WO2017011720A1

WO2017011720A1 - Solod forms 4-((4-(cyclopentyloxy)-5-(2-methylbenzo[d] oxazol-6-yl)17h-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-n-methylbenzamide, compositions thereof and methods of their use

Info

Publication number: WO2017011720A1
Application number: PCT/US2016/042405
Authority: WO
Inventors: Ying Li; Alexander L. Ruchelman; Jean Xu
Original assignee: Signal Pharmaceuticals, Llc
Priority date: 2015-07-16
Filing date: 2016-07-15
Publication date: 2017-01-19

Abstract

Provided herein are solid forms of 4-((4-(cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6- yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide, compositions thereof, and methods of their use for treating or preventing a cancer, in particular solid tumors and hematological cancers as described herein.

Description

SOLID FORMS OF 4-((4-(CYCLOPENTYLOXY)-5-(2-METHYLBENZO[Z)]OXAZOL-6-

YL)-7H-PYRROLO[2,3-Z⁾]PYRIMIDIN-2-YL)AMINO)-3-METHOXY-N- METHYLBENZAMIDE, COMPOSITIONS THEREOF AND METHODS OF THEIR USE

[0001] This application claims the benefit of priority to United States Provisional

Application Serial No. 62/193,167, filed July 16, 2015, which is incorporated herein by reference in its entirety and for all purposes.

1. FIELD

[0002] Provided herein are solid forms of 4-((4-(cyclopentyloxy)-5-(2- methylbenzo[ii]oxazol-6-yl)-7H-pyrrolo[2,3-<i]pyrimidin-2-yl)amino)-3-methoxy-N- methylbenzamide, compositions thereof, and methods of their use for treating or preventing a cancer, in particular solid tumors and hematological cancers as described herein.

2. BACKGROUND

2.1 SOLID FORMS OF PHARMACEUTICAL COMPOUNDS

[0003] The identification and selection of a solid form of a pharmaceutical compound are complex, given that a change in solid form may affect a variety of physical and chemical properties, which may provide benefits or drawbacks in processing, formulation, stability, bioavailability, storage, handling (e.g., shipping), among other important pharmaceutical characteristics. Useful pharmaceutical solids include crystalline solids and amorphous solids, depending on the product and its mode of administration. Amorphous solids are characterized by a lack of long-range structural order, whereas crystalline solids are characterized by structural periodicity. The desired class of pharmaceutical solid depends upon the specific application; amorphous solids are sometimes selected on the basis of, e.g., an enhanced dissolution profile, while crystalline solids may be desirable for properties such as, e.g., physical or chemical stability (see, e.g., S. R. Vippagunta et al, Adv. Drug. Deliv. Rev., (2001) 48:3-26; L. Yu, Adv. Drug. Deliv. Rev., (2001) 48:27-42).

[0004] Whether crystalline or amorphous, solid forms of a pharmaceutical compound include single-component and multiple-component solids. Single-component solids consist essentially of the pharmaceutical compound or active ingredient in the absence of other compounds. Variety among single-component crystalline materials may potentially arise from the phenomenon of polymorphism, wherein multiple three-dimensional arrangements exist for a particular pharmaceutical compound {see, e.g., S. R. Byrn et al, Solid State Chemistry of Drugs, (1999) SSCI, West Lafayette). The importance of discovering polymorphs was underscored by the case of Ritonavir™, an HIV protease inhibitor that was formulated as soft gelatin capsules. About two years after the product was launched, the unanticipated precipitation of a new, less soluble polymorph in the formulation necessitated the withdrawal of the product from the market until a more consistent formulation could be developed {see S. R. Chemburkar et al, Org.

Process Res. Dev., (2000) 4:413-417).

[0005] Additional diversity among the potential solid forms of a pharmaceutical compound may arise from the possibility of multiple-component solids. Crystalline solids comprising two or more ionic species may be termed salts {see, e.g., Handbook of

Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl and C. G. Wermuth, Eds., (2002), Wiley, Weinheim). Additional types of multiple-component solids that may potentially offer other property improvements for a pharmaceutical compound or salt thereof include, e.g., hydrates, solvates, co-crystals and clathrates, among others {see, e.g., S. R. Byrn et al, Solid State Chemistry of Drugs, (1999) SSCI, West Lafayette). Moreover, multiple-component crystal forms may potentially be susceptible to polymorphism, wherein a given multiple-component composition may exist in more than one three-dimensional crystalline arrangement.

[0006] Notably, it is not possible to predict a priori if crystalline forms of a compound even exist, let alone how to successfully prepare them {see, e.g., Braga and Grepioni, 2005, "Making crystals from crystals: a green route to crystal engineering and polymorphism," Chem. Commun. :3635-3645 (with respect to crystal engineering, if instructions are not very precise and/or if other external factors affect the process, the result can be unpredictable); Jones et al, 2006, Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement," MRS Bulletin 37:875-879 (At present it is not generally possible to computationally predict the number of observable polymorphs of even the simplest molecules); Price, 2004, "The computational prediction of pharmaceutical crystal structures and polymorphism," Advanced Drug Delivery Reviews 5(5:301-319 ("Price"); and Bernstein, 2004, "Crystal Structure Prediction and Polymorphism," ACA Transactions 39: 14-23 (a great deal still needs to be learned and done before one can state with any degree of confidence the ability to predict a crystal structure, much less polymorphic forms)).

[0007] The compound chemically named 4-((4-(cyclopentyloxy)-5-(2- methylbenzo[d]oxazol-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-N- methylbenzamide and tautomers thereof (collectively referred to herein as "Compound 1") are disclosed in U.S. Patent Application Publication No. 2014/0200206, published on July 17, 2014, the entirety of which is incorporated by reference herein.

[0008] The variety of possible solid forms creates potential diversity in physical and chemical properties for a given pharmaceutical compound. The discovery and selection of solid forms are of great importance in the development of an effective, stable and marketable pharmaceutical product.

2.2 CANCER

[0009] Cancer is characterized primarily by an increase in the number of abnormal cells derived from a given normal tissue, invasion of adjacent tissues by these abnormal cells, or lymphatic or blood-borne spread of malignant cells to regional lymph nodes and to distant sites (metastasis). Clinical data and molecular biologic studies indicate that cancer is a multistep process that begins with minor preneoplastic changes, which may under certain conditions progress to neoplasia. The neoplastic lesion may evolve clonally and develop an increasing capacity for invasion, growth, metastasis and heterogeneity, especially under conditions in which the neoplastic cells escape the host's immune surveillance. See Roitt, L, Brostoff, J and Kale, D., Immunology, 17.1-17.12 (3rd ed., Mosby, St. Louis, MO, 1993).

[0010] Cancers figure among the leading causes of death worldwide, accounting for

8.2 million deaths in 2012. It is expected that annual cancer cases will rise from 14 million in 2012 to 22 million within the next two decades. See Cancer Fact sheet N°297, World Health Organization, February 2014, retrieved 10 June 2014 and Globocan 2012, IARC.

[0011] Each year more than 1.3 million new cases of breast cancer are diagnosed worldwide. In spite of advances in prevention, surgical resection, chemotherapy and targeted therapy in the past decade, it is estimated that approximately 450,000 women will die of this disease globally each year. Triple negative breast cancer (TNBC) is a subtype that encompasses a heterogeneous subset of tumors that share three defining characteristics: lack of estrogen receptor (ER) and progesterone receptor (PR), and lack of human epidermal growth factor receptor 2 (HER2) overexpression. The majority of T BCs are of high histologic grade, with more than 90% of TNBC reported to be of invasive ductal histology. Those tumors also account for a large proportion of metastatic breast cancers. Currently, standard chemotherapy remains the cornerstone of treatment for patients with TNBC in the preoperative and adjuvant settings.

However, TNBC tumors have a high risk of relapse, irrespective of grade and stage. Even though TNBC accounts for only 15% to 20% of breast cancer, it is responsible for a disproportionate number of breast cancer deaths, due to the lack of effective agents. Therefore, TNBC remains a major challenge to physicians and patients. The search for effective therapies for this disease is a major focus for drug discovery and development efforts.

[0012] The current drugs used in cancer treatment are highly toxic and often nonspecific. Current anticancer therapy strategies are typically focused on rapid proliferating cells, which can shrink primary and metastatic tumors, but such effects are usually transient and tumor relapse of most metastatic cancers frequently occur. One possible reason for failure is the existence of cancer stem cells. Unlike most cells within the tumor, cancer stem cells are resistant to well-defined chemotherapy and after treatment, they can regenerate all the cell types in the tumor through their stem cell-like behavior of largely quiescent nature and their abundant expression of drug transporters.

[0013] There is an enormous variety of cancers which are described in detail in the medical literature. The incidence of cancer continues to climb as the general population ages, as new cancers develop, and as susceptible populations (e.g., people infected with AIDS or excessively exposed to sunlight) grow. However, options for the treatment of cancer are limited. A tremendous demand therefore exists for new methods and compositions that can be used to treat patients with cancer.

[0014] Citation or identification of any reference in Section 2 of this application is not to be construed as an admission that the reference is prior art to the present application.

3. SUMMARY

[0015] Provided herein are solid forms of Compound 1 :

1

having the name 4-((4-(cyclopentyloxy)-5-(2-methylbenzo[<i]oxazol-6-yl)-7H- pyrrolo[2,3-<i]pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide, including tautomers thereof. Also provided are methods of preparing, isolating and characterizing the solid forms.

[0016] Provided herein are methods of treating a cancer, in particular a solid tumor or a hematological cancer, comprising administering to a subject in need thereof an effective amount of one or more solid forms of Compound 1.

[0017] Also provided herein are methods for preventing cancer metastasis, comprising administering to a subject in need thereof an effective amount of one or more solid forms of Compound 1. Additionally, provided herein are methods of eradicating cancer stem cells in a subject, comprising administering to a subject in need thereof an effective amount of one or more solid forms of Compound 1. Also provided are methods of inducing differentiation in cancer stem cells in a subject, comprising administering to a subject in need thereof an effective amount of one or more solid forms of Compound 1. In another aspect, provided are methods of inducing cancer stem cell death in a subject, comprising administering to a subject in need thereof an effective amount of one or more solid forms of Compound 1.

[0018] In one aspect, provided herein are methods for treating or preventing breast cancer, in particular triple negative breast cancer (T BC), comprising administering to a subject in need thereof an effective amount of one or more solid forms of Compound 1 as described herein.

[0019] In another aspect, provided herein are methods for treating or preventing a cancer provided herein, comprising administering to a subject in need thereof an effective amount of one or more solid forms of Compound 1 as described herein and a pharmaceutically acceptable carrier, excipient or vehicle. [0020] In another aspect provided herein are one or more solid forms of Compound 1 as described herein and a pharmaceutically acceptable carrier, excipient or vehicle for use in a method for treating or preventing a cancer.

[0021] The present embodiments can be understood more fully by reference to the detailed description and examples, which are intended to exemplify non-limiting embodiments.

4. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] FIG. 1 depicts an XRPD pattern of Form A.

[0023] FIG. 2 depicts an XRPD pattern of Form B .

[0024] FIG. 3 depicts an XRPD pattern of Form C.

[0025] FIG. 4 depicts an XRPD pattern of Form D.

[0026] FIG. 5 depicts an XRPD pattern of Form E.

[0027] FIG. 6 depicts an XRPD pattern of Form F.

[0028] FIG. 7 depicts an XRPD pattern of Form G.

[0029] FIG. 8 depicts an XRPD pattern of Form H.

[0030] FIG. 9 depicts an XRPD pattern of Form I.

[0031] FIG. 10 depicts an XRPD pattern of Form J.

[0032] FIG. 11 depicts an XRPD pattern of Form K.

[0033] FIG. 12 depicts an XRPD pattern of Form L.

[0034] FIG. 13 depicts an XRPD pattern of Form M.

[0035] FIG. 14 depicts an XRPD pattern of Form N.

[0036] FIG. 15 depicts an XRPD pattern of Form O.

[0037] FIG. 16 depicts an XRPD pattern of Form P.

[0038] FIG. 17 depicts a schematic form conversion among the solid forms.

[0039] FIG. 18 depicts a SEM picture of Form A .

[0040] FIG. 19 depicts a TGA thermogram of Form A.

[0041] FIG. 20 depicts a DSC thermogram of Form A.

[0042] FIG. 21 depicts a DVS isotherm plot Form A.

[0043] FIG. 22 depicts a comparison of XRPD Patterns of Form A: (a) before and (b) after compression. [0044] FIG. 23 depicts a SEM picture of Form B.

[0045] FIG. 24 depicts a TGA thermogram of Form B.

[0046] FIG. 25 depicts a DSC thermogram of Form B.

[0047] FIG. 26 depicts a 1H NMR spectra of Form B .

[0048] FIG. 27 depicts a DVS isotherm plot Form B.

[0049] FIG. 28 depicts a SEM picture of Form C.

[0050] FIG. 29 depicts a TGA thermogram of Form C.

[0051] FIG. 30 depicts a DSC thermograms of Form C.

[0052] FIG. 31 depicts a DVS isotherm plot of Form C.

[0053] FIG. 32 depicts a comparison of XRPD Patterns of Form C: (a) before and (b) after compression.

[0054] FIG. 33 depicts a SEM picture of Form D.

[0055] FIG. 34 depicts a TGA thermogram of Form D.

[0056] FIG. 35 depicts a DSC thermogram of Form D.

[0057] FIG. 36 depicts a 1H NMR spectra of Form D.

[0058] FIG. 37 depicts a DVS isotherm plot Form D.

[0059] FIG. 38 depicts a SEM picture of Form E.

[0060] FIG. 39 depicts a TGA thermogram of Form E.

[0061] FIG. 40 depicts a DSC thermogram of Form E.

[0062] FIG. 41 depicts a DVS isotherm plot Form E.

[0063] FIG. 42 depicts a comparison of XRPD Patterns of Form E: (a) before and (b) after compression.

[0064] FIG. 43 depicts a SEM picture of Form F.

[0065] FIG. 44 depicts a TGA thermogram of Form F.

[0066] FIG. 45 depicts a DSC thermogram of Form F.

[0067] FIG. 46 depicts a 1H NMR spectra of Form F.

[0068] FIG. 47 depicts a DVS isotherm plot Form F.

[0069] FIG. 48 depicts a DSC thermogram of Form G.

[0070] FIG. 49 depicts a 1H NMR spectra of Form G.

[0071] FIG. 50 depicts a SEM picture of Form H. [0072] FIG. 51 depicts a TGA thermogram of Form H.

[0073] FIG. 52 depicts a DSC thermogram of Form H.

[0074] FIG. 53 depicts a DVS isotherm plot Form H.

[0075] FIG. 54 depicts a TGA thermogram of Form I.

[0076] FIG. 55 depicts a DSC thermogram of Form I.

[0077] FIG. 56 depicts a 1H NMR spectra of Form I.

[0078] FIG. 57 depicts a TGA thermogram of Form J.

[0079] FIG. 58 depicts a DSC thermogram of Form J.

[0080] FIG. 59 depicts a 1H NMR spectra of Form J.

[0081] FIG. 60 depicts a DVS isotherm plot of Form J.

[0082] FIG. 61 depicts a TGA thermogram of Form K.

[0083] FIG. 62 depicts a DSC thermogram of Form K.

[0084] FIG. 63 depicts a 1H NMR spectra of Form K.

[0085] FIG. 64 depicts a TGA thermogram of Form L.

[0086] FIG. 65 depicts a DSC thermogram of Form L.

[0087] FIG. 66 depicts a 1H NMR spectra of Form L.

[0088] FIG. 67 depicts a DVS isotherm plot Form L.

[0089] FIG. 68 depicts a TGA thermogram of Form M.

[0090] FIG. 69 depicts a DSC thermogram of Form M.

[0091] FIG. 70 depicts a DVS isotherm plot Form M.

[0092] FIG. 71 depicts a TGA thermogram of Form N.

[0093] FIG. 72 depicts a DSC thermogram of Form N.

[0094] FIG. 73 depicts a 1H NMR spectra of Form N.

[0095] FIG. 74 depicts a DVS isotherm plot of Form N.

[0096] FIG. 75 depicts a SEM picture of Form O.

[0097] FIG. 76 depicts a TGA thermogram of Form O.

[0098] FIG. 77 depicts a DSC thermogram of Form O.

[0099] FIG. 78 depicts a 1H NMR spectra of Form O.

[00100] FIG. 79 depicts a SEM picture of Form P.

[00101] FIG. 80 depicts a TGA thermogram of Form P. [00102] FIG. 81 depicts a DSC thermogram of Form P.

[00103] FIG. 82 depicts a 1H NMR spectra of Form P.

5. DETAILED DESCRIPTION

5.1 DEFINITIONS

[00104] As used herein, and unless otherwise specified, the terms "about" and

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

[00105] As used herein, and unless otherwise specified, the terms "about" and

"approximately," when used in connection with a numeric value or range of values which is provided to characterize a particular solid form, e.g., a specific temperature or temperature range, such as, for example, that describes a melting, dehydration, desolvation, or glass transition temperature; a mass change, such as, for example, a mass change as a function of temperature or humidity; a solvent or water content, in terms of, for example, mass or a percentage; or a peak position, such as, for example, in analysis by, for example, IR or Raman spectroscopy or XRPD; indicate that the value or range of values may deviate to an extent deemed reasonable to one of ordinary skill in the art while still describing the solid form. Techniques for characterizing crystal forms and amorphous forms include, but are not limited to, thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), single- crystal X-ray diffractometry, vibrational spectroscopy, e.g., infrared (IR) and Raman

spectroscopy, solid-state and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies, and dissolution studies. In certain embodiments, the terms "about" and "approximately," when used in this context, indicate that the numeric value or range of values may vary within 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or

0.25% of the recited value or range of values. For example, in some embodiments, the value of an XRPD peak position may vary by up to ±0.2 ⁰ 2Θ while still describing the particular XRPD peak.

[00106] As used herein, and unless otherwise specified, a crystalline form that is "pure,"

1. e., substantially free of other crystalline or amorphous forms, contains less than about 10% by weight of one or more other crystalline or amorphous forms, less than about 5% by weight of one or more other crystalline or amorphous forms, less than about 3% by weight of one or more other crystalline or amorphous forms, or less than about 1% by weight of one or more other crystalline or amorphous forms.

[00107] As used herein, and unless otherwise specified, a solid form that is "substantially physically pure" is substantially free from other solid forms, such as crystalline forms or amorphous forms. In certain embodiments, a solid form that is substantially physically pure contains less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%), 0.05%), or 0.01%) of one or more other solid forms on a weight basis. The detection of other solid forms can be accomplished by any method apparent to a person of ordinary skill in the art, including, but not limited to, diffraction analysis, thermal analysis, elemental combustion analysis and/or spectroscopic analysis.

[00108] As used herein, and unless otherwise specified, a solid form that is "substantially chemically pure" is substantially free from other chemical compounds (i.e., chemical impurities). In certain embodiments, a solid form that is substantially chemically pure contains less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.01%) of one or more other chemical compounds on a weight basis. The detection of other chemical compounds can be accomplished by any method apparent to a person of ordinary skill in the art, including, but not limited to, methods of chemical analysis, such as, e.g., mass spectrometry analysis, spectroscopic analysis, thermal analysis, elemental combustion analysis and/or chromatographic analysis. In certain embodiment, provided herein is a solid form of Compound 1 that is substantially chemically pure.

[00109] As used herein, and unless otherwise indicated, a chemical compound, solid form, or composition that is "substantially free" of another chemical compound, solid form, or composition means that the chemical compound, solid form, or composition contains, in certain embodiments, less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2% 0.1%), 0.05%), or 0.01%> by weight of the other chemical compound, solid form, or composition.

[00110] Unless otherwise specified, the terms "solvate" and "solvated," as used herein, refer to a solid form of a substance which contains solvent. The terms "hydrate" and "hydrated" refer to a solvate wherein the solvent is water. "Polymorphs of solvates" refer to the existence of more than one solid form for a particular solvate composition. Similarly, "polymorphs of hydrates" refer to the existence of more than one solid form for a particular hydrate composition. The term "desolvated solvate," as used herein, refers to a solid form of a substance which can be made by removing the solvent from a solvate. The terms "solvate" and "solvated," as used herein, can also refer to a solvate of a salt, cocrystal, or molecular complex. The terms "hydrate" and "hydrated," as used herein, can also refer to a hydrate of a salt, cocrystal, or molecular complex.

[00111] "Tautomers" refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, in aqueous solution, pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:

[00112] As readily understood by one skilled in the art, a wide variety of functional groups and other structures may exhibit tautomerism and all tautomers of Compound 1 are within the scope of the present invention.

[00113] Unless otherwise specified, the term "composition" as used herein is intended to encompass a product comprising the specified ingredient(s) (and in the specified amount(s), if indicated), as well as any product which results, directly or indirectly, from combination of the specified ingredient(s) in the specified amount(s). By "pharmaceutically acceptable," it is meant a diluent, excipient, or carrier in a formulation must be compatible with the other ingredient(s) of the formulation and not deleterious to the recipient thereof.

[00114] The term "solid form" refers to a physical form which is not predominantly in a liquid or a gaseous state. As used herein and unless otherwise specified, the term "solid form," when used herein to refer to Compound 1, refers to a physical form comprising Compound 1 which is not predominantly in a liquid or a gaseous state. A solid form may be a crystalline form or a mixture thereof. In certain embodiments, a solid form may be a liquid crystal. In certain embodiments, the term "solid forms comprising Compound 1" includes crystal forms comprising Compound 1. In certain embodiments, the solid form of Compound 1 is Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, Form M, Form N, Form O, Form P, or a mixture thereof.

[00115] As used herein and unless otherwise specified, the term "crystalline" when used to describe a compound, substance, modification, material, component or product, unless otherwise specified, means that the compound, substance, modification, material, component or product is substantially crystalline as determined by X-ray diffraction. See, e.g., Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams and Wilkins, Baltimore, MD (2005); The United States Pharmacopeia, 23^rd ed., 1843-1844 (1995).

