having Formula (I) comprises at least 60% by weight of crystalline form A. In some embodiments, the solid state form of the compound having Formula (I) comprises at least 65% by weight of crystalline form A. In some embodiments, the solid state form of the compound having Formula (I) comprises at least 70% by weight of crystalline form A. In some embodiments, the solid state form of the compound having Formula (I) comprises at least 75% by weight of crystalline form A. In some embodiments, the solid state form of the compound having Formula (I) comprises at least 80% by weight of crystalline form A. In some embodiments, the solid state form of the compound having Formula (I) comprises at least 85% by weight of crystalline form A. In some embodiments, the solid state form of the compound having Formula (I) comprises at least 90% by weight of crystalline form A. In some embodiments, the solid state form of the compound having Formula (I) comprises at least 95% by weight of crystalline form A. In some embodiments, the solid state form of the compound having Formula (I) comprises at least 99% by weight of crystalline form A.

[0266] In some embodiments, the solid form of the compound having formula (I) comprises formula (I) as a free base. In some embodiments, the solid form is a solid form of formula (I) as a free base.

[0267] In some embodiments, the present disclosure provides solid state Form V of the compound having formula (I).

[0268] In one embodiment, the disclosure provides solid form V of the compound having formula (I), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.2, 10.9, and 16.5 degrees 2θ (±0.2 degrees 2θ). In one embodiment, the disclosure provides solid form V of the compound having formula (I), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.2, 10.4, 10.9, and 16.5 degrees 2θ (±0.2 degrees 2θ). In one embodiment, the disclosure provides solid form V of the compound having formula (I), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.2, 10.4, 10.9, 12.3, and 16.5 degrees 2θ (±0.2 degrees 2θ).

[0269] In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 12.5, 21.3, 26.1, 27.5, and 28.6 °2θ (±0.2 °2θ). In some embodiments, the X-ray powder diffraction pattern further comprises peaks at 8.9, 19.9, 22.6, and 23.4 °2θ (±0.2 °2θ). In some embodiments, solid state Form V of the compound of Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.2, 10.4, 10.9, 12.3, 12.5, 16.5, 21.3, 26.1, 27.5, and 28.6 °2θ (±0.2 °2θ) (i.e., the first 10 peaks ranked according to % relative peak intensity). In some embodiments, solid form V of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.2, 10.4, 10.9, 12.3, and 16.5 °2θ (±0.2 °2θ). In some embodiments, solid form V of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least two peaks selected from 6.2, 10.4, 10.9, 12.3, and 16.5 °2θ (±0.2 °2θ). In some embodiments, solid form V of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks selected from 6.2, 10.4, 10.9, 12.3, and 16.5 °2θ (±0.2 °2θ). In some embodiments, solid form V of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least any of four peaks selected from 6.2, 10.4, 10.9, 12.3, and 16.5 °2θ (±0.2 °2θ). In some embodiments, solid form V is characterized by an X-ray powder diffraction (XRPD) pattern comprising one, two, three, four, five, or more peaks listed in Table 2. In some embodiments, solid form V is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five peaks listed in Table 2.In some embodiments, solid form V is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four peaks listed in Table 2. In some embodiments, solid form V is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three peaks listed in Table 2.

[0270] In some embodiments, solid state Form V of the compound having Formula (I) is characterized by an X-ray powder diffraction pattern substantially in accordance with FIG.

[0271] In some embodiments, solid form V is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 321.6° C. In some embodiments, solid form V is further characterized by a differential scanning calorimetry (DSC) thermogram comprising an onset temperature at about 316.3° C. and an endothermic peak at about 321.6° C.

[0272] In some embodiments, solid form V is further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with FIG.

[0273] In some embodiments, solid form V is further characterized by a weight percent loss of about 0.7% when heated to about 200° C. as measured by thermogravimetric analysis (TGA).

[0274] In some embodiments, solid form V is further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with FIG.

[0275] In some embodiments, solid form V is further characterized by a polarized light microscopy (PLM) profile substantially as shown in Figure 4. In some embodiments, solid form V is an acicular particle characterized by a polarized light microscopy (PLM) profile substantially as shown in Figure 4.

[0276] Solid Form V is anhydrous.

[0277] In some embodiments, solid form V is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 1, and further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 2. In some embodiments, solid form V is characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 1, and further characterized by a differential scanning calorimetry (DSC) thermogram substantially in accordance with Figure 2, and further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 3.

[0278] IV. Substantially amorphous morphology In a second aspect, the disclosure provides a substantially amorphous form of a compound having Formula (I). In some embodiments, the substantially amorphous form is substantially free of other crystalline forms of the compound having Formula (I). In some embodiments, the substantially amorphous form contains about 10% or less of other crystalline forms of the compound having Formula (I). In some embodiments, the substantially amorphous form contains about 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or 0.5% or less of other crystalline forms of the compound having Formula (I). In some embodiments, the substantially amorphous form contains about 5% or less of other crystalline forms of the compound having Formula (I).

[0279] In some embodiments, the substantially amorphous form is prepared by milling any one of crystalline forms A-U, each of which is defined and described herein. In some embodiments, any one of crystalline forms A-U is milled (e.g., dry-milled) in the absence of a solvent or water, thereby providing a substantially amorphous form. In some embodiments, any one of crystalline forms A-U is milled (e.g., wet-milled) in the presence of a solvent (e.g., ethanol), thereby obtaining a substantially amorphous form. In some embodiments, the substantially amorphous form is prepared by milling solid form V (e.g., dry-milling or wet-milling in ethanol). In some embodiments, the substantially amorphous form is prepared by milling form A (e.g., dry-milling or wet-milling in ethanol). In some embodiments, the substantially amorphous form is prepared by milling form D (e.g., dry-milling or wet-milling in ethanol). In some embodiments, the substantially amorphous form is prepared by milling form T (e.g., dry-milling or wet-milling in ethanol). In some embodiments, the substantially amorphous form is prepared by milling Form T in the absence of solvent or water (eg, dry milling).

[0280] Generally, dry milling or wet milling can be performed using methods known in the art, for example, manually or mechanically, hi some embodiments, dry milling or wet milling is performed manually.

[0281] In some embodiments, the substantially amorphous form of the compound having Formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG.

[0282] In some embodiments, the present disclosure provides a substantially amorphous form of a compound having Formula (I), the substantially amorphous form being prepared by milling (e.g., dry-milling or wet-milling in ethanol) any one of crystalline Forms A-U, and characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with Figure 68.

[0283] In some embodiments, the present disclosure provides a substantially amorphous form of a compound having Formula (I), the substantially amorphous form being prepared by milling (e.g., dry milling) Form T in the absence of solvent or water, and characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with Figure 68.

[0284] V. Composition The crystalline forms of the compound of formula (I) described herein may be in the form of a composition suitable for administration to a subject. Generally, such compositions are pharmaceutical compositions comprising the crystalline forms of the compound of formula (I) described herein and one or more pharmaceutically or physiologically acceptable excipients.

[0285] The substantially amorphous form of the compound of formula (I) described herein may be in the form of a composition suitable for administration to a subject. Generally, such a composition is a pharmaceutical composition comprising the substantially amorphous form of the compound of formula (I) described herein and one or more pharmaceutically or physiologically acceptable excipients.

[0286] In some embodiments, the crystalline form of the compound of Formula (I) described herein is present in a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises any one of crystalline Forms A-U of the compound of Formula (I) described herein or a solid form of the compound of Formula (I) described herein and one or more pharmaceutically or physiologically acceptable excipients. In some embodiments, the pharmaceutical composition comprises crystalline Form A of the compound of Formula (I) described herein and one or more pharmaceutically or physiologically acceptable excipients. In some embodiments, the pharmaceutical composition comprises crystalline Form B of the compound of Formula (I) described herein and one or more pharmaceutically or physiologically acceptable excipients. In some embodiments, the pharmaceutical composition comprises crystalline Form C of the compound of Formula (I) described herein and one or more pharmaceutically or physiologically acceptable excipients. In some embodiments, the pharmaceutical composition comprises crystalline Form D of the compound of Formula (I) described herein and one or more pharmaceutically or physiologically acceptable excipients. In some embodiments, a pharmaceutical composition comprises crystalline Form E of the compound of Formula (I) described herein and one or more pharmaceutically or physiologically acceptable excipients. In some embodiments, a pharmaceutical composition comprises crystalline Form F of the compound of Formula (I) described herein and one or more pharmaceutically or physiologically acceptable excipients. In some embodiments, a pharmaceutical composition comprises crystalline Form G of the compound of Formula (I) described herein and one or more pharmaceutically or physiologically acceptable excipients. In some embodiments, a pharmaceutical composition comprises crystalline Form H of the compound of Formula (I) described herein and one or more pharmaceutically or physiologically acceptable excipients. In some embodiments, a pharmaceutical composition comprises crystalline Form I of the compound of Formula (I) described herein and one or more pharmaceutically or physiologically acceptable excipients. In some embodiments, a pharmaceutical composition comprises crystalline Form J of the compound of Formula (I) described herein and one or more pharmaceutically or physiologically acceptable excipients.In some embodiments, a pharmaceutical composition comprises crystalline Form K of the compound of Formula (I) described herein and one or more pharmaceutically acceptable excipients or physiologically acceptable excipients. In some embodiments, a pharmaceutical composition comprises crystalline Form L of the compound of Formula (I) described herein and one or more pharmaceutically acceptable excipients or physiologically acceptable excipients. In some embodiments, a pharmaceutical composition comprises crystalline Form M of the compound of Formula (I) described herein and one or more pharmaceutically acceptable excipients or physiologically acceptable excipients. In some embodiments, a pharmaceutical composition comprises crystalline Form N of the compound of Formula (I) described herein and one or more pharmaceutically acceptable excipients or physiologically acceptable excipients. In some embodiments, a pharmaceutical composition comprises crystalline Form O of the compound of Formula (I) described herein and one or more pharmaceutically acceptable excipients or physiologically acceptable excipients. In some embodiments, a pharmaceutical composition comprises crystalline Form P of the compound of Formula (I) described herein and one or more pharmaceutically acceptable excipients or physiologically acceptable excipients. In some embodiments, a pharmaceutical composition comprises crystalline Form Q of the compound of Formula (I) described herein and one or more pharmaceutically acceptable excipients or physiologically acceptable excipients. In some embodiments, a pharmaceutical composition comprises crystalline Form S of the compound of Formula (I) described herein and one or more pharmaceutically acceptable excipients or physiologically acceptable excipients. In some embodiments, a pharmaceutical composition comprises crystalline Form T of the compound of Formula (I) described herein and one or more pharmaceutically acceptable excipients or physiologically acceptable excipients. In some embodiments, a pharmaceutical composition comprises crystalline Form U of the compound of Formula (I) described herein and one or more pharmaceutically acceptable excipients or physiologically acceptable excipients. In some embodiments, a pharmaceutical composition comprises a solid form of the compound of Formula (I) described herein and one or more pharmaceutically acceptable excipients or physiologically acceptable excipients. In some embodiments, a pharmaceutical composition comprises solid form V described herein and one or more pharmaceutically acceptable excipients or physiologically acceptable excipients.

[0287] In some embodiments, the pharmaceutical composition comprises a substantially amorphous form of a compound of Formula (I) described herein and one or more pharmaceutically acceptable excipients or physiologically acceptable excipients.

[0288] Pharmaceutical compositions may be used in the methods disclosed herein; thus, for example, pharmaceutical compositions may be administered in vivo or in vitro to a subject to practice the therapeutic methods and uses described herein.

[0289] Pharmaceutical compositions can be formulated to be compatible with the intended method or route of administration, exemplary routes of administration being described herein. Additionally, pharmaceutical compositions may be used in combination with other therapeutically active agents or compounds described herein to treat the diseases, disorders, and conditions contemplated by the present disclosure.

[0290] Pharmaceutical compositions comprising the active ingredient (e.g., a crystalline or substantially amorphous form of a compound of Formula (I) described herein) may be in a form suitable for oral use, such as a tablet, capsule, troche, lozenge, aqueous or oily suspension, dispersible powder or granules, emulsion, hard or soft capsule, or syrup, solution, microbeads, or elixir. Pharmaceutical compositions intended for oral use may be prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more agents, such as, for example, sweeteners, flavoring agents, coloring agents, and preservatives, to provide a pharmaceutically elegant and palatable formulation. Tablets, capsules, etc. comprise the active ingredient mixed with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets, capsules, etc. These excipients may be, for example, diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binders, such as starch, gelatin, or acacia; and lubricants, such as magnesium stearate, stearic acid, or talc.

[0291] Tablets, capsules, and the like suitable for oral administration may be uncoated, or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used. Tablets may also be coated by techniques known in the art to form osmotic therapeutic tablets for controlled release. Additional agents include biodegradable or biocompatible particles or polymeric materials to control delivery of the administered composition, such as polyesters, polyamic acids, hydrogels, polyvinylpyrrolidone, polyanhydrides, polyglycolic acid, ethylene-vinyl acetate, methylcellulose, carboxymethylcellulose, protamine sulfate, or copolymers of lactide and glycolide, copolymers of polylactide and glycolide, or ethylene-vinyl acetate copolymers. For example, oral agents can be encapsulated in microcapsules prepared by coacervation techniques or interfacial polymerization, microcapsules prepared by using hydroxymethylcellulose or gelatin microcapsules or poly(methyl methacrylate) microcapsules, respectively, or colloidal drug delivery systems. Colloidal dispersion systems include macromolecule complexes, nanocapsules, microspheres, microbeads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes. Methods for preparing such formulations are known in the art.

[0292] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, kaolin, or microcrystalline cellulose, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0293] Aqueous suspensions contain the active substance mixed with excipients suitable for their manufacture. Such excipients may be suspending agents, such as sodium carboxymethylcellulose, methylcellulose, (hydroxypropyl)methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum; dispersing or wetting agents, such as naturally occurring phospholipids (e.g., lecithin), or condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), or condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptodecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives.

[0294] Oily suspensions may be formulated by suspending the active ingredient in vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or mineral oil, such as liquid paraffin.Oily suspensions may contain thickening agents, such as beeswax, hard paraffin, or cetyl alcohol.Sweeteners and flavoring agents, as mentioned above, may be added to provide a palatable oral preparation.

[0295] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified herein.

[0296] The pharmaceutical composition may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may include natural gums, such as acacia gum or tragacanth gum, naturally occurring phospholipids, such as soybeans, lecithin, and esters or partial esters derived from fatty acids, hexitol anhydrides, such as sorbitan monooleate, and condensation products of partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.

[0297] Pharmaceutical compositions typically contain a therapeutically effective amount of a crystalline form of the compound of Formula (I) or a salt thereof described herein and one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfite), preservatives (e.g., benzyl alcohol, methylparaben, ethyl or n-propyl, p-hydroxybenzoate), emulsifiers, suspending agents, dispersing agents, solvents, fillers, extenders, surfactants, buffers, vehicles, diluents, and / or adjuvants. For example, suitable vehicles may be physiological saline solution or citrate-buffered saline, sometimes supplemented with other substances commonly used in pharmaceutical compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. Those skilled in the art will readily recognize various buffers that can be used in the pharmaceutical compositions and dosage forms contemplated herein. Typical buffer solutions include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. For example, buffer components can be water-soluble substances such as phosphoric acid, tartaric acid, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof. Acceptable buffering agents include, for example, Tris buffer, N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES), 2-(N-morpholino)ethanesulfonic acid (MES), 2-(N-morpholino)ethanesulfonic acid sodium salt (MES), 3-(N-morpholino)propanesulfonic acid (MOPS), and N-tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).

[0298] After the pharmaceutical composition has been formulated, it may be stored in a sterile vial as a solution, suspension, gel, emulsion, solid, or dehydrated or lyophilized powder. Such formulations may be stored in a ready-to-use form, a lyophilized form that must be reconstituted before use, a liquid form that must be diluted before use, or other acceptable form. In some embodiments, the pharmaceutical composition is provided in a single-use container (e.g., a single-use vial, an ampoule, a syringe, or an autoinjector (such as an EpiPen®)), while in other embodiments, it is provided in a multi-use container (e.g., a multi-use vial).

[0299] The formulation may also include a carrier to protect the composition from rapid degradation or elimination from the body, such as a controlled-release formulation, including liposomes, hydrogels, prodrugs, and microencapsulated delivery systems. For example, a time-delay material such as glyceryl monostearate or glyceryl stearate may be used alone or in combination with a wax. Any drug delivery device known to those skilled in the art may be used to deliver the compounds of Formula (I) or subembodiments or salts thereof described herein, including implants (e.g., implantable pumps) and catheter systems, slow infusion pumps and devices.

