NZ629866B - SOLID FORMS COMPRISING 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, AND A COFORMER, COMPOSITIONS AND METHODS OF USE THEREOF - Google Patents

Abstract

Disclosed is the compound 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 (formula (I)). Also disclosed are solid forms with coformers, in particular benzoic acid, fumaic acid, gentisic acid, nicotinamide, succinic acid or mandelic acid. Further disclosed are crystal forms with x-ray powder diffraction peaks (XRPD) listed in the specification. The compounds are useful mTOR inhibitors Further disclosed are crystal forms with x-ray powder diffraction peaks (XRPD) listed in the specification. The compounds are useful mTOR inhibitors

Description

Patents Form No. 5 N.Z. No. 629866 NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION SOLID FORMS COMPRISING 1-ETHYL(2-METHYL(1H-1,2,4-TRIAZOL YL)PYRIDINYL)-3,4-DIHYDROPYRAZINO[2,3-b]PYRAZIN-2(1H)-ONE, AND A COFORMER, COMPOSITIONS AND S OF USE THEREOF We, Signal Pharmaceuticals, LLC a company of the United States of America of 10300 Campus Point Drive, Suite 100. San Diego, CA 92121, UNITED STATES OF AMERICA 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 COMPRISING 1-ETHYL(2-METHYL(1H-1,2,4-TRIAZOL YL)PYRIDINYL)-3,4-DIHYDROPYRAZINO[2,3-b]PYRAZIN-2(1H)-ONE, AND A COFORMER, ITIONS AND METHODS OF USE THEREOF 1. FIELD Provided herein are solid forms sing 1-ethyl(2-methyl(1H-1,2,4- triazolyl)pyridinyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one and a coformer.

Pharmaceutical compositions comprising such solid forms (e.g., cocrystals) and s of use for treating, preventing, and managing various disorders are also provided herein. 2. BACKGROUND The identification and selection of a solid form of a pharmaceutical compound is complex, given that a change in a solid form may affect a variety of physical and chemical properties, which may provide benefits or drawbacks in sing, formulation, stability and ilability, among other important pharmaceutical characteristics. Potential pharmaceutical solids include crystalline solids and ous solids. Amorphous solids are characterized by a lack of ange structural order, whereas crystalline solids are characterized by structural periodicity. The desired class of pharmaceutical solid depends upon the specific application; amorphous solids are sometimes selected on the basis of, e.g., an enhanced dissolution profile, while crystalline solids may be desirable for properties such as, e.g., physical or chemical stability (see, e.g., S. R. Vippagunta et al., Adv. Drug. Deliv.

Rev., (2001) 48:3-26; L. Yu, Adv. Drug. Deliv. Rev., (2001) 48:27-42).

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 nd in the e of other compounds. Variety among single-component lline materials may potentially arise from the phenomenon of polymorphism, wherein multiple dimensional arrangements exist for a particular pharmaceutical compound (see, e.g., S. R. Byrn et al., Solid State Chemistry of Drugs, (1999) SSCI, West Lafayette). The importance of discovering polymorphs was underscored by the case of Ritonavir, an HIV protease inhibitor that was formulated as soft gelatin capsules. About two years after the t was launched, the unanticipated itation of a new, less soluble polymorph in the formulation necessitated the withdrawal of the product from the market until a more tent formulation could be developed (see S. R. Chemburkar et al., Org. Process Res. Dev., (2000) 4:413-417).

Additional diversity among the potential solid forms of a ceutical compound may arise from the possibility of multiple-component . lline solids sing 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, im). Additional types of multiple-component solids that may ially offer other property improvements for a pharmaceutical nd or salt thereof include, e.g., hydrates, solvates, cocrystals 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 rphism, wherein 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, effective, stable and marketable ceutical compound.

Notably, it is not possible to predict a priori if crystalline forms of a compound even exist, let alone how to successfully prepare them (see, e.g., Braga and Grepioni, 2005, “Making crystals from crystals: a green route to crystal engineering and polymorphism,” Chem. Commun.:3635-3645 (with respect to crystal ering, if instructions are not very precise and/or if other external factors affect the process, the result can be unpredictable); Jones et al., 2006, Pharmaceutical Cocrystals: An Emerging Approach to al Property Enhancement,” MRS Bulletin 31:875-879 (At present it is not generally possible to computationally predict the number of observable polymorphs of even the simplest molecules); Price, 2004, “The ational prediction of pharmaceutical crystal structures and polymorphism,” Advanced Drug Delivery Reviews 56:301-319 (“Price”); and Bernstein, 2004, “Crystal Structure Prediction and Polymorphism,” ACA Transactions 39:14- 23 (a great deal still needs to be learned and done before one can state with any degree of confidence the ability to predict a crystal structure, much less polymorphic forms)).

Cocrystals are crystalline molecular complexes of two or more non-volatile compounds bound together in a crystal lattice by non-ionic interactions. Pharmaceutical cocrystals are tals of a therapeutic compound, e.g., an active pharmaceutical ingredient (API), and one or more non-volatile compound(s) (referred to herein as coformer). A coformer in a pharmaceutical cocrystal is typically ed from non-toxic pharmaceutically acceptable molecules, such as, for example, food additives, preservatives, pharmaceutical excipients, or other APIs. In recent years, pharmaceutical cocrystals have emerged as a possible alternative approach to enhance physicochemical properties of drug products. The variety ofpossible solid forms creates potential diversity in physical and chemical properties for a given ceutical nd.

The compound chemically named 1-ethyl(2-methyl(lH-1,2,4-t1iazol yl)pyridin—3-yl)-3,4—dihydropyrazino[2,3—b]pyrazin—2(lH)—one and tautomers thereof (collectively referred to herein as “Compound 1”) are sed in US. Pat. No. 8,110,578, issued on February 7, 2012, and International Pub. No. , the entireties of each ofwhich are orated by reference herein.

Citation or identification of any reference in Section 2 of this application is not to be construed as an admission that the nce is prior art to the present application. 3. SUMNIARY Provided herein are solid forms (e.g., cocrystal forms or mixtures thereof) comprising Compound 1: having the name l-ethyl(2-methyl(1H-l,2,4-t1iazolyl)py1idinyl)— 3,4-dihydropyrazino[2,3-b]pyrazin—2(lH)-one, including tautomers thereof, and a coformer.

Also provided are s ofpreparing, isolating, and characterizing the solid forms.

Also provided herein are pharmaceutical compositions and single unit dosage forms, which se one or more solid forms provided herein.

In n embodiments, solid forms of Compound 1 are useful for treating or preventing cancer and conditions treatable or preventable by tion of a kinase pathway, for example, the mTOR/PI3IQAkt pathway.

The present embodiments can be understood more fully by reference to the detailed description and examples, which are intended to exemplify non-limiting embodiments. 4. BRIEF DESCRIPTION OF THE DRAWINGS depicts an X-ray powder diffractogram stack plot of Compound 1, Form 1 and benzoic acid (from bottom to top). depicts a gravimetric analysis coupled with mass oscopy of Form 1. depicts a thermogravimetrical analysis and single differential thermal is of Form 1. depicts high performance liquid tography coupled with mass spectrometry of Form 1. depicts a fourier transform infrared spectroscopy (FTIR) overlay of Compound 1, Form 1 and benzoic acid. depicts a FTIR overlay of Compound 1, Form 1 and benzoic acid in the region of 1800-400 cm-1. depicts an X-ray powder diffractogram stack plot of Compound 1, Form 2, Form 3 and c acid. depicts a thermogravimetric analysis coupled with mass spectroscopy of Form 2. depicts a thermogravimetrical analysis and single ential l analysis of Form 2. depicts high performance liquid chromatography coupled with mass spectrometry of Form 2. depicts a FTIR overlay of Compound 1, Form 2 and benzoic acid. s a FTIR overlay of Compound 1, Form 2 and benzoic acid in the region of 1800-400 cm-1. depicts a thermogravimetric analysis coupled with mass spectroscopy of Form 3. depicts a thermogravimetrical analysis and single differential thermal analysis of Form 3. depicts high performance liquid chromatography coupled with mass spectrometry of Form 3. depicts a FTIR overlay of Compound 1, Form 3 and benzoic acid. depicts a FTIR overlay of Compound 1, Form 3 and benzoic acid in the region of 1800-400 cm-1. depicts an X-ray powder diffractogram stack plot of Compound 1, Form 4, Form 5 and gentisic acid. depicts a thermogravimetric analysis coupled with mass spectroscopy of Form 4. depicts a thermogravimetrical is and single differential thermal analysis of Form 4. s high performance liquid chromatography coupled with mass spectrometry of Form 4. depicts a FTIR y of Compound 1, Form 4 and gentisic acid. depicts a FTIR overlay of Compound 1, Form 4 and gentisic acid in the region of 1800-400 cm-1. depicts a thermogravimetric analysis coupled with mass spectroscopy of Form 5. depicts a thermogravimetrical analysis and single differential thermal analysis of Form 5. depicts high mance liquid tography coupled with mass spectrometry of Form 5. depicts a FTIR overlay of Compound 1, Form 5 and gentisic acid. depicts a FTIR overlay of Compound 1, Form 5 and gentisic acid in the region of 1800-400 cm-1. depicts an X-ray powder diffractogram stack plot of Compound 1, Form 6 and nicotinamide. depicts a thermogravimetric analysis coupled with mass oscopy of Form 6. depicts a thermogravimetrical is and single differential thermal analysis of Form 6. depicts high performance liquid chromatography coupled with mass ometry of Form 6. depicts a fourier transform infrared spectroscopy (FTIR) overlay of Compound 1, Form 6 and nicotinamide. depicts a FTIR overlay of Compound 1, Form 6 and nicotinamide in the region of 1800-400 cm-1. depicts an X-ray powder diffractogram stack plot of Compound 1, Form 7 and succinic acid. depicts a thermogravimetric analysis coupled with mass spectroscopy of Form 7. depicts a thermogravimetrical analysis and single differential thermal analysis of Form 7. depicts high performance liquid chromatography coupled with mass spectrometry of Form 7. depicts a fourier transform infrared spectroscopy (FTIR) y of Compound 1, Form 7 and succinic acid. s a FTIR overlay of Compound 1, Form 7 and ic acid in the region of 1800-400 cm-1. depicts an X-ray powder diffractogram stack plot of Compound 1, Form 8 and maleic acid. depicts a thermogravimetric analysis coupled with mass oscopy of Form 8. depicts a thermogravimetrical analysis and single differential thermal analysis of Form 8. depicts high mance liquid tography coupled with mass spectrometry of Form 8. depicts a fourier transform infrared spectroscopy (FTIR) overlay of Compound 1, Form 8 and maleic acid. depicts a FTIR y of Compound 1, Form 8 and maleic acid in the region of 1800-400 cm-1.

. ED DESCRIPTION .1 DEFINITIONS As used herein, and in the specification and the accompanying claims, the nite articles “a” and “an” and the definite article “the” include plural as well as single referents, unless the context clearly indicates otherwise.

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

As used herein, and unless otherwise specified, the terms “about” and “approximately,” when used in connection with a numeric value or range of values which is provided to characterize a particular solid form, e.g., a ic temperature or temperature range, such as, for example, that bes a g, ation, desolvation, or glass transition temperature; a mass change, such as, for example, a mass change as a function of temperature or humidity; a solvent or water content, in terms of, for example, mass or a percentage; or a peak position, such as, for example, in analysis by, for example, IR or Raman spectroscopy or XRPD; indicate that the value or range of values may deviate to an extent deemed reasonable to one of ordinary skill in the art while still describing the solid form. Techniques for characterizing crystal forms and amorphous forms include, but are not limited to, thermal etric analysis (TGA), differential scanning calorimetry (DSC), X- ray powder ctometry (XRPD), single-crystal X-ray diffractometry, vibrational spectroscopy, e.g., infrared (IR) and Raman spectroscopy, solid-state and solution nuclear ic resonance (NMR) spectroscopy, optical microscopy, hot stage l microscopy, scanning electron copy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies, and ution studies.

In certain embodiments, the terms “about” and “approximately,” when used in this t, indicate that the numeric value or range of values may vary within 30%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the recited value or range of values. For example, in some embodiments, the value of an XRPD peak position may vary by up to ±0.2 degrees two theta while still describing the particular XRPD peak.

As used herein, and unless otherwise specified, a crystalline that is “pure,” i.e., substantially free of other crystalline or amorphous forms, contains less than about 10% by weight of one or more other crystalline or amorphous forms, less than about 5% by weight of one or more other crystalline or amorphous forms, less than about 3% by weight of one or more other crystalline or amorphous forms, or less than about 1% by weight of one or more other crystalline or amorphous forms.

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

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

As used herein, and unless otherwise ted, a chemical compound, solid form, or composition that is “substantially free” of another chemical compound, solid form, or composition means that the nd, solid form, or composition contains, in certain ments, less than about 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2% 0.1%, 0.05%, or 0.01% by weight of the other compound, solid form, or composition.

