Crystalline forms of KRAS g12d inhibitor and uses thereof

Abstract

Provided are crystalline and amorphous forms of (Compound 1), and pharmaceutically acceptable salts and compositions thereof, as well as the use of such for treating conditions associated with the inhibition of KRAS(G12D).

Description

CRYSTALLINE FORMS OF KRAS G12D INHIBITOR AND USES THEREOFRELATED APPLICATIONS

[0001] This application claims the benefit of priority to PCT / CN2024 / 093436, filed May 15, 2024, the entire contents of which are incorporated herein by reference.BACKGROUND

[0002] Discovered as a human oncogene in the early 1980s, the Kirsten rat sarcoma virus homolog (KRAS) gene encodes a monomeric small 21 kDa GTPase that has long been an elusive cancer drug target (Chang et al., PNAS, 1982, 79:4848-52; McCoy et al., Nature, 1983, 302:79-8). KRAS functions as a molecular switch for promoting cell growth by cycling between GTP- and GDP-bound states. In the GTP-bound state, KRAS signals for growth through the RAF-MAPK and PI3K-AKT-MTOR pathways. KRAS subsequently hydrolyzes GTP to GDP with the aid of GTPase activating proteins (GAPs). This GDP- bound state switches “off’ KRAS pro-growth signaling. KRAS can then be switched back “on” by GDP to GTP exchange through the aid of guanine nucleotide exchange factors, such as SOS1 (Cox and Der, Small GTPases, 2010, 1:2-27; Kerk et al., Nat Rev Cancer, 2021, 21:510-525). Preventing this exchange by locking KRAS in the GDP-bound state is a practical method for inhibiting its growth promoting activity.

[0003] The human KRAS gene is encoded on Chromosome 12pl2.1 and is among the most frequently mutated genes in human cancers (Pylayeva-Gupta et al., Nat Rev Cancer, 2011, 11:761-774). Mutations that prevent GTP-hydrolysis lock KRAS in the active GTP- bound state and reprogram cells for perpetual proliferation. KRAS mutated from glycine (G) at the 12th codon to aspartate (D) creates a chronically active KRAS(G12D) oncoprotein, the gene for which is observed in 6.8% of cancers cases as analyzed by nextgeneration sequencing (Zhou et al., Pathol Oncol Res, 2020, 26:2835-2837). In tumor typespecific studies, KRAS(G12D) is associated with poor clinical outcomes and observed in 17% of lung, 14.3% of colorectal, and 48% of pancreatic tumors (Aredo et al., Lung Cancer, 2019, 133:144-150; Olmedillas-Lopez et al., World J Gastroenterol, 2017, 23(39):7087-709; Miglio et al., Pathol Res Pract, 2014, 210:307-11; Gou et al., Br J Cancer, 2020, 22:857- 867), among other cancers. Historically, oncogenic KRAS mutants have been considered undruggable (McCormick F, Biochem J, 2019, 476:356-74), however the discovery of an allosteric pocket in GDP-bound KRAS has allowed the search for small molecule inhibitors (Ostrem et al., Nature, 2013, 503: 548-51). The G12D mutation moreover provides a uniquechemical moiety-binding space due to the encoding of an acidic amino acid residue (D) in place of a small flexible amino acid residue possessing only a hydrogen side chain (G). This alteration of the KRAS protein structure provides a unique space that may be targeted with small molecules drugs that specifically inhibit KRAS(G12D) oncogenic activity. It is therefore desirable to design and develop small molecule drugs that target KRAS(G12D) with sufficient bioavailability to treat diseases such as cancer.

[0004] Polymorphism is the formation of a variety of crystalline forms of the same compound having distinct crystal structures and physical properties like melting points, X- ray diffraction pattern, infrared absorption pattern in fingerprint region, and solid state NMR spectrum. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubility. The difference in the physical properties of different crystalline forms results in Some forms having distinct advantageous physical properties compared to other crystalline forms of the same compound. The discovery of new polymorphic forms of pharmaceutically useful compounds provides a new opportunity to improve the performance characteristics of a pharmaceutical product. Those skilled in the art understand that crystallization of an active pharmaceutical ingredient offers the best method for controlling important qualities like chemical quality, particle size, and polymorphic content.

[0005] Hence there is a need in the art for the preparation of new polymorphic forms of pharmaceutically acceptable salts of KRAS(G12D) inhibitors as well as intermediates thereof.SUMMARY

[0006] Provided herein are crystalline forms of Compound 1 as well as pharmaceutically acceptable salts thereof.(Compound 1)

[0007] Also provided are amorphous forms of Compound 1 as well as pharmaceutically acceptable salts thereof.

[0008] Further provided are pharmaceutical compositions comprising the described crystalline and amorphous forms, as well as their use to treat conditions responsive to the inhibition of KRAS(G12D) (e.g., cancer).BRIEF SUMMARY OF THE FIGURES

[0009] FIG. 1 shows the XRPD pattern of amorphous form of compound 1.

[0010] FIG. 2 shows the DSC thermogram of amorphous form of compound 1.

[0011] FIG. 3 presents the XRPD pattern of crystalline Form I of compound 1.

[0012] FIG. 4 shows the DSC thermogram of crystalline Form I of compound 1.

[0013] FIG. 5 presents the XRPD pattern of crystalline Form II of compound 1.

[0014] FIG. 6 shows the DSC thermogram of crystalline Form II of compound 1.

[0015] FIG. 7 presents the XRPD pattern of crystalline Form III of compound 1.

[0016] FIG. 8 shows the DSC thermogram of crystalline Form III of compound 1.

[0017] FIG. 9 presents the XRPD pattern of crystalline Form IV of compound 1.

[0018] FIG. 10 shows the DSC thermogram of crystalline Form IV of compound 1.

[0019] FIG. 11 presents the XRPD pattern of crystalline Form V of compound 1.

[0020] FIG. 12 shows the DSC thermogram of crystalline Form V of compound 1.

[0021] FIG. 13 presents the XRPD pattern of crystalline Form VI of compound 1.

[0022] FIG. 14 shows the DSC thermogram of crystalline Form VI of compound 1.

[0023] FIG. 15 presents the XRPD pattern of crystalline Form VII of compound 1.

[0024] FIG. 16 presents the XRPD pattern of crystalline Form VII of compound 1 before and after DVS.

[0025] FIG. 17 presents the XRPD pattern of crystalline Form VIII of compound 1.

[0026] FIG. 18 shows the DSC thermogram of crystalline Form VIII of compound 1.

[0027] FIG. 19 presents the XRPD pattern of crystalline Form IX of compound 1.

[0028] FIG. 20 shows the DSC thermogram of crystalline Form IX of compound 1.

[0029] FIG. 21 presents the XRPD pattern of crystalline Form X of compound 1.

[0030] FIG. 22 shows the DSC thermogram of crystalline Form X of compound 1.

[0031] FIG. 23 shows the XRPD pattern of crystalline crude Form of compound 1 made by the process described Scheme 1.

[0032] FIG. 24 shows the DSC thermogram of crystalline crude Form of compound 1 made by the process described Scheme 1.DETAILED DESCRIPTIONDefinitions

[0033] As used herein, “crystalline” refers to a solid form of a compound wherein there exists long-range atomic order in the positions of the atoms. The crystalline nature of a solid can be confirmed, for example, by examination of the X-ray powder diffraction pattern.

[0034] In one embodiment, the described crystalline forms are each single crystalline forms. A “single crystalline form” means that the recited compound, i.e., Compound 1, is present as a single crystal or a plurality of crystals in which each crystal has the same crystal form. Percent by weight of a particular crystal form is determined by the weight of the particular crystal form divided by the sum weight of the particular crystal, plus the weight of the other crystal form(s) present plus the weight of amorphous form, if present, multiplied by 100%. In some instances, the described crystalline forms are at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% a single crystalline form. “Pure single crystalline form” means that Compound 1 is present as a single crystal or a plurality of crystals in which each crystal has the same crystal form with no other detectable amounts of other crystal forms present and / or amorphous forms.

[0035] Chemical purity refers to extent by which the disclosed form is free from materials having different chemical structures. Chemical purity of the compound in the disclosed crystal forms means the weight of the compound divided by the sum of the weight of the compound plus materials / impurities having different chemical structures multiplied by 100%, i.e., percent by weight.

[0036] The term “amorphous” refers to a solid that is present in a non-crystalline state or form. Amorphous solids are disordered arrangements of molecules and therefore possess no distinguishable crystal lattice or unit cell and consequently have no definable long range ordering. Solid state ordering of solids may be determined by standard techniques known in the art, e.g., by X-ray powder diffraction (XRPD) or differential scanning calorimetry (DSC).

[0037] The term “anhydrous” and “anhydrate” are used interchangeably and mean that the referenced crystalline form has substantially no water in the crystal lattice, e.g., less than 1% by weight as determined by Karl Fisher analysis

[0038] The 2-theta values of the X-ray powder diffraction patterns for the crystalline forms described herein may vary slightly from one instrument to another and also depending on variations in sample preparation and batch to batch variation due to factorssuch as temperature variation, sample displacement, and the presence or absence of an internal standard. Therefore, unless otherwise defined, the XRPD patterns / assignments recited herein are not to be construed as absolute and can vary ± 0.2 degrees. It is well known in the art that this variability will account for the above factors without hindering the unequivocal identification of a crystal form. Unless otherwise specified, the 2-theta values provided herein were obtained using Cu Kai radiation.

[0039] Temperature values, e.g., for DSC peaks herein may vary slightly from one instrument to another and also depending on variations in sample preparation, batch to batch variation, and environmental factors. Therefore, unless otherwise defined, temperature values recited herein are not to be construed as absolute and can vary ± 5 degrees or ± 2 degrees.

[0040] "Substantially the same XRPD pattern” or “an X-ray powder diffraction pattern substantially similar to” a defined figure means that for comparison purposes, at least 90% of the peaks shown are present. It is to be further understood that for comparison purposes some variability in peak intensities from those shown are allowed, such as ± 0.2 degrees.

[0041] As used herein the terms “subject” and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment.