[0300] Depot injections, typically administered subcutaneously or intramuscularly, may be used to release the compound of formula (I) or its salt described herein over a predetermined period of time. Depot injections are typically solid or oil-based and typically contain at least one of the formulation components described herein. Those skilled in the art are familiar with the possible formulations and uses of depot injections.

[0301] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. Suspensions may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents mentioned herein. Sterile injectable preparations may also be sterile injectable solutions or suspensions in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Diluents, solvents, and dispersion media that can be used include water, Ringer's solution, isotonic sodium chloride solution, Cremophor EL™ (BASF, Parsippany, NJ) or phosphate-buffered saline (PBS), ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil, including synthetic monoglycerides or diglycerides, may be used. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectables. Prolonged absorption of certain injectable formulations can be achieved by including an agent that delays absorption, for example, aluminum monostearate or gelatin.

[0302] The crystalline or substantially amorphous form of the compound of formula (I) described herein may also be administered as a suppository for rectal administration or as a spray for nasal or inhalation use. Suppositories can be prepared by mixing a drug with a suitable non-irritating excipient that is solid at normal temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter and polyethylene glycol.

[0303] VI. Methods for Preparing Crystalline Forms In a third aspect, the present disclosure provides a method for preparing solid state Form V of a compound having formula (I), the method comprising: a) forming a first slurry comprising a crude compound of Formula (I) and a first organic solvent; b) isolating the first precipitate of step a); c) forming a second slurry comprising the first precipitate of step b) and a second organic solvent; d) isolating the second precipitate; and e) drying the second precipitate to obtain solid form V of formula (I); and the first organic solvent comprises C 1~4 The first organic solvent is an alkyl alcohol and the second organic solvent is a chlorinated aprotic solvent.

[0304] In some embodiments, the first organic solvent is methanol, ethanol, isopropyl, or a mixture thereof. In some embodiments, the first organic solvent is ethanol.

[0305] In some embodiments, the second organic solvent is dichloromethane.

[0306] In some embodiments, the first organic solvent is ethanol and the second organic solvent is dichloromethane.

[0307] Steps a) through d) can be performed at any temperature, for example, at a temperature between 10° C. and 50° C. In some embodiments, steps a) through d) are performed at a temperature between 20° C. and 30° C. In some embodiments, steps a) through d) are performed at a temperature of about 25° C. In some embodiments, steps a) through d) are performed at room temperature.

[0308] In some embodiments, the first slurry in step a) is formed at a temperature of about 25° C. and maintained for 30 minutes to 2 hours. In some embodiments, the first slurry in step a) is formed at a temperature of about 25° C. and maintained for about 1 hour.

[0309] In some embodiments, the second slurry in step c) is formed at a temperature of about 25° C. and maintained for 30 minutes to 2 hours. In some embodiments, the second slurry in step c) is formed at a temperature of about 25° C. and maintained for about 1 hour.

[0310] The isolation in step b) and / or step d) can be performed by any method known in the art, hi some embodiments, the isolation in step b) and / or step d) is performed by filtration.

[0311] The drying in step e) can be carried out by any method known in the art, for example, under vacuum at a temperature between room temperature and 80°C. In some embodiments, the drying in step e) is carried out at a temperature between 30°C and 50°C. In some embodiments, the drying in step e) is carried out at a temperature of about 40°C. In some embodiments, the drying in step e) is carried out under vacuum at a temperature between 30°C and 50°C. In some embodiments, the drying in step e) is carried out under vacuum at a temperature of about 40°C. In some embodiments, the drying in step e) is carried out under vacuum at a temperature of about 40°C for 1 to 5 hours. In some embodiments, the drying in step e) is carried out under vacuum at a temperature of about 40°C for about 3 hours.

[0312] In some embodiments, the crude compound of Formula (I) is present in the first slurry and / or the second slurry in an amount of about 25 g / L to 100 g / L. In some embodiments, the crude compound of Formula (I) is present in the first slurry in an amount of about 25 g / L to 100 g / L. In some embodiments, the crude compound of Formula (I) is present in the first slurry in an amount of about 50 g / L to 90 g / L. In some embodiments, the crude compound of Formula (I) is present in the first slurry in an amount of about 50 g / L to 70 g / L. In some embodiments, the crude compound of Formula (I) is present in the first slurry in an amount of about 60 g / L. In some embodiments, the compound of Formula (I) in step b) is present in the second slurry in an amount of about 25 g / L to 100 g / L. In some embodiments, the compound of Formula (I) in step b) is present in the second slurry in an amount of about 50 g / L to 70 g / L. In some embodiments, the compound of formula (I) in step b) is present in the second slurry in an amount of about 60 g / L.

[0313] In some embodiments, prior to step a), the method further comprises: a-1) suspending the crude compound of formula (I) in water and stirring the suspension for 6 to 24 hours; a-2) removing the precipitate by filtration to obtain a filtrate containing the crude compound of formula (I); a-3) Concentrating the filtrate to obtain a crude compound of formula (I); Further includes:

[0314] In a fourth aspect, the present disclosure provides a method for preparing crystalline form A of a compound having formula (I), the method comprising: a) forming a first mixture comprising a crude compound of formula (I), ACN, and water; b) solvent exchange with water at a temperature of about 65°C or less to form a second mixture; c) cooling and stirring the second mixture to form a third precipitate; d) isolating the third precipitate; and e) forming a slurry comprising the third precipitate, methyl ethyl ketone (MEK), and water; f) isolating the fourth precipitate of step e); g) drying the fourth precipitate to obtain crystalline Form A of Formula (I); Includes:

[0315] In step a), in some embodiments, the ratio of ACN to water is about 5:1 to about 2:1 by volume, hi some embodiments, the ratio of ACN to water is about 4:1 by volume.

[0316] Step a) can be carried out at an elevated temperature, for example, at a temperature of about 75° C. to 80° C. In some embodiments, step a) is carried out at a temperature of about 75° C. to 80° C.

[0317] In step b), in some embodiments, the solvent exchange with water is carried out by 1) concentrating the first mixture of step a), 2) adding water, 3) concentrating, and 4) adding a final portion of water.

[0318] In some embodiments, the method further comprises adding a crystalline seed of the compound of Formula (I) (e.g., Form A) to the first mixture of step a) before or during the solvent exchange of step b). In some embodiments, the crystalline seed of the compound of Formula (I) (e.g., Form A) is added after concentrating the first mixture of step a). In some embodiments, the crystalline seed of the compound of Formula (I) is Form A.

[0319] Step b) can be carried out at an elevated temperature of about 65° C. or less. In some embodiments, step b) is carried out at a temperature of about 65° C. or less.

[0320] Step c) can be carried out at a cooled temperature, for example, at a temperature of about 0°C to 5°C. In some embodiments, step c) is carried out at a temperature of about 0°C to 5°C. The stirring in step c) can be carried out for about 5 hours to 24 hours. In some embodiments, the stirring in step c) is carried out for about 10 hours to 18 hours. In some embodiments, the stirring in step c) is carried out for about 13 hours.

[0321] In some embodiments, the third precipitate of step c) is formed at a temperature of about 0° C. to 5° C. and stirred for 10 to 18 hours. In some embodiments, the third precipitate of step c) is formed at a temperature of about 0° C. to 5° C. and stirred for about 13 hours.

[0322] In step e), in some embodiments, the ratio of methyl ethyl ketone (MEK) to water is about 20:1 to 5:1 by volume. In step e), in some embodiments, the ratio of methyl ethyl ketone (MEK) to water is about 12:1 to 8:1 by volume. In step e), in some embodiments, the ratio of methyl ethyl ketone (MEK) to water is about 11:1 to 9:1 by volume. In some embodiments, the ratio of methyl ethyl ketone (MEK) to water is about 10:1 by volume. In some embodiments, the mixture in step e) has a water content of about 9 to 10% by weight. In some embodiments, the mixture in step e) has a water content of about 8% to about 11% by weight.

[0323] In some embodiments, the slurry in step e) is formed at a temperature of about 60°C-65°C and stirred for about 15-24 hours. In some embodiments, the slurry in step e) is formed at a temperature of about 60°C-65°C and stirred for about 17-22 hours. In some embodiments, the slurry in step e) is further cooled to a temperature of about 0°C-5°C. In some embodiments, the slurry in step e) is further cooled to a temperature of about 0°C-5°C and stirred for about 15-24 hours. In some embodiments, the slurry in step e) is further cooled to a temperature of about 0°C, stirred for about 4 hours, and further stirred at a temperature of about 0°C-5°C for about 16 hours.

[0324] The isolation in step d) and / or step f) can be performed by any method known in the art, hi some embodiments, the isolation in step d) and / or step f) is performed by filtration.

[0325] Drying in step g) can be carried out by any method known in the art, for example, under vacuum at a temperature between room temperature and 80°C. In some embodiments, drying in step e) is carried out at a temperature between 65°C and 70°C. In some embodiments, drying in step e) is carried out under vacuum at a temperature between about 65°C and 70°C for 1 to 4 days. In some embodiments, drying in step e) is carried out under vacuum at a temperature between about 65°C and 70°C for about 3 days.

[0326] In some embodiments, the crude compound of Formula (I) is present in the first mixture in an amount of about 10 g / L to 100 g / L, about 20 g / L to 100 g / L, about 30 g / L to 100 g / L, about 10 g / L to 50 g / L, about 20 g / L to 50 g / L, or about 30 g / L to 50 g / L. In some embodiments, the crude compound of Formula (I) is present in the first mixture in an amount of about 20 g / L to 100 g / L. In some embodiments, the crude compound of Formula (I) is present in the first mixture in an amount of about 20 g / L to 50 g / L. In some embodiments, the crude compound of Formula (I) is present in the first mixture in an amount of about 30 g / L.

[0327] The first crude compound of formula (I) can be obtained from the amination reaction shown below. [ka]

[0328] In some embodiments, the crude first compound of formula (I) is obtained by concentrating the reaction mixture of the amination reaction.

[0329] The first crude compound of formula (I) can be obtained from a two step reaction as shown below. [ka]

[0330] The crystalline forms of the present disclosure can be prepared from the compound of formula (I) by any one of the methods described herein, and the crystalline form is any one of crystalline forms A-U.

[0331] In some embodiments, the present disclosure provides a method for preparing a crystalline form of a compound having formula (I), wherein the crystalline form is any one of crystalline forms A-U, and the method comprises a step of: a) equilibration with the solvent (e.g., stirring a suspension of a compound of formula (I) in the solvent at 25°C for 14 days or at 50°C for 7 days); b) temperature cycling (e.g., equilibrating the compound of formula (I) with the solvent over six temperature cycles from 5°C to 50°C at a heating / cooling rate of 0.2°C / min); d) crystallization at room temperature by slow evaporation (e.g., evaporating a solution containing a compound of formula (I) under ambient conditions); e) crystallization at room temperature by fast evaporation (for example, evaporating a solution containing a compound of formula (I) under a stream of nitrogen); f) Precipitation by adding an anti-solvent (e.g., dissolving the compound of formula (I) in a solvent and slowly adding an anti-solvent to form a precipitate); g) crystallization by slow cooling from a hot saturated solution (e.g., dissolving a compound of formula (I) in a solvent at 50°C and cooling the filtered solution to 5°C at 0.1°C / min); h) crystallization by rapid cooling from a hot saturated solution (e.g., dissolving a compound of formula (I) in a solvent at 50°C and cooling the filtered solution in an ice bath); i) vapor diffusion (e.g., placing a clear solution of a compound of formula (I) in a small, open glass vial, placing the small, open vial at the bottom of a larger glass vial containing an antisolvent, and allowing the capped large vial to stand at room temperature); and j) Competitive equilibration (for example, placing two crystalline forms of the compound of formula (I) in a solvent and stirring the resulting suspension at 25° C. and / or 50° C. for 7 days).

[0332] In a fifth aspect, the present disclosure provides a method for preparing a crystalline form of a compound having formula (I), the method comprising: a) forming a slurry comprising Solid Form V of Formula (I) and a solvent; b) stirring the slurry for at least 1 day; c) isolating the precipitate; and d) drying the precipitate to obtain the crystalline form of formula (I); wherein the crystalline form is crystalline form C, D, E, I, or A-1, and the solvent is methanol, water, a mixture of methanol and water, a mixture of acetone and water, or a mixture of acetonitrile and water.

[0333] In some embodiments, the crystalline form is crystalline form C and the solvent is methanol.

[0334] In some embodiments, the crystalline form is crystalline form D and the solvent is water.

[0335] In some embodiments, the crystalline form is crystalline form E and the solvent is a mixture of methanol and water. In some embodiments, the ratio of methanol to water is about 1:1 by volume.

[0336] In some embodiments, the crystalline form is crystalline form I and the solvent is a mixture of acetone and water. In some embodiments, the ratio of acetone to water is about 1:1 by volume.

[0337] In some embodiments, the crystalline form is crystalline form A and the solvent is a mixture of acetonitrile and water, in some embodiments, the ratio of acetonitrile to water is about 1:1 by volume.

[0338] In some embodiments, the stirring in step b) is performed at a temperature of about 25° C. and / or about 50° C. In some embodiments, the stirring in step b) is performed at a temperature of about 25° C. In some embodiments, the stirring in step b) is performed at a temperature of about 50° C. In some embodiments, the stirring in step b) is performed at a temperature of about 25° C. and about 50° C.

[0339] In some embodiments, the stirring in step b) is carried out for 3 to 6 days. In some embodiments, the stirring in step b) is carried out at a first temperature of about 50°C for a first period of 3 days and at a second temperature of about 25°C for a second period of 3 days. In some embodiments, the stirring in step b) is carried out at a temperature of about 50°C for 6 days. In some embodiments, the stirring in step b) is carried out at a temperature of about 50°C for 3 days. In some embodiments, the stirring in step b) is carried out at a temperature of about 25°C for 6 days.

[0340] The isolation in step c) can be performed by any method known in the art, hi some embodiments, the isolation in step c) is performed by filtration.

[0341] The drying in step d) can be performed by any method known in the art. In some embodiments, the drying in step d) is performed at room temperature. In some embodiments, the drying in step d) is performed at room temperature for 10 to 72 hours. In some embodiments, the drying in step d) is performed at room temperature for 20 to 72 hours. In some embodiments, the drying in step d) is performed at room temperature for about 20 hours. In some embodiments, the drying in step d) is performed at room temperature for about 65 hours.

[0342] In some embodiments, solid form V of Formula (I) is present in the slurry in an amount of 50 mg / mL to 120 mg / mL. In some embodiments, solid form V of Formula (I) is present in the slurry in an amount of 60 mg / mL to 100 mg / mL. In some embodiments, solid form V of Formula (I) is present in the slurry in an amount of about 70 mg / mL in methanol. In some embodiments, solid form V of Formula (I) is present in the slurry in an amount of about 100 mg / mL in water. In some embodiments, solid form V of Formula (I) is present in the slurry in an amount of about 83 mg / mL in a mixture of methanol and water, wherein the ratio of methanol to water is about 1:1 by volume. In some embodiments, solid form V of Formula (I) is present in the slurry in an amount of about 63 mg / mL in a mixture of acetone and water, wherein the ratio of acetone to water is about 1:1 by volume. In some embodiments, solid Form V of Formula (I) is present in a slurry in an amount of about 65 mg / mL in a mixture of acetonitrile and water, wherein the ratio of acetonitrile to water is about 1:1 by volume.

[0343] In some embodiments, the present disclosure provides a method for preparing crystalline form C of a compound having formula (I), the method comprising: a) forming a slurry comprising Solid Form V of Formula (I) and methanol; b) stirring the slurry at a first temperature of about 50° C. for a first period of 3 days and at a second temperature of about 25° C. for a second period of 3 days; c) isolating the precipitate by filtration; d) drying the precipitate at room temperature to obtain crystalline form C of formula (I); Includes:

[0344] In some embodiments of the process for preparing crystalline Form C, solid Form V of Formula (I) is present in a slurry in methanol in an amount of about 70 mg / mL. In some embodiments, the drying in step d) is carried out at room temperature for about 20 hours.

[0345] In some embodiments, the present disclosure provides a method for preparing crystalline form D of a compound having formula (I), the method comprising: a) forming a slurry comprising solid form V of formula (I) and water; b) stirring the slurry at a temperature of about 50°C for 6 days; c) isolating the precipitate by filtration; d) drying the precipitate at room temperature to obtain crystalline form D of formula (I); Includes:

[0346] In some embodiments of the method for preparing crystalline form D, solid form V of Formula (I) is present in a slurry in water in an amount of about 100 mg / mL. In some embodiments, the drying in step d) is carried out at room temperature for about 20 hours.