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

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

Unless otherwise specified, the term “composition” as used herein is intended to ass a product sing the ied ingredient(s) (and in the specified (s), if ted), as well as any product which results, directly or indirectly, from combination of the specified ingredient(s) in the specified amount(s). By “pharmaceutically acceptable,” it is meant a diluent, excipient, or carrier in a formulation must be ible with the other ingredient(s) of the formulation and not rious to the recipient thereof.

The term “solid form” refers to a physical form which is not predominantly in a liquid or a gaseous state. As used herein and unless otherwise specified, the term “solid form,” when used herein to refer to Compound 1, refers to a physical form sing Compound 1 which is not predominantly in a liquid or a gaseous state. A solid form may be a crystalline form or a mixture thereof. In certain embodiments, a solid form may be a liquid crystal. In certain embodiments, the term “solid forms comprising Compound 1” includes l forms comprising Compound 1. In certain embodiments, the solid form of nd 1 is Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7 and Form 8 or a mixture thereof.

As used herein and unless otherwise ied, the term “crystalline” when used to describe a compound, substance, modification, material, component or product, unless otherwise specified, means that the compound, substance, modification, material, ent or product is substantially crystalline as determined by X-ray diffraction. See, e.g., Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams and Wilkins, Baltimore, MD (2005); The United States Pharmacopeia, 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 include salts. In certain embodiments, a l form of a substance may be substantially free of amorphous forms and/or other crystal forms. In certain embodiments, a l 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 l form of a substance may be physically and/or chemically pure. In certain embodiments, a crystal form of a substance may be about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, or about 90% physically and/or chemically pure.

Unless otherwise specified, the terms “polymorph,” “polymorphic form,” “polymorphs,” “polymorphic forms,” and related terms herein refer to two or more crystal forms that consist ially of the same molecule, molecules or ions. ent polymorphs may have different physical properties, such as, for example, melting atures, heats of fusion, solubilities, ution rates, and/or vibrational spectra as a result of a different ement or conformation of the molecules or ions in the crystal lattice. The differences in physical properties exhibited by rphs may affect pharmaceutical parameters, such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rate (an important factor in bioavailability). Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical changes (e.g., tablets crumble on storage as a cally favored polymorph converts to thermodynamically a more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity). As a result of solubility/dissolution differences, in the extreme case, some polymorphic tions may result in lack of potency or, at the other extreme, toxicity. In on, the physical ties of the crystal may be important in processing; for example, one polymorph might be more likely to form solvates or might be difficult to filter and wash free of impurities (e.g., particle shape and size distribution might be different between polymorphs).

Unless ise specified, the term stal” as used herein, refers to a crystalline material sed of Compound 1, including tautomers thereof, and one or more non-volative compounds bound together in a crystal e by non-covalent interactions.

Unless otherwise specified, the term “amorphous” or “amorphous form” means that the substance, component, or product in question is not substantially crystalline as determined by X-ray diffraction. In particular, the term “amorphous form” describes a disordered solid form, i.e., a solid form lacking long range crystalline order. In certain embodiments, an amorphous form of a substance may be substantially free of other ous 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 %, 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 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 er, or symptoms associated with the disease or disorder.

“Preventing” as used herein, means prevention of the onset, recurrence, or spread of the disease or disorder, or symptoms associated with the disorder or disease, in a patient at risk for developing the disease or disorder.

The term “effective amount” in connection with a solid form of Compound 1 means, in one embodiment, an amount capable of alleviating, in whole or in part, symptoms ated with a disorder or disease, or slowing or halting further progression or worsening of those symptoms, or, in another embodiment, an amount capable of preventing or providing prophylaxis for the disease or disorder in a subject at risk for ping the disease or disorder as disclosed herein, such as cancer. In one embodiment, an ive amount of a solid form 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 ation thereof. In some embodiments, the effective amount of a solid form of Compound 1 inhibits the kinase in a cell by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 99%, compared to the activity of the kinase in an untreated cell. The effective amount of a solid form of Compound 1, for example in a pharmaceutical composition, may be at a level that will exercise the desired effect; for example, about 0.005 mg/kg of a subject’s body weight to about 100 mg/kg of a patient’s body weight in unit dosage for 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 a solid form of Compound 1 disclosed herein may vary depending on the indication being d, e.g., the effective amount of a solid form of Compound 1 would likely be different for ng patients suffering from, or at risk for, inflammatory ions relative to the effective amount of a solid form of Compound 1 for treating patients suffering from, or at risk of, a ent disorder, e.g., cancer or a metabolic disorder.

“Patient” or “subject” is defined herein to e animals, such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, monkeys, chickens, turkeys, quails, or guinea pigs and the like. In specific ments, the patient or subject is a human.

The term “cancer” refers to any of various ant neoplasms characterized by the proliferation of cells that can invade surrounding tissue and metastasize to new body sites. Both benign and malignant tumors are fied according to the type of tissue in which they are found. For example, fibromas are neoplasms of fibrous connective tissue, and melanomas are abnormal growths of pigment (melanin) cells. Malignant tumors originating from epithelial tissue, e.g., in skin, bronchi, and stomach, are termed carcinomas.

Malignancies of epithelial glandular tissue such as are found in the breast, prostate, and colon, are known as adenocarcinomas. Malignant growths of connective tissue, e.g., muscle, cartilage, lymph tissue, and bone, are called sarcomas. Lymphomas and leukemias are ancies arising among white blood cells. h the process of metastasis, tumor cell migration to other areas of the body establishes neoplasms in areas away from the site of l appearance. Bone tissues are one of the most d sites of metastases of malignant tumors, occurring in about 30% of all cancer cases. Among malignant tumors, cancers of the lung, breast, prostate or the like are particularly known to be likely to metastasize to bone.

In the context of sm, cancer, tumor growth or tumor cell growth, inhibition may be assessed by d appearance of primary or secondary tumors, slowed development of y or secondary tumors, decreased occurrence of primary or secondary tumors, slowed or decreased severity of secondary effects of disease, arrested tumor growth and regression of tumors, among others. In the extreme, complete inhibition, is referred to herein as prevention or chemoprevention. In this context, the term ntion” includes either preventing the onset of clinically evident neoplasia altogether or preventing the onset of a preclinically t stage of neoplasia in individuals at risk. Also intended to be encompassed by this definition is the prevention of transformation into malignant cells or to arrest or reverse the progression of premalignant cells to malignant cells. This includes prophylactic treatment of those at risk of developing the neoplasia.

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

Oncol: 2007: (25) 579-586), using the se and endpoint definitions shown below: Response tion Nodal Masses Spleen, liver Bone Marrow CR Disappearance (a) FDG-avid or PET Not Infiltrate cleared of all evidence 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 immunohistochemi PET negative; regression stry to normal size on CT should be negative PR Regression of ≥50% se 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 s (for should be specified (a) FDG-avid 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) FDG-avid or PET attain CR/PR positive prior to therapy; or PD PET positive at prior sites of disease and no new sites on CT or PET (b) ly FDG-avid or PET negative; 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 se 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 er 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 ion; FDG, [18F]fluorodeoxyglucose; PET, positron emission tomography; CT, computed tomography; PR, l remission; SPD, sum of the product of the diameters; SD, stable disease; PD, progressive e.

End point Patients Definition Measured from Primary l survival All Death as a result of any cause Entry onto study Progression-free All Disease ssion or death as a result of survival any cause Entry onto study Secondary Event-free survival All Failure of treatment or death as result of any Entry onto cause study Time to All Time to progression or death as a result of Entry onto progression lymphoma study Disease-free In CR Time to relapse or death as a result of Documentation survival lymphoma or acute toxicity of treatment of se Response duration In CR Time to relapse or progression Documentation or PR of response Lymphoma- All Time to death as a result of lymphoma Entry onto specific survival study 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 t symptoms, transfusion requirements, frequent infections, or other parameters. Time to reappearance or progression of lymphoma-related symptoms can also be used in this end point.

In certain embodiments, the ent of CLL may be assessed by the International Workshop Guidelines for CLL (see Hallek M, Cheson BD, Catovsky D, et al.

Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood, 2008; (111) 12: 5446-5456) using the response and endpoint tions shown therein and in particular: Parameter CR PR PD Group A Lymphadenopathy† None > 1.5 cm Decrease ≥ 50% Increase ≥ 50% Hepatomegaly None Decrease ≥ 50% Increase ≥ 50% Splenomegaly None Decrease ≥ 50% Increase ≥ 50% se ≥ 50% Increase ≥ 50% Blood lymphocytes < 4000/μL from baseline over ne Normocellular, < 30% lymphocytes, no B- 50% reduction in Marrow‡ lymphoid nodules. marrow infiltrate, or Hypocellular marrow B-lymphoid nodules defines CRi ).

Group B > 100 000/μL or se of ≥ 50% et count > 100 000/μL from baseline secondary to CLL increase ≥ 50% over baseline > 11 g/dL or Decrease of > 2 Hemoglobin > 11.0 g/dL se ≥ 50% over g/dL from baseline baseline secondary to CLL > 1500/μL or > 50% Neutrophils‡ > 1500/μL improvement over Group A criteria define the tumor load; Group B criteria define the function of the hematopoietic system (or marrow). CR (complete remission): all of the criteria have to be met, and patients have to lack disease-related constitutional ms; 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 ted by CT scans in clinical trials, or by physical examination in general practice). These parameters are vant for some se categories.

In certain embodiments, the treatment of multiple myeloma may be assessed by the International Uniform Response ia for Multiple Myeloma (IURC) (see Durie BGM, seau J-L, Miguel JS, et al. International uniform se criteria for multiple a. Leukemia, 2006; (10) 10: 1-7), using the response and endpoint definitions 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 fluorescencec CR Negative immunofixation on the serum and urine and Disappearance of any soft tissue cytomas and <5% plasma cells in bone marrowb VGPR Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level <100mg per 24 h PR ≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein by≥90% or to <200mg per 24 h If the serum and urine M-protein are unmeasurable,d a ≥50% decrease in the difference between involved and uninvolved FLC levels is required in place of the M- protein criteria If serum and urine M-protein are unmeasurable, and serum free light assay is also unmeasurable, ≥50% ion in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was ≥30% In addition to the above listed ia, if present at baseline, a ≥50% reduction in the size of soft tissue plasmacytomas is also required SD (not recommended for use as Not meeting criteria for CR, VGPR, PR or progressive an indicator of response; stability e of 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 response categories require two consecutive assessments made at anytime before the institution of any new therapy; all categories also require no known evidence of progressive or new bone s if radiographic studies were performed. Radiographic studies are not required to satisfy these response ements; 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 gm/l)[10 g/l]; Urine M-protein ≥200 mg/24 h; Serum FLC assay: Involved 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 Evaluation Criteria in Solid Tumors (RECIST 1.1) (see Thereasse P., et al. New Guidelines to Evaluate the Response to Treatment in Solid Tumors. J. of the National Cancer Institute; 2000; (92) 205-216 and Eisenhauer E.A., Therasse P., Bogaerts J., et al. New response evaluation ia 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 s with our without the appearance of new lesions are as s: Target s Non-target lesions New s 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 = l se; 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 se (PR) is at least a 30% se in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter, progressive disease (PD) is at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions and stable disease (SD) is neither sufficient shrinkage to qualify for l response nor sufficient increase to qualify for progressive e, taking as reference the smallest sum longest diameter since the treatment started.

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

The procedures, conventions, and definitions described below provide guidance for implementing the recommendations from the Response Assessment for Neuro- Oncology (RANO) Working Group regarding response criteria for high-grade gliomas (Wen P., Macdonald, DR., Reardon, DA., et al. d response assessment criteria for highgrade gliomas: se assessment in oncology working group. J Clin Oncol 2010; 28: 1963-1972). Primary modifications to the RANO criteria for Criteria for Time Point Responses (TPR) can include the addition of operational conventions for defining changes in glucocorticoid dose, and the l of subjects’ clinical deterioration component to focus on objective radiologic assessments. The ne MRI scan is defined as the assessment performed at the end of the post-surgery rest period, prior to re-initiating compound treatment. The baseline MRI is used as the reference for assessing complete response (CR) and partial response (PR). Whereas, the smallest SPD (sum of the products of perpendicular diameters) obtained either at baseline or at subsequent assessments will be designated the nadir assessment and ed as the reference for determining progression.

For the 5 days preceding any protocol-defined MRI scan, ts 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 bed above. The following definitions will be used.

Measurable Lesions: able s 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 measurable lesion is set as 5 mm by 5 mm. Larger diameters may be required for inclusion and/or designation as target lesions. After baseline, target lesions that become smaller than the m requirement for measurement or become no longer amenable to bidimensional measurement will be recorded at the default value of 5 mm for each diameter below 5 mm. Lesions that disappear will be recorded as 0 mm by 0 mm.