[0042] The term “pharmaceutically acceptable carrier” refers to a non-toxic carrier, adjuvant, or vehicle that does not adversely affect the pharmacological activity of the compound with which it is formulated, and which is also safe for human use.Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, magnesium stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, dicalcium phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyvinylpyrrolidone-vinyl acetate, cellulose-based substances (e.g., microcrystalline cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose Phthalate), starch, lactose monohydrate,mannitol, sodium lauryl sulfate, and crosscarmellose sodium, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, polymethacrylate, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0043] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, reducing the likelihood of developing, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.The term “effective amount” or “therapeutically effective amount” includes an amount of a compound described herein that will elicit a biological or medical response of a subject, e.g., a dosage of between 0.001 - 100 mg / kg body weight / day of Compound 1.Exemplary Forms

[0044] In one aspect, provided is crystalline Form I of a compound having the structural formula:or a pharmaceutically acceptable salt thereof, wherein the crystalline form is characterized by at least three X-ray powder diffraction pattern peaks at 20 angles selected from 7.3 ± 0.2, 11.7 ± 0.2, 12.9 ± 0.2, 16.4 ± 0.2, and 20.9 ± 0.2. In some aspects, crystalline Form I is characterized by at least four X-ray powder diffraction pattern peaks at 20 angles selected from 7.3 ± 0.2, 11.7 ± 0.2, 12.9 ± 0.2, 16.4 ± 0.2, and 20.9 ± 0.2. In some aspects, crystalline Form I is characterized by X-ray powder diffraction pattern peaks at 20 angles selected from 7.3 ± 0.2, 11.7 ± 0.2, 12.9 ± 0.2, 16.4 ± 0.2, and 20.9 ± 0.2. In some aspects, crystalline Form I is further characterized by at least one, at least two, at least three, at least four, at least five, or at least six additional X-ray powder diffraction pattern peaks at 20 angles selected from 10.8 ± 0.2, 12.7 ± 0.2, 17.0 ± 0.2, 18.9 ± 0.2, 20.1 ± 0.2, 20.4 ± 0.2,25.0 ± 0.2, and 26.8+ 0.2. In some aspects, crystalline Form I is characterized by three or more X-ray powder diffraction pattern peaks at 20 angles selected from those in Table 8. In some aspects, crystalline Form I is characterized by an X-ray powder diffractogram substantially as shown in FIG. 3. In some aspects, crystalline Form I is characterized by a differential scanning calorimetry thermogram having an endotherm with an onset temperature of about 236 °C. In some aspects, crystalline Form I is a hydrate. In some aspects, crystalline Form I is a channel hydrate. In some aspects, crystalline Form I is a sesquihydrate.

[0045] In one aspect, provided is crystalline Form II of a compound having the structural formula:or a pharmaceutically acceptable salt thereof, wherein the crystalline form is characterized by at least three X-ray powder diffraction pattern peaks at 20 angles selected from 7.7 + 0.2, 11.3 + 0.2, 12.1 + 0.2, 13.6 + 0.2, and 17.9 + 0.2. In some aspects, crystalline Form II is characterized by at least four X-ray powder diffraction pattern peaks at 20 angles selected from 7.7 + 0.2, 11.3 + 0.2, 12.1 + 0.2, 13.6 + 0.2, and 17.9 + 0.2. In some aspects, crystalline Form II is characterized by X-ray powder diffraction pattern peaks at 20 angles selected from 7.7 + 0.2, 11.3 + 0.2, 12.1 + 0.2, 13.6 + 0.2, and 17.9 + 0.2. In some aspects, crystalline Form II is further characterized by at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, or at least twelve additional X-ray powder diffraction pattern peaks at 20 angles selected from 8.1 + 0.2, 9.2 + 0.2, 9.7 + 0.2, 15.6 + 0.2, 16.4 + 0.2, 17.1 + 0.2, 19.6 + 0.2, 21.6 + 0.2, 22.1 + 0.2, 22.7 + 0.2, 23.0 + 0.2, 23.4 + 0.2, and 24.9 + 0.2. In some aspects, crystalline Form II is characterized by three or more X-ray powder diffraction pattern peaks at 20 angles selected from those in Table 9. In some aspects, crystalline Form II is characterized by an X-ray powder diffractogram substantially as shown in FIG. 5. In some aspects, crystalline Form II is characterized by a differential scanning calorimetry thermogram having an endotherm with an onset temperature of about 118 °C. In some aspects, crystalline Form II is a hydrate.

[0046] In one aspect, provided is crystalline Form III of a compound having the structural formula:or a pharmaceutically acceptable salt thereof, wherein the crystalline form is characterized by at least three X-ray powder diffraction pattern peaks at 20 angles selected from 7.8 ± 0.2, 11.9 ± 0.2, 12.4 ± 0.2, 17.0 ± 0.2, 17.4 ± 0.2, and 17.9 ± 0.2. In some aspects, crystalline Form III is characterized by at least four X-ray powder diffraction pattern peaks at 20 angles selected from 7.8 ± 0.2, 11.9 ± 0.2, 12.4 ± 0.2, 17.0 ± 0.2, 17.4 ± 0.2, and 17.9 ± 0.2. In some aspects, crystalline Form III is characterized by at least five X-ray powder diffraction pattern peaks at 20 angles selected from 7.8 ± 0.2, 11.9 ± 0.2, 12.4 ± 0.2, 17.0 ± 0.2, 17.4 ± 0.2, and 17.9 ± 0.2. In some aspects, crystalline Form III is characterized by X- ray powder diffraction pattern peaks at 20 angles selected from 7.8 ± 0.2, 11.9 ± 0.2, 12.4 ± 0.2, 17.0 ± 0.2, 17.4 ± 0.2, and 17.9 ± 0.2. In some aspects, crystalline Form III is further characterized by at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, and at least eleven additional X- ray powder diffraction pattern peaks at 20 angles selected from 8.5 ± 0.2, 9.7 ± 0.2, 10.5 ± 0.2, 11.7 ± 0.2, 13.8 ± 0.2, 15.2 ± 0.2, 19.6 ± 0.2, 20.5 ± 0.2, 21.7 ± 0.2, 22.7 ± 0.2, 23.0 ± 0.2, and 25.0 ± 0.2. In some aspects, crystalline Form III is characterized by three or more X-ray powder diffraction pattern peaks at 20 angles selected from those in Table 10. In some aspects, crystalline Form III is characterized by an X-ray powder diffractogram substantially as shown in FIG. 7. In some aspects, crystalline Form III is characterized by a differential scanning calorimetry thermogram having an endotherm with an onset temperature of about 182 °C. In some aspects, crystalline Form III is a hydrate. In some aspects, crystalline Form III is an L-tartaric acid salt.

[0047] In one aspect, provided is crystalline Form IV of a compound having the structural formula:or a pharmaceutically acceptable salt thereof, wherein the crystalline form is characterized by at least three X-ray powder diffraction pattern peaks at 20 angles selected from 6.8 ± 0.2, 18.4 ± 0.2, 20.4 ± 0.2, 20.7 ± 0.2, 21.7 ± 0.2, and 24.8 ± 0.2. In some aspects crystalline Form IV is characterized by at least four X-ray powder diffraction pattern peaks at 20 angles selected from 6.8 ± 0.2, 18.4 ± 0.2, 20.4 ± 0.2, 20.7 ± 0.2, 21.7 ± 0.2, and 24.8 ± 0.2. In some aspects crystalline Form IV is characterized by at least five X-ray powder diffraction pattern peaks at 20 angles selected from 6.8 ± 0.2, 18.4 ± 0.2, 20.4 ± 0.2, 20.7 ± 0.2, 21.7 ± 0.2, and 24.8 ± 0.2. In some aspects crystalline Form IV is characterized by X- ray powder diffraction pattern peaks at 20 angles selected from 6.8 ± 0.2, 18.4 ± 0.2, 20.4 ± 0.2, 20.7 ± 0.2, 21.7 ± 0.2, and 24.8 ± 0.2. In some aspects crystalline Form IV is characterized by at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, and at least sixteen additional X-ray powder diffraction pattern peaks at 20 angles selected from 9.7 ± 0.2, 11.2 ± 0.2, 12.0 ± 0.2, 12.3 ± 0.2, 12.8 ± 0.2, 13.7 ± 0.2, 14.0 ± 0.2, 15.4 ± 0.2, 15.8 ± 0.2, 16.3 ± 0.2, 17.0 ± 0.2, 17.5 ± 0.2, 19.1 ± 0.2, 19.6 ± 0.2, 19.8 ± 0.2, 22.2 ± 0.2, and 23.0 ± 0.2. In some aspects crystalline Form IV is characterized by three or more X-ray powder diffraction pattern peaks at 20 angles selected from those in Table 11. In some aspects crystalline Form IV is characterized by an X-ray powder diffractogram substantially as shown in FIG. 9. In some aspects crystalline Form IV is characterized by a differential scanning calorimetry thermogram having an endotherm with an onset temperature of about 110 °C. In some aspects crystalline Form IV is an anisole solvate.

[0048] In one aspect, provided is crystalline Form V of a compound having the structural formula:or a pharmaceutically acceptable salt thereof, wherein the crystalline form is characterized by at least three X-ray powder diffraction pattern peaks at 20 angles selected from 7.2 ± 0.2, 11.7 ± 0.2, 13.0 ± 0.2, 16.4 ± 0.2, 20.4 ± 0.2, and 21.0 ± 0.2. In some aspects, crystalline form V is characterized by at least four X-ray powder diffraction pattern peaks at 20 angles selected from 7.2 ± 0.2, 11.7 ± 0.2, 13.0 ± 0.2, 16.4 ± 0.2, 20.4 ± 0.2, and 21.0 ± 0.2. In some aspects, crystalline form V is characterized by at least five X-ray powder diffraction pattern peaks at 20 angles selected from 7.2 ± 0.2, 11.7 ± 0.2, 13.0 ± 0.2, 16.4 ± 0.2, 20.4 ± 0.2, and 21.0 ± 0.2. In some aspects, crystalline form V is characterized by X- ray powder diffraction pattern peaks at 20 angles selected from 7.2 ± 0.2, 11.7 ± 0.2, 13.0 ± 0.2, 16.4 ± 0.2, 20.4 ± 0.2, and 21.0 ± 0.2. In some aspects, crystalline form V is further characterized by at least one or at least two additional X-ray powder diffraction pattern peaks at 20 angles selected from 14.6 ± 0.2, 20.1 ± 0.2, and 26.7 ± 0.2. In some aspects, crystalline form V is characterized by at least three X-ray powder diffraction pattern peaks at 20 angles selected from those in Table 12. In some aspects, crystalline form V is characterized by an X-ray powder diffractogram substantially as shown in FIG. 11. In some aspects, crystalline form V is characterized by a differential scanning calorimetry thermogram substantially as shown in FIG. 12.