[0347] In some embodiments, the present disclosure provides a method for preparing crystalline form E of a compound having formula (I), the method comprising: a) forming a slurry comprising solid Form V of Formula (I) and a mixture of methanol and water; b) stirring the slurry at a first temperature of about 50° C. for a first period of 3 days and at a second temperature of about 25° C. for a second period of 3 days; c) isolating the precipitate by filtration; d) drying the precipitate at room temperature to obtain crystalline form E of formula (I); and a methanol to water ratio of about 1:1 by volume.

[0348] In some embodiments of the process for preparing crystalline form E, solid form V of Formula (I) is present in a slurry in an amount of about 83 mg / mL in a mixture of methanol and water, wherein the ratio of methanol to water is about 1:1 by volume. In some embodiments, the drying in step d) is carried out at room temperature for about 20 hours.

[0349] In some embodiments, the present disclosure provides a method for preparing crystalline Form I of a compound having formula (I), the method comprising: a) forming a slurry comprising Solid Form V of Formula (I) and a mixture of acetone and water; b) stirring the slurry at a temperature of about 50°C for 3 days; c) isolating the precipitate by filtration; d) drying the precipitate at room temperature to obtain crystalline Form I of formula (I); and a ratio of acetone to water of about 1:1 by volume.

[0350] In some embodiments of the method for preparing crystalline Form I, solid Form V of Formula (I) is present in a slurry in an amount of about 63 mg / mL in a mixture of acetone and water, wherein the ratio of acetone to water is about 1:1 by volume. In some embodiments, the drying in step d) is carried out at room temperature for about 65 hours.

[0351] In some embodiments, the present disclosure provides a method for preparing crystalline form A of a compound having formula (I), the method comprising: a) forming a slurry comprising Solid Form V of Formula (I) and a mixture of acetonitrile and water; b) stirring the slurry for 6 days at a temperature of about 25°C; c) isolating the precipitate by filtration; d) drying the precipitate at room temperature to obtain crystalline form A of formula (I). and a ratio of acetonitrile to water of about 1:1 by volume.

[0352] In some embodiments of the method for preparing crystalline Form A, solid Form V of Formula (I) is present in a slurry in an amount of about 68 mg / mL in a mixture of acetonitrile and water, wherein the ratio of acetonitrile to water is about 1:1 by volume. In some embodiments, the drying in step d) is carried out at room temperature for about 20 to 72 hours.

[0353] VII. Treatment method In a sixth aspect, the present disclosure provides a method for treating a disease mediated by MAT2A in a patient, the method comprising administering to the patient a therapeutically effective amount of a crystalline or substantially amorphous form of a compound of Formula (I) described herein or a pharmaceutical composition thereof described herein. In some embodiments, the disease is cancer.

[0354] Overexpression of the enzyme MAT2A has been shown to mediate certain cancers. In one embodiment, the cancer is selected from the group consisting of neuroblastoma, intestinal cancer (such as rectal cancer, colon cancer, familial polyposis coli cancer, and hereditary nonpolyposis colorectal cancer), esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, breast cancer, urinary tract cancer, melanoma, brain tumors (glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumors), Hodgkin's lymphoma, esophagogastric cancer, gastrointestinal cancer, and esophageal cancer. GI cancer, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia, hepatocellular carcinoma, gallbladder carcinoma, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma.

[0355] In another embodiment, the cancer is lung cancer, non-small cell lung (NSLC) cancer, bronchioloalveolar cell lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, vaginal cancer, vulvar cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urinary cancer of the bladder, bladder, kidney or ureter, renal cell carcinoma, renal pelvis carcinoma, mesothelioma, hepatocellular carcinoma, biliary tract cancer, chronic or acute leukemia, lymphocytic lymphoma, central nervous system (CNS) tumor, spinal axis tumor, brain stem glioma, glioblastoma multiforme, astrocytoma, schwannoma, ependymoma, medulloblastoma, meningioma, squamous cell carcinoma, pituitary adenoma, a refractory form of any of the above cancers, or a combination of one or more of the above cancers.

[0356] Methylthioadenosine phosphorylase (MTAP) is an enzyme found in all normal tissues that catalyzes the conversion of methylthioadenosine (MTA) to adenine and 5-methylthioribose-1-phosphate. Adenine is recycled to generate adenosine monophosphate, which is then converted to methionine and formate. This salvage pathway allows MTA to serve as an alternative purine source when de novo purine synthesis is inhibited, for example, by antimetabolites such as L-alanosine.

[0357] Many human and mouse malignant cells lack MTAP activity. MTAP deficiency is not only found in tissue culture cells, but also in primary leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSLC), bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin's lymphoma, and mesothelioma. K. Marjon et al., Cell Reports 15 (2016) 574-587, incorporated herein by reference, reported that knocking down MAT2A expression with shRNA inhibits the growth of MTAP-null cancer cells. MTAP-null cancer refers to cancer in which the MTAP gene is deleted, lost, or inactivated, or in which the function of the MTAP protein is reduced or impaired.

[0358] In a seventh aspect, the present disclosure provides a method of treating an MTAP-null cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of a crystalline or substantially amorphous form of a compound of Formula (I) described herein or a pharmaceutical composition thereof described herein. Accordingly, embodiments of the present disclosure also provide a method for treating an MTAP-null cancer in a patient, the cancer being characterized by reduced or absent MTAP expression, or the absence of the MTAP gene, reduced levels of MTAP protein, reduced function of MTAP protein, or a combination thereof, compared to cancers in which the MTAP gene is present and fully functional, comprising administering to a patient in need thereof a therapeutically effective amount of a crystalline or substantially amorphous form of a compound of Formula (I) described herein or a pharmaceutical composition thereof described herein. In one embodiment, the MTAP null cancer is leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSLC), bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin's lymphoma, or mesothelioma. In another embodiment, the MTAP null cancer is pancreatic cancer. In yet another embodiment, the MTAP null cancer is bladder cancer, melanoma, brain cancer, lung cancer, pancreatic cancer, breast cancer, esophageal cancer, head and neck cancer, kidney cancer, colon cancer, diffuse large B-cell lymphoma (DLBCL), acute lymphoblastic leukemia (ALL), or mantle cell lymphoma (MCL). In yet another embodiment, the MTAP null cancer is gastric cancer. In yet another embodiment, the cancer is colon cancer. In yet another embodiment, the MTAP null cancer is liver cancer. In yet another embodiment, the MTAP null cancer is glioblastoma multiforme (GBM). In yet another embodiment, the MTAP null cancer is bladder cancer. In yet another embodiment, the MTAP null cancer is esophageal cancer. In yet another embodiment, the MTAP null cancer is breast cancer. In yet another embodiment, the MTAP null cancer is NSLCC. In yet another embodiment, the MTAP null cancer is MCL. In yet another embodiment, the MTAP null cancer is DLBCL. In yet another embodiment, the MTAP null cancer is ALL.

[0359] In yet another embodiment, the cancer is selected from the group consisting of leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, anal cancer, stomach cancer, colon cancer, colorectal cancer, soft tissue sarcoma, non-Hodgkin's lymphoma, gastric cancer, esophagogastric cancer, esophageal cancer, malignant peripheral nerve sheath tumor, and mesothelioma. In one embodiment, the cancer is mesothelioma. In one embodiment, the cancer is non-small cell lung cancer. In another embodiment, the cancer is non-squamous non-small cell lung cancer. In one embodiment, the cancer is colon cancer or rectal cancer. In one embodiment, the cancer is colon or rectal adenocarcinoma. In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is breast adenocarcinoma. In one embodiment, the cancer is gastric cancer. In one embodiment, the cancer is gastric adenocarcinoma. In one embodiment, the cancer is pancreatic cancer. In one embodiment, the cancer is pancreatic adenocarcinoma. In one embodiment, the cancer is bladder cancer. In one embodiment, the cancer is characterized by being MTAP-null. In one embodiment, the cancer is characterized by MTAP-deficiency. In yet another embodiment, the cancer is a solid tumor. In yet another embodiment, the cancer is an MTAP-deficient solid tumor. In yet another embodiment, the cancer is a metastatic MTAP-deficient solid tumor. In yet another embodiment, the cancer is metastatic. In yet another embodiment, the cancer is a solid malignant tumor. In yet another embodiment, the cancer is a solid tumor. In yet another embodiment, the cancer is MTAP-deficient lung cancer or MTAP-deficient pancreatic cancer, including MTAP-deficient NSCLC, MTAP-deficient pancreatic ductal adenocarcinoma (PDAC), or MTAP-deficient esophageal cancer. In another embodiment, the cancer is a tumor with a deletion of the MTAP gene. In any one of the embodiments herein, the cancer is a solid tumor or a hematological cancer. In one embodiment, the tumor is MTAP-deficient. In another embodiment, the tumor is normal for MTAP expression. In yet another embodiment, the cancer is NSCLC, mesothelioma, head and neck squamous cell carcinoma, salivary gland tumor, urothelial carcinoma, sarcoma, or ovarian cancer. In yet another embodiment, the cancer is NSCLC, esophagogastric cancer, or pancreatic cancer.In yet another embodiment, the cancer is characterized by reduced or absent MTAP gene expression, absent MTAP gene, reduced MTAP protein function, reduced or absent MTAP protein levels, accumulation of MTA, or a combination thereof. In yet another embodiment, the cancer is characterized by reduced or absent MTAP gene expression. In yet another embodiment, the cancer is characterized by reduced MTAP protein function. In yet another embodiment, the cancer is characterized by reduced or absent MTAP protein levels. In yet another embodiment, the cancer is characterized by accumulation of MTA.

[0360] Genomic analysis of MTAP-null cell lines showed that those that also incorporated KRAS or p53 mutations were sensitive to MAT2A inhibition.

[0361] In an eighth aspect, the present disclosure provides a method for treating cancer in a patient, the cancer being characterized by reduced or absent MTAP gene expression, the absence of the MTAP gene, reduced MTAP protein levels, reduced MTAP protein function, the absence of MTAP protein, or a combination thereof, the method comprising administering a therapeutically effective amount of a crystalline or substantially amorphous form of a compound of Formula (I) described herein or a pharmaceutical composition thereof described herein to the subject. Accordingly, there is also provided a method for treating cancer in a patient, the cancer being characterized by reduced or absent MTAP expression or the absence of the MTAP gene, reduced MTAP protein levels, reduced MTAP protein function, the absence of MTAP protein (i.e., MTAP null), or a combination thereof, and further characterized by the presence of mutant KRAS and / or mutant p53, the method comprising administering to the patient a therapeutically effective amount of a crystalline or substantially amorphous form of a compound of Formula (I) described herein. In one embodiment, the cancer is MTAP null and KRAS mutant. In another embodiment, the cancer is MTAP null and p53 mutant. In yet another embodiment, the cancer is MTAP null, KRAS mutant and p53 mutant.

[0362] The term "mutant KRAS" or "KRAS mutation" refers to a KRAS protein (or a gene encoding the protein) that incorporates an activating mutation that alters its normal function. For example, a mutant KRAS protein may incorporate a single amino acid substitution at position 12 or 13. In certain embodiments, the KRAS mutant incorporates a G12X or G13X substitution (X represents any amino acid change at the designated position). In certain embodiments, the substitution is G12V, G12R, G12C, or G13D. In another embodiment, the substitution is G13D. "Mutant p53" or "p53 mutation" refers to a p53 protein (or a gene encoding the protein) that incorporates a mutation that inhibits or eliminates tumor suppressor function. In one embodiment, the p53 mutation is Y126_splice, K132Q, M133K, R174fs, R175H, R196*, C238S, C242Y, G245S, R248W, R248Q, I255T, D259V, S261_splice, R267P, R273C, R282W, A159V, or R280K. In one embodiment, the cancer is non-small cell lung cancer (NSLCC), pancreatic cancer, head and neck cancer, gastric cancer, breast cancer, colon cancer, or ovarian cancer.

[0363] In some embodiments, the cancer is selected from the group consisting of leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin's lymphoma, and mesothelioma.

[0364] VIII. Embodiments Embodiment 1. A compound having formula (I): [ka] Crystalline form of.

[0365] Embodiment 2. A compound having formula (I): [ka] Crystalline form A of.

[0366] The crystalline form A of embodiment 2, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 3.6.1, 11.1, and 16.6 degrees two-theta (±0.2 degrees two-theta).

[0367] The crystalline form A of embodiment 2, characterized by an X-ray powder diffraction (XRPD) pattern comprising any of three peaks selected from 4.6.1, 6.6, 10.0, 11.1, 12.1, 15.6, and 16.6 degrees two-theta (±0.2 degrees two-theta).

[0368] The crystalline form A of embodiment 2, characterized by an X-ray powder diffraction (XRPD) pattern comprising any of four peaks selected from 5.6.1, 6.6, 10.0, 11.1, 12.1, 15.6, and 16.6 degrees two-theta (±0.2 degrees two-theta).

[0369] The crystalline form A of embodiment 2, characterized by an X-ray powder diffraction (XRPD) pattern comprising any of five peaks selected from 6.6.1, 6.6, 10.0, 11.1, 12.1, 15.6, and 16.6 degrees two-theta (±0.2 degrees two-theta).

[0370] Embodiment 7. The crystalline form A of embodiment 2, characterized by an X-ray powder diffraction pattern comprising peaks at 6, 15.6, 22.4, 27.4, and 28.4 degrees two-theta (±0.2 degrees two-theta).

[0371] Embodiment 8. The crystalline form A of any of embodiments 2-7, characterized by an X-ray powder diffraction pattern comprising peaks at 10.0, 18.5, 20.8, 25.3, and 25.7 degrees 2θ (±0.2 degrees 2θ).

[0372] Embodiment 9. The crystalline form A of embodiment 2, characterized by an X-ray powder diffraction pattern substantially in accordance with FIG.

[0373] Crystal form A of any of Embodiments 2-9, substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0374] Embodiment 11. Crystal form A of any of Embodiments 2-10, further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 323.5 °C.

[0375] Embodiment 12. Crystal form A of Embodiment 11, wherein the DSC thermogram substantially coincides with FIG. 7.

[0376] Embodiment 13. Crystal form A of any of Embodiments 2-12, further characterized by a weight percent loss of about 1.0% when heated to about 220 °C, measured by thermogravimetric analysis (TGA).

[0377] Embodiment 14. Crystal form A of any of Embodiments 2-13, further characterized by a thermogravimetric analysis (TGA) thermogram substantially coinciding with FIG. 8.

[0378] Embodiment 15. Crystal form A of any of Embodiments 2-14, further characterized by a polarized light microscopy (PLM) profile substantially shown in FIG. 9.

[0379] Embodiment 16. A compound having formula (I):

Chemical formula

[0380] Embodiment 17. Crystal form B of Embodiment 16, wherein the X-ray powder diffraction pattern further comprises peaks at 11.5, 11.8, 12.0, 19.7, and 28.3 °2θ (±0.2 °2θ).

[0381] Embodiment 18. The crystalline form B of embodiment 16 or 17, wherein the X-ray powder diffraction pattern further comprises peaks at 17.3, 20.3, 22.1, 24.2, and 29.6 degrees 2θ (±0.2 degrees 2θ).

[0382] Embodiment 19. The crystalline form B of embodiment 16, having an X-ray powder diffraction pattern substantially in accordance with FIG. 12.

[0383] Embodiment 20. Crystalline Form B of any of Embodiments 16-19, which is substantially free of other crystalline or amorphous forms of the compound having Formula (I).

[0384] Embodiment 21. A compound having formula (I): [ka] Crystalline form C of.

[0385] Embodiment 22. The crystalline form C of embodiment 21, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 11.8, 16.6, 17.5, 27.2, and 28.2 degrees two-theta (±0.2 degrees two-theta).

[0386] Embodiment 23. The crystalline form C of embodiment 21, wherein the X-ray powder diffraction pattern further comprises peaks at 19.7, 20.3, 23.7, 24.5, and 29.8 degrees 2θ (±0.2 degrees 2θ).

[0387] Embodiment 24. The crystalline form C of any of embodiments 21-23, wherein the X-ray powder diffraction pattern further comprises peaks at 10.9, 17.8, 21.8, 26.0, and 26.6 degrees 2θ (±0.2 degrees 2θ).

[0388] Embodiment 25. The crystalline form C of embodiment 21, having an X-ray powder diffraction pattern substantially in accordance with FIG. 13.