Multicentric Lesions: Lesions that are ered multicentric (as opposed to continuous) are lesions where there is normal intervening brain tissue between the two (or more) s. For multicentric s that are te 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 measurable disease as defined above will be considered non-measurable lesions, as well as all nonenhancing and other truly nonmeasurable lesions. surable lesions include foci of enhancement that are less than the ied st diameter (ie., less than 5 mm by 5 mm), nonenhancing lesions (eg., as seen on T1-weighted post-contrast, T2-weighted, or fluidattenuated inversion recovery (FLAIR) images), hemorrhagic or predominantly cystic or necrotic s, and eningeal tumor. Hemorrhagic lesions often have intrinsic T1-weighted hyperintensity that could be misinterpreted as ing tumor, and for this , the pre-contrast ghted image may be examined to exclude baseline or interval ute hemorrhage.

At baseline, lesions will be classified as follows: Target lesions: Up to measurable lesions can be selected as target s 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 lesions are to be measured as described in the definition for measurable lesions and the SPD of all target lesions is to be determined. The presence of all other lesions is to be documented. At all post-treatment evaluations, the baseline classification of lesions as target and non-target lesions will be maintained and lesions will be documented and described in a consistent fashion over time (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 tion, target lesions will be measured and the SPD calculated. Non-target lesions will be assessed qualitatively and new lesions, if any, will be documented separately.

At each evaluation, a time point response will be determined for target lesions, non-target lesions, and new . Tumor progression can be established even if only a subset of s is assessed. However, unless progression is observed, objective status (stable disease, PR or CR) can only be determined when all lesions are ed.

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

In n embodiments, treatment of a cancer may be assessed by the inhibition 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 tor. 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 tion 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, , during, and/or after TOR kinase inhibitor treatment. In one embodiment, the skin sample is irradiated by UV light.

In the e, complete inhibition, is ed to herein as prevention or chemoprevention. In this context, the term “prevention” includes either preventing the onset of clinically t cancer altogether or preventing the onset of a preclinically t stage of a cancer. Also intended to be encompassed by this definition is the prevention of transformation into malignant cells or to arrest or reverse the progression of premalignant cells to malignant cells. This includes prophylactic treatment of those at risk of developing a cancer.

Unless otherwise specified, to the extent that there is a discrepancy between a depicted chemical structure of a compound provided herein and a chemical name of a compound provided herein, the al structure shall control. .2 COMPOUND 1 The solid forms, formulations and methods ofuse provided herein relate to solid forms (e.g., tals) of Compound 1: «PNC N/“NINNKO having the name 1-ethyl—7-(2—methyl—6-(1H-l,2,4—triazol—3-yl)pyridin—3-yl)— 3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one, including tautomers thereof.

Tautomers ofCompound 1 include the following: N~ HN~ </ \N <\ x“ N / N / | ‘=‘ | N/ N N/ N H H Compound 1 can be ed using reagents and methods known in the art, including the methods provided in US Patent No. 8,110,578, issued on February 7, 2012; US Patent Publication Application No. 2011/0137028, published on June 9, 201 l; and US Provisional Patent Application No. ,064, filed on April 17, 2013, the entire contents of each h are incorporated herein by reference.

] It should be noted that if there is a pancy between a depicted structure and a name given that structure, the depicted structure is to be accorded more weight. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated with, for e, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. .3 SOLID FORM COCRYSTALS OF COMPOUND 1 While not intending to be bound by any particular theory, certain solid form cocrystals are characterized by al properties, e.g., stability, solubility and dissolution rate, appropriate for pharmaceutical and therapeutic dosage forms. Moreover, while not wishing to be bound by any particular theory, certain solid form cocrystals are characterized by physical properties (e.g., density, compressibility, hardness, morphology, cleavage, stickiness, solubility, water uptake, electrical properties, thermal behavior, solid-state vity, physical stability, and chemical stability) affecting particular processes (e.g., yield, filtration, washing, drying, milling, mixing, tableting, ility, dissolution, formulation, and lyophilization) which make n solid form tals suitable for the manufacture of a solid dosage form. Such properties can be determined using particular analytical chemical techniques, including solid-state analytical techniques (e.g., X-ray diffraction, copy, spectroscopy and thermal analysis), as described herein and known in the art.

In one embodiment, provided herein are solid forms (e.g., crystal forms, amorphous forms, or mixtures thereof) comprising (a) Compound 1; and (b) a coformer. In one embodiment, provided herein are solid forms (e.g., crystal forms, amorphous forms, or mixtures f) sing (a) a free base of Compound 1; and (b) a coformer. Compound 1 can be synthesized or obtained according to a method known in the literature or based upon the teachings , including the methods described in detail in the examples .

In certain embodiments, the coformer is benzoic acid, fumaric acid, gentisic acid, namide, succinic acid or maleic acid.

In one embodiment, solid forms ed herein may be a crystal form or an amorphous form or mixtures thereof (e.g., mixtures of crystal forms, or mixtures of crystal and amorphous , which comprises (a) Compound 1; and (b) a coformer. In one embodiment, provided herein is a crystal form comprising (a) Compound 1; and (b) a coformer. In one embodiment, provided herein is a cocrystal comprising (a) Compound 1; and (b) a coformer. In one embodiment, provided herein is an amorphous form comprising (a) Compound 1; and (b) a coformer. In one embodiment, provided herein is a mixture comprising (i) a cocrystal comprising (a) Compound 1; and (b) a coformer; and (ii) a crystal form of Compound 1. In one embodiment, provided herein is a mixture sing (i) a cocrystal comprising (a) Compound 1; and (b) a coformer; and (ii) an amorphous form of Compound 1.

In one embodiment, provided herein is a solid form comprising (a) Compound 1 and (b) a coformer that is substantially lline. In one embodiment, provided herein is a solid form comprising a cocrystal sing (a) Compound 1 and (b) a coformer. In one embodiment, ed herein is a solid form sing (i) a cocrystal comprising (a) Compound 1 and (b) a coformer and (ii) an amorphous form of nd 1. In one embodiment, provided herein is a solid form comprising (i) a cocrystal comprising (a) Compound 1 and (b) a coformer and (ii) one or more additional crystal forms of Compound In one embodiment, provided herein is an unsolvated solid form comprising (a) Compound 1 and (b) a coformer. In one embodiment, provided herein is an anhydrous solid form comprising (a) Compound 1 and (b) a coformer. In one embodiment, provided herein is an unsolvated crystal form comprising (a) Compound 1 and (b) a coformer. In one embodiment, provided herein is an anhydrous crystal form comprising (a) Compound 1 and (b) a coformer. In one embodiment, provided herein is an unsolvated amorphous form comprising (a) Compound 1 and (b) a coformer. In one embodiment, provided herein is an anhydrous ous form comprising (a) Compound 1 and (b) a coformer. In one embodiment, ed herein is a ed solid form comprising (a) Compound 1 and (b) a coformer. In one embodiment, provided herein is a hydrated solid form sing (a) Compound 1 and (b) a coformer (e.g., a e having a stoichiometric or ichiometric amount of water). In one embodiment, provided herein is a hydrated form of (a) Compound 1 and (b) a coformer, including, but not limited to, a hemihydrate, a monohydrate, a dihydrate, a trihydrate, and the like. In one embodiment, the hydrated form is substantially crystalline. In one embodiment, the hydrated form is substantially amorphous.

In one embodiment, the anhydrous form is substantially crystalline. In one embodiment, the anhydrous form is substantially amorphous. In one embodiment, provided herein is an unsolvated cocrystal comprising (a) Compound 1 and (b) a er. In one embodiment, provided herein is an anhydrous tal comprising (a) Compound 1 and (b) a coformer. In one embodiment, provided herein is a hydrated cocrystal comprising (a) Compound 1 and (b) a coformer. In one embodiment, ed herein is a solvated cocrystal comprising (a) Compound 1 and (b) a coformer.

Solid forms provided herein can be prepared by the methods described herein, or by ques, including, but not limited to, heating, g, freeze drying, spray drying, lyophilization, quench cooling the melt, rapid solvent evaporation, slow solvent evaporation, solvent recrystallization, antisolvent addition, slurry recrystallization, crystallization from the melt, desolvation, recrystallization in confined , such as, e.g., in nanopores or aries, recrystallization on surfaces or templates, such as, e.g., on polymers, recrystallization in the ce of ves, such as, e.g., cocrystal counter-molecules, desolvation, dehydration, rapid cooling, slow cooling, exposure to solvent and/or water, drying, including, e.g., vacuum drying, vapor diffusion, sublimation, grinding (including, e.g., cryo-grinding and solvent-drop grinding), microwave-induced precipitation, sonication- induced precipitation, laser-induced precipitation, and precipitation from a supercritical fluid.

The particle size of the resulting solid forms, which can vary (e.g., from nanometer dimensions to millimeter ions), can be controlled, e.g., by varying crystallization conditions, such as, e.g., the rate of crystallization and/or the crystallization solvent , or by particle-size reduction ques, e.g., grinding, milling, micronizing, or sonication.

] In some embodiments, the cocrystal comprising (a) Compound 1 and (b) a coformer can be obtained by crystallization from certain solvent systems, for e, t systems comprising one or more of the following solvents: tetrahydrofuran (THF), methanol and water, a mixture of THF and water, and a mixture of methanol and water. In certain embodiments, a solid form ed herein (e.g., a cocrystal comprising (a) nd 1 and (b) a coformer) can be obtained by cooling evaporation crystallization, powder in saturated solutions crystallization, slurry crystallization, and grinding crystallization.

In n embodiments, the non-covalent forces are one or more hydrogen bonds (H-bonds). The coformer may be H-bonded directly to Compound 1 or may be H- bonded to an onal molecule which is bound to Compound 1. The additional molecule may be H-bonded to Compound 1 or bound ionically or covalently to nd 1. The additional molecule could also be a different active or inactive ingredient. In certain embodiments, the cocrystals may include one or more solvate molecules in the crystalline lattice, i.e., solvates of cocrystals, or a cocrystal further comprising a solvent or nd that is a liquid at room temperature. In certain embodiments, the cocrystals may be a cocrystal between a coformer and a salt of Compound 1. In certain embodiments, the noncovalent forces are pi-stacking, guest-host complexation and/or van der Waals interactions.

Hydrogen bonding can result in several ent intermolecular configurations. For example, en bonds can result in the formation of , linear chains, or cyclic structures.

These configurations can further include extended (two-dimensional) hydrogen bond networks and isolated triads.

In certain embodiments, the coformer is a solid under ambient temperature conditions when in its pure form.

In certain embodiments, cocrystals can be prepared using solid-state s such as solid-state grinding and solvent-drop grinding. In certain ments, cocrystals can be prepared using high-throughput screening. In certain embodiments cocrystals can be prepared using solution-based crystallization.

In certain embodiments, cocrystals formation can lead to enchancment of physical properties of the resulting solid forms, such as solubility, dissolution rate, bioavailablity, al stability, chemical ity, flowability, bility, or compressibility.

] In certain embodiments, provided herein are cooling evaporative methods for making a solid form cocrystal of Compound 1, comprising 1) obtaining a close-to saturated solution of Compound 1 and coformers in a ratio (e.g., about 1:1.1 or about 1:1.4) in a solvent; 2) heating the solution to a first temperature (e.g., about 30 oC to about 50 oC); 3) g the solution to a second temperature (e.g., about -5 oC to about 15 oC); 4) keeping the on at the second temperature for a period of time (e.g., 48 hours); 5) filtering the solution to yield a solid if there is precipitation; and 6) evaporating the solvent to collect a solid if there is no precipitation after step 4. In certain embodiments, provided herein are cooling evaporative methods for making a solid form cocrystal of nd 1, sing 1) obtaining a close-to saturated solution of Compound 1 and coformers in a solvent; 2) heating the solution to about 40 oC); 3) cooling the solution to about 2 oC); 4) keeping the solution at about 2 oC for about 48 hours; 5) filtering the solution to yield a solid if there is precipitation; and 6) evaporating the solvent to collect a solid if there is no precipitation after step 4. In certain embodiements, the solvent is methanol, THF, a mixture of methanol and water (50/50) or a mixture of THF and water (50/50). In one embodiment, the molar ratio of Compound 1 and the coformers in step 1 is about 1:1.1 or about 1:1.4.

In certain embodiments, provided herein are powder in ted solutions s for making a solid form cocrystal of Compound 1, comprising 1) obtaining a saturated on of Compound 1 in a solvent; 2) adding coformers into the solution; 3) stirring the solution at ambient temperature for a period of time; 4) filtering the solution to yield a first solid and 5) evaporate the t to collect a second solid. In certain embodiements, the solvent is methanol, THF, a e of methanol and water (50/50) or a mixture of THF and water (50/50). In one embodiment, the molar ratio of Compound 1 and the coformers is about 1:5. In one embodiment, the period of time is about 4 hours.

