NZ629877B - SOLID FORMS OF 1-ETHYL-7-(2-METHYL-6-(1H-1,2,4-TRIAZOL-3-YL)PYRIDIN-3-YL)-3,4-DIHYDROPYRAZINO[2,3-b]PYRAZIN-2(1H)-ONE, COMPOSITIONS THEREOF AND METHODS OF THEIR USE - Google Patents

Abstract

Disclosed are crystal and amorphous forms of 1-Ethyl-7-(2-Methyl-6-(1H-1,2,4-Triazol-3-yl)Pyridin-3-yl)-3,4-Dihydropyrazino[2,3-B]Pyrazin-2(1H)-One. The solid forms of the Compound are useful for treating or preventing cancer and conditions treatable or preventable by inhibition of a kinase pathway, for example, the mTOR/PI3K/Akt pathway. for example, the mTOR/PI3K/Akt pathway.

Description

Patents Form No. 5 N.Z. No. 629877 NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION SOLID FORMS OF 1-ETHYL(2-METHYL(1H-1,2,4-TRIAZOLYL)PYRIDIN YL)-3,4-DIHYDROPYRAZINO[2,3-b]PYRAZIN-2(1H)-ONE, COMPOSITIONS THEREOF AND METHODS OF THEIR USE We, Signal Pharmaceuticals, LLC, a United States company of 10300 Campus Point Drive, Suite 100, San Diego, CA 92121, UNITED STATES OF A do hereby e the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- SOLID FORMS OF L(2-METHYL(1H-1,2,4-TRIAZOLYL)PYRIDINYL)- 3,4-DIHYDROPYRAZINO[2,3-b]PYRAZIN-2(1H)-ONE, COMPOSITIONS THEREOF AND METHODS OF THEIR USE 1. FIELD Provided herein are solid forms of 1-ethyl(2-methyl(1H-1,2,4-triazol yl)pyridinyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, itions thereof, and methods of their use for the treatment of a disease, disorder, or condition. 2. BACKGROUND The identification and selection of a solid form of a pharmaceutical compound is 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 and bioavailability, among other important pharmaceutical characteristics. Potential pharmaceutical solids include crystalline solids and amorphous solids. ous solids are characterized by a lack of long-range structural order, s crystalline solids are characterized by ural periodicity. The desired class of ceutical 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) 42).

Whether crystalline or amorphous, potential solid forms of a pharmaceutical compound include single-component and multiple-component solids. Single-component solids consist essentially of the pharmaceutical compound in the absence of other compounds. Variety among single-component crystalline materials may potentially arise from the enon of polymorphism, wherein multiple three-dimensional ements 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 ation could be ped (see S. R. Chemburkar et al., Org. Process Res.

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

Additional ity 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 are 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 nd 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, n a given multiple-component composition may exist in more than one three-dimensional crystalline arrangement. The discovery of solid forms is of great importance in the development of a safe, ive, stable and marketable pharmaceutical compound.

Notably, it is not possible to predict a priori if crystalline forms of a compound even exist, let alone how to sfully prepare them (see, e.g., Braga and Grepioni, 2005, “Making crystals from ls: 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 s, the result can be unpredictable); Jones et al., 2006, ceutical Cocrystals: An Emerging Approach to Physical ty Enhancement,” MRS Bulletin 31:875-879 (At present it is not generally possible to ationally 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 -319 (“Price”); and ein, 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)).

The compound chemically named 1-ethyl(2-methyl(1H-1,2,4-triazol yl)pyridinyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one and tautomers thereof (collectively referred to herein as “Compound 1”) was disclosed in U.S. Pat. App. No. ,791, filed October 26, 2009, and International Pub. No. , the entireties of each ofwhich are incorporated by reference herein. We have discovered le solid forms of 1-ethyl(2-methyl(lH-1,2,4-triazolyl)pyridinyl)- 3,4—dihydropyrazino[2,3—b]pyrazin—2(lH)—one. on 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 t application. 3. SUMMARY Provided herein are solid forms ofCompound 1: </ P N / H | K N\ N\ N O N N having the name 1-ethyl—7-(2-methyl(1H-1,2,4—t1iazolyl)pyridin- 3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(lH)-one and tautomers thereof. [0008a] In particular the present application provides crystal forms of Compound 1 having an x-ray powder pattem comprising peaks at: (i) 6.18, 21.74 and 26.7 i0.2 °20; (ii) 3.5, 9.26 and 18.62 i0.2 °20; (iii) 10.66, 21.94 and 26.26 i0.2 °20; or (iv) 9.26, 11.7 and 26.18 $0.2 °20.

Also provided herein are formulations of solid forms ofCompound 1 and tautomers thereof.

In certain embodiments, solid forms ofCompound 1 and tautomers are useful for treating or preventing cancer and conditions treatable or preventable by inhibition of a kinase pathway, for example, the mTOR/PI3K/Akt pathway.

Followed by 4A [0010a] Particularly provided is the use of the solid forms of Compound 1, in the manufacture of a medicament for treating or preventing cancer, an matory condition, an immunological condition, a neurodegenerative disease, diabete, obesity, a neurological disorder, an lated disease, a cardiovascular condition, or a conditions treatable or preventable by inhibition of a kinase pathway, a subject in need thereof, for achieving a Response Evaluation Criteria in Solid Tumors T 1.1) of complete response, partial response or stable disease in a subject having a solid tumor and/or for ing International op ia (IWC) for NHL, International Uniform Response Criteria for Multiple Myeloma (IURC), Eastern Cooperative Oncology Group Performance Status (ECOG) or Response Assessment for Neuro-Oncology (RANO) Working Group for GBM.

The present embodiments can be understood more fully by reference to the detailed ption and examples, which are intended to exemplify non-limiting embodiments. 4. BRIEF DESCRIPTION OF THE GS depicts an X-ray powder diffractogram stack plot of Forms 1, 2, 3, 4 and 5 of Compound 1. depicts an X-ray powder diffractogram plot of Form 1 of Compound 1. depicts a digital image of Form 1 of Compound 1.

Followed by 5 depicts a thermogravimetrical analysis and single differential thermal analysis of Form 1 of Compound 1. depicts a thermogravimetric is coupled with mass spectroscopy of Form 1 of Compound 1. depicts high performance liquid chromatography coupled with mass spectrometry of Form 1 of Compound 1. s an X-ray powder diffractogram stack plot of Form 1, Form 2, and Form 2 after exposure to accelerated aging conditions (AAC) of Compound 1. depicts a digital image of Form 2 of Compound 1. depicts a digital image of Form 2 of Compound 1 after exposure to accelerated aging conditions. depicts a thermogravimetrical analysis and single differential thermal analysis of Form 2 of Compound 1. depicts a thermogravimetric is coupled with mass spectroscopy of Form 2 of Compound 1. depicts high performance liquid chromatography coupled with mass ometry of Form 2 of nd 1. depicts an X-ray powder ctogram stack plot of Form 1, Form 3, and Form 3 after exposure to accelerated aging ions (AAC) of Compound 1.

A depicts a digital image of Form 3 of Compound 1.

B depicts a digital image of Form 3 of nd 1 after exposure to accelerated aging conditions. depicts a thermogravimetrical analysis and single differential thermal analysis of Form 3 of Compound 1. depicts a thermogravimetric analysis coupled with mass spectroscopy of Form 3 of Compound 1. depicts high performance liquid chromatography coupled with mass ometry of Form 3 of Compound 1. depicts an X-ray powder diffractogram stack plot of Form 1, Form 4 as wet solid, Form 4 as dry solid, amorphous form of Compound 1 and the mixture of Forms 1 and 4 as dry solid after exposure to accelerated aging conditions (AAC) of Compound 1.

A depicts a digital image of Form 4 of Compound 1 as wet solid.

B depicts a digital image of Form 4 of Compound 1 as dry solid. depicts a gravimetrical is and single differential thermal analysis of Form 4 of Compound 1. depicts a thermogravimetric analysis coupled with mass spectroscopy of Form 4 of Compound 1. depicts high mance liquid chromatography d with mass spectrometry of Form 4 of Compound 1. depicts an X-ray powder diffractogram stack plot of Form 1, Form 5, and Form 5 after exposure to accelerated aging conditions (AAC) of Compound 1.

A depicts a digital image of Form 5 of Compound 1.

B depicts a digital image of Form 5 of Compound 1 after exposure to rated aging ions. depicts a thermogravimetrical analysis and single differential thermal analysis of Form 5 of Compound 1. depicts a thermogravimetric analysis coupled with mass spectroscopy of Form 5 of Compound 1. depicts high performance liquid chromatography coupled with mass spectrometry of Form 5 of Compound 1. depicts a differential scanning calorimetry thermogram of amorphous Compound 1. depicts an X-ray powder diffractogram of amorphous Compound 1. depicts a Raman um of amorphous Compound 1. depicts a proton nuclear magnetic resonance spectrum of amorphous Compound 1. depicts high performance liquid chromatography coupled with mass spectrometry of amorphous Compound 1. depicts a differential scanning calorimetry thermogram of amorphous nd 1 for determination of its glass transition temperature.

. DETAILED DESCRIPTION .1 DEFINITIONS As used herein, the term “pharmaceutically acceptable salt(s)” refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base including an inorganic acid and base and an organic acid and base. le ceutically acceptable base addition salts include, but are not limited to metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, ibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and c acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, ic, hydrobromic, hydrochloric, isethionic, , maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, acetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric, and esulfonic acids. es of specific salts thus include hydrochloride and mesylate salts. Others are well-known in the art, see for example, Remington’s Pharmaceutical Sciences, 18th eds., Mack Publishing, Easton PA (1990) or Remington: The e and Practice of cy, 19th eds., Mack Publishing, Easton PA .

Pharmaceutically acceptable salts of Compound 1 can be formed by conventional and known techniques, such as by ng Compound 1 with a suitable acid as disclosed above.

Such salts are typically formed in high yields at moderate temperatures, and often are prepared by merely isolating the compound from a suitable acidic wash in the final step of the synthesis.

The salt-forming acid may dissolved in an appropriate c solvent, or aqueous organic t, such as an alkanol, ketone or ester. On the other hand, if Compound 1 is desired in the free base form, it may be isolated from a basic final wash step, according to known techniques.

For example, a typical technique for preparing hydrochloride salt is to dissolve the free base of Compound 1 in a suitable solvent, and dry the solution thoroughly, as over molecular sieves, before bubbling hydrogen chloride gas through it.

As used herein and unless otherwise indicated, the term “stereoisomer” or “stereomerically pure” means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. For example, a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A merically pure compound having two chiral centers will be substantially free of other diastereomers of the nd. A typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the nd, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other isomers of the compound, or greater than about 97% by weight of one stereoisomer of the nd and less than about 3% by weight of the other stereoisomers of the nd. nds can have chiral centers and can occur as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms are included within the embodiments sed , including mixtures thereof. The use of stereomerically pure forms of such compounds, as well as the use of mixtures of those forms are encompassed by the embodiments disclosed herein. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular compound may be used in methods and compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard ques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and tions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).

It should also be noted the compounds can include E and Z isomers, or a mixture thereof, and cis and trans isomers or a mixture thereof. In certain embodiments, compounds are isolated as either the cis or trans isomer. In other embodiments, compounds are a mixture of the cis and trans isomers.

“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 s solution. For example, in aqueous solution, pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other: N N HN N 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.

It should also be noted that nd 1 can contain unnatural proportions of atomic isotopes at one or more of the atoms. For example, Compound 1 may be radiolabeled with radioactive es, such as for e tritium (3H), or carbon-14 (14C), or may be isotopically enriched, such as with deuterium (2H), carbon-13 (13C), or nitrogen-15 (15N). As used herein, an “isotopologue” is an isotopically enriched compound. The term “isotopically enriched” refers to an atom having an isotopic composition other than the l isotopic composition of that atom. “Isotopically ed” may also refer to a compound ning at least one atom having an ic composition other than the natural isotopic composition of that atom. The term “isotopic composition” refers to the amount of each isotope present for a given atom. Radiolabeled and isotopically encriched compounds are useful as therapeutic agents, e.g., cancer and inflammation therapeutic agents, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of nd 1, whether radioactive or not, are intended to be encompassed within the scope of the embodiments provided herein. In some embodiments, there are provided isotopologues of Compound 1, for example, the isotopologues are deuterium, -13, or nitrogen-15 enriched Compound 1.

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 al form sing Compound 1 which is not predominantly in a liquid or a gaseous state. A solid form may be a crystalline form, an amorphous form, or a mixture thereof. In certain embodiments, a solid form may be a liquid crystal. In certain embodiments, the term “solid forms comprising nd 1” includes crystal forms sing Compound 1, amorphous forms comprising Compound 1, and mixtures thereof. In certain embodiments, the solid form of Compound 1 is Form 1, Form 2, Form 3, Form 4, Form 5, amorphous or a mixture thereof.

As used herein and unless otherwise specified, the term “crystalline” when used to describe a compound, substance, cation, material, component or product, unless otherwise specified, means that the compound, nce, modification, material, component or product is substantially crystalline as ined 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, 23rd ed., 1843-1844 (1995).

The term “crystal form” or “crystalline form” refers to a solid form that is crystalline. In certain embodiments, crystal forms e 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 nce may be physically and/or ally pure. In certain embodiments, a l form of a nce 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.

The term “amorphous” or “amorphous form” means that the substance, ent, 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 lline order. In certain embodiments, an amorphous form of a substance may be substantially free of other amorphous forms and/or crystal forms. In certain embodiments, an amorphous 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 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about %, less than about 40%, less than about 45%, or less than about 50% by weight of one or more other amorphous forms and/or crystal forms on a weight basis. In certain embodiments, an amorphous form of a substance may be physically and/or chemically pure. In certain embodiments, an ous form of a nce 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.

“Treating” as used herein, means an alleviation, in whole or in part, of the disease or disorder, or symptoms associated with the disease or disorder, or slowing, or halting of further progression or worsening of the disease or disorder, or symptoms ated with the disease or disorder.

“Preventing” as used herein, means tion of the onset, ence, or spread of the disease or er, or ms associated with the disorder or disease, in a patient at risk for developing the disease or disorder.

The term “effective ” in connection with a solid form of Compound 1 means, in one ment, an amount capable of alleviating, in whole or in part, symptoms associated with a disorder or disease, or slowing or halting further ssion or worsening of those symptoms, or, in another embodiment, an amount e of preventing or providing prophylaxis for the disease or disorder in a subject at risk for developing the disease or disorder as disclosed herein, such as cancer. In one embodiment an effective amount of Compound 1 is an amount that inhibits a kinase in a cell, such as, for e, in vitro or in vivo. In one embodiment the kinase is mTOR, DNA-PK, PI3K or a combination thereof. In some embodiments, the effective amount of Compound 1 inhibits the kinase in a cell by 10%, 20%, %, 40%, 50%, 60%, 70%, 80%, 90% or 99%, compared to the activity of the kinase in an untreated cell. The effective amount 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 both oral and parenteral administration. As will be apparent to those skilled in the art, it is to be expected that the effective amount of Compound 1 disclosed herein may vary depending on the tion being treated, e.g., the effective amount of Compound 1 would likely be different for treating patients suffering from, or at risk for, inflammatory conditions relative to the effective amount of Compound 1 for treating patients suffering from, or at risk of, a different disorder, e.g., cancer or a metabolic disorder.

The term “patient” includes an animal, including, but not d to, an animal such as a cow, , horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig, in one embodiment a mammal, in another embodiment a human.

The term “cancer” refers to any of various malignant neoplasms characterized by the proliferation of cells that can invade surrounding tissue and metastasize to new body sites.

Both benign and malignant tumors are classified according to the type of tissue in which they are found. For example, fibromas are neoplasms of s connective tissue, and melanomas are abnormal growths of pigment (melanin) cells. Malignant tumors originating from lial tissue, e.g., in skin, bronchi, and stomach, are termed carcinomas. Malignancies of lial lar tissue such as are found in the breast, te, and colon, are known as adenocarcinomas. Malignant growths of connective tissue, e.g., muscle, cartilage, lymph , and bone, are called sarcomas. Lymphomas and leukemias are malignancies arising among white blood cells. Through the process of metastasis, tumor cell migration to other areas of the body establishes neoplasms in areas away from the site of initial appearance. Bone tissues are one of the most favored sites of metastases of malignant , occurring in about 30% of all cancer cases. Among malignant tumors, cancers of the lung, breast, prostate or the like are ularly known to be likely to metastasize to bone.

In the context of neoplasm, cancer, tumor growth or tumor cell growth, tion may be assessed by 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 ary effects of disease, arrested tumor growth and regression of tumors, among others. In the extreme, complete inhibition, is referred to herein as tion or chemoprevention. In this context, the term “prevention” includes either preventing the onset of clinically evident sia altogether or preventing the onset of a preclinically evident stage of neoplasia in individuals at risk. Also ed 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 the neoplasia.

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: Response Definition Nodal Masses Spleen, liver Bone Marrow CR Disappearance (a) id or PET Not Infiltrate cleared of all ce positive prior to therapy; palpable, on repeat biopsy; if of disease mass of any size permitted s indeterminate by if PET negative disappeared morphology, (b) Variably FDG-avid or immunohisto- PET negative; regression chemistry to normal size on CT should be negative PR Regression of ≥50% decrease in SPD of ≥50% Irrelevant if measurable up to 6 largest dominant decrease in positive prior to disease and no masses; no increase in size SPD of therapy; cell type new sites of other nodes nodules (for should be specified (a) id or PET single positive prior to therapy; nodule in one or more PET positive greatest at previously involved site transverse (b) Variably FDG-avid or diameter); PET negative; regression no increase on CT in size of liver or spleen SD Failure to (a) id or PET attain CR/PR ve prior to therapy; or PD PET positive at prior sites of disease and no new sites on CT or PET (b) Variably FDG-avid or PET ve; no change in size of previous lesions on CT Response Definition Nodal Masses Spleen, liver Bone Marrow PD or Any new Appearance of a new ≥50% New or recurrent relapsed lesion or lesion(s) ≥1.5 cm in any increase involvement disease increase by ≥ axis, ≥50% increase in from nadir in 50% of SPD of more than one the SPD of previously node, any previous involved sites or ≥50% increase in lesions from nadir longest diameter of a previously identifed node ≥1 cm in short axis Lesions PET positive if FDG-avid lymphoma or PET positive prior to therapy Abbreviations: CR, complete remission; FDG, luorodeoxyglucose; PET, positron emission tomography; CT, ed tomography; PR, partial ion; SPD, sum of the product of the diameters; SD, stable disease; PD, progressive disease.