[0389] Embodiment 26. Crystalline Form C of any of embodiments 21-25, which is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0390] Embodiment 27. The crystalline form C of any of embodiments 21-26, further characterized by a differential scanning calorimetry (DSC) thermogram comprising one or more endothermic peaks at about 69.5°C, about 197.5°C, and about 326.6°C.

[0391] Embodiment 28. The crystalline form C of embodiment 27, wherein the DSC thermogram is substantially in accordance with Figure 14.

[0392] Embodiment 29. The crystalline form C of any of embodiments 21-28, further characterized by a weight percent loss of about 3.9% when heated to about 220° C. as measured by thermogravimetric analysis (TGA).

[0393] Embodiment 30. The crystalline form C of any of embodiments 21-29, further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with FIG. 15.

[0394] Embodiment 31. The crystalline form C of any of embodiments 21-30, further characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 16.

[0395] Embodiment 32. The crystalline form C of any of embodiments 21-31, further characterized by a water content of about 2.6% by weight, as measured by the Karl Fischer (KF) method.

[0396] Embodiment 33. Crystalline form C of any of embodiments 21 to 32 in the form of a hydrate.

[0397] Embodiment 34. A compound having formula (I): [ka] Crystalline form D.

[0398] Embodiment 35. The crystalline form D of embodiment 34, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.1, 12.4, 13.7, 16.5, 27.6 degrees 2θ (±0.2 degrees 2θ).

[0399] Embodiment 36. The crystalline form D of embodiment 34, wherein the X-ray powder diffraction pattern further comprises peaks at 10.9, 14.8, 25.2, 26.7, and 27.9 degrees 2θ (±0.2 degrees 2θ).

[0400] Embodiment 37. The crystalline form D of any of embodiments 34-36, wherein the X-ray powder diffraction pattern further comprises peaks at 10.3, 19.3, 21.2, 24.1, and 29.9 degrees 2θ (±0.2 degrees 2θ).

[0401] Embodiment 38. The crystalline form D of embodiment 34, having an X-ray powder diffraction pattern substantially in accordance with FIG. 19.

[0402] Embodiment 39. Crystalline form D of any of embodiments 34-38, which is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0403] Embodiment 40. The crystalline form D of any of embodiments 34-39, further characterized by a differential scanning calorimetry (DSC) thermogram comprising one or more endothermic peaks at about 66.8°C and about 322.0°C.

[0404] Embodiment 41. The crystalline form D of embodiment 40, wherein the DSC thermogram is substantially in accordance with Figure 20.

[0405] Embodiment 42. The crystalline form D of any of embodiments 34-41, further characterized by a weight percent loss of about 2.1% when heated to about 220° C. as measured by thermogravimetric analysis (TGA).

[0406] Embodiment 43. The crystalline form D of any of embodiments 34-42, further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with FIG. 21.

[0407] Embodiment 44. The crystalline form D of any of embodiments 34-43, further characterized by a polarized light microscope (PLM) profile substantially as shown in FIG. 22.

[0408] Embodiment 45. The crystalline form D of any of embodiments 34-44, further characterized by a water content of about 2.3% by weight as measured by the Karl Fischer (KF) method.

[0409] Embodiment 46. Crystalline form D of any of embodiments 34 to 45 in the form of a hydrate.

[0410] Embodiment 47. A compound having formula (I): [ka] Crystalline form of E.

[0411] Embodiment 48. The crystalline form E of embodiment 47, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 12.3, 13.7, 19.4, 26.7, and 27.6 degrees two-theta (±0.2 degrees two-theta).

[0412] Embodiment 49. The crystalline form E of embodiment 47, wherein the X-ray powder diffraction pattern further comprises peaks at 20.8, 24.5, 25.3, 28.1, and 30.0 degrees 2θ (±0.2 degrees 2θ).

[0413] Embodiment 50. The crystalline form E of any of embodiments 47-49, wherein the X-ray powder diffraction pattern further comprises peaks at 7.2, 14.6, 14.9, 18.2, and 22.5 degrees 2θ (±0.2 degrees 2θ).

[0414] Embodiment 51. The crystalline form E of embodiment 47, having an X-ray powder diffraction pattern substantially in accordance with FIG. 25.

[0415] Embodiment 52. Crystalline form E of any of embodiments 47-51, which is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0416] Embodiment 53. Crystal form E of any one of Embodiments 47 - 52, further characterized by a differential scanning calorimetry (DSC) thermogram comprising one or more endothermic peaks at about 85.9 °C and about 325.0 °C.

[0417] Embodiment 54. Crystal form E of Embodiment 53, wherein the DSC thermogram substantially coincides with FIG. 26.

[0418] Embodiment 55. Crystal form E of any one of Embodiments 47 - 54, further characterized by a weight percent loss of about 4.3% when heated to about 195 °C, measured by thermogravimetric analysis (TGA).

[0419] Embodiment 56. Crystal form E of any one of Embodiments 47 - 55, further characterized by a thermogravimetric analysis (TGA) thermogram substantially coinciding with FIG. 27.

[0420] Embodiment 57. Crystal form E of any one of Embodiments 47 - 56, further characterized by a polarized light microscopy (PLM) profile substantially shown in FIG. 28.

[0421] Embodiment 58. Crystal form E of any one of Embodiments 47 - 57, further characterized by a water content of about 4.4 weight %, measured by the Karl Fischer (KF) method.

[0422] Embodiment 59. Crystal form E of any one of Embodiments 47 - 58 in the form of a hydrate.

[0423] Embodiment 60. A compound having the formula (I):

Chemical formula

[0424] Embodiment 61. The crystalline form F of embodiment 60, wherein the X-ray powder diffraction pattern further comprises peaks at 14.7, 15.7, 17.8, 24.9, and 25.4 degrees 2θ (±0.2 degrees 2θ).

[0425] Embodiment 62. The crystalline form F of embodiment 60 or 61, wherein the X-ray powder diffraction pattern further comprises peaks at 12.4, 13.1, 17.3, 19.7, and 21.3 degrees 2θ (±0.2 degrees 2θ).

[0426] Embodiment 63. The crystalline form F of embodiment 52, having an X-ray powder diffraction pattern substantially in accordance with FIG. 30.

[0427] Embodiment 64. Crystalline form F of any of embodiments 60-63, which is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0428] Embodiment 65. The crystalline form F of any of embodiments 60-64, further characterized by a differential scanning calorimetry (DSC) thermogram comprising one or more endothermic peaks at about 74.9°C, 212.0°C, and about 325.8°C.

[0429] Embodiment 66. The crystalline form F of embodiment 65, wherein the DSC thermogram is substantially in accordance with Figure 31.

[0430] Embodiment 67. The crystalline form F of any of embodiments 60-66, further characterized by a weight percent loss of about 3.2% when heated to about 200° C. as measured by thermogravimetric analysis (TGA).

[0431] Embodiment 68. The crystalline form F of any of embodiments 60-67, further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with FIG. 32.

[0432] Embodiment 69. The crystalline form F of any of embodiments 60-68, further characterized by a water content of about 2.4% by weight as measured by the Karl Fischer (KF) method.

[0433] Embodiment 70. A compound having the formula (I): [Chemical formula] Crystal form G thereof, characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 5.5, 10.0, 15.6, 17.2, and 23.4° 2θ (±0.2° 2θ).

[0434] Embodiment 71. Crystal form G of Embodiment 70, wherein the X-ray powder diffraction pattern further includes peaks at 7.4, 7.8, 20.9, 24.5, and 27.7° 2θ (±0.2° 2θ).

[0435] Embodiment 72. Crystal form G of Embodiment 70, wherein the X-ray powder diffraction pattern is substantially identical to FIG. 33.

[0436] Embodiment 73. Crystal form G of any one of Embodiments 70 to 72, substantially free of other crystal forms or amorphous forms of the compound having the formula (I).

[0437] Embodiment 74. Crystal form G of any one of Embodiments 70 to 73, further characterized by a differential scanning calorimetry (DSC) thermogram including an endothermic peak at about 322.3 °C.

[0438] Embodiment 75. Crystal form G of Embodiment 74, wherein the DSC thermogram is substantially identical to FIG. 34.

[0439] Embodiment 76. Crystal form G of any one of Embodiments 70 to 75, further characterized by a first weight percent loss of 2.5% when heated to about 160 °C and a second weight percent loss of about 0.9% when heated to about 233 °C, measured by thermogravimetric analysis (TGA).

[0440] Embodiment 77. Crystal form G of any one of Embodiments 70 to 76, further characterized by a thermogravimetric analysis (TGA) thermogram substantially identical to FIG. 35.

[0441] Embodiment 78. A compound having the formula (I):

Chemical formula

[0442] Embodiment 79. The crystal form H of Embodiment 78, wherein the X-ray powder diffraction pattern further comprises peaks at 7.8, 11.9, 17.3, and 28.3° 2θ (±0.2° 2θ).

[0443] Embodiment 80. The crystal form H of Embodiment 78, wherein the X-ray powder diffraction pattern is substantially identical to FIG. 37.

[0444] Embodiment 81. The crystal form H of any one of Embodiments 78 to 80, substantially free of other crystal forms or amorphous forms of the compound having the formula (I).

[0445] Embodiment 82. The crystal form H of any one of Embodiments 78 to 81, further characterized by a differential scanning calorimetry (DSC) thermogram comprising one or more endothermic peaks at about 226.3 °C and about 322.6 °C.

[0446] Embodiment 83. The crystal form H of Embodiment 82, wherein the DSC thermogram is substantially identical to FIG. 38.

[0447] Embodiment 84. The crystal form H of any one of Embodiments 78 to 83, further characterized by a weight percent loss of about 8.7% when heated to about 238 °C, measured by thermogravimetric analysis (TGA).

[0448] Embodiment  85. The crystal form H of any one of Embodiments 78 to 84, further characterized by a thermogravimetric analysis (TGA) thermogram substantially identical to FIG. 39.

[0449] Embodiment 86. A compound having formula (I): [ka] Crystalline form I of.

[0450] Embodiment 87. The crystalline form I of embodiment 86, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.8, 6.4, 16.1, 16.5, and 27.7 degrees 2θ (±0.2 degrees 2θ).

[0451] Embodiment 88. The crystalline form I of embodiment 86, wherein the X-ray powder diffraction pattern further comprises peaks at 10.0, 10.8, 13.1, 25.5, and 29.0 degrees 2θ (±0.2 degrees 2θ).

[0452] Embodiment 89. The crystalline form I of embodiment 86 or 88, wherein the X-ray powder diffraction pattern further comprises peaks at 8.4, 11.9, 17.7, 19.6, and 23.3 degrees 2θ (±0.2 degrees 2θ).

[0453] Embodiment 90. The crystalline form I of embodiment 86, having an X-ray powder diffraction pattern substantially in accordance with FIG. 41.

[0454] Embodiment 91. Crystalline Form I of any of embodiments 86-90, which is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0455] Embodiment 92. The crystalline form I of any of embodiments 86-91, further characterized by a differential scanning calorimetry (DSC) thermogram comprising one or more endothermic peaks at about 267.05°C and about 323.7°C.

[0456] Embodiment 93. The crystalline form I of embodiment 92, wherein the DSC thermogram is substantially in accordance with Figure 42.

[0457] Embodiment 94. Crystal Form I of any one of Embodiments 86 to 93, further characterized by a weight percent loss of about 1.1% when heated to about 220 °C, measured by thermogravimetric analysis (TGA).

[0458] Embodiment 95. Crystal Form I of any one of Embodiments 86 to 94, further characterized by a thermogravimetric analysis (TGA) thermogram that substantially coincides with FIG. 43.

[0459] Embodiment 96. Crystal Form I of any one of Embodiments 86 to 95, further characterized by a polarized light microscopy (PLM) profile substantially shown in FIG. 44.

[0460] Embodiment 97. Crystal Form I of any one of Embodiments 86 to 96, further characterized by a moisture content of about 1.4% by weight, measured by the Karl Fischer (KF) method.

[0461] Embodiment 98. A compound having the formula (I): [Chemical formula] Crystal Form J, characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 7.7, 12.9, 14.6, 26.9, and 27.6 °2θ (±0 .2 °2θ).

[0462] Embodiment 99. Crystal Form J of Embodiment 98, wherein the X-ray powder diffraction pattern further includes peaks at 18.1, 22.2, 23.2, 25.3, and 27.4 °2θ (±0 .2 °2θ).

[0463] Embodiment 100. Crystal Form J of Embodiment 98 or 99, wherein the X-ray powder diffraction pattern further includes peaks at 17.4, 21.3, 23.8, 26.0, and 26.8 °2θ (±0 .2 °2θ).

[0464] Embodiment 101. Crystal Form J of Embodiment 98, wherein the X-ray powder diffraction pattern substantially coincides with FIG. 46.

[0465] Embodiment 102. The crystalline form J of any of embodiments 98-101, which is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0466] Embodiment 103. The crystalline form J of any of embodiments 98-102, further characterized by a differential scanning calorimetry (DSC) thermogram comprising one or more endothermic peaks at about 131.9°C, 212.0°C, and about 324.0°C.

[0467] Embodiment 104. The crystalline form J of embodiment 103, wherein the DSC thermogram is substantially in accordance with Figure 47.

[0468] Embodiment 105. The crystalline form J of any of embodiments 98-104, further characterized by a weight percent loss of about 9.9% when heated to about 200° C. as measured by thermogravimetric analysis (TGA).

[0469] Embodiment 106. The crystalline form J of any of embodiments 98-105, further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with FIG. 48.

[0470] Embodiment 107. The crystalline form J of any of embodiments 98 to 106 in the form of an isopropanol solvate.

[0471] Embodiment 108. A compound having formula (I): [ka] 1. Crystalline form K of the formula (I), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.5, 11.1, 16.5, 27.1, and 27.7 degrees 2θ (±0.2 degrees 2θ).

[0472] Embodiment 109. The crystalline form K of embodiment 108, wherein the X-ray powder diffraction pattern further comprises peaks at 13.8, 17.5, 22.2, 25.2, and 28.9 degrees 2θ (±0.2 degrees 2θ).

[0473] Embodiment 110. The crystalline form K of Embodiment 108, wherein the X-ray powder diffraction pattern substantially coincides with FIG. 50.

[0474] Embodiment 111. The crystalline form K of any one of Embodiments 108 to 110, substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0475] Embodiment 112. A compound having formula (I): [Chemical formula] The crystalline form L, characterized by an X-ray powder diffraction (XRPD) pattern including peaks at 11.7, 17.9, 18.4, 26.3, and 27.0° 2θ (±0.2° 2θ).

[0476] Embodiment 113. The crystalline form L of Embodiment 112, wherein the X-ray powder diffraction pattern further includes peaks at 10.8, 12.3, 16.3, 16.6, and 22.2° 2θ (±0.2° 2θ).

[0477] Embodiment 114. The crystalline form L of Embodiment 112 or 113, wherein the X-ray powder diffraction pattern further includes peaks at 17.0, 19.7, 20.3, 23.3, and 28.1° 2θ (±0.2° 2θ).

[0478] Embodiment 115. The crystalline form L of Embodiment 112, wherein the X-ray powder diffraction pattern substantially coincides with FIG. 51.

[0479] Embodiment 116. The crystalline form L of any one of Embodiments 112 to 115, substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0480] Embodiment 117. The crystalline form L of any one of Embodiments 112 to 116, further characterized by a differential scanning calorimetry (DSC) thermogram including one or more endothermic peaks at about

[0481] Embodiment 118. The crystalline form L of embodiment 117, having a DSC thermogram substantially in accordance with Figure 52.

[0482] Embodiment 119. The crystalline form L of any of embodiments 112-118, further characterized by a weight percent loss of about 2.0% when heated to about 220°C as measured by thermogravimetric analysis (TGA).

[0483] Embodiment 120. The crystalline form L of any of embodiments 112-119, further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with FIG. 53.

[0484] Embodiment 121. A compound having formula (I): [ka] 1. Crystalline form M of the formula (I), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.2, 6.7, 10.5, 12.4, and 13.4 degrees 2θ (±0.2 degrees 2θ).

[0485] Embodiment 122. The crystalline form M of embodiment 121, wherein the X-ray powder diffraction pattern further comprises peaks at 16.1, 17.6, 24.2, 27.1, and 28.3 degrees 2θ (±0.2 degrees 2θ).

[0486] Embodiment 123. The crystalline form M of embodiment 121 or 122, wherein the X-ray powder diffraction pattern further comprises peaks at 17.0, 20.2, 22.7, 23.1, and 26.5 degrees 2θ (±0.2 degrees 2θ).

[0487] Embodiment 124. The crystalline form M of embodiment 121, having an X-ray powder diffraction pattern substantially in accordance with FIG. 54.