[00116] The term "crystal form" or "crystalline form" refers to a solid form that is crystalline. In certain embodiments, crystal forms include salts. In certain embodiments, a crystal form of a substance may be substantially free of amorphous forms and/or other crystal forms. In certain embodiments, a crystal form of a substance may contain less than about 1%, less than about 2%, less than about 3%, less than about 4%, less than about 5%, less than about 6%, less than about 7%, less than about 8%, less than about 9%, less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, less than about 40%, less than about 45%, or less than about 50% by weight of one or more amorphous forms and/or other crystal forms. In certain embodiments, a crystal form of a substance may be physically and/or chemically pure. In certain embodiments, a crystal form of a substance may be about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%), about 92%), about 91%, or about 90% physically and/or chemically pure. [00117] Unless otherwise specified, the term "amorphous" or "amorphous form" means that the substance, component, or product in question is not substantially crystalline as determined by X-ray diffraction. In particular, the term "amorphous form" describes a disordered solid form, i.e., a solid form lacking long range crystalline order.

[00118] "Treating" as used herein, means an alleviation, in whole or in part, of a disorder, disease or condition, or one or more of the symptoms associated with a disorder, disease, or condition, or slowing or halting of further progression or worsening of those symptoms, or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself. In one embodiment, the disorder is a cancer, in particular, a solid tumor or hematological cancer. In some embodiments, "treating" means an alleviation, in whole or in part, of a cancer, or symptoms associated with a cancer, in particular, a solid tumor or hematological cancer, or a slowing, or halting of further progression or worsening of those symptoms.

[00119] "Preventing" as used herein, means a method of delaying and/or precluding the onset, recurrence or spread, in whole or in part, of a disorder, disease or condition, or one or more of the symptoms associated with a disorder, disease, or condition, in particular, a solid tumor or hematological cancer; barring a subject from acquiring a cancer, in particular, a solid tumor or hematological cancer; or reducing a subject's risk of acquiring a cancer, in particular, a solid tumor or hematological cancer.

[00120] The term "effective amount" in connection with a solid form of Compound 1 means an amount capable of treating or preventing a disorder, disease or condition, or symptoms thereof, as disclosed herein. The effective amount of a solid form of Compound 1, for example in a pharmaceutical composition, may be at a level that will exercise the desired effect; for example, about 0.005 mg/kg of a subject's body weight to about 100 mg/kg of a patient's body weight in unit dosage for parenteral administration. As will be apparent to those skilled in the art, it is to be expected that the effective amount of a solid form of Compound 1 disclosed herein may vary depending on the severity of the indication being treated.

[00121] The terms "patient" and "subject" as used herein include an animal, including, but not limited to, an animal such a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig, in one embodiment a mammal, in another embodiment a human. In one embodiment, a subject is a human having or at risk for having a solid tumor or hematological cancer, or a symptom thereof. In one embodiment, a patient is a human having histologically or cytologically-confirmed TNBC, including subjects who have progressed on (or not been able to tolerate) standard anticancer therapy or for whom no standard anticancer therapy exists.

[00122] As used herein, and unless otherwise specified, the terms "cancer" refers to or describes the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include solid tumors and hematological cancer. In some embodiments, the cancer is a primary cancer, in others, the cancer is metastasized. In one embodiment, the cancer is breast cancer. In another embodiment, the cancer is triple negative breast cancer.

[00123] "Triple negative breast cancer (TNBC)" as used herein, means breast cancer that does not express the proteins corresponding to the estrogen receptor (ER)- and progesterone receptor (PR), and that does not overexpress the human epidermal growth factor receptor 2 (Her2/neu) protein.

[00124] As used herein "solid tumors" includes, but is not limited to, bladder cancer (including, but not limited to, superficial bladder cancer), breast cancer (including, but not limited to, luminal B type, ER+, PR+ and Her2+ breast cancer), central nervous system cancer (including, but no tlimited to, glioblastoma multiforme (GBM), glioma, medulloblastoma, and astrocytoma), colorectal cancer, gastrointestinal cancer (including, but not limited to, stomach cancer, oesophagus cancer, and rectum cancer), endocrine cancer ( including, but not imited to, thyroid cancer, and adrenal gland cancer), eye cancer (including, but not limited to,

retinoblastoma), female genitourinary cancer (including, but not limited to, cancer of the placenta, uterus, vulva, ovary, cervix), head and neck cancer (including, but not limited to, cancer of the pharynx, oesophagus, and tongue), liver cancer, lung cancer (including, but not limited to, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC),

mucoepidermoid, bronchogenic, squamous cell carcinoma (SQCC), and analplastic/NSCLC), skin cancer (including, but not limited to, melanoma, and SQCC), soft tissue cancer (including but not limited to, sarcoma, Ewing's sarcoma, and rhabdomyosarcoma), bone cancer (including, but not limited to, sarcoma, Ewing's sarcoma, and osteosarcoma), squamous cell cancer (including, but not limited to, lung, esophageal, cervical, and head and neck cancer), pancreas cancer, kidney cancer (including, but not limited to, renal Wilm's tumor and renal cell carcinoma), and prostate cancer. In some embodiments, the solid tumor is breast cancer, colon cancer, lung cancer or bladder cancer. In one such embodiment, the solid tumor is superficial bladder cancer. In another, the solid tumor is lung squamous cell carcinoma. In yet another embodiment, the solid tumor is luminal B type breast cancer.

[00125] As used herein "hematological cancer" includes, but is not limited to, leukemia (including, but not limited to, acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), acute T-cell leukemia, B cell precursor leukemia, acute promyelocytic leukemia

(APML), plasma cell leukemia, myelomonoblastic/T-ALL, B myelomonocytic leukemia, erythroleukemia, and acute myeloid leukemia (AML)), lymphoma (including but not limited to Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), Burkitt's lymphoma (BL), B cell lymphoma, lymphoblastic lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), large cell immunoblastic lymphoma), and multiple myeloma.

[00126] In the context of a cancer, inhibition may be assessed by inhibition of disease progression, inhibition of tumor growth, reduction of primary tumor, relief of tumor-related symptoms, inhibition of tumor secreted factors (including tumor secreted hormones, such as those that contribute to carcinoid syndrome), delayed appearance of primary or secondary tumors, slowed development of primary or secondary tumors, decreased occurrence of primary or secondary tumors, slowed or decreased severity of secondary effects of disease, arrested tumor growth and regression of tumors, increased Time To Progression (TTP), increased Progression Free Survival (PFS), increased Overall Survival (OS), among others. OS as used herein means the time from randomization until death from any cause, and is measured in the intent-to-treat population. TTP as used herein means the time from randomization until objective tumor progression; TTP does not include deaths. As used herein, PFS means the time from randomization until objective tumor progression or death. In one embodiment, PFS rates will be computed using the Kaplan-Meier estimates. In the extreme, complete inhibition, is referred to herein as prevention or chemoprevention. In this context, the term "prevention" includes either preventing the onset of clinically evident cancer altogether or preventing the onset of a preclinically evident stage of a cancer. Also intended to be encompassed by this definition is the prevention of transformation into malignant cells or to arrest or reverse the progression of premalignant cells to malignant cells. This includes prophylactic treatment of those at risk of developing a cancer.

[00127] In certain embodiments, the treatment of lymphoma may be assessed by the International Workshop Criteria (IWC) for non-Hodgkin lymphoma (NHL) {see Cheson BD, Pfistner B, Juweid, ME, et. al. Revised Response Criteria for Malignant Lymphoma. J. Clin.

Oncol: 2007: (25) 579-586), using the response and endpoint definitions shown below:

positron emission tomography; CT, computed tomography; PR, partial remission; SPD, sum of the product of the diameters; SD, stable disease; PD, progressive disease.

End point Patients Definition Measured from

Primary

Overall survival All Death as a result of any cause Entry onto study

Progression-free All Disease progression or death as a result Entry onto study survival of any cause

Secondary

Event-free All Failure of treatment or death as result Entry onto study survival of any cause

Time to All Time to progression or death as a result Entry onto study progression of lymphoma

Disease-free In CR Time to relapse or death as a result of Documentation of survival lymphoma or acute toxicity of response

treatment

Response In CR or Time to relapse or progression Documentation of duration PR response

Lymphoma- All Time to death as a result of lymphoma Entry onto study specific survival

Time to next All Time to new treatment End of primary treatment treatment

Abbreviations: CR: complete remission; PR: partial remission.

[00129] In one embodiment, the end point for lymphoma is evidence of clinical benefit.

Clinical benefit may reflect improvement in quality of life, or reduction in patient symptoms, transfusion requirements, frequent infections, or other parameters. Time to reappearance or progression of lymphoma-related symptoms can also be used in this end point.

[00130] In certain embodiments, the treatment of CLL may be assessed by the

International Workshop Guidelines for CLL (see Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the

International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood, 2008; (111) 12: 5446-5456) using the response and endpoint definitions shown therein and in particular:

[00131] Group A criteria define the tumor load; Group B criteria define the function of the hematopoietic system (or marrow). CR (complete remission): all of the criteria have to be met, and patients have to lack disease-related constitutional symptoms; PR (partial remission): at least two of the criteria of group A plus one of the criteria of group B have to be met; SD is absence of progressive disease (PD) and failure to achieve at least a PR; PD: at least one of the above criteria of group A or group B has to be met. Sum of the products of multiple lymph nodes (as evaluated by CT scans in clinical trials, or by physical examination in general practice). These parameters are irrelevant for some response categories.

[00132] In certain embodiments, the treatment of multiple myeloma may be assessed by the International Uniform Response Criteria for Multiple Myeloma (IURC) (see Durie BGM, Harousseau J-L, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia, 2006; (10) 10: 1-7), using the response and endpoint definitions shown below:

Response Response Criteria^a

Subcategory

sCR CR as defined below plus

Normal FLC ratio and

Absence of clonal cells in bone marrow^b by immunohistochemistry or immunofluorescence⁰

CR Negative immunofixation on the serum and urine and

Disappearance of any soft tissue plasmacytomas and

<5% plasma cells in bone marrow^b

VGPR Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level <100mg per 24 h

PR >50% reduction of serum M-protein and reduction in 24-h urinary

M-protein by>90% or to <200mg per 24 h

If the serum and urine M-protein are unmeasurable,^d a >50%

decrease in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria

If serum and urine M-protein are unmeasurable, and serum free light assay is also unmeasurable, >50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was >30%

In addition to the above listed criteria, if present at baseline, a >50% reduction in the size of soft tissue plasmacytomas is also required

SD (not Not meeting criteria for CR, VGPR, PR or progressive disease recommended for

use as an indicator of

response; stability of

disease is best

described by

providing the time to

progression

estimates)

[00133] Abbreviations: CR, complete response; FLC, free light chain; PR, partial response; SD, stable disease; sCR, stringent complete response; VGPR, very good partial response; ^aAll response categories require two consecutive assessments made at anytime before the institution of any new therapy; all categories also require no known evidence of progressive or new bone lesions if radiographic studies were performed. Radiographic studies are not required to satisfy these response requirements; Confirmation with repeat bone marrow biopsy not needed; ^cPresence/absence of clonal cells is based upon the κ/λ ratio. An abnormal κ/λ ratio by immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of an abnormal clone is κ/λ of >4: 1 or <l :2.^dMeasurable disease defined by at least one of the following measurements: Bone marrow plasma cells >30%; Serum M-protein >1 g/dl (>10 gm/l)[10 g/1]; Urine M-protein >200 mg/24 h; Serum FLC assay: Involved FLC level >10 mg/dl (>100 mg/1); provided serum FLC ratio is abnormal.

[00134] In certain embodiments, the treatment of a cancer may be assessed by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) (see Thereasse P., et al. New Guidelines to Evaluate the Response to Treatment in Solid Tumors. J. of the National Cancer Institute; 2000; (92) 205-216 and Eisenhauer E.A., Therasse P., Bogaerts J., et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). European J. Cancer; 2009; (45) 228-247). Overall responses for all possible combinations of tumor responses in target and non-target lesions with our without the appearance of new lesions are as follows:

[00135] CR = complete response; PR = partial response; SD = stable disease; and PD = progressive disease.

[00136] With respect to the evaluation of target lesions, complete response (CR) is the disappearance of all target lesions, partial response (PR) is at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter, progressive disease (PD) is at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions and stable disease (SD) is neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started.

[00137] With respect to the evaluation of non-target lesions, complete response (CR) is the disappearance of all non-target lesions and normalization of tumor marker level; incomplete response/stable disease (SD) is the persistence of one or more non-target lesion(s) and/or the maintenance of tumor marker level above the normal limits, and progressive disease (PD) is the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.

[00138] The procedures, conventions, and definitions described below provide guidance for implementing the recommendations from the Response Assessment for Neuro-Oncology (RANO) Working Group regarding response criteria for high-grade gliomas (Wen P.,

Macdonald, DR., Reardon, DA., et al. Updated response assessment criteria for highgrade gliomas: Response assessment in neuro-oncology working group. J Clin Oncol 2010; 28: 1963- 1972). Primary modifications to the RANO criteria for Criteria for Time Point Responses (TPR) can include the addition of operational conventions for defining changes in glucocorticoid dose, and the removal of subjects' clinical deterioration component to focus on objective radiologic assessments. The baseline MRI scan is defined as the assessment performed at the end of the post-surgery rest period, prior to re-initiating compound treatment. The baseline MRI is used as the reference for assessing complete response (CR) and partial response (PR). Whereas, the smallest SPD (sum of the products of perpendicular diameters) obtained either at baseline or at subsequent assessments will be designated the nadir assessment and utilized as the reference for determining progression. For the 5 days preceding any protocol-defined MRI scan, subjects receive either no glucocorticoids or are on a stable dose of glucocorticoids. A stable dose is defined as the same daily dose for the 5 consecutive days preceding the MRI scan. If the prescribed glucocorticoid dose is changed in the 5 days before the baseline scan, a new baseline scan is required with glucocorticoid use meeting the criteria described above. The following definitions will be used.

[00139] Measurable Lesions: Measurable lesions are contrast-enhancing lesions that can be measured bidimensionally. A measurement is made of the maximal enhancing tumor diameter (also known as the longest diameter, LD). The greatest perpendicular diameter is measured on the same image. The cross hairs of bidimensional measurements should cross and the product of these diameters will be calculated.

[00140] Minimal Diameter: Tl -weighted image in which the sections are 5 mm with 1 mm skip. The minimal LD of a measurable lesion is set as 5 mm by 5 mm. Larger diameters may be required for inclusion and/or designation as target lesions. After baseline, target lesions that become smaller than the minimum requirement for measurement or become no longer amenable to bidimensional measurement will be recorded at the default value of 5 mm for each diameter below 5 mm. Lesions that disappear will be recorded as 0 mm by 0 mm.

[00141] Multicentric Lesions: Lesions that are considered multicentric (as opposed to continuous) are lesions where there is normal intervening brain tissue between the two (or more) lesions. For multicentric lesions that are discrete foci of enhancement, the approach is to separately measure each enhancing lesion that meets the inclusion criteria. If there is no normal brain tissue between two (or more) lesions, they will be considered the same lesion.

[00142] Nonmeasurable Lesions: All lesions that do not meet the criteria for measurable disease as defined above will be considered non-measurable lesions, as well as all nonenhancing and other truly nonmeasurable lesions. Nonmeasurable lesions include foci of enhancement that are less than the specified smallest diameter (i.e., less than 5 mm by 5 mm), nonenhancing lesions (e.g., as seen on Tl -weighted post-contrast, T2 -weighted, or fluid-attenuated inversion recovery (FLAIR) images), hemorrhagic or predominantly cystic or necrotic lesions, and leptomeningeal tumor. Hemorrhagic lesions often have intrinsic Tl -weighted hyperintensity that could be misinterpreted as enhancing tumor, and for this reason, the pre-contrast Tl -weighted image may be examined to exclude baseline or interval sub-acute hemorrhage.

[00143] At baseline, lesions will be classified as follows: Target lesions: Up to

5 measurable lesions can be selected as target lesions with each measuring at least 10 mm by 5 mm, representative of the subject' s disease; Non-target lesions: All other lesions, including all nonmeasurable lesions (including mass effects and T2/FLAIR findings) and any measurable lesion not selected as a target lesion. At baseline, target lesions are to be measured as described in the definition for measurable lesions and the SPD of all target lesions is to be determined. The presence of all other lesions is to be documented. At all post-treatment evaluations, the baseline classification of lesions as target and non-target lesions will be maintained and lesions will be documented and described in a consistent fashion over time (e.g., recorded in the same order on source documents and eCRFs). All measurable and nonmeasurable lesions must be assessed using the same technique as at baseline (e.g., subjects should be imaged on the same MRI scanner or at least with the same magnet strength) for the duration of the study to reduce difficulties in interpreting changes. At each evaluation, target lesions will be measured and the SPD calculated. Non-target lesions will be assessed qualitatively and new lesions, if any, will be documented separately. At each evaluation, a time point response will be determined for target lesions, non-target lesions, and new lesion. Tumor progression can be established even if only a subset of lesions is assessed. However, unless progression is observed, objective status (stable disease, PR or CR) can only be determined when all lesions are assessed.

[00144] Confirmation assessments for overall time point responses of CR and PR will be performed at the next scheduled assessment, but confirmation may not occur if scans have an interval of < 28 days. Best response, incorporating confirmation requirements, will be derived from the series of time points.

5.2 COMPOUND 1

[00145] The solid forms, formulations and methods of use provided herein relate to

Compound 1 :

1 [00146] having the name 4-((4-(cyclopentyloxy)-5-(2-methylbenzo[<i]oxazol-6-yl)-7H- pyrrolo[2,3-<i]pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide, including tautomers thereof.

[00147] Compound 1 can be prepared using reagents and methods known in the art, including the methods provided in U.S. Patent Application Publication No. 2014/0200206, published on July 17, 2014, the entire content of which is incorporated herein by reference.

[00148] It should be noted that if there is a discrepancy between a depicted structure and a name given that structure, the depicted structure is to be accorded more weight. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it.

5.3 SOLID FORMS OF COMPOUND 1

[00149] In certain embodiments, provided herein are solid forms of Compound 1. In certain embodiments, the solid form is crystalline. In certain embodiments, the solid form is a single-component solid form. In certain embodiments, the solid form is a solvate.

[00150] While not intending to be bound by any particular theory, certain solid forms are characterized by physical properties, e.g., stability, solubility and dissolution rate, appropriate for pharmaceutical and therapeutic dosage forms. Moreover, while not wishing to be bound by any particular theory, certain solid forms are characterized by physical properties (e.g., density, compressibility, hardness, morphology, cleavage, stickiness, solubility, water uptake, electrical properties, thermal behavior, solid-state reactivity, physical stability, and chemical stability) affecting particular processes (e.g., yield, filtration, washing, drying, milling, mixing, tableting, flowability, dissolution, formulation, and lyophilization) which make certain solid forms suitable for the manufacture of a solid dosage form. Such properties can be determined using particular analytical chemical techniques, including solid-state analytical techniques (e.g., X-ray diffraction, microscopy, spectroscopy and thermal analysis), as described herein and known in the art.

[00151] The solid forms provided herein (e.g., Form A, Form B, Form C, Form D, Form

E, Form F, Form G, Form H, Form I, Form J, Form K, Form L, Form M, Form N, Form O and Form P of Compound 1) may be characterized using a number of methods known to a person skilled in the art, including, but not limited to, X-ray powder diffraction (XRPD), microscopy (e.g., scanning electron microscopy (SEM)) and thermal analysis (e.g., thermal gravimetric analysis (TGA) and differential scanning calorimetry (DSC)). The particle size and size distribution of the solid form provided herein may be determined by conventional methods, such as laser light scattering technique.

[00152] It should be understood that the numerical values of the peaks of an X-ray powder diffraction pattern may vary slightly from one machine to another or from one sample to another, and so the values quoted are not to be construed as absolute, but with an allowable variability, such as ±0.2 ⁰ 2Θ (see United State Pharmacopoeia, page 2228 (2003)).

5.3.1 Form A

[00153] In certain embodiments, provided herein is Form A.

[00154] In one embodiment, Form A is a solid form of Compound 1. In one embodiment,

Form A is an anhydrous solid form of Compound 1. In another embodiment, Form A is crystalline. In another embodiment, Form A is monotropically related to Form E.

[00155] In certain embodiments, Form A provided herein is obtained by evaporation experiment.

[00156] In certain embodiments, provided herein are evaporation methods for making

Form A, comprising 1) dissolving Compound 1 in a solvent (e.g., DCM/MeOH 90: 10) to yield a solution; 2) filtering the solution; and 3) evaporating the solution under certain air pressure (e.g., about 0.5-1.5 atm) at a certain temperature (e.g., about 20-30 °C or about 45-55 °C) to yield a solid. In certain embodiments, provided herein are evaporation methods for making Form A, comprising 1) dissolving Compound 1 in a solvent (e.g., DCM/MeOH 90: 10) to yield a solution; 2) filtering the solution (e.g., filtering through 0.45 μπι PTEE syringe filters) if Compound 1 does not dissolve completely; and 3) evaporating the solution under about 1 atm air pressure at about 25 °C or about 50 °C under nitrogen to yield a solid.

[00157] In certain embodiments, a solid form provided herein, e.g., Form A, is

substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form A has an X-ray powder diffraction pattern substantially as shown in FIG. 1. In one embodiment, Form A has one or more characteristic X-ray powder diffraction peaks at approximately 5.1, 6.7, 9.5, 10.1, 13.0, 13.8, 14.4, 15.2, 16.3, 18.6, 19.1, 20.1, 21.6, 22.3, 22.8, 23.2, 23.7, 24.1, 24.8, 25.9, 26.5, 27.1, 27.3, 27.7, 28.4, 32.1, 34.0, 36.6, 38.8 or 39.6 ⁰ 2Θ as depicted in FIG. 1. In a specific embodiment, Form A has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 5.1, 6.7, 10.1, 13.0, 18.6, 19.1, 20.1, 23.2 ⁰ 2Θ. In another embodiment, Form A has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 5.1, 18.6, 19.1 or 20.1 ⁰ 2Θ. In another embodiment, Form A has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty- two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine or thirty characteristic X-ray powder diffraction peaks as set forth in Table 9.