[0049] In one aspect, provided is crystalline Form VI of a compound having the structural formula:or a pharmaceutically acceptable salt thereof, wherein the crystalline form is characterized by at least three X-ray powder diffraction pattern peaks at 20 angles selected from 6.8 ± 0.2, 13.7 ± 0.2, 18.1 ± 0.2, 19.4 ± 0.2, 20.7 ± 0.2, and 24.9 ± 0.2. In some aspects,crystalline form VI is characterized by at least four X-ray powder diffraction pattern peaks at 20 angles selected from 6.8 ± 0.2, 13.7 ± 0.2, 18.1 ± 0.2, 19.4 ± 0.2, 20.7 ± 0.2, and 24.9 ± 0.2. In some aspects, crystalline form VI is characterized by at least five X-ray powder diffraction pattern peaks at 20 angles selected from 6.8 ± 0.2, 13.7 ± 0.2, 18.1 ± 0.2, 19.4 ± 0.2, 20.7 ± 0.2, and 24.9 ± 0.2. In some aspects, crystalline form VI is characterized by X- ray powder diffraction pattern peaks at 20 angles selected from 6.8 ± 0.2, 13.7 ± 0.2, 18.1 ± 0.2, 19.4 ± 0.2, 20.7 ± 0.2, and 24.9 ± 0.2. In some aspects, crystalline form VI is further characterized by at least one, at least two, at least three, at least four, at least five, or at least six additional X-ray powder diffraction pattern peaks at 20 angles selected from 12.3 ± 0.2, 16.1 ± 0.2, 19.0 ± 0.2, 21.7 ± 0.2, 22.1 ± 0.2, 22.8 ± 0.2, and 23.6 ± 0.2. In some aspects, crystalline form VI is characterized by at least three X-ray powder diffraction pattern peaks at 20 angles selected from those in Table 13. In some aspects, crystalline form VI is characterized by an X-ray powder diffractogram substantially as shown in FIG. 13. In some aspects, crystalline form VI is characterized by a differential scanning calorimetry thermogram having an endotherm with an onset temperature of about 94 °C. In some aspects, crystalline form VI is a solvate.

[0050] In one aspect, provided is crystalline Form VII of a compound having the structural formula:or a pharmaceutically acceptable salt thereof, wherein the crystalline form is characterized by at least three X-ray powder diffraction pattern peaks at 20 angles selected from 7.3 ± 0.2, 11.7 ± 0.2, 12.9 ± 0.2, 16.4 ± 0.2, and 20.9 ± 0.2. In some aspects, crystalline Form VII is characterized by at least four X-ray powder diffraction pattern peaks at 20 angles selected from 7.3 ± 0.2, 11.7 ± 0.2, 12.9 ± 0.2, 16.4 ± 0.2, and 20.9 ± 0.2. In some aspects, crystalline Form VII is characterized by X-ray powder diffraction pattern peaks at 20 angles selected from 7.3 ± 0.2, 11.7 ± 0.2, 12.9 ± 0.2, 16.4 ± 0.2, and 20.9 ± 0.2. In some aspects, crystalline Form VII is characterized by at least one, at least two, or at least three additional X-ray powder diffraction pattern peaks at 20 angles selected from 12.7 ± 0.2,20.1 ± 0.2, 20.4 ± 0.2, and 26.8 ± 0.2. In some aspects, crystalline Form VII is characterizedby at least three X-ray powder diffraction pattern peaks at 20 angles selected from those in Table 14. In some aspects, crystalline Form VII is characterized by an X-ray powder diffractogram substantially as shown in FIG. 15. In some aspects, crystalline Form VII is characterized by an X-ray powder diffractogram substantially as shown in FIG. 16. In some aspects, crystalline Form VII is a hydrate.

[0051] In one aspect, provided is crystalline Form VIII of a compound having the structural formula:or a pharmaceutically acceptable salt thereof, wherein the crystalline form is characterized by at least three X-ray powder diffraction pattern peaks at 20 angles selected from 3.6 ± 0.2, 6.8 ± 0.2, 10.3 ± 0.2, 13.8 ± 0.2, 18.1 ± 0.2, and 21.0 ± 0.2. In some aspects, crystalline Form VIII is characterized by at least four X-ray powder diffraction pattern peaks at 20 angles selected from 3.6 ± 0.2, 6.8 ± 0.2, 10.3 ± 0.2, 13.8 ± 0.2, 18.1 ± 0.2, and 21.0 ± 0.2. In some aspects, crystalline Form VIII is characterized by at least five X-ray powder diffraction pattern peaks at 20 angles selected from 3.6 ± 0.2, 6.8 ± 0.2, 10.3 ± 0.2, 13.8 ± 0.2, 18.1 ± 0.2, and 21.0 ± 0.2. In some aspects, crystalline Form VIII is characterized by X- ray powder diffraction pattern peaks at 20 angles selected from 3.6 ± 0.2, 6.8 ± 0.2, 10.3 ± 0.2, 13.8 ± 0.2, 18.1 ± 0.2, and 21.0 ± 0.2. In some aspects, crystalline Form VIII is characterized by at least one, at least two, or at least three additional X-ray powder diffraction pattern peaks at 20 angles selected from 11.7 ± 0.2, 14.7 ± 0.2, 19.1 ± 0.2, and 23.6 ± 0.2. In some aspects, crystalline Form VIII is characterized by at least three X-ray powder diffraction pattern peaks at 20 angles selected from those in Table 15. In some aspects, crystalline Form VIII is characterized by an X-ray powder diffractogram substantially as shown in FIG. 17. In some aspects, crystalline Form VIII is characterized by a differential scanning calorimetry thermogram having an endotherm with an onset temperature of about 126 °C. In some aspects, crystalline Form VIII is a solvate.

[0052] In one aspect, provided is crystalline Form IX of a compound having the structural formula:or a pharmaceutically acceptable salt thereof, wherein the crystalline form is characterized by at least three X-ray powder diffraction pattern peaks at 20 angles selected from 3.8 ± 0.2, 5.9 ± 0.2, 8.0 ± 0.2, 11.2 ± 0.2, 12.3 ± 0.2, and 22.7 ± 0.2. In some aspects, crystalline Form IX is characterized by at least four X-ray powder diffraction pattern peaks at 20 angles selected from 3.8 ± 0.2, 5.9 ± 0.2, 8.0 ± 0.2, 11.2 ± 0.2, 12.3 ± 0.2, and 22.7 ± 0.2. In some aspects, crystalline Form IX is characterized by at least five X-ray powder diffraction pattern peaks at 20 angles selected from 3.8 ± 0.2, 5.9 ± 0.2, 8.0 ± 0.2, 11.2 ± 0.2, 12.3 ± 0.2, and 22.7 ± 0.2. In some aspects, crystalline Form IX is characterized by X-ray powder diffraction pattern peaks at 20 angles selected from 3.8 ± 0.2, 5.9 ± 0.2, 8.0 ± 0.2, 11.2 ± 0.2, 12.3 ± 0.2, and 22.7 ± 0.2. In some aspects, crystalline Form IX is characterized by at least one or at least two additional X-ray powder diffraction pattern peaks at 20 angles selected from 10.5 ± 0.2, 18.3 ± 0.2, and 18.8 ± 0.2. In some aspects, crystalline Form IX is characterized by at least three X-ray powder diffraction pattern peaks at 20 angles selected from those in Table 16. In some aspects, crystalline Form IX is characterized by an X-ray powder diffractogram substantially as shown in FIG. 19. In some aspects, crystalline Form IX is characterized by a differential scanning calorimetry thermogram having an endotherm with an onset temperature of about 124 °C. In some aspects, crystalline Form IX is an NMP solvate.

[0053] In one aspect, provided is crystalline Form X of a compound having the structural formula:or a pharmaceutically acceptable salt thereof, wherein the crystalline form is characterized by at least three X-ray powder diffraction pattern peaks at 20 angles selected from 10.1 ±0.2, 14.0 ± 0.2, 15.7 ± 0.2, 16.3 ± 0.2, 21.3 ± 0.2, and 22.0 ± 0.2. In some aspects, the crystalline Form X is characterized by at least four X-ray powder diffraction pattern peaks at 20 angles selected from 10.1 ± 0.2, 14.0 ± 0.2, 15.7 ± 0.2, 16.3 ± 0.2, 21.3 ± 0.2, and 22.0 ± 0.2. In some aspects, the crystalline Form X is characterized by at least five X-ray powder diffraction pattern peaks at 20 angles selected from 10.1 ± 0.2, 14.0 ± 0.2, 15.7 ± 0.2, 16.3 ± 0.2, 21.3 ± 0.2, and 22.0 ± 0.2. In some aspects, the crystalline Form X is characterized by X-ray powder diffraction pattern peaks at 20 angles selected from 10.1 ± 0.2, 14.0 ± 0.2, 15.7 ± 0.2, 16.3 ± 0.2, 21.3 ± 0.2, and 22.0 ± 0.2. In some aspects, the crystalline Form X is further characterized by at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or at least eight additional X-ray powder diffraction pattern peaks at 20 angles selected from 5.6 ± 0.2, 11.1 ± 0.2, 11.7 ± 0.2, 12.2 ± 0.2, 12.9 ± 0.2, 13.5 ± 0.2, 17.1 ± 0.2, 19.2 ± 0.2, and 20.1 ± 0.2. In some aspects, the crystalline Form X is characterized by at least three X-ray powder diffraction pattern peaks at 20 angles selected from those in Table 17. In some aspects, the crystalline Form X is characterized by an X-ray powder diffractogram substantially as shown in FIG. 21. In some aspects, the crystalline Form X is characterized by a differential scanning calorimetry thermogram having an endotherm with an onset temperature of about 136 °C. In some aspects, the crystalline Form X is an acetic acid solvate.

[0054] In one aspect, the crystalline forms described herein are at least 60% a single crystalline form, at least 70% a single crystalline form, at least 80% a single crystalline form, at least 90% a single crystalline form, at least 95% a single crystalline form, or at least 99% a single crystalline form by weight.

[0055] In one aspect, the crystalline forms described herein have a chemical purity of at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% by weight.

[0056] In one aspect, provided herein is an amorphous form of a compound having the structural formula:or a pharmaceutically acceptable salt thereof.

[0057] In some aspects, the amorphous form of Compound 1 is substantially free of crystalline forms of the compound.Uses, Formulation and Administration

[0058] Also provided are pharmaceutical compositions comprising one or more of the disclosed crystalline forms or the amorphous form; and a pharmaceutically acceptable carrier.

[0059] Compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.

[0060] The amount of provided crystalline form or amorphous form that may be combined with carrier materials to produce a composition in a single dosage form will vary depending upon the patient to be treated and the particular mode of administration.Provided compositions may be formulated such that a dosage of between 0.001 - 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0061] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated. The amount of a provided crystalline form in the composition will also depend upon the particular compound in the composition.

[0062] The crystalline and amorphous forms described herein are generally useful as anticancer therapies. In one aspect, the described crystalline and amorphous forms behave as inhibitors of KRAS(G12D). Their mechanisms of action include, but are not limited to, inhibiting KRAS(G12D) and thereby impeding down-stream signals that may result in inhibition of cancer cell growth and / or induction of cancer cell death or other KRAS or KRAS(G12D) functions. In one aspect, the described crystalline and amorphous forms effectuate the inhibition of KRAS(G12D).