[0488] Embodiment 125. The crystalline form M of any of embodiments 121-124, which is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0489] Compound having formula (I):

Chem.

[0490] Embodiment 127. Crystal form N of Embodiment 126, wherein the X-ray powder diffraction pattern substantially coincides with FIG. 55.

[0491] Embodiment 128. Crystal form N of Embodiment 126 or 127, substantially free of other crystal forms or amorphous forms of the compound having formula (I).

[0492] Compound having formula (I):

Chem.

[0493] Embodiment 130. Crystal form O of Embodiment 129, wherein the X-ray powder diffraction pattern further comprises peaks at 12.8, 15.3, 26.9, 27.9, and 29.0° 2θ (±0.2° 2θ).

[0494] Embodiment 131. Crystal form O of Embodiment 129, wherein the X-ray powder diffraction pattern substantially coincides with FIG. 56.

[0495] Embodiment 132. Crystal form O of any one of Embodiments 129 to 131, substantially free of other crystal forms or amorphous forms of the compound having formula (I).

[0496] Compound having formula (I): [[ID=4[ka] 1. Crystalline form P of the formula (I), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.6, 6.0, 17.1, 26.6, and 27.9 degrees 2θ (±0.2 degrees 2θ).

[0497] Embodiment 134. The crystalline form P of embodiment 133, wherein the X-ray powder diffraction pattern further comprises peaks at 10.8, 12.0, 14.3, 14.8, and 18.1 degrees 2θ (±0.2 degrees 2θ).

[0498] Embodiment 135. The crystalline form P of embodiment 133, having an X-ray powder diffraction pattern substantially in accordance with Figure 57.

[0499] Embodiment 136. The crystalline form P of any of embodiments 133-135, which is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0500] Embodiment 137. A compound having formula (I): [ka] 1. Crystalline form Q of the compound of claim 1, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 3.3, 5.4, 16.1, 27.0, and 31.7 degrees 2θ (±0.2 degrees 2θ).

[0501] Embodiment 138. The crystalline form Q of embodiment 137, wherein the X-ray powder diffraction pattern further comprises peaks at 4.0, 10.7, 25.0, 27.9, 28.0 degrees 2θ (±0.2 degrees 2θ).

[0502] Embodiment 139. The crystalline form Q of embodiment 137, having an X-ray powder diffraction pattern substantially in accordance with Figure 58.

[0503] Embodiment 140. The crystalline form Q of any of embodiments 137-139, which is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0504] Embodiment 141. A compound having formula (I): [ka] 20.4, 21.6, 22.4, 22.9, 23.4, 24.5, 27.4, 27.9, and 28.4 degrees 2θ (±0.2 degrees 2θ).

[0505] Embodiment 142. The crystalline form R of embodiment 141, having an X-ray powder diffraction pattern substantially in accordance with FIG. 59.

[0506] Embodiment 143. The crystalline form R of embodiment 141 or 142, which is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0507] Embodiment 144. A compound having formula (I): [ka] 1. Crystalline form S of the compound of claim 1, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.1, 10.4, 10.8, 13.5, and 16.5 degrees 2θ (±0.2 degrees 2θ).

[0508] Embodiment 145. The crystalline form S of embodiment 144, wherein the X-ray powder diffraction pattern further comprises peaks at 12.3, 12.4, 14.0, 17.4, and 28.6 degrees 2θ (±0.2 degrees 2θ).

[0509] Embodiment 146. The crystalline form S of 144, having an X-ray powder diffraction pattern substantially in accordance with FIG. 60.

[0510] Embodiment 147. The crystalline form S of any of embodiments 144-146, which is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0511] Embodiment 148. A compound having formula (I): [ka] The crystalline form of T.

[0512] Embodiment 149. The crystalline form T of embodiment 148, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.5, 10.9, 12.4, 13.0, and 16.9 degrees 2θ (±0.2 degrees 2θ).

[0513] Embodiment 150. The crystalline form T of embodiment 148, wherein the X-ray powder diffraction pattern further comprises peaks at 10.5, 16.6, 22.2, 27.5, and 27.9 degrees 2θ (±0.2 degrees 2θ).

[0514] Embodiment 151. The crystalline form T of embodiment 148, having an X-ray powder diffraction pattern substantially in accordance with Figure 61.

[0515] Embodiment 152. The crystalline form T of any of embodiments 148-151, which is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0516] Embodiment 153. The crystalline form T of any of embodiments 148-152, further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 319.4°C.

[0517] Embodiment 154. The crystalline form T of embodiment 153, wherein the DSC thermogram is substantially in accordance with Figure 62.

[0518] Embodiment 155. The crystalline form T of any of embodiments 148-154, further characterized by a weight percent loss of about 0.8% when heated to about 220°C as measured by thermogravimetric analysis (TGA).

[0519] Embodiment 156. The crystalline form T of any of embodiments 148-155, further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with FIG. 63.

[0520] Embodiment 157. The crystalline form T of any of embodiments 148-156, further characterized by a polarized light microscope (PLM) profile substantially as shown in Figure 64.

[0521] Embodiment 158. The crystalline form T of any of embodiments 148-157, further characterized by a water content of about 1.7% by weight, as measured by the Karl Fischer (KF) method.

[0522] Embodiment 159. A compound having formula (I): [ka] 1. Crystalline form U of the formula (I), characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.2, 10.3, 10.8, 12.4, and 16.4 degrees 2θ (±0.2 degrees 2θ).

[0523] Embodiment 160. The crystalline form U of embodiment 159, wherein the X-ray powder diffraction pattern further comprises peaks at 17.6, 21.3, 22.4, 27.2, and 28.5 degrees 2θ (±0.2 degrees 2θ).

[0524] Embodiment 161. The crystalline form U of embodiment 159, having an X-ray powder diffraction pattern substantially in accordance with FIG. 67.

[0525] Embodiment 162. The crystalline form U of any of embodiments 159-161, which is substantially free of other crystalline or amorphous forms of the compound having formula (I).

[0526] Embodiment 163. A compound having formula (I): [ka] or a solid form of a pharmaceutically acceptable salt thereof.

[0527] Embodiment 164. The solid form of embodiment 163, wherein the solid form is substantially crystalline.

[0528] Embodiment 165. The solid form of embodiment 163 or 164, which is a solid form of Formula (I) as the free base.

[0529] Embodiment 166. The solid form of embodiment 163 or 164, which is a solid form of Formula (I) as a pharmaceutically acceptable salt thereof.

[0530] Embodiment 167. The solid state form of any of embodiments 163-166, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.2, 10.9, and 16.5 degrees two-theta (±0.2 degrees two-theta).

[0531] Embodiment 168. The solid form of any of embodiments 163-166, characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 1.

[0532] Embodiment 169. The solid state form of any of embodiments 163-166, comprising at least 30% by weight of a particular crystalline form, at least 40% by weight of a particular crystalline form, at least 50% by weight of a particular crystalline form, at least 60% by weight of a particular crystalline form, at least 70% by weight of a particular crystalline form, at least 80% by weight of a particular crystalline form, at least 90% by weight of a particular crystalline form, at least 95% by weight of a particular crystalline form, or at least 99% by weight of a particular crystalline form.

[0533] Embodiment 170. The solid state form of any of embodiments 163-166, comprising at least 50% by weight of a particular crystalline form, at least 60% by weight of a particular crystalline form, at least 70% by weight of a particular crystalline form, at least 80% by weight of a particular crystalline form, at least 90% by weight of a particular crystalline form, at least 95% by weight of a particular crystalline form, or at least 99% by weight of a particular crystalline form.

[0534] Embodiment 171. The solid state form of the two previous embodiments, wherein the specific crystalline form is any one of embodiments 1 to 162.

[0535] Embodiment 172. The solid-state form of the above two embodiments, wherein the specific crystalline form is crystalline form A.

[0536] Embodiment 173. A pharmaceutical composition comprising the crystalline form of any of embodiments 2 to 162 and at least one pharmaceutically acceptable excipient.

[0537] Embodiment 174. A pharmaceutical composition comprising the solid form of any of embodiments 163 to 172 and at least one pharmaceutically acceptable excipient.

[0538] Embodiment 175. The pharmaceutical composition of embodiment 174, wherein the specific crystalline form is crystalline form A.

[0539] Embodiment 176. A pharmaceutical composition comprising crystalline form A.

[0540] Embodiment 177. A pharmaceutical composition comprising crystalline form A and at least one pharmaceutically acceptable excipient.

[0541] Embodiment 178. A pharmaceutical composition comprising the crystalline form of any of embodiments 2 to 162 and one or more pharmaceutically or physiologically acceptable excipients.

[0542] Embodiment 179. A method for treating a disease treatable by MAT2A inhibition in a patient, comprising administering to the patient a therapeutically effective amount of the crystalline form of any of embodiments 2 to 162, the solid state form of any of embodiments 163 to 172, or the pharmaceutical composition of any of embodiments 173 to 178.

[0543] Embodiment 180. The method of embodiment 179, wherein the disease is cancer.

[0544] Embodiment 181. A method of treating an MTAP-null cancer in a patient, comprising administering to the patient a therapeutically effective amount of any of the forms of embodiments 2-162, the solid form of any of embodiments 163-172, or the pharmaceutical composition of any of embodiments 173-178.

[0545] Embodiment 182. A method for treating cancer in a patient, wherein the cancer is characterized by reduced or absent MTAP gene expression, absence of the MTAP gene, reduced levels of MTAP protein, reduced function of MTAP protein, absence of MTAP protein, or a combination thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form of any of embodiments 2 to 162, a solid state form of any of embodiments 163 to 172, or a pharmaceutical composition of any of embodiments 173 to 178.

[0546] Embodiment 183. The method of any of embodiments 180-182, wherein the cancer is selected from the group consisting of leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin's lymphoma, esophagogastric cancer, gastrointestinal (GI) cancer, or mesothelioma.

[0547] Embodiment 184. A method for producing a pharmaceutical composition, comprising mixing crystalline form A with at least one pharmaceutically acceptable excipient.

[0548] Embodiment 185. A method for producing a pharmaceutical composition, comprising mixing the solid form of any of embodiments 163 to 172 with at least one pharmaceutically acceptable excipient.

[0549] Embodiment 186. A pharmaceutical composition prepared by combining crystalline form A with at least one pharmaceutically acceptable excipient.

[0550] Embodiment 187. A pharmaceutical composition prepared by combining the solid form of any of embodiments 163-172 with at least one pharmaceutically acceptable excipient.

[0551] Embodiment 188. A compound having formula (I): [ka] 1. A process for preparing crystalline form A of a) forming a first mixture comprising a crude compound of formula (I), ACN, and water; b) solvent exchange with water at a temperature of about 65°C or less to form a second mixture; c) cooling and stirring the second mixture to form a third precipitate; d) isolating the third precipitate; and e) forming a slurry comprising the third precipitate, methyl ethyl ketone (MEK), and water; f) isolating the fourth precipitate of step e); g) drying the fourth precipitate to obtain crystalline Form A of Formula (I); A method comprising:

[0552] Embodiment 189. The method of embodiment 188, wherein step a) is carried out at a temperature of about 75°C to 80°C.

[0553] Embodiment 190. The method of embodiment 188 or 190, wherein in step a), the ratio of ACN to water is about 4:1 by volume.

[0554] Embodiment 191. The method of any of embodiments 188-190, wherein step c) is carried out at a temperature of about 0°C to 5°C and stirred for about 12 to 16 hours.

[0555] Embodiment 192. The method of any of embodiments 188-191, wherein in step e), the ratio of MEK to water is about 10:1 by volume.

[0556] Embodiment 193. The method of any of embodiments 188-192, wherein step e) is carried out at a temperature of about 60°C to 65°C, stirred for about 17 to 22 hours, and further cooled to a temperature of about 0°C to 5°C, and stirred for about 15 to 24 hours.

[0557] Embodiment 194. The method of any of embodiments 188 to 193, wherein the isolation of step d) and / or step e) is carried out by filtration.

[0558] Embodiment 195. The method of any of embodiments 188 to 193, wherein the drying in step g) is carried out at a temperature of 65°C to 70°C.

[0559] Embodiment 196. The method of any of embodiments 188-195, wherein the crude compound of Formula (I) is present in the first mixture in an amount of about 20 g / L to 100 g / L.

[0560] Embodiment 197. A compound having formula (I): [ka] 1. A method for preparing a crystalline form of a) forming a slurry comprising Solid Form V of Formula (I) and a solvent; b) stirring the slurry for at least 1 day; c) isolating the precipitate; and d) drying the precipitate to obtain the crystalline form of formula (I); wherein the crystalline form is crystalline form C, D, E, I, or A-1, and the solvent is methanol, water, a mixture of methanol and water, a mixture of acetone and water, or a mixture of acetonitrile and water.

[0561] Embodiment 198. The method of embodiment 197, wherein the crystalline form is crystalline form C and the solvent is methanol.

[0562] Embodiment 199. The method of embodiment 197, wherein the crystalline form is crystalline form D and the solvent is water.

[0563] Embodiment 200. The method of embodiment 197, wherein the crystalline form is crystalline form E and the solvent is a mixture of methanol and water.

[0564] Embodiment 201. The method of embodiment 200, wherein the ratio of methanol to water is about 1:1 by volume.

[0565] Embodiment 202. The method of embodiment 197, wherein the crystalline form is crystalline form I and the solvent is a mixture of acetone and water.

[0566] Embodiment 203. The method of embodiment 202, wherein the ratio of seton to water is about 1:1 by volume.

[0567] Embodiment 204. The method of embodiment 197, wherein the crystalline form is crystalline form A and the solvent is a mixture of acetonitrile and water.

[0568] Embodiment 205. The method of embodiment 204, wherein the ratio of acetonitrile to water is about 1:1 by volume.

[0569] Embodiment 206. The method of any of embodiments 197-205, wherein the stirring in step b) is carried out at a temperature of about 25°C and / or about 50°C.

[0570] Embodiment 207. The method of any of embodiments 197-206, wherein the stirring in step b) is carried out for 3 to 6 days.

[0571] Embodiment 208. The method of any of embodiments 197-207, wherein the stirring in step b) is carried out at a first temperature of about 50°C for a first period of 3 days and at a second temperature of about 25°C for a second period of 3 days.

[0572] Embodiment 209. The method of any of embodiments 197-207, wherein the stirring in step b) is carried out at a temperature of about 50° C. for 6 days.

[0573] Embodiment 210. The method of any of embodiments 197-207, wherein the stirring in step b) is carried out at a temperature of about 50° C. for 3 days.

[0574] Embodiment 211. The method of any of embodiments 197-207, wherein the stirring in step b) is carried out at a temperature of about 25° C. for 6 days.

[0575] Embodiment 212. The method of any of embodiments 197 to 211, wherein the isolation in step c) is carried out by filtration.

[0576] Embodiment 213. The method of any of embodiments 197-212, wherein the drying in step d) is carried out at room temperature.

[0577] Embodiment 214. The method of any of embodiments 197-213, wherein the crystalline solid form V of Formula (I) is present in the slurry in an amount of 50 mg / mL to 120 mg / mL. [Example]

[0578] IX. Working Example The following examples are offered to illustrate, but not to limit, the present description.

[0579] Standard abbreviations are used, including: d = doublet, dd = doublet of doublet, DIPEA = N,N-diisopropylethylamine, DMSO = dimethylsulfoxide, EDTA = ethylenediaminetetraacetic acid, EtOH = ethanol, g = gram, mg = milligram, μg = microgram, ng = nanogram, μM = micromol, mM = millimol, nM = nanomol, h or hr = hour, min = minute, kDa = kilodalton, kg = kilogram, l or L = liter, ml or mL = milliliter, μl or μL = microliter, LC = liquid chromatography, LCMS = liquid chromatography HPLC-mass spectrometry, m / z = mass-to-charge ratio, m = multiplet, MeCN / ACN = acetonitrile, MS = mass spectrometry, N = standard, NMR = nuclear magnetic resonance, PE = petroleum ether, rac = racemic, Rt = retention time, sat. = saturated, t = triplet, THF = tetrahydrofuran, TLC = thin layer chromatography, TsOH = p-toluenesulfonic acid, TsOH = p-toluenesulfonic acid, MsOH = methanesulfonic acid, TfOH = trifluoromethanesulfonic acid, (COCl) = oxalyl chloride, t-BuOH = tert-butyl alcohol, MTBE = methyl tert-butyl ether. [Table 1-1] [Table 1-2] [Table 1-3]

[0580] Example 1: Preparation of 4-amino-1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one (compound of formula (I)) Step 1: [ka] To a solution of compound 1 (300 g, 1.34 mol, 1.00 equiv) in THF (2.40 L) was added (COCl) (178 g, 1.41 mol, 123 mL, 1.05 equiv) dropwise over 10 min at 25 °C. The reaction mixture was heated to 70 °C over 1 h, and then the mixture was stirred at 70 °C for 4.5 h. The reaction mixture was cooled to 30 °C over 0.5 h, and compound 1a (180 g, 1.41 mol, 149 mL, 1.05 equiv) was added dropwise over 15 min to the reaction mixture. The reaction mixture was stirred at 30 °C for 2.5 h. The two reaction mixtures were concentrated in vacuo to give an off-white solid, which was triturated with methanol (1.20 L) for 0.5 h. The mixture was then filtered and the solid was dried under vacuum to give compound 2 (900 g, 2.27 mol, 84.5% yield, 95.1% purity) as a white solid. LCMS: RT=0.982 min, m / z=377.9 (M+H). + . HPLC: RT=3.164 min, purity 95.1% (220nm). 1 H NMR:(400MHz DMSO-d6)δ11.69(s,1H), 10.73(s,1H), 8.42(d,J=8.0Hz,1H), 8.21(d,J=4.0Hz,1H) , 8.10(d,J=7.2Hz,1H), 7.55(d,J=6.4Hz,1H), 7.40-7.20(m,1H), 7.18-7.15(m,1H).