In certain embodiments, provided herein are slurry methods for making a solid form cocrystal of Compound 1, comprising 1) obtaining a slurry of nd 1 and coformers in a ratio in a solvent; 2) stirring the slurry for a period of time; 3) collecting a solid from the slurry by filtration (e.g., centrifuge tion). In certain embodiements, the solvent is methanol, THF, a mixture of methanol and water (50/50) or a mixture of THF and water (50/50). In one embodiment, the molar ratio of Compound 1 and the coformers is about 1:1.1. In one embodiment, the period of time is about 3 days.

In certain embodiments, provided herein are grinding methods for making a solid form cocrystal of Compound 1, comprising 1) adding nd 1, coformers and a solvent into a grinding machine; 2) g the container for a period of time at a particular frequency; 3) collecting the resulting solid by filtration (e.g., centrifuge filtration). In n embodiements, the solvent is methanol, THF, a mixture of methanol and water (50/50) or a mixture of THF and water (50/50). In one embodiment, the molar ratio of nd 1 and the coformers is about 1:1.1. In one embodiment, the period of time is about 1 hour. In one embodiment, the frequency is about 30 Hz.

] The solid form cocrystals provided herein (e.g., Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7 and Form 8) may be characterized using a number of methods known to a person having ry skill in the art, including, but not limited to, single crystal X-ray diffraction, X-ray powder ction , copy (e.g., ng electron microscopy (SEM)), thermal analysis (e.g., differential scanning calorimetry (DSC), l gravimetric analysis (TGA), and hot-stage microscopy), spectroscopy (e.g., infrared, Raman, and solid-state nuclear magnetic resonance), single differential thermal analysis (SDTA), high performance liquid chromatography coupled with mass oscopy (HPLC-MS), thermogravimetrical analysis coupled with single differential thermal analysis (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 methods, such as laser light scattering technique.

The purity of the solid form cocrystals 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 ly from one machine to another or from one sample to another, and so the values quoted are not to be ued as absolute, but with an ble variability, such as ±0.2 s 2 theta (see United State Pharmacopoeia, page 2228 (2003)). .3.1 Cocrystal Form 1 comprising Compound 1 and Benzoic Acid ] Provided herein is cocrystal Form 1, comprising Compound 1 and benzoic acid. In one embodiment, provided herein is a cocrystal comprising nd 1 and benzoic acid that is substantially crystalline. In one embodiment, provided herein is a solid form comprising (i) a cocrystal comprising Compound 1 and benzoic acid and (ii) an amorphous form of Compound 1. In one embodiment, provided herein is a solid form comprising (i) a cocrystal comprising Compound 1 and benzoic acid and (ii) one or more additional crystal forms of Compound 1. Provided herein are various embodiments, preparations, or modifications of a cocrystal comprising Compound 1 and benzoic acid.

In one embodiment, Form 1 is a methanol solvated form comprising Compound 1 and benzoic acid. In another embodiment, Form 1 is lline.

In certain embodiments, Form 1 is obtained by grinding experiments comprising 1) adding Compound 1, c acid and a solvent into a grinding container containing grinding balls; 2) shaking the container for a period of time at a particular frequency; 3) collecting the resulting solid by filtration (e.g., centrifuge filtration). In certain embodiements, the solvent is a mixture of methanol and water (50/50). In one embodiment, the molar ratio of Compound 1 and benzoic acid is about 1:1.1. In one embodiment, the period of time is about 1 hour. In one ment, the frequency is about 30 Hz.

] In certain embodiments, a solid form provided herein, e.g., Form 1, is substantially crystalline, as ted by, e.g., X-ray powder ction measurements. In one embodiment, Form 1 of Compound 1 has an X-ray powder diffraction pattern substantially as shown in (middle pattern). In one embodiment, Form 1 of Compound 1 has one or more characteristic X-ray powder diffraction peaks at a eta angle of approximately 7.78, 13.02, 13.54, 20.62, 24.26, 25.02 or 26.1 degrees as depicted in 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 7.78, 13.02, 25.02 or 26.1 degrees. In another embodiment, Form 1 of Compound 1 has one, two, three, four, five, six, or seven characteristic X-ray powder diffraction peaks as set forth in Table 12.

In one embodiment, ed herein is Form 1 having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in In n embodiments, the lline form exhibits a TGA thermogram sing a total mass loss of imately 5.0% of the total mass of the sample between approximately 35 °C and approximately 105 °C when heated from approximately 25 °C to approximately 300 °C. Thus, in certain embodiments, the crystalline form loses about 5.0% of its total mass when heated from about ambient temperature to about 300 °C.

In one embodiment, provided herein is Form 1 having a single differential thermal analysis (SDTA) thermogram as depicted in comprising an endothermic event with a maximum at about 89 °C, followed by decomposition starting at about 200 °C, when heated from imately 25 °C to approximately 300 °C.

In still another embodiment, Form 1 of Compound 1 is substantially pure. In certain 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 Cocrystal Form 2 comprising Compound 1 and Fumaric Acid Provided herein is cocrystal Form 2, sing Compound 1 and fumaric acid. In one embodiment, provided herein is a cocrystal comprising nd 1 and fumaric acid that is substantially lline. In one embodiment, provided herein is a solid form comprising (i) a cocrystal comprising Compound 1 and fumaric acid and (ii) an amorphous form of Compound 1. In one embodiment, provided herein is a solid form comprising (i) a cocrystal comprising Compound 1 and fumaric acid and (ii) one or more additional crystal forms of Compound 1. Provided herein are various embodiments, preparations, or modifications of a cocrystal comprising Compound 1 and fumaric acid.

In one embodiment, Form 2 is a hydrated form comprising Compound 1 and fumaric acid. In another embodiment, Form 2 is crystalline.

] In certain ments, Form 2 is obtained by grinding experiments comprising 1) adding Compound 1, fumaric acid and a solvent into a grinding container containing ng balls; 2) shaking the container for a period of time at a particular frequency; 3) ting the resulting solid by filtration (e.g., centrifuge filtration). In certain embodiements, the solvent is a mixture of methanol and water (50/50). In one embodiment, the molar ratio of Compound 1 and benzoic acid is about 1:1.1. In one embodiment, the period of time is about 1 hour. In one embodiment, the frequency is about 30 Hz.

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 d pattern from bottom). 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 7.66, 10.42, 14.02, 17.46, 18.38, 19.3, 24.06 or 27.02 degrees as depicted in (second pattern from bottom). 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 7.66, 10.42, 24.06 or 27.02 degrees. In another embodiment, Form 2 of Compound 1 has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks as set forth in Table 13.

In one embodiment, provided herein is Form 2 having a gravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in In certain embodiments, the lline form exhibits a TGA thermogram comprising a total mass loss of approximately 5.1% of the total mass of the sample between imately 35 °C and approximately 135 °C when heated from approximately 25 °C to approximately 300 °C. Thus, in certain ments, the crystalline form loses about 5.1% of its total mass when heated from about ambient temperature to about 300 °C.

In one embodiment, provided herein is Form 2 having a single differential thermal analysis (SDTA) thermogram as ed in comprising an endothermic event with a maximum at about 115 °C, followed by an endothermic melt event at about 177 °C and then immediate decomposition, when heated from approximately 25 °C to approximately 300 °C.

In still another embodiment, Form 2 of nd 1 is substantially pure. In certain ments, 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 Cocrystal Form 3 sing Compound 1 and Fumaric Acid Provided herein is cocrystal Form 3, comprising Compound 1 and fumaric acid. In one embodiment, provided herein is a solid form comprising Compound 1 and fumaric acid that is substantially crystalline. In one embodiment, provided herein is a solid form comprising (i) a cocrystal comprising Compound 1 and fumaric acid and (ii) an amorphous form of Compound 1. In one embodiment, provided herein is a solid form comprising (i) a cocrystal comprising Compound 1 and fumaric acid and (ii) one or more additional crystal forms of Compound 1. Provided herein are various embodiments, preparations, or modifications of a cocrystal sing Compound 1 and fumaric acid.

In certain embodiments, Form 3 is obtained by cooling evaporative experiments comprising 1) obtaining a close-to saturated solution of Compound 1 and fumaric acid in a ratio (e.g., about 1:1.4) in a solvent; 2) heating the solution to a first temperature (e.g., about 30 oC to about 50 oC); 3) cooling the solution to a second temperature (e.g., about -5 oC to about 15 oC); 4) keeping the solution at the second temperature for a period of time (e.g., 48 hours); 5) filtering the solution to yield a solid if there is precipitation; and 6) evaporating the solvent to collect a solid if there is no precipitation after step 4. In certain ments, Form 3 is obtained by g evaporative experiments, sing 1) obtaining a close-to saturated solution of nd 1 and fumaric acid in a solvent; 2) heating the solution to about 40 oC); 3) cooling the solution to about 2 oC); 4) keeping the solution at about 2 oC for about 48 hours; 5) filtering the solution to yield a solid if there is itation; and 6) evaporating the t to collect a solid if there is no precipitation after step 4. In certain embodiements, the solvent is ol. In one embodiment, the molar ratio of Compound 1 and fumaric acid in step 1 is about 1:1.4.

In certain embodiments, a solid form provided herein, e.g., Form 3, is substantially crystalline, 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 (third n from ). 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 9.06, 13.66, 17.14, 22.74, 24.58, 26.06, 26.9 or 28.7 degrees as ed in (third n from bottom). 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 9.06, 26.06, 26.9 or 28.7 degrees. In another embodiment, Form 3 of Compound 1 has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks as set forth in Table 14.

] In one embodiment, provided herein is Form 3 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 4.2% of the total mass of the sample between approximately 35 °C and approximately 105 °C when heated from approximately 25 °C to approximately 300 °C. Thus, in certain embodiments, the lline form loses about 4.2% of its total mass when heated from about ambient temperature to about 300 °C.

In one embodiment, provided herein is Form 3 having a single differential thermal analysis (SDTA) thermogram as depicted in comprising an ermic event with a maximum at about 93 °C, followed by an endothermic melt event at about 178.1 °C and then immediate decomposition, when heated from approximately 25 °C to approximately 300 °C.

In still another embodiment, Form 3 of Compound 1 is ntially pure. In certain embodiments, the substantially pure Form 3 of nd 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 Cocrystal Form 4 sing Compound 1 and Gentisic Acid Provided herein is cocrystal Form 4, comprising Compound 1 and gentisic acid. In one ment, provided herein is a solid form sing Compound 1 and gentisic acid that is substantially crystalline. In one embodiment, ed herein is a solid form comprising (i) a cocrystal comprising Compound 1 and gentisic acid and (ii) an amorphous form of Compound 1. In one embodiment, provided herein is a solid form sing (i) a cocrystal comprising Compound 1 and gentisic acid and (ii) one or more additional crystal forms of Compound 1. Provided herein are various embodiments, preparations, or cations of a cocrystal comprising Compound 1 and gentisic acid.

In one embodiment, Form 4 is a hydrate comprising Compound 1 and gentisic acid. In another embodiment, Form 4 is crystalline.

In n embodiments, Form 4 is ed by cooling evaporative experiments comprising 1) obtaining a close-to saturated solution of Compound 1 and gentisic acid in a ratio (e.g., about 1:1.1) in a solvent; 2) heating the solution to a first temperature (e.g., about 30 oC to about 50 oC); 3) cooling the solution to a second temperature (e.g., about -5 oC to about 15 oC); 4) keeping the solution at the second temperature for a period of time (e.g., 48 ; 5) filtering the solution to yield a solid if there is precipitation; and 6) evaporating the solvent to t a solid if there is no precipitation after step 4. In certain embodiments, Form 4 is obtained by cooling ative experiments, comprising 1) obtaining a close-to saturated solution of Compound 1 and gentisic acid in a solvent; 2) heating the solution to about 40oC); 3) cooling the solution to about 2 oC); 4) keeping the solution at about 2 oC for about 48 hours; 5) filtering the solution to yield a solid if there is precipitation; and 6) evaporating the solvent to collect a solid if there is no precipitation after step 4. In certain embodiements, the solvent is a mixture of methanol and water (50/50). In one ment, the molar ratio of Compound 1 and gentisic acid is about 1:1.1.

In certain embodiments, a solid form ed 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 (second pattern from bottom). In one embodiment, Form 4 of Compound 1 has one or more characteristic X-ray powder ction peaks at a two-theta angle of approximately 6.62, 7.58, 8.9, 9.42, 12.22, 12.82, 13.34, 13.9, 14.34, 16.14, 18.94, .46, 22.34, 22.9, 23.66, 24.22, 25.18, 26.62, 27.46 or 33.02 degrees as depicted in (second pattern from bottom). In a specific embodiment, Form 4 of Compound 1 has one, two, three, four, five, six, seven or eight teristic X-ray powder ction peaks at a two-theta angle of approximately 7.58, 12.22, 13.34, 22.34, 22.9, 23.66, 24.22 or 25.18 degrees. In another embodiment, Form 4 of Compound 1 has one, two, three or four characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 12.22, 13.34, 22.9 or 25.18 degrees. In another embodiment, Form 4 of Compound 1 has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen or twenty characteristic X-ray powder ction peaks as set forth in Table 15.