[0063] Thus, provided herein are methods of treating conditions which are responsive to the inhibition of KRAS(G12D) comprising administering to a subject in need thereof, a therapeutically effective amount of one or more crystalline or amorphous forms describedherein. Also provided is the use of one or more crystalline or amorphous forms described herein in the manufacture of a medicament for treating conditions which are responsive to the inhibition of KRAS(G12D). Further provided is the use of a crystalline or amorphous form described herein for treating conditions which are responsive to the inhibition of KRAS(G12D).

[0064] In one aspect, the condition treated by the present compounds and compositions is a cancer. The terms "cancer" or "tumor" are well known in the art and refer to the presence, e.g., in a subject, of cells possessing characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, decreased cell death / apoptosis, and certain characteristic morphological features. Cancer cells are often in the form of a solid tumor. However, cancer also includes non-solid tumors, e.g., blood tumors, e.g., leukemia, wherein the cancer cells are derived from bone marrow. As used herein, the term "cancer" includes pre-malignant as well as malignant cancers. Cancers include, but are not limited to, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B- cell lymphoma, Burkitt's lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endothelio sarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphagioendothelio sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin and non-Hodgkin), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin, and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, non-small cell lung cancer, oligodendroglioma,oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor. Other cancers include primary cancer, metastatic cancer, oropharyngeal cancer, hypopharyngeal cancer, liver cancer, gall bladder cancer, bile duct cancer, small intestine cancer, urinary tract cancer, kidney cancer, urothelium cancer, female genital tract cancer, uterine cancer, gestational trophoblastic disease, male genital tract cancer, seminal vesicle cancer, testicular cancer, germ cell tumors, endocrine gland tumors, thyroid cancer, adrenal cancer, pituitary gland cancer, hemangioma, sarcoma arising from bone and soft tissues, Kaposi's sarcoma, nerve cancer, ocular cancer, meningial cancer, glioblastomas, neuromas, neuroblastomas, Schwannomas, solid tumors arising from hematopoietic malignancies such as leukemias, metastatic melanoma, recurrent or persistent ovarian epithelial cancer, fallopian tube cancer, primary peritoneal cancer, gastrointestinal stromal tumors, colorectal cancer, gastric cancer, melanoma, glioblastoma multiforme, non-squamous non-small-cell lung cancer, malignant glioma, epithelial ovarian cancer, primary peritoneal serous cancer, metastatic liver cancer, neuroendocrine carcinoma, refractory malignancy, triple negative breast cancer, HER2- amplified breast cancer, nasopharageal cancer, oral cancer, biliary tract, hepatocellular carcinoma, squamous cell carcinomas of the head and neck (SCCHN), non-medullary thyroid carcinoma, recurrent glioblastoma multiforme, neurofibromatosis type 1, CNS cancer, liposarcoma, leiomyosarcoma, salivary gland cancer, mucosal melanoma, acral / lentiginous melanoma, paraganglioma, pheochromocytoma, advanced metastatic cancer, solid tumor, triple negative breast cancer, colorectal cancer, sarcoma, melanoma, renal carcinoma, endometrial cancer, thyroid cancer, rhabdomysarcoma, multiple myeloma, ovarian cancer, glioblastoma, gastrointestinal stromal tumor, mantle cell lymphoma, and refractory malignancy.

[0065] Solid tumor," as used herein, is understood as any pathogenic tumor that can be palpated or detected using imaging methods as an abnormal growth having three dimensions. A solid tumor is differentiated from a blood tumor such as leukemia. However,cells of a blood tumor are derived from bone marrow; therefore, the tissue producing the cancer cells is a solid tissue that can be hypoxic.

[0066] "Tumor tissue” or “tumorous tissue" are understood as cells, extracellular matrix, and other naturally occurring components associated with the solid tumor.

[0067] The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.EXEMPLIFICATIONAbbreviations

[0068] Abbreviations which have been used in the descriptions of the schemes and the examples that follow are:

[0069] All other abbreviations used herein, which are not specifically delineated above, shall be accorded the meaning which one of ordinary skill in the art would attach.INSTRUMENT AND PARAMETERS

[0070] Polarized Light Microscopy (PLM)

[0071] Light microscopy analysis was performed using an ECLIPSE LV100POL (Nikon, JPN) microscope. Each sample was placed on a glass slide with a drop of immersion oil and covered with a glass slip. The sample was observed using a lOx objective with polarized light.

[0072] X-Ray Powder Diffraction (XRPD)

[0073] XRPD diffractograms were collected with an X-ray diffractometer. The sample was prepared on a zero-background silicon wafer by gently pressing onto the flat surface. The sample was analyzed with the parameters listed in Table 1.Table 1. Parameters of XRPD Test

[0074] Thermal Gravimetric Analysis (TGA)

[0075] TGA analysis was performed using a TA Instrument. About 1-3 mg of a sample was loaded onto a pre-tared aluminum pan and heated with the parameters given in Table . The data was analyzed using TRIOS.Table 2. Parameters of TGA Testing

[0076] Differential Scanning Calorimetry (DSC) and mDSC

[0077] DSC analysis was performed with a TA Instrument. About 1-3 mg of a sample was placed into an aluminum pan with pin-hole and heated with the parameters in Table 2. The data was analyzed using TRIOS.Table 2. Parameters of DSC Analysis

[0078] mDSC analysis was conducted using TA Instrument. About 1.39 mg sample was placed into an aluminum pan with pin-hole and heated with the parameters presented in Table 3.Table 3. Parameters of mDSC Analysis

[0079] 'H-NMR

[0080] 1H-NMR spectra were collected on a Bruker 400 MHz instrument. Unless specified, samples were prepared in DMSO-t / 6 solvent. As for solids obtained from DMSO, it was prepared in McOH-r / 4 to determine the content of residual DMSO. All the samples were measured with the parameters given in Table 4. The data was analyzed using MestReNova.Table 4. Parameters for 1H-NMR Analysis

[0081] Dynamic Vapor Sorption (DVS)

[0082] Moisture sorption / desorption data were collected on a DVS instrument. About 20 mg of sample was placed into a tared sample chamber and automatically weighed. The sample was analyzed with the setting parameters presented in Table .Table 6. Parameters of DVS Analysis

[0083] HPLC

[0084] HPLC analysis was performed with an Agilent HPLC 1260 series instrument.HPLC methods for stability testing of Form I and Form V are presented in Table .Table 7. HPLC Method for Stability EvaluationSynthetic Processes for Forming the Starting Material

[0085] Compound 1 was prepared following synthetic processes described below, and this material, assigned as “crystalline crude Form” was used the starting material for polymorph formation. The XRPD pattern of the crystalline crude Form is shown in FIG. 23 and appears to be a mixture of various crystalline forms. The crystalline crude Form showed about 1.9% of weight loss form 29 °C to 110 °C and 0.2% of weight loss from 110 °C to150 °C in TGA, and a corresponding broad endothermic peak at 83 °C and a small endothermic peak at 120 °C were detected by DSC, which was presumably caused by loss of water and residual solvent, respectively.

[0086] Scheme 1Compound 1

[0087] Step 1: Preparation of Compound b. To a solution of compound a (1.3 Kg, 2.77 mol, 1.0 eq.) in DCM (13.0 L, 13.0 V) was added TBAF (1 M, 533 ml, 0.20 eq.) at 25 ± 5 °C. Then the mixture solution was heated to 40 ± 5 °C. A solution of Oxone (2.55 Kg, 4.15 mol, 1.50 eq.) in H2O (10.4 L, 8.0 V) was added slowly over at least 6 hours into the mixture. Then m-CPBA (562 g, 2.77 mol, 1.0 eq.) was added e into the mixture. The reaction mixture was stirred at 20 + 5 °C for 8 hours and monitored by HPLC until compound a < 3%. The reaction mixture was separated and the aqueous layer was extracted once with DCM (3.9 L, 3.0 V). The organic layer was combined and washed twice with H2O (3.9 L, 3.0 V). 10% aq. Na2SOa (6.5 L, 5.0 V) was added drop-wise to the organic phase and stirred for at least 1 hours. Then the organic layer was separated and washed with H2O (6.5 L, 5.0 V) and 10% aq. NaCl (6.5 L, 5.0 V) separately, concentrated to 4-5 V blow 40 °C. IP Ac (10.4 L, 8.0 V) was added and the mixture was concentrated to 5-6 V.Additional IP Ac (10.4 L, 8.0V) was added to the mixture and stirred at 25 ± 5 °C for 2 hours. Then the mixture was cooled to 0 ± 5 °C for at least 6 hours. The cake was collected by filtration and washed with IP Ac (2.6 L, 2.0 V) and dried under vacuum for at least 8 hours maintaining 30 ± 10 °C to provide the desired compound b (1.15 Kg, 82.7% yield, HPLC, purity: 93.7%) as a white solid.JH NMR (400 MHz, CDCh) 5 4.32 (s, 2H), 4.11 (s, 3H), 3.95 - 3.43 (m, 2H), 3.38 (s, 3H), 3.37 - 3.21 (m, 1H), 1.97 - 1.63 (m, 4H), 1.52 (s, 9H). LCMS (ES, m / z): 502.12 [M+H]+.

[0088] Step 2: Preparation of Compound c. To a solution of compound 2A (720 g, 4.30 mol, 1.2 eq.) in toluene (18.0 L, 10.0 V) was charged t-BuONa (689 g, 7.17 mol, 2.00 eq.) in 5 portions at 0 ± 5 °C and stirred for at least 2 hours. Then compound b (1.80 Kg, 3.59 mol, 1.00 eq.) was added to the mixture at 0 ± 5 °C. The reaction mixture was stirred at least 2 hours and monitored by HPLC until compound b was < 1%. 10% aq. NH4CI (6.0 L) was charged slowly over at least 2 hours to the reaction mixture at 0 ± 5 °C and stirred for 2 hours. The organic layer was separated and EA (18.0 L, 10.0 V) was added to the organic phase. 10% aq. NaCl (6.0 L) was charged to the organic layer and stirred for at least 0.5 hour. The organic layer was washed with 10% aq. NaCl (6.0 L) and concentrated to 3-4 V blow 40 °C. n-hcptanc (18.0 L, 10.0 V) was added and the mixture was concentrated to 4-5 V. Additional n-hcptanc (18.0 L, 10.0 V) was added and the mixture was concentrated to 4- 5 V. n-heptane(18.0 L, 10.0 V) was added to the mixture, then cooled to 0 ± 5 °C and stirred for at least 6 hours. The cake was filtrated and washed twice with n-hcptanc (7.2 L, 4.0 V), dried under vacuum for at least 6 hours maintaining 35 ± 10 °C to provide the desired compound c (1.75 Kg, 82.9% yield, HPLC, purity: 96.5%) as a white solid. ’ H NMR (400 MHz, CDCh ) 5 4.28 (s, 4H), 4.05 (s, 3H), 3.68 - 3.27 (m, 2H), 3.03 (d, J = 8.5 Hz, 2H), 2.45 (s, 2H), 2.25 (d, J = 8.5 Hz, 2H), 1.87 (d, J= 8.0 Hz, 2H), 1.69 (d, J= 19.0 Hz, 2H), 1.28 (t, J = 5.3 Hz, 3H), 0.88 (q, J= 5.6, 4.7 Hz, 1H), 0.76 - 0.50 (m, 3H), 0.47 - 0.35 (m, 2H), 0.25 (td, J = 7.6, 3.8 Hz, 1H). LCMS (ES, / z) 588.26 [M+H]+.