[0581] Step 2 [ka] To a solution of compound 2 (292 g, 734 mmol, 1.00 equiv.) in THF (3.00 L), t-BuONa (155 g, 1.61 mol, 2.20 equiv.) was slowly added over 0.5 h at 25°C to 50°C. (Upon addition of t-BuONa, the temperature rose from 25°C to 50°C, and the mixture became clear and quickly turned into a yellow suspension.) After the addition of t-BuONa, the mixture was stirred for an additional 0.5 h at 25°C to 50°C. The four reaction mixtures were poured into 1N HCl (10.0 L) with stirring and extracted with ethyl acetate (5.00 L × 2). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo at 50° C. to give a yellow solid, which was triturated with MTBE (2.00 L) at 25° C. for 0.5 h, filtered, and dried in vacuo at 50° C. to give compound 3 (750 g, 2.07 mol, 70.5% yield, 94.2% purity) as an off-white solid. LCMS: RT=1.100 min, m / z=342.0 (M+H). + . HPLC: RT=2.692 min, purity 94.2% (220nm). 1 H NMR: (400MHz DMSO-d6) δ12.31(s,1H), 8.68(d,J=8.0Hz,1H), 7.79(d,J=8.0Hz,1H), 7.70-7.67(m,1H), 7.58-7.52(m,3H).

[0582] Step 3: [ka] To a solution of compound 3 (300 g, 878 mmol, 1.00 equiv.) and DIPEA (227 g, 1.76 mol, 305 mL, 2.00 equiv.) in CHCN (3.00 L) was added POCl (202 g, 1.32 mol, 122 mL, 1.50 equiv.) dropwise at 25 °C. The mixture was then stirred at 80 °C for 2 h. The reaction mixture was concentrated by distillation at 50 °C to give crude compound 4 as a brown oil (640 g).

[0583] Step 4: [ka] To a solution of compound 4 (99.35 g, 275 mmol) in CHCN (1.00 L) was added a solution of NH / THF (4 M, 689 mL, 10.0 equiv.) dropwise at 0 °C (a large amount of yellow solid precipitated). The mixture was warmed to 25 °C and stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo to give a yellow solid. 1.00 L of water was added with stirring for 12 h. The suspension was filtered, and the resulting yellow solid was slurried in EtOH (800 mL) at 25 °C for 1 h and then filtered. The resulting yellow solid was slurried in DCM (1.00 L) at 25 °C for 1 h, filtered, and then dried on an oil pump at 40 °C for 3 h to give (I) (52.0 g, 151 mmol, 54.9% yield, 99.2% purity) as a yellow solid. LCMS: Rt=1.909 min, m / z=341.2(M+H) + . HPLC: Rt=2.415 minutes, purity 99.2% (220nm). 1 H NMR:(400MHz,DMSO-d6)δ8.83(d,J=8.0Hz,1H), 8.57(br.s,2H), 7.79(d,J=8.0Hz,1H), 7.65-7.62(m,1H), 7.49-7.46(m,3H).

[0584] Example 2: Recrystallization of compound of formula (I) to provide Form A [ka] Crude compound of Formula (I) (100 g, 0.29 mol, 1.0 equiv.) was dissolved in MeCN (2.18 kg, 28 vol, 21.8 fold) and HO (700 g, 7 vol, 7 fold) at 75-80°C for 1-3 hours. The mixture was adjusted to 60-65°C and concentrated to 30 volumes below 65°C. Seed crystals of Form A (2 g, 0.02 fold) were then added, and the mixture was stirred at 60-65°C for 1.5 hours. The mixture was concentrated to 20 volumes at 65°C. 1 kg (10 vol, 10 fold) of water was added to the mixture. The mixture was again concentrated to 20 volumes below 65°C. 1 kg (10 vol, 10 fold) of water was added to the mixture. The mixture was cooled to 0-5°C over 1.5 hours. The mixture was then stirred at 0-5°C for 13 hours. After filtration, the wet cake was washed three times with 156 g (2 vol, 1-2 fold) of MeCN. The wet cake was then charged to a reactor, and MEK (405 g, 5 vol, 4.05 fold) and HO (48 g, 0.48 vol, 0.48 fold) were added to adjust the KF to 9.0-10.0 wt% (9.4%). The mixture was then stirred at 60-65°C for 17-22 hours. The mixture was cooled to 0°C over 4 hours and stirred at 0-5°C for 16 hours. A sample was taken to confirm the form (Form A) and the supernatant residual final product (FP) (1.3 wt%). After filtration, the wet cake was washed twice with MEK (156 g, 2 vol, 1.62 fold). The wet cake was dried at 65-70°C for 69 hours to give Form A product (89.45g, 99.8% purity, 100% assay) in 89% yield.

[0585] Example 3: Phosphate Sensor Fluorescence Assay of Compounds of Formula (I) The MAT2A enzyme inhibitory ability of the compounds of formula (I) described in Example 1 was measured using the phosphate sensor fluorescence assay described below.

[0586] MAT2A enzyme is incubated in a microtiter plate with a test compound in DMSO or DMSO and its substrate (L-methionine and ATP). The enzyme reaction is stopped by the addition of Working Phosphate Sensor Mixture. The plate is analyzed for fluorescence at 450 nm. The high control (DMSO containing the enzyme and its substrate) gives high fluorescence, indicating uninhibited enzyme activity, while the low control (DMSO containing the MAT2A substrate but no enzyme) gives low fluorescence, indicating complete inhibition of enzyme activity.

[0587] material: Human MAT2A: Ceptor, amino acids 1-395

[0588] Tris, pH 7.5: Invitrogen catalog number 15567-027

[0589] KC1: Ambion Catalog Number AM9640G

[0590] MgCl2: Ambion Catalog Number AM9530G

[0591] Brij-35: Sigma catalog BB4184-10ML

[0592] DTT: Goldbio Catalog Number DTT100

[0593] BGG:Sigma Catalog Number G5009-25G

[0594] PNP: Novus Biologicals Catalog Number NBP1-50872

[0595] 7-MEG: Cayman Chemical Catalog No. 15988

[0596] L-Methionine: Alfa Aesar Catalog Number J61904

[0597] ATP: Alfa Aesar Catalog Number J60336

[0598] Phosphate sensor: Thermo Fisher catalog number PV4407

[0599] EDTA: Life Tech Catalog Number 15575-038

[0600] Assay Plates: 384-well black polypropylene plates: Thomas Scientific Catalog No. 1149Q35

[0601] Final assay conditions: Assay buffer: 50 mM Tris, pH 7.5 / 50 mM KCl / 10 mM MgCl2 / 0.01% Brij-35 / 1 mM DTT / 0.1% BGG / 40n MPNP / 6 μM 7-MEG

[0602] MAT2A: 10 nM, Cepter clone ID329, lot 00023-123 (before adding working phosphate sensor mix) 5 nM, Cepter clone ID334, lot 00023-148 (before adding working phosphate sensor mix)

[0603] L-methionine: 500 μM (before adding the working phosphate sensor mixture)

[0604] ATP: 500 μM (before adding the working phosphate sensor mixture)

[0605] procedure: For the assay, 1 mM L-methionine / 1 mM ATP in assay buffer (2x the pre-stopped final concentration), MAT2A in assay buffer (2x the pre-stopped final concentration), and working phosphate sensor mix (1.5 μM phosphate sensor / 30 mM EDTA in assay buffer, 3x the final concentration) were prepared. Using a D300e digital dispenser, test compounds or DMSO were added to the appropriate wells. 5 μl / well of assay buffer was added to wells corresponding to the negative control, and 5 μl / well of MAT2A was added to all wells except those corresponding to the negative control. After incubating the plate at room temperature for 15 minutes, 5 μl / well of 1 mM L-methionine / 1 mM ATP mix was added to all wells. The plate was centrifuged at 1000 rpm for 1 minute and then incubated at room temperature for 1 hour. 5 μL of working phosphate sensor mix was added to all wells, and the plate was centrifuged at 1000 rpm for 1 minute. Plates were read for fluorescence at 450 nm after excitation at 430 nm.

[0606] Data analysis Percent inhibition was calculated with the Chemical and Biological Information System (CBIS) (Chemlnnovation Software Inc.). Curves were fitted by CBIS using a four-parameter inhibition model as % inhibition versus log [compound concentration]: Fit=(A+((BA) / (1+((C / x)^D)))) Res=(y-Fit)

[0607] IC of compounds of formula (I) 50 are listed as ++++, and "++++" is IC 50 <200nM.

[0608] Example 4: Solid Form V Solid Form V is a solid form of intermediate crystallinity.

[0609] Solid Form V was prepared from the compound of Formula (I) (approximately 100 g). The starting material was a yellow solid precipitated after amination and vacuum concentration (described in Step 4 of Example 1). 1.00 L of water was added to the yellow solid with stirring for 12 hours. The suspension was filtered and concentrated to give a second yellow solid. The second yellow solid was slurried with EtOH (800 mL) at 25° C. for 1 hour. The mixture was then filtered hard to give a third yellow solid, which was then slurried with DCM (1.0 L) at 25° C. for 1 hour. The mixture was then filtered hard to give the final yellow solid. The final yellow solid was dried by oil pump at 40° C. for 3 hours to give solid Form V of the compound of Formula (I) (52.0 g, purity 99.3%). [Table 2] [Table 3]

[0610] Example 5: Crystalline Form A Approximately 1.5 g of solid Form V was equilibrated in 22 mL of ACN / water (1 / 1, V / V) with magnetic stirring at 25° C. for approximately 6 days. The precipitate was filtered and dried at room temperature for approximately 18 hours. 1.36 g of an off-white solid was obtained in 90% yield. Crystalline Form A was characterized by an X-ray powder diffraction pattern substantially in accordance with FIG. 6. [Table 4]

[0611] Characterized by dynamic vapor sorption (DVS), Form A is slightly hygroscopic, absorbing 0.7% water at RH 95% and 25° C. No change in morphology was observed after the DVS test. [Table 5]

[0612] Example 6: Crystalline Form B Crystalline Form B was obtained from any one of the equilibration, temperature cycling, slow cooling, and quenching experiments in methanol, methanol / water, or ethanol / water solvent systems described herein. Crystalline Form B was prepared by a temperature cycling experiment in methanol and characterized by an X-ray powder diffraction pattern substantially in accordance with FIG. [Table 6]

[0613] Example 7: Crystalline Form C Crystalline Form C was obtained from any one of the equilibration, temperature cycling, slow cooling, and quenching experiments in methanol, methanol / water, or ethanol / water systems described herein.

[0614] Crystalline Form C was scaled up according to the following procedure: Approximately 500 mg of solid Form V was equilibrated in 7 mL of MeOH at 50° C. with magnetic stirring for approximately 3 days. It was then allowed to cool to 25° C. and stirred at 25° C. for approximately 3 days. The precipitate was filtered and dried at room temperature for approximately 20 hours. 366.6 mg of a white solid was obtained in 73% yield. [Table 7]

[0615] Characterized by dynamic vapor sorption (DVS), crystalline form C has a constant moisture content between 30% and 95% RH. However, when humidity is below 30% RH, crystalline form C begins to lose moisture and converts to crystalline form L. Crystalline form L absorbs moisture and converts back to crystalline form C at RH above 80%. [Table 7-1]

[0616] Example 8: Crystalline Form D Crystalline Form D was obtained from either one of the equilibration experiments in water at 50° C. and antisolvent experiments in methanol / water systems described herein.

[0617] Crystalline Form D was scaled up according to the following procedure: Approximately 500 mg of solid Form V was equilibrated in 5 mL of water with magnetic stirring at 50° C. for approximately 6 days. The precipitate was filtered and dried at room temperature for approximately 20 hours. 410.8 mg of an off-white solid was obtained in 82% yield. [Table 7-2]

[0618] Characterization by dynamic vapor sorption (DVS) showed that crystalline form D maintains its water content between 10% and 95% RH but is slightly hygroscopic, absorbing approximately 0.9% water between 40% and 95% RH. Form D begins to lose water when the humidity is below 20% RH and regains its water content when the relative humidity is above 20% RH. No change in morphology was observed after DVS testing. [Table 8]

[0619] Example 9: Crystalline Form E Crystalline Form E was obtained from any one of the equilibration experiments in methanol / water systems described herein.

[0620] Crystalline Form E was scaled up according to the following procedure: Approximately 500 mg of solid Form V was equilibrated in 6 mL of a mixed solvent of MeOH / water (1 / 1, V / V) at 50° C. for approximately 3 days with magnetic stirring. It was then allowed to cool to 25° C. and stirred at 25° C. for approximately 3 days. The precipitate was filtered and dried at room temperature for approximately 20 hours. 475.1 mg of an off-white solid was obtained in 95% yield. [Table 9] [Table 10]

[0621] Example 10: Crystalline Form F Crystalline Form F was obtained from any one of the temperature cycling, slow cooling, and antisolvent experiments in ethanol or ethanol / water solvent systems described herein. Crystalline Form F was prepared by a temperature cycling experiment in ethanol-water and characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 30, a DSC thermogram substantially in accordance with Figure 31, and a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 32. The form is 1 It contains about 0.2 equivalents (2.7 wt%) of ethanol based on H NMR results and about 0.5 equivalents (2.4 wt%) of water based on KF results. The form has a T of 45.2 °C. 開始 followed by a desolvation / dehydration peak at T of 205.2 °C. 開始 It exhibits an endothermic solid-solid transition peak at 7°C with an enthalpy of approximately 3 J / g. The form undergoes decomposition and ultimately melts at 319.7°C. TGA shows a weight loss of approximately 3.2% at approximately 200°C. [Table 11]

[0622] Example 11: Crystalline Form G Crystalline Form G was obtained from any one of the equilibration, temperature cycling, slow evaporation, and quenching experiments in acetone or acetone-water systems described herein. Crystalline Form G was also obtained from any one of the slow evaporation and fast evaporation experiments in MEK, slow cooling experiments in ethanol / acetone systems, and antisolvent experiments in ethanol / heptane. Crystalline Form G was prepared by a temperature cycling experiment in acetone-water and was characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 33, a DSC thermogram substantially in accordance with Figure 34, and a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 35. [Table 12]

[0623] Example 12: Crystalline Form H Crystalline Form H was obtained from any one of the equilibration, temperature cycling experiments in MTBE and MTBE / water systems, or any one of the slow-cool, quench, and anti-solvent experiments in a methanol / MTBE system, as described herein. Crystalline Form H was prepared by a temperature cycling experiment in MTBE-water and was characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 37, a DSC thermogram substantially in accordance with Figure 38, and a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 39. The form has a T of 210.5°C. 開始 with an enthalpy of about 9 J / g, followed by a T 開始 The form had a melting peak at about 240°C, which was accompanied by decomposition. TGA showed a weight loss of about 8.7% at about 240°C. 1 It contains approximately 0.3 equivalents (8.1% by weight) of MTBE based on H NMR results. Crystalline form H is an MTBE solvate. [Table 13]

[0624] Example 13: Crystalline Form I Crystalline Form I was obtained from equilibration experiments in acetone / water system at 50° C. as described herein.