End point ts Definition Measured from Primary Overall survival All Death as a result of any cause Entry onto study ssion-free All Disease progression or death as a result of Entry onto study survival any cause Secondary Event-free survival All e of treatment or death as result of any Entry onto study cause Time to All Time to progression or death as a result of Entry onto study progression lymphoma Disease-free In CR Time to relapse or death as a result of Documentation survival lymphoma or acute toxicity of treatment of response Response on In CR or Time to relapse or progression Documentation PR of response Lymphoma- All Time to death as a result of lymphoma Entry onto study ic survival Time to next All Time to new treatment End of primary treatment treatment Abbreviations: CR: complete remission; PR: partial remission.

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, usion requirements, frequent infections, or other parameters. Time to reappearance or progression of lymphoma-related symptoms can also be used in this end point.

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 cytic leukemia: a report from the International Workshop on Chronic Lymphocytic ia updating the National Cancer Institute-Working Group 1996 guidelines. Blood, 2008; (111) 12: 5446-5456) using the response and endpoint tions shown therein and in ular: Parameter CR PR PD Group A Lymphadenopathy† None > 1.5 cm Decrease ≥ 50% se ≥ 50% Hepatomegaly None se ≥ 50% Increase ≥ 50% Splenomegaly None Decrease ≥ 50% Increase ≥ 50% Decrease ≥ 50% Increase ≥ 50% over Blood lymphocytes < L from baseline baseline Normocellular, < 30% lymphocytes, no B- 50% reduction in Marrow‡ lymphoid nodules. marrow infiltrate, or llular marrow B-lymphoid nodules defines CRi (5.1.6).

Group B > 100 000/μL or Decrease of ≥ 50% Platelet count > 100 000/μL from baseline secondary to CLL increase ≥ 50% over baseline > 11 g/dL or Decrease of > 2 g/dL Hemoglobin > 11.0 g/dL increase ≥ 50% over from baseline baseline secondary to CLL > 1500/μL or > 50% Neutrophils‡ > 1500/μL improvement over baseline Group A ia define the tumor load; Group B criteria define the function of the hematopoietic system (or marrow). CR ete 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 , or by physical examination in l practice). These parameters are irrelevant for some response categories.

In certain embodiments, the treatment of multiple myeloma may be assessed by the International Uniform Response Criteria for le 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 tions shown below: Response Subcategory Response Criteriaa sCR CR as defined below plus Normal FLC ratio and Absence of clonal cells in bone marrowb by immunohistochemistry or immunofluorescencec CR Negative fixation on the serum and urine and Disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrowb VGPR Serum and urine ein 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 y M-protein by≥90% or to <200mg per 24 h If the serum and urine M-protein are urable,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 on to the above listed criteria, if present at baseline, a ≥50% reduction in the size of soft tissue plasmacytomas is also required SD (not recommended for use as an Not meeting criteria for CR, VGPR, PR or progressive indicator of response; ity of disease disease is best described by providing the time to progression estimates) Abbreviations: CR, complete response; FLC, free light chain; PR, partial response; SD, stable disease; sCR, stringent complete response; VGPR, very good partial response; aAll se categories require two consecutive ments made at e before the ution of any new therapy; all categories also require no known evidence of progressive or new bone lesions if raphic studies were performed. raphic studies are not required to satisfy these response requirements; bConfirmation 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 <1:2.dMeasurable disease defined by at least one of the following measurements: Bone marrow plasma cells ≥30%; Serum M-protein ≥1 g/dl (≥10 10 g/l]; Urine M-protein ≥200 mg/24 h; Serum FLC assay: ed FLC level ≥10 mg/dl (≥100 mg/l); provided serum FLC ratio is abnormal.

In certain embodiments, the treatment of a cancer may be assessed by Response tion 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: Target lesions rget lesions New lesions Overall response CR CR No CR CR Incomplete No PR response/SD PR Non-PD No PR SD Non-PD No SD PD Any Yes or no PD Any PD Yes or no PD Any Any Yes PD CR = complete response; PR = partial response; SD = stable disease; and PD = progressive disease.

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 t diameter of target lesions, taking as reference the smallest sum longest diameter ed 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 ent started.

With respect to the tion 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 s and/or unequivocal progression of existing non-target lesions.

The ures, conventions, and definitions described below provide guidance for implementing the recommendations from the Response Assessment for Oncology (RANO) g Group regarding response criteria for high-grade gliomas (Wen P., Macdonald, DR., Reardon, DA., et al. Updated response assessment criteria for highgrade gliomas: se assessment in neuro-oncology working group. J Clin Oncol 2010; 28: 1963- 1972). Primary cations to the RANO criteria for ia 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 med 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 dicular diameters) ed either at baseline or at subsequent assessments will be designated the nadir assessment and utilized as the nce for ining 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 ia described above. The following definitions will be used.

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.

Minimal Diameter: T1-weighted image in which the sections are 5 mm with 1 mm skip. The minimal LD of a able lesion is set as 5 mm by 5 mm. Larger ers may be ed 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 le to bidimensional measurement will be recorded at the default value of 5 mm for each diameter below 5 mm. Lesions that ear will be recorded as 0 mm by 0 mm.

Multicentric Lesions: Lesions that are ered multicentric (as opposed to uous) are lesions where there is normal intervening brain tissue n 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.

Nonmeasurable Lesions: All lesions that do not meet the criteria for able disease as d 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 ied smallest diameter (ie., less than 5 mm by 5 mm), nonenhancing lesions (eg., as seen on T1-weighted post-contrast, T2-weighted, or fluid-attenuated inversion ry (FLAIR) images), hemorrhagic or predominantly cystic or necrotic lesions, and leptomeningeal tumor. Hemorrhagic lesions often have intrinsic T1-weighted hyperintensity that could be misinterpreted as enhancing tumor, and for this reason, the pre-contrast T1-weighted image may be ed to exclude baseline or interval sub-acute hemorrhage.

At baseline, lesions will be classified as s: Target s: Up to measurable lesions can be selected as target lesions with each measuring at least 10 mm by 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 s 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 s will be documented and bed in a consistent fashion over time (eg., 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 tely. At each tion, a time point response will be determined for target lesions, non-target lesions, and new lesion. Tumor progression can be ished even if only a subset of lesions is ed. However, unless progression is observed, objective status (stable disease, PR or CR) can only be determined when all lesions are assessed. mation assessments for overall time point ses of CR and PR will be performed at the next scheduled ment, 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 .

In certain embodiments, treatment of a cancer may be assessed by the tion of phosphorylation of S6RP, 4E-BP1, AKT and/or DNA-PK in circulating blood and/or tumor cells, and/or skin biopsies or tumor biopsies/aspirates, before, during and/or after treatment with a TOR kinase inhibitor. For example, the inhibition of phosphorylation of S6RP, 4E-BP1, AKT and/or DNA-PK is assessed in B-cells, T-cells and/or monocytes. In other embodiments, treatment of a cancer may be assessed by the inhibition of DNA-dependent protein kinase (DNA-PK) activity in skin samples and/or tumor biopsies/aspirates, such as by assessment of the amount of pDNA-PK S2056 as a biomarker for DNA damage pathways, before, during, and/or afier TOR kinase inhibitor treatment. In one embodiment, the skin sample is irradiated by UV light.

In the extreme, complete inhibition, is referred to herein as tion or chemoprevention. In this context, the term “prevention” includes either preventing the onset of ally 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 ofpremalignant cells to malignant cells. This includes prophylactic treatment of those at risk of developing a cancer. .2 ND 1 The solid forms, formulations and methods ofuse provided herein relate to Compound 1: </ i“ N / H | K N \ N N O N N having the name 1-ethyl(2-methyl(1H-1,2,4-tn'azolyl)pyridinyl)-3,4- opyrazino[2,3-b]pyrazin—2(lH)—one, and tautomers.

Tautomers ofCompound 1 include the following: N~N HN~N <’\ (\\ uN/I\ NrIJ/o NN/l\ NNKO IIT=\ IIT\ / / N N H N” Compound 1 can be prepared using reagents and methods known in the art, including the methods provided in US Patent No. 8,110,578, filed on October 26, 2009; US Patent Publication Application No. 2011/0137028, filed on October 25, 2010; and US Provisional Patent Application No. 61/813,064, filed on April 17, 2013, the entire contents of each of which are incorporated herein by reference.

It should be noted that if there is a discrepancy between a depicted ure 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 ure is to be interpreted as encompassing all stereoisomers of it. .3 SOLID FORMS OF COMPOUND 1 In certain embodiments, provided herein are solid forms of Compound 1 or tautomers f. 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.

While not intending to be bound by any particular theory, n solid forms are characterized by physical properties, e.g., stability, solubility and dissolution rate, riate for pharmaceutical and therapeutic dosage forms. Moreover, while not wishing to be bound by any particular theory, certain solid forms are characterized by al 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, tion, washing, drying, milling, , tableting, flowability, dissolution, formulation, and lyophilization) which make certain solid forms suitable for the manufacture of a solid dosage form. Such ties can be determined using particular ical chemical techniques, including solid-state analytical techniques (e.g., X-ray diffraction, microscopy, spectroscopy and l analysis), as described herein and known in the art.

The solid forms provided herein (e.g., Form 1, Form 2, Form 3, Form 4, Form 5 and ous of nd 1) may be characterized using a number of methods known to a person having ordinary skill in the art, ing, but not limited to, single crystal X-ray diffraction, X-ray powder diffraction (XRPD), microscopy (e.g., scanning electron microscopy (SEM)), thermal analysis (e.g., differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), and hot-stage copy), spectroscopy (e.g., infrared, Raman, and solid-state nuclear magnetic resonance), single differential thermal analysis (SDTA), high performance liquid chromatography coupled with mass spectroscopy (HPLC-MS), thermogravimetrical analysis coupled with single differential l is (TGA-SDTA), and thermogravimetric analysis coupled with mass spectroscopy (TGA-MS). The particle size and size distribution of the solid form provided herein may be determined by conventional s, such as laser light scattering technique.

The purity of the solid forms provided herein may be determined by standard analytical methods, such as thin layer chromatography (TLC), gel electrophoresis, gas chromatography, high performance liquid chromatography (HPLC), and mass spectrometry (MS).

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 r 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 degrees 2 theta (see United State copoeia, page 2228 (2003)). .3.1 Form 1 of Compound 1 In certain embodiments, provided herein is Form 1 of Compound 1.

In one embodiment, Form 1 is an anhydrous form of nd 1. In another ment, Form 1 of Compound 1 is crystalline.

In certain embodiments, a solid form provided herein, e.g., Form 1, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form 1 of Compound 1 has an X-ray powder diffraction pattern substantially as shown in In one embodiment, Form 1 of Compound 1 has one or more characteristic X-ray powder diffraction peaks at a eta angle of imately 7.94, 9.74, 11.94, 15.86, 17.3, 17.86, 19.46, 25.14, 26.42, 27.06, 27.98 or 29.38 degrees as depicted in In a specific embodiment, Form 1 of nd 1 has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 9.74, 11.94, .86, 17.3, 25.14, 26.42, 27.06 or 27.98 degrees. In another embodiment, Form 1 of Compound 1 has one, two, three or four characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 9.74, 15.86, 25.14 or 27.06 degrees. In another embodiment, Form 1 of Compound 1 has one, two, three, four, five, six, seven, eight, nine, ten, eleven or twelve characteristic X-ray powder ction peaks as set forth in Table 25.

In one embodiment, Form 1 of Compound 1 has a digital image ntially as shown in In one embodiment, provided herein is a crystalline form of Compound 1 having a single differential thermal analysis (SDTA) thermogram as depicted in comprising an ermic event n about 240 °C and about 285 °C with a maximum at about 268.9 °C when heated from approximately 25 °C to approximately 300 °C (see Table 24).

In one embodiment, provided herein is a crystalline form of Compound 1 having a gravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in In n embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 0.44% of the total mass of the sample between approximately 30 °C and approximately 250 °C when heated from approximately 20 °C to approximately 300 °C. Thus, in certain embodiments, the crystalline form loses about 0.44% of its total mass when heated from about ambient temperature to about 300 °C.

In still another embodiment, Form 1 of Compound 1 is ntially pure. In n embodiments, the substantially pure Form 1 of Compound 1 is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form 1 of Compound 1 is no less than about 95% pure, no less than about 96% pure, no less than about 97% pure, no less than about 98% pure, no less than about 98.5% pure, no less than about 99% pure, no less than about 99.5% pure, or no less than about 99.8% pure. .3.2 Form 2 of Compound 1 In certain ments, provided herein is Form 2 of Compound 1.

In certain embodiments, Form 2 is obtained by crystallization from certain solvent systems, for example, solvent systems comprising one or more of the following solvents or solvent combinations: 1,2-ethanediol and THF. In certain embodiments, Form 2 provided herein is ed by slurry crystallization, evaporation crystallization or thermocycling crystallization (see Table 23).

In certain embodiments, ed herein are methods for making Form 2 of Compound 1, comprising obtaining a slurry of Form 1 of Compound 1 in a solvent, stirring the slurry, collecting solid from the slurry by filtration (e.g., fuge filtration) and optionally g (e.g., washing with the solvent) and drying. In certain embodiments, provided herein are methods for making Form 2 of Compound 1, comprising obtaining a slurry of Compound 1 in hanediol, stirring the slurry, collecting solid from the slurry by centrifuge filtration and optionally washing with 1,2-ethanediol and drying.

In certain embodiments, provided herein are methods for making Form 2 of Compound 1, comprising dissolving Form 1 of Compound 1 in a solvent to yield a on, filtering the solution if Form 1 does not dissolve completely, and evaporating the solution under certain air pressure to yield a solid. In certain embodiments, provided herein are methods for making Form 2 of Compound 1, sing ving Form 1 of Compound 1 in 1,2-ethanediol/THF (50/50) to yield a on, filtering the solution if Form 1 does not dissolve completely, and evaporating the solution under 200 mbar air pressure to yield a solid.

In certain embodiments, provided herein are methods for making Form 2 of Compound 1, comprising 1) obtaining a slurry of Form 1 of Compound 1 in a solvent; 2) heating the slurry until a first temperature (e.g., about 30 °C to about 50 °C); 3) cooling the slurry to a second temperature (e.g., about -5 °C to about 15 °C); 4) keeping the slurry at the second temperature for a period of time; 5) stirring the slurry during steps 1-5; 6) repeating steps 2-5 (e.g., from 6 to 10 times); and 7) filtering the slurry to yield a solid. In certain embodiments, provided herein are s for making Form 2 of Compound 1, comprising 1) obtaining a slurry of Form 1 of nd 1 in 1,2-ethanediol; 2) heating the slurry to about 40 °C; 3) g the slurry to about 5 °C; 4) keeping the slurry at about 5 °C for about 30 minutes; ) stirring the slurry during steps 1-5; 6) repeating steps 2-5 8 times; and 7) filtering the slurry to yield a solid.

In one embodiment, Form 2 is a 1,2-ethanediol solvated form of Compound 1. In one embodiment, Form 2 is a 1,2-ethanediol mono-solvated form of Compound 1. In another embodiment, Form 2 of Compound 1 is crystalline.

In certain embodiments, a solid form provided herein, e.g., Form 2, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form 2 of Compound 1 has an X-ray powder diffraction pattern substantially as shown in (middle n). In one embodiment, Form 2 of Compound 1 has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 6.18, 10.02, 11.54, 12.34, 13.86, 18.54, 21.74, 22.5, 23.42, 24.54, 25.5, 26.02, 26.7, 27.82, 28.34 or 34.14 degrees as depicted in In a specific embodiment, Form 2 of Compound 1 has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 6.18, 12.34, 18.54, 21.74, 22.5, 23.42, 26.7 or 28.34 degrees. In another embodiment, Form 2 of Compound 1 has one, two, three or four characteristic X-ray powder diffraction peaks at a two-theta angle of imately 6.18, 12.34, 21.74 or 26.7 degrees. In another embodiment, Form 2 of Compound 1 has one, two, three, four, five, six, seven, eight, nine, ten, eleven, , thirteen, fourteen, fifteen or sixteen characteristic X-ray powder diffraction peaks as set forth in Table 26.

In one embodiment, Form 2 of Compound 1 has a digital image substantially as shown in .

In one ment, provided herein is a crystalline form of Compound 1 having a thermogravimetric (TGA) thermograph corresponding ntially to the entative TGA thermogram as depicted in . In certain ments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 15.5% of the total mass of the sample n approximately 95 °C and approximately 175 °C when heated from approximately 25 °C to approximately 300 °C. Thus, in certain embodiments, the crystalline form loses about 15.5% of its total mass when heated from about t temperature to about 300 °C. In certain ments, the crystalline form contains 1 molar equivalent of t in the crystal lattice corresponding to imately 1 mole of 1,2-ethanediol per mole of Compound 1. The theoretical 1,2-ethanediol content of a 1,2-ethanediol mono-solvate of Compound 1 is 15.6 % by weight, matching the TGA weight loss observed. In certain embodiments, the crystalline form is a 1,2-ethanediol mono-solvate of Compound 1.

In one embodiment, provided herein is a crystalline form of Compound 1 having a single differential thermal analysis (SDTA) thermogram as depicted in comprising an ermic event between about 95 °C and about 176 °C with a maximum at about 137 °C when heated from approximately 25 °C to approximately 300 °C (see Table 24).