[00158] In one embodiment, Form A has a SEM image substantially as shown in FIG. 18.

[00159] In one embodiment, provided herein is Form A having a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 19. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising minimal mass loss of the total mass of the sample up to the melting of Form A with an onset melting temperature of about 244 °C when heated from approximately 20 °C to approximately 300 °C.

[00160] In one embodiment, provided herein is Form A having a DSC thermogram substantially as depicted in FIG. 20 comprising an endothermic event with a maximum at about 244 °C when heated from approximately 25 °C to approximately 300 °C.

[00161] In one embodiment, Form A is not hygroscopic with about 0.9% water uptake up to 95%) RH substantially as shown in FIG. 21.

[00162] In still another embodiment, Form A is substantially pure. In certain

embodiments, the substantially pure Form A is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form A is no less than about 95%>, no less than about 96%>, no less than about 97%>, no less than about 98%>, no less than about 98.5%>, no less than about 99%>, no less than about 99.5%>, or no less than about 99.8%.

5.3.2 Form B [00163] In certain embodiments, provided herein is Form B.

[00164] In one embodiment, Form B is a solid form of Compound 1. In one embodiment,

Form B is a hydrate of Compound 1. In another embodiment, Form B is crystalline.

[00165] In certain embodiments, Form B provided herein is obtained by equilibration experiments and evaporation experiments (see Table 1).

[00166] In certain embodiments, provided herein are equilibration or slurry methods for making Form B, comprising 1) obtaining a slurry of Form A in a solvent (e.g., THF/H₂O (from about 2: 1 to about 1 :2)); 2) stirring the slurry for a period of time (e.g., about 12-48 hours) at a certain temperature (e.g., about 20-30 °C or about 45-55 °C); and 3) collecting solids from the slurry by filtration and optionally drying. In certain embodiments, provided herein are equilibration or slurry methods for making Form B, comprising 1) obtaining a slurry of Form A in a solvent (e.g., THF/H₂0 (about 1 : 1)); 2) stirring the slurry for about 24 hours at about 25 °C or about 50 °C; and 3) collecting solids from the slurry and optionally air drying.

[00167] In certain embodiments, provided herein are evaporation methods for making

Form B, comprising 1) dissolving Form A in a solvent to yield a solution (e.g., THF/H₂0 (from about 2: 1 to about 1 :2) or IP A); 2) filtering the solution; and 3) evaporating the solution under certain air pressure (e.g., about 0.5-1.5 atm) at a certain temperature (e.g., about 20-30 °C or about 45-55 °C) to yield a solid. In certain embodiments, provided herein are evaporation methods for making Form B, comprising 1) dissolving Form A in a solvent (e.g., THF/H₂0

(about 1 : 1) or IP A) to yield a solution; 2) filtering the solution (e.g., filtering through 0.45 μπι PTFE syringe filters); and 3) evaporating the solution under about 1 atm air pressure at about 25 °C or about 50 °C under nitrogen to yield a solid.

[00168] In certain embodiments, the solvent is IP A or THF/H₂0. Ine one embodiment, the solvent is THF/H₂0 (about 1 : 1).

[00169] In one embodiment, Form B is observed to convert to Form M. In another embodiment, Form B is observed to convert to Form M at approximately 40 °C under vacuum.

[00170] In certain embodiments, a solid form provided herein, e.g., Form B, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form B has an X-ray powder diffraction pattern substantially as shown in FIG. 2. In one embodiment, Form B has one or more characteristic X-ray powder diffraction peaks at approximately 5.1, 5.4, 11.2, 13.9, 19.8, 10.9, 26.5, 18.4, 19.6, 9.2, 14.8, 15.3, 16.8, 18.7, 13.5, 23.8, 25.4, 23.4, 28.9, 23.1, 27.9, 30.0, 17.9, 22.4, 26.9, 24.4, 33.2 or 34.2 ⁰ 2Θ as depicted in FIG. 2. In a specific embodiment, Form B has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 5.1, 5.4, 10.9, 11.2, 13.9, 18.4, 19.8 or 26.5 ⁰ 2Θ. In another embodiment, Form B has one, two, three or four characteristic X- ray powder diffraction peaks at approximately 5.1, 5.4, 11.2 or 13.9 ⁰ 2Θ. In another

embodiment, Form B has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty- two, twenty -three, twenty-four, twenty-five, twenty-six, twenty-seven or twenty-eight characteristic X-ray powder diffraction peaks as set forth in Table 10.

[00171] In one embodiment, Form B has a SEM image substantially as shown in FIG. 23.

[00172] In one embodiment, provided herein is Form B having a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 24. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 10 % of the total mass of the sample around approximately 57 °C when heated from approximately 20 °C to approximately 300 °C. Thus, in certain embodiments, the crystalline form loses about 10 % of its total mass when heated from about ambient temperature to about 300 °C.

[00173] In one embodiment, provided herein is Form B having a DSC thermogram substantially as depicted in FIG. 25 comprising an endothermic event with a maximum at about 57 °C when heated from approximately 25 °C to approximately 300 °C.

[00174] In one embodiment, Form B has about 15% water uptake up to 95%> RH substantially as shown in FIG. 27.

[00175] In still another embodiment, Form B is substantially pure. In certain

embodiments, the substantially pure Form B is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form B is no less than about 95%>, no less than about 96%>, no less than about 97%>, no less than about 98%>, no less than about 98.5%>, no less than about 99%>, no less than about 99.5%>, or no less than about 99.8%. 5.3.3 Form C [00176] In certain embodiments, provided herein is Form C.

[00177] In one embodiment, Form C is a solid form of Compound 1. In one embodiment,

Form C is an anhydrous solid form of Compound 1. In another embodiment, Form C is crystalline. In another embodiment, Form C is monotropically related to Form E. In another embodiment, Form C is the kinectically favored form. In one embodiment, Form C melts at about 227 °C. In another embodiment, Form C is recrystallized to Form E at about 231 °C.

[00178] In certain embodiments, Form C provided herein is obtained by equilibration experiments, evaporation experiments, cooling recrystallization, crash cooling recrystallization and anti-solvent recrystallization experiments (see Table 1, Table 2, Table 3 and Table 4).

[00179] In certain embodiments, provided herein are equilibration or slurry methods for making Form C, comprising 1) obtaining a slurry of Form D, Form H, Form M, or Form A mixed with Form L, in a solvent (e.g., acetone, EtOH, IPA or THF); 2) stirring the slurry for a period of time (e.g., about 12-48 hours) at a certain temperature (e.g., about 20-30 °C or about 45-55 °C); and 3) collecting solids from the slurry by filtration and optionally drying. In certain embodiments, provided herein are equilibration or slurry methods for making Form C, comprising 1) obtaining a slurry of Form D, Form H, Form M, or Form A mixed with Form L in a solvent (e.g., acetone, EtOH, IPA or THF); 2) stirring the slurry for about 24 hours at about 25 °C or about 50 °C; and 3) collecting solids from the slurry and optionally air drying.

[00180] In certain embodiments, provided herein are evaporation methods for making

Form C, comprising 1) dissolving Form A in a solvent to yield a solution (e.g., THF); 2) filtering the solution; and 3) evaporating the solution under certain air pressure (e.g., about 0.5-1.5 atm) at a certain temperature (e.g., about 20-30 °C or about 45-55 °C) to yield a solid. In certain embodiments, provided herein are evaporation methods for making Form C, comprising 1) dissolving Form A in a solvent to yield a solution (e.g., THF); 2) filtering the solution (e.g., filtering through 0.45 μπι PTFE syringe filters); and 3) evaporating the solution under about 1 atm air pressure at about 25 °C or about 50 °C under nitrogen to yield a solid.

[00181] In certain embodiments, provided herein are cooling recrystallization methods for making Form C, comprising 1) obtaining a saturated solution of Form A in a solvent (e.g., acetone, EtOAc or MEK) at a first temperature (e.g., about 55 to 75 °C); 2) stirring the solution at the first temperature for a period of time (e.g., about 5-30 minutes); 3) filtering the solution; 4) cooling the solution slowly to a second temperature (e.g., about -4 °C to about 14 °C); and 5) isolating solids from the solution and optionally drying. In certain embodiments, provided herein are cooling recrystallization methods for making Form C, comprising 1) obtaining a saturated solution of Form A in a solvent (e.g., acetone, EtOAc or MEK) at about 65 °C; 2) stirring the solution at about 65 °C for about 10 minutes; 3) filtering the solution (e.g., filtering through 0.45 μπι PTFE syringe filters); 4) cooling the solution slowly to about 4 °C; and 5) isolating solids from the solution and optionally air-drying.

[00182] In certain embodiments, provided herein are crash cooling recrystallization methods for making Form C, comprising 1) obtaining a saturated solution of Form A in a solvent (e.g., THF) at a first temperature (e.g., about 55 to 75 °C); 2) stirring the solution at the first temperature for a period of time (e.g., about 5-30 minutes); 3) filtering the solution; 4) cooling the solution to a second temperature (e.g., about -30 °C to about -10 °C); and 5) isolating solids from the solution and optionally drying. In certain embodiments, provided herein are crash cooling recrystallization methods for making Form C, comprising 1) obtaining a saturated solution of Form A in a solvent (e.g., THF) at about 65 °C; 2) stirring the solution at about 65 °C for about 10 minutes; 3) filtering the solution (e.g., filtering through 0.45 μπι PTFE syringe filters); 4) cooling the solution to about -20 °C; and 5) isolating solids from the solution and optionally air-drying.

[00183] In certain embodiments, provided herein are anti-solvent recrystallization methods for making Form C, comprising 1) obtaining a saturated solution of Form A in a solvent (e.g., acetone, CH₃OH, DMSO, THF, THF/MeOH (e.g., from about 4: 1 to about 2: 1), MEK or THF/water (e.g., from about 40: 1 to about 10: 1)) at a first temperature (e.g., about 55-75 °C); 2) filtering the solution; 3) adding an anti-solvent (e.g., CH₃CN, water or isopropyl acetate) into the saturated solution at the first temperature; 3) cooling down to a second temperature (e.g., about - 5 °C to about 15 °C); and 5) collecting a solid if there is precipitation, and evaporating the solvent to collect a solid if there is no precipitation; and 6) optionally drying. In certain embodiments, provided herein are anti-solvent recrystallization methods for making Form C, comprising 1) obtaining a saturated solution of Form A in a solvent (e.g., acetone, CH₃OH, DMSO, THF, THF/MeOH (e.g., about 3 : 1), MEK or THF/water (e.g., about 95 :5)) at about 65 °C; 2) filtering the solution (e.g., filtering through 0.45 μιη PTFE syringe filters); 3) adding an anti-solvent (e.g., CH₃CN, water or isopropyl acetate) into the saturated solution at about 65 °C; 4) cooling down to about 5 °C; and 5) collecting a solid if there is precipitation, and evaporating the solvent to collect a solid if there is no precipitation; and 6) optionally air drying. In certain embodiments, the ratio by volume of solvent and anti-solvent is about 1 :9.

[00184] In certain embodiments, Form C is obtained from certain solvent systems including acetone, CH₃CN, DMSO, EtOAc, isopropyl acetate, MEK, THF, THF/MeOH (e.g., about 3 : 1), TUF/water (e.g., about 95 :5) and water.

[00185] In certain embodiments, a solid form provided herein, e.g., Form C, is

substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form C has an X-ray powder diffraction pattern substantially as shown in FIG. 3. In one embodiment, Form C has one or more characteristic X-ray powder diffraction peaks at approximately 3.7, 7.4, 8.0, 8.8, 1 1.1, 12.8, 14.2, 15.4, 16.4, 17.0, 17.8, 18.4, 18.9, 19.6, 20.5, 3.7, 7.4, 8.0, 1 1.1, 18.4, 18.9, 21.9, 25.1, 26.3, 27.1, 28.5, 29.5 or 30.6 ⁰ 2Θ as depicted in FIG. 3. In a specific embodiment, Form C has one, two, three, four, five, six, seven or eight

characteristic X-ray powder diffraction peaks at approximately 10.55, 13.61, 17.20, 17.85, 18.04, 19.84, 22.90 or 24.36 ⁰ 2Θ. In another embodiment, Form C has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 3.7, 7.4, 21.9 or 25.1 ⁰ 2Θ. In another embodiment, Form C has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two or twenty-three characteristic X-ray powder diffraction peaks as set forth in Table 1 1.

[00186] In one embodiment, Form C has a SEM image substantially as shown in FIG. 28.

[00187] In one embodiment, provided herein is Form C having a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 29. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising minimal mass loss of the total mass of the sample up to the melting of Form C with an onset melting

temperature of about 227 °C when heated from approximately 20 °C to approximately 300 °C. [00188] In one embodiment, provided herein is Form C having a DSC thermogram substantially as depicted in FIG. 30 comprising an endothermic event with a maximum at about

227 °C when heated from approximately 25 °C to approximately 300 °C.

[00189] In one embodiment, provided herein is Form C having a DSC thermogram substantially as depicted in FIG. 30 comprising an exothermic event with a maximum at about

231 °C when heated from approximately 25 °C to approximately 300 °C.

[00190] In one embodiment, provided herein is Form C having a DSC thermogram substantially as depicted in FIG. 30 comprising an endothermic event with a maximum at about

257 °C when heated from approximately 25 °C to approximately 300 °C.

[00191] In one embodiment, Form C is not hygroscopic with about 1.0% water uptake up to 95% RH as shown in FIG. 31.

[00192] In still another embodiment, Form C is substantially pure. In certain

embodiments, the substantially pure Form C is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form C is no less than about 95%>, no less than about 96%>, no less than about 97%>, no less than about 98%>, no less than about 98.5%>, no less than about 99%>, no less than about 99.5%>, or no less than about 99.8%.

5.3.4 Form D [00193] In certain embodiments, provided herein is Form D.

[00194] In one embodiment, Form D is a solid form of Compound 1. In one embodiment,

Form D is a hydrate of Compound 1. In one embodiment, Form D is an unstable hydrate of Compound 1. In another embodiment, Form D is crystalline. In another embodiment, Form D is converted to Form C after a dynamic vapor sorption experiment.

[00195] In certain embodiments, Form D provided herein is obtained by evaporation experiments and and anti-solvent recrystallization experiments (see Table 1 and Table 4).

[00196] In certain embodiments, provided herein are evaporation methods for making

Form D, comprising 1) dissolving Form A in a solvent to yield a solution (e.g., TUF); 2) filtering the solution; and 3) evaporating the solution under certain air pressure (e.g., about 0.5-1.5 atm) at a certain temperature (e.g., about 20-30 °C or about 45-55 °C) to yield a solid. In certain embodiments, provided herein are evaporation methods for making Form D, comprising 1) dissolving Form A in a solvent (e.g., TUF) to yield a solution; 2) filtering the solution (e.g., filtering through 0.45 μπι PTFE syringe filters); and 3) evaporating the solution under about 1 atm air pressure at about 25 °C or about 50 °C under nitrogen to yield a solid.

[00197] In certain embodiments, provided herein are anti-solvent recrystallization methods for making Form D, comprising 1) obtaining a saturated solution of Form A in a solvent (e.g., DMSO) at a first temperature (e.g., about 55-75 °C); 2) filtering the solution; 3) adding an anti-solvent (e.g., CH₃CN) into the saturated solution at the first temperature; 4) cooling down to a second temperature (e.g., about -5 °C to about 15 °C); and 5) collecting a solid if there is precipitation, and evaporating the solvent to collect a solid if there is no precipitation; and 6) optionally drying. In certain embodiments, provided herein are anti-solvent recrystallization methods for making Form D, comprising 1) obtaining a saturated solution of Form A in a solvent (e.g., DMSO) at about 65 °C; 2) filtering the solution (e.g., filtering through 0.45 μιη PTFE syringe filters); 3) adding an anti-solvent (e.g., CH₃CN) into the saturated solution at about 65 °C; 4) cooling down to about 5 °C; and 5) collecting a solid if there is precipitation, and evaporating the solvent to collect a solid if there is no precipitation; and 6) optionally air drying. In certain embodiments, the ratio by volume of solvent and anti-solvent is from about 1 :5 to about 1 :20. In certain embodiments, the ratio by volume of solvent and anti-solvent is about 1 : 10.

[00198] In certain embodiments, a solid form provided herein, e.g., Form D, is

substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form D has an X-ray powder diffraction pattern substantially as shown in FIG. 4. In one embodiment, Form D has one or more characteristic X-ray powder diffraction peaks at approximately 3.6, 7.3, 7.7, 8.2, 10.6, 10.9, 1 1.6, 12.5, 13.7, 15.1, 16.0, 16.5, 16.9, 17.8, 18.2, 18.6, 19.0, 19.6, 20.2, 21.4, 22.3, 22.9, 23.6, 24.4, 25.9, 26.4, 26.9, 27.8, 28.9, 29.5, 30.3, 30.9 or 36.7 ⁰ 2Θ as depicted in FIG. 4. In a specific embodiment, Form D has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 3.6, 7.3, 10.6, 15.1, 18.6, 21.4, 23.6 or 24.4 ⁰ 2Θ. In another embodiment, Form D has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 3.6, 7.3, 10.6 or 18.6 ⁰ 2Θ. In another embodiment, Form D has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty-two or thirty-three characteristic X-ray powder diffraction peaks as set forth in Table 12.

[00199] In one embodiment, Form D has a SEM image substantially as shown in FIG. 33.

[00200] In one embodiment, provided herein is Form D having a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 34. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 5.1 % of the total mass of the sample between approximately 50 °C and approximately 165 °C when heated from approximately 20 °C to approximately 300 °C. Thus, in certain embodiments, the crystalline form loses about 5.1 % of its total mass when heated from about ambient temperature to about 300 °C.

[00201] In one embodiment, provided herein is Form D having a DSC thermogram substantially as depicted in FIG. 35 comprising an endothermic event with a maximum at about 228 °C when heated from approximately 25 °C to approximately 300 °C.

[00202] In still another embodiment, Form D is substantially pure. In certain

embodiments, the substantially pure Form D is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form D is no less than about 95%, no less than about 96%>, no less than about 97%>, no less than about 98%>, no less than about 98.5%>, no less than about 99%>, no less than about 99.5%>, or no less than about 99.8%.

5.3.5 Form E

[00203] In certain embodiments, provided herein is Form E.

[00204] In one embodiment, Form E is a solid form of Compound 1. In one embodiment,

Form E is an anhydrous solid form of Compound 1. In another embodiment, Form E is crystalline. In another embodiment, Form E is converted to Form C after a dynamic vapor sorption experiment. In one embodiment, Form E melts at about 256 °C. In another

embodiment, Form E is the most thermodynamically stable form of Compound 1. [00205] In certain embodiments, Form E provided herein is obtained by equilibration experiments, evaporation experiments, and anti-solvent recrystallization experiments (see Table 1, Table 5 and Table 6).

[00206] In certain embodiments, provided herein are equilibration or slurry methods for making Form E, comprising 1) obtaining a slurry of Form A in a solvent (e.g., MEK, MeOAc, toluene, acetone, isopropanol or MeOH); 2) stirring the slurry for a period of time (e.g., about 12-48 hours) at a certain temperature (e.g., about 20-30 °C or about 45-55 °C); and 3) collecting solids from the slurry by filtration and optionally drying. In certain embodiments, provided herein are methods for making Form E, comprising 1) obtaining a slurry of Form A in a solvent (e.g., MEK, MeOAc, toluene, acetone, isopropanol or MeOH); 2) stirring the slurry for about 24 hours at about 25 °C or about 50 °C; and 3) collecting solids from the slurry and optionally air drying.

[00207] In certain embodiments, provided herein are evaporation methods for making

Form E, comprising 1) dissolving Form A in a solvent (e.g., n-BuOH, IP A, MEK or MeOAc) to yield a solution; 2) filtering the solution; and 3) evaporating the solution under certain air pressure (e.g., about 0.5-1.5 atm) at a certain temperature (e.g., about 20-30 °C or about 45-55 °C) to yield a solid. In certain embodiments, provided herein are methods for making Form E, comprising 1) dissolving Form A in a solvent (e.g., n-BuOH, IP A, MEK or MeOAc) to yield a solution; 2) filtering the solution (e.g., filtering through 0.45 μπι PTFE syringe filters); and 3) evaporating the solution under about 1 atm air pressure at about 25 °C or about 50 °C under nitrogen to yield a solid.

[00208] In certain embodiments, provided herein are anti-solvent recrystallization methods for making Form E, comprising 1) obtaining a saturated solution of Form A in a solvent (e.g., THF/MeOH (e.g., from about 4: 1 to about 2: 1) or THF/water (e.g., from about 40: 1 to about 10: 1)) at a first temperature (e.g., about 55-75 °C); 2) filtering the solution; 3) adding an anti-solvent (e.g., MeOH or water) into the saturated solution at the first temperature; 4) cooling down to a second temperature (e.g., about -5 °C to about 15 °C); and 5) collecting a solid if there is precipitation, and evaporating the solvent to collect a solid if there is no precipitation; and 6) optionally drying. In certain embodiments, provided herein are methods for making Form E, comprising 1) obtaining a saturated solution of Form A in a solvent (e.g., THF/iPrOH (e.g., about 3 : 1) or THF/water (e.g., about 95 :5)) at about 65 °C; 2) filtering the solution (e.g., filtering through 0.45 μιη PTFE syringe filters); 3) adding an anti-solvent (e.g., MeOH or water) into the saturated solution at about 65 °C; 4) cooling down to about 5 °C; and 5) collecting a solid if there is precipitation, and evaporating the solvent to collect a solid if there is no precipitation; and 6) optionally air drying. In certain embodiments, the ratio by volume of solvent and anti-solvent is from about 40: 1 to about 10: 1. In certain embodiments, the ratio by volume of solvent and anti- solvent is about 20: 1.