[0625] Crystalline Form I was scaled up according to the following procedure: Approximately 100 mg of solid Form V was equilibrated in 1.6 mL of a mixed solvent of acetone / water (1 / 1, V / V) at 50°C for approximately 3 days with magnetic stirring. The precipitate was filtered and dried at room temperature for approximately 65 hours. 71.6 mg of a white solid was obtained in a yield of 71%. [Table 14] [Table 15]

[0626] Example 14: Crystalline Form J Crystalline Form J was obtained from the slow evaporation or quenching experiments in isopropanol described herein. Crystalline Form J was prepared by quenching in isopropanol and characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 46, a DSC thermogram substantially in accordance with Figure 47, and a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 48. The form has a T of 84.2°C. 開始 followed by a desolvation peak at T of 204.0 °C. 開始 The form exhibits an endothermic solid-solid transition peak at 319.4°C. The form eventually melts at 319.4°C, accompanied by decomposition. TGA showed a weight loss of about 9.9% at about 200°C. 1 Based on H-NMR results, it contains approximately 2.3 equivalents (28.5% by weight) of IPA. Crystalline Form J is an isopropanol solvate form. [Table 16-1] [Table 16-2]

[0627] Example 15: Crystalline Form K Crystalline Form K was obtained from slow evaporation or fast evaporation experiments in THF as described herein. Crystalline Form K was also prepared by competitive equilibration in THF and characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 50. [Table 17]

[0628] Example 16: Crystalline Form L Crystalline form L was prepared by heating crystalline form C to 120° C. Crystalline form L was characterized by an X-ray powder diffraction pattern substantially in accordance with FIG. 51, a DSC thermogram substantially in accordance with FIG. 52, and a thermogravimetric analysis (TGA) thermogram substantially in accordance with FIG. 53. [Table 18]

[0629] Example 17: Crystalline Form M Crystalline Form M was obtained from water activity experiments in acetonitrile / water systems at 50° C. as described herein or from equilibration experiments with solid Form V in acetonitrile at 50° C. Crystalline Form M was prepared from ACN-water and characterized by an X-ray powder diffraction pattern substantially in accordance with FIG. [Table 19]

[0630] Example 18: Crystalline Form N Crystalline Form N was prepared from any one of the equilibration experiments of solid state Form V in acetonitrile at 30° C., 40° C., and 45° C. described herein. Crystalline Form N was prepared from equilibration experiments of solid state Form V in acetonitrile at 30° C. and was characterized by an X-ray powder diffraction pattern substantially in accordance with FIG. [Table 20]

[0631] Example 19: Crystalline Form O Crystalline Form O was prepared from any one of the equilibration experiments of solid state Form V in ethanol at 30-50° C. described herein. Crystalline Form O was prepared from equilibration experiments of solid state Form V in ethanol at 30° C. and was characterized by an X-ray powder diffraction pattern substantially in accordance with FIG. [Table 21]

[0632] Example 20: Crystalline Form P Crystalline Form P was prepared from an equilibration experiment of solid state Form V in ACN at 50° C. as described herein. Crystalline Form P was characterized by an X-ray powder diffraction pattern substantially in accordance with FIG. [Table 22]

[0633] Example 21: Crystalline Form Q Crystalline Form Q was obtained from the solubility study with Form A in simulated gastric fluid (SGF, pH 2.0) described herein. Crystalline Form Q was characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 58. [Table 23]

[0634] Example 22: Crystalline Form R Crystalline Form R was obtained from a solubility study using Form A in 0.1 N HCl solution and contained approximately 68.5% impurities based on HPLC results. Crystalline Form R was characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 59. [Table 24]

[0635] Example 23: Crystalline Form S Crystalline Form S was obtained from any one of the variable temperature XRPD experiments described herein by heating Form D to 130° C. or any one of the variable humidity XRPD experiments of Form D when the humidity was less than 10% RH. Crystalline Form S was prepared by heating Form D to 130° C. and was characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 60. Form S is an anhydrous form. [Table 25]

[0636] Example 24: Crystalline Form T Crystalline Form T was characterized by an X-ray powder diffraction pattern substantially in accordance with Figure 61. Form T is further characterized according to Table 26. Crystalline Form T was obtained from any one of the variable-temperature XRPD experiments described herein by heating solid form V to 250°C and then cooling to 25°C. [Table 26]

[0637] Characterized by dynamic vapor sorption (DVS), Form T is slightly hygroscopic, absorbing 0.8% water at RH 95% and 25° C. No change in morphology was observed after the DVS test. [Table 27]

[0638] Example 25: Crystalline Form U Crystalline form U was obtained by heating crystalline form A to 250° C. Crystalline form U transformed into crystalline form T after cooling to 25° C. There was no apparent thermal event in the DSC curve of form U. Crystalline form U was characterized by an X-ray powder diffraction pattern substantially in accordance with FIG. 67. [Table 28]

[0639] Example 26: Substantially Amorphous Form A substantially amorphous form was obtained by manually dry-milling Form T. The X-ray powder diffraction pattern of the substantially amorphous form is shown in Figure 68.

[0640] Example 27: Approximate solubility of solid form V at 25°C and 50°C Approximately 5 mg of solid Form V was weighed into a 2 mL glass vial, and a 20 μL aliquot of each solvent was added and stirred for approximately 10 minutes to measure the solubility at 25° C. Approximately 10 mg of solid Form V was weighed into a 2 mL glass vial, and a 20 μL aliquot of each solvent was added and stirred for approximately 10 minutes to measure the solubility at 50° C. The maximum volume of each solvent was 1 mL. The approximate solubility was determined visually. [Table 29]

[0641] Example 28: Equilibration with solvent for 2 weeks at 25°C Approximately 50 mg of solid Form V was equilibrated in 0.8 mL of solvent at 25° C. for 2 weeks using a stir plate. The resulting suspension was filtered. The solid portion (wet cake) was examined by XRPD. If differences were observed, additional investigations (e.g., DSC, TGA, etc.) were performed. [Table 30]

[0642] Example 29: Equilibration in solvent at 50°C for 1 week Approximately 50 mg of solid Form V was equilibrated in 0.8 mL of solvent at 50° C. for 1 week using a stir plate. The resulting suspension was filtered. The solid portion (wet cake) was examined by XRPD. If differences were observed, additional investigations (e.g., DSC, TGA, etc.) were performed. [Table 31]

[0643] Example 30: Temperature cycling experiments Approximately 50 mg of solid Form V was equilibrated in 0.8 mL of solvent with a temperature cycle from 5°C to 50°C at a heating / cooling rate of 0.2°C / min for six cycles. After six cycles, the precipitate was collected by centrifugation at 5°C. The solid portion (wet cake) was examined by XRPD. If differences were observed, additional investigations (e.g., DSC, TGA, etc.) were performed. [Table 32]

[0644] Example 31: Crystallization by slow evaporation at room temperature In conjunction with the approximate solubility experiments, the solubility samples were filtered through a 0.45 μm nylon filter. The resulting solutions were allowed to slowly evaporate at ambient conditions. The solid residues were examined for polymorphic forms. [Table 33]

[0645] Example 32: Crystallization by fast evaporation at room temperature Approximately 10 mg of solid Form V was equilibrated in 0.8-3.0 mL of solvent at 25 °C. The sample was filtered through a 0.45 μm nylon filter. The resulting solution was rapidly evaporated under a stream of nitrogen. The solid residue was examined for polymorphic forms. [Table 34]

[0646] Example 33: Precipitation by addition of antisolvent Approximately 30-50 mg of solid Form V was dissolved in a good solvent. A poor solvent was slowly added to the resulting solution. The precipitate was collected by filtration. The solid portion (wet cake) was examined by XRPD. If differences were observed, further investigations (e.g., 1 H NMR, etc. [Table 35]

[0647] Example 34: Crystallization by slow cooling from a hot saturated solution Approximately 50 mg of solid Form V was dissolved in 1.7-6.0 mL of the selected solvent at 50°C. The resulting solution or suspension was filtered through a 0.45 μm syringe membrane filter. The clear solution was cooled to 5°C at 0.1°C / min. The precipitate was collected by filtration. The solid portion (wet cake) was examined by XRPD. If differences were observed, additional investigations (e.g., DSC, TGA, etc.) were performed. [Table 36]

[0648] Example 35: Crystallization by rapid cooling from a hot saturated solution Approximately 50 mg of solid Form V was dissolved in 1.7-8.0 mL of the selected solvent at 50°C. The resulting solution or suspension was filtered through a 0.45 μm syringe membrane filter. The clear solution was placed in an ice bath and stirred. The precipitate was collected by filtration. The solid portion (wet cake) was examined by XRPD. If differences were observed, additional investigations (e.g., DSC, TGA, etc.) were performed. [Table 37]

[0649] Example 36: Vapor diffusion experiments Approximately 25-50 mg of solid Form V was added to a glass vial and dissolved in 3 mL of a good solvent. After approximately 30 seconds of sonication, the resulting solution or suspension was filtered through a 0.45 μm syringe membrane filter to obtain a clear solution. A suitable volume of the clear solution was transferred to a small, open glass vial (8 mL), and the small, open vial was placed at the bottom of a large glass vial (40 mL) containing an antisolvent (solvent:antisolvent = 1:4, v / v). The large vial was tightly capped and allowed to stand at room temperature. The precipitate was collected by filtration. The solid portion (wet cake) was examined by XRPD. [Table 38]

[0650] Example 37: Water Activity Studies In the first study, a mixture of about 5 mg of solid Form V, about 5 mg of Form C, about 5 mg of Form D, and about 5 mg of Form E was equilibrated in 0.5 mL of ACN / water mixed solvent, and the water activity was evaluated at 5°C, 25°C, and 50°C. These solvent mixtures were saturated with the compound of formula (I) before adding polymorph seeds. In the second study, about 30 mg of solid Form V was equilibrated in 0.5 mL of EtOH / water and MeOH / water mixed solvents, and the water activity was evaluated at 25°C. These solvent mixtures were saturated with the compound of formula (I) before adding polymorph seeds. The resulting suspension was filtered. The solid portion (wet cake) was examined by XRPD. [Table 39] [Table 40] a: Low crystallinity Form F (suspension and dried solid tested without Kapton film); and b: Form E (suspension and dried solid tested without Kapton film).

[0651] Example 38: Competitive equilibration experiments A mixture of approximately 5 mg of solid Form V and 5 mg of Form I was added to 0.5 mL of a selected solvent. After saturating the solvent with the compound of formula (I), polymorph seeds were added. The resulting suspension was stirred at 25° C. or 50° C. for 5 days. The solid portion (wet cake) was isolated by filtration and characterized by XRPD. [Table 41]

[0652] Example 39: Investigation of changes in Form A Approximately 30 mg of Form A was equilibrated in 0.5 mL of ACN or EtOH at 30° C., 40° C., 45° C., and 50° C. for 3 days using a stir plate. The resulting suspension was filtered. The solid portion (wet cake) was examined by XRPD. [Table 42]

[0653] Example 40: Hygroscopicity - Moisture adsorption and desorption experiments The moisture sorption and desorption behavior of Forms A, C, D, and T was investigated by DVS at 25°C under a 40-0-95-0-40% RH cycle. Dm / dt was 0.002. The minimum equilibration time was 60 minutes. The maximum equilibration time was 360 minutes. XRPD was measured after the DVS test to determine potential form changes.

[0654] Form A is slightly hygroscopic, absorbing 0.7% water at 95% RH and 25° C. No change in morphology was observed after DVS testing. The dynamic vapor sorption (DVS) profile of Form A is substantially shown in FIG.

[0655] Form C exhibits a constant water content between 30% and 95% RH. Form C begins to lose water when humidity is below 30%. Variable-humidity XRPD analysis reveals that Form L is a dehydration product of Form C. DVS and variable-humidity XRPD analysis reveal that Form L absorbs water and converts back to Form C at humidity levels above 80% RH. Because the DVS test was set to stop at 40% RH during the second sorption cycle, a mixture of Form L and Form C was obtained after the DVS test. The dynamic vapor sorption (DVS) profile of Form C is substantially shown in Figure 18.

[0656] Form D is slightly hygroscopic, absorbing approximately 0.9% water at 40% to 95% humidity. Form D begins to lose water when humidity is below 20%. Variable humidity XRPD analysis revealed that Form S is a dehydration product of Form D. Form S absorbs water and converts back to Form D when relative humidity is higher than 20%. No change in form was observed after DVS testing. The dynamic vapor sorption (DVS) profile of Form D is substantially shown in Figure 24.

[0657] Form T is slightly hygroscopic, absorbing approximately 0.8% water at 25° C. and 95% RH. No change in morphology was observed after DVS testing. The dynamic vapor sorption (DVS) profile of Form T is substantially shown in Figure 66.

[0658] Example 41: Variable Humidity and Temperature XRPD Experiments Based on the DVS and DSC results of Form C, Form C begins to lose moisture when the humidity is less than 30% or the temperature is higher than about 44°C. Furthermore, the DSC curve shows a solid-solid transition at about 184°C. To determine the identity of potential morphological changes after dehydration and during the solid-solid transition, variable humidity and temperature XRPD techniques were applied. The XRPD patterns of the samples were measured online under the following conditions: 25°C / ambient (initial), -120°C / N2 protection, -25°C / ambient, -25°C / 80% RH (40 min), -25°C / 0% RH (15 h), and 25°C / ambient (initial), -250°C / N2 protection, -25°C / ambient. The results show that Form C converts to Form L after dehydration by controlling the relative humidity to 0% or the temperature to 120°C or higher. Form L converts back to Form C after exposure to 25°C / 80% RH for 40 minutes. Form L transforms to solid form V at temperatures above 250°C, indicating that the solid-solid transition in the DSC curve is a phase transition from form L to A and that the two polymorphs are enantiotropically related. [Table 43] [Table 44]

[0659] Based on the DVS and DSC results of Form D, Form D begins to lose moisture when the humidity is below 10% or the temperature is above 46°C. To determine the identity of the dehydration product, variable humidity and temperature XRPD methods were applied. The XRPD patterns of the samples were measured online through a temperature cycle of 25°C / ambient temperature (initial)-130°C / N2 protection (10 min)-25°C / N2 protection-25°C / ambient temperature (3 h) and two moisture sorption and desorption cycles of 50% RH (initial)-90% RH (3 h)-60% RH (2 h)-40% RH (2 h)-20% RH (3 h)-10% RH (3 h)-0% RH (6 h)-10% RH (3 h)-20% RH (3 h)-50% RH at 25°C. The results show that Form D converts to Form S when the humidity is below 10% or the temperature is 130°C (higher than the dehydration temperature). Form S converts back to Form D after 3 hours of exposure to ambient conditions. [Table 45] [Table 46]

[0660] To investigate the potential morphological changes of Form A upon heating, variable-temperature XRPD technique was applied. The XRPD patterns of the samples were measured online at a temperature cycle of 25°C (initial), 50°C / N2 protection, 70°C / N2 protection, 250°C / N2 protection, 25°C / N2 protection, 25°C / ambient temperature (3 hours). The results show that there is no morphological change after heating to 70°C. Form A transforms to Form U when the temperature is 250°C, and Form U transforms to Form T after cooling to 25°C. [Table 47]

[0661] Example 42: Behavior during compression Approximately 50-55 mg of solid forms V, A, D, T, and the substantially amorphous form (obtained by grinding form T) were compressed at 4 MPa or 2 MPa for 2 minutes using a hydraulic press and characterized by XRPD to investigate their polymorphic behavior under compression. [Table 48]

[0662] Example 43: Milling simulation experiment - dry milling Approximately 20 mg of Forms A, D, and T were manually ground using a mortar and pestle for 5 minutes or 1 minute. Potential form transitions and crystallinity were assessed by XRPD. All three forms (A, D, and T) exhibited low resistance to dry grinding. Substantially amorphous forms were obtained after dry grinding. [Table 49]

[0663] Example 44: Milling simulation experiment - wet milling Water or ethanol was added dropwise to approximately 20 mg of Form A, Form D, or Form T until the solid was sufficiently wetted. Vortexing was applied between each addition. The samples were allowed to dry under ambient conditions for 10 minutes. Potential form transitions and crystallinity were assessed by XRPD.

[0664] Forms A and D showed poor resistance to trituration with ethanol or water. After trituration with ethanol, a substantially amorphous form was obtained. After trituration with water, a mixture of solid forms V and D was obtained. Forms D and T showed good resistance to trituration with water, with no change in morphology. [Table 50]

[0665] Example 45: Bulk stability of crystalline forms Solid forms V, A, D, T, and a substantially amorphous form (obtained by grinding form T) were subjected to stress at 25° C. / 92% RH, 40° C. / 75% RH, and 60° C. The solids obtained after bulk stability testing were characterized by XRPD and HPLC.