In one embodiment, provided herein is Form 4 having a thermogravimetric (TGA) graph 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 1.7% of the total mass of the sample between approximately 110 °C and approximately 150 °C when heated from approximately 25 °C to approximately 300 °C. Thus, in certain embodiments, the crystalline form loses about 1.7% of its total mass when heated from about ambient temperature to about 300 °C.

In one embodiment, provided herein is Form 4 having a single differential thermal analysis (SDTA) thermogram as depicted in comprising an endothermic event with two ms at about 101.3 and 141.6 °C, followed by an endothermic melt event at about 199 °C and then ate decomposition, when heated from approximately °C to approximately 300 °C.

In still another embodiment, Form 4 of Compound 1 is ntially pure. In certain 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 Cocrystal Form 5 comprising Compound 1 and ic Acid Provided herein is tal Form 5, comprising Compound 1 and gentisic acid. In one embodiment, provided herein is a solid form comprising Compound 1 and gentisic acid that is substantially crystalline. In one embodiment, provided herein is a solid form comprising (i) a cocrystal comprising Compound 1 and gentisic acid and (ii) an amorphous form of Compound 1. In one embodiment, provided herein is a solid form comprising (i) a tal comprising Compound 1 and gentisic acid and (ii) one or more additional crystal forms of Compound 1. Provided herein are various embodiments, ations, or modifications of a cocrystal comprising Compound 1 and gentisic acid.

In one embodiment, Form 5 is a hydrate comprising Compound 1 and gentisic acid. In another embodiment, Form 5 are crystalline.

] In certain embodiments, Form 5 is obtained by g evaporative experiments comprising 1) obtaining a to saturated solution of Compound 1 and gentisic acid in a ratio (e.g., about in a solvent; 2) heating the solution to a first temperature (e.g., about 30 oC to about 50 oC); 3) cooling the solution to a second ature (e.g., about -5 oC to about 15 oC); 4) keeping the solution at the second temperature for a period of time (e.g., 48 hours); 5) filtering the solution to yield a solid if there is precipitation; and 6) evaporating the solvent to collect a solid if there is no precipitation after step 4. In certain embodiments, Form 5 is obtained by g evaporative ments, comprising 1) obtaining a to saturated solution of Compound 1 and gentisic acid in a solvent; 2) heating the solution to about 40oC); 3) cooling the solution to about 2 oC); 4) keeping the solution at about 2 oC for about 48 hours; 5) filtering the solution to yield a solid if there is precipitation; and 6) evaporating the solvent to collect a solid if there is no precipitation after step 4. In certain embodiements, the solvent is methanol. In one embodiment, the molar ratio of Compound 1 and gentisic acid in step 1 is about 1:1.1.

In n embodiments, a solid form provided herein, e.g., Form 5, is substantially lline, 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 (third pattern from bottom). In one embodiment, Form 5 of Compound 1 has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 10.82, 16.9, 17.42, 19.3, 24.7, 28.34, 30.86 or 37.58 degrees as depicted in (third pattern from bottom). In another ment, Form 5 of Compound 1 has one, two, three or four characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 17.42, 24.7, 28.34 or 30.86 degrees. In r embodiment, Form 5 of Compound 1 has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks as set forth in Table 16.

] In one embodiment, provided herein is Form 5 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 1.6% of the total mass of the sample between approximately 35 °C and approximately 155 °C when heated from approximately 25 °C to approximately 300 °C. Thus, in certain embodiments, the crystalline form loses about 1.6% of its total mass when heated from about ambient temperature to about 300 °C.

In one embodiment, provided herein is Form 5 having a single differential thermal analysis (SDTA) gram as depicted in comprising an endothermic event with a maximum at about 180 °C, followed by immediate decomposition at about 236 oC, when heated from approximately 25 °C to approximately 300 °C.

In still another embodiment, Form 5 of Compound 1 is substantially pure. In certain embodiments, the substantially pure Form 5 of Compound 1 is substantially free of other solid forms, e.g., amorphous form. In certain 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 tal Form 6 comprising Compound 1 and Nicotinamide Provide herein is cocrystal Form 6, comprising Compound 1 and nicotinamide. In one embodiment, provided herein is a solid form sing Compound 1 and nicotinamide that is substantially crystalline. In one embodiment, provided herein is a solid form comprising (i) a cocrystal comprising Compound 1 and nicotinamide and (ii) an ous form of Compound 1. In one embodiment, provided herein is a solid form comprising (i) a cocrystal comprising Compound 1 and nicotinamide and (ii) one or more additional crystal forms of Compound 1. ed herein are various embodiments, preparations, or modifications of a cocrystal comprising Compound 1 and namide.

In one embodiment, Form 6 is a THF and water solvate sing Compound 1 and nicotinamide. In another ment, Form 6 is crystalline.

In n embodiments, Form 6 is obtained by grinding experiments comprising 1) adding Compound 1, nicotinamide and a solvent into a grinding container containing grinding balls; 2) shaking the container for a period of time at a particular frequency; 3) collecting the resulting solid by filtration (e.g., centrifuge filtration). In certain ements, the solvent is a mixture of THF and water (50/50). In one embodiment, the molar ratio of Compound 1 and nicotinamide is about 1:1.1. In one embodiment, the period of time is about 1 hour. In one embodiment, the frequency is about 30 Hz.

In certain embodiments, a solid form provided herein, e.g., Form 6, is substantially lline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form 6 of Compound 1 has an X-ray powder diffraction pattern substantially as shown in (middle pattern). In one embodiment, Form 6 of Compound 1 has one or more characteristic X-ray powder ction peaks at a two-theta angle of approximately 6.02, 7.46, 11.5, 13.3, 14.9, 18.66, 20.38, 23.42, 24.18, 25.06, 26.1, 26.9, 27.98 or 28.78 degrees as depicted in . In a ic em nt, Form 6 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 6.02, 7.46, 11.5, 14.9, 23.42, 24.18, .06 or 26.1 degrees. In another embodiment, Form 6 of Compound 1 has one, two, three or four characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 11.5, 23.42, 24.18 or 25.06 degrees. In another embodiment, Form 6 of Compound 1 has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen or fourteen characteristic X-ray powder diffraction peaks as set forth in Table 17.

In one ment, provided herein is Form 6 having a thermogravimetric (TGA) thermograph corresponding substantially to the representative TGA thermogram as depicted in . In certain embodiments, the lline form exhibits a TGA thermogram comprising a total mass loss of approximately 3.8% of the total mass of the sample between approximately 35 °C and approximately 145 °C when heated from approximately 25 °C to approximately 300 °C. Thus, in n embodiments, the crystalline form loses about 3.8% of its total mass when heated from about ambient temperature to about 300 °C.

In one embodiment, ed herein is Form 6 having a single differential thermal analysis (SDTA) thermogram as depicted in sing an endothermic event with a maximum at about 89 °C, ed by immediate decomposition at about 200 °C, when heated from approximately 25 °C to approximately 300 °C.

In still another embodiment, Form 6 of Compound 1 is substantially pure. In certain embodiments, the substantially pure Form 6 of Compound 1 is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form 6 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. .3.7 tal Form 7 comprising Compound 1 and Succinic acid Provided herein is cocrystal Form 7, comprising Compound 1 and succinic acid. In one embodiment, provided herein is a solid form comprising nd 1 and succinic acid that is substantially crystalline. In one embodiment, provided herein is a solid form comprising (i) a cocrystal comprising Compound 1 and succinic acid and (ii) an amorphous form of nd 1. In one embodiment, provided herein is a solid form comprising (i) a tal sing Compound 1 and succinic acid and (ii) one or more additional crystal forms of Compound 1. Provided herein are various embodiments, preparations, or modifications of a cocrystal comprising Compound 1 and succinic acid.

In one embodiment, Form 7 is a hydrate comprising Compound 1 and succinic acid. In another embodiment, Form 7 is crystalline.

In certain embodiments, Form 7 is ed by grinding experiments comprising 1) adding nd 1, ic acid and a solvent into a grinding container containing grinding balls; 2) shaking the container for a period of time at a particular frequency; 3) collecting the resulting solid by filtration (e.g., centrifuge filtration). In certain ements, the solvent is a mixture of methanol and water (50/50). In one ment, the molar ratio of Compound 1 and succinic acid is about 1:1.1. In one embodiment, the period of time is about 1 hour. In one embodiment, the frequency is about 30 Hz.

In certain embodiments, a solid form provided herein, e.g., Form 7, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one embodiment, Form 7 of Compound 1 has an X-ray powder diffraction pattern substantially as shown in (middle pattern). In one embodiment, Form 7 of Compound 1 has one or more characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 7.62, 10.54, 13.82, 17.46, 17.94, 19.34, 24.26, 26.7 or 27.38 degrees as depicted in . In a specific em bodiment, Form 7 of Compound 1 has one, two, three, four, five, six, seven or eight characteristic X-ray powder diffraction peaks at a twotheta angle of approximately 7.62, 10.54, 13.82, 17.46, 17.94, 19.34, 24.26 or 26.7 degrees.

In r embodiment, Form 7 of Compound 1 has one, two, three or four characteristic X- ray powder diffraction peaks at a eta angle of approximately 7.62, 10.54, 13.82 or 26.7 degrees. In another embodiment, Form 7 of Compound 1 has one, two, three, four, five, six, seven, eight or nine teristic X-ray powder diffraction peaks as set forth in Table 18.

In one embodiment, provided herein is Form 7 having a gravimetric (TGA) gram corresponding substantially to the representative TGA thermogram as depicted in . In certain embodiments, the crystalline form exhibits a TGA thermogram sing a total mass loss of approximately 3.8% of the total mass of the sample between approximately 35 °C and approximately 145 °C when heated from approximately 25 °C to approximately 300 °C. Thus, in certain embodiments, the crystalline form loses about 3.8% of its total mass when heated from about t temperature to about 300 °C.

In one embodiment, ed herein is Form 7 having a single differential l analysis (SDTA) thermogram as depicted in comprising an endothermic event with a maximum at about 108.8 °C, followed by immediate decomposition at about 163.4 °C, when heated from approximately 25 °C to approximately 300 °C.

In still another embodiment, Form 7 of Compound 1 is ntially pure. In certain embodiments, the substantially pure Form 7 of Compound 1 is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form 7 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. .3.8 Cocrystal Form 8 comprising Compound 1 and Maleic acid Provided herein is cocrystal Form 8, comprising nd 1 and maleic acid.

In one embodiment, provided herein is a solid form comprising Compound 1 and maleic acid that is substantially crystalline. In one ment, provided herein is a solid form comprising (i) a cocrystal comprising Compound 1 and maleic acid and (ii) an amorphous form of nd 1. In one embodiment, provided herein is a solid form comprising (i) a cocrystal comprising Compound 1 and maleic acid and (ii) one or more additional crystal forms of Compound 1. Provided herein are various embodiments, preparations, or modifications of a cocrystal sing Compound 1 and maleic acid.

In one embodiment, Form 8 is a hydrate sing Compound 1 and maleic acid. In another embodiment, Form 8 is crystalline.

In certain embodiments, Form 8 is obtained by grinding experiments comprising 1) adding Compound 1, maleic acid and a t into a grinding container containing grinding balls; 2) shaking the container for a period of time at a particular frequency; 3) collecting the resulting solid by filtration (e.g., centrifuge filtration). In n embodiements, the solvent is a mixture of ol and water (50/50). In one embodiment, the molar ratio of Compound 1 and maleic acid is about 1:1.1. In one embodiment, the period of time is about 1 hour. In one embodiment, the frequency is about 30 Hz.

In certain embodiments, a solid form provided herein, e.g., Form 8, is substantially crystalline, as indicated by, e.g., X-ray powder diffraction measurements. In one ment, Form 8 of Compound 1 has an X-ray powder diffraction pattern substantially as shown in (middle pattern). In one embodiment, Form 8 of Compound 1 has one or more characteristic X-ray powder ction peaks at a eta angle of approximately 6.94, 12.54, 13.82, 16.54, 20.82, 22.18, 22.78, 24.46, 26.22, 26.98, 27.66, 28.7 or 29.66 degrees as depicted in . In a specific em bodiment, Form 8 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 6.94, 13.82, 22.18, 22.78, 24.46, 26.22, 26.98 or 27.66 degrees. In another ment, Form 8 of Compound 1 has one, two, three or four characteristic X-ray powder diffraction peaks at a two-theta angle of approximately 6.94, 13.82, 26.98 or 27.66 degrees. In another embodiment, Form 8 of Compound 1 has one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve or thirteen characteristic X-ray powder diffraction peaks as set forth in Table 19.