[00209] In certain embodiments, Form E is obtained from certain solvent systems including acetone, «-BuOH, IP A, MeOAc, MeOH, MEK, THF, THF/IPA (e.g., about 3 : 1), THF/water (e.g., about 95 :5) and THF/MeOH.

[00210] In certain embodiments, a solid form provided herein, e.g., Form E, is

substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form E has an X-ray powder diffraction pattern substantially as shown in FIG. 5. In one embodiment, Form E has one or more characteristic X-ray powder diffraction peaks at approximately 5.5, 6.5, 7.9, 9.0, 9.5, 1 1.1, 13.3, 15.0, 15.9, 16.7, 17.0, 18.0, 18.4, 18.8, 19.7, 20.2, 21.3, 23.2, 24.5, 26.3 or 30.4 ⁰ 2Θ as depicted in FIG. 5. In a specific embodiment, Form E has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 5.5, 6.5, 9.0, 1 1.1, 15.0, 18.0, 18.8 or 20.2 ⁰ 2Θ. In another embodiment, Form E has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 5.5, 1 1.1, 15.0 or 18.8 ⁰ 2Θ. In another embodiment, Form E has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty or twenty-one characteristic X-ray powder diffraction peaks as set forth in Table 13.

[00211] In one embodiment, Form E has a SEM image substantially as shown in FIG. 38.

[00212] In one embodiment, provided herein is Form E having a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 39. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising minimal mass loss of the total mass of the sample up to the melting of Form E with an onset melting temperature of about 256 °C when heated from approximately 20 °C to approximately 300 °C. [00213] In one embodiment, provided herein is Form E having a DSC thermogram substantially as depicted in FIG. 40 comprising an endothermic event with an onset temperature at about 256 °C when heated from approximately 25 °C to approximately 300 °C.

[00214] In one embodiment, Form E is not hygroscopic with about 1.0% water uptake up to 95%) RH substantially as shown in FIG. 41.

[00215] In still another embodiment, Form E is substantially pure. In certain

embodiments, the substantially pure Form E is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form E is no less than about 95%>, no less than about 96%>, no less than about 97%>, no less than about 98%>, no less than about 98.5%>, no less than about 99%>, no less than about 99.5%>, or no less than about 99.8%.

5.3.6 Form F

[00216] In certain embodiments, provided herein is Form F.

[00217] In one embodiment, Form F is a solid form of Compound 1. In one embodiment,

Form F is a hydrate of Compound 1. In another embodiment, Form F is crystalline.

[00218] In certain embodiments, Form F provided herein is obtained by equilibration experiment and evaporation experiments (see Table 1 and Table 6).

[00219] In certain embodiments, provided herein are equilibration or slurry methods for making Form F, comprising 1) obtaining a slurry of Form A in a solvent (e.g., EtOH/water (e.g., from about 2: 1 to about 1 :2)); 2) stirring the slurry for a period of time (e.g., about 12-48 hours) at a certain temperature (e.g., about 20-30 °C or about 45-55 °C); and 3) collecting solids from the slurry by filtration and optionally drying. In certain embodiments, provided herein are equilibration or slurry methods for making Form F, comprising 1) obtaining a slurry of Form A in a solvent (e.g., EtOH/water (e.g., 1 : 1)); 2) stirring the slurry for about 24 hours at about 25 °C or about 50 °C; and 3) collecting solids from the slurry and optionally air drying.

[00220] In certain embodiments, provided herein are evaporation methods for making

Form F, comprising 1) dissolving Form A in a solvent to yield a solution (e.g., EtOH, IPA or EtOAc); 2) filtering the solution; and 3) evaporating the solution under certain air pressure (e.g., about 0.5-1.5 atm) at a certain temperature (e.g., about 20-30 °C or about 45-55 °C) to yield a solid. In certain embodiments, provided herein are evaporation methods for making Form F, comprising 1) dissolving Form A in a solvent (e.g., EtOH, IPA or EtOAc) to yield a solution; 2) filtering the solution (e.g., filtering through 0.45 μπι PTFE syringe filters); and 3) evaporating the solution under about 1 atm air pressure at about 25 °C or about 50 °C under nitrogen to yield a solid.

[00221] In certain embodiments, the solvent is EtOAc, EtOH, IPA or EtOH/H₂0.

[00222] In certain embodiments, a solid form provided herein, e.g., Form F, is

substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form F has an X-ray powder diffraction pattern substantially as shown in FIG. 6. In one embodiment, Form F has one or more characteristic X-ray powder diffraction peaks at approximately 5.4, 5.9, 7.6, 8.1, 10.8, 11.7, 12.5, 13.2, 13.9, 15.3, 16.6, 17.6, 18.0, 21.2, 24.1, 24.5, 26.4 or 28.0 ⁰ 2Θ as depicted in FIG. 6. In a specific embodiment, Form F has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at

approximately 5.4, 5.9, 7.6, 8.1, 11.7, 13.2, 16.6 or 17.6 ⁰ 2Θ. In another embodiment, Form F has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 5.4, 5.9, 11.7 or 13.2 ⁰ 2Θ. In another embodiment, Form F has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen or eighteen characteristic X-ray powder diffraction peaks as set forth in Table 14.

[00223] In one embodiment, Form F has a SEM image substantially as shown in FIG. 43.

[00224] In one embodiment, provided herein is Form F having a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 44. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 0.4 % of the total mass of the sample between approximately 150 °C and approximately 200 °C when heated from approximately 20 °C to approximately 300 °C.

[00225] In one embodiment, provided herein is Form F having a DSC thermogram substantially as depicted in FIG. 45 comprising an endothermic event with a maximum at about 204 °C when heated from approximately 25 °C to approximately 300 °C.

[00226] In one embodiment, the DVS isotherm plot of Form F shows about 3.8% water uptake up to 95% RH substantially as shown in FIG. 47. [00227] In still another embodiment, Form F is substantially pure. In certain embodiments, the substantially pure Form F is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form F is no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.

5.3.7 Form G

[00228] In certain embodiments, provided herein is Form G.

[00229] In one embodiment, Form G is a solid form of Compound 1. In one embodiment,

Form G is a hydrate of Compound 1. In another embodiment, Form G is crystalline.

[00230] In certain embodiments, Form G provided herein is obtained by evaporation experiments (see Table 1).

[00231] In certain embodiments, provided herein are evaporation methods for making

Form G, comprising 1) dissolving Form A in a solvent (e.g., acetone) to yield a solution; 2) filtering the solution; and 3) evaporating the solution under certain air pressure (e.g., about 0.5- 1.5 atm) at a certain temperature (e.g., about 20-30 °C or about 45-55 °C) to yield a solid. In certain embodiments, provided herein are evaporation methods for making Form G, comprising 1) dissolving Form A in a solvent (e.g., acetone) to yield a solution; 2) filtering the solution (e.g., filtering through 0.45 μπι PTFE syringe filters); and 3) evaporating the solution under about 1 atm air pressure at about 25 °C or about 50 °C under nitrogen to yield a solid.

[00232] In certain embodiments, the solvent is acetone.

[00233] In certain embodiments, a solid form provided herein, e.g., Form G, is

substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form G has an X-ray powder diffraction pattern substantially as shown in FIG. 7. In one embodiment, Form G has one or more characteristic X-ray powder diffraction peaks at approximately 3.3, 5.1, 6.6, 8.0, 8.6, 9.8, 10.4, 10.8, 12.0, 12.8, 13.2, 13.8, 14.7, 16.0, 17.1, 18.4, 18.9, 20.1, 21.7, 22.6, 23.6, 24.9, 26.6 or 29.8 ⁰ 2Θ as depicted in FIG. 7. In a specific embodiment, Form G has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 3.3, 6.6, 8.0, 10.4, 10.8, 17.1, 21.7 or 24.9 ⁰ 2Θ. In another embodiment, Form G has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 3.3, 8.0, 17.1 or 21.7 ° 20. In another embodiment, Form G has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty -two, twenty -three or twenty -four characteristic X-ray powder diffraction peaks as set forth in Table 15.

[00234] In one embodiment, provided herein is Form G having a DSC thermogram substantially as depicted in FIG. 48 comprising an endothermic event with a maximum at about 212 °C when heated from approximately 25 °C to approximately 300 °C.

[00235] In still another embodiment, Form G is substantially pure. In certain

embodiments, the substantially pure Form G is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form G is no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.

5.3.8 Form H

[00236] In certain embodiments, provided herein is Form H.

[00237] In one embodiment, Form H is a solid form of Compound 1. In one embodiment,

Form H is a hydrate of Compound 1. In another embodiment, Form H is crystalline.

[00238] In certain embodiments, Form H provided herein is obtained by evaporation experiments and cooling recrystallization experiments (see Table 1 and Table 2).

[00239] In certain embodiments, provided herein are evaporation methods for making

Form H, comprising 1) dissolving Form A in a solvent (e.g., MeOH) to yield a solution; 2) filtering the solution; and 3) evaporating the solution under certain air pressure (e.g., about 0.5- 1.5 atm) at a certain temperature (e.g., about 20-30 °C or about 45-55 °C) to yield a solid. In certain embodiments, provided herein are evaporation methods for making Form H, comprising 1) dissolving Form A in a solvent (e.g., MeOH) to yield a solution; 2) filtering the solution (e.g., filtering through 0.45 μπι PTFE syringe filters); and 3) evaporating the solution under about 1 atm air pressure at about 25 °C or about 50 °C under nitrogen to yield a solid. [00240] In certain embodiments, provided herein are cooling recrystallization methods for making Form H, comprising 1) obtaining a saturated solution of Form A in a solvent (e.g., MeOH) at a first temperature (e.g., about 55 to 75 °C); 2) stirring the solution at the first temperature for a period of time (e.g., 5-30 minutes); 3) filtering the solution; 4) cooling the solution slowly to a second temperature (e.g., about -4 °C to about 14 °C); and 5) isolating solids from the solution and optionally drying. In certain embodiments, provided herein are cooling recrystallization methods for making Form H, comprising 1) obtaining a saturated solution of Form A in a solvent (e.g., MeOH) at about 65 °C; 2) stirring the solution at about 65 °C for 10 minutes; 3) filtering the solution (e.g., filtering through 0.45 μπι PTFE syringe filters); 4) cooling the solution slowly to about 4 °C; and 5) isolating solids from the solution and optionally air- drying.

[00241] In one embodiment, the solvent is MeOH.

[00242] In certain embodiments, a solid form provided herein, e.g., Form H, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form H has an X-ray powder diffraction pattern substantially as shown in FIG. 8. In one embodiment, Form H has one or more characteristic X-ray powder diffraction peaks at approximately 3.7, 5.1, 5.3, 7.3, 8.4, 10.2, 10.7, 1 1.4, 1 1.9, 13.0, 13.7, 15.0, 15.3, 16.3, 16.8, 18.0, 19.0, 19.5, 21.2, 22.7, 23.2, 25.9, 27.5 or 29.3 ⁰ 2Θ as depicted in FIG. 8. In a specific embodiment, Form H has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 5.1, 5.3, 7.3, 10.2, 13.0, 15.0, 15.3 or 16.3 ⁰ 2Θ. In another embodiment, Form H has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 5.1, 5.3, 7.3 or 10.2 ⁰ 2Θ. In another embodiment, Form H has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty -two, twenty -three or twenty -four characteristic X-ray powder diffraction peaks as set forth in Table 16.

[00243] In one embodiment, Form H has a SEM image substantially as shown in FIG. 50.

[00244] In one embodiment, provided herein is Form H having a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 51. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 3.2 % of the total mass of the sample between approximately 25 °C and approximately 130 °C when heated from approximately 20 °C to approximately 300 °C. Thus, in certain embodiments, the crystalline form loses about 3.2 % of its total mass when heated from about ambient temperature to about 300 °C.

[00245] In one embodiment, provided herein is Form H having a DSC thermogram substantially as depicted in FIG. 52 comprising an endothermic event with a maximum at about 132 °C when heated from approximately 25 °C to approximately 300 °C.

[00246] In one embodiment, the DVS isotherm plot of Form H shows about 3.9 % water uptake up to 95% RH substantially as shown in FIG. 53.

[00247] In still another embodiment, Form H is substantially pure. In certain

embodiments, the substantially pure Form H is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form H is no less than about 95%>, no less than about 96%>, no less than about 97%>, no less than about 98%>, no less than about 98.5%>, no less than about 99%>, no less than about 99.5%>, or no less than about 99.8%.

5.3.9 Form I

[00248] In certain embodiments, provided herein is Form I.

[00249] In one embodiment, Form I is a solid form of Compound 1. In one embodiment,

Form I is a solvate of Compound 1. In one embodiment, Form I is an IPA solvate of Compound 1. In another embodiment, Form I is a hydrate of Compound 1. In another embodiment, Form I is crystalline.

[00250] In certain embodiments, Form I provided herein is obtained by evaporation experiments (see Table 1).

[00251] In certain embodiments, provided herein are evaporation methods for making

Form I, comprising 1) dissolving Form A in a solvent (e.g., IPA or EtOH) to yield a solution; 2) filtering the solution; and 3) evaporating the solution under certain air pressure (e.g., about 0.5- 1.5 atm) at a certain temperature (e.g., about 20-30 °C or about 45-55 °C) to yield a solid. In certain embodiments, provided herein are evaporation methods for making Form I, comprising 1) dissolving Form A in a solvent (e.g., IPA or EtOH) to yield a solution; 2) filtering the solution (e.g., filtering through 0.45 μηι PTFE syringe filters); and 3) evaporating the solution under about 1 atm air pressure at about 25 °C or about 50 °C under nitrogen to yield a solid.

[00252] In certain embodiments, the solvent is IPA or EtOH.

[00253] In certain embodiments, a solid form provided herein, e.g., Form I, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form I has an X-ray powder diffraction pattern substantially as shown in FIG. 9. In one embodiment, Form I has one or more characteristic X-ray powder diffraction peaks at approximately 4.3, 6.4, 8.8, 12.4, 12.9, 14.9, 16.4, 17.4, 18.4, 19.4, 20.5, 21.3, 24.8 or 25.6 ⁰ 2Θ as depicted in FIG. 9. In a specific embodiment, Form I has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 4.3, 6.4, 12.4, 12.9, 14.9, 17.4, 18.4 or 21.3 ⁰ 2Θ. In another embodiment, Form I has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 4.3, 6.4, 12.4 or 14.9 ⁰ 2Θ. In another embodiment, Form I has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen or fourteen characteristic X-ray powder diffraction peaks as set forth in Table 17.

[00254] In one embodiment, provided herein is Form I having a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 54. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 4.3 % of the total mass of the sample between approximately 25 °C and approximately 230 °C when heated from approximately 20 °C to approximately 300 °C. Thus, in certain embodiments, the crystalline form loses about 4 % of its total mass when heated from about ambient temperature to about 300 °C.

[00255] In one embodiment, provided herein is Form I having a DSC thermogram substantially as depicted in FIG. 55 comprising an exothermic event with a maximum at about 197 °C when heated from approximately 25 °C to approximately 300 °C.

[00256] In one embodiment, 1H MR of Form I shows that Form I contains about 1.6 wt% IPA substantially as shown in FIG. 56.

[00257] In still another embodiment, Form I is substantially pure. In certain

embodiments, the substantially pure Form I is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form I is no less than about 95%, no less than about 96%>, no less than about 97%>, no less than about 98%>, no less than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.

5.3.10 Form J

[00258] In certain embodiments, provided herein is Form J.

[00259] In one embodiment, Form J is a solid form of Compound 1. In one embodiment,

Form J is a hydrate of Compound 1. In another embodiment, Form J is crystalline. In another embodiment, Form J is converted to Form F after a dynamic vapor sorption experiment. In another embodiment, Form J is a less stable hydrate than Form F.

[00260] In certain embodiments, Form J provided herein is obtained by equilibration experiments, evaporation experiments and anti-solvent recrystallization experiments (see Table 1, Table 4 and Table 6).

[00261] In certain embodiments, provided herein are equilibration or slurry methods for making Form J, comprising 1) obtaining a slurry of Form H in a solvent (e.g., EtOH/H₂0 (e.g., from about 2: 1 to about 1 :2) and IP A); 2) stirring the slurry for a period of time (e.g., about 12- 48 hours) at a certain temperature (e.g., about 20-30 °C or about 45-55 °C); and 3) collecting solids from the slurry by filtration and optionally drying. In certain embodiments, provided herein are equilibration or slurry methods for making Form J, comprising 1) obtaining a slurry of Form H in a solvent (e.g., EtOH/H₂0 (about 1 : 1) and IP A); 2) stirring the slurry for about 24 hours at about 25 °C or about 50 °C; and 3) collecting solids from the slurry and optionally air drying.

[00262] In certain embodiments, provided herein are evaporation methods for making

Form J, comprising 1) dissolving Form A in a solvent (e.g., n-BuOH) to yield a solution; 2) filtering the solution; and 3) evaporating the solution under certain air pressure (e.g., about 0.5- 1.5 atm) at a certain temperature (e.g., about 20-30 °C or about 45-55 °C) to yield a solid. In certain embodiments, provided herein are evaporation methods for making Form J, comprising 1) dissolving Form A in a solvent (e.g., n-BuOH) to yield a solution; 2) filtering the solution (e.g., filtering through 0.45 μπι PTFE syringe filters); and 3) evaporating the solution under about 1 atm air pressure at about 25 °C or about 50 °C under nitrogen to yield a solid. [00263] In certain embodiments, provided herein are anti-solvent recrystallization methods for making Form J, comprising 1) obtaining a saturated solution of Form A in a solvent (e.g., THF) at a first temperature (e.g., about 55-75 °C); 2) filtering the solution; 3) adding an anti-solvent (e.g., heptane) into the saturated solution at the first temperature; 4) cooling down to a second temperature (e.g., about -5 °C to about 15 °C); and 5) collecting a solid if there is precipitation, and evaporating the solvent to collect a solid if there is no precipitation; and 6) optionally drying. In certain embodiments, provided herein are anti-solvent recrystallization methods for making Form J, comprising 1) obtaining a saturated solution of Form A in a solvent (e.g., THF) at about 65 °C; 2) filtering the solution (e.g., filtering through 0.45 μπι PTFE syringe filters); 3) adding an anti-solvent (e.g., heptane) into the saturated solution at about 65 °C; 4) cooling down to about 5 °C; and 5) collecting a solid if there is precipitation, and evaporating the solvent to collect a solid if there is no precipitation; and 6) optionally air drying. In certain embodiments, the ratio by volume of solvent and anti-solvent is from about 1 :5 to about 1 :20. In certain embodiments, the ratio by volume of solvent and anti-solvent is about 1 : 10.

[00264] In certain embodiments, Form J is obtained from certain solvent systems including EtOH/H₂0, THF/heptane and «-BuOH. In one embodiment, the solvent system is EtOH/H₂0 (about 1 : 1) or THF/heptanes (about 1 : 10).

[00265] In certain embodiments, a solid form provided herein, e.g., Form J, is

substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form J has an X-ray powder diffraction pattern substantially as shown in FIG. 10. In one embodiment, Form J has one or more characteristic X-ray powder diffraction peaks at approximately 5.2, 5.7, 8.7, 9.7, 10.5, 11.5, 13.0, 13.4, 14.2, 14.6, 14.8, 15.5, 15.8, 17.1, 17.5, 18.1, 18.6, 19.1, 19.5, 20.7, 21.1, 21.7, 22.3, 23.5, 24.6, 25.8, 27.1, 28.7 or 30.9 ⁰ 2Θ as depicted in FIG. 10. In a specific embodiment, Form J has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 5.2, 5.7, 8.7, 14.2, 19.1, 20.7, 21.1 or 24.6 ⁰ 2Θ. In another embodiment, Form J has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 5.2, 5.7, 20.7 or 24.6 ⁰ 2Θ. In another embodiment, Form J has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty -two, twenty - three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine or thirty characteristic X-ray powder diffraction peaks as set forth in Table 18.

[00266] In one embodiment, provided herein is Form J having a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 57. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 0.16 % of the total mass of the sample between approximately 25 °C and approximately 80 °C when heated from approximately 20 °C to approximately 300 °C.

[00267] In one embodiment, provided herein is Form J having a DSC thermogram substantially as depicted in FIG. 58 comprising an endothermic event with a maximum at about 46 °C when heated from approximately 25 °C to approximately 300 °C.

[00268] In still another embodiment, Form J is substantially pure. In certain

embodiments, the substantially pure Form J is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form J is no less than about 95%, no less than about 96%>, no less than about 97%>, no less than about 98%>, no less than about 98.5%>, no less than about 99%>, no less than about 99.5%>, or no less than about 99.8%.

5.3.1 1 Form K [00269] In certain embodiments, provided herein is Form K.

[00270] In one embodiment, Form K is a solid form of Compound 1. In one embodiment,

Form K is a solvate of Compound 1. In another embodiment, Form K is an acetone solvate of Compound 1. In another embodiment, Form K is a 0.8 molar equivalent acetone solvate of Compound 1. In another embodiment, Form K is crystalline.

[00271] In certain embodiments, Form K provided herein is obtained by crash cooling recrystallization experiments and cooling recrystallization experiments (see Table 3 and Table 5).

[00272] In certain embodiments, provided herein are cooling recrystallization methods for making Form K, comprising 1) obtaining a saturated solution of Form A in a solvent (e.g., acetone) at a first temperature (e.g., about 55 to 75 °C); 2) stirring the solution at the first temperature for a period of time (e.g., about 5-30 minutes); 3) filtering the solution; 4) cooling the solution slowly to a second temperature (e.g., about -4 °C to about 14 °C); and 5) isolating solids from the solution and optionally drying. In certain embodiments, provided herein are methods for making Form K, comprising 1) obtaining a saturated solution of Form A in a solvent at about 65 °C; 2) stirring the solution at about 65 °C for 10 minutes; 3) filtering the solution (e.g., filtering through 0.45 μπι PTFE syringe filters); 4) cooling the solution slowly to about 4 °C; and 5) isolating solids from the solution and optionally air-drying.