[0089] Step 3: Preparation of Compound d. To a solution of compound c (1.50 Kg, 2.55 mol, 1.00 eq.), compound 3A (1.91 Kg, 2.06 mol, 1.20 eq.), K3PO4 (810 g, 3.82 mol, 1.50 eq.) in 1,4-dioxane (15.0 L, 10.0 V) and H2O (4.5 L, 3.0 V) under N2 at 25 + 5 °C was charged cataCXium A Pd G3 (92.0 g, 127 mmol, 0.05 eq.). The mixture was warmed to 60 + 5 °C and stirred for at least 3 hours and monitored by HPLC until compound c was < 1%. The reaction mixture was cooled to 25 + 5 °C. H2O (6.0 L) and EA (4.0 L) was added to the reaction mixture and stirred for 0.5 hours. The aqueous phase was separated and extractedwith EA (4.0 L). The organic phase was combined and washed with H2O (6.0 L) and 10% aq. NaCl (6.0 L), then concentrated to 4-5 V blow 50 °C. EA (15.0 L) was added to the mixture and concentrated to 1-2 V blow 50 °C. MeOH (20.0 L) was added to the mixture and stirred for at least 4 hours. The cake was filtrated and dried under vacuum for at least 6 hours maintaining 35 ±10 °C until LOD < 2% to provide the desired compound d (2.28 Kg, 85.1% yield, HPLC, purity: 97.8%) as a light yellow solid.1H-NMR(400 Hz, CDCh) 8 7.70 (dd, J = 9.0, 5.7 Hz, 1H), 7.28 (d, J = 2.3 Hz, 1H), 7.25 (d, J = 3.2 Hz, 2H), 4.72 (s, 1H), 4.27 (s, 3H), 3.98 (s, 3H), 3.58 (s, 2H), 3.22 (s, 1H), 3.06 (dd, J= 8.4, 3.3 Hz, 2H), 2.48 (s, 2H), 2.25 (d, J = 8.4 Hz, 2H), 2.11 (s, 1H), 1.89 (s, 2H), 1.51 (s, 10H), 1.40 - 1.19 (m, 6H), 1.13 (d, J= 7.2 Hz, 22H), 0.87 (dd, J = 7.4, 2.8 Hz, 20H), 0.75 - 0.51 (m, 4H), 0.42 (s, 2H). LCMS (ES, m / z): 1051.62 [M+H]+.

[0090] Step 4: Preparation of Compound e. To a solution of compound d (2.80 Kg, 2.66 mol, 1.00 eq.) in DMF (14.0 L, 5.0 V) at 25 ± 5 °C was charged CsF (2.83 Kg, 18.6 mol, 7.00 eq.) in portions. The mixture was stirred at 40 ± 5 °C for at least 20 hours and monitored by HPLC until compound d was < 0.5%. 10% aq. NH4CI (60.0 L) was charged to the reaction mixture and stirred for 0.5 hours. The aqueous phase was separated and extracted with EA (8.0 L) twice. The organic phase was combined and washed with 10% aq. NaCl (6.0 L) twice. Oxalic acid (280 g, 1.1 eq.) was added to the combined organic phase at 25 ± 5 °C and stirred for at least 14 hours. The cake was filtrated and washed with MTBE (1.0 L), dried under vacuum for at least 6 hours maintaining 35 ± 10 °C to provide the desired compound e (1.90 Kg, 86.2% yield, HPLC, purity: 97.3%) as a light yellow solid.1H-NMR(400 Hz, DMSO-d6) 8 7.94 (dd, J = 9.2, 5.9 Hz, 1H), 7.48 - 7.37 (m, 2H), 7.34 (s, OH), 7.26 (d, J= 2.5 Hz, 1H), 4.35 - 4.15 (m, 4H), 4.03 (d, J= 12.6 Hz, 1H), 3.94 (d, J= 1.1 Hz, 1H), 3.90 (s, 3H), 3.51 (d, J = 10.5 Hz, 2H), 3.36 (dd, J = 12.6, 6.3 Hz, 2H), 3.22 - 3.15 (m, 1H), 3.07 (d, J = 10.7 Hz, 3H), 1.78 (s, 3H), 1.64 (s, 3H), 1.43 (s, 9H), 1.25 - 1.11 (m, 1H), 1.07 (s, 3H), 0.82 - 0.67 (m, 5H), 0.58 (s, 1H). LCMS (ES, m / z) 739.33 [M+H]+.

[0091] Step 5: Preparation of Compound 1. To a solution of compound e (1.90 Kg, 2.29 mol, 1.00 eq.) in ACN (10.0 L, 5.2 V) at 0 + 5 °C was charged 30% H2S04 (10.0 L, 5.2 V) in portions. The mixture was stirred at 20 + 5 °C for 4 hours and monitored by HPLC until compound e was < 2%. 20% Na2COa aqueous (15.0 L) and MTBE (10.0 L) was added drop-wise to the reaction mixture at 0 + 10 °C, adjusted pH to 8-9 and then stirred for 0.5 hours. The cake was filtrated and washed with H2O (20.0 L). Slurry the cake with IPA (20.0L) at 45 ± 5°C. Then slurry the cake with H2O (20.0 L) at 20 ± 5 °C for at least 16 hours. After filtration, the cake was dried at 45 ± 10 °C to provide the compound 1 (1.60Kg, 65.9% yield, HPLC, purity: 98.3%) as a light yellow solid.1H-NMR(400 Hz, DMSO-de) 5 7.97 (dd, J = 9.2, 5.9 Hz, 1H), 7.46 (t, J = 9.0 Hz, 1H), 7.39 (d, J = 2.6 Hz, 1H), 7.24 (d, J = 2.5 Hz, 1H), 4.30 - 4.17 (m, 2H), 4.13 (d, J = 12.3 Hz, 1H), 3.87 (d, J = 11.6 Hz, 5H), 3.41 (d, J = 12.5 Hz, 1H), 3.34 (d, J = 12.4 Hz, 1H), 2.96 (dd, J = 8.6, 3.7 Hz, 2H), 2.46 - 2.29 (m, 2H), 2.28 - 2.17 (m, 2H), 1.70 - 1.51 (m, 4H), 1.30 (dt, J = 6.4, 3.0 Hz, 2H), 0.57 (q, J = 3.8 Hz, 3H), 0.38 (t, J = 2.9 Hz, 2H), 0.25 (td, J = 7.6, 3.7 Hz, 1H). LCMS (ES, m / z) 638.70 [M+H]+.Crystalline and Amorphous Form Preparations

[0092] In an effort to improve the characteristics and properties of Compound 1 for formulation development and administration, salt forms of Compound 1 were investigated. These included chloride, phosphate, sulfate, tosylate, oxalate, maleate, camphor sulfonate, gentisate, fumarate, 1,5-naphthalene, acetate and mesylate salts. Surprisingly, none of the these salts displayed particularly advantageous thermal properties based on DSC data or appeared of lower crystallinity. As such, the free base was selected for polymorph development due to its higher chemical stability than the investigated salts. Various solvents and different methods, including slurry, evaporation, anti-solvent precipitation and thermal treatments, were employed to find new crystalline forms. Ten crystalline forms were identified and assigned as Forms I-X as further detailed below.

[0093] Among them, Form I / II / VII are hydrates, Form V is an anhydrate, Form III is a hydrate / solvate, and Form I V / V 1 / VI I I / IX / X are solvates. Form I, VII and V had similar XRPD patterns. The characterization data suggested that Forms I / V / VII have the same packing arrangement and contain channels to accommodate water. The presence of water led to additional small XRPD diffraction peaks in Form I and VII, the water in the channel showed some variation when changes with humidity 0-90%RH. Extra XRPD peaks were observed in some samples, which might be associated with channels in the crystal lattice and how tightly water or solvent molecules interact with the compound through hydrogen binding. Competitive slurry study among the hydrates and anhydrate suggested that Form I was more stable at aw> 0.42. XRPD pattern similar with Form I was obtained at aw < 0.23 or in pure organic solvents. Form I remained unchanged after exposure to > 15%RH, and DVS data suggested that the water content varied from 3.2 to 5.2% at 10-90%RH. Form V 1is an anhydrate, which is stable under basic conditions and slightly hygroscopic by DVS. Solid-state stability study showed Form I and Form V was both physically and chemically stable under 40 °C / 75%RH (open) and 60 °C (capped) conditions for 1 week.Considering Form I, a channel hydrate, easily loss water under stressed conditions, Form I should be stored under RH > 15% and dried under certain humidity. Compared with Form I, Form V is an anhydrate and showed better solid-state properties, and is preferred for further development.

[0094] Example 1. Preparation of Amorphous Form of Compound 1

[0095] About 30 mg of crystalline crude Form was dissolved into 0.75ml HFIP at 50 °C. 2.25ml of H2O was dropwise added into the solution until it became turbid. Then the mixture was cooled to 25 °C. Solids precipitated out were filtered and characterized by XRPD. The wet cake was dried under vacuum condition at 40 °C for 2 h to afford the amorphous form. The amorphous form can also be obtained from evaporation in HFIP or from anti-solvent precipitation in DMSO / Water or HFIP / MTBE.