In one ment, provided herein is Form 8 having a thermogravimetric (TGA) thermograph corresponding ntially to the representative TGA thermogram as depicted in . In certain embodiments, the lline form exhibits a TGA thermogram comprising a total mass loss of approximately 4.6% of the total mass of the sample between approximately 35 °C and approximately 145 °C when heated from approximately 25 °C to approximately 300 °C. Thus, in certain embodiments, the crystalline form loses about 4.6% of its total mass when heated from about t temperature to about 300 °C.

In one embodiment, provided herein is Form 8 having a single differential thermal analysis (SDTA) thermogram as depicted in comprising an endothermic event with a maximum at about 118.7 °C, followed by ate decomposition, when heated from approximately 25 °C to approximately 300 °C.

In still another embodiment, Form 8 of Compound 1 is substantially pure. In certain embodiments, the substantially pure Form 8 of nd 1 is substantially free of other solid forms, e.g., amorphous form. In certain embodiments, the purity of the substantially pure Form 8 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. .4 METHODS OF USE Provided herein are methods for treating or preventing a cancer, comprising administering a solid form of nd 1 provided herein or a pharmaceutical composition thereof to a patient having a cancer. [00180A] In an embodiment, ed herein is a use of Compound 1 provided herein or a pharmaceutical composition thereof in the manufacture of a medicament for treating or preventing cancer, an inflammatory condition, an immunological condition, a neurodegenerative e, diabetes, obesity, a neurological disorder, an age-related e, a cardiovascular condition, or a conditions treatable or preventable by inhibition of a kinase In some embodiments, the cancer is an advanced 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 patient 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 standard therapy. In one embodiment, the cancer is a neoplasm metastasis.

] In certain ments, the cancer is a bloodborne tumor.

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

In certain ments, the cancer is non-Hodgkin’s lymphoma. In certain ments, the non-Hodgkin’s lymphoma is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), acute myeloid leukemia (AML), mantle cell lymphoma (MCL), or ALK+ anaplastic large cell lymphoma. In one embodiment, 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 ma (DLBCL).

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

In certain embodiments, 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 lymphoma (including extranodal marginal zone B-cell lymphoma and nodal marginal zone B-cell lymphoma), lymphoplasmacytic ma/Waldenstrom macroglobulinemia. In some embodiments, the B-cell lymphoma is chronic 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 ma is refractory B-cell non-Hodgkin’s lymphoma. In one embodiment, the B-cell non-Hodgkin’s lymphoma is ed B-cell non-Hodgkin’s lymphoma.

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

The B-cell disorders chronic lymphocytic leukemia/small lymphocytic lymphoma LL) 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 embodiments, the cancer is a cancer of the head, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, urinary bladder, uterine, cervix, breast, ovaries, testicles or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, as, 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 embodiments, the neuroendocrine tumor is a neuroendocrine tumor of gut origin. In certain ments, the neuroendocrine tumor is of non-pancreatic . In certain embodiments, the neuroendocrine tumor is ncreatic of gut origin. In certain embodiments, the neuroendocrine tumor is of n primary . In certain embodiments, the neuroendocrine tumor is a symptomatic endocrine producing tumor or a nonfunctional tumor.

In certain embodiments, the neuroendocrine tumor is locally unresectable, metastatic moderate, well differentiated, low (grade 1) or intermediate (grade 2). In certain embodiments, the neuroendocrine tumor is of non-gut origin. In one embodiment, the neuroendocrine tumor of non-gut , 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 ndocrine tumor, or a thyroid neuroendocrine tumor. In one embodiment, the neuroendocrine tumor of non-gut origin is a symptomatic endocrine producing tumor or a nonfunctional tumor. In one embodiment, the neuroendocrine tumor of t origin is y unresectable, metastatic te, 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 or ve (ER+, ER+/Her2 or ER+/Her2+). In one embodiment, the breast cancer is estrogen receptor negative (ER-/Her2+). In one ment, the breast cancer is triple negative (TN) (breast cancer that does not express 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 ment, the cancer is head and neck squamous cell carcinoma.

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

In another embodiment, the cancer is glioblastoma multiforme (GBM) characterized by O6-methylguanine-DNA methyltransferase (MGMT) methylation.

In other embodiments, the cancer is a cancer associated with the ys involving mTOR, PI3K, or Akt kinases and mutants or isoforms thereof. Other cancers within the scope of the methods provided herein include those associated with the ys 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 associated with mTOR/ PI3K/Akt pathways include solid and blood-borne tumors, for example, multiple myeloma, mantle cell ma, diffused large B-cell lymphoma, acute myeloid ma, follicular lymphoma, c lymphocytic leukemia; and solid tumors, for example, breast, lung, endometrial, ovarian, gastric, cervical, and prostate cancer; glioblastoma; renal carcinoma; hepatocellular carcinoma; colon carcinoma; neuroendocrine tumors; head and neck tumors; and sarcomas, such as Ewing’s sarcoma.

In certain ments, provided herein are methods for achieving a Response Evaluation Criteria in Solid Tumors (for example, RECIST 1.1) of complete response, partial response or stable disease 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 a related embodiment, provided herein is a use of a solid form of Compound 1 provided herein or a pharmaceutical ition thereof in the manufacture of a medicament for ing a Response Evaluation Criteria in Solid Tumors (RECIST 1.1) of complete response, partial response or stable e in a subject having a solid tumor. In certain embodiments, provided herein are methods for achieving a National Cancer Institute- Sponsored Working Group on Chronic Lymphocytic Leukemia (NCI-WG CLL) of complete se, partial response or stable disease in a patient having leukemia, comprising stering a solid form of Compound 1 provided herein or a ceutical composition thereof to said patient. In n embodiments, provided herein are methods for achieving a Prostate Cancer Working Group 2 (PCWG2) Criteria of complete response, partial response or stable disease in a patient having prostate cancer, 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 an International Workshop Criteria (IWC) for non-Hodgkin’s ma of complete response, partial response or stable disease in a patient having non-Hodgkin’s lymphoma, comprising administering a solid form of Compound 1 provided herein or a pharmaceutical composition f to said patient. In certain embodiments, provided herein are methods for achieving an International Uniform se Criteria (IURC) for multiple myeloma of complete se, partial 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 ment for Neuro-Oncology (RANO) Working Group for glioblastoma multiforme of complete response, partial se or stable disease in a patient having astoma multiforme, comprising administering a solid form of Compound 1 provided herein or a pharmaceutical composition thereof to said patient. In a related embodiment, provided herein is a use of a solid form of Compound 1 provided herein or a pharmaceutical ition thereof in the manufacture of a medicament for improving ational Workshop Criteria (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.

In certain embodiments, provided herein are s for increasing al without disease progression of a patient having a , 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 treating a cancer, the methods comprising administering a solid form of Compound 1 provided herein or a pharmaceutical composition f to a patient having a cancer, wherein the treatment s 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 , the methods comprising administering a solid form of Compound 1 provided herein or a pharmaceutical composition thereof to a patient having a cancer, wherein the treatment results in one or more of tion of disease progression, increased Time To Progression (TTP), increased Progression Free al (PFS), and/or increased Overall Survival (OS), among others.

Provided herein are methods of using the solid forms and compositions provided herein in the treatment, prevention, or management of conditions and disorders ing, but not d to: a bloodborne tumor, a lymphoma, a ia, a multiple myeloma, non-Hodgkin’s lymphoma, large B-cell lymphoma (DLBCL), follicular lymphoma (FL), acute myeloid leukemia (AML), mantle cell lymphoma (MCL), ALK+ anaplastic large cell ma, advanced solid non-Hodgkin’s lymphoma, diffuse large B-cell ma (DLBCL), B-cell lymphoma, B-cell non-Hodgkin’s lymphoma, diffuse large B-cell lymphoma, Burkitt’s lymphoma/leukemia, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, ular lymphoma, marginal zone lymphoma (including extranodal marginal zone B-cell lymphoma and nodal marginal zone B-cell lymphoma), lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Waldenstrom macroglobulinemia, refractory B-cell non-Hodgkin’s lymphoma, relapsed B-cell dgkin’s lymphoma, T- cell lymphoma, a multiple myeloma, a solid tumor, a relapsed or refractory solid tumor, a neuroendocrine tumor, the neuroendocrine tumor, a neuroendocrine tumor of gut origin, neuroendocrine tumor, non-pancreatic origin, neuroendocrine tumor, a symptomatic endocrine producing tumor, a nonfunctional tumor, a ial neuroendocrine tumor, a laryngeal neuroendocrine tumor, a pharyngeal neuroendocrine tumor, a thyroid neuroendocrine tumor, a symptomatic endocrine ing tumor, a nonfunctional tumor, a non-small cell lung cancer (NSCLC), a glioblastoma multiforme (GBM), a hepatocellular carcinoma (HCC), a breast cancer, a head and neck squamous cell carcinoma, an ty six (ETS) overexpressing castration-resistant prostate cancer, an E-twenty six (ETS) overexpressing Ewings sarcoma, a head and neck us cell carcinoma (HNSCC) characterized by on of chromosome 11q22 or loss of ataxia telangiectasia mutated (ATM) expression, a glioblastoma multiforme (GBM) characterized by O6-methylguanine- DNA methyltransferase (MGMT) methylation, a cancer associated with the pathways involving mTOR, PI3K, or Akt kinases and mutants or ms, s associated with the pathways of the following kinases: PI3K, PI3Kβ, PI3Kδ, KDR, GSK3, GSK3β, ATM, ATX, ATR, cFMS, and/or DNA-PK s and mutants or ms, multiple myeloma, mantle cell lymphoma, diffused large B-cell lymphoma, acute myeloid lymphoma, follicular lymphoma, and solid tumors, for example, breast, lung, endometrial, ovarian, gastric, cervical, and prostate cancer, glioblastoma, renal carcinoma, hepatocellular carcinoma, colon carcinoma, neuroendocrine tumors, head and neck tumors, and sarcomas, such as Ewing’s .5 PHARMACEUTICAL COMPOSITIONS Solid forms of Compound 1 provided herein are useful for the preparation of pharmaceutical itions, comprising an effective amount of a solid form of Compound 1 and a pharmaceutically acceptable carrier or vehicle. In some embodiments, the pharmaceutical compositions described herein are suitable for oral, parenteral, mucosal, transdermal or topical administration.

In certain embodiments, provided herein are compositions comprising one or more solid forms of Compound 1. Also provided herein are compositions sing: (i) one or more solid forms of nd 1 provided herein (e.g., one or more cocrystal forms or mixtures thereof), and (ii) other active or inactive ingredient(s).

In one ment, 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 pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical compositions provided herein comprise Form 2 of Compound 1 and one or more pharmaceutically acceptable excipients or carriers.

In one embodiment, the pharmaceutical compositions provided herein comprise Form 3 of Compound 1 and one or more pharmaceutically able excipients or carriers. In one embodiment, 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 comprise Form 6 of Compound 1 and one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical compositions ed herein comprise Form 7 of Compound 1 and one or more pharmaceutically acceptable ents or rs. In one embodiment, the ceutical compositions provided herein se Form 8 of Compound 1 and one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical compositions provided herein comprise one or more of the following solid forms or a mixture thereof: Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7 and Form 8 of Compound 1 and one or more pharmaceutically acceptable excipients or rs.

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

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

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

In n embodiments, the disintegrants include, but are not limited to, starch (e.g., corn starch) and ymethyl cellulose (e.g., croscarmellose sodium, such as AC-DI-SOL®). In one ment, the disintegrant is starch. In another embodiment, the disintegrant is corn starch. In yet another embodiment, the disintegrant is carboxymethyl cellulose. In yet another embodiment, the disintegrant is rmellose sodium. In still another embodiment, the disintegrant 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 embodiment, the ant is starch. In another embodiment, the lubricant is corn starch. In yet another embodiment, the lubricant is magnesium te. In still another embodiment, the lubricant is stearic acid.

In r embodiment, the pharmaceutical compositions provided herein comprise a solid form of Compound 1 and one or more pharmaceutically acceptable ents or carriers, each independently selected from ymethyl cellulose, ose, lactose, magnesium stearate, , 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 embodiment, 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 e, about 0.5% by weight of stearic acid, and about 0.65% by weight of magnesium stearate.

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

In another ment, the pharmaceutical compositions provided herein comprise about 10% by weight of a solid form of Compound 1, about 58.95% by weight of ol, 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 0.5% disodium EDTA, about 0.4% BHT, and about 0.65% by weight of magnesium stearate.

In certain embodiments, provided herein are pharmaceutical itions comprising an opaque g. 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 formulated 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 tablet.

In n ments, provided herein are pharmaceutical itions, n 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 ed 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 dually as is known in the art. Each unit-dose contains a predetermined quantity of an active ingredient(s) sufficient to produce the desired therapeutic effect, in association with the required ceutical carriers or excipients. Examples of a unitdosage form include an individually packaged tablet or capsule. A unit-dosage form may be administered in fractions or multiples thereof. A multiple-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, provided 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 pharmaceutically acceptable salt, isotopologue or solid form thereof.