[00273] In certain embodiments, provided herein are crash cooling recrystallization methods for making Form K, comprising 1) obtaining a saturated solution of Form A in a solvent (e.g., acetone) at a first temperature (e.g., about 55 to 75 °C); 2) stirring the solution at the first temperature for a period of time (e.g., about 5-30 minutes); 3) filtering the solution; 4) cooling the solution to a second temperature (e.g., about -30 °C to about -10 °C); and 5) isolating solids from the solution and optionally drying. In certain embodiments, provided herein are methods for making Form K, comprising 1) obtaining a saturated solution of Form A in a solvent at about 65 °C; 2) stirring the solution at about 65 °C for 10 minutes; 3) filtering the solution (e.g., filtering through 0.45 μπι PTFE syringe filters); 4) cooling the solution to about -20 °C; and 5) isolating solids from the solution and optionally air-drying.

[00274] In certain embodiments, Form K is obtained from certain solvent systems including acetone.

[00275] In certain embodiments, a solid form provided herein, e.g., Form K, is

substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form K has an X-ray powder diffraction pattern substantially as shown in FIG. 1 1. In one embodiment, Form K has one or more characteristic X-ray powder diffraction peaks at approximately 4.2, 10.4, 1 1.6, 1 1.9, 12.1, 12.8, 13.1, 13.4, 14.8, 16.3, 16.9, 17.4, 17.9, 18.2, 19.2, 20.1, 20.3, 20.7, 21.4, 22.2, 22.6, 23.4, 23.8, 25.1, 25.9, 27.3, 27.7, 28.4, 28.6 or 30.1 ⁰ 2Θ as depicted in FIG. 1 1. In a specific embodiment, Form K has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 4.2, 10.4, 1 1.6, 12.1, 16.3, 17.9, 18.2 or 25.9 ⁰ 2Θ. In another embodiment, Form K has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 4.2, 10.4, 16.3 or 25.9 ⁰ 2Θ. In another embodiment, Form K has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine or thirty characteristic X-ray powder diffraction peaks as set forth in Table 19.

[00276] In one embodiment, provided herein is Form K having a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 61. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 10.4 % of the total mass of the sample between approximately 25 °C and approximately 175 °C when heated from approximately 20 °C to approximately 300 °C.

[00277] In one embodiment, provided herein is Form K having a DSC thermogram substantially as depicted in FIG. 62 comprising an endothermic event with a maximum at about 150 °C when heated from approximately 25 °C to approximately 300 °C. In one embodiment, the DSC thermogram further comprises an endothermic event with a maximum at about 269 °C when heated from approximately 25 °C to approximately 300 °C.

[00278] In one embodiment, 1H MR of Form K shows that Form K contains about 0.8 molar equivalent acetone substantially as shown in FIG. 63.

[00279] In still another embodiment, Form K is substantially pure. In certain

embodiments, the substantially pure Form K is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form K is no less than about 95%, no less than about 96%>, no less than about 97%>, no less than about 98%>, no less than about 98.5%>, no less than about 99%>, no less than about 99.5%>, or no less than about 99.8%.

5.3.12 Form L

[00280] In certain embodiments, provided herein is Form L.

[00281] In one embodiment, Form L is a solid form of Compound 1. In one embodiment,

Form L is an anhydrous solid form of Compound 1. In another embodiment, Form L is crystalline. In another embodiment, Form L is enantiotropically related to Form E. In one embodiment, Form L melts at about 268 °C.

[00282] In one embodiment, Form L is obtained by heating a solvate of Compound 1. In one embodiment, the solvate is Form K. In one embodiment, the solvate is heated to between about 240 °C to about 280 °C to give Form L. In one embodiment, the solvate is heated to about 260 °C to give Form L. See Table 6.

[00283] In certain embodiments, a solid form provided herein, e.g., Form L, is

substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form L has an X-ray powder diffraction pattern substantially as shown in FIG. 12. In one embodiment, Form L has one or more characteristic X-ray powder diffraction peaks at approximately 6.3, 7.3, 9.6, 11.9, 12.6, 13.1, 13.7, 14.6, 15.1, 15.8, 16.8, 17.0, 17.8, 18.2, 18.9, 19.3, 19.9, 20.4, 21.6, 22.2, 22.8, 23.4, 24.0, 25.1, 25.9, 26.7, 27.7, 28.0, 30.5, 31.2, 34.7 or 35.6 ⁰ 2Θ as depicted in FIG. 12. In a specific embodiment, Form L has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 7.3, 13.7, 16.8, 17.0, 17.8, 18.9, 22.8 or 24.0 ⁰ 2Θ. In another embodiment, Form L has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 7.3, 17.8, 22.8 or 24.0 ⁰ 2Θ. In another embodiment, Form L has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one or thirty-two, characteristic X-ray powder diffraction peaks as set forth in Table 20.

[00284] In one embodiment, provided herein is Form L having a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 64. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising minimal mass loss of the total mass of the sample up to the melting of Form L with an onset temperature at about 268 °C when heated from approximately 20 °C to approximately 300 °C.

[00285] In one embodiment, provided herein is Form L having a DSC thermogram substantially as depicted in FIG. 65 comprising an endothermic event with an onset temperature at about 268 °C when heated from approximately 25 °C to approximately 300 °C.

[00286] In one embodiment, Form L is slightly hygroscopic with about 1.8% water uptake up to 95% RH substantially as shown in FIG. 67.

[00287] In still another embodiment, Form L is substantially pure. In certain

embodiments, the substantially pure Form L is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form L is no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.

5.3.13 Form M

[00288] In certain embodiments, provided herein is Form M.

[00289] In one embodiment, Form M is a solid form of Compound 1. In one embodiment,

Form M is a dehydrated form of Compound 1. In another embodiment, Form M is crystalline. In one embodiment, Form M melts at about 173 °C.

[00290] In one embodiment, Form M is obtained by heating a hydrate of Compound 1. In one embodiment, the hydrate is Form B. In one embodiment, Form B is heated to between about 20 °C to 60 °C to give Form M. In one embodiment, Form B is heated to about 40 °C under vacuum to give Form M.

[00291] In one embodiment, Form M is heated to about 160 to 200 °C to give the amorphous form of Compound 1.

[00292] In certain embodiments, a solid form provided herein, e.g., Form M, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form M has an X-ray powder diffraction pattern substantially as shown in FIG. 13. In one embodiment, Form M has one or more characteristic X-ray powder diffraction peaks at approximately 5.7, 6.2, 9.6, 10.5, 11.5, 14.8, 15.8, 16.3, 16.5, 17.3, 19.2, 20.3, 21.0, 21.3, 22.0, 22.7, 23.1, 23.7, 25.8, 27.1 or 27.7 ⁰ 2Θ as depicted in FIG. 13. In a specific embodiment, Form M has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 5.7, 6.2, 9.6, 11.5, 14.8, 15.8, 16.5 or 17.3 ⁰ 2Θ. In another embodiment, Form M has one, two, three or four characteristic X-ray powder diffraction peaks at

approximately 5.7, 6.2, 9.6 or 11.5 ⁰ 2Θ. In another embodiment, Form M has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty or twenty-one characteristic X-ray powder diffraction peaks as set forth in Table 21.

[00293] In one embodiment, provided herein is Form M having a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 68. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising minimal mass loss of the total mass of the sample up to the melting of Form M between approximately 25 °C to approximately 250 °C when heated from approximately 20 °C to approximately 300 °C.

[00294] In one embodiment, provided herein is Form M having a DSC thermogram substantially as depicted in FIG. 69 comprising an endothermic event with a maximum at about 173 °C when heated from approximately 25 °C to approximately 300 °C. In one embodiment, the DSC thermogram further comprises an exothermic event with a maximum at about 193 °C when heated from approximately 25 °C to approximately 300 °C.

[00295] In one embodiment, Form M is slightly hygroscopic with about 1.3 wt% water uptake up to 95% RH substantially as shown in FIG. 70.

[00296] In still another embodiment, Form M is substantially pure. In certain

embodiments, the substantially pure Form M is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form M is no less than about 95%>, no less than about 96%>, no less than about 97%>, no less than about 98%>, no less than about 98.5%>, no less than about 99%>, no less than about 99.5%>, or no less than about 99.8%.

5.3.14 Form N [00297] In certain embodiments, provided herein is Form N.

[00298] In one embodiment, Form N is a solid form of Compound 1. In one embodiment,

Form N is a hydrate of Compound 1. In another embodiment, Form N is crystalline.

[00299] In certain embodiments, Form N provided herein is obtained by equilibration experiments and crash cooling recrystallization experiments (see Table 3 and Table 6).

[00300] In certain embodiments, provided herein are equilibration or slurry methods for making Form N, comprising 1) obtaining a slurry of Form C mixed with Form E in a solvent (e.g., MeOH); 2) stirring the slurry for a period of time (e.g., about 12-48 hours) at a certain temperature (e.g., about 20-30 °C or about 45-55 °C); and 3) collecting solids from the slurry by filtration and optionally drying. In certain embodiments, provided herein are methods for making Form N, comprising 1) obtaining a slurry of Form C mixed with Form E in a solvent (e.g., MeOH); 2) stirring the slurry for about 24 hours at about 25 °C or about 50 °C; and 3) collecting solids from the slurry and optionally air drying.

[00301]

[00302] In certain embodiments, provided herein are crash cooling recrystallization methods for making Form N, comprising 1) obtaining a saturated solution of Form A in a solvent (e.g., MeOH) at a first temperature (e.g., about 55 to 75 °C); 2) stirring the solution at the first temperature for a period of time (e.g., 5-30 minutes); 3) filtering the solution; 4) cooling the solution to a second temperature (e.g., about -30 °C to about -10 °C); and 5) isolating solids from the solution and optionally drying. In certain embodiments, provided herein are methods for making Form N, comprising 1) obtaining a saturated solution of Form A in a solvent (e.g., MeOH) at about 65 °C; 2) stirring the solution at about 65 °C for 10 minutes; 3) filtering the solution (e.g., filtering through 0.45 μπι PTFE syringe filters); 4) cooling the solution to about - 20 °C; and 5) isolating solids from the solution and optionally air-drying.

[00303] In certain embodiments, Form N is obtained from certain solvent systems including MeOH.

[00304] In certain embodiments, a solid form provided herein, e.g., Form N, is

substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form N has an X-ray powder diffraction pattern substantially as shown in FIG. 14. In one embodiment, Form N has one or more characteristic X-ray powder diffraction peaks at approximately 6.3, 7.9, 9.5, 10.7, 12.3, 14.1, 16.7, 17.8, 18.5, 19.3, 21.5, 23.2, 26.2, 27.8, 29.4 or 33.3 ⁰ 2Θ as depicted in FIG. 14. In a specific embodiment, Form N has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 6.3, 7.9, 9.5, 10.7, 12.3, 14.1, 16.7 or 23.2 ⁰ 2Θ. In another embodiment, Form N has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 6.3, 10.7, 14.1 or 23.2 ⁰ 2Θ. In another embodiment, Form N has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen or sixteen characteristic X-ray powder diffraction peaks as set forth in Table 22.

[00305] In one embodiment, provided herein is Form N having a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 71. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 1.6 % of the total mass of the sample between approximately 25 °C and approximately 170 °C when heated from approximately 20 °C to approximately 300 °C. Thus, in certain embodiments, the crystalline form loses about 1.6 % of its total mass when heated from about ambient temperature to about 300 °C.

[00306] In one embodiment, provided herein is Form N having a DSC thermogram substantially as depicted in FIG. 72 comprising an endothermic event with a maximum at about

258 °C when heated from approximately 25 °C to approximately 300 °C.

[00307] In one embodiment, provided herein is Form N having a DSC thermogram substantially as depicted in FIG. 72 comprising an endothermic event with a maximum at about

270 °C when heated from approximately 25 °C to approximately 300 °C.

[00308] In one embodiment, the DVS isotherm plot of Form N shows about 5.0 % water uptake up to 95% RH substantially as shown in FIG. 74.

[00309] In still another embodiment, Form N is substantially pure. In certain

embodiments, the substantially pure Form N is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form N is no less than about 95%>, no less than about 96%>, no less than about 97%>, no less than about 98%>, no less than about 98.5%>, no less than about 99%>, no less than about 99.5%>, or no less than about 99.8%.

5.3.15 Form O

[00310] In certain embodiments, provided herein is Form O.

[00311] In one embodiment, Form O is a solid form of Compound 1. In one embodiment,

Form O is a solvate of Compound 1. In another embodiment, Form O is an acetone solvate of Compound 1. In another embodiment, Form O is a 0.9 molar equivalent acetone solvate of Compound 1. In another embodiment, Form O is crystalline.

[00312] In certain embodiments, Form O provided herein is obtained by equilibration experiments and crash cooling recrystallization experiments (see Table 3 and Table 6).

[00313] In certain embodiments, provided herein are equilibration or slurry methods for making Form O, comprising 1) obtaining a slurry of Form C mixed with Form E in a solvent (e.g., acetone); 2) stirring the slurry for a period of time (e.g., about 12-48 hours) at a certain temperature (e.g., about 45-55 °C); and 3) collecting solids from the slurry by filtration and optionally drying. In certain embodiments, provided herein are methods for making Form O, comprising 1) obtaining a slurry of Form C mixed with Form E in a solvent (e.g., acetone); 2) stirring the slurry for about 24 hours at about 50 °C; and 3) collecting solids from the slurry and optionally air drying.

[00314] In certain embodiments, provided herein are crash cooling recrystallization methods for making Form O, comprising 1) obtaining a saturated solution of Form A in a solvent (e.g., acetone) at a first temperature (e.g., about 55 to 75 °C); 2) stirring the solution at the first temperature for a period of time (e.g., 5-30 minutes); 3) filtering the solution; 4) cooling the solution to a second temperature (e.g., about -30 °C to about -10 °C); and 5) isolating solids from the solution and optionally drying. In certain embodiments, provided herein are methods for making Form O, comprising 1) obtaining a saturated solution of Form A in a solvent (e.g., acetone) at about 65 °C; 2) stirring the solution at about 65 °C for 10 minutes; 3) filtering the solution (e.g., filtering through 0.45 μπι PTFE syringe filters); 4) cooling the solution to about - 20 °C; and 5) isolating solids from the solution and optionally air-drying.

[00315] In certain embodiments, Form O is obtained from certain solvent systems including acetone.

[00316] In certain embodiments, a solid form provided herein, e.g., Form O, is

substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form O has an X-ray powder diffraction pattern substantially as shown in FIG. 15. In one embodiment, Form O has one or more characteristic X-ray powder diffraction peaks at approximately 5.2, 8.4, 10.3, 1 1.3, 12.2, 12.5, 13.8, 14.2, 15.1, 15.5, 15.9, 16.1, 16.7, 17.2, 17.8, 19.0, 19.2, 19.4, 19.8, 20.0, 20.5, 20.6, 22.1, 22.6, 22.9, 23.3, 23.5, 24.4, 25.0, 25.2, 25.5, 26.0, 27.2, 27.7, 28.2, 28.6, 30.2, 31.1, 32.1, 33.9, 34.6, 35.1, 36.9 or 38.8 ⁰ 2Θ as depicted in FIG. 15. In a specific embodiment, Form O has one, two, three, four, five, six, seven or eight

characteristic X-ray powder diffraction peaks at approximately 1 1.3, 14.2, 16.7, 17.2, 22.9, 23.3, 24.4 or 26.0 ⁰ 2Θ. In another embodiment, Form O has one, two, three or four characteristic X- ray powder diffraction peaks at approximately 16.7, 22.9, 24.4 or 26.0 ⁰ 2Θ. In another embodiment, Form O has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty- two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty- nine, thirty, thirty-one, thirty-two, thirty-three, thirty-four, thirty-five, thirty-six, thirty-seven, thirty-eight, thirty-nine, forty, forty-one, forty-two, forty-three or forty-four characteristic X-ray powder diffraction peaks as set forth in Table 23.

[00317] In one embodiment, Form O has a SEM image substantially as shown in FIG. 75.

[00318] In one embodiment, provided herein is Form O having a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 76. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 10.4 % of the total mass of the sample between approximately 25 °C and approximately 240 °C when heated from approximately 20 °C to approximately 300 °C. Thus, in certain embodiments, the crystalline form loses about 10.4 % of its total mass when heated from about ambient temperature to about 300 °C.

[00319] In one embodiment, provided herein is Form O having a DSC thermogram substantially as depicted in FIG. 77 comprising an endothermic event with a maximum at about

153 °C when heated from approximately 25 °C to approximately 300 °C.

[00320] In one embodiment, provided herein is Form O having a DSC thermogram substantially as depicted in FIG. 77 comprising an exothermic event with a maximum at about

215 °C when heated from approximately 25 °C to approximately 300 °C.

[00321] In one embodiment, provided herein is Form O having a DSC thermogram substantially as depicted in FIG. 77 comprising an endothermic event with a maximum at about

257 °C when heated from approximately 25 °C to approximately 300 °C.

[00322] In one embodiment, provided herein is Form O having a DSC thermogram substantially as depicted in FIG. 77 comprising an endothermic event with a maximum at about

269 °C when heated from approximately 25 °C to approximately 300 °C.

[00323] In one embodiment, 1H MR of Form O shows that Form O contains about 0.9 molar equivalent acetone substantially as shown in FIG. 78.

[00324] In still another embodiment, Form O is substantially pure. In certain

embodiments, the substantially pure Form O is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form O is no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 98.5%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.

5.3.16 Form P

[00325] In certain embodiments, provided herein is Form P.

[00326] In one embodiment, Form P is a solid form of Compound 1. In one embodiment,

Form P is a solvate of Compound 1. In another embodiment, Form P is an EtOH solvate of Compound 1. In another embodiment, Form P is a 0.9 molar equivalent EtOH solvate of Compound 1. In another embodiment, Form P is crystalline.

[00327] In certain embodiments, Form P provided herein is obtained by equilibration experiments and crash cooling recrystallization experiments (see Table 3 and Table 6).

[00328] In certain embodiments, provided herein are equilibration or slurry methods for making Form P, comprising 1) obtaining a slurry of Form B, Form D, or Form F in a solvent (e.g., EtOH); 2) stirring the slurry for a period of time (e.g., about 12-48 hours) at a certain temperature (e.g., about 20-30 °C or about 45-55 °C); and 3) collecting solids from the slurry by filtration and optionally drying. In certain embodiments, provided herein are methods for making Form P, comprising 1) obtaining a slurry of Form B, Form D, or Form F in a solvent (e.g., EtOH); 2) stirring the slurry for about 24 hours at about 25 °C or about 50 °C; and 3) collecting solids from the slurry and optionally air drying.

[00329] In certain embodiments, provided herein are crash cooling recrystallization methods for making Form P, comprising 1) obtaining a saturated solution of Form A in a solvent (e.g., EtOH) at a first temperature (e.g., about 55 to 75 °C); 2) stirring the solution at the first temperature for a period of time (e.g., 5-30 minutes); 3) filtering the solution; 4) cooling the solution to a second temperature (e.g., about -30 °C to about -10 °C); and 5) isolating solids from the solution and optionally drying. In certain embodiments, provided herein are methods for making Form P, comprising 1) obtaining a saturated solution of Form A in a solvent (e.g., EtOH) at about 65 °C; 2) stirring the solution at about 65 °C for 10 minutes; 3) filtering the solution (e.g., filtering through 0.45 μπι PTFE syringe filters); 4) cooling the solution to about -20 °C; and 5) isolating solids from the solution and optionally air-drying. [00330] In certain embodiments, Form P is obtained from certain solvent systems including EtOH.

[00331] In certain embodiments, a solid form provided herein, e.g., Form P, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form P has an X-ray powder diffraction pattern substantially as shown in FIG. 16. In one embodiment, Form P has one or more characteristic X-ray powder diffraction peaks at approximately 8.9, 9.7, 9.9, 11.3, 12.1, 12.3, 13.5, 14.0, 14.2, 15.0, 15.3, 16.4, 16.7, 17.3, 17.8, 18.1, 18.7, 19.1, 19.4, 19.9, 20.3, 20.7, 21.2, 21.5, 21.9, 22.3, 22.6, 22.9, 23.7, 24.4, 24.8, 25.4, 26.0, 26.6, 27.2, 28.2, 28.5, 29.1, 30.1, 31.1, 32.0, 32.7, 35.3, 35.8, 36.6, 37.5, 38.5 or 38.8 ⁰ 2Θ as depicted in FIG. 16. In a specific embodiment, Form P has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at approximately 12.1, 13.5, 16.4, 19.4, 23.7, 24.4, 24.8 or 26.6 ⁰ 2Θ. In another embodiment, Form P has one, two, three or four characteristic X-ray powder diffraction peaks at approximately 13.5, 19.4, 24.8 or 26.6 ⁰ 2Θ. In another embodiment, Form P has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirty, thirty-one, thirty -two, thirty -three, thirty -four, thirty-five, thirty-six, thirty- seven, thirty-eight, thirty-nine, forty, forty-one, forty -two, forty -three, forty-four, forty -five, forty-six, forty-seven or forty-eight characteristic X-ray powder diffraction peaks as set forth in Table 24.

[00332] In one embodiment, Form P has a SEM image substantially as shown in FIG. 79.

[00333] In one embodiment, provided herein is Form P having a TGA thermogram corresponding substantially to the representative TGA thermogram as depicted in FIG. 80. In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 7.4 % of the total mass of the sample between approximately 25 °C and approximately 170 °C when heated from approximately 20 °C to approximately 300 °C. Thus, in certain embodiments, the crystalline form loses about 7.4 % of its total mass when heated from about ambient temperature to about 300 °C. [00334] In one embodiment, provided herein is Form P having a DSC thermogram substantially as depicted in FIG. 81 comprising an endothermic event with a maximum at about

257 °C when heated from approximately 25 °C to approximately 300 °C.

[00335] In one embodiment, provided herein is Form P having a DSC thermogram substantially as depicted in FIG. 81 comprising an endothermic event with a maximum at about

269 °C when heated from approximately 25 °C to approximately 300 °C.