In one embodiment, provided herein is a lline form of Compound 1 having a single differential thermal analysis (SDTA) gram as depicted in comprising an endothermic event between about 240 °C and about 285 °C with a maximum at about 264 °C when heated from approximately 25 °C to imately 300 °C (see Table 24).

In still another embodiment, Form 2 of Compound 1 is substantially pure. In certain embodiments, the substantially pure Form 2 of Compound 1 is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form 2 of Compound 1 is no less than about 95% pure, no less than about 96% pure, no less than about 97% pure, no less than about 98% pure, no less than about 98.5% pure, no less than about 99% pure, no less than about 99.5% pure, or no less than about 99.8% pure. .3.3 Form 3 of Compound 1 In certain embodiments, provided herein is Form 3 of Compound 1.

In certain embodiments, Form 3 is obtained by crystallization from certain solvent systems, for e, solvent systems comprising one or more of the following solvents or solvent combinations: 2,2,2-trifluoroethanol (TFE) combined with either water or cyclohexane, chloroform and the t mixture of panol and acetone. In certain embodiments, Form 3 is obtained by evaporative crystallization, hot-filtration crystallization, vapor diffusion into liquid crystallization or vapor ion onto solid crystallization (see Table 23).

In certain embodiments, provided herein are methods for making Form 3 of Compound 1, comprising mixing Form 1 of Compound 1 with a solvent or t e, filtering the e to yield a solution if Form 1 does not dissolve completely, and evaporating the solution under certain air pressure to yield a solid. In certain embodiments, provided herein are methods for making Form 3 of Compound 1, comprising mixing Form 1 of Compound 1 with a 1:1 solution of TFE and water, filtering the mixture to yield a solution if Form 1 does not dissolve completely, and evaporating the solution of TFE and water under 200 mbar air pressure to yield a solid.

In certain embodiments, provided herein are methods for making Form 3 of Compound 1, comprising obtaining a slurry of Form 1 of Compound 1 in a solvent, heating the slurry to a first temperature (e.g., about 50 °C to about 70 °C), filtering the slurry to yield a solution, cooling down the solution to a second temperature (e.g., about 15 °C to about 35 °C) to yield solid precipitation, and collecting the solid. In certain embodiments, provided herein are methods for making Form 3 of nd 1, comprising obtaining a slurry of Form 1 of Compound 1 in a 1:1 solution of acetone and isopropanol, heating the slurry to about 60 °C, filtering the slurry to yield a solution, cooling down the solution to about 25 °C to yield solid precipitation, and collecting the solid.

In certain ments, provided herein are methods for making Form 3 of nd 1, comprising obtaining a saturated solution of Form 1 of Compound 1 in a solvent, diffusing an anti-solvent into the saturated solution, collecting precipitated solid if there is precipitation, and evaporating the solvent to collect solid if there is no precipitation. In certain embodiments, provided herein are methods for making Form 3 of Compound 1, comprising obtaining a saturated solution of Form 1 of Compound 1 in TFE, diffusing cyclohexane into the saturated solution, collecting itated solid if there is precipitation, and evaporating the solvent to collect solid if there is no itation.

In n ments, provided herein are methods for making Form 3 of Compound 1, comprising obtaining ous form of Compound 1, diffusing a t on to the amorphous form of Compound 1 for a period of time (e.g., about 1 week to about 1 month), and collecting the solid. In certain embodiments, provided herein are methods for making Form 3 of Compound 1, comprising obtaining amorphous form of Compound 1 by grinding Form 1 of Compound 1 for about two hours, ing chloroform on to the amorphous form of Compound 1 for about two weeks, and collecting the solid.

In one embodiment, Form 3 is a trifluoroethanol solvated form of Compound 1. In one embodiment, Form 3 is a 2,2,2-trifluoroethanol hemi-solvated form of Compound 1. In another embodiment, Form 3 of Compound 1 is crystalline.

In one embodiment, Form 3 is a chloroform solvated form of Compound 1. In one embodiment, Form 3 is a form olvated form of Compound 1.

In one embodiment, Form 3 is an acetone solvated form of Compound 1. In one embodiment, Form 3 is an acetone hemi-solvated form of Compound 1.

In one embodiment, Form 3 is an isopropanol solvated form of Compound 1. In one embodiment, Form 3 is an isopropanol hemi-solvated form of Compound 1.

In certain embodiments, a solid form provided herein (e.g., Form 3) is substantially lline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form 3 of Compound 1 has an X-ray powder diffraction pattern substantially as shown in (middle pattern). In one embodiment, Form 3 of Compound 1 has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of imately 3.5, 7.06, 9.26, 10.5, 12.66, 15.3 or 18.62 degrees as depicted in . In another embodiment, Form 3 of Compound 1 has one, two, three or four characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 3.5, 9.26, 15.3 or 18.62 s. In r ment, Form 3 of Compound 1 has one, two, three, four, five, six or seven characteristic X-ray powder diffraction peaks as set forth in Table 27.

In one embodiment, Form 3 of Compound 1 has a digital image substantially as shown in A.

In one embodiment, provided herein is a crystalline form of Compound 1 having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in . In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 12.8% of the total mass of the sample between approximately 35 °C and approximately 190 °C when heated from approximately 25 °C to approximately 300 °C. Thus, in certain embodiments, the crystalline form loses about 12.8% of its total mass when heated from about ambient temperature to about 300 °C. In certain ments, the crystalline form contains 0.5 molar lents of solvent in the crystal lattice corresponding to approximately 0.5 mole of 2,2,2-trifluoroethanol per mole of Compound 1. The theoretical 2,2,2-trifluoroethanol content of a 2,2,2-trifluoroethanol hemisolvate of Compound 1 is 11.5 % by weight, matching the TGA weight loss observed. In certain embodiments, the crystalline form is a trifluoroethanol hemi-solvate of Compound 1.

In one embodiment, provided herein is a crystalline form of Compound 1 having a single differential thermal analysis (SDTA) thermogram as depicted in comprising an endothermic event between about 110 °C and about 175 °C with a maximum at about 149 °C when heated from approximately 25 °C to imately 300 °C (see Table 24).

In one embodiment, ed herein is a crystalline form of Compound 1 having a SDTA thermogram comprising an endothermic event as ed in between about 225 °C and about 275 °C with a maximum at about 254 °C when heated from approximately °C to approximately 300 °C (see Table 24).

In still another ment, Form 3 of Compound 1 is substantially pure. In certain embodiments, the substantially pure Form 3 of Compound 1 is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form 3 of Compound 1 is no less than about 95% pure, no less than about 96% pure, no less than about 97% pure, no less than about 98% pure, no less than about 98.5% pure, no less than about 99% pure, no less than about 99.5% pure, or no less than about 99.8% pure. .3.4 Form 4 of Compound 1 In certain embodiments, provided herein is Form 4 of Compound 1.

In n embodiments, Form 4 is obtained by crystallization from n solvent systems, for example, solvent systems comprising one or more of the following ts or t combinations: dimethylsulfoxide, water and toluene. In certain embodiments, Form 4 is obtained by anti-solvent crystallization and vapor ion into liquid crystallization.

In certain embodiments, provided herein are methods for making Form 4 of Compound 1, comprising dissolving Form 1 of Compound 1 in a solvent, adding an anti-solvent, collecting solid from the solution by filtration, and optionally washing (e.g., washing with the mixture of solvent and anti-solvent at the same ratio of the solution) and drying. In certain embodiments, provided herein are methods for making Form 4 of Compound 1, comprising dissolving Form 1 of nd 1 in dimethylsulfoxide, adding water, collecting solid from the solution by filtration, and optionally washing with the mixture of dimethylsulfoxide and water at the same ratio of the solution and drying. In certain embodiments, provided herein are methods for making Form 4 of Compound 1, comprising dissolving Form 1 of Compound 1 in dimethylsulfoxide, adding toluene, collecting solid from the on by filtration, and optionally washing with the mixture of ylsulfoxide and toluene at the same ratio of the solution and drying.

In certain embodiments, provided herein are methods for making Form 4 of Compound 1, comprising obtaining a saturated solution of Form 1 of Compound 1 in a solvent, diffusing an olvent into the saturated on, collecting itated solid if there is precipitation, and evaporating the solvent to collect solid if there is no precipitation. In certain embodiments, provided herein are methods for making Form 4 of Compound 1, comprising obtaining a saturated solution of Form 1 of Compound 1 in DMSO, diffusing water into the saturated solution, collecting precipitated solid if there is precipitation, and evaporating the solvent to collect solid if there is no precipitation.

In one embodiment, Form 4 is a dimethylsulfoxide solvated form of Compound 1.

In one embodiment, Form 4 is a 0.8 molar equivalent dimethylsulfoxide solvated form of Compound 1. In another ment, Form 4 of Compound 1 is crystalline.

In certain embodiments, a solid form provided herein, e.g., Form 4, is ntially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form 4 of Compound 1 has an X-ray powder diffraction pattern substantially as shown in (middle pattern). In one embodiment, Form 4 of Compound 1 has one or more characteristic X-ray powder diffraction peaks at a eta angle of approximately 8.22, .14, 10.66, 14.02, 18.1, 20.62, 21.94, 22.66, 23.78, 24.34, 25.42 or 26.26 degrees as depicted in . In a specific embodiment, Form 4 of Compound 1 has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 10.14, 10.66, 18.1, 20.62, 21.94, 22.66, 24.34 or 26.26 degrees. In r embodiment, Form 4 of Compound 1 has one, two, three or four characteristic X-ray powder ction peaks at a two-theta angle of approximately 10.14, 10.66, 21.94 or 26.26 degrees. In r embodiment, Form 4 of Compound 1 has one, two, three, four, five, six, seven, eight, nine, ten, eleven or twelve characteristic X-ray powder ction peaks as set forth in Table 28.

] In one embodiment, Form 4 of Compound 1 as wet solid has a digital image substantially as shown in A. In one embodiment, Form 4 of Compound 1 as dry solid has a digital image substantially as shown in B.

In one embodiment, provided herein is a crystalline form of Compound 1 having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in . In n embodiments, the crystalline form ts a TGA thermogram comprising a total mass loss of approximately 16.4% of the total mass of the sample between approximately 35 °C and approximately 180 °C when heated from imately 25 °C to approximately 300 °C. Thus, in certain ments, the crystalline form loses about 16.4% of its total mass when heated from about ambient temperature to about 300 °C. In certain embodiments, the crystalline form contains 0.8 molar equivalents of solvent in the crystal lattice corresponding to imately 0.8 mole of dimethylsulfoxide per mole of Compound 1. The tical dimethylsulfoxide content of a 0.8 molar equivalent dimethylsulfoxide solvate of Compound 1 is 18.9 % by weight, matching the TGA weight loss observed. In certain embodiments, the crystalline form is a 0.8 molar equivalent dimethylsulfoxide solvate of Compound 1.

In one ment, provided herein is a crystalline form of Compound 1 having a SDTA thermogram as depicted in comprising an endothermic event between about 100 °C and about 175 °C with a maximum at about 139 °C when heated from approximately °C to approximately 300 °C (see Table 24).

In one embodiment, provided herein is a crystalline form of Compound 1 having a SDTA thermogram as depicted in sing an endothermic event between about 235 °C and about 275 °C with a maximum at about 258 °C when heated from approximately °C to approximately 300 °C (see Table 24).

In still another embodiment, Form 4 of Compound 1 is substantially pure. In n embodiments, the substantially pure Form 4 of Compound 1 is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form 4 of Compound 1 is no less than about 95% pure, no less than about 96% pure, no less than about 97% pure, no less than about 98% pure, no less than about 98.5% pure, no less than about 99% pure, no less than about 99.5% pure, or no less than about 99.8% pure. .3.5 Form 5 of Compound 1 In certain embodiments, provided herein is Form 5 of Compound 1.

In certain embodiments, Form 5 is obtained by llization from certain solvent systems, for e, solvent systems comprising one or more of the following solvents or solvent combinations: THF, water, 1,4-dioxane, ol and ethanol. In certain embodiments, Form 5 is obtained by hot-filtration llization, anti-solvent crystallization or ative crystallization.

In certain embodiments, ed herein are methods for making Form 5 of Compound 1, comprising obtaining a slurry of Form 1 of Compound 1 in a solvent, heating the slurry to a temperature (e.g., about 50 °C to about 70 °C) for a period of time (e.g., about minutes to about 2 hours), filtering the slurry to yield a solution, cooling down the solution to a temperature (e.g., about 10 °C to about 35 °C), collecting solid from the solution by filtration, and optionally g (e.g., washing with the solvent) and drying. In certain embodiments, provided herein are methods for making Form 5 of Compound 1, comprising obtaining a slurry of Form 1 of Compound 1 in a t mixture of THF and water (50/50), heating the slurry at about 60 °C for about one hour, filtering the slurry to yield a solution, cooling down the solution to about 25 °C, collecting solid from the solution by filtration, and optionally washing with the solvent mixture of THF and water (50/50) and . In certain ments, provided herein are methods for making Form 5 of Compound 1, comprising obtaining a slurry of Form 1 of Compound 1 in a solvent e of methanol and water (50/50), heating the slurry at about 60 °C for about one hour, filtering the slurry to yield a solution, cooling down the solution to about 25 °C, collecting solid from the solution by filtration, and optionally washing with the solvent mixture of methanol and water (50/50) and drying. In certain embodiments, provided herein are methods for making Form 5 of Compound 1, comprising obtaining a slurry of Form 1 of Compound 1 in a t mixture of oxane and water (50/50), heating the slurry at about 60 °C for about one hour, filtering the slurry to yield a solution, cooling down the solution to about 25 °C, collecting solid from the solution by filtration, and optionally washing with the solvent mixture of 1,4-dioxane and water (50/50) and drying. In certain embodiments, provided herein are methods for making Form 5 of Compound 1, comprising obtaining a slurry of Form 1 of Compound 1 in a solvent mixture of ethanol and water (50/50), heating the slurry at about 60 °C for about one hour, filtering the slurry to yield a solution, cooling down the on to about 25 °C, collecting solid from the solution by filtration, and optionally washing with solvent mixture of ethanol and water (50/50) and drying.

In n ments, provided herein are methods for making Form 5 of Compound 1, comprising obtaining a saturated solution of Form 1 of Compound 1 in a solvent, diffusing an olvent into the saturated solution, ting precipitated solid if there is precipitation, and evaporating the solvent to t solid if there is no precipitation. In certain embodiments, provided herein are methods for making Form 5 of Compound 1, comprising obtaining a saturated solution of Form 1 of Compound 1 in THF, diffusing water into the saturated solution, collecting precipitated solid if there is precipitation, and evaporating the t to collect solid if there is no precipitation.

In certain embodiments, provided herein are methods for making Form 5 of Compound 1, comprising mixing Form 5 of Compound 1 with a solvent, filtering the mixture to yield a solution if Form 1 does not dissolve completely, and evaporating the solution under certain air pressure to yield solid. In n ments, provided herein are methods for making Form 5 of Compound 1, comprising mixing Form 1 of Compound 1 with ter (50:50), filtering the mixture to yield a solution if Form 1 does not dissolve completely, and evaporating the solution under 200 mbar air pressure to yield solid.

In one embodiment, Form 5 is a hydrated form of Compound 1. In one embodiment, Form 5 is a dihydrated form of Compound 1. In another embodiment, Form 5 of Compound 1 is crystalline.

In n embodiments, a solid form provided herein, e.g., Form 5, is ntially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form 5 of Compound 1 has an X-ray powder diffraction pattern substantially as shown in (middle pattern). In one embodiment, Form 5 of nd 1 has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 6.02, 7.46, 9.26, 11.7, 12.18, 19.78, 22.02, 23.74, 24.26, 24.94, 26.18, 27.06 or 29.86 degrees as depicted in . In a ic embodiment, Form 5 of Compound 1 has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 7.46, 9.26, 11.7, 22.02, 23.74, 24.26, 24.94 or 26.18 degrees. In another ment, Form 5 of Compound 1 has one, two, three or four characteristic X-ray powder ction peaks at a two-theta angle of approximately 9.26, 11.7, 24.94 or 26.18 s. In another embodiment, Form 5 of Compound 1 has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve or thirteen characteristic X-ray powder ction peaks as set forth in Table 29.

In one embodiment, Form 5 of nd 1 has a digital image substantially as shown in A.

In one embodiment, provided herein is a crystalline form of Compound 1 having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in . In certain embodiments, the crystalline form exhibits a TGA thermogram comprising a total mass loss of approximately 9.4% of the total mass of the sample between approximately 35 °C and approximately 240 °C when heated from approximately 25 °C to approximately 300 °C. Thus, in certain ments, the crystalline form loses about 9.4% of its total mass when heated from about ambient temperature to about 300 °C. In certain embodiments, the crystalline form contains 2 molar equivalents of solvent in the crystal lattice corresponding to approximately 2 moles of water per mole of Compound 1.

The theoretical water content of a dihydrate of Compound 1 is 10.2 % by weight, matching the TGA weight loss observed. In certain embodiments, the crystalline form is a dihydrated form of Compound 1.

In one embodiment, provided herein is a crystalline form of Compound 1 having a SDTA thermogram as depicted in comprising an endothermic event between about 50 °C and about 140 °C with a maximum at about 80 °C when heated from approximately 25 °C to approximately 300 °C (see Table 24).

In one ment, provided herein is a lline form of Compound 1 having a SDTA thermogram as depicted in comprising an exothermic event between about 160 °C and about 200 °C with a maximum at about 181 °C when heated from approximately °C to approximately 300 °C (see Table 24).

In one embodiment, provided herein is a crystalline form of nd 1 having a SDTA thermogram as depicted in comprising an endothermic event between about 225 °C and about 275 °C with a maximum at about 251 °C when heated from approximately °C to approximately 300 °C (see Table 24).