[0096] Example 2. Preparation of Form I of Compound 1

[0097] About 30 mg of crystalline crude Form was suspended in 0.8 mL of ACN / Water (19 / 1, v / v) at about 22 °C, stirred for 7 days, the solids (wet cake) were isolated by filtration using 0.22 pm membrane and injector, the wet solids were dried under vacuum condition at 40 °C for 1-2 hours to afford Form I. Form I is a sesquihydrate with calculated water content of 4.1%, which was obtained from water by slurry or anti-solvent precipitation in organic solvents containing water with aw> 0.42. About 2.6% of weight loss from 50 to 95 °C was observed in TGA, and a corresponding broad endothermic peak at 87 °C was detected by DSC, attributed to loss of water. Results showed that Form I showed 4.9% of water uptake at 80% RH and 5.2% at 90% RH. The water content of Form I varied from 3.2 to 5.2% (about 1 eq. to 2 eq.) at 10-90% RH. The dynamic phase boundary between Form I and the dehydrated form is likely close to 10% RH. XRPD peaks lists of Form I are presented in Table .Table 8. XRPD Peaks Lists of Form I

[0098] Example 3. Preparation of Form II of Compound (I)

[0099] About 30 mg of crystalline crude Form was suspended in 0.8 mL of ACN / Water (19 / 1, v / v) at about 22 °C, and then 1.1 eq. of p-toluenesulfonic acid was added. Oil was observed initially, and it became suspension mixed with trace oil after stirring for 21 h at about 22 °C. Solids were collected by filtration and dried under vacuum condition at 40 °C for 2-3 h to afford Form II. About 3.0% of weight loss prior to 100 °C and 0.3% of weight loss from 100 °C to 140 °C was observed in TGA, and a corresponding broad endothermic peak at 73 °C and small endothermic peak at 118 °C were detected by DSC, likely due to loss of water. XRPD peaks lists of Form II are presented in Table .Table 9. XRPD Peaks Lists of Form II

[0100] Example 4. Preparation of Form III of Compound (I)

[0101] About 30 mg of crystalline crude Form was suspended in 0.5 mL of ACN / W ater (19 / 1, v / v) at about 22 °C, and then 1.1 eq. of L-tartaric acid was added. Suspension was obtained initially, and it became oil after stirring for 24 h at RT, then it was transferred to 50 °C and kept stirring for 7 d. It was still oil, then it became suspension after stirring for 2 d at 50 °C. Solids were collected by filtration and dried under vacuum condition at 40 °C for 2 h to afford Form III. About 2.7% of weight loss at 40-100 °C and 2.5% of weight loss at 100- 170 °C due to loss of water and solvent was observed. There were three endothermic peaks with peak temperature at 78 °C, 118 °C and 190 °C observed in DSC. XRPD peaks lists of Form III represented in Table .Table 10. XRPD Peaks Lists of Form III

[0102] Example 5. Preparation of Form IV of Compound (I)

[0103] About 30 mg of crystalline crude Form was suspended in 0.6 mL of anisole and kept stirring at 80°C for 4 days. At Day 4, the solids (wet cake) were isolated by filtration using 0.22 pm membrane and injector, and then tested by XRPD to determine the crystal form. The wet solids were dried under vacuum condition at 40 °C for 1-2 hours to afford Form IV. About 8.7% of anisole residue was detected by 1H-NMR. TGA showed 1.3% of weight loss at 38-90 °C and 6.0% of weight loss at 90-170 °C, due to loss of solvent, which caused two endothermic peaks with peak temperature at 58 °C and 140 °C in DSC. XRPD peaks lists of Form IV are presented in Table .Table 11. XRPD Peaks Lists of Form IV

[0104] Example 6. Preparation of Form V of Compound (I)

[0105] About 30 mg of crystalline crude Form was dissolved in 2-MeTHF (7.5 V) andDMSO (2.5 V) at 25+5 °C, and stirred for at least 6 hours, and then the mixture of IPA (6.0v), H20 (4.0 v) and Ammonia (1.0 eq.) was charged drop- wise to the reaction mixture. The mixture was stirred for at least 6 hours at 25+5 °C. After filtration, the wet cake was slurried with DMSO (10 v) at 50+5 °C for at least 4 hours. After filtration, the wet cake was slurried with IPA (10 v) at 25+5 °C for at least 4 hours. After filtration, the wet cake was slurried with purified water (10 v) at 25+5 °C for at least 4 hours. After filtration, the wet cake was dried at 60+10 °C for at least 8 hours under vacuum to afford Form V. By TGA, about 0.33% of weight loss was detected from 31 °C to 50 °C, related with IPA residue and water. No obvious endotherm was observed in DSC. DVS results showed that Form V was slightly hygroscopic with 1.2% of water uptake at 80% RH and 1.3% at 90% RH. XRPD peaks lists of Form V are presented in Table .

[0106] Form V can also be prepared from alkaline conditions, like solvents with addition of base, such as NaOH, Na2COa, NaHCOa, meglumine, and ammonia; or by slurrying in alkaline solution at RT. In one embodiment, Form V was prepared from ACN / Water (19 / 1, v / v) with addition of 1.1 eq. of NaOH. In another embodiment, Form V was prepared using mechanical paddle by anti-solvent precipitation from DMSO / 2-Me- THF / IPA / water with addition of 1 eq. of ammonia.Table 12. XRPD Peaks Lists of Form V

[0107] Example 7. Preparation of Form VI of Compound (I)

[0108] About 30 mg of crystalline crude Form was suspended in 0.6 mL of DMSO and kept stirring at RT (about 23 °C) for 7 days. At Day 7, the solids (wet cake) were isolated by filtration using 0.22 pm membrane and injector, the wet solids were dried under vacuum condition at 40 °C for 1-2 hours to afford Form VI. XRPD peaks lists of Form VI are presented in Table . Form VI can also be prepared from similar conditions using MeOH, IPA, acetone, EtOAc, ACN, or 2-Me-THF. Form VI converted to Form V or a mixture of Form V and VI once the solids were exposed to ambient condition.Table 13. XRPD Peaks Lists of Form VI

[0109] Example 8. Preparation of Form VII of Compound 1

[0110] About 30 mg of crystalline crude Form was suspended in 0.6 mL of ACN and kept stirring at RT (about 23 °C) for 7 days. The solids (wet cake) were isolated by filtration using 0.22 pm membrane and injector, the wet solids were dried under vacuum condition at 40 °C for 4 days to afford Form VII. Form I with trace Form VII was obtained after DVS analysis, indicating that Form VII converted to Form I at high humidity during DVS testing. Form VII is a hydrate containing lower water content, compared with Form I, Form VII converted to Form I, likely due to dehydrated form easily absorbed moisture and converted to the hydrate Form I under high humidity (73%RH). XRPD peaks lists of Form VII are presented in Table .Table 14. XRPD Peaks Lists of Form VII

[0111] Example 9. Preparation of Form VIII of Compound 1

[0112] About 30 mg of crystalline crude Form was suspended in 0.6 mL of MTBE and kept stirring at RT (about 23 °C) for 7 days. At Day 7, the solids (wet cake) were isolated by filtration using 0.22 m membrane and injector, the wet solids were dried under vacuum condition at 40 °C for 1-2 hours to afford Form VIII. About 2.3% of weight loss from 35 °C to 70 °C and 16.5% of weight loss from 70 °C to 180 °C were detected by TGA, and three endothermic peaks with peak temperature at 70 °C, 110 °C and 149 °C were detected in DSC. XRPD peaks lists of Form VIII are presented in Table . Form VIII is likely a solvate.Table 15. XRPD Peaks Lists of Form VIII

[0113] Example 10. Preparation of Form IX of Compound 1

[0114] About 30 mg of crystalline crude Form was dissolved or nearly dissolved into0.6 ml of NMP, then thin suspensions were observed and filtered using injector with 0.22 pm membrane or centrifugated with 10000 rpm / min for 2 min. 1.2 ml of MTBE was dropwise added into drug solution until it became turbid and kept stirring at RT (about 23 °C) for 3 days. Solids precipitated out were filtered. The wet cake was dried under vacuum condition at 40 °C for 2 h to afford Form IX. There were 0.9% of residual MTBE and 7.2% of NMP detected by1H-NMR. TGA showed 1.9% of weight loss from 40 °C to 95 °C and 7.0% of weight loss from 95 °C to 190 °C, attributed to loss of solvent. Two correspondingendothermic peaks with peak temperature of 55 °C and 155 °C were observed in DSC.XRPD peaks lists of Form IX are presented in Table .Table 16. XRPD Peaks Lists of Form IX

[0115] Example 11. Preparation of Form X of Compound 1

[0116] About 30 mg of crystalline crude Form was dissolved or nearly dissolved into 0.6 ml of HAc, then thin suspensions were observed and filtered using injector with 0.22 pm membrane or centrifugated with 10000 rpm / min for 2 min. 0.4 ml of MTBE was dropwise added into drug solution until it became turbid and kept stirring at RT (about 23 °C) for 3 days. Solids precipitated out were filtered. The wet cake was dried under vacuum condition at 40 °C for 2 h to afford Form X. There were 0.8% of residual MTBE and 27% of HAc detected by1H-NMR. TGA showed 1.4% of weight loss from 35 to 80 °C and 22.4% of weight loss from 80 to 200 °C, attributed to loss of water and residual solvent.Two corresponding endothermic peaks with peak temperature of 47 °C and 177 °C were observed in DSC. XRPD peaks lists of Form X are presented in Table .Table 17. XRPD Peaks Lists of Form X

[0117] Example 12. Accelerated Solid-state Stability Study of Form I

[0118] Form I is a channel hydrate. To avoid moisture uptake from air, the sample obtained from 60 °C (capped) was covered by mylar and then analyzed by XRPD. The results are summarized and presented in Table 18. Form I was both physically and chemically stable under these stressed conditions for 7 days, as its crystal form remained as Form I and no obvious degradation was detected by HPLC.Table 18. Accelerated Solid-state Stability Study of Form I

[0119] Example 13. Accelerated Solid-state Stability Study of Form V

[0120] As shown in Table 19, Form V was both physically and chemically stable under 40 °C&75% RH (open) condition and 60 °C (capped) stressed conditions for 7 days, as its crystal form remained as Form V and no obvious degradation was detected by HPLC.Table 19. Accelerated Solid-state Stability Study of Form V

[0121] Although the disclosure has been described in connection with specific embodiments, it should be understood that the disclosure as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the disclosure are intended and understood by those skilled in the relevant field in which this disclosure resides to be within the scope of the disclosure as represented by the following claims.

[0122] All patents and publications mentioned in this specification are herein incorporated by reference to the same extent as if each independent patent and publication was specifically and individually indicated to be incorporated by reference.

Claims

CLAIMS1. A crystalline form of a compound having the structural formula:or a pharmaceutically acceptable salt thereof.

2. The crystalline form of Claim 1, wherein the crystalline form is crystalline Form I characterized by at least three X-ray powder diffraction pattern peaks at 20 angles selected from 7.3 ± 0.2, 11.7 + 0.2, 12.9 + 0.2, 16.4 + 0.2, and 20.9 + 0.2.

3. The crystalline form of Claim 1 or 2, wherein the crystalline form is crystalline Form I characterized by at least four X-ray powder diffraction pattern peaks at 20 angles selected from 7.3 + 0.2, 11.7 + 0.2, 12.9 + 0.2, 16.4 + 0.2, and 20.9 + 0.2.

4. The crystalline form of any one of Claims 1 to 3, wherein the crystalline form is crystalline Form I characterized by X-ray powder diffraction pattern peaks at 20 angles selected from 7.3 + 0.2, 11.7 + 0.2, 12.9 + 0.2, 16.4 + 0.2, and 20.9 + 0.2.

5. The crystalline form of any one of Claims 1 to 4, wherein the crystalline Form I is further characterized by at least one, at least two, at least three, at least four, at least five, or at least six additional X-ray powder diffraction pattern peaks at 20 angles selected from 10.8 + 0.2, 12.7 + 0.2, 17.0 + 0.2, 18.9 + 0.2, 20.1 + 0.2, 20.4 + 0.2, 25.0 + 0.2, and 26.8+ 0.2.