In a particular embodiment, provided herein are unit dosage formulation comprising 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 formulations that comprise about 2.5 mg, about mg, about 7.5 mg, about 8 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 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 pharmaceutically able salt, tautomer, isotopologue or stereoisomer 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 In some embodiments, a unit dosage form comprising Compound 1, or a pharmaceutically acceptable salt, isotopologue or solid form 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, Form 6, Form 7 or Form 8) and the desired amount of excipients (such as e monohydrate, croscarmellose sodium and/or rystalline cellulose); (ii) mixing or blending the solid form of Compound 1 and the excipients; (iii) passing the mixture of the solid form of Compound 1 and ents through a screen (such as a 25 mesh screen); (iv) mixing or blending the solid form of Compound 1 and the ents after passage through the screen; (v) ng 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 35 mesh screen); (vii) mixing or blending the solid form of Compound 1, the excipients and the lubricating agents; (viii) compressing the mixture of the solid form of nd 1, the excipients and the lubricating agents (such as into a tablet form); and optionally (ix) g the compressed e of the solid form of Compound 1 thereof, the excipients and the ating agents with a coating agent (such as Opadry pink, yellow or beige). In certain embodiments, the methods for ing a composition provided herein are carried out in the dark, under yellow light or in the absence of UV light.

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

In certain embodiments, the pharmaceutical compositions provided herein comprise Form 2 of Compound 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 ments, the pharmaceutical compositions provided herein comprise Form 4 of Compound 1, including substantially pure Form 4.

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

In certain embodiments, the pharmaceutical compositions provided herein comprise Form 6 of Compound 1, ing substantially pure Form 6.

In certain embodiments, the pharmaceutical itions provided herein comprise Form 7 of nd 1, including ntially pure Form 7.

In certain embodiments, the pharmaceutical compositions provided herein comprise Form 8 of Compound 1, including substantially pure Form 8. 6. EXAMPLES The following Examples are presented by way of illustration, not limitation.

The following abbreviations are used in descriptions and examples: 2MXETOH: 2-Methoxyethanol AAC: Accelerated aging conditions (48 hours at 40°C and 75% RH) ACN: Acetonitril Am: Amorphous AmPhos: p-Dimethylamino phenylditbutylphosphine API: Active Pharmaceutical Ingredient AS: ID for anti-solvent crystallization experiment Boc: utoxycarbonyl dba: Dibenzylidene acetone DCM: Dichloromethane DIPEA: N,N-Diisopropylethylamine DMF: N,N-Dimethylformide DMSO: Dimethylsulfoxide DSC: Differential Scanning Calorimetry ECP: ID for evaporative experiment EDTA: Ethylenediamine tetraacetate ESI: Electronspray tion EtOH: Ethanol FTIR: Fourier Transform Infra Red oscopy GRP: Grinding experiment HF: ID for hot-filtration crystallization experiment HPLC: High mance liquid chromatography IPA: 2-Propanol LCMS: Liquid Chromatography with Mass Spectroscopy MeOH: Methanol mp: Melting point MS: Mass ometry Ms: Mesylate or methanesulfonyl MTBE: utyl methyl ether MTBE: methyl tert-butyl 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 ments RH: Relative Humidity RT: Room Temperature S: Solvent SDTA: Single Differential Thermal Analysis SLP: ID for slurry experiment SM: Starting al TA: Thermal is TCP: ID for thermocycling and reflux experiment Tf: triflate or trifluoromethanesulfonyl TFA: Trifluoroacetic acid TFE: 2,2,2-Trifluoroethanol TGA: Thermogravimetric Analysis TGA-MS/TG-MS: Thermogravimetric 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 Analytical Methods XRPD patterns were obtained using the Crystallics T2 high-throughput XRPD set-up. The plates were mounted on a Bruker GADDS diffractometer equipped with a Hi- Star area detector. The XRPD platform was calibrated using Silver Behenate for the long dspacings and Corundum for the short ings. Data collection was carried out at room temperature using monochromatic CuKα radiation in the 2θ region between 1.5o and 41.5o, which is the most distinctive part of the XRPD pattern. The ction pattern of each well was collected in two 2θ ranges (1.5o ≤ 2θ ≤ 21.5o for the first frame, and 19.5o ≤ 2θ ≤ 41.5o for the second frame) with an re time of 90s for each frame. No background subtraction or curve smoothing was applied to the XRPD patterns. The carrier material used during XRPD analysis was transparent to X-rays and buted only slightly to the background.

DSC analyses were performed on a DSC822e instrument (Mettler-Toledo GmbH, Switzerland). The e was calibrated for temperature and enthalpy with a small piece of indium (m.p. is 156.6°C; ΔHf is 28.45 J/g). Samples were sealed in standard 40µl aluminum pans, pin-holed and heated in the DSC from 25 °C to 300 °C, at a heating rate of 10 °C/min. Dry N2 gas, at a flow rate of 50 ml/min was used to purge the DSC ent during measurement. The cycling DSC’s were ed in standard 40µl aluminum pans, led and heated in the DSC from 25°C to 190°C, then cooled back to 25°C. The heating and cooling rate was 10°C/min. Dry N2 gas, at a flow rate of 50 ml/min was used to purge the DSC equipment during measurement.

TGA/SDTA analysis was adopted to determine mass loss caused by solvent or water loss from crystals. Monitoring the sample weight, during heating in a TGA/SDTA851e instrument (Mettler- Toledo GmbH, Switzerland), results in a weight vs. temperature curve.

The TGA/SDTA851e was calibrated for temperature with indium and aluminum. s were weighed into 100 µL um crucibles and sealed. The seals were pin-holed and the crucibles heated in the TGA from 25°C to 300°C at a heating rate of 10°C/min. Dry N2 gas was used for purging. The gases evolved from the TGA samples were analyzed by a mass spectrometer Omnistar GSD 301 T2 (Pfeiffer Vacuum GmbH, Germany). The latter is a quadrupole mass spectrometer, which analyses masses in the range of 0-200 amu. l images were automatically collected for all the wells of each wellplate , employing a Philips PCVC 840K CCD camera controlled by Crystallics lider software.

FTIR spectra were recorded on a ThermoFischer Scientific FT-IR: t 6700.

Morphology analysis of the samples was carried out on an Olympus microscope. Small amounts of samples were dispersed in l oil on a glass slide with cover slips and viewed with 20x or 50x magnification.

Hygroscopicity was determined on a Surface Measurement 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 relative humidity was increased from 0 % to 90 %RH at 10%RH step then 95 %RH. The relative humidity was then sed in a similar manner to accomplish a full adsorption/desorption cycle. For selected hydrated forms, the is started at 50 %RH and increased to 90 %RH at 10 %RH step. The relative humidity was then decreased in a similar 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) experimental conditions cturer 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 UV-Detector DAD Range 200 – 400 nm Wavelength 254 nm Slit width 4 nm Time 0-12 min ector MSD Scan positive Mass Range 70 – 1000 amu Fragmentator 70 Time 0-12 min Autosampler: Temperature Not controlled Injection mode loop Injection volume 5 µL Needle wash 2/3; O (v/v) Dilution solvent 0.1% TFA water/acetonitrile (v/v=50/50) Table 2. High Performance Liquid Chromatography (HPLC) mental gradient program Time (mins) %A %B 0 90 10 1 90 10 6 10 90 9 10 90 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:  areapeak areapeak %   %100  areatotal ] The peak-area percentage of the compound of st is ed as an tion of the purity of the ent in the sample.

Crystal16® multiple-reactor system (Avantium Technologies) holds 16 (4 x 4) standard HPLC glass vials (11.5 mm diameter, flat bottomed, 1.8 mL volume). A unit consists of four independently heated aluminum reactor blocks encased in a robust bench top setup. These blocks are electrically heated and cooled by a combination of r 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 control accuracy 0.1°C Heating/cooling ramps Programmable between 0°C and 20°C/min Stirrer speed (magnetic stirrer Programmable from 0 - 1250 rpm bars) Turbidity measurement Per individual reactor in transmission 6.2 y of Cocrystal Formation Screen A total of 316 cocrystal formation experiments were divided over four different crystallization methods. Based on the al structure of Compound 1, 15 different ers were selected (Table 5). The cocrystal formation experiments were performed as described in § 6.3.

Physical stability of all samples was studied by ng all solids to accelerated ageing conditions (40°C/75% RH for 48 hours) followed by re-analysis by XRPD and digital imaging. After exposure to accelerated ageing conditions, all solids were reclassified on the basis of their new XRPD patterns. The assignment of solid forms was primarily based on the XRPD analysis.

] The cocrystals formed with Benzoic acid (Form 1), Fumaric acid (Form 2 and Form 3), Gentisic acid (Form 4 and Form 5), Nicotinamide (Form 6) and Succinic acid (Form 7) appear to be stable at accelerated aging conditions (40°C and 75%RH). However, the cocrystals show a relatively high t of an impurity. The impurity was determined either by FT-IR or HPLC.

The cocrystal with maleic acid (Form 8) was stable after exposure to accelerated ageing ions for (40°C/75% RH for 48 hours) and confirmed by TGMS, FTIR and HPLC is. Concluding remarks per analysis of these solids are given in Table Table 4. Summary table of the analytical experiments, results and conclusions of the cocrystals of Compound 1 Form 1 Form 2 Form 3 Form 4 XRPD Unique pattern Unique pattern Unique pattern Unique pattern TGMS 5% mass loss 5.1% mass loss 4.2% mass loss 1.7% mass loss (methanol) (water) (water & methanol ) (water) SDTA Series of Series of Series of Series of endothermic endothermic events endothermic events ermic events events (Tpeak is 101.3; (Tpeak is 89 & (Tpeak is 115 & (Tpeak is 93 & 141.6; 169.4 & 259°C 177°C) 178.1°C) 199°C) Exotermic decomposition) event 173°C HPLC Purity of Cmpd 1 Purity of Cmpd 1 Purity of Cmpd 1 Purity of Cmpd 1 (97.5%) Impurity (97.9%) ty (99.6%) (100%) RT=4.54min with RT=4.54min with 1.34% 0.9% FTIR Changes in the Changes in the s in the Changes in the spectrum as spectrum as spectrum as spectrum as compared compared to compared to that of compared to that of to that of the starting that of the the starting the starting material 1800- starting al material 1800- material 1800- 1400cm-1 shifts 1800-1400cm-1 1400cm-1 shifts 1400cm-1 shifts tertiary amines shifts tertiary tertiary amines but tertiary amines but , but also also presence of also presence of presence of the the ty the impurity impurity determined by determined by determined by HPLC HPLC HPLC Conclusio Cocrystal of Cocrystal of Cocrystal of Cmpd Cocrystal of Cmpd 1 n Cmpd 1 with Cmpd 1 with 1 with fumaric acid with gentisic acid benzoic acid fumaric acid, Form 5 Form 6 Form 7 Form 8 XRPD Unique pattern Unique pattern Unique pattern Unique pattern TGMS 1.6% mass loss 3.8% mass loss 3.8% mass loss 4.6% mass loss (water) (THF & water) (water) (water) SDTA Series of Series of Series of Single melting point endothermic events endothermic events endothermic events (Tpeak is 118.7 °C) (Tpeak is 194 & 236 (Tpeak is 115.7 & (Tpeak is 108.8; °C) 133.8 °C) 163.4 & 260 °C decomposition) HPLC Purity of Cmpd 1 Purity of Cmpd 1 Purity of Cmpd 1 Purity of Cmpd 1 (92%) (100%) ) Impurity (100%) RT=4.54min with 0.6% FTIR Changes in the Changes in the s in the s in the spectrum as spectrum as spectrum as spectrum as compared compared to that compared to that ed to that to that of the starting of the starting of the starting of the starting material 1800- material 1800- material 1800- material 1800- 1600cm-1 shifts 1400cm-1 shifts 1400cm-1 shifts 1400cm-1 shifts tertiary amines ry amines, tertiary amines, tertiary amines, but also presence but also presence but also presence of the ty as of an impurity of the impurity as determined by determined by HPLC as well HPLC as well Conclusio Cocrystal of Cocrystal of Cmpd Cocrystal of Cmpd Cocrystal of Cmpd 1 n Cmpd 1 with 1 with 1 with succinic with maleic acid gentisic acid nicotinamide acid Form 1, a tal solid form of Compound 1 with benzoic acid, is a methanol solvated form which ates at 89 oC and undergoes degradation starting with 200 oC. Both HPLC and FT-IR indicated the presence of an impurity with retention time of 4.54 minutes. Nevertheless the FT-IR spectrum indicated that Compound 1 forms cocrystals with c acid.