[00336] In one embodiment, 1H MR of Form P shows that Form P contains about 0.9 molar equivalent EtOH as depicted in FIG. 82.

[00337] In still another embodiment, Form P is substantially pure. In certain

embodiments, the substantially pure Form P is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form P is no less than about 95%, no less than about 96%>, no less than about 97%>, no less than about 98%>, no less than about 98.5%>, no less than about 99%>, no less than about 99.5%>, or no less than about 99.8%.

5.4 METHODS OF USE

[00338] The solid forms of Compound 1 have utility as a pharmaceutical to treat, prevent or improve cancer in animals or humans. Accordingly, provided herein are uses of a solid form of Compound 1, including the treatment or prevention of those cancers set forth herein. The methods provided herein comprise the administration of an effective amount of a solid form of Compound 1 to a subject in need thereof.

[00339] In another aspect provided herein are methods for treating or preventing a cancer, comprising administering to a subject in need thereof an effective amount of a solid form of Compound 1, as described herein. In some embodiments, the cancer is a solid tumor or a hematological tumor. In some embodiments, the cancer is triple negative breast cancer (TNBC).

[00340] In some embodiments, the solid tumor is bladder cancer (including superficial bladder cancer), breast cancer (including luminal B type, ER+, PR+ and Her2+ breast cancer), central nervous system cancer (including glioblastoma multiforme (GBM), glioma,

medulloblastoma, and astrocytoma), colorectal cancer, gastrointestinal cancer (including stomach cancer, oesophagus cancer, and rectum cancer), endocrine cancer ( including thyroid cancer, and adrenal gland cancer), eye cancer (including retinoblastoma), female genitourinary cancer (including cancer of the placenta, uterus, vulva, ovary, cervix), head and neck cancer (including cancer of the pharynx, oesophagus, and tongue), liver cancer, lung cancer (including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), mucoepidermoid, bronchogenic, squamous cell carcinoma (SQCC), and analplastic/NSCLC), skin cancer

(including melanoma, and SQCC), soft tissue cancer (including sarcoma, Ewing's sarcoma, and rhabdomyosarcoma), bone cancer (including sarcoma, Ewing's sarcoma, and osteosarcoma), squamous cell cancer (including lung, esophageal, cervical, and head and neck cancer), pancreas cancer, kidney cancer (including renal Wilm's tumor and renal cell carcinoma), or prostate cancer. In some embodiments, the solid tumor is triple negative breast cancer. In some embodiments, the solid tumor is breast cancer, colon cancer, lung cancer or bladder cancer. In one such embodiment, the solid tumor is superficial bladder cancer. In another, the solid tumor is lung squamous cell carcinoma. In yet another embodiment, the solid tumor is luminal B type breast cancer.

[00341] In some embodiments, the hematological cancer is leukemia (including acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), acute T-cell leukemia, B cell precursor leukemia, acute promyelocytic leukemia (APML), plasma cell leukemia,

myelomonoblastic/T-ALL, B myelomonocytic leukemia, erythroleukemia, and acute myeloid leukemia (AML)), lymphoma (including Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), Burkitt's lymphoma (BL), B cell lymphoma, lymphoblastic lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and large cell immunoblastic lymphoma), or multiple myeloma.

[00342] In some embodiments, provided herein are methods for preventing cancer metastasis, comprising administering to a subject in need thereof an effective amount of a solid form of Compound 1, as described herein. In some embodiments, the cancer is a metastatic cancer, in particular, a metastatic solid tumor or metastatic hematologic cancer, wherein the solid tumor and hematologic cancer is as described herein. In other embodiments, provided herein are methods of preventing cancer metastasis, comprising administering to a subject in need thereof an effective amount of a solid form of Compound 1, as described herein. In yet another aspect, provided herein are methods of eradicating cancer stem cells in a subject, comprising administering to a subject in need thereof an effective amount of a solid form of Compound 1, as described herein. In other embodiments, provided herein are methods of inducing differentiation in cancer stem cells in a subject, comprising administering to a subject in need thereof an effective amount of a solid form of Compound 1, as described herein. In other embodiments, provided herein are methods of inducing cancer stem cell death in a subject, comprising administering to a subject in need thereof an effective amount of a solid form of Compound 1, as described herein. In some such embodiments, the cancer is a solid tumor, for example a CNS cancer (e.g. GBM) or breast cancer, or a hematological cancer, such as leukemia.

[00343] In one embodiment, provided herein are methods for achieving a Response Evaluation Criteria in Solid Tumors (RECIST 1.1) of complete response, partial response or stable disease in a patient comprising administering an effective amount of a solid form of Compound 1 to a patient having a cancer, in particular a solid tumor as described herein. In another embodiment, provided herein are methods to increase Progression Free Survival rates, as determined by Kaplan-Meier estimates.

[00344] In one embodiment, provided herein are methods for preventing or delaying a

Response Evaluation Criteria in Solid Tumors (RECIST 1.1) of progressive disease in a patient, comprising administering an effective amount of a solid form of Compound 1 to a patient having a solid tumor as described herein. In one embodiment the prevention or delaying of progressive disease is characterized or achieved by a change in overall size of the target lesions, of for example, between -30% and +20% compared to pre-treatment. In another embodiment, the change in size of the target lesions is a reduction in overall size of more than 30%, for example, more than 50% reduction in target lesion size compared to pre-treatment. In another, the prevention is characterized or achieved by a reduction in size or a delay in progression of non- target lesions compared to pre-treatment. In one embodiment, the prevention is achieved or characterized by a reduction in the number of target lesions compared to pre-treatment. In another, the prevention is achieved or characterized by a reduction in the number or quality of non-target lesions compared to pre-treatment. In one embodiment, the prevention is achieved or characterized by the absence or the disappearance of target lesions compared to pre-treatment. In another, the prevention is achieved or characterized by the absence or the disappearance of non-target lesions compared to pre-treatment. In another embodiment, the prevention is achieved or characterized by the prevention of new lesions compared to pre-treatment. In yet another embodiment, the prevention is achieved or characterized by the prevention of clinical signs or symptoms of disease progression compared to pre-treatment, such as cancer-related cachexia or increased pain.

[00345] In certain embodiments, provided herein are methods for decreasing the size of target lesions in a patient compared to pre-treatment, comprising administering an effective amount of a solid form of Compound 1 to a patient having a cancer, in particular a solid tumor as described herein.

[00346] In certain embodiments, provided herein are methods for decreasing the size of a non-target lesion in a patient compared to pre-treatment, comprising administering an effective amount of a solid form of Compound 1 to a patient having a cancer, in particular a solid tumor as described herein.

[00347] In certain embodiments, provided herein are methods for achieving a reduction in the number of target lesions in a patient compared to pre-treatment, comprising administering an effective amount of a solid form of Compound 1 to a patient having a cancer, in particular a solid tumor as described herein.

[00348] In certain embodiments, provided herein are methods for achieving a reduction in the number of non-target lesions in a patient compared to pre-treatment, comprising

administering an effective amount of a solid form of Compound 1 to a patient having a cancer, in particular a solid tumor as described herein.

[00349] In certain embodiments, provided herein are methods for achieving an absence of all target lesions in a patient, comprising administering an effective amount of a solid form of Compound 1 to a patient having a cancer, in particular a solid tumor as described herein.

[00350] In certain embodiments, provided herein are methods for achieving an absence of all non-target lesions in a patient, comprising administering an effective amount of a solid form of Compound 1 to a patient having a cancer, in particular a solid tumor as described herein.

[00351] In certain embodiments, provided herein are methods for treating a cancer, in particular a solid tumor as described herein, the methods comprising administering an effective amount of a solid form of Compound 1 to a patient having a cancer, in particular a solid tumor, wherein the treatment results in a complete response, partial response or stable disease, as determined by Response Evaluation Criteria in Solid Tumors (RECIST 1.1).

[00352] In certain embodiments, provided herein are methods for treating a cancer, in particular a solid tumor as described herein, the methods comprising administering an effective amount of a solid form of Compound 1 to a patient having a cancer, in particular a solid tumor as described herein, wherein the treatment results in a reduction in target lesion size, a reduction in non-target lesion size and/or the absence of new target and/or non-target lesions, compared to pre-treatment.

[00353] In certain embodiments, provided herein are methods for treating a cancer, in particular a solid tumor as described herein, the methods comprising administering an effective amount of a solid form of Compound 1 to a patient having a cancer, in particular a solid tumor as described herein, wherein the treatment results in prevention or retarding of clinical progression, such as cancer-related cachexia or increased pain.

[00354] In another embodiment, provided herein are methods for inducing a therapeutic response characterized with the International Workshop Criteria (IWC) for NHL (see Cheson BD, Pfistner B, Juweid, ME, et. al. Revised Response Criteria for Malignant Lymphoma. J. Clin. Oncol: 2007: (25) 579-586) of a patient, comprising administering an effective amount of a solid form of Compound 1 to a patient having a cancer, in particular hematological cancers such as lymphoma, as described herein. In another embodiment, provided herein are methods for achieving complete remission, partial remission or stable disease, as determined by the

International Workshop Criteria (IWC) for NHL in a patient, comprising administering an effective amount of a solid form of Compound 1 to a patient having a cancer, in particular hematological cancers such as lymphoma, as described herein. In another embodiment, provided herein are methods for achieving an increase in overall survival, progression-free survival, event- free survival, time to progression, disease-free survival or lymphoma-free survival as determined by the International Workshop Criteria (IWC) for NHL in a patient, comprising administering an effective amount of a solid form of Compound 1 to a patient having a cancer, in particular hematological cancers such as lymphoma, as described herein.

[00355] In another embodiment, provided herein are methods for inducing a therapeutic response assessed with the International Uniform Response Criteria for Multiple Myeloma (IURC) (see Durie BGM, Harousseau J-L, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia, 2006; (10) 10: 1-7) of a patient, comprising

administering an effective amount of a solid form of Compound 1 to a patient having a cancer, in particular multiple myeloma. In another embodiment, provided herein are methods for achieving a stringent complete response, complete response, or very good partial response, as determined by the International Uniform Response Criteria for Multiple Myeloma (IURC) in a patient, comprising administering an effective amount of a solid form of Compound 1 to a patient having a cancer, in particular multiple myeloma. In another embodiment, provided herein are methods for achieving an increase in overall survival, progression-free survival, event-free survival, time to progression, or disease-free survival in a patient, comprising administering an effective amount of a solid form of Compound 1 to a patient having a cancer, in particular multiple myeloma.

[00356] In another embodiment, provided herein are methods for inducing a therapeutic response assessed with the Response Assessment for Neuro-Oncology (RANO) Working Group for GBM (see Wen P., Macdonald, DR., Reardon, DA., et al. Updated response assessment criteria for highgrade gliomas: Response assessment in neuro-oncology working group. J. Clin. Oncol. 2010; 28: 1963-1972) of a patient, comprising administering an effective amount of a solid form of Compound 1 to a patient having a cancer, in particular glioblastoma multiforme (GBM). In one embodiment, RANO will be used to establish the proportion of subjects progression-free at 6 months from Day 1 relative to efficacy evaluable subjects in the GBM type.

[00357] In another embodiment, provided herein are methods for improving the Eastern

Cooperative Oncology Group Performance Status (ECOG) of a patient, comprising

administering an effective amount of a solid form of Compound 1 to a patient having a cancer, in particular a solid tumor or hematological cancer as described herein.

[00358] In another embodiment, provided herein are methods for inducing a therapeutic response assessed by Positron Emission Tomography (PET) outcome of a patient, comprising administering an effective amount of a solid form of Compound 1 to a patient having a cancer, in particular a solid tumor or hematological cancer as described herein. In certain embodiments, provided herein are methods for treating a cancer, in particular a solid tumor or hematological cancer as described herein, the methods comprising administering an effective amount of a solid form of Compound 1 to a patient having a cancer, in particular a solid tumor or hematological cancer as described herein, wherein the treatment results in a reduction in tumor metabolic activity, for example, as measured by PET imaging.

[00359] Further provided herein are methods for treating patients who have been previously treated for a cancer, in particular a solid tumor or a hematological cancer as described herein, as well as those who have not previously been treated. Because patients with a cancer have heterogenous clinical manifestations and varying clinical outcomes, the treatment given to a patient may vary, depending on his/her prognosis. The skilled clinician will be able to readily determine without undue experimentation specific secondary agents, types of surgery, and types of non-drug based standard therapy that can be effectively used to treat an individual patient with a cancer.

5.5 PHARMACEUTICAL COMPOSITIONS AND ROUTES OF

ADMINISTRATION

[00360] The solid forms of Compound 1 can be administered to a subject parenterally in the conventional form of preparations, such as injections, suspensions, solutions and emulsions. Vehicles that can be useful, either alone or in combination, to provide intravenous formulations of a solid form of Compound 1 include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water- miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and

polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. An intravenous formulation can be prepared by reconstituting a solid form of Compound 1 with such a suitable liquid vehicle. A desired concentration of the intravenous formulation can be obtained by reconstituting an appropriate amount of a solid form of Compound 1 with an appropriate volume of liquid vehicle. A desired concentration of the intravenous formulation provides a therapeutically effective amount of Compound 1 to the patient in need of the intravenous formulation and maintains a therapeutically effective level of Compound 1 in the patient. The dose which is therapeutically effective will depend on the rate at which the intravenous formulation is delivered to the patient and the concentration of the intravenous formulation.

[00361] The effective amount of a solid form of Compound 1 in the pharmaceutical composition may be at a level that will exercise the desired effect; for example, about

0.005 mg/kg of a subject's body weight to about 100 mg/kg of a subject's body weight in unit dosage for parenteral administration.

[00362] The dose of a solid form of Compound 1 to be administered to a subject is rather widely variable and can be subject to the judgment of a health-care practitioner. In general, a solid form of Compound 1 can be administered one to seven times a week, once every two weeks, once every three weeks or once every four weeks in a dose of about 0.005 mg/kg of a subject's body weight to about 10 mg/kg of a subject's body weight in a subject, but the above dosage may be properly varied depending on the age, body weight and medical condition of the subject and the type of administration. In one embodiment, the dose is about 0.01 mg/kg of a subject's body weight to about 5 mg/kg of a subject's body weight, about 0.05 mg/kg of a subject's body weight to about 1 mg/kg of a subject's body weight, about 0.1 mg/kg of a subject's body weight to about 0.75 mg/kg of a subject's body weight or about 0.25 mg/kg of a subject's body weight to about 0.5 mg/kg of a subject's body weight. In one embodiment, one dose is given per week. In others, one dose is given two, three or four times per week. In still others, one dose is given per two weeks, per three weeks or per four weeks. In any given case, the amount of a solid form of Compound 1 administered will depend on such factors as the solubility of the active component, the formulation used and the route of administration.

[00363] In another embodiment, provided herein are methods for the treatment or prevention of a disease or disorder comprising the administration of about 0.375 mg/dose to about 750 mg/dose, about 0.75 mg/dose to about 375 mg/dose, about 3.75 mg/dose to about 75 mg/dose, about 7.5 mg/dose to about 55 mg/dose or about 18 mg/dose to about 37 mg/dose of a solid form of Compound 1 to a subject in need thereof.

[00364] In another embodiment, provided herein are methods for the treatment or prevention of a disease or disorder comprising the administration of about 1 mg/dose to about 1200 mg/dose, about 10 mg/dose to about 1200 mg/dose, about 100 mg/dose to about

1200 mg/dose, about 400 mg/dose to about 1200 mg/dose, about 600 mg/dose to about 1200 mg/dose, about 400 mg/dose to about 800 mg/dose or about 600 mg/dose to about

800 mg/dose of a solid form of Compound 1 to a subject in need thereof. In a particular embodiment, the methods disclosed herein comprise the administration of 400 mg/dose,

600 mg/dose or 800 mg/dose of a solid form of Compound 1 to a subject in need thereof. In a particular embodiment, the methods disclosed herein comprise the administration of 20 mg/dose,

40 mg/dose, 80 mg/dose, 160 mg/dose, 320 mg/dose or 650 mg/dose of a solid form of

Compound 1 to a subject in need thereof.

[00365] In another embodiment, provided herein are unit dosage formulations that comprise between about 1 mg and 200 mg, about 35 mg and about 1400 mg, about 125 mg and about 1000 mg, about 250 mg and about 1000 mg, or about 500 mg and about 1000 mg of a solid form of Compound 1.

[00366] In a particular embodiment, provided herein are unit dosage formulations comprising about 100 mg or 400 mg of a solid form of Compound 1. In a particular

embodiment, provided herein are unit dosage formulations comprising about 20 mg, about 40 mg, about 80 mg, about 160 mg, about 320 mg or about 650 mg of a solid form of Compound 1.

[00367] In another embodiment, provided herein are unit dosage formulations that comprise 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 40 mg, 50 mg, 70 mg, 80 mg, 100 mg, 125 mg, 134 mg, 140 mg, 160 mg, 175 mg, 200 mg, 250 mg, 280 mg, 320 mg, 350 mg, 500 mg, 560 mg, 637 mg, 650 mg, 700 mg, 750 mg, 805 mg, 1000 mg or 1400 mg of a solid form of Compound 1.

[00368] The solid form of Compound 1 can be administered once, twice, three, four or more times daily. In a particular embodiment, doses of 600 mg or less are administered as a once daily dose and doses of more than 600 mg are administered twice daily in an amount equal to one half of the total daily dose.

[00369] In another embodiment, provided herein are compositions comprising an effective amount of a solid form of Compound 1 and a pharmaceutically acceptable carrier or vehicle, wherein a pharmaceutically acceptable carrier or vehicle can comprise an excipient, diluent, or a mixture thereof. In one embodiment, the composition is a pharmaceutical composition.

[00370] The compositions can be in the form of solutions, parenteral solutions, and suspensions and the like. Compositions can be formulated to contain a single dose, or a convenient fraction of a single dose, in a dosage unit, which may be a single vial or convenient volume of a liquid. In one embodiment, the solutions are prepared from water-soluble salts, such as the hydrochloride salt. In general, all of the compositions are prepared according to known methods in pharmaceutical chemistry.

[00371] The effect of a solid form of Compound 1 can be delayed or prolonged by proper formulation. The parenteral preparations can be made long-acting, by dissolving or suspending a solid form of Compound 1 in oily or emulsified vehicles that allow it to disperse slowly in the serum.

6. EXAMPLES

[00372] The following Examples are presented by way of illustration, not limitation. The following abbreviations are used in descriptions and examples:

DCM Di chl oromethane

DSC Differential scanning calorimetry

DMSO Dimethyl sulfoxide

DVS Dynamic vapor sorption

EtOH Ethanol

HPLC High performance liquid chromatography

IPA Isopropyl alcohol

KF Karl Fischer

MEK Methyl ethyl ketone

MeOH Methanol

MTBE Methyl tertiary -butyl ether

MR Nuclear magnetic resonance

PEG Polyethylene glycol

SEM Scanning Electron Microscope

TGA Thermogravimetric analysis

THF Tetrahydrofuran

XRPD X-Ray Powder Diffraction

6.1 SUMMARY OF POLYMORPH SCREEN OF COMPOUND 1

[00373] Multiple unique crystalline forms of Compound 1 were prepared, including four anhydrous forms (Forms A, C, E and L) and at least six hydrate forms (Forms B, D, F, H, J, and N). Form E was found to be the most thermodynamically stable anhydrate. [00374] Form A was used as the starting material for preparation of the other solid forms of Compound 1. The approximate solubility was first determined to select solvents for recrystallization and slurry experiments. The equilibration and evaporation experiments afforded many solid forms with unique X-ray powder diffraction (XRPD) patterns (Table 1). These forms along with the unique forms generated from cooling recrystallization (Table 2 and Table 3), anti- solvent recrystallization (Table 4), scale-up experiments (Table 5), and form transfer

experiments (Table 6) were further characterized by various techniques, including differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), Karl Fisher (KF), and ¹H-Nuclear Magnetic Resonance (1H NMR). The characterization of the sixteen forms is summarized in Table 7. The schematic form conversion among the forms is presented in FIG. 17.

[00375] Table 1. Summary of Equilibration (EQ) and Evaporation (EV) Results for

Compound 1.

MeOAc A - A + E A + E

[00376] - : n/a: no experiment

[00377] - Not analyzable.

[00378] * pattern showing only a few diffraction peaks or diffuse pattern

[00379] Table 2. Results from Cooling Recrystallization (65 °C to 4 °C).

- no precipitation

[00380] Table 3. Results from Crash Cooling Recrystallization (65 °C to -20 °C).

[00381] Table 4. Results from Anti-Solvent Recrystallization.

THF Acetone 1:20 -

THF MeCN 1:10 C

THF IPA 1:25 -

THF MeCN 1:25 C

acetone MeCN 1:25 C

MeOH MeCN 1:25 C

EtOH/H20 MeCN 1:25 -

MEK MeCN 1:25 C

[00382] - no precipitation

Reaction conditions: add anti-solvent at 65 °C; place into refrigerator and then

[00384] Table 5. Results from scale-up experiments.

[00385] Table 6. Form Transfer Experiments of Compound 1.

Form M surry n EtOHwater RT, 2 ays an 10 ays Form F

[00386] Note: [L+E] or [E+L] were form mixtures that were generated by heating a Form

K sample to 240-245 °C.