6. The crystalline form of any one of Claims 1 to 5, wherein the crystalline Form I is characterized by an X-ray powder diffractogram substantially as shown in FIG. 3.

7. The crystalline form of any one of Claims 1 to 6, wherein the crystalline Form I is characterized by a differential scanning calorimetry thermogram having an endotherm with an onset temperature of about 236 °C.

8. The crystalline form of any one of Claims 1 to 7, wherein the crystalline Form I is a hydrate.

9. The crystalline form of any one of Claims 1 to 8, wherein the crystalline Form I is a channel hydrate.

10. The crystalline form of any one of Claims 1 to 8, wherein the crystalline Form I is a sesquihydrate.

11. The crystalline form of Claim 1, wherein the crystalline form is crystalline Form II characterized by at least three X-ray powder diffraction pattern peaks at 20 angles selected from 7.7 ± 0.2, 11.3 + 0.2, 12.1 + 0.2, 13.6 + 0.2, and 17.9 + 0.2.

12. The crystalline form of Claim 1 or 11, wherein the crystalline form is crystalline Form II characterized by at least four X-ray powder diffraction pattern peaks at 20 angles selected from 7.7 + 0.2, 11.3 + 0.2, 12.1 + 0.2, 13.6 + 0.2, and 17.9 + 0.2.

13. The crystalline form of any one of Claims 1, 11, and 12, wherein the crystalline form is crystalline Form II characterized by X-ray powder diffraction pattern peaks at 20 angles selected from 7.7 + 0.2, 11.3 + 0.2, 12.1 + 0.2, 13.6 + 0.2, and 17.9 + 0.2.

14. The crystalline form of any one of Claims 1 and 11 to 13, wherein the crystalline Form II is further characterized by at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, or at least twelve additional X-ray powder diffraction pattern peaks at 20 angles selected from 8.1 + 0.2, 9.2 + 0.2, 9.7 + 0.2, 15.6 + 0.2, 16.4 + 0.2, 17.1 + 0.2, 19.6 + 0.2, 21.6 + 0.2, 22.1 + 0.2, 22.7 + 0.2, 23.0 + 0.2, 23.4 + 0.2, and 24.9 + 0.2.

15. The crystalline form of any one of Claims 1 and 11 to 14, wherein the crystalline Form II is characterized by an X-ray powder diffractogram substantially as shown in FIG. 5.

16. The crystalline form of any one of Claims 1 and 11 to 15, wherein the crystalline Form II is characterized by a differential scanning calorimetry thermogram having an endotherm with an onset temperature of about 118 °C.

17. The crystalline form of any one of Claims 1 and 11 to 16, wherein the crystalline Form II is a hydrate18. The crystalline form of Claim 1, wherein the crystalline form is crystalline Form III characterized by at least three X-ray powder diffraction pattern peaks at 20 angles selected from 7.8 ± 0.2, 11.9 + 0.2, 12.4 + 0.2, 17.0 + 0.2, 17.4 + 0.2, and 17.9 + 0.2.

19. The crystalline form of Claim 1 or 18, wherein the crystalline form is crystalline Form III characterized by at least four X-ray powder diffraction pattern peaks at 20 angles selected from 7.8 + 0.2, 11.9 + 0.2, 12.4 + 0.2, 17.0 + 0.2, 17.4 + 0.2, and 17.9 + 0.2.

20. The crystalline form of any one of Claims 1, 18, and 19, wherein the crystalline form is crystalline Form III characterized by at least five X-ray powder diffraction pattern peaks at 20 angles selected from 7.8 + 0.2, 11.9 + 0.2, 12.4 + 0.2, 17.0 + 0.2, 17.4 + 0.2, and 17.9 + 0.2.

21. The crystalline form of any one of Claims 1 and 18 to 20, wherein the crystalline form is crystalline Form III characterized by X-ray powder diffraction pattern peaks at 20 angles selected from 7.8 + 0.2, 11.9 + 0.2, 12.4 + 0.2, 17.0 + 0.2, 17.4 + 0.2, and 17.9 + 0.2.

22. The crystalline form of any one of Claims 1 and 18 to 21, wherein the crystalline Form III is further characterized by at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, and at least eleven additional X-ray powder diffraction pattern peaks at 20 angles selected from 8.5 + 0.2, 9.7 + 0.2, 10.5 + 0.2, 11.7 + 0.2, 13.8 + 0.2, 15.2 + 0.2, 19.6 + 0.2, 20.5 + 0.2, 21.7 + 0.2, 22.7 + 0.2, 23.0 + 0.2, and 25.0 + 0.2.

23. The crystalline form of any one of Claims 1 and 18 to 22, wherein the crystalline Form III is characterized by an X-ray powder diffractogram substantially as shown in FIG.7.

24. The crystalline form of any one of Claims 1 and 18 to 23, wherein the crystalline Form III is characterized by a differential scanning calorimetry thermogram having an endotherm with an onset temperature of about 182 °C.

25. The crystalline form of any one of Claims 1 and 18 to 24, wherein the crystalline Form III is a hydrate.

26. The crystalline form of any one of Claims 1 and 18 to 25, wherein the crystalline Form III is an L-tartaric acid salt.

27. The crystalline form of Claim 1, wherein the crystalline form is crystalline Form IV characterized by at least three X-ray powder diffraction pattern peaks at 20 angles selected from 6.8 ± 0.2, 18.4 ± 0.2, 20.4 ± 0.2, 20.7 ± 0.2, 21.7 ± 0.2, and 24.8 ± 0.2.

28. The crystalline form of Claim 1 or 27, wherein the crystalline form is crystalline Form IV characterized by at least four X-ray powder diffraction pattern peaks at 20 angles selected from 6.8 ± 0.2, 18.4 ± 0.2, 20.4 ± 0.2, 20.7 ± 0.2, 21.7 ± 0.2, and 24.8 ± 0.2.

29. The crystalline form of any one of Claims 1, 27, and 28, wherein the crystalline form is crystalline Form IV characterized by at least five X-ray powder diffraction pattern peaks at 20 angles selected from 6.8 ± 0.2, 18.4 ± 0.2, 20.4 ± 0.2, 20.7 ± 0.2, 21.7 ± 0.2, and 24.8 ± 0.2.

30. The crystalline form of any one of Claims 1 and 27 to 29, wherein the crystalline form is crystalline Form IV characterized by X-ray powder diffraction pattern peaks at 20 angles selected from 6.8 ± 0.2, 18.4 ± 0.2, 20.4 ± 0.2, 20.7 ± 0.2, 21.7 ± 0.2, and 24.8 ± 0.2.

31. The crystalline form of any one of Claims 1 and 27 to 30, wherein the crystalline Form IV is further characterized by at least one, at least two, at least three, at least four, atleast five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, and at least sixteen additional X-ray powder diffraction pattern peaks at 20 angles selected from 9.7 ± 0.2, 11.2 + 0.2, 12.0 + 0.2, 12.3 + 0.2, 12.8 + 0.2, 13.7 + 0.2, 14.0 + 0.2, 15.4 + 0.2, 15.8 + 0.2, 16.3 + 0.2, 17.0 + 0.2, 17.5 + 0.2, 19.1 + 0.2, 19.6 + 0.2, 19.8 + 0.2, 22.2 + 0.2, and 23.0 + 0.2.

32. The crystalline form of any one of Claims 1 and 27 to 31, wherein the crystalline Form IV is characterized by an X-ray powder diffractogram substantially as shown in FIG.9.

33. The crystalline form of any one of Claims 1 and 27 to 32, wherein the crystalline Form IV is characterized by a differential scanning calorimetry thermogram having an endotherm with an onset temperature of about 110 °C.

34. The crystalline form of any one of Claims 1 and 27 to 33, wherein the crystalline Form IV is an anisole solvate.

35. The crystalline form of Claim 1, wherein the crystalline form is crystalline Form V characterized by at least three X-ray powder diffraction pattern peaks at 20 angles selected from 7.2 ± 0.2, 11.7 + 0.2, 13.0 + 0.2, 16.4 + 0.2, 20.4 + 0.2, and 21.0 + 0.2.

36. The crystalline form of Claim 1 or 35, wherein the crystalline form is crystalline Form V characterized by at least four X-ray powder diffraction pattern peaks at 20 angles selected from 7.2 + 0.2, 11.7 + 0.2, 13.0 + 0.2, 16.4 + 0.2, 20.4 + 0.2, and 21.0 + 0.2.

37. The crystalline form of any one of Claims 1, 35, and 36, wherein the crystalline form is crystalline Form V characterized by at least five X-ray powder diffraction pattern peaks at 20 angles selected from 7.2 + 0.2, 11.7 + 0.2, 13.0 + 0.2, 16.4 + 0.2, 20.4 + 0.2, and 21.0 + 0.2.

38. The crystalline form of any one of Claims 1 and 35 to 37, wherein the crystalline form is crystalline Form V characterized by X-ray powder diffraction pattern peaks at 20 angles selected from 7.2 + 0.2, 11.7 + 0.2, 13.0 + 0.2, 16.4 + 0.2, 20.4 + 0.2, and 21.0 + 0.2.

39. The crystalline form of any one of Claims 1 and 35 to 38, wherein the crystalline Form V is further characterized by at least one or at least two additional X-ray powder diffraction pattern peaks at 20 angles selected from 14.6 ± 0.2, 20.1 ± 0.2, and 26.7 ± 0.2.

40. The crystalline form of any one of Claims 1 and 35 to 39, wherein the crystalline Form V is characterized by an X-ray powder diffractogram substantially as shown in FIG. 11.

41. The crystalline form of any one of Claims 1 and 35 to 40, wherein the crystalline Form V is characterized by a differential scanning calorimetry thermogram substantially as shown in FIG. 12.

42. The crystalline form of any one of Claims 1 and 35 to 41, wherein the crystalline Form V is an anhydrate.

43. The crystalline form of Claim 1, wherein the crystalline form is crystalline Form VI characterized by at least three X-ray powder diffraction pattern peaks at 20 angles selected from 6.8 ± 0.2, 13.7 ± 0.2, 18.1 ± 0.2, 19.4 ± 0.2, 20.7 ± 0.2, and 24.9 ± 0.2.

44. The crystalline form of Claim 1 or 43, wherein the crystalline form is crystalline Form VI characterized by at least four X-ray powder diffraction pattern peaks at 20 angles selected from 6.8 ± 0.2, 13.7 ± 0.2, 18.1 ± 0.2, 19.4 ± 0.2, 20.7 ± 0.2, and 24.9 ± 0.2.