In still another embodiment, Form 5 of Compound 1 is substantially pure. In n embodiments, the substantially pure Form 5 of Compound 1 is substantially free of other solid forms, e.g., amorphous form. In n embodiments, the purity of the substantially pure Form 5 of Compound 1 is no less than about 95% pure, no less than about 96% pure, no less than about 97% pure, no less than about 98% pure, no less than about 98.5% pure, no less than about 99% pure, no less than about 99.5% pure, or no less than about 99.8% pure. .3.6 Amorphous Compound 1 In certain embodiments, ed herein is amorphous Compound 1.

In n embodiments, provided herein are methods for making amorphous Compound 1, comprising 1) equilibrating the temperature of a sample of one of the solid forms of Compound 1 provided herein at room temperature; 2) heating the sample to a first temperature at a first rate; 3) holding the sample isothermally for a period of time; 4) cooling the sample to a second temperature at a second rate; 5) heating the sample to a third temperature at about a third rate; and 6) ting remaining solids. In one embodiment, the sample is Form 1 of Compound 1. In one embodiment, the first temperature is higher than the melting point of one of the solid forms of Compound 1 provided herein. In one embodiment, the second temperature is lower than room temperature. In another embodiment, the third temperature is higher than the glass transition temperature of the ous solid form of Compound 1 provided herein. In another embodiment, the first and third rates are about 10 ºC/min and the second rate is about 30 ºC/min, independently from each other. In one embodiment, the period of time at which the sample is held isothermally is about 5 minutes.

In certain embodiments, ed herein are methods for making amorphous Compound 1, comprising 1) brating the temperature of a sample of Form 1 at about 25 ºC; 2) heating the sample to about 275 ºC at a rate of about 10 ºC/min; 3) holding the sample isothermally for about 5 minutes; 4) cooling the sample to about -10 ºC at a rate of about 30 ºC/min; 5) g the sample to about 150 ºC at about 10 ºC at a rate of about 10 ºC/min; and 6) ting remaining solids.

In one embodiment, ous Compound 1 has a glass transition temperature (Tg) at about 120 ºC.

In one embodiment, ous Compound 1 has an X-ray powder diffraction pattern substantially as shown in .

In one embodiment, provided herein is an ous solid form of Compound 1 having a DSC thermogram as depicted in comprising an endothermic event between about 160 °C and about 200 °C with a maximum at about 188.1 °C when heated from approximately 25 °C to approximately 300 °C (see ).

In still another embodiment, ous Compound 1 is substantially pure. In certain embodiments, the substantially pure amorphous Compound 1 is substantially free of other solid forms, e.g., Form 1, Form 2, Form 3, Form 4 or Form 5. In certain embodiments, the purity of the substantially pure amorphous Compound 1 is no less than about 95% pure, no less than about 96% pure, no less than about 97% pure, no less than about 98% pure, no less than about 98.5% pure, no less than about 99% pure, no less than about 99.5% pure, or no less than about 99.8% pure. .4 METHODS OF USE Provided herein are methods for treating or preventing a cancer, comprising administering a solid form of Compound 1 provided herein or a pharmaceutical composition thereof to a patient having a cancer.

In some embodiments, the cancer is an ed unresectable solid tumor, or a hematologic malignancy. For example, the hematologic malignancy is CLL, NHL, or MM. In some such embodiments, the cancer has progressed on standard anti-cancer therapy, or the t is not able to tolerate standard anti-cancer therapy. In yet others, the cancer is a cancer for which no approved therapy exists. In some embodiments, the cancer is resistant to standard therapy. In another, the patient has relapsed after rd therapy. In one embodiment, the cancer is a neoplasm metastasis.

In certain embodiments, the cancer is a bloodborne tumor.

] In certain embodiments, the cancer is a ma, a leukemia or a multiple myeloma.

] In certain embodiments, the cancer is non-Hodgkin’s lymphoma. In certain embodiments, the non-Hodgkin’s lymphoma is diffuse large B-cell lymphoma (DLBCL), ular lymphoma (FL), acute myeloid leukemia (AML), mantle cell lymphoma (MCL), or ALK+ anaplastic large cell lymphoma. In one ment, the non-Hodgkin’s lymphoma is advanced solid non-Hodgkin’s lymphoma. In one embodiment, the non-Hodgkin’s lymphoma is diffuse large B-cell lymphoma (DLBCL).

In certain embodiments, the cancer is a B-cell lymphoma.

In certain ments, the B-cell lymphoma is a B-cell non-Hodgkin’s lymphoma selected from diffuse large B-cell lymphoma, Burkitt’s lymphoma/leukemia, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, follicular lymphoma, marginal zone ma ding extranodal marginal zone B-cell lymphoma and nodal marginal zone B-cell lymphoma), lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia. In some embodiments, the B-cell lymphoma is c lymphocytic leukemia/small lymphocytic lymphoma LL). In one embodiment, the B-cell lymphoma is Waldenstrom macroglobulinemia.

] In one embodiment, the B-cell non-Hodgkin’s lymphoma is refractory B-cell non- n’s lymphoma. In one embodiment, the B-cell non-Hodgkin’s lymphoma is relapsed B- cell non-Hodgkin’s lymphoma.

In certain embodiments, the cancer is a T-cell lymphoma.

The B-cell disorders c lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) represent 2 ends of a spectrum of the same disease process differing in the degree of blood/marrow involvement (CLL) versus lymph node involvement (SLL).

In another embodiment, the cancer is CLL characterized by deletion of chromosome 11q22, loss of ATM expression, mutation of IgVH, wild type IgVH, wild type p53/ATM, mutation of p53 or dysfunctional p53.

In other embodiments, the cancer is a multiple myeloma.

In certain ments, the cancer is a cancer of the head, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, , stomach, prostate, urinary bladder, uterine, cervix, breast, ovaries, testicles or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, and brain or central nervous system.

In other embodiments, the cancer is a solid tumor. In certain embodiments, the solid tumor is a relapsed or refractory solid tumor.

In one embodiment, the solid tumor is a neuroendocrine tumor. In certain ments, the neuroendocrine tumor is a neuroendocrine tumor of gut origin. In certain ments, the neuroendocrine tumor is of non-pancreatic . In certain embodiments, the ndocrine tumor is non-pancreatic of gut origin. In certain embodiments, the neuroendocrine tumor is of unknown primary origin. In certain embodiments, the ndocrine tumor is a symptomatic endocrine producing tumor or a nonfunctional tumor. In n embodiments, the neuroendocrine tumor is locally unresectable, metastatic moderate, well differentiated, low (grade 1) or intermediate (grade 2). In n embodiments, the neuroendocrine tumor is of non-gut origin. In one embodiment, the ndocrine tumor of non-gut origin, is rapamycin resistant. In one embodiment, the neuroendocrine tumor of non-gut origin is a bronchial neuroendocrine tumor, or a neuroendocrine tumor with origin in an organ above the diaphragm, for example, a laryngeal neuroendocrine tumor, a pharyngeal neuroendocrine tumor, or a thyroid neuroendocrine tumor. In one embodiment, the neuroendocrine tumor of non-gut origin is a symptomatic ine producing tumor or a nonfunctional tumor. In one embodiment, the neuroendocrine tumor of non-gut origin is locally unresectable, metastatic moderate, well differentiated, low (grade 1) or intermediate (grade 2).

In one embodiment, the solid tumor is non-small cell lung cancer (NSCLC).

In another embodiments the solid tumor is glioblastoma multiforme (GBM).

In another embodiment, the solid tumor is hepatocellular carcinoma (HCC).

In another embodiment, the solid tumor is breast cancer. In one embodiment, the breast cancer is hormone receptor positive. In one embodiment, the breast cancer is estrogen receptor ve (ER+, ER+/Her2 or ER+/Her2+). In one embodiment, the breast cancer is estrogen or negative (ER-/Her2+). In one embodiment, the breast cancer is triple negative (TN) (breast cancer that does not s the genes and/or protein corresponding to the estrogen receptor (ER), progesterone receptor (PR), and that does not overexpress the Her2/neu protein).

In one embodiment, the solid tumor is an advanced solid tumor.

In another embodiment, the cancer is head and neck squamous cell carcinoma.

In another embodiment, the cancer is E-twenty six (ETS) overexpressing castration-resistant prostate cancer.

In another embodiment, the cancer is E-twenty six (ETS) overexpressing Ewings sarcoma.

In another embodiment, the cancer is head and neck squamous cell carcinoma (HNSCC) characterized by deletion of chromosome 11q22 or loss of ataxia telangiectasia mutated (ATM) expression.

In another embodiment, the cancer is glioblastoma multiforme (GBM) characterized by hylguanine-DNA methyltransferase (MGMT) methylation.

In other embodiments, the cancer is a cancer associated with the pathways involving mTOR, PI3K, or Akt kinases and mutants or isoforms thereof. Other s within the scope of the methods provided herein e those associated with the pathways of the following kinases: PI3K, PI3K, PI3K, KDR, GSK3, GSK3, ATM, ATX, ATR, cFMS, and/or DNA-PK kinases and s or isoforms thereof. In some embodiments, the cancers ated with mTOR/ PI3K/Akt ys e solid and borne tumors, for example, multiple myeloma, mantle cell lymphoma, diffused large B-cell lymphoma, acute myeloid lymphoma, follicular lymphoma, chronic lymphocytic leukemia; and solid tumors, for example, , lung, endometrial, ovarian, gastric, cervical, and prostate cancer; glioblastoma; renal carcinoma; hepatocellular carcinoma; colon carcinoma; ndocrine tumors; head and neck tumors; and sarcomas, such as Ewing’s sarcoma.

In certain embodiments, provided herein are methods for achieving a Response Evaluation Criteria in Solid Tumors (for example, RECIST 1.1) of complete response, l response or stable e in a patient having a solid tumor, comprising administering a solid form of Compound 1 provided herein or a pharmaceutical composition thereof to said patient. In certain embodiments, ed herein are methods for achieving a National Cancer Institute- Sponsored Working Group on Chronic Lymphocytic Leukemia (NCI-WG CLL) of complete response, partial response or stable disease in a patient having leukemia, comprising administering a solid form of Compound 1 ed herein or a pharmaceutical composition thereof to said patient. In certain embodiments, provided herein are methods for achieving a Prostate Cancer Working Group 2 ) Criteria of complete response, l response or stable disease in a patient having prostate cancer, comprising administering a solid form of Compound 1 provided herein or a pharmaceutical ition thereof to said patient. In certain embodiments, provided herein are methods for achieving an International Workshop Criteria (IWC) for non-Hodgkin’s lymphoma of complete response, l response or stable disease in a t having dgkin’s lymphoma, comprising administering a solid form of Compound 1 provided herein or a pharmaceutical composition thereof to said patient. In certain embodiments, provided herein are methods for ing an International m Response Criteria (IURC) for multiple myeloma of complete response, l response or stable disease in a patient having multiple myeloma, comprising administering a solid form of Compound 1 provided herein or a pharmaceutical composition thereof to said patient. In certain embodiments, provided herein are methods for achieving a Responses Assessment for Neuro- Oncology (RANO) Working Group for glioblastoma multiforme of te response, partial response or stable disease in a patient having glioblastoma multiforme, comprising stering a solid form of Compound 1 provided herein or a pharmaceutical composition thereof to said patient.

In certain embodiments, provided herein are methods for increasing al t disease progression of a t having a cancer, comprising administering a solid form of Compound 1 provided herein or a ceutical composition thereof to said patient.

In certain ments, provided herein are methods for treating a cancer, the methods comprising administering a solid form of Compound 1 provided herein or a ceutical composition thereof to a patient having a cancer, wherein the treatment results in prevention or retarding of clinical progression, such as cancer-related cachexia or increased pain.

In some embodiments, provided herein are methods for treating a cancer, the methods comprising administering a solid form of Compound 1 provided herein or a ceutical composition thereof to a patient having a cancer, wherein the treatment results in one or more of inhibition of e progression, increased Time To Progression (TTP), increased Progression Free Survival (PFS), and/or increased Overall Survival (OS), among .5 PHARMACEUTICAL COMPOSITIONS Solid forms of Compound 1 provided herein are useful for the preparation of pharmaceutical compositions, comprising an effective amount of a solid form of Compound 1 and a pharmaceutically acceptable carrier or e. In some ments, the pharmaceutical compositions described herein are suitable for oral, parenteral, mucosal, transdermal or topical administration.

In one embodiment, the pharmaceutical compositions provided herein comprise a solid form of Compound 1 and one or more pharmaceutically acceptable excipients or carriers.

In one embodiment, the pharmaceutical compositions provided herein comprise Form 1 of Compound 1 and one or more ceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical compositions provided herein comprise Form 2 of Compound 1 and one or more pharmaceutically able excipients or carriers. In one embodiment, the pharmaceutical compositions provided herein comprise Form 3 of nd 1 and one or more pharmaceutically acceptable excipients or rs. In one ment, the pharmaceutical compositions provided herein comprise Form 4 of Compound 1 and one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical compositions provided herein comprise Form 5 of Compound 1 and one or more pharmaceutically able excipients or carriers. In one embodiment, the pharmaceutical compositions provided herein se amorphous nd 1 and one or more pharmaceutically acceptable excipients or carriers. In one ment, the pharmaceutical compositions provided herein comprise one or more of the following solid forms or solid form combinations: Form 1, Form 2, Form 3, Form 4, Form 5 and amorphous form of Compound 1 and one or more pharmaceutically acceptable excipients or carriers.

In one embodiment, the pharmaceutical compositions provided herein comprise tautomers of one or more solid forms of Compound 1 and one or more pharmaceutically acceptable excipients or carriers.

In one embodiment, the pharmaceutically acceptable excipients and carriers are selected from binders, diluents, disintegrants and lubricants. In r embodiment, the pharmaceutically acceptable excipients and carriers further include one or more antioxidants (e.g.¸ EDTA or BHT).

In certain embodiments, the binders include, but are not limited to, cellulose (e.g., microcrystalline cellulose, such as AVICEL® PH 101, AVICEL® PH112, and AVICEL® PH 102) and starch (e.g., pregelatinized starch (STARCH 1500®)). In one embodiment, the binder is cellulose. In another embodiment, the binder is rystalline cellulose. In yet another embodiment, the binder is AVICEL® PH 101. In yet another embodiment, the binder is AVICEL® PH 102. In yet another embodiment, the binder is starch. In yet another embodiment, the binder is pregelatinized starch. In still r embodiment, the binder is STARCH 1500®.

In certain embodiments, the diluents include, but are not limited to, lactose (e.g., lactose monohydrate (FAST FLO® 316) and lactose anhydrous), cellulose (e.g., microcrystalline ose, such as AVICEL® PH 101 and AVICEL® PH 102) , and mannitol. In one embodiment, the diluent is lactose. In another ment, the diluent is e monohydrate. In yet another embodiment, the diluent is FAST FLO® 316. In yet another embodiment, the t is lactose anhydrous. In yet another ment, the diluent is cellulose. In yet another embodiment, the diluent is microcrystalline cellulose. In yet another embodiment, the diluent is ® PH 101. In still another embodiment, the diluent is AVICEL® PH 102).

In certain embodiments, the disintegrants include, but are not d to, starch (e.g., corn starch) and carboxymethyl cellulose (e.g., croscarmellose sodium, such as AC-DI-SOL®), and sodium starch glycolate. In one embodiment, the disintegrant is starch. In another ment, the disintegrant is corn starch. In yet another embodiment, the disintegrant is carboxymethyl cellulose. In yet another embodiment, the disintegrant is croscarmellose sodium. In still another embodiment, the egrant is AC-DI-SOL®.

] In certain embodiments, the lubricants include, but are not limited to, starch (e.g., corn starch), magnesium stearate, and stearic acid. In one ment, the lubricant is starch. In r embodiment, the lubricant is corn starch. In yet another embodiment, the lubricant is magnesium stearate. In still another embodiment, the lubricant is stearic acid.

In another embodiment, the pharmaceutical compositions provided herein comprise a solid form of Compound 1 and one or more pharmaceutically able ents or carriers, each independently selected from carboxymethyl cellulose, cellulose, lactose, magnesium te, starch, and stearic acid.

In one embodiment, the pharmaceutical compositions provided herein comprise about 2.5-10% by weight of a solid form of Compound 1, about 70-90% by weight of diluent(s)/binder(s), about 1-5% by weight of disintegrant(s), and about 0.1-2% by weight of lubricant(s).

In another ment, the pharmaceutical compositions provided herein comprise about 10% by weight of a solid form of Compound 1, about 59.85% by weight of mannitol, about 25% by weight of microcrystalline cellulose, about 3% by weight of sodium starch glycolate, about 1% by weight of silicon dioxide, about 0.5% by weight of c acid, and about 0.65% by weight of magnesium stearate.

In another embodiment, the pharmaceutical compositions provided herein se about 10% by weight of a solid form of Compound 1, about 59.45% by weight of mannitol, about 25% by weight of microcrystalline cellulose, about 3% by weight of sodium starch glycolate, about 1% by weight of silicon dioxide, about 0.5% by weight of stearic acid, about 0.4% BHT, and about 0.65% by weight of magnesium stearate.

In another embodiment, the pharmaceutical compositions provided herein se about 10% by weight of a solid form of Compound 1, about 59.35% by weight of mannitol, about 25% by weight of microcrystalline ose, about 3% by weight of sodium starch glycolate, about 1% by weight of silicon dioxide, about 0.5% by weight of stearic acid, about 0.5% disodium EDTA, and about 0.65% by weight of magnesium stearate.

In r embodiment, the pharmaceutical compositions provided herein comprise about 10% by weight of a solid form of Compound 1, about 58.95% by weight of mannitol, about 25% by weight of rystalline cellulose, about 3% by weight of sodium starch glycolate, about 1% by weight of silicon dioxide, about 0.5% by weight of stearic acid, about 0.5% disodium EDTA, about 0.4% BHT, and about 0.65% by weight of ium stearate.