[00387] Table 7. Summary of Characterization Data for of Compound 1

F hydrate Evap. from IP A 204, ^A208, 0.1, 0.4 3.8 wt% water uptake or EtOH, slurry 256, 269 up to 95 %RH. 4.0 from wt% water by KF

G hydrate Evap. from 212, ^A227, n/a No significant

acetone 252 residual acetone by

Ή NMR

H hydrate Evap. or Rx from -132, ^A214, 3.2 3.9 wt% water uptake

MeOH, roto-vap 257 up to 95 %RH. 3.5 from wt% water by KF

MeOH/DCM

I solvate Evap. from IP A ^A197, 255 ~ 4, ~ 1.6 wt% IPA by 1H at 50 °C continuou NMR

s

J hydrate Evap. from n- 46, 208, ^A216, variable converts to Form F

BuOH, Rx from 257 during DVS test THF/heptane

K solvate Rx from acetone 149, ^A201, 10.4 0.8 molar acetone by

257, 269 1H NMR (8.3 wt%)

L anhydrate Heat solvates or 268 (onset, 0 -1.8 wt% water

hydrates to 260 AH_f = 100 uptake up to 95 %RH

°C J/g)

M dehydrate Dry Form B at ~ 173, ^A193, - 0.1 -1.3 wt% water

40 °C under 257, 270 uptake up to 95 %RH vacuum

N hydrate Slurry or Rx in 159, ^A202, 1.6 -5.0 wt% water

MeOH 248, 258, 270 uptake up to 95

%RH. 2.2 wt% water by KF

0 solvate Rx from acetone 153, ^A215, 10.4 0.9 molar acetone by

257, 269 1H NMR (9.3 wt%)

P solvate Rx from EtOH 144, 198, 7.4 0.9 molar EtOH by

217, 251, 1H NMR (7.5 wt%) 257, 269

[00388] Note: ^A exotherm; ... broad endotherm with undefined DSC peak.

[00389] Several crystallization conditions were investigated for the production of different polymorphs of Compound 1 (Table 1). These experiments were conducted on small scale (typically <2 g) as a screen of conditions for production and isolation. [00390] Table 8. Crystallization conditions investigated for Compound 1

6.2 ANALYTICAL METHODS

[00391] Solid samples were analyzed by XRPD. XRPD analysis was conducted on a PANalytical Empyrean or a Thermo ARL X'TRA X-ray powder diffractometer using Cu Ka radiation at 1.54 A. [00392] The PANalytical Empyrean instrument was equipped with a fine focus X-ray tube. The voltage and amperage of the X-ray generator were set at 45 kV and 40 mA, respectively. The divergence slits were set at 1/16° and 1/8°, and the receiving slits was set at 1/16°. Diffracted radiation was measured using a Pixel 2D detector. A theta-two theta continuous scan was set at step size 0.013 or 0.026 from 3° to 40° 26'with sample spinning rate at 4. A sintered alumina standard was used to check the peak positions.

[00393] The Thermo ARL X'TRA instrument was equipped with a fine focus X-ray tube.

The voltage and amperage of the X-ray generator were set at 45 kV and 40 mA, respectively. The divergence slits were set at 4 mm and 2 mm and the measuring slits were set at 0.5 mm and 0.2 mm. Diffracted radiation was measured using a Peltier-cooled Si (Li) solid-state detector. A theta-two theta continuous scan at 2.40°/min (0.5 sec/0.02° step) from 1.5° to 40° 26* was used. A sintered alumina standard was used to check the peak positions.

[00394] DSC analyses were performed on a TA Discovery Differential Scanning

Calorimeter. Indium was used as the calibration standard. Approximately 2-5 mg of sample was placed into a DSC pan. The sample was heated under nitrogen at a rate of 10 °C/min, up to a final temperature of 300 °C. Melting points were reported as the extrapolated onset

temperatures.

[00395] Morphology analysis of the samples was carried out on an Even Mini SEM.

Small amounts of samples were dispersed on a sample holder, and then coating with gold and viewed with 500x magnification.

6.3 FORM A

[00396] Form A is anhydrous and melts at 244 °C. Form A is monotropically related to

Form E which melts at 256 °C.

[00397] Form A has a SEM picture as shown in FIG. 18. TGA and DSC thermograms of

Form A are shown in FIG. 19 and FIG. 20, respectively. Minimal TGA weight loss was observed up to melting of Form A, with an onset melting temperature of 244 °C on the DSC thermogram. The heat of fusion for Form A is 104 J/g. A small endotherm at 258 °C was also observed and corresponds to melting of Form E. Form A is slightly hygroscopic, with about 0.9 % w/w water uptake between 0 and 90 %RH on DVS (FIG. 21). These results suggested that Form A is an anhydrate.

[00398] The stability of Form A was further characterized by compression test and form transfer experiments. Upon application of 2000-psi pressure for about 1 minute, the material was still Form A (FIG. 22). Results from form transfer experiments in Table 6 confirmed that Form

A is less stable than Form E; therefore, Form A is monotropically related to Form E.

[00399] FIG. 1 provides an XRPD pattern of Form A. A list of X-Ray Diffraction Peaks for Form A is provided below in Table 9.

[00400] Table 9. X-Ray Diffraction Peaks for Form A

Relative

Two-theta angle (°) d Space (A)

Intensity (%)

34.0 2.6360 1

36.6 2.4571 1

38.8 2.3236 2

39.6 2.2784 1

6.4 FORM B

[00401] Form B was generated by slurry or evaporation from TFIF/water (1 : 1). Form B has a SEM picture as shown in FIG. 23. TGA and DSC thermograms of Form B are shown in FIG. 24 and FIG. 25, respectively. The DSC thermogram of Form B showed a prominent endothermic event around 57 °C, corresponding to TGA weight loss of 10 wt% around the same temperature range. No significant degradation or residual solvent was observed by 1H NMR (FIG. 26). The DVS isotherm plot showed about 15 wt% water uptake up to 95 % RH (FIG. 27). These observations along with the KF result of 7 wt% water confirmed that Form B is a hydrate. Form B was observed to convert to a dehydrated form, Form M, upon drying at 40 °C under vacuum.

[00402] FIG. 2 provides an XRPD pattern of Form B. A list of X-Ray Diffraction Peaks for Form B is provided below in Table 10.

[00403] Table 10. X-Ray Diffraction Peaks for Form B

Relative

Two-theta angle (°) d Space (A)

Intensity (%)

18.4 4.8236 7

18.7 4.7365 3

19.6 4.5391 7

19.8 4.4778 10

22.4 3.9674 2

23.1 3.8565 2

23.4 3.7965 3

23.8 3.7439 3

24.4 3.6458 2

25.4 3.5070 3

26.5 3.3629 8

26.9 3.3103 2

27.9 3.1983 2

28.9 3.0863 3

30.0 2.9792 2

33.2 2.6976 1

34.2 2.6255 1

6.5 FORM C

[00404] Form C was generated from many recrystallization and slurry conditions and is believed to be the kinetically favored form. Form C is anhydrous and melts at 227°C. Form C has a SEM picture as shown in FIG. 28. TGA and DSC thermograms of Form C are shown in FIG. 29 and FIG. 30, respectively. Minimal TGA weight loss was observed up to melting of Form C, with an onset melting temperature of 227 °C on the DSC thermogram. The heat of fusion for Form C is 88 J/g. Recrystallization exotherm at 231 °C and melting endotherm at 257 °C were also observed for some Form C samples. Form C is slightly hygroscopic, with about 1.0 % w/w water uptake between 0 and 90 %RH on DVS (FIG. 31). These results suggested that Form C is an anhydrate. The stability of Form C was further characterized by compression test and form transfer experiments. Upon application of 2000-psi pressure for about 1 minute, the material was still Form C (FIG. 32). Results from form transfer experiments (Table 6) confirmed that Form C is less stable than Form E; therefore, Form C is monotropically related to Form E. [00405] FIG. 3 provides an XRPD pattern of Form C. A list of X-Ray Diffraction Peaks for Form C is provided below in Table 11.

[00406] Table 11. X-Ray Diffraction Peaks for Form C

6.6 FORM D

[00407] Form D was generated by recrystallization in DMSO/MeCN or by evaporation from THF. Form D has a SEM picture as shown in FIG. 33. TGA and DSC thermograms of Form D are shown in FIG. 34 and FIG. 35, respectively. The TGA thermogram of Form D showed a weight loss of 5.1 wt%, corresponding to small and broad DSC endotherms around 50 and 165 °C. The melting endotherm at 228 °C matched with Form C melting. No significant degradation or residual solvent was observed by ^XH NMR (FIG. 36). These observations suggested that Form D is most likely a hydrate. The DVS isotherm plot of Form D showed a significant mass change between 80 to 90%RH during adsortion and then upon desoprtion (FIG. 37). Form D was found to convert to Form C after DVS experiment, indicating Form D is an unstable hydrate.

[00408] FIG. 4 provides an XRPD pattern of Form D. A list of X-Ray Diffraction Peaks for Form D is provided below in Table 12.

[00409] Table 12. X-Ray Diffraction Peaks for Form D

Relative

Two-theta angle (°) d Space (A)

Intensity (%)

29.5 3.0300 5

30.3 2.9524 4

30.9 2.8935 3

36.7 2.4482 1

6.7 FORM E

[00410] Form E was generated by evaporation from MEK or by recrystallization in

TFIF/MeOH. Form E melts at 256°C and is the most thermodynamically stable form of

Compound 1. It was found that Form E dissolves slowly in PEG/ethanol. The dissolving process may require up to 10 hours to complete.

[00411] Form E has a SEM picture as shown in FIG. 38. TGA and DSC thermograms of

Form E are shown in FIG. 39 and FIG. 40, respectively. Minimal TGA weight loss was observed up to melting of Form E, with an onset melting temperature of 256 °C on the DSC thermogram. The heat of fusion for Form E is 108 J/g, which is the highest among Compound 1 anhydrous forms. Form E is slightly hygroscopic, with about 0.8 % w/w water uptake between 0 and 90 %RH on DVS (FIG. 41).

[00412] The stability of Form E was further characterized by compression test and form transfer experiments. Upon application of 2000-psi pressure for about 1 minute, the material was still Form E (FIG. 42). Results from form transfer experiments (Table 6) confirmed that Form E is the most stable anhydrous form of Compound 1.

[00413] FIG. 5 provides an XRPD pattern of Form E. A list of X-Ray Diffraction Peaks for Form E is provided below in Table 13.

[00414] Table 13. X-Ray Diffraction Peaks for Form E

Relative

Two-theta angle (°) d Space (A)

Intensity (%)

9.5 9.2671 6

11.1 7.9637 36

13.3 6.6480 4

15.0 5.8997 31

15.9 5.5698 4

16.7 5.2990 6

17.0 5.2090 5

18.0 4.9154 13

18.4 4.8339 6

18.8 4.7320 32

19.7 4.5011 2

20.2 4.3857 11

21.3 4.1635 1

23.2 3.8400 1

24.5 3.6327 6

26.3 3.3859 1

30.4 2.9448 2

6.8 FORM F

[00415] Form F was generated by evaporation from IPA or EtOH. Form F has a SEM picture as shown in FIG. 43. TGA and DSC thermograms of Form F are shown in FIG. 44 and FIG. 45, respectively. The TGA thermogram of Form F showed a step weight loss of 0.4 wt% between 150-200 °C, corresponding to the endo/exo-thermic DSC event around 204 °C. No significant degradation or residual solvent was observed by 1H NMR (FIG. 46). The DVS isotherm plot showed about 3.8 wt% mass change between 0 and 90 %RH (FIG. 47). These observations along with the KF result of 4.0 wt% water confirmed that Form F is a hydrate.

[00416] FIG. 6 provides an XRPD pattern of Form F. A list of X-Ray Diffraction Peaks for Form F is provided below in Table 14.

[00417] Table 14. X-Ray Diffraction Peaks for Form F

Relative

Two-theta angle (°) d Space (A)

Intensity (%)

5.9 15.0694 100

7.6 11.5757 11

8.1 10.8705 10

10.8 8.1684 3

11.7 7.5437 14

12.5 7.1004 5

13.2 6.7121 12

13.9 6.3625 1

15.3 5.7882 7

16.6 5.3509 8

17.6 5.0260 10

18.0 4.9248 6

21.2 4.1883 2

24.1 3.6910 1

24.5 3.6262 2

26.4 3.3779 2

28.0 3.1920 1

6.9 FORM G

[00418] Form G was generated by evaporation from acetone. The DSC thermogram in

FIG. 48 showed a small endothermic event around 50 °C, likely due to loss of water or solvent. No significant degradation or residual acetone was observed in 1H NMR (FIG. 49). Based on these observations, Form G is likely a hydrate.

[00419] FIG. 7 provides an XRPD pattern of Form G. A list of X-Ray Diffraction Peaks for Form G is provided below in Table 15.

[00420] Table 15. X-Ray Diffraction Peaks for Form G

Relative

Two-theta angle (°) d Space (A)

Intensity (%)

9.8 9.0194 4

10.4 8.5186 14

10.8 8.2031 14

12.0 7.3453 7

12.8 6.8920 5

13.2 6.7039 3

13.8 6.4096 9

14.7 6.0102 5

16.0 5.5537 3

17.1 5.1984 16

18.4 4.8306 4

18.9 4.6843 9

20.1 4.4207 6

21.7 4.0969 23

22.6 3.9423 4

23.6 3.7713 8

24.9 3.5801 11

26.6 3.3535 6

29.8 2.9979 2

6.10 FORM H

[00421] Form H was generated by recrystallization in MeOH or by rotary evaporation from MeOH/DCM (1 : 1). No significant degradation or residual solvent was observed by 1H NMR. Form H has a SEM picture as shown in FIG. 50. TGA and DSC thermograms of Form H are shown in FIG. 51 and FIG. 52, respectively. The DSC thermogram of Form H showed an endothermic event around 132 °C, corresponding to TGA weight loss of 3.2 wt% up to 130°C. Recrystallization exotherm and melting edotherm were also observed at higher temperatures on DSC thermogram. The DVS isotherm plot showed about 3.9 wt% mass change up to 95 % RH and a steep mass change between 0 and 10 %RH (FIG. 53). These observations along with the KF result of 3.5 wt% water confirmed that Form H is a hydrate.

[00422] FIG. 8 provides an XRPD pattern of Form H. A list of X-Ray Diffraction Peaks for Form H is provided below in Table 16.

[00423] Table 16. X-Ray Diffraction Peaks for Form H Relative

Two-theta angle (°) d Space (A)

Intensity (%)

3.7 24.1365 17

5.1 17.4332 100

5.3 16.5421 75

7.3 12.0432 41

8.4 10.5620 6

10.2 8.7076 39

10.7 8.2463 12

11.4 7.7394 10

11.9 7.4202 3

13.0 6.8265 25

13.7 6.4757 8

15.0 5.9082 21

15.3 5.7863 20

16.3 5.4516 20

16.8 5.2681 10

18.0 4.9261 5

19.0 4.6703 7

19.5 4.5539 11

21.2 4.1981 2

22.7 3.9250 3

23.2 3.8360 3

25.9 3.4377 5

27.5 3.2387 1

29.3 3.0509 1

6.11 FORM I

[00424] Form I was generated by evaporation from IPA at 50 °C. TGA and DSC thermograms of Form I are shown in FIG. 54 and FIG. 55, respectively. The DSC thermograms showed small endothermic events around 50 °C and around 190 °C, likely due to loss of water or solvent. Recrystallization exotherm and melting edotherm were also observed at higher temperatures. A gradual weight loss of 4.3 wt% was observed up to 230 °C. About 1.6 wt% IPA was observed by 1H NMR (FIG. 56). Based on these observations, Form I is likely a solvate or hydrate.

[00425] FIG. 9 provides an XRPD pattern of Form I. A list of X-Ray Diffraction Peaks for Form I is provided below in Table 17. [00426] Table 17. X-Ray Diffraction Peaks for Form I

6.12 FORM J

[00427] Form J was generated by recrystallization in THF/heptane or by evaporation from n-BuOH. TGA and DSC thermograms of Form J are shown in FIG. 57 and FIG. 58, respectively. The DSC thermogram of Form J showed an endothermic event around 46 °C likely due to loss of water or solvent, but only a small weight loss of 0.16 wt% was observed from TGA. No significant degradation or residual solvent was observed by 1H NMR (FIG. 59). The DVS isothmerm plot of Form J showed 1.3 wt% mass change between 0 and 90 %RH, but a step mass change was not observed (FIG. 60). These observations suggested that Form J is likely a non-stoichemetric hydrate. Form J was found to convert to Form F after DVS, indicating Form J is a less stable hydrate than Form F.

[00428] FIG. 10 provides an XRPD pattern of Form J. A list of X-Ray Diffraction Peaks for Form J is provided below in Table 18.

[00429] Table 18. X-Ray Diffraction Peaks for Form J

Relative

Two-theta angle (°) d Space (A)

Intensity (%)

5.2 16.8915 100

5.7 15.5692 44

8.7 10.1589 11

9.7 9.1184 7

10.5 8.4047 8

11.5 7.7040 3

13.0 6.8001 4

13.4 6.5982 5

14.2 6.2320 11

14.6 6.0725 7

14.8 6.0021 5

15.5 5.7281 8

15.8 5.5957 2

17.1 5.1849 4

17.5 5.0715 7

18.1 4.9133 8

18.6 4.7825 10

19.1 4.6515 14

19.5 4.5628 5

20.7 4.2918 23

21.1 4.2045 15

21.7 4.1035 5

22.3 3.9791 10

23.5 3.7877 5

24.6 3.6155 28

25.8 3.4521 2

27.1 3.2848 8

28.7 3.1156 7

30.9 2.8965 1

6.13 FORM K

[00430] Form K was generated from crash cooling recrystallization in acetone. TGA and

DSC thermograms of Form K are shown in FIG. 61 and FIG. 62, respectively. TGA weight loss of 10.4 wt% was observed around 150 °C, corresponding to the DSC endotherm at the same temperature range. Recrystallization exotherm and melting edotherm were also observed at higher temperatures, especially a melting endotherm at 269 °C. The Form K sample was then heated to 260 °C and generated a unique form later designated as Form L. About 0.8 molar equivalent of acetone was observed by 1H NMR (FIG. 63), matching the TGA weight loss observed. Based on these observations, Form K is most likely an acetone solvate.

[00431] FIG. 11 provides an XRPD pattern of Form K. A list of X-Ray Diffraction Peaks for Form K is provided below in Table 19.

[00432] Table 19. X-Ray Diffraction Peaks for Form K

6.14 FORM L

[00433] Form L was generated by heating a solvate of Compound 1, such as Form K, to about 260 °C. TGA and DSC thermograms of Form L are shown in FIG. 64 and FIG. 65, respectively. Form L melts at about 268 °C and shows no weight loss upon heating. The heat of fusion for Form L is 100 J/g, lower than the heat of fusion for Form E. No significant degradation was observed by 1H NMR (FIG. 66). Form L is slightly hygroscopic, with about 1.8 wt% water uptake up to 95 %RH (FIG. 67). These observations confirmed that Form L is an anhydrate and is enantiotropically related to Form E. The relative stability between Form L and Form E was further characterized by form transfer experiments (Table 6). Results from slurry experiments showed that Form E is more stable than Form L at ambient and below 100 °C in solvent mediated conditions.

[00434] FIG. 12 provides an XRPD pattern of Form L. A list of X-Ray Diffraction Peaks for Form L is provided below in Table 20.

[00435] Table 20. X-Ray Diffraction Peaks for Form L

Relative

Two-theta angle (°) d Space (A)

Intensity (%)

19.9 4.4526 13

20.4 4.3572 1

21.6 4.1218 11

22.2 4.0036 7

22.8 3.9006 100

23.4 3.8017 5

24.0 3.7153 61

25.1 3.5460 3

25.9 3.4392 9

26.7 3.3437 8

27.7 3.2199 5

28.0 3.1890 2

30.5 2.9277 1

31.2 2.8655 1

34.7 2.5838 2

35.6 2.5205 3

6.15 FORM M

[00436] Form M was generated by heating Form B at around 40 °C under vacuum. TGA and DSC thermograms of Form M are shown in FIG. 68 and FIG. 69, respectively. Form M showed minimal TGA weight loss below 250 °C. The DSC thermogram showed an endotherm around 173 °C followed by an exotherm at 193 °C. Recrystallization exotherm and melting endotherms were also observed at higher temperatures on DSC thermogram. The material obtained by heating Form M at 180 °C was amorphous as identified by XRPD. Further DSC experiments performed with heat-cool cycles showed that the event at 173 °C was not observed on the second heat cycle, thus likely not a real melting transition. These observations suggested that Form M is most likely a dehydrated form, not an anhydrous form. Form M is slightly hygroscopic, with about 1.3 wt% water uptake up to 95 % RH on DVS (FIG. 70).

[00437] FIG. 13 provides an XRPD pattern of Form M. A list of X-Ray Diffraction Peaks for Form M is provided below in Table 21.

[00438] Table 21. X-Ray Diffraction Peaks for Form M Relative

Two-theta angle (°) d Space (A)

Intensity (%)

5.7 15.4315 79

6.2 14.1951 100

9.6 9.1955 22

10.5 8.3941 7

11.5 7.7077 24

14.8 5.9828 12

15.8 5.5992 14

16.3 5.4415 8

16.5 5.3701 10

17.3 5.1295 22

19.2 4.6141 4

20.3 4.3682 4

21.0 4.2244 4

21.3 4.1672 7

22.0 4.0402 2

22.7 3.9142 3

23.1 3.8481 2

23.7 3.7561 3

25.8 3.4522 2

27.1 3.2852 2

27.7 3.2242 1

6.16 FORM N

[00439] Form N was generated by slurry or recrystallization in MeOH. TGA and DSC thermograms of Form N are shown in FIG. 71 and FIG. 72, respectively. DSC thermogram of Form N showed a small broad endotherm around 50 °C, which seemed to correspond to the 1.6 wt% of TGA weight loss observed. Recrystallization exotherm and melting endotherms were also observed at higher temperatures on DSC thermogram. No significant degradation or residual MeOH was observed in 1H NMR (FIG. 73). The DVS data of Form N showed about 5.0 wt% water uptake up to 95 % RH (FIG. 74). These observations along with the KF result of 2.2 wt% water confirmed that Form N is a hydrate.

[00440] FIG. 14 provides an XRPD pattern of Form N. A list of X-Ray Diffraction Peaks for Form N is provided below in Table 22.