45. The crystalline form of any one of Claims 1, 43, and 44, wherein the crystalline form is crystalline Form VI characterized by at least five X-ray powder diffraction pattern peaks at 20 angles selected from 6.8 ± 0.2, 13.7 ± 0.2, 18.1 ± 0.2, 19.4 ± 0.2, 20.7 ± 0.2, and 24.9 ± 0.2.

46. The crystalline form of any one of Claims 1 and 43 to 45, wherein the crystalline form is crystalline Form VI characterized by X-ray powder diffraction pattern peaks at 20 angles selected from 6.8 ± 0.2, 13.7 ± 0.2, 18.1 ± 0.2, 19.4 ± 0.2, 20.7 ± 0.2, and 24.9 ± 0.2.

47. The crystalline form of any one of Claims 1 and 43 to 46, wherein the crystallineForm VI is further characterized by at least one, at least two, at least three, at least four, at least five, or at least six additional X-ray powder diffraction pattern peaks at 20 angles selected from 12.3 ± 0.2, 16.1 ± 0.2, 19.0 ± 0.2, 21.7 ± 0.2, 22.1 ± 0.2, 22.8 ± 0.2, and 23.6 ± 0.2.

48. The crystalline form of any one of Claims 1 and 43 to 47, wherein the crystalline Form VI is characterized by an X-ray powder diffractogram substantially as shown in FIG. 13.

49. The crystalline form of any one of Claims 1 and 43 to 48, wherein the crystalline Form VI is characterized by a differential scanning calorimetry thermogram having an endotherm with an onset temperature of about 94 °C.

50. The crystalline form of any one of Claims 1 and 43 to 49, wherein the crystalline Form VI is a solvate.

51. The crystalline form of Claim 1, wherein the crystalline form is crystalline Form VII characterized by at least three X-ray powder diffraction pattern peaks at 20 angles selected from 7.3 ± 0.2, 11.7 ± 0.2, 12.9 ± 0.2, 16.4 ± 0.2, and 20.9 ± 0.2.

52. The crystalline form of Claim 1 or 51, wherein the crystalline form is crystalline Form VII characterized by at least four X-ray powder diffraction pattern peaks at 20 angles selected from 7.3 ± 0.2, 11.7 ± 0.2, 12.9 ± 0.2, 16.4 ± 0.2, and 20.9 ± 0.2.

53. The crystalline form of any one of Claims 1, 51, and 52, wherein the crystalline form is crystalline Form VII characterized by X-ray powder diffraction pattern peaks at 20 angles selected from 7.3 ± 0.2, 11.7 ± 0.2, 12.9 ± 0.2, 16.4 ± 0.2, and 20.9 ± 0.2.

54. The crystalline form of any one of Claims 1 and 51 to 53, wherein the crystalline Form VII is further characterized by at least one, at least two, or at least three additional X- ray powder diffraction pattern peaks at 20 angles selected from 12.7 ± 0.2, 20.1 ± 0.2, 20.4 ± 0.2, and 26.8 ± 0.2.

55. The crystalline form of any one of Claims 1 and 51 to 54, wherein the crystalline Form VII is characterized by an X-ray powder diffractogram substantially as shown in FIG.15.

56. The crystalline form of any one of Claims 1 and 51 to 55, wherein the crystalline Form VII is characterized by an X-ray powder diffractogram substantially as shown in FIG.16.

57. The crystalline form of any one of Claims 1 and 51 to 56, wherein the crystalline Form VII is a hydrate58. The crystalline form of Claim 1, wherein the crystalline form is crystalline Form VIII characterized by at least three X-ray powder diffraction pattern peaks at 20 angles selected from 3.6 + 0.2, 6.8 + 0.2, 10.3 + 0.2, 13.8 + 0.2, 18.1 + 0.2, and 21.0 + 0.2.

59. The crystalline form of Claim 1 or 58, wherein the crystalline form is crystalline Form VIII characterized by at least four X-ray powder diffraction pattern peaks at 20 angles selected from 3.6 ± 0.2, 6.8 ± 0.2, 10.3 ± 0.2, 13.8 ± 0.2, 18.1 ± 0.2, and 21.0 ± 0.2.

60. The crystalline form of any one of Claims 1, 58, and 59, wherein the crystalline form is crystalline Form VIII characterized by at least five X-ray powder diffraction pattern peaks at 20 angles selected from 3.6 ± 0.2, 6.8 ± 0.2, 10.3 ± 0.2, 13.8 ± 0.2, 18.1 ± 0.2, and 21.0 + 0.2.

61. The crystalline form of any one of Claims 1 and 58 to 60, wherein the crystalline form is crystalline Form VIII characterized by X-ray powder diffraction pattern peaks at 20 angles selected from 3.6 + 0.2, 6.8 + 0.2, 10.3 + 0.2, 13.8 + 0.2, 18.1 + 0.2, and 21.0 + 0.2.

62. The crystalline form of any one of Claims 1 and 58 to 61, wherein the crystalline Form VIII is further characterized by at least one, at least two, or at least three additional X- ray powder diffraction pattern peaks at 20 angles selected from 11.7 + 0.2, 14.7 + 0.2, 19.1 + 0.2, and 23.6 + 0.2.

63. The crystalline form of any one of Claims 1 and 58 to 62, wherein the crystalline Form VIII is characterized by an X-ray powder diffractogram substantially as shown inFIG. 17.

64. The crystalline form of any one of Claims 1 and 58 to 63, wherein the crystalline Form VIII is characterized by a differential scanning calorimetry thermogram having an endotherm with an onset temperature of about 126 °C.

65. The crystalline form of any one of Claims 1 and 58 to 64, wherein the crystalline Form VIII is a solvate.

66. The crystalline form of Claim 1, wherein the crystalline form is crystalline Form IX characterized by at least three X-ray powder diffraction pattern peaks at 20 angles selected from 3.8 ± 0.2, 5.9 ± 0.2, 8.0 ± 0.2, 11.2 ± 0.2, 12.3 ± 0.2, and 22.7 ± 0.2.

67. The crystalline form of Claim 1 or 66, wherein the crystalline form is crystalline Form IX characterized by at least four X-ray powder diffraction pattern peaks at 20 angles selected from 3.8 ± 0.2, 5.9 ± 0.2, 8.0 ± 0.2, 11.2 ± 0.2, 12.3 ± 0.2, and 22.7 ± 0.2.

68. The crystalline form of any one of Claims 1, 66, and 67, wherein the crystalline form is crystalline Form IX characterized by at least five X-ray powder diffraction pattern peaks at 20 angles selected from 3.8 ± 0.2, 5.9 ± 0.2, 8.0 ± 0.2, 11.2 ± 0.2, 12.3 ± 0.2, and 22.7 ± 0.2.

69. The crystalline form of any one of Claims 1 and 55 to 68, wherein the crystalline form is crystalline Form IX characterized by X-ray powder diffraction pattern peaks at 20 angles selected from 3.8 ± 0.2, 5.9 ± 0.2, 8.0 ± 0.2, 11.2 ± 0.2, 12.3 ± 0.2, and 22.7 ± 0.2.

70. The crystalline form of any one of Claims 1 and 66 to 69, wherein the crystalline Form IX is further characterized by at least one or at least two additional X-ray powder diffraction pattern peaks at 20 angles selected from 10.5 ± 0.2, 18.3 ± 0.2, and 18.8 ± 0.2.

71. The crystalline form of any one of Claims 1 and 66 to 70, wherein the crystalline Form IX is characterized by an X-ray powder diffractogram substantially as shown in FIG. 19.'ll. The crystalline form of any one of Claims 1 and 66 to 71, wherein the crystalline Form IX is characterized by a differential scanning calorimetry thermogram having an endotherm with an onset temperature of about 124 °C.

73. The crystalline form of any one of Claims 1 and 66 to 72, wherein the crystalline Form IX is NMP solvate.

74. The crystalline form of Claim 1, wherein the crystalline form is crystalline Form X characterized by at least three X-ray powder diffraction pattern peaks at 20 angles selected from 10.1 ± 0.2, 14.0 ± 0.2, 15.7 ± 0.2, 16.3 ± 0.2, 21.3 ± 0.2, and 22.0 ± 0.2.

75. The crystalline form of Claim 1 or 74, wherein the crystalline form is crystalline Form X characterized by at least four X-ray powder diffraction pattern peaks at 20 angles selected from 10.1 ± 0.2, 14.0 ± 0.2, 15.7 ± 0.2, 16.3 ± 0.2, 21.3 ± 0.2, and 22.0 ± 0.2.

76. The crystalline form of any one of Claims 1, 74, and 75, wherein the crystalline form is crystalline Form X characterized by at least five X-ray powder diffraction pattern peaks at 20 angles selected from 10.1 ± 0.2, 14.0 ± 0.2, 15.7 ± 0.2, 16.3 ± 0.2, 21.3 ± 0.2, and 22.0 ± 0.2.

77. The crystalline form of any one of Claims 1 and 74 to 76, wherein the crystalline form is crystalline Form X characterized by X-ray powder diffraction pattern peaks at 20 angles selected from 10.1 ± 0.2, 14.0 ± 0.2, 15.7 ± 0.2, 16.3 ± 0.2, 21.3 ± 0.2, and 22.0 ± 0.2.

78. The crystalline form of any one of Claims 1 and 74 to 77, wherein the crystalline Form X is further characterized by at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or at least eight additional X-ray powder diffractionpattern peaks at 20 angles selected from 5.6 ± 0.2, 11.1 ± 0.2, 11.7 ± 0.2, 12.2 ± 0.2, 12.9 ± 0.2, 13.5 ± 0.2, 17.1 ± 0.2, 19.2 ± 0.2, and 20.1 ± 0.2.

79. The crystalline form of any one of Claims 1 and 74 to 78, wherein the crystalline Form X is characterized by an X-ray powder diffractogram substantially as shown in FIG.21.

80. The crystalline form of any one of Claims 1 and 74 to 79, wherein the crystalline Form X is characterized by a differential scanning calorimetry thermogram having an endotherm with an onset temperature of about 136 °C.

81. The crystalline form of any one of Claims 1 and 74 to 79, wherein the crystalline Form X is an acetic acid solvate.

82. The crystalline form of any one of Claims 1 to 81, wherein the crystalline form is at least 95% a single crystalline form, at least 98% a single crystalline form, or at least 99% a single crystalline form by weight.

83. An amorphous form of a compound having the structural formula:or a pharmaceutically acceptable salt thereof.

84. The amorphous Form of Claim 83, wherein the compound is substantially free of crystalline forms of the compound.

85. A pharmaceutical composition comprising the crystalline form of any one of Claims 1 to 82, or the amorphous form of Claim 83 or 84; and a pharmaceutically acceptable carrier.

86. A method for treating cancer in a subject comprising administering to the subject and effective amount of the crystalline form of any one of Claims 1 to 82, or the amorphous form of Claim 83 or 84, or the pharmaceutically acceptable composition of Claim 85.

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