[0666] Solid forms V, A, D, and T exhibited good chemical and physical stability. The substantially amorphous form was physically stable but showed slight degradation after exposure to 40°C / 75% RH in an open container and 60°C in a closed container. [Table 51] Color A: No discoloration [Table 52] Color A: No discoloration at all; Color B: Slight discoloration

[0667] Example 46: Equilibrated Solubility of Crystalline Forms Approximately 5 mg of solid Forms V, A, C, D, E, F, T, and the substantially amorphous form (dry-milled Form T) were equilibrated for 24 hours at 37°C in approximately 5 mL of fed simulated intestinal fluid (FeSSIF) and fasted simulated intestinal fluid (FaSSIF) separately using a stir plate. The solid and liquid portions were separated by filtration. Solubility was determined by HPLC. The solid portion (wet cake) was examined by XRPD.

[0668] Approximately 5 mg of solid Form V and Form A were equilibrated separately in approximately 5 mL of simulated gastric fluid (SGF) (pH=2.0), 0.1 N HCl (pH=1.2), and phosphate buffer (pH=8.0) at 37°C for 24 hours using a stir plate. The solid and liquid portions were separated by filtration. Solubility was measured by HPLC. The solid portion (wet cake) was examined by XRPD.

[0669] The results show that all forms exhibited comparable solubility in the media tested. XRPD analysis showed no change in form after the solubility test, except that two new patterns were obtained from the Form A sample in 0.1 N HCl and SGF. Furthermore, a significant increase in the impurity (compound 3) was found in the acidic conditions of 0.1 N HCl (pH 1.2) and SGF (pH 2.0). [Table 53] a. Solubility was tested by HPLC Method 1. b. Solubility was tested by HPLC Method 2.

[0670] Example 47: Evaluation of intrinsic dissolution rate The intrinsic dissolution rates (IDR) of solid forms V, A, T, and a substantially amorphous form (obtained by milling form T) were compared in FaSSIF (pH 6.5).

[0671] Approximately 100 mg of solid Form V, Form A, Form T, and the substantially amorphous form (obtained by grinding Form T) were compressed at 2 MPa for 2 minutes to form compact disks 8 mm in diameter. Only one side of the pellet (surface area = 0.50 cm) was compressed. 2 ) was exposed to 900 mL of FaSSIF, a dissolution medium. The temperature of the chamber medium was set at 37 ± 0.5°C. The shaft rotation speed was 100 rpm, and sampling times were 2, 5, 10, 15, 20, 25, 30, 35, 40, 50, 60, and 120 minutes. 2 mL of sample solution was withdrawn at each time point and centrifuged at 14,000 rpm for 5 minutes to isolate the supernatant. The concentration of the supernatant was then analyzed by HPLC. After 120 minutes, XRPD of the disk surface was measured.

[0672] All forms showed no dissolution in FaSSIF. No change in form was observed after IDR testing. The detected concentrations in solid forms V and A are believed to be caused by amorphous content generated during disk compression. [Table 54]

[0673] Forms A, C, D, E, and I are relatively stable anhydrates or hydrates. Their relationships were investigated by competitive equilibration, water activity, and VT-XRPD experiments, and a transition temperature or critical water activity was assigned at which the form transformation occurs. The relative stabilities of Forms A, C, D, and E were investigated by water activity experiments in acetonitrile / water systems at different temperatures. At 5°C and 25°C, highly crystalline Form A was obtained in all solvent mixtures. The relative stabilities of Forms A and I were investigated by competitive equilibration experiments at 25°C and 50°C. Form A was obtained in all experiments. The formulation process feasibility of each form was also evaluated by compression, milling, and milling simulation experiments. Form A was found to be a stable polymorph and suitable for further development.

[0674] Although the foregoing invention has been described in some detail by way of illustration and example for clarity of understanding, those skilled in the art will recognize that certain changes and modifications can be made within the scope of the appended claims. Furthermore, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference were individually incorporated by reference. In the event of a conflict between this application and a reference provided herein, this application will control.

Claims

1. Compounds having formula (I): 【Chemistry 1】 Crystalline form A of

2. 2. The crystalline form A of claim 1, characterized by an X-ray powder diffraction (XRPD) pattern comprising angles 6.1, 11.1, and 16.6 degrees 2θ (±0.2 degrees 2θ).

3. 2. The crystalline form A of claim 1, characterized by an X-ray powder diffraction (XRPD) pattern comprising any of three peaks selected from 6.1, 6.6, 10.0, 11.1, 12.1, 15.6, and 16.6 degrees 2θ (±0.2 degrees 2θ).

4. 2. The crystalline form A of claim 1, characterized by an X-ray powder diffraction (XRPD) pattern comprising any of four peaks selected from 6.1, 6.6, 10.0, 11.1, 12.1, 15.6, and 16.6 degrees 2θ (±0.2 degrees 2θ).

5. 2. The crystalline form A of claim 1, characterized by an X-ray powder diffraction (XRPD) pattern comprising any of five peaks selected from 6.1, 6.6, 10.0, 11.1, 12.1, 15.6, and 16.6 degrees 2θ (±0.2 degrees 2θ).

6. 2. The crystalline form A of claim 1, characterized by an X-ray powder diffraction pattern comprising peaks at 6.1, 6.6, 11.1, 12.1, and 16.6 degrees 2θ (±0.2 degrees 2θ).

7. 10. The crystalline form A of claim 1, 2, or 6, characterized by an X-ray powder diffraction pattern comprising peaks at 10.0, 18.5, 20.8, 25.3, and 25.7 degrees 2θ (±0.2 degrees 2θ).

8. 10. The crystalline form A of claim 1, characterized by an X-ray powder diffraction pattern substantially in accordance with FIG.

9. 9. The crystalline form A of any one of claims 1 to 8, further characterized by a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 323.5°C.

10. 10. The crystalline form A of claim 9, wherein the DSC thermogram is substantially in accordance with Figure 7.

11. 11. The crystalline form A of any one of claims 1 to 10, further characterized by a weight percent loss of about 1.0% when heated to about 220°C as measured by thermogravimetric analysis (TGA).

12. 12. Crystalline Form A according to any one of claims 1 to 11, further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 8.

13. 13. Crystalline form A according to any one of claims 1 to 12, further characterized by a polarized light microscope (PLM) profile substantially as shown in Figure 9.

14. Compounds having formula (I): 【Chemistry 2】 Crystalline form C of

15. 15. The crystalline form C of claim 14, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 11.8, 16.6, 17.5, 27.2, and 28.2 degrees two-theta (±0.2 degrees two-theta).

16. 15. The crystalline form C of claim 14, wherein the X-ray powder diffraction pattern further comprises peaks at 19.7, 20.3, 23.7, 24.5, and 29.8 degrees 2θ (±0.2 degrees 2θ).

17. 17. The crystalline form C of claim 14 or 16, wherein the X-ray powder diffraction pattern further comprises peaks at 10.9, 17.8, 21.8, 26.0, and 26.6 degrees 2θ (±0.2 degrees 2θ).

18. 15. The crystalline form C of claim 14, wherein the X-ray powder diffraction pattern is substantially in accordance with Figure 13.

19. 19. Crystalline form C according to any one of claims 14 to 18, wherein the DSC thermogram is substantially in accordance with Figure 14.

20. 20. The crystalline form C of any one of claims 14 to 19, further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 15.

21. 21. Crystalline form C according to any one of claims 14 to 20, further characterized by a polarized light microscope (PLM) profile substantially as shown in Figure 16.

22. Compounds having formula (I): 【Transformation 3】 Crystalline form D of

23. 23. The crystalline form D of claim 22, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.1, 12.4, 13.7, 16.5, 27.6 degrees 2θ (±0.2 degrees 2θ).

24. 23. The crystalline form D of claim 22, wherein the X-ray powder diffraction pattern further comprises peaks at 10.9, 14.8, 25.2, 26.7, and 27.9 degrees 2θ (±0.2 degrees 2θ).

25. 25. The crystalline form D of claim 22 or 24, wherein the X-ray powder diffraction pattern further comprises peaks at 10.3, 19.3, 21.2, 24.1, and 29.9 degrees 2θ (±0.2 degrees 2θ).

26. 23. The crystalline form D of claim 22, wherein the X-ray powder diffraction pattern is substantially in accordance with Figure 19.

27. 27. Crystalline form D according to any one of claims 22 to 26, wherein the DSC thermogram is substantially in accordance with Figure 20.

28. 28. Crystalline form D according to any one of claims 22 to 27, further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 21.

29. 29. Crystalline form D according to any one of claims 22 to 28, further characterized by a polarized light microscope (PLM) profile substantially as shown in Figure 22.

30. Compounds having formula (I): 【Chemistry 4】 Crystalline form E of

31. 31. The crystalline form E of claim 30, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 12.3, 13.7, 19.4, 26.7, and 27.6 degrees two-theta (±0.2 degrees two-theta).

32. 31. The crystalline form E of claim 30, wherein the X-ray powder diffraction pattern further comprises peaks at 20.8, 24.5, 25.3, 28.1, and 30.0 degrees 2θ (±0.2 degrees 2θ).

33. 33. The crystalline form E of claim 30 or 32, wherein the X-ray powder diffraction pattern further comprises peaks at 7.2, 14.6, 14.9, 18.2, and 22.5 degrees 2θ (±0.2 degrees 2θ).

34. 31. The crystalline form E of claim 30, wherein the X-ray powder diffraction pattern is substantially in accordance with Figure 25.

35. 35. Crystalline form E according to any one of claims 30 to 34, wherein the DSC thermogram is substantially in accordance with Figure 26.

36. 36. Crystalline form E of any one of claims 30-35, further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 27.

37. 37. Crystalline form E according to any one of claims 30 to 36, further characterized by a polarized light microscope (PLM) profile substantially as shown in Figure 28.

38. Compounds having formula (I): 【Transformation 5】 Crystalline form I of

39. 39. Crystalline Form I of claim 38, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 5.8, 6.4, 16.1, 16.5, and 27.7 degrees 2θ (±0.2 degrees 2θ).

40. 39. The crystalline form I of claim 38, wherein the X-ray powder diffraction pattern further comprises peaks at 10.0, 10.8, 13.1, 25.5, and 29.0 degrees 2θ (±0.2 degrees 2θ).

41. 41. Crystalline Form I according to claim 38 or 40, wherein the X-ray powder diffraction pattern further comprises peaks at 8.4, 11.9, 17.7, 19.6, and 23.3 degrees 2θ (±0.2 degrees 2θ).

42. 39. Crystalline Form I according to claim 38, wherein the X-ray powder diffraction pattern is substantially in accordance with Figure 41.

43. 43. The crystalline form I of any one of claims 38-42, wherein the DSC thermogram is substantially in accordance with Figure 42.

44. 44. Crystalline Form I of any one of claims 38-43, further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 43.

45. 45. The crystalline form I of any one of claims 38-44, further characterized by a polarized light microscope (PLM) profile substantially as shown in Figure 44.

46. Compounds having formula (I): 【Transformation 6】 Crystalline form T of

47. 47. The crystalline form T of claim 46, characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.5, 10.9, 12.4, 13.0, and 16.9 degrees 2θ (±0.2 degrees 2θ).

48. 47. The crystalline form T of claim 46, wherein the X-ray powder diffraction pattern further comprises peaks at 10.5, 16.6, 22.2, 27.5, and 27.9 degrees 2θ (±0.2 degrees 2θ).

49. 47. The crystalline form T of claim 46, wherein the X-ray powder diffraction pattern is substantially in accordance with Figure 61.

50. 50. The crystalline form T of any one of claims 46-49, wherein the DSC thermogram is substantially in accordance with Figure 62.

51. 51. The crystalline form T of any one of claims 46-50, further characterized by a thermogravimetric analysis (TGA) thermogram substantially in accordance with Figure 63.

52. 52. Crystalline form T according to any one of claims 46 to 51, further characterized by a polarized light microscope (PLM) profile substantially as shown in Figure 64.

53. Compounds having formula (I): 【Transformation 7】 or a pharmaceutically acceptable salt thereof, the solid state form comprises at least 50% by weight of a particular crystalline form, at least 60% by weight of a particular crystalline form, at least 70% by weight of a particular crystalline form, at least 80% by weight of a particular crystalline form, at least 90% by weight of a particular crystalline form, at least 95% by weight of a particular crystalline form, or at least 99% by weight of a particular crystalline form; The specific crystalline form is a crystalline form according to any one of claims 2 to 52. The solid form.

54. 54. The solid state form of claim 53, wherein the particular crystalline form is crystalline form A.

55. A pharmaceutical composition comprising the crystalline form of any one of claims 2 to 52 and at least one pharmaceutically acceptable excipient.

56. 55. A pharmaceutical composition comprising the solid form of claim 53 or 54 and at least one pharmaceutically acceptable excipient.

57. 57. A method for treating a disease treatable by MAT2A inhibition in a patient, the method comprising administering to the patient a therapeutically effective amount of the crystalline form of any one of claims 2 to 52, the solid state form of claim 53 or 54, or the pharmaceutical composition of claim 55 or 56.

58. 58. The method of claim 57, wherein the disease is cancer.

59. 57. A method of treating an MTAP-null cancer in a patient, comprising administering to the patient a therapeutically effective amount of the crystalline form of any one of claims 2-52, the solid state form of claim 53 or 54, or the pharmaceutical composition of claim 55 or 56.

60. 57. A method for treating cancer in a patient, wherein the cancer is characterized by reduced or absent MTAP gene expression, absent MTAP gene, reduced levels of MTAP protein, reduced function of MTAP protein, absent MTAP protein, or a combination thereof, comprising administering to the patient a therapeutically effective amount of the crystalline form of any one of claims 2 to 52, the solid state form of claim 53 or 54, or the pharmaceutical composition of claim 55 or 56.

61. 61. The method of claim 59 or 60, wherein the cancer is selected from the group consisting of leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin's lymphoma, esophagogastric cancer, gastrointestinal (GI) cancer, or mesothelioma.

62. A method for preparing a pharmaceutical composition, comprising mixing crystalline Form A with at least one pharmaceutically acceptable excipient.

63. 55. A method of producing a pharmaceutical composition, comprising mixing the solid form of claim 53 or 54 with at least one pharmaceutically acceptable excipient.

64. A pharmaceutical composition prepared by combining crystalline form A with at least one pharmaceutically acceptable excipient.

65. 55. A pharmaceutical composition prepared by combining the solid state form of claim 53 or 54 with at least one pharmaceutically acceptable excipient.

66. Compounds having formula (I): 【Transformation 8】 A method for preparing crystalline form A of a) forming a first mixture comprising a crude compound of formula (I), ACN, and water; b) solvent exchange with water at a temperature of about 65° C. or less to form a second mixture; c) cooling and stirring the second mixture to form a third precipitate; d) isolating the third precipitate; and e) forming a slurry comprising the third precipitate, methyl ethyl ketone (MEK), and water; f) isolating the fourth precipitate of step e); g) drying the fourth precipitate to obtain crystalline form A of formula (I); A method comprising:

67. 67. The method of claim 66, wherein step a) is carried out at a temperature of about 75°C to 80°C.

68. 68. The method of claim 66 or 67, wherein in step a), the ratio of ACN to water is about 4:1 by volume.

69. 69. The method of any one of claims 66 to 68, wherein step c) is carried out at a temperature of about 0°C to 5°C and stirred for about 12 to 16 hours.

70. 70. The method of any one of claims 66-69, wherein in step e), the ratio of MEK to water is about 10:1 by volume.

71. 71. The method of any one of claims 66 to 70, wherein step e) is carried out at a temperature of about 60°C to 65°C, stirred for about 17 to 22 hours, and further cooled to a temperature of about 0°C to 5°C and stirred for about 15 to 24 hours.

72. 72. The method of any one of claims 66 to 71, wherein the isolation of step d) and / or step e) is carried out by filtration.

73. 72. The method of any one of claims 66 to 71, wherein the drying in step g) is carried out at a temperature of from 65°C to 70°C.

74. 74. The method of any one of claims 66 to 73, wherein the crude compound of formula (I) is present in the first mixture in an amount of about 20 g / L to 100 g / L.

75. Compounds having formula (I): 【Chemistry 9】 1. A method for preparing a crystalline form of a) forming a slurry comprising solid form V of formula (I) and a solvent; b) stirring the slurry for at least 1 day; c) isolating the precipitate; and d) drying the precipitate to obtain the crystalline form of formula (I); Including, the crystalline form is crystalline form C, D, E, I, or A-1; The process wherein the solvent is methanol, water, a mixture of methanol and water, a mixture of acetone and water, or a mixture of acetonitrile and water.

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