In certain embodiments, provided herein are pharmaceutical compositions comprising an opaque coating. Without being limited by theory, it was found that a more opaque coating protected the drug product from degradation. In some embodiments, the pharmaceutical composition is ated as a tablet. In some such embodiments, the tablet is film coated. In some embodiments, the tablet is film coated to a weight gain of 1-8%. In others, the film coating is about 5% by weight of the .

In certain embodiments, provided herein are pharmaceutical compositions, wherein the amounts of the recited components can independently be varied by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20% or 25%.

The pharmaceutical compositions provided herein can be provided in a unitdosage form or multiple-dosage form. A unit-dosage form, as used herein, refers to physically discrete unit suitable for administration to a human and animal subject, and packaged individually as is known in the art. Each unit-dose contains a predetermined ty of an active ient(s) sufficient to produce the desired eutic effect, in association with the required pharmaceutical carriers or excipients. Examples of a unit-dosage form include an individually packaged tablet or capsule. A unit-dosage form may be administered in fractions or multiples thereof. A le-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in ated unit-dosage form.

In another embodiment, ed herein are unit dosage formulations that comprise between about 0.1 mg and about 2000 mg, 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 solid form of Compound 1, or a solid form thereof.

In a particular embodiment, provided herein are unit dosage formulation sing about 0.1 mg, about 0.25 mg, about 0.5 mg, about 1 mg, about 2 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 8 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 100 mg, about 125 mg, about 140 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 280 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, about 560 mg, about 600 mg, about 700 mg, about 750 mg, about 800 mg, about 1000 mg or about 1400 mg of a solid form of Compound 1. In a particular embodiment, provided herein are unit dosage ations that comprise about 2.5 mg, about 5 mg, about 7.5 mg, about 8 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg or about 100 mg of a solid form of Compound 1 or a tautomer thereof.

In a particular embodiment, provided herein are unit dosage formulations that comprise about 1 mg, about 2 mg, about 5 mg, about 7.5 mg and about 10 mg.

In some embodiments, a unit dosage form comprising Compound 1, or a tautomer thereof can be administered once daily (QD), twice daily (BID), three times daily, four times daily or more often.

In certain embodiments, provided herein are methods for preparing a composition provided herein, comprising: (i) weighing out the desired amount of a solid form of Compound 1 (e.g., Form 1, Form 2, Form 3, Form 4, Form 5 or amorphous) and the desired amount of excipients (such as e monohydrate, croscarmellose sodium and/or microcrystalline cellulose); (ii) mixing or blending the solid form of nd 1 and the excipients; (iii) g the mixture of the solid form of Compound 1 and excipients through a screen (such as a 25 mesh ); (iv) mixing or blending the solid form of Compound 1 and the excipients after passage through the screen; (v) weighing out the desired amount of lubricating agents (such as stearic acid and magnesium stearate); (vi) passing the lubricating agents through a screen (such as a mesh ); (vii) mixing or blending the solid form of Compound 1, the excipients and the lubricating ; (viii) compressing the mixture of the solid form of Compound 1, the excipients and the lubricating agents (such as into a tablet form); and optionally (ix) coating the compressed mixture of the solid form of Compound 1 thereof, the excipients and the lubricating agents with a coating agent (such as Opadry pink, yellow or . In certain ments, the methods for ing a composition provided herein are d out in the dark, under yellow light or in the absence of UV light.

In certain embodiments, the pharmaceutical compositions provided herein comprise Form 1 of Compound 1, including substantially pure Form 1.

In certain embodiments, the pharmaceutical compositions provided herein comprise Form 2 of nd 1, including substantially pure Form 2.

In certain embodiments, the pharmaceutical compositions provided herein comprise Form 3 of Compound 1, including substantially pure Form 3.

In certain embodiments, the pharmaceutical compositions provided herein comprise Form 4 of Compound 1, including substantially pure Form 4.

In certain embodiments, the ceutical compositions provided herein comprise Form 5 of Compound 1, including substantially pure Form 5.

In certain embodiments, the pharmaceutical compositions provided herein comprise amorphous Compound 1, including ntially pure amorphous Compound 1. 6. EXAMPLES The following es are presented by way of illustration, not limitation. The following abbreviations are used in descriptions and examples: 2MXETOH: oxyethanol AAC: Accelerated aging conditions (48 hours at 40 °C and 75% RH) ACN: Acetonitril Am: ous AmPhos: p-Dimethylamino phenylditbutylphosphine API: Active Pharmaceutical Ingredient AS: ID for anti-solvent crystallization experiment Boc: tert-Butoxycarbonyl dba: Dibenzylidene acetone DCM: Dichloromethane DIPEA: N,N-Diisopropylethylamine DMF: N,N-Dimethylformide DMSO: Dimethylsulfoxide DSC: Differential Scanning metry ECP: ID for ative experiment EDTA: Ethylenediamine tetraacetate ESI: Electronspray ionization EtOH: Ethanol FTIR: Fourier Transform Infra Red Spectroscopy GRP: Grinding experiment HF: ID for ltration crystallization experiment HPLC: High performance liquid chromatography IPA: 2-Propanol LCMS: Liquid Chromatography with Mass Spectroscopy MeOH: Methanol mp: Melting point MS: Mass spectrometry Ms: Mesylate or methanesulfonyl MTBE: tert-Butyl methyl ether MTBE: methyl utyl ether NBS: N-Bromosuccinimide NMP: N-Methylpyrrolidone NMP: N-methylpyrrolidinone NMR: Nuclear magnetic resonance PSU: ID for cooling-evaporative crystallization experiment QSA: ID for Phase 1 experiments RH: Relative Humidity RT: Room Temperature S: Solvent SDTA: Single Differential Thermal Analysis SLP: ID for slurry experiment SM: ng material TA: Thermal Analysis TCP: ID for thermocycling and reflux experiment Tf: triflate or trifluoromethanesulfonyl TFA: oroacetic acid TFE: 2,2,2-Trifluoroethanol TGA: Thermogravimetric is TGA-MS/TG-MS: gravimetric Analysis coupled with Mass Spectroscopy THF: Tetrahydrofuran TLC: Thin layer chromatography VDL: ID for vapor diffusion into solutions experiment VDS: ID for vapor diffusion onto solids experiment XRPD: X-Ray Powder Diffraction 6.1 SOLID FORMS 6.1.1 Polymorph Screen A polymorph screen of Compound 1 was performed to investigate whether different solid forms could be ted under various conditions, such as different solvents, ature and humidity changes.

] The solvents used in the polymorph screen were either HPLC or reagent grade, including acetone, acetonitrile (ACN), n-butanol (n-BuOH), absolute ethanol (EtOH), ethanol/water (1:1), methanol (MeOH), 2-propanol (IPA), ethyl acetate (EtOAc), methylene chloride (DCM), methyl ethyl ketone (MEK), methyl t-butyl ether (MTBE), heptane, toluene, tetrahydrofuran (THF), dimethyl sufoxide (DMSO), N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF) and water.

All of the solid samples generated in the polymorph screen were analyzed by XRPD. XRPD analysis was conducted on a Crystallics T2 high-throughput X-ray powder diffractometer using Cu K radiation at 1.54 Å. The instrument was equipped with a fine focus X-ray tube. The voltage and ge 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 or. A theta-two theta continuous scan at 2.40 º/minutes (0.5 sec/0.02 º step) from 1.5 ° to 41.5 ° 2 was used. A sintered alumina standard was used to check the peak positions.

DSC analyses were med on a DSC822e instrument er-Toledo GmbH, Switzerland). 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.

TGA analyses were performed on a TA instrument Q5000 gravimetric Analyzer. Calcium oxalate was used for a mance check. Approximately 5-20 mg of accurately weighed sample was placed on a pan and loaded into the TGA furnace. The sample was heated under nitrogen at a rate of 10 C/min, up to a final temperature of 300 C.

TGA/SDTA analyses were performed on a TGA/SDTA851e instrument (Mettler- Toledo GmbH, Switzerland). The TA851e instrument was ated for temperature with indium and aluminium. Samples were weighed into 100 µl aluminium crucibles and sealed.

The seals were pin-holed and the crucibles heated in the TGA from 25 to 300 °C at a heating rate of 10 °C/min. Dry N2 gas was used for purging. logy analysis of the s was carried out on an Olympus microscope.

Small amounts of samples were dispersed in mineral oil on a glass slide with cover slips and viewed with 20x or 50x magnification.

Hygroscopicity was determined on a Surface ement Systems DVS.

Typically a sample size of 2-10 mg was loaded into the DVS instrument sample pan and the sample was analyzed on a DVS automated sorption analyzer at room temperature. The ve humidity was increased from 0 % to 90 % RH at 10% RH step then 95 % RH. The relative humidity was then decreased in a similar manner to accomplish a full adsorption/desorption cycle. For selected hydrated forms, the analysis started at 50 % RH and increased to 90 % RH at % RH step. The relative humidity was then decreased in a r manner to 0 % RH followed by increasing to 50 % RH.

High Performance Liquid Chromatography (HPLC) was performed according to the conditions in Table 1 and gradient program in Table 2.

Table 1. High Performance Liquid Chromatography (HPLC) emental conditions Manufacturer Agilent HPLC HP1200sl UV-detector HP DAD MS-detector HP1100 API-ES MSD VL-type Column Waters Sunfire C18 (100 x 4.6mm; 3.5µm) Column Temperature 35 °C Mobile Phase A 10 mM ammonium acetate Mobile Phase B Acetonitrile 100% Flow Rate 1.0 ml/min Post time 1 min ector DAD Range 200 – 400 nm Wavelength 254 nm Slit width 4 nm Time 0-20 min MS-Detector MSD Scan positive Mass Range 70 – 1000 amu Fragmentator 70 Time 0-12 min Autosampler: ature Not controlled Injection mode loop Injection volume 5 µL Needle wash 2/3; ACN/H2O (v/v) Dilution solvent 0.1% TFA water/acetonitrile (v/v=50/50) Table 2. High Performance Liquid Chromatography (HPLC) experiemental gradient program Time (mins) % A % B 0 90 10 16 10 90 10 90 21 90 10 The compound integrity is expressed as a peak-area percentage, calculated from the area of each peak in the chromatogram, except the ‘injection peak’, and the total peak-area, as follows: peak  area peak  area %  100 % total  area The peak-area percentage of the compound of interest is employed as an indication of the purity of the component in the sample. l16® le-reactor system (Avantium Technologies) holds 16 (4 x 4) rd HPLC glass vials (11.5 mm diameter, flat bottomed, 1.8 mL volume). A unit consists of four independently heated aluminum reactor blocks d in a robust bench top setup.

These blocks are electrically heated and cooled by a combination of Peltier elements and a cryostat. In order to prevent condensation of water on the reactor blocks and electronics during runs at temperatures below 10 °C, the Crystal16® system provides an inlet for a dry purge gas (typically nitrogen). Operating Parameters are provided in Table 3.

Table 3. Operating Parameters of l16® multiple-reactor system Temperature range -15 °C to 150 °C Heating/cooling Individually programmable per reactor block Temperature profile Unlimited heating/cooling/hold steps per run programmable Temperature l cy 0.1 °C Heating/cooling ramps Programmable between 0 °C and 20 °C/min Stirrer speed (magnetic stirrer bars) Programmable from 0 - 1250 rpm Turbidity ement Per individual reactor in transmission 6.1.2 Experiments and Methods 6.1.2.1 Solubility experiment: In order to select the screening solvents and to determine the concentration range to be used in the , a quantitative solubility assessment was performed on the ng material, Form 1 of Compound 1. A set of 15 solvents was analyzed. For each solvent, a standard 1.8 ml screw cap vial was loaded with about 30 mg of the starting material, Form 1 of Compound 1, 400 µL of solvent and a magnetic stirring bar. The vials were then closed and equilibrated at 25 °C for 24 h while stirring. The resulting mixtures (slurries) were filtered (0.5 micron) and the isolated mother liquors diluted to two dilutions selected according to the calibration curve. Quantities of Compound 1 in the diluted solutions were determined via HPLC analysis. The calibration curve was obtained from two independently prepared stock solutions of nd 1 in 0.1% TFA in Acetonitrile (50:50).

] Subsequent to the solubility determination, the wet solids were harvested and analyzed by XRPD. er, the residual solvent was evaporated from each vial (slurry) under vacuum at ambient temperature. All of the resulting residues were analyzed by XRPD to check for new (crystalline) forms.

In addition to the solubility determination, 15 slurry experiments of Form 1 of Compound 1 were performed with at 50°C for 24 hours in 15 solvents (same 15 ts). Table 4 summarizes the experimental conditions. At the end of the slurry time, the solids were separated from the solutions by centrifugation, harvested wet and dried and analyzed by XRPD and digital imaging.

Table 4: Experimental conditions for 30 slurry conversion experiments, combined with solubility ination Sample Mass t Solvent Dissolved Temperature (oC) (mg) Volume (µL) 1,2-Ethanediol 32.9 400 No 25 1,4-Dioxane 33.0 400 No 25 Diethyl Ether 33.5 400 No 25 Chloroform 31.1 400 No 25 2-Methoxyethanol 29.3 400 No 25 Cyclohexane 30.3 400 No 25 p-Xylene 27.5 400 No 25 Cumene 29.7 400 No 25 Isopropyl Acetate 29.2 400 No 25 Anisole 30.8 400 No 25 Ethyl formate 32.7 400 No 25 1-Propanol 29.8 400 No 25 Sample Mass Solvent Solvent Dissolved Temperature (oC) (mg) Volume (µL) 1,2-Dimethoxyethane 30.4 400 No 25 2-Butanone 28.6 400 No 25 Acetonitrile 30.8 400 No 25 1,2-Ethanediol 46.5 400 No 50 1,4-Dioxane 48.4 400 No 50 Diethyl Ether 51.0 400 No 50 Chloroform 53.0 400 No 50 2-Methoxyethanol 50.0 400 No 50 cyclohexane 51.9 400 No 50 p-Xylene 41.7 400 No 50 Cumene 47.4 400 No 50 Isopropyl Acetate 48.1 400 No 50 Anisole 51.3 400 No 50 Ethyl formate 50.7 400 No 50 anol 48.2 400 No 50 1,2-Dimethoxyethane 51.5 400 No 50 2-Butanone 46.5 400 No 50 Acetonitrile 55.9 400 No 50 6.1.2.2 Feasibility study The experimental conditions of the feasibility study with Compound 1 are summarized in Table 5. The freeze drying experiments were performed in 1.8 ml vials.

Approximately 20 mg of starting al were weight in a HPLC vial and dissolved in five different solvent mixtures. The starting al, Form 1, did not ve in THF/water (90/10 or 50/50) and l/water (90/10); therefore these experimental s were not freeze-dried.

Form 1 dissolved in TFE and TFE/water (90/10). These two experimental samples were freezedried in liquid nitrogen, followed by placing the vials in a freeze-dryer for 24 hours. The obtained solid was then harvested and analyzed by XRPD and digital imaging.

] Grinding experiments were performed in stainless steel grinding vials, containing 2 stainless steel grinding balls and a frequency of 30Hz. Following the experiments, XRPD analysis was performed to assess the crystallinity of the materials.

Table 5: Conditions applied for the feasibility study on Form 1 Sample Mass Solvent Solubility t Dissolved Comments (mg) Volume (µL) (mg/mL) THF/water 24.8 1000 <25 No Freeze drying Ethanol/water 24.2 400 <60 No Freeze drying (90/10) THF /Water .1 1000 <25 No Freeze drying (50/50) .7 1000 21 Yes Freeze drying (90/10) 21.9 TFE 1000 22 Yes Freeze drying .0 None Grinding 1 hour .0 None Grinding 2 hours 6.1.2.3 Physical stability study at room temperature and different RH Physical stability studies over a prolonged period of time (e.g., 4 weeks) were conducted in desiccators at defined relative humidity (0%, 50%, 75% and 100%). At regular intervals (e.g., 3 days, 1 week, 2 weeks, 3 weeks and 4 weeks), the materials were analyzed by XRPD. To determine if the material absorb water molecules under different relative humidity levels, four more onal vials were placed in the desiccators to weight them back periodically and ine the change in mass (see Table 7 and Table 8). The materials used in desiccators to reach the defined relative ty are presented in Table 6.

Table 6: Preparation of the different humidity ranges Relative Humidity at RT Method 0% P2O5 (powder) 50% MgNO3 (saturated solution) 75% NaCl (saturated solution) 100% Climate chamber with water vapors ] Table 7: Initial experimental conditions for the four vials used to determine the water uptake Relative Humidity Empty vial weight Empty vial weight + Starting material (mg) Starting material (mg) weight (mg) 0% 2297.5 2318.2 20.7 50% 2314.1 2334.5 20.4 75% 2285.5 2306.3 20.8 100% 2333.3 2354.2 20.9 Table 8: Experimental conditions for the 20 stability tests Relative humidity Time Starting material weight (mg) 0% 3 days 5.7 1 weeks 4.5 2 weeks 6.2 3 weeks 4.8 4 weeks 6.2 50% 3 days 6.3 1 weeks 5.1 2 weeks 4.6 3 weeks 5.2 4 weeks 5.5 75% 3 days 4.6 1 weeks 4.4 2 weeks 5.4 3 weeks 5.1 4 weeks 5.2 100% 3 days 5.3 1 weeks 5.9 2 weeks 5.6 3 weeks 5.3 4 weeks 6.3 6.1.2.4 Experimental methods of the polymorph screening: The screening experiments for Compound 1 comprised 96 experiments at microliter (µL) scale and 125 experiments at milliliter (mL) scale. The following ten crystallization procedures were applied: g-evaporation, evaporative, cooling crystallization with hot filtration, crash crystallization with olvent on, slurry conversion, vapor diffusion into ons, vapor diffusion onto solid, thermocycling, reflux and grinding.