[00441] Table 22. X-Ray Diffraction Peaks for Form N Relative

Two-theta angle (°) d Space (A)

Intensity (%)

6.3 14.0949 100

7.9 11.2474 21

9.5 9.3221 24

10.7 8.3047 53

12.3 7.1783 25

14.1 6.2952 34

16.7 5.3227 24

17.8 4.9841 16

18.5 4.7981 12

19.3 4.5940 11

21.5 4.1421 17

23.2 3.8362 60

26.2 3.4047 3

27.8 3.2088 5

29.4 3.0380 7

33.3 2.6870 1

6.17 FORM O

[00442] Form O was generated by crash cooling recrystallization in acetone. Form O has a SEM picture as shown in FIG. 75. TGA and DSC thermograms of Form O are shown in FIG. 76 and FIG. 77, respectively. The DSC thermogram showed an endotherm at 153 °C for desolvation, corresponding to the 10.4 wt% of TGA weight loss. Recrystallization exotherm and melting endotherms were also observed at higher temperatures on DSC thermogram. The ^XH NMR (FIG. 78) showed 0.9 molar equivalent of acetone, matching the TGA weight loss. These observations confirmed that Form O is an acetone solvate.

[00443] FIG. 15 provides an XRPD pattern of Form O. A list of X-Ray Diffraction Peaks for Form O is provided below in Table 23.

[00444] Table 23. X-Ray Diffraction Peaks for Form O

Relative

Two-theta angle (°) d Space (A)

Intensity (%)

10.3 8.5650 3

11.3 7.8168 46

12.2 7.2612 21

12.5 7.0565 11

13.8 6.4340 22

14.2 6.2280 36

15.1 5.8623 5

15.5 5.7120 2

15.9 5.5713 8

16.1 5.4877 21

16.7 5.3047 47

17.2 5.1617 35

17.8 4.9825 5

19.0 4.6711 14

19.2 4.6225 24

19.4 4.5725 28

19.8 4.4800 6

20.0 4.4382 7

20.5 4.3409 24

20.6 4.3126 25

22.1 4.0159 9

22.6 3.9353 6

22.9 3.8823 47

23.3 3.8142 43

23.5 3.7808 32

24.4 3.6409 86

25.0 3.5635 19

25.2 3.5365 18

25.5 3.4920 18

26.0 3.4242 100

27.2 3.2790 4

27.7 3.2248 5

28.2 3.1668 6

28.6 3.1208 6

30.2 2.9610 5

31.1 2.8797 2

32.1 2.7865 1

33.9 2.6475 1

34.6 2.5955 3 Relative

Two-theta angle (°) d Space (A)

Intensity (%)

35.1 2.5581 3

36.9 2.4373 2

38.8 2.3212 2

6.18 FORM P

[00445] Form P was generated from crash cooling recrystallization in EtOH. Form P has a SEM picture as shown in FIG. 79. TGA and DSC thermograms of Form P are shown in FIG. 80 and FIG. 81, respectively. The DSC thermogram showed an endothermic events for desolvation, corresponding to the 7.4 wt% of TGA weight loss. Recrystallization exotherm and melting endotherms were also observed at higher temperatures on DSC thermogram. The ^XH NMR spectrum (FIG. 82) showed 0.9 molar equivalent of EtOH, matching the TGA weight loss. These observation confirmed that Form P is an EtOH solvate.

[00446] FIG. 16 provides an XRPD pattern of Form P. A list of X-Ray Diffraction Peaks for Form P is provided below in Table 24.

[00447] Table 24. X-Ray Diffraction Peaks for Form P

Relative

Two-theta angle (°) d Space (A)

Intensity (%)

18.1 4.9140 19

18.7 4.7570 3

19.1 4.6393 18

19.4 4.5711 94

19.9 4.4722 25

20.3 4.3754 5

20.7 4.2937 1

21.2 4.1855 12

21.5 4.1301 7

21.9 4.0674 11

22.3 3.9940 10

22.6 3.9288 30

22.9 3.8772 22

23.7 3.7556 55

24.4 3.6467 54

24.8 3.5923 85

25.4 3.5090 7

26.0 3.4237 7

26.6 3.3492 94

27.2 3.2762 9

28.2 3.1698 4

28.5 3.1357 16

29.1 3.0728 27

30.1 2.9700 2

31.1 2.8754 1

32.0 2.7967 4

32.7 2.7420 1

35.3 2.5436 3

35.8 2.5051 2

36.6 2.4537 2

37.5 2.3959 5

38.5 2.3393 1

38.8 2.3183 1

[00448] The embodiments disclosed herein are not to be limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of a few aspects of the disclosed embodiments and any embodiments that are functionally equivalent are encompassed by the present disclosure. Indeed, various modifications of the embodiments disclosed herein are in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

[00449] A number of references have been cited, the disclosures of which are incorporated herein by reference in their entirety.

Claims

What is claimed is:

A crystal form comprising Compound 1, or a tautomer thereof:

1

which has an X-ray powder diffraction pattern comprising peaks at approximately 5.1, 18.6 and 19.1 °2Θ.

2. The crystal form of claim 1 which has an X-ray powder diffraction pattern further comprising peaks at approximately 6.7, 13.0 and 20.1 °2Θ. 3. The crystal form of claim 1 which has a thermogravimetric analysis thermogram comprising a total mass loss of approximately 0.1 % of the total mass of the crystal form when heated from about 25 °C to about 300 °C.

4. The crystal form of claim 1 which has a differential scanning calorimetry

thermogram comprising an endotherm with with an onset temperature at approximately 244 °C when heated from about 25 °C to about 300 °C.

5. The crystal form of claim 1 which is anhydrous. 6. The crystal form of claim 1 which is substantially pure. 7. A crystal form comprising Compound 1, or a tautomer thereof:

1

which has an X-ray powder diffraction pattern comprising peaks at approximately 5.1, 5.4 and 11.2 °2Θ.

The crystal form of claim 7 which has an X-ray powder diffraction pattern further comprising peaks at approximately 10.9, 13.9 and 19.8 °2Θ.

The crystal form of claim 7 which has a thermogravimetric analysis thermogram comprising a total mass loss of approximately 10% of the total mass of the crystal form when heated from about 25 °C to about 300 °C.

10. The crystal form of claim 7 which has a differential scanning calorimetry

thermogram comprising an endotherm with a maximum at approximately 57 °C when heated from about 25 °C to about 300 °C.

11. The crystal form of claim 7 which is a hydrate. 12. The crystal form of claim 7 which is substantially pure. 13. A crystal form comprising Compound 1, or a tautomer thereof:

1 which has an X-ray powder diffraction pattern comprising peaks at approximately 3.7, 7.4 and 25.1 °2Θ.

14. The crystal form of claim 13 which has an X-ray powder diffraction pattern further comprising peaks at approximately 8.0, 11.1 and 21.9 °2Θ. 15. The crystal form of claim 13 which has a differential scanning calorimetry

thermogram comprising an endotherm with with an onset temperature at approximately 227 °C when heated from about 25 °C to about 300 °C.

16. The crystal form of claim 13 which has a differential scanning calorimetry

thermogram comprising an exotherm with a maximum at approximately 231 °C when heated from about 25 °C to about 300 °C.

17. The crystal form of claim 13 which has a differential scanning calorimetry

thermogram comprising an exotherm with a maximum at approximately 257 °C when heated from about 25 °C to about 300 °C.

18. The crystal form of claim 13 which is anhydrous. 19. The crystal form of claim 13 which is substantially pure. 20. A crystal form comprising Compound 1, or a tautomer thereof:

1

which has an X-ray powder diffraction pattern comprising peaks at approximately 3.6, 7.3 and 18.6 °2Θ.

21. The crystal form of claim 20 which has an X-ray powder diffraction pattern further comprising peaks at approximately 10.6, 15.1 and 21.4 °2Θ. 22. The crystal form of claim 20 which has a thermogravimetric analysis thermogram comprising a total mass loss of approximately 5.1% of the total mass of the crystal form when heated from about 25 °C to about 300 °C.

23. The crystal form of claim 20 which has a differential scanning calorimetry

thermogram comprising an endotherm with a maximum at approximately 228 °C when heated from about 25 °C to about 300 °C.

24. The crystal form of claim 20 which is hydrate. 25. The crystal form of claim 20 which is substantially pure. 26. A crystal form comprising Compound 1, or a tautomer thereof:

which has an X-ray powder diffraction pattern comprising peaks at approximately 5.5, 11.1 and 18.8 °2Θ.

27. The crystal form of claim 26 which has an X-ray powder diffraction pattern further comprising peaks at approximately 6.5, 15.0 and 18.0 °2Θ.

28. The crystal form of claim 26 which has a thermogravimetric analysis thermogram comprising a total mass loss of approximately 0.2 % of the total mass of the crystal form when heated from about 25 °C to about 300 °C.

29. The crystal form of claim 26 which has a differential scanning calorimetry thermogram comprising an endotherm with an onset temperature at approximately 256 °C when heated from about 25 °C to about 300 °C.

30. The crystal form of claim 26 which is anhydrous. 31. The crystal form of claim 26 which is substantially pure. 32. A crystal form comprising Compound 1, or a tautomer thereof:

which has an X-ray powder diffraction pattern comprising peaks at approximately 5.4, 5.9 and 11.7 °2Θ.

33. The crystal form of claim 32 which has an X-ray powder diffraction pattern further comprising peaks at approximately 7.6, 8.1 and 13.2 °2Θ. 34. The crystal form of claim 32 which has a thermogravimetric analysis thermogram comprising a total mass loss of approximately 0.4 % of the total mass of the crystal form when heated from about 25 °C to about 300 °C.

35. The crystal form of claim 32 which has a differential scanning calorimetry

thermogram comprising an endotherm with a maximum at approximately 256 °C when heated from about 25 °C to about 300 °C.

36. The crystal form of claim 32 which is hydrate. 37. The crystal form of claim 32 which is substantially pure. A crystal form comprising Compound 1, or a tautomer thereof:

1

which has an X-ray powder diffraction pattern comprising peaks at approximately 3.3, 8.0 and 21.7 °2Θ.

The crystal form of claim 38 which has an X-ray powder diffraction pattern further comprising peaks at approximately 10.4, 10.8 and 17.1 °2Θ.

The crystal form of claim 38 which has a differential scanning calorimetry thermogram comprising an endotherm with a maximum at approximately 50 °C when heated from about 25 °C to about 300 °C.

The crystal form of claim 38 which is a hydrate.

The crystal form of claim 38 which is substantially pure.

A crystal form comprising Compound 1, or a tautomer thereof:

1

which has an X-ray powder diffraction pattern comprising peaks at approximately 5.1, 5.3 and 7.3 °2Θ.

44. The crystal form of claim 43 which has an X-ray powder diffraction pattern further comprising peaks at approximately 10.2, 13.0 and 15.0 °2Θ. 45. The crystal form of claim 43 which has a thermogravimetric analysis thermogram comprising a total mass loss of approximately 3.2% of the total mass of the crystal form when heated from about 25 °C to about 130 °C.

46. The crystal form of claim 43 which has a differential scanning calorimetry

thermogram comprising an endotherm with a maximum at approximately 132 °C when heated from about 25 °C to about 300 °C.

47. The crystal form of claim 43 which is a hydrate. 48. The crystal form of claim 43 which is substantially pure. 49. A crystal form comprising Compound 1, or a tautomer thereof:

which has an X-ray powder diffraction pattern comprising peaks at approximately 4.3, 6.4 and 12.4 °2Θ.

50. The crystal form of claim 49 which has an X-ray powder diffraction pattern further comprising peaks at approximately 14.9, 17.4 and 21.3 °2Θ.

51. The crystal form of claim 49 which has a thermogravimetric analysis thermogram comprising a total mass loss of approximately 4% of the total mass of the crystal form when heated from about 25 °C to about 230 °C.

52. The crystal form of claim 49 which has a differential scanning calorimetry thermogram comprising an endotherm with a maximum at approximately 50 °C when heated from about 25 °C to about 300 °C.

53. The crystal form of claim 49 which has a differential scanning calorimetry

thermogram comprising an endotherm with a maximum at approximately 190 °C when heated from about 25 °C to about 300 °C.

54. The crystal form of claim 49 which is a hydrate. 55. The crystal form of claim 49 which is a solvate. 56. The crystal form of claim 49 which is an isopropyl alcohol solvate. 57. The crystal form of claim 49 which is substantially pure. 58. A crystal form comprising Compound 1, or a tautomer thereof:

which has an X-ray powder diffraction pattern comprising peaks at approximately 5.2, 5.7 and 24.6 °2Θ.

59. The crystal form of claim 58 which has an X-ray powder diffraction pattern further comprising peaks at approximately 19.1, 20.7 and 21.1 °2Θ.

60. The crystal form of claim 58 which has a thermogravimetric analysis thermogram comprising a total mass loss of approximately 0.16 % of the total mass of the crystal form when heated from about 25 °C to about 300 °C.

61. The crystal form of claim 58 which has a differential scanning calorimetry thermogram comprising an endotherm with a maximum at approximately 46 °C when heated from about 25 °C to about 300 °C.

62. The crystal form of claim 58 which is a hydrate. 63. The crystal form of claim 58 which is substantially pure. 64. A crystal form comprising Compound 1, or a tautomer thereof:

which has an X-ray powder diffraction pattern comprising peaks at approximately 4.2, 10.4 and 25.9 °2Θ.

65. The crystal form of claim 64 which has an X-ray powder diffraction pattern further comprising peaks at approximately 16.3, 17.9 and 18.2 °2Θ.

66. The crystal form of claim 64 which has a thermogravimetric analysis thermogram comprising a total mass loss of approximately 10.4 % of the total mass of the crystal form when heated from about 25 °C to about 300 °C.

67. The crystal form of claim 64 which has a differential scanning calorimetry

thermogram comprising an endotherm with a maximum at approximately 149 °C when heated from about 25 °C to about 300 °C.

68. The crystal form of claim 64 which has a differential scanning calorimetry

69. The crystal form of claim 64 which has a differential scanning calorimetry thermogram comprising an endotherm with a maximum at approximately 269 °C when heated from about 25 °C to about 300 °C.

70. The crystal form of claim 64 which is a solvate. 71. The crystal form of claim 64 which is an acetone solvate. 72. The crystal form of claim 64 which is a 0.8 molar equivalent acetone solvate. 73. The crystal form of claim 64 which is substantially pure. 74. A crystal form comprising Compound 1, or a tautomer thereof:

which has an X-ray powder diffraction pattern comprising peaks at approximately 7.3, 22.8 and 24.0 °2Θ.

75. The crystal form of claim 74 which has an X-ray powder diffraction pattern further comprising peaks at approximately 16.8, 17.0 and 17.8 °2Θ. 76. The crystal form of claim 74 which has a differential scanning calorimetry

thermogram comprising an endotherm with an onset temperature at approximately 268 °C when heated from about 25 °C to about 300 °C.

77. The crystal form of claim 74 which is anhydrous. 78. The crystal form of claim 74 which is substantially pure. A crystal form comprising Compound 1, or a tautomer thereof:

1

which has an X-ray powder diffraction pattern comprising peaks at approximately 5.7, 6.2 and 11.5 °2Θ.

80. The crystal form of claim 79 which has an X-ray powder diffraction pattern further comprising peaks at approximately 9.6, 15.8 and 17.3 °2Θ. 81. The crystal form of claim 79 which has a differential scanning calorimetry

thermogram comprising an endotherm with a maximum at approximately 173 °C when heated from about 25 °C to about 300 °C.

82. The crystal form of claim 79 which has a differential scanning calorimetry

thermogram comprising an exotherm with a maximum at approximately 193 °C when heated from about 25 °C to about 300 °C.

83. The crystal form of claim 79 which is a dehydrate form. 84. The crystal form of claim 79 which is substantially pure. 85. A crystal form comprising Compound 1, or a tautomer thereof:

1

which has an X-ray powder diffraction pattern comprising peaks at approximately 6.3, 10.7 and 23.2 °2Θ.

86. The crystal form of claim 85 which has an X-ray powder diffraction pattern further comprising peaks at approximately 9.5, 12.3 and 14.1 °2Θ. 87. The crystal form of claim 85 which has a thermogravimetric analysis thermogram comprising a total mass loss of approximately 1.6 % of the total mass of the crystal form when heated from about 25 °C to about 300 °C.

88. The crystal form of claim 85 which has a differential scanning calorimetry

thermogram comprising an endotherm with a maximum at approximately 258 °C when heated from about 25 °C to about 300 °C.

89. The crystal form of claim 85 which has a differential scanning calorimetry

thermogram comprising an endotherm with a maximum at approximately 270 °C when heated from about 25 °C to about 300 °C.

90. The crystal form of claim 85 which is a hydrate. 91. The crystal form of claim 85 which is substantially pure. 92. A crystal form comprising Compound 1, or a tautomer thereof:

1

which has an X-ray powder diffraction pattern comprising peaks at approximately 22.9, 24.4 and 26.0 °2Θ.

93. The crystal form of claim 92 which has an X-ray powder diffraction pattern further comprising peaks at approximately 11.3, 16.7 and 23.3 °2Θ.

94. The crystal form of claim 92 which has a thermogravimetric analysis thermogram comprising a total mass loss of approximately 10.4 % of the total mass of the crystal form when heated from about 25 °C to about 300 °C.

95. The crystal form of claim 92 which has a differential scanning calorimetry

thermogram comprising an endotherm with a maximum at approximately 153 °C when heated from about 25 °C to about 300 °C.

96. The crystal form of claim 92 which has a differential scanning calorimetry

thermogram comprising an exotherm with a maximum at approximately 215 °C when heated from about 25 °C to about 300 °C.

97. The crystal form of claim 92 which has a differential scanning calorimetry

thermogram comprising an endotherm with a maximum at approximately 257 °C when heated from about 25 °C to about 300 °C.

98. The crystal form of claim 92 which has a differential scanning calorimetry

thermogram comprising an endotherm with a maximum at approximately 269 °C when heated from about 25 °C to about 300 °C.

99. The crystal form of claim 92 which is a solvate.

100. The crystal form of claim 92 which is an acetone solvate.

101. The crystal form of claim 92 which is a 0.9 molar equivalent acetone solvate.

102. The crystal form of claim 92 which is substantially pure.

103. A crystal form comprising Compound 1, or a tautomer thereof:

which has an X-ray powder diffraction pattern comprising peaks at approximately 13.5, 19.4 and 26.6 °2Θ.

104. The crystal form of claim 103 which has an X-ray powder diffraction pattern further comprising peaks at approximately 16.4, 23.7 and 24.8 °2Θ.

105. The crystal form of claim 103 which has a thermogravimetric analysis thermogram comprising a total mass loss of approximately 7.4 % of the total mass of the crystal form when heated from about 25 °C to about 300 °C.

106. The crystal form of claim 103 which has a differential scanning calorimetry

107. The crystal form of claim 103 which has a differential scanning calorimetry

108. The crystal form of claim 103 which is a solvate.

109. The crystal form of claim 103 which is an ethanol solvate.

110. The crystal form of claim 103 which is a 0.9 molar equivalent ethanol solvate.

111. The crystal form of claim 103 which is substantially pure.

112. A method for treating or preventing a cancer, comprising administering to a subject in need thereof an effective amount of a crystal form of claim 1, 7, 13, 20, 26, 32, 38, 43, 49, 58, 64, 74, 79, 85, 92 or 103, wherein the cancer is a solid tumor or a hematological cancer.

113. The method of claim 112, wherein the solid tumor is bladder cancer, breast cancer, central nervous system cancer, colorectal cancer, gastrointestinal cancer, endocrine cancer, eye cancer, female genitourinary cancer, head and neck cancer, liver cancer, lung cancer, skin cancer, soft tissue cancer, bone cancer, squamous cell cancer, pancreas cancer, kidney cancer, prostate cancer or triple negative breast cancer.

114. The method of claim 112, wherein the solid tumor is triple negative breast cancer.

115. The method of claim 112, wherein the hematological cancer is leukemia, lymphoma or multiple myeloma.

116. The method of claim 115, wherein the leukemia is selected from acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), acute T-cell leukemia, B cell precursor leukemia, acute promyelocytic leukemia (APML), plasma cell leukemia, myelomonoblastic/T-ALL, B myelomonocytic leukemia, erythroleukemia, M-CML, and M-AML.

117. The method of claim 115, wherein the lymphoma is selected from Hodgkin's

lymphoma, non Hodgkin's lymphoma (NHL), Burkitt's lymphoma (BL), B cell lymphoma, lymphoblastic lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and large cell immunoblastic lymphoma.

118. The method of claim 112, wherein the the hematological cancer is multiple

myeloma.

119. A method for preventing cancer metastasis, comprising administering to a subject in need thereof an effective amount of a crystal form of claim 1, 7, 13, 20, 26, 32, 38, 43, 49, 58, 64, 74, 79, 85, 92 or 103.

120. A method for eradicating cancer stem cells, comprising administering to a subject in need thereof an effective amount of a crystal form of claim 1, 7, 13, 20, 26, 32, 38, 43, 49, 58, 64, 74, 79, 85, 92 or 103.

121. A method for inducing differentiation in cancer stem cells, comprising administering to a subject in need thereof an effective amount of a crystal form of claim 1, 7, 13, 20, 26, 32, 38, 43, 49, 58, 64, 74, 79, 85, 92 or 103.

122. A method for inducing cancer stem cell death, comprising administering to a subject in need thereof an effective amount of a crystal form of claim 1, 7, 13, 20, 26, 32, 38, 43, 49, 58, 64, 74, 79, 85, 92 or 103.

123. The method of claim 119, 120, 121 or 122, wherein the cancer is a solid tumor or a hematological cancer.

124. The method of claim 123, wherein the solid tumor is bladder cancer, breast cancer, central nervous system cancer, colorectal cancer, gastrointestinal cancer, endocrine cancer, eye cancer, female genitourinary cancer, head and neck cancer, liver cancer, lung cancer, skin cancer, soft tissue cancer, bone cancer, squamous cell cancer, pancreas cancer, kidney cancer, prostate cancer or triple negative breast cancer.

125. The method of claim 123, wherein the solid tumor is triple negative breast cancer.

126. The method of claim 123, wherein the hematological cancer is leukemia.