Cooling-evaporative crystallization experiments at µl scale: The 96 cooling-evaporative experiments at µL scale were performed in well plates, employing 12 different solvents and 12 mixtures of ts in Table 9 and four temperature profiles in Table 9. About 4 mg solid dose of Compound 1 was in each well of the microliter well plate. Subsequently, 80 µL of the screening t was added into the well to reach a concentration of 50 mg/ml.

] The plates, with each well individually sealed, were placed in a Crystal Breeder to undergo a temperature profile as described in Table 10. The plates were placed under vacuum after completion of the temperature profile. The solvents were evaporated for several days at 200 mbar or 5 mbar and analyzed by XRPD and digital g. Following, the solid samples were exposed to accelerated aging conditions (2 days at 40 °C/75% RH) and re-analyzed by XRPD and digital imaging.

Table 9: Experimental conditions for the 96 µl cooling-evaporation experiments Solvent ature Conditions 1,2-Ethanediol Temperature Temperature Temperature Temperature Profile #1 Profile #2 Profile #3 Profile #4 Anisole Temperature Temperature ature Temperature Profile #1 Profile #2 Profile #3 Profile #4 2-Methoxyethanol Temperature Temperature Temperature Temperature Profile #1 Profile #2 Profile #3 Profile #4 Acetonitrile/Anisole ) Temperature Temperature Temperature Temperature e #1 Profile #2 Profile #3 e #4 1,2-Dimethoxyethane/1- Temperature Temperature Temperature Temperature Pentanol (50/50) Profile #1 Profile #2 Profile #3 Profile #4 Isobutanol Temperature Temperature Temperature Temperature Profile #1 Profile #2 Profile #3 Profile #4 pyl Acetate/2- Temperature Temperature Temperature Temperature Methoxyethanol (50/50) e #1 Profile #2 Profile #3 Profile #4 Water Temperature Temperature Temperature Temperature Profile #1 Profile #2 Profile #3 Profile #4 oxane /Water ) Temperature Temperature Temperature Temperature Profile #1 Profile #2 Profile #3 Profile #4 1,4-Dioxane Temperature ature Temperature Temperature Profile #1 Profile #2 Profile #3 Profile #4 Water/Ethanol (50/50) Temperature Temperature ature Temperature Profile #1 Profile #2 Profile #3 Profile #4 pyl Acetate ature Temperature Temperature Temperature Profile #1 Profile #2 Profile #3 Profile #4 Solvent Temperature Conditions Water/Methanol ) Temperature Temperature ature Temperature Profile #1 Profile #2 Profile #3 Profile #4 Acetonitrile Temperature Temperature Temperature Temperature Profile #1 Profile #2 Profile #3 Profile #4 isopropanol/Tetrahydrofuran ature Temperature Temperature Temperature ) Profile #1 Profile #2 Profile #3 Profile #4 Methanol/Acetonitrile Temperature Temperature Temperature Temperature (50/50) Profile #1 Profile #2 Profile #3 Profile #4 Tetrahydrofuran/Ethanol Temperature Temperature Temperature Temperature (50/50) Profile #1 Profile #2 Profile #3 Profile #4 Tetrahydrofuran Temperature Temperature Temperature Temperature Profile #1 Profile #2 Profile #3 Profile #4 Methanol Temperature Temperature Temperature Temperature Profile #1 e #2 Profile #3 Profile #4 Tetrahydrofuran/Chloroform Temperature Temperature Temperature Temperature (50/50) Profile #1 Profile #2 Profile #3 Profile #4 Methanol/Chloroform Temperature Temperature Temperature Temperature (50/50) Profile #1 e #2 Profile #3 Profile #4 form Temperature Temperature Temperature Temperature e #1 Profile #2 Profile #3 Profile #4 Acetonitrile/Dichloromethane Temperature Temperature Temperature ature ) Profile #1 Profile #2 Profile #3 Profile #4 Ethyl Formate Temperature Temperature Temperature Temperature Profile #1 Profile #2 Profile #3 Profile #4 Table 10: ature profiles employed for the 96 cooling-evaporative ments ature Tstart (°C) Heating Tmax (°C) Hold Cooling Tend (°C) Age time profile # rate time rate (h) (°C/min) (min) (°C/h) 1 20 10.0 60 60 1.0 5 48 2 20 10.0 60 60 20.0 5 3 3 20 10.0 60 60 1.0 20 48 4 20 10.0 60 60 20.0 20 3 6.1.2.5 Cooling crystallization with hot filtration: The crystallization method with hot filtration comprised 15 solvent mixtures. aturated solutions were prepared by stirring slurries (see Table 12) at 60 °C for one hour and then filtering the slurries. All the solutions were then placed in a Crystal16® system to undergo a cooling profile and aged for 62 h (see Table 11). If solids precipitated after the temperature profile, they were harvested wet and dried and analyzed by XRPD and digital imaging. The experiments with no solid after the temperature profile were left to ate under vacuum. The obtained dry solid samples were analyzed by XRPD and l imaging.

All the solid samples were exposed to accelerated aging conditions (2 days at 40 °C/75% RH) and re- analyzed by XRPD and digital imaging.

Table 11: g profile employed for the hot filtration experiments Tinitial (oC) Hold (min) Cooling rate (oC/h) Tfinal(oC) Hold (hrs) 60 60 1 5 62 Table 12: Experimental conditions and results for the hot filtration ments Exp. No. Stock t description Solvent Starting Solid after volume (µL) material Temperature weight (mg) profile 1 Acetonitrile/Ethyl Formate 5000 30.0 No 2 Tetrahydrofuran/Water 2000 30.0 Yes 3 Water/Methanol 5000 30.0 Yes 4 methylformamide 3000 30.0 No /Cumene 1,4-Dioxane 3000 30.0 Yes 6 Isopropanol/Acetone 5000 30.0 Yes 7 Ethanol/Water 5000 30.0 Yes 8 Ethanol/N-Methyl 2000 30.0 No pyrrolidone 9 Tetrahydrofuran/1,2- 4000 28.0 Yes Dimethoxyethane Dimethyl Sulfoxide/Water 5000 30.0 No 11 Isopropyl Acetate/Diethyl 5000 30.0 No Ether 12 2-Methoxyethanol 2000 32.0 Yes /Chloroform 13 Tetrahydrofuran/Acetonitrile 5000 30.0 Yes 14 Anisole/Chloroform 5000 30.0 No Butanone, 2-/N-Methyl 2000 30.0 No pyrrolidone 6.1.2.6 Anti-solvent crystallization: For the crash-crystallization experiments with anti-solvent on, 15 different crystallization conditions were applied, using the selected solvents and eleven different anti-solvents (see Table 14). Stock solutions were prepared in each solvent (see Table 13).

These ons were ted with Form 1 of Compound 1 and equilibrated for 24 h before filtering. The stock solutions were then liquid dosed into the experimental vials, followed by the anti-solvent on. The anti-solvent was added to each solvent vial with a solvent to antisolvent ratio of 1:0.25. In the case of no precipitation occurred, this ratio was increased to 1:1 or 1:4 with a waiting time of 60 minutes between the additions. After the last addition the samples were left stirring at t temperature for 24 hours. The precipitated solids were isolated from the mother liquor and analyzed wet and dried by XRPD and digital imaging. The samples, in which no precipitation occurred, were placed under vacuum and the dried solids were analyzed by XRPD and digital imaging. All the solids were exposed to accelerated aging conditions (2 days at 40 °C/75% RH) and re-analyzed by XRPD and digital g.

Table 13: Stock on for the anti-solvent addition experiments Exp. No. Solvent(s) Starting material Solvent Solution weight (mg) volume (µL) concentration (mg/mL) 1 Tetrahydrofuran 30 5000 6 2 2-Methoxyethanol 30 5000 6 3 Tetrahydrofuran 30 5000 6 4 ylpyrrolidone 60 500 120 1,4-Dioxane 30 5000 6 6 methylformamide 30 1000 30 7 N-Methylpyrrolidone 60 500 120 8 1,4-Dioxane 30 5000 6 9 N-Methylpyrrolidone 30 500 60 Tetrahydrofuran 30 5000 6 11 2-Methoxyethanol 30 5000 6 12 N,N-Dimethylformamide 30 1000 30 13 Tetrahydrofuran 30 5000 6 14 Dimethyl Sulfoxide 30 500 60 Dimethyl Sulfoxide 30 500 60 Table 14: Results and experimental conditions for the anti-solvent addition experiments Exp Solvent Solvent Anti-solvent Starting A* B* C* AS:S No. volume Material ratio (µL) wt (mg) 1 THF 5000 e 30.0 Yes - - 0.25 2 2MXETOH 5000 Cumene 30.0 No No No 4 3 THF 5000 Cyclohexane 30.0 No Yes - 1 4 N-Methyl- 500 Ethyl 60.0 No No Yes 4 2- formate idone 1,4-Dioxane 5000 p-Xylene 30.0 No No Yes 4 6 DMF 1000 Isopropyl 30.0 No Yes - 1 ether 7 NMP 500 Cyclohexane 60.0 No Yes - 1 8 1,4-Dioxane 5000 Heptane 30.0 No Yes - 1 9 NMP 500 TBME 30.0 No No Yes 4 THF 5000 2,2,4- 30.0 Yes - - 0.25 Trimethyl pentane 11 2MXETOH 5000 Ethyl acetate 30.0 No No Yes 4 12 DMF 1000 Water 30.0 Yes - - 0.25 13 THF 5000 Water 30.0 No No No 4 14 DMSO 500 Water 30.0 Yes - - 0.25 DMSO 500 Toluene 30.0 No No Yes 4 *A= whether or not any precipitation after addition to 0.25:1 (AS:S); B= r or not any precipitation after addition to 1:1 (AS:S); C= whether or not any precipitation after addition to 4:1 (AS:S). 6.1.2.7 Slurry conversion experiment: Experiments were carried out by adding about 30 mg of Form 1 of Compound 1 to 500 µL of a test solvent. The resulting mixture was agitated for at least 24 hours at 25 °C.

Upon ng brium, the saturated supernatant solution was removed. The solid resulting from the equilibration was filtered and air-dried before analysis.

A total of ten slurry experiments were performed with Form 1 of Compound 1 with ten solvents at ambient temperature for two weeks (see Table 15). After the slurry time, the solids were ted from the solutions by centrifugation, harvested wet and analyzed by XRPD and digital imaging. The solids were then exposed to accelerated aging conditions (2 days at 40 °C/75% RH), followed by XRPD re-analysis.

Table 15: Experimental conditions of the slurry experiments Exp Solvent Solvent volume Starting Concentration Dissolved Solids No. (µL) Material (mg/mL) at initial after two wt (mg) temperature weeks 1 Water 500 29.7 59.4 No Yes 2 Methanol / 500 30.0 60 No Yes Water (50/50) 3 Ethanol / 500 30.0 60 No Yes Water (50/50) 4 itrile 500 30.4 60.8 No Yes 1,2- 500 30.5 61 No Yes diol 6 Isopropyl 500 31.0 62 No Yes Acetate 7 p-Xylene 500 30.3 60.6 No Yes 8 2-Butanone 500 29.8 59.6 No Yes 9 Cumene 500 29.8 59.6 No Yes Anisole 500 30.1 60.2 No Yes 6.1.2.8 Evaporative experiments The 15 evaporative experiments were done by dissolving Form 1 of Compound 1 in 15 different solvent mixtures in Table 16. The starting material, Form 1 of Compound 1 was added into solvent and if the starting material did not ve in the solvent comletely, the mixtures were filtered and then the clear ons were evaporated. The solvents were slowly evaporated under vacuum (200 mbar or 5 mbar) until dryness to yield solid. The solid was analyzed by XRPD and digital imaging. The solid was then exposed to rated aging ions (2 days at 40 °C/75% RH), followed by XRPD re-analysis and digital imaging.

Table 16: Experimental conditions of the evaporative experiments Exp No. Starting Solvent Solvent Concentration D* al wt volume (mg/mL) (mg) (µL) 1 30.2 Ethanol/Chloroform (50/50) 5000 60.4 Yes 2 31.5 2,2,2-trifluoroethanol/Water 5000 63 No (50/50) Exp No. Starting Solvent t Concentration D* Material wt volume (mg/mL) (mg) (µL) 3 29.8 1,4-Dioxane/Ethyl formate 5000 59.6 No (50/50) 4 28.7 Methanol/Acetonitrile (50/50) 5000 57.4 No 26.5 Acetonitrile/Chloroform 5000 53 No (50/50) 6 30.1 Water/Tetrahydrofuran (50/50) 5000 60.2 Yes 7 31 Isopropanol/2-Butanone 5000 62 No (50/50) 8 29.5 Methanol/1,4-Dioxane (50/50) 5000 59 Yes 9 28.9 2-Methoxyethanol/Isopropyl 5000 57.8 No Acetate (50/50) 30.4 Ethanol / Water (50/50) 5000 60.8 No 11 29.4 Water / NMP (50/50) 5000 58.8 No 12 29.8 THF / TBME (50/50) 5000 59.6 No 13 30.6 1,4-Dioxane / Water ) 5000 61.2 No 14 28.8 1,2-Ethanediol/THF (50/50) 5000 57.6 Yes 30.1 Acetone/isopropanol (50/50) 5000 60.2 No *D= whether or not all the starting material ved at initial temperature. 6.1.2.9 Vapor Diffusion into solutions: For the 15 vapor diffusion into solution ments, saturated solutions of Form 1 of Compound 1 were exposed to solvent vapors at room temperature for two weeks. Stock ons were prepared in each t. These solutions were saturated with Form 1 of Compound 1 and equilibrated for 24 h before filtering into a set of 8 ml vials. These vials were left open and placed in closed 40 ml vials containing 2 ml of anti-solvent (see Table 17). After two weeks, the samples were d on solid formation. When solid was formed the solid samples were analyzed wet by XRPD and digital imaging. If no precipitation occurred, the samples were placed under vacuum and the resuled solid s were analyzed by XRPD and digital imaging. Subsequently, all the solid samples were exposed to accelerated aging conditions (2 days at 40 °C/75% RH) , followed by XRPD re-analysis and digital imaging.

] Table 17: Experimental conditions of the vapor diffusion into on experiments Exp Starting Solvent Solvent Anti-solvent S* No. Material wt volume (mg) (µL) 1 29.8 2-Methoxyethanol 5000 Anisole No 2 30.5 DMF 1000 Acetonitrile Yes 3 30.1 Tetrahydrofuran 5000 Diethyl ether Yes 4 29.9 Dimethyl Sulfoxide 600 Water Yes 29.6 1,4-Dioxane 5000 Cyclohexane No 6 29.9 DMF 1000 n-Pentane No 7 29.7 NMP 600 Ethanol No 8 29.8 2,2,2-trifluoroethanol 1000 Cyclohexane No 9 30.1 NMP 600 Heptane No 29.6 Dimethyl Sulfoxide 500 Isopropyl ether No 11 30.0 2-Methoxyethanol 5000 Acetone No 12 29.9 Tetrahydrofuran 5000 Chloroform No 13 30.4 Dimethyl ide 500 Ethyl acetate No 14 30.5 Tetrahydrofuran 5000 n-Pentane Yes 29.9 1,4-Dioxane 5000 Dichloromethane No *S= whether or not there is any solid formed after two weeks. 6.1.2.10 Vapor Diffusion onto solids For the 15 vapor diffusion onto solids experiments, amorphous Compound 1 was prepared by grinding lline Compound 1 for two hours. The ous material was transferred into 1.8 ml vials, which were left open and placed in closed 40 ml vials containing 2 ml of solvent (see Table 18). The al was exposed to solvent vapors at room temperature for two weeks. After that time, the experiments were harvested and analyzed by XRPD and digital imaging. Following, all the solids were exposed to accelerated aging conditions (40 °C and 75% RH) for two days, ed by XRPD re-analysis and digital imaging.

Table 18: Experimental conditions of the vapor ion onto solids experiments Exp ng Solvent Solvent S* No. Material wt volume (mg) (µL) 1 30.3 tert-Butyl methyl ether 2000 Yes 2 30.2 1,2-Ethanediol 2000 Yes 3 29.8 Chloroform 2000 Yes 4 30.3 Methanol 2000 Yes 30.0 Ethyl Formate 2000 Yes 6 29.8 Cyclohexane 2000 Yes 7 30.6 Acetonitrile 2000 Yes 8 30.3 Heptane 2000 Yes 9 29.7 isopropyl ether 2000 Yes 29.8 Pentane, n- 2000 Yes 11 30.3 e 2000 Yes 12 29.7 Isobutyl acetate 2000 Yes 13 30.5 2-Ethoxyethanol 2000 Yes 14 30.0 Water 2000 Yes 29.7 Acetone 2000 Yes * S= whether or not there was any solid left after two weeks. 6.1.2.11 Thermocycling experiments A total of 15 es of Compound 1 in solvents were prepared at room temperature (see Table 19). The mixtures were placed in the Crystal Breeder to undergo the temperature profile as follows: a) heated with a g rate of 5 °C/h until reaching 40 °C; b) cooled with a cooling rate of 5 °C/h until reaching 5 °C; c) held at 5 °C for 30 min; d) repeated the cycle 8 times; and e) being stirred at 300 rpm during the temperature profile.

After the completion of the cycling m, the solids were separated from the liquids and analyzed wet and dried by XRPD and digital imaging. All the solids were then exposed to accelerated aging conditions (2 days at 40 °C/75% RH), followed by XRPD reanalysis and digital imaging.

Table 19: Experimental conditions of the thermocycling experiments Exp Starting Solvent Solvent Concentration Dissolved S* No. Material volume ) at initial wt (mg) (µL) temperature 1 29.7 tert-Butyl methyl ether 1000 29.7 No Yes 2 30.8 form 1000 30.8 No Yes 3 29.5 ol 1000 29.5 No Yes 4 29.5 1,2-Dimethoxyethane 1000 29.5 No Yes 29.8 ne 1000 29.8 No Yes 6 29.7 Acetonitrile 1000 29.7 No Yes 7 30.0 Water 1000 30 No Yes 8 29.7 Acetone 1000 29.7 No Yes 9 30.0 1,4-Dioxane 1000 30 No Yes 30.1 1,2-Ethanediol 1000 30.1 No Yes 11 30.5 Ethyl Formate 1000 30.5 No Yes 12 30.6 2-Butanone 1000 30.6 No Yes 13 30.0 Isopropanol 1000 30 No Yes 14 30.3 Tetrahydrofuran 1000 30.3 No Yes 30.1 Cumene 1000 30.1 No Yes * S= whether or not there was any solid left after the eight cycles. 6.1.2.12 Reflux experiments In the 15 reflux experiments (see Table 21), the ng material, Form 1 of Compound 1, was mixed with selected solvents in 1.8 mL vials to give slurries. The slurries were then kept at a constant temperature (slightly below the corresponding boiling point of the chosen solvent) for one week and afterwards at 5 °C for two days (see Table 20).

Table 20: Temperature profile (Tprofile) applied to the reflux experiments Exp Tstart (°C) Heating Tmax (°C) Hold time Cooling Tend (°C) Age time No. rate (h) rate (h) (°C/min) (°C/h) 1 25 5 50 168 10 5 48 2 25 5 60 168 10 5 48 Exp Tstart (°C) Heating Tmax (°C) Hold time Cooling Tend (°C) Age time No. rate (h) rate (h) (°C/min) (°C/h) 3 25 5 70 168 10 5 48 4 25 5 80 168 10 5 48 After the temperature profile the solids were analyzed wet by XRPD and l imaging. Then all the solids were exposed to accelerated aging conditions (2 days at 40 °C/75% RH), followed by XRPD re-analysis and digital imaging.

Table 21: Experimental ions for the reflux ments Exp Starting Solvent Solvent Concentration ved S* No. Material volume (mg/mL) at initial wt (mg) (µL) temperature 1 29.5 Ethyl formate 1000 29.5 No Yes 2 29.7 tert-Butyl methyl ether 1000 29.7 No Yes 3 30.1 Acetone 1000 30.1 No Yes 4 30.0 Methyl acetate 1000 30 No Yes 29.5 Chloroform 1000 29.5 No Yes 6 30.1 Methanol 1000 30.1 No Yes 7 29.8 Tetrahydrofuran 1000 29.8 No Yes 8 30.1 Isopropyl ether 1000 30.1 No Yes 9 29.8 Ethyl e 1000 29.8 No Yes 31.3 2-Methyl 1000 31.3 No Yes tetrahydrofuran 11 29.5 Ethanol 1000 29.5 No Yes 12 30.6 2-Butanone 1000 30.6 No Yes 13 29.5 Cyclohexane 1000 29.5 No Yes 14 29.5 Acetonitrile 1000 29.5 No Yes 29.5 Isopropanol 1000 29.5 No Yes *S= whether or not there was any solid left after Tprofile in Table 20. 6.1.2.13 Grinding experiments In ten grinding experiments (see Table 22), about 30 mg Form 1 of Compound 1 was ground in metal grinding vials charged with two metal grinding balls. Then 10 µl of solvent was added. The samples were ground for 1 hour with a frequency of 30 Hz.

The ground solids were harvested and analyzed by XRPD and digital imaging.

Then the solids were exposed to accelerated aging conditions (40 °C/75% RH) for two days, followed by XRPD re-analysis and digital imaging.

Table 22: Experimental conditions for the grinding experiments Exp Starting Material wt t Solvent volume Concentration No. (mg) (µL) (mg/mL) 1 29.9 Ethanol 10 2990 2 30.3 1,2-Ethanediol 10 3030 3 30.7 Acetonitrile 10 3070 4 30.0 Isobutanol 10 3000 29.6 Toluene 10 2960 6 29.7 Isopropyl Acetate 10 2970 7 30.6 Anisole 10 3060 8 29.8 Water 10 2980 9 29.9 Acetone 10 2990 30.1 Cumene 10 3010 ed herein are five crystalline forms identified by the polymer screen. Form 1 was found to be a stable anhydrous crystalline form that melts at approximated 268.9 °C.

Form 2, a 1,2-ethanediol mono-solvated form of Compound 1, was prepared at least when 1,2-ethanediol was used as solvent in a slurry conversion experiment. Form 3, a 2,2,2-trifluorotoluene hemi-solvated form of Compound 1, was prepared from at least one evaporative experiment in TFE/water (50:50). Form 4, a 0.8 molar equivalent DMSO solvated form of Compound 1, was prepared at least from anti-solvent crystallization by using DMSO as t and water as anti-solvent. Form 5, a ated form of Compound 1, was ed in hot-filtration experiments at least when water was used as part of the crystallization solvent. A summary of the experimental conditions which the new solid forms were ed is presented in Table 23. A summary of al data of solid forms is presented in Table 24.

Table 23. Summary of experimental conditions of the solid forms Form Crystallization Method Solvent Evaporative 1,2-ethanediol 2 Slurry Thermocycling ative 2,2,2-trifuoroethanol Hot-filtration Isopropanol/acetone (50:5) Vapor diffusion into liquids 2,2,2-trifuoroethanol (s), cyclohexane (AS) Vapor diffusion onto solids Chloroform Anti-solvent DMSO (S), water (AS) 4 Anti-solvent DMSO (S), toluene (AS) Vapor diffusion into liquids DMSO (S), water (AS) Hot-filtration ter (50:50) Hot-filtration Water/methanol (50:50) ltration Water/1,4-dioxane (50:50) Hot-filtration Ethanol/water (50:50) olvent THF (S), water (AS) ative Water/THF (50:50) Table 24. Physical Characterization of Solid Forms of Compound 1 Physical stability Purity (% by (existing forms Form Form Nature Endotherms (°C) HPLC) after 48 h 40 °C/75% RH) 1 Anhydrate 268.9 99.9 Stable Solvate (15.5% of 1,2-ethanediol– 2 95-176 (broad), 264 100 Form 2 1 molecule of 1,2-ethanediol per molecule of API) Solvate 3 (12.8% of TFE – 0.5 molecule of 149 (broad), 254 91.7 Form 3 TFE per molecule of API) Solvate 4 (16.4% of DMSO – 0.8 molecule of 139 (broad), 258 93.6 Forms 1+4 DMSO per molecule of API) al stability Purity (% by (existing forms Form Form Nature Endotherms (°C) HPLC) after 48 h 40 °C/75% RH) Hydrate 80 (broad), 181 (9.4% of water – 1.9 molecules of 90.1 Form 5 (exo), 251 water per molecule of API) 6.1.2.14 Form 1 The XRPD pattern, l habit, TGA, SDTA, TGA-MS, HPLC and MS of Form 1 of Compound 1 are shown in FIGs. 2-6. provides an XRPD pattern of Form 1 of Compound 1. A list of X-Ray Diffraction Peaks for Form 2 of Compound 1 is ed below in Table 25.

Table 25. X-Ray Diffraction Peaks for Form 1 of Compound 1 Relative Two-theta angle (°) d Space (Å) Intensity (%) 7.94 11.12 11.54 9.74 9.07 87.52 11.94 7.4 33.02 .86 5.58 37.83 17.3 5.12 26.24 17.86 4.96 20.51 19.46 4.56 11.69 .14 3.54 79.73 26.42 3.37 25.15 27.06 3.29 44.83 27.98 3.19 26.77 29.38 3.04 10.14 ] is a digital image of Form 1 of Compound 1.

FIGs. 4 and 5 provide TGA/SDTA signal and TGA-MS data, respectively, of Form 1.

The TGA thermogram of Form 1 in does not shows any significant mass loss when heated from 25 °C to 300 °C. The SDTA data of Form 1 in shows a melting event at 268.9 °C, corresponding to the melting point of Form 1 of Compound 1.

The TGA thermogram of Form 1 in comprises a total mass loss of approximately 0.44% of the total mass of the sample between approximately 30 °C and approximately 250 °C when heated from approximately 25 °C to approximately 300 °C. Thus, Form 1 loses about 0.44% of its total mass when heated from about ambient temperature to about 300 °C. These observations suggest that Form 1 is anhydrous crystalline material. provides HPLC and MS data of Form 1. The peak retention time is 4.9 s and indicates the sample purity is 99.90% (area %).

Form 2 The XRPD pattern, crystal habit, TGA, SDTA, TGA-MS, HPLC and MS of Form 2 of Compound 1 are shown in FIGs. 7-11. Form 2 was prepared in slurry conversion experiments when 1,2-ethanediol was used as solvent. Form 2 appears stable under accelerated aging conditions (2 days at 40 °C/75% RH). es an overlay of XRPD patterns (from bottom to top) of: starting al (Form 1 of Compound 1), Form 2 as obtained from slurry conversion experiment in 1,2 ethanediol and Form 2 after exposure to accelerated aging conditions (AAC). A list of X-Ray Diffraction Peaks for Form 2 of Compound 1 is provided below in Table 26.

Table 26. X-Ray Diffraction Peaks for Form 2 of Compound 1 Relative Two-theta angle (°) d Space (Å) Intensity (%) 6.18 14.28 86.62 .02 8.82 17.74 11.54 7.66 28.21 12.34 7.16 49.02 13.86 6.38 19.58 18.54 4.78 32.73 21.74 4.08 71.24 22.5 3.95 35.65 23.42 3.79 47.77 24.54 3.62 30.05 .5 3.49 12.63 26.02 3.42 20.22 26.7 3.33 81.52 27.82 3.2 15.25 28.34 3.15 34.21 Two-theta angle (°) d Space (Å) Intensity (%) 34.14 2.62 16.39 is a digital image of Form 2 of nd 1. is a l image of Form 2 of Compound 1 after exposure to accelerated aging conditions.

FIGs. 9 and 10 provide TGA/SDTA signal and TGA-MS data, respectively, of Form 2 as obtained from a slurry conversion experiment in 1,2-ethanediol.

The TGA thermogram of Form 2 in shows a mass loss corresponding to a broad endothermic event observed in the SDTA signal between 95 and 176 °C with a maximum at about 137 °C, which may be the desolvation of Form 2 of Compound 1. After the desolvation, the SDTA data of Form 2 in shows a melting event at 264 °C, corresponding to the melting point of Form 1 of Compound 1.

The TGA thermogram of Form 2 in comprises a total mass loss of approximately 15.5% of the total mass of the sample between approximately 95 °C and approximately 175 °C when heated from approximately 25 °C to approximately 300 °C. Thus, Form 2 loses about 15.5% of its total mass when heated from about ambient temperature to about 300 °C. The thermal data indicates that Form 2 ns 1 molar equivalent of solvent in the crystal lattice ponding to approximately 1 mole of 1,2-ethanediol per mole of Compound 1. The theoretical 1,2-ethanediol content of a 1,2-ethanediol mono-solvate of nd 1 is .6 % by weight, matching the TGA weight loss observed. These observations suggest that Form 2 is a 1,2-ethanediol mono-solvate of Compound 1. provides HPLC and MS data of Form 2 as obtained from the slurry conversion experiment in 1,2-ethanediol. The peak retention time is 4.8 minutes and indicates the sample purity is 100% (area %). 6.1.2.16 Form 3 The XRPD pattern, crystal habit, TGA, SDTA, TGA-MS, HPLC and MS of Form 3 of Compound 1 are shown in FIGs. 12-16. Form 3 was produced in a variety of crystallization solvents, including: 2,2,2-trifluoroethanol (TFE) ed with either water or cyclohexane, chloroform and the solvent mixture of panol and acetone. Most of the Form 3 samples showed a yellowish color. The samples used for further analyses were prepared in the evaporative experiment in TFE/water (50:50). provides an overlay of XRPD patterns (from bottom to top) of: starting al (Form 1 of Compound 1), Form 3 as obtained from ative experiment in TFE/water (50:50) and Form 3 after exposure to rated aging conditions (AAC: 2 days at 40 °C/75% RH). A list of X-Ray Diffraction Peaks for Form 3 of Compound 1 is provided below in Table 27.

Table 27. X-Ray Diffraction Peaks for Form 3 of Compound 1 Relative Two-theta angle (°) d Space (Å) Intensity (%) 3.5 25.21 29.74 7.06 12.51 16.87 9.26 9.54 79.97 .5 8.42 11.23 12.66 6.98 13.38 .3 5.78 19.31 18.62 4.76 20.63 A is a digital image of Form 3 of Compound 1. B is a digital image of Form 3 of Compound 1 after exposure to accelerated aging conditions.

FIGs. 14 and 15 provide TGA/SDTA signal and TGA-MS data, respectively, of Form 3 as obtained from an evaporative ment in ter (50:50).

The TGA thermogram of Form 3 in shows a mass loss corresponding to a broad endothermic event observed in the SDTA signal between 110 °C and 175 °C with a m at about 149 °C, which may be the desolvation of Form 3. After the desolvation, the SDTA data of Form 3 in shows a melting event at 254 °C, corresponding to the melting point of the starting material, Form 1 of Compound 1. The temperature difference of the melting of the anhydrous Form 1 (Tpeak 264 °C) and after desolvation of Form 3 (Tpeak 254 °C) can be attributed to the partial degradation observed in the HPLC is. The chemical purity of Form 3 sample was determined by HPLC in to be 91.8%.

The TGA gram of Form 3 in comprises a total mass loss of approximately 12.8% of the total mass of the sample between approximately 40 °C and approximately 190 °C when heated from approximately 25 °C to approximately 300 °C. Thus, Form 3 loses about 12.8% of its total mass when heated from about ambient temperature to about 300 °C. The thermal data indicates that Form 3 contains 0.5 molar equivalents of solvent in the l lattice ponding to approximately 0.5 mole of 2,2,2-trifluoroethanol per mole of Compound 1. The theoretical 2,2,2-trifluoroethanol content of a 2,2,2-trifluoroethanol hemi-solvate of Compound 1 is 11.5 % by weight, matching the TGA weight loss observed.

These observations suggest that Form 3 is a 2,2,2-trifluoroethanol hemi-solvate of Compound 1. provides HPLC and MS data of Form 3 as ed from an evaporative experiment in TFE/water (50:50). The peak retention time is 4.8 minutes with a sample purity of 91.8% (area %). 6.1.2.17 Form 4 The XRPD pattern, crystal habit, TGA, SDTA, TGA-MS, HPLC and MS of Form 4 of Compound 1 are shown in FIGs. 17-21. Form 4 was prepared by anti-solvent crystallization with DMSO as solvent and water as anti-solvent. Form 4 is physically unstable and converses to Form 1 or mixtures of Forms 1 and 4 upon exposure to accelerated aging conditions. Most likely after long term ity conditions, full conversion to Form 1 may occur. ] provides an overlay of XRPD patterns (from bottom to top) of: starting material, Form 1 of Compound 1; Form 4 as wet solid ed from an olvent experiment using DMSO as t and water as anti-solvent; Form 4 as dried solid obtained from an antisolvent experiment using DMSO as solvent and water as anti-solvent; Amorphous Form of Compound 1 as wet solid from an anti-solvent experiment using DMSO as solvent and water as anti-solvent after exposure to accelerated aging conditions (AAC: 2 days at 40 °C/75% RH); e of Forms 1 and 4 as dried solid obtained after exposure to accelerated aging conditions (AAC). A list of X-Ray Diffraction Peaks for Form 4 of Compound 1 is provided below in Table 28.

Table 28. X-Ray Diffraction Peaks for Form 4 of Compound 1 Relative Two-theta angle (°) d Space (Å) Intensity (%) 8.22 10.74 12.38 .14 8.71 28.85 .66 8.29 42.92 14.02 6.31 19.57 Relative Two-theta angle (°) d Space (Å) Intensity (%) 18.1 4.9 25.78 .62 4.3 24.43 21.94 4.05 84.94 22.66 3.92 27.92 23.78 3.74 19.31 24.34 3.65 24.73 .42 3.5 18.72 26.26 3.39 29.32 A is a l image of Form 4 of Compound 1 as wet solid obtained from an anti-solvent experiment using DMSO as solvent and water as olvent. B is a l image of Form 4 of Compound 1 as dry solid obtained from an anti-solvent experiment using DMSO as solvent and water as anti-solvent.

FIGs. 19 and 20 provide TGA/SDTA signal and TGA-MS data, respectively, of Form 4 as obtained from an anti-solvent experiment using DMSO as solvent and water as antisolvent.

The TGA thermogram of Form 4 in shows a mass loss corresponding to a broad endothermic event observed in the SDTA signal between 100 and 175 °C with a maximum at about 140 °C, which may be the desolvation of Form 4. After desolvation, the SDTA shows a melting event at 258 °C, corresponding to the melting point of Form 1 of Compound 1. The temperature difference between the melting of the anhydrous Form 1 (Tpeak 264 °C) and the melting after desolvation of Form 4 (Tpeak 258 °C) can be attributed to the partial degradation ed in the HPLC analysis. The chemical purity of Form 4 sample was determined by HPLC in to be 93.6%.

The TGA gram of Form 4 in comprises a total mass loss of approximately 16.4% of the total mass of the sample between approximately 35 °C and approximately 180 °C when heated from approximately 25 °C to approximately 300 °C. Thus, Form 4 loses about 16.4% of its total mass when heated from about ambient ature to about 300 °C. The thermal data indicate that Form 4 contains 0.8 molar equivalents of solvent in the crystal lattice corresponding to imately 0.8 mole of dimethylsulfoxide per mole of nd 1. The theoretical dimethylsulfoxide content of a 0.8 molar equivalent dimethylsulfoxide solvate of Compound 1 is 18.9 % by weight, matching the TGA weight loss observed. These observations suggest that Form 4 is a dimethylsulfoxide solvate of Compound 1. provides HPLC and MS data of Form 4 as obtained from an anti-solvent experiment using DMSO as solvent and water as anti-solvent. The peak retention time is 4.8 minutes with a sample purity of 93.6% (area %). 6.1.2.18 Form 5 The XRPD n, crystal habit, TGA, SDTA, TGA-MS, HPLC and MS of Form of Compound 1 are shown in FIGs. 22-26. Form 5 was prepared in hot-filtration experiments in THF/water (50:50). Form 5 appears stable for at least two days under accelerated aging ions. provides an overlay of XRPD patterns (from bottom to top) of: starting material, Form 1 of nd 1; Form 5 of Compound 1; and Form 5 of Compound 1 after exposure to accelerated aging conditions (AAC: 2 days at 40 °C/75% RH). A list of X-Ray ction Peaks for Form 5 of Compound 1 is provided below in Table 29.

Table 29. X-Ray Diffraction Peaks for Form 5 of Compound 1 Relative Two-theta angle (°) d Space (Å) Intensity (%) 6.02 14.66 13 7.46 11.84 31.65 9.26 9.54 76.44 11.7 7.55 79.47 12.18 7.26 19.72 19.78 4.48 8.74 22.02 4.03 24.68 23.74 3.74 26.68 24.26 3.66 28.87 24.94 3.57 32.55 26.18 3.4 55.24 27.06 3.29 16.87 29.86 2.99 16.03 ] A is a l image of Form 5 of Compound 1. B is a digital image of Form 5 of Compound 1 after exposure to accelerated aging conditions.

FIGs. 24 and 25 e TGA/SDTA signal and TGA-MS data, respectively, of Form 5 obtained from a ltration experiment in THF/water (50:50).

The TGA thermogram of Form 5 in shows a mass loss ponding to a broad endothermic event observed in the SDTA signal at Tpeak 80 °C which is likely related to the ation process, followed by re-crystallization at 181 °C and melting of Form 1 at 251 °C. The large difference of the melting temperature of Form 1 here compared to that of the starting material Form 1 (264 °C) can be attributed to the different history of the two solids.

Note that Form 5 was produced only when water was used in mixture with other solvents, e.g., THF, 1,4-dioxane, ol and ethanol. The slurry experiment in water for two weeks at room temperature produced the anhydrous starting material, Form 1. This observation might be explained by the fact that Form 1 of Compound 1 is practically insoluble in water. Some dissolution of the starting material is needed to produce the dihydrated Form 5, which is provided by the organic solvent (THF, 1,4-dioxane, methanol or ethanol), followed by precipitation of Form 5. The chemical purity of Form 5 sample was determined by HPLC in to be 90.1%.

The TGA thermogram of Form 5 in comprises a total mass loss of approximately 9.4% of the total mass of the sample between approximately 35 °C and approximately 240 °C when heated from approximately 25 °C to approximately 300 °C. Thus, Form 5 loses about 9.4% of its total mass when heated from about ambient temperature to about 300 °C. The thermal data tes that Form 5 contains 2 molar equivalents of solvent in the l e corresponding to approximately 2 moles of water per mole of Compound 1. The theoretical water content of a dihydrate of nd 1 is 10.2 % by weight, matching the TGA weight loss ed. These observations suggest that Form 5 is a dihydrated form of nd 1. provides HPLC and MS data of Form 5 as solid obtained from a hot- filtration experiment in THF/water (50:50). The peak retention time is 4.8 minutes with a sample purity of 89.9% (area %). 6.1.2.19 Amorphous Form The DSC, XRPD pattern, Raman spectrum, NMR, HPLC and MS of amorphous Compound 1 are shown in FIGs. 27-32.

Amorphous Compound 1 was prepared by 1) equilibrating the temperature of a sample of Form 1 at 25 ºC; 2) heating up the sample to 275 ºC at a rate of 10 ºC/min; 3) g the sample isothermally for 5 minutes; 4) cooling the sample to -10 ºC at a rate of 30 ºC/min; 5) heating the sample to 150 ºC at a rate of 10 ºC/min; and 6) collecting remaining solids.

The differential scanning calorimetry thermal analysis of amorphous Compound 1 in shows that the glass transition temperature (Tg) of amorphous Compound 1 is at 120 provides an XRPD pattern of amorphous Compound 1. provides a proton r ic resonance spectrum of amorphous Compound 1. provides HPLC and MS data of amorphous Compound 1.

The DSC thermogram of amorphous Compound 1 in shows a broad endothermic event between 160 and 200 °C with a maximum at about 188.1 °C 6.2 BIOLOGICAL EXAMPLES 6.2.1 Biochemical assays TOR HTR-FRET Assay. The following is an example of an assay that can be used to determine the TOR kinase inhibitory activity of solid forms of Compound 1. A solid form of Compound 1 is dissolved in DMSO and prepared as 10 mM stocks and diluted appropriately for the ments. Reagents are prepared as s: e TOR buffer” (used to dilute high ol TOR fraction): 10 mM Tris pH 7.4, 100 mM NaCl, 0.1% Tween-20, 1 mM DTT. Invitrogen recombinant TOR enzyme (cat# PV4753) is diluted in this buffer to an assay concentration of 0.200 µg/mL.

ATP/Substrate solution: 0.075 mM ATP, 12.5 mM MnCl2, 50 mM Hepes, pH 7.4, 50 mM -GOP, 250 nM Microcystin LR, 0.25 mM EDTA, 5 mM DTT, and 3.5 µg/mL GST- p70S6.

Detection reagent solution: 50 mM HEPES, pH 7.4, 0.01% Triton X-100, 0.01% BSA, 0.1 mM EDTA, 12.7 µg/mL ST Amersham (Cat#PA92002V), 9 ng/mL phospho p70S6 (Thr389) (Cell Signaling Mouse Monoclonal #9206L), 627 ng/mL mouse Lance Eu n Elmer Cat#AD0077).

To 20 uL ofthe Simple TOR buffer is added 0.5 uL of test solid form in DMSO.

To initiate the reaction 5 [IL ofATP/Substrate solution is added to 20 uL of the Simple TOR buffer solution ol) and to the compound solution prepared above. The assay is stopped after 60 minutes by adding 5 uL of a 60 mM EDTA solution: 10 [IL of detection reagent solution is then added and the mixture is allowed to sit for at least 2 hours before reading on a Perkin- Elmer Envision Microplate Reader set to detect LANCE Eu T (excitation at 320 nm and emission at 495/520 nm).

] DNA—PK assay. DNA-PK assay is performed using the procedures supplied in the Promega DNA-PK assay kit (catalog # V7870). DNA-PK enzyme can be purchased from Promega (Promega cat#V58l 1). 6.3 FORMULATION EXAMPLES Certain formulations comprising solid forms of Compound 1 are prepared and tested for a number ofphysical and chemical properties. Modifications are made and subsequent formulations are also tested, until formulations sing desirable physical and chemical properties are found. The following e describes these formulations and their testing.

] M A 23‘1 study evaluates the effect ofdiluents, disintegrant and drug loading on tablet physical properties and chemical stability. Examples of formulation compositions are shown in Table 30. l tablet pment is carried out in normal room UV light.

Table 30: Exemplary Formulation Composition OfVarious Tablet Formulations SondFormorComoundl m Microcrystalline Cellulose (mg) 63.75 83.75 59.25 79.25 _-n-n. _----m 30 30 “-“- “”-- “—Il—Il mumm- Immu- total coatedtabler m M A study is conducted to evaluate the effect of antioxidant (e.g. , ted hydroxyl toluene, BHT) and chelating agent (e.g. , um te, Nag-EDTA) on the stability of solid forms of Compound 1 in formulated t. The impact ofdosage form (tablet vs e) on the stability of solid forms of Compound 1 is evaluated.

Examples of formulation compositions are shown in Table 31. All of the processes are carried out in dark.

Table 31: ary Formulation Composition . % w/w Comound 1 Manno em EZ Sodium starch 1 colate _-toluene _—__ _—————— mum-mm“ M Further study can be conducted to study the influence ofcoating and desiccant on the stability of Compound 1 tablets. All processes can be carried out under yellow light to prevent any UV light exposure to the Compound 1 formulations.

An exemplary formulation composition is provided in Table 32.

Table 32: Exemplary Formulation Composition OfTablet Solid form of Comound 1 0.5 Mannitol (Mannogem MCC PH112 Sodium starch -l colate stearic acid Butylated hydroxy toluene Naz- EDTA Mg stearate Total Table 33: Exemplary Tablet Formulations % w/w m_ Batch # .- In a ts _ Solid form ofCompound 1 active in edient Mannitol anno - em EZ “ a n“ Microcrystalline Cellulose - PH 112 25 25 Sodium Starch G1 colate 3 Silicon dioxide — Stearic acid 0.5 Disodium EDTA _ wH'-l Ma 2 esium Stearate 065 0.65 O ChKI! O 0‘LII Total Color Yellow Yellow Yellow Preparation of Tablets: The blends according to Table 34 to Table 39 are prepared as follows. rystalline cellulose is weighed and added to an amber colored straight sided glass jar. The lid is closed and the jar is shakend in order to coate the inside of the jar. Active ingredient (solid form of Comp01md 1) is added and blended for 10 minutes at 46 1pm using a a mixer. The blend is passed through a 25 mesh screen and blended again for 10 minutes at 46 1pm using a a mixer. The resulting blend is passed through a 35 mesh screen.

Remaining excipients are added. except for lubricant (magnesium te). The resulting mixture is blended for 10 minutes at 46 rpm using a Turbula mixer. 6 grams of the resulting blend is added an amber glass jar. Lubricant is added and blended for 1 minute and 35 seconds at 46 rpm using a Turbula mixer. For low strength tablet ations, 140 mg s are prepared using a 7.14 mm punch and die. For high strength tablet formulations, 400 mg tablets are prepared using a 10.3 mm punch and die.

Table 34: Exemplary Low Strength Tablet Formulation #1 ient Source Amount (weight %) Solid form of 0.7 Compound 1 microcrystalline FMC 38.1 cellulose Biopolymer Mannitol te 57.2 sodium FMC 3.0 carboxymethylcellulose Biopolymer magnesium stearate Nitika 1.0 Chemicals Table 35: Exemplary Low Strength Tablet Formulation #2 Ingredient Source Amount (weight %) Solid form of 0.7 Compound 1 microcrystalline FMC 75.3 cellulose ymer pregelatinized starch Colorcon 20.0 sodium FMC 3.0 carboxymethylcellulose Biopolymer magnesium stearate Nitika 1.0 Chemicals Table 36: Exemplary Low Strength Tablet Formulation #3 Ingredient Source Amount (weight %) Solid form of 0.7 Compound 1 microcrystalline FMC 38.1 cellulose Biopolymer Lactose monohydrate Meggle 57.2 Pharma sodium FMC 3.0 carboxymethylcellulose Biopolymer magnesium stearate Nitika 1.0 Chemicals Table 37: Exemplary High Strength Tablet Formulation #1 Ingredient Source Amount (weight %) Solid form of 25.0 Compound 1 microcrystalline FMC 28.4 cellulose Biopolymer ol Roquette 42.6 sodium FMC 3.0 carboxymethylcellulose Biopolymer magnesium stearate Nitika 1.0 Chemicals ] Table 38: Exemplary High Strength Tablet Formulation #2 Ingredient Source Amount (weight %) Solid form of 25.0 Compound 1 microcrystalline FMC 51.0 cellulose Biopolymer pregelatinized starch Colorcon 20.0 sodium FMC 3.0 ymethylcellulose Biopolymer magnesium stearate Nitika 1.0 Chemicals Table 39: Exemplary High Strength Tablet Formulation #3 Ingredient Source Amount (weight %) Solid form of 25.0 nd 1 rystalline FMC 28.4 cellulose Biopolymer Lactose monohydrate Meggle 42.6 Pharma sodium FMC 3.0 carboxymethylcellulose Biopolymer magnesium te Nitika 1.0 Chemicals The above formulations are subjected to a 6 week stability study.

The embodiments disclosed herein are not to be d in scope by the specific embodiments disclosed in the examples which are ed 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 sed 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.

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

Claims (44)

What we claim is:

1. A l form comprising the compound of formula (I), or a tautomer thereof: </ \N N / H I K N \ N\ N O I I T N N which has an X-ray powder diffraction n comprising peaks at 6.18, 21.74 and 26.7 i0.2 °26.

2. The crystal form of claim 1 which has an X-ray powder diffraction pattern further comprising peaks at 12.34, 22.5 and 23.42 i0.2 °26.

3. The crystal form of claim 1 which has a thermogravimetric analysis thermogram comprising a total mass loss of approximately 15.5% 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 single differential thermal analysis thermogram comprising an endotherm between about 90 °C and about 185 °C with a maximum at approximately 140 °C when heated from about 25 °C to about 300 °C.

5. The crystal form of claim 4 wherein the single differential thermal analysis thermogram further comprises an endotherm between about 240 °C and about 285 °C with a maximum at approximately 264 °C.

6. The crystal form of claim 1 which is 1,2-ethanediol ed.

7. The crystal form of claim 6 comprises 1 molar equivalent of 1,2-ethanediol.

8. The crystal form of claim 1 which is ntially pure.

9. A crystal form comprising the compound of a (I), or a tautomer thereof: (MNN‘ N / I-IN|\ NNKO 'IT\ which has an X-ray powder diffraction pattern comprising peaks at 3.5, 9.26 and 18.62 i0.2 °26.

10. The crystal form of claim 9 which has an X-ray powder diffraction pattern further comprising peaks at 7.06, 12.66 and 15.3 i0.2 °26.

11. The crystal form of claim 9 which has a thermogravimetric analysis thermogram comprising a total mass loss of approximately 12.8% of the total mass of the crystal form when heated from about 25 °C to about 300 °C.

12. The crystal form of claim 9 which has a single difi‘erential l analysis thermogram comprising an endotherm between about 110 °C and about 175 °C with a maximum at imately 160 °C when heated from about 25 °C to about 300 °C.

13. The l form of claim 12 wherein the single differential thermal analysis thermogram further comprises an endotherm between about 225 °C and about 275 °C with a maximum at approximately 254 °C.

14. The crystal form of claim 9 which is 2,2,2-tn'fluoroethanol solvated.

15. The crystal form of claim 14 comprises 0.5 molar lents of t1ifluoroethanol.

16. The crystal form of claim 9 which is substantially pure.

17. A crystal form comprising the compound of formula 0), or a tautomer thereof: (MNN‘ N / I-IN|\ NNKO 'IT\ which has an X-ray powder diffraction n comprising peaks at 10.66, 21.94 and 26.26 i0.2 °26.

18. The crystal form of claim 17 which has an X-ray powder diffraction pattern further comprising peaks at 10.14, 18.1 and 22.66 i0.2 °20.

19. The crystal form of claim 17 which has a thermogravimetric analysis thermogram comprising a total mass loss of approximately 16.4% of the total mass of the crystal form when heated from about 25 °C to about 300 °C.

20. The crystal form of claim 17 which has a single difi'erential thermal analysis thermogram comprising an endotherm between about 100 °C and about 175 °C with a maximum at approximately 140 °C when heated from about 25 °C to about 300 °C.

21. The crystal form of claim 20 wherein the single ential l analysis thermogram further comprises an endotherm n about 235 °C and about 275 °C with a maximum at approximately 258 °C.

22. The crystal form of claim 17 which is dimethylsulfoxide solvated.

23. The crystal form of claim 22 comprises 0.8 molar equivalents of dimethylsulfoxide.

24. The crystal form of claim 17 which is ntially pure.

25. A crystal form comprising the compound of formula (I), or a tautomer thereof: (MNN~ N / H NI\ N NKO N N which has an X-ray powder ction pattern comprising peaks at 9.26, 11.7 and 26.18 ±0.2 °2θ.

26. The crystal form of claim 25 which has an X-ray powder diffraction pattern further comprising peaks at approximately 7.46, 24.26 and 24.94 °2θ.

27. The crystal form of claim 25 which has a thermogravimetric analysis thermogram comprising a total mass loss of approximately 9.4% of the total mass of the crystal form when heated from about 25 °C to about 300 °C.

28. The crystal form of claim 25 which has a single differential thermal analysis thermogram comprising an endotherm between about 50 °C and about 140 °C with a maximum at approximately 80 °C when heated from about 25 °C to about 300 °C.

29. The crystal form of claim 28 wherein the single differential thermal is thermogram r comprises an exotherm n about 160 °C and about 200 °C with a m at approximately 181 °C.

30. The crystal form of claim 29 wherein the single differential thermal analysis thermogram further comprises an erm between about 225 °C and about 275 °C with a maximum at approximately 251 °C.

31. The crystal form of claim 25 which is hydrated.

32. The crystal form of claim 31 comprises 2 molar equivalents of water.

33. The crystal form of claim 25 which is substantially pure.

34. The use of a crystal form according to any one of claims 1 to 33, in the manufacture of a medicament for treating or preventing , an inflammatory condition, an immunological condition, a neurodegenerative disease, diabete, obesity, a neurological disorder, an age-related disease, a cardiovascular condition, or a conditions treatable or preventable by inhibition of a kinase pathway, a t in need thereof.

35. The use of claim 34, wherein the kinase pathway is the TOR kinase pathway.

36. The use of a crystal form according to any one of claims 1 to 33, in the manufacture of a medicament for achieving a se Evaluation Criteria in Solid Tumors (RECIST 1.1) of te response, partial response or stable disease in a subject having a solid tumor.

37. The use of a crystal form according to any one of claims 1 to 33, in the manufacture of a medicament for improving International Workshop Criteria (IWC) for NHL, International Uniform Response Criteria for Multiple Myeloma (IURC), Eastern Cooperative Oncology Group Performance Status (ECOG) or Response Assessment for Oncology (RANO) Working Group for GBM.

38. A crystal form according to claim 1, substantially as herein described or exemplified.

39. A crystal form ing to claim 9, substantially as herein described or exemplified.

40. A crystal form according to claim 17, ntially as herein described or exemplified.

41. A crystal form according to claim 25, substantially as herein described or exemplified.

42. A use according to claim 34, substantially as herein described or exemplified.

43. A use according to claim 36, substantially as herein described or exemplified.

44. A use according to claim 37, ntially as herein described or exemplified.