Form 2 and Form 3 are two cocrystal solid forms of Compound 1 with fumaric acid. Form 2 is a e and Form 3 is a mixed hydrate/solvate with methanol. Apparently both Form 2 and Form 3 undergo desolvation and melt at a temperature around 177 oC. The FT-IR spectra of Form 2 and Form 3 indicated that Compound 1 forms cocrystals with fumaric acid, although impurities were more visible in the Fum 2 spectra. Nevertheless, the HPLC data of Form 2 indicates the existence of the impurity with retention time 4.54 minutes.

Form 4 and Form 5 are two cocrystal solid forms of Compound 1 with gentisic acid. FT-IR spectrum confirms cocrystallization for both Form 4 and Form 5. Nevertheless, Form 5 seems to contain impurity based on both HPLC and FT-IR analysis. On the other hand Form 4 is a chemically pure material, but SDTA signal of Form 4 showes that Form 4 may undergo through several solid state transformations during the SDTA analysis. Form 4 first desolvates and the process is followed by another series of endothermic events. Also the coformer alone was observed in the SDTA signal of Form 4.

] Form 6 is a cocrystal formed by nd 1 with nicotinamide and seems to be a mixed solvate/hydrate with THF. Form 6 first desolvates at a temperature around 115 oC, followed by melt event at 134 oC and decomposition starting with 200 oC. Although HPLC data shows a high sample purity, some traces of impurity were detected by FT-IR.

Form 7 is a cocrystal formed by nd 1 with ic acid which desolvates at 108 oC and melts at 163 oC. Degradation of the cocrystal takes place at 200 oC and the melting event of the free base was observed at around 260 oC. The FT-IR spectra confirms the co- crystallization of Compound 1 with succinic acid. Nevertheless, the impurity with a ion time of 4.54 s was also observed in samples.

Form 8 is a cocrystal formed by Compound 1 with maleic acid. The SDTA signal shows that Form 8 dehydrates and melts at around 120 oC followed by immediate decomposition. The FT-IT spectrum confirms the cocrystal formation of nd 1 with maleic acid. Purity of Form 8 sample was assessed as 100%(area) by HPLC.

Almost all the igated cocrystals (Form 1, Form 2, Form 3, Form 4, Form , Form 6 and Form 7) with the exception of Form 8 show multiple endothermic events by the SDTA signal suggesting their solvated/hydrated nature and also possible solid-state phase transformations that may take place at molecular level.

TGMS analysis of all the cocrystals (Form 1, Form 2, Form 3, Form 4, Form , Form 6, Form 7 and Form 8) reveal that these cocrystals are solvated and/or hydrated.

Form 8 has a g point above 120°C but significantly lower than Compound 1 free base and therefore it might be an indication of a higher solubility of this cocrystal over that of the free base.

HPLC analysis of Form 1, Form 2, Form 5 and Form 7 show the presence of an impurity with a retention time of 4.54 minutes.

The FT-IR spectra of Form 1, Form 2, Form 3, Form 4, Form 5, Form 6, Form 7 and Form 8 clearly show significant changes in the shifts at around 1800-1400cm-1 indicating the interaction of co- former les with the nitrogens of Compound 1.

On the basis of the results presented above, it is possible to make co- crystals of Compound 1 with both aliphatic and ic carboxylic acids (e.g., fumaric, maleic, succinic, benzoic and gentisic acid) as well as with amides (e.g., nicotinamides). 6.3 Experimental Methods In total, 316 experiments were performed, including 124 cooling evaporative experiments, 64 slurry experiments, 64 powder in saturated solution experiments and 64 grinding experiments. In all methods, 4 solvents (see Table 6) and 15 coformers were tested (see Table 5), including 4 blank experiments per . The coformers and the solvents used were the same for all four methods. The coformers have been selected on the basis of their H-bonding capability, diversity, pharmaceutical ability and solubility in the proposed solvents. An overview of the ation of s and ts used is provided in Table 5 and Table 6. The ts used in the polymorph screen were either HPLC or reagent grade.

Table 5. Coformers used in the cocrystal screen # Cocrystal former # Cocrystal former 1 N-methyl-D-Glucamine 9 Cinnamamide 2 Maleic acid 10 Saccharin 3 Glutamic acid, L- 11 L-Tyrosine 4 c Acid 12 Dihydroxybenzoic acid, 2,5- L(+)-Arginine 13 Choline chloride 6 Nicotinamide 14 Succinic acid 7 Fumaric acid 15 Lysine-,L 8 Tromethamine - - Table 6. Solvents used in the cocrystal screen # Solvents 1 Methanol 2 Tetrahydrofuran 3 Methanol / Water (50/50) 4 Tetrahydrofuran / Water (50/50) 6.3.1 Cooling evaporative experiments The cooling evaporative experiments employed 6 coformers, 4 solvents and two Compound 1:coformer ratios (see Table 8). Compound 1 free base (the starting al) and coformers were solid dosed in 1.8 mL experimental vials. A suitable volume of t was added to reach a close-to saturated solution. Following, the HPLC vials were capped and placed in the Crystal16® system to undergo the temperature profile as described in Table 7.

Also 4 control experiments were performed. At the end of the temperature profile, the solids were separated from the liquids, dried and analyzed by XRPD and digital imaging. The mother liquids after tion of solids were evaporated and the remaining solids analyzed by XRPD and digital imaging too.

Subsequently, all solids were placed in a e chamber at 40°C and 75% RH for 48 hours and again analyzed by XRPD and l imaging.

Table 7: ature profiles (Tprofile) for the cocrystallization experiments Tstart (°C) Heating rate Tmax (°C) Hold Cooling Tend Age time (h) (°C/min) (minute) rate (°C/h) (°C) 10 40 60 1 2 48 Table 8: Experimental conditions of the cocrystal g evaporation experiments Coformer (CI) Solvent Mass of Mass Ratio Dissolved Solids starting CI (SM:CI) before after material (mg) Tprofile Tprofile (mg) Maleic acid MeOH 30.4 11.60 No Yes THF 30.7 11.80 No Yes MeOH/Water 29.8 12.10 1:1.1 No Yes THF/Water 30.1 11.70 No Yes (50/50) MeOH 30.5 41.60 1:4 No Yes THF 29.5 41.30 No Yes MeOH/Water 30.0 42.10 No Yes (50/50) THF/Water 30.2 41.40 No No (50/50) MeOH 30.1 12.60 No Yes THF 30.5 11.90 No Yes MeOH/Water 31.6 12.00 1:1.1 No Yes (50/50) THF/Water 30.4 12.90 No Yes Benzoic Acid (50/50) MeOH 30.3 44.40 No Yes THF 29.8 44.50 No Yes MeOH/Water 30.0 43.80 1:4 No Yes (50/50) ter 30.0 44.50 No Yes (50/50) MeOH 29.8 12.70 No Yes THF 30.8 11.90 No Yes MeOH/Water 31.1 12.50 1:1.1 No Yes (50/50) ter 29.7 12.50 No Yes Nicotinamide (50/50) MeOH 30.0 44.70 No Yes THF 30.3 44.70 No Yes MeOH/Water 30.5 46.20 1:4 No Yes (50/50) THF/Water 29.8 44.10 No Yes (50/50) MeOH 30.0 11.90 No Yes THF 30.2 13.80 No Yes MeOH/Water 29.8 12.00 1:1.1 No Yes (50/50) THF/Water 29.9 11.70 No Yes Fumaric acid ) MeOH 29.6 42.40 No Yes THF 29.6 41.80 No Yes MeOH/Water 30.2 41.90 1:4 No Yes (50/50) THF/Water 30.2 42.10 No Yes (50/50) Gentisic acid MeOH 30.9 15.40 1:1.1 No Yes (Dihydroxy THF 29.8 15.90 No Yes benzoic acid, 2,5-) ater 29.6 15.50 No Yes (50/50) THF/Water 29.7 15.50 No Yes MeOH 29.6 55.30 No Yes THF 30.1 55.30 No Yes MeOH/Water 30.6 56.30 1:4 No Yes (50/50) THF/Water 30.3 55.00 No Yes (50/50) MeOH 29.8 12.00 No Yes THF 30.7 11.70 No Yes MeOH/Water 30.4 11.80 1:1.1 No Yes (50/50) THF/Water 29.8 12.00 No Yes (50/50) Succinic acid MeOH 29.8 42.40 No Yes THF 30.7 43.00 No Yes MeOH/Water 29.7 43.20 1:4 No Yes (50/50) THF/Water 30.1 42.60 No Yes (50/50) MeOH 30.0 - No Yes THF 30.1 - No Yes none MeOH/Water 30.2 - No - Yes (50/50) THF/Water 29.9 - No Yes (50/50) Volume of solvent is 1000 µL. 6.3.2 Powder in saturated solutions experiments In these experiments 6 coformers and 4 solvents were tested (see Table 9). In each solvent, saturated solutions of Compound 1 were prepared. To the saturated solutions the solid coformers were added until the coformer did not ve e or precipitation occurred. The samples remained for 4 hours at ambient temperature, while stirring. In addition, 6 control experiments were performed. Subsequently, the solids were separated from the liquids. The solids were dried and mother liquors evaporated under vacuum. All obtained solids were then analyzed by XRPD and digital imaging.

The solids were placed in a e chamber at 40°C and 75% RH for 48hr after which they were analyzed by XRPD and digital g.

Table 9. Experimental conditions for the “powder in saturated solutions” experiments er (CI) Solvent Mass of Mass of Molar Dissolved Solids Cmpd 1 Coformer Ratio before after (mg) (mg) (Cmpd 1: Tprofile Tprofile Coformer) THF 20.0 34.90 1:5 No Yes MeOH/Water 20.0 34.90 1:5 No No Maleic acid (50/50) THF/Water 20.0 34.90 1:5 No No MeOH 20.0 34.90 1:5 No Yes THF 20.0 36.70 1:5 No No MeOH/Water 20.0 36.70 1:5 No Yes Benzoic Acid (50/50) THF/Water 20.0 36.70 1:5 No No (50/50) MeOH 20.0 36.70 1:5 No Yes THF 20.0 36.30 1:5 No Yes MeOH/Water 20.0 36.30 1:5 No No Nicotinamide (50/50) THF/Water 20.0 36.30 1:5 No Yes MeOH 20.0 36.30 1:5 No Yes THF 20.0 34.90 1:5 No Yes MeOH/Water 20.0 34.90 1:5 No Yes Fumaric acid (50/50) THF/Water 20.0 34.90 1:5 No Yes (50/50) MeOH 20.0 34.90 1:5 No Yes THF 20.0 46.30 1:5 No Yes ater 20.0 46.30 1:5 No Yes Gentisic acid (50/50) (Dihydroxy THF/Water 20.0 46.30 1:5 No Yes benzoic acid, 2,5-) (50/50) MeOH 20.0 46.30 1:5 No No THF 20.0 35.50 1:5 No Yes MeOH/Water 20.0 35.50 1:5 No No (50/50) Succinic acid THF/Water 20.0 35.50 1:5 No Yes (50/50) MeOH 20.0 35.50 1:5 No Yes THF 20.0 - 1:5 No No MeOH/Water 20.0 - 1:5 No No (50/50) none THF/Water 20.0 - 1:5 No No (50/50) MeOH 20.0 - 1:5 No Yes Volume of solvent is 1000 µL. 6.3.3 Slurry experiments Compound 1 free base was solid dosed in 1.8 mL scale mental vials.

The coformer was added with a ratio of 1:1.1 (Compound 1:coformer). The solvent and a stirring bar were added to the vials. The experiments used 6 ers and 4 solvents (see Table 10) and 4 control experiments without coformer were also performed. Then the vials were capped and stirred at ambient conditions for 3 days. After the solids were separated from the liquids, the solids were analyzed wet by XRPD and l imaging. Then both the solids and mother liquors were dried and evaporated under vacuum at t temperature (10 mbar for 24 hours). The solids obtained were then analyzed by XRPD and digital g. Subsequently, the solids were incubated in a climate chamber at 40°C and 75% RH for 48 hours and again analyzed by XRPD and digital imaging.

Table 10. Experimental conditions of the cocrystal slurry experiments Coformer (CI) Solvent Mass of Mass Molar Dissolved Solids Cmpd 1 CI Ratio before after (mg) (mg) (Cmpd 1: Tprofile Tprofile Coformer) Maleic acid MeOH 30.3 12.00 1:1.1 No Yes THF 30.3 11.40 1:1.1 No Yes MeOH/Water 29.9 11.60 1:1.1 No Yes (50/50) THF/Water ) 30.6 11.90 1:1.1 No Yes MeOH 30.2 12.00 1:1.1 No Yes THF 30.1 12.60 1:1.1 No Yes Benzoic Acid MeOH/Water 30.4 13.00 1:1.1 No Yes (50/50) THF/Water (50/50) 30.1 13.40 1:1.1 No Yes MeOH 30.1 12.40 1:1.1 No Yes THF 30.0 12.40 1:1.1 No Yes Nicotinamide MeOH/Water 30.4 12.30 1:1.1 No Yes THF/Water (50/50) 29.8 12.70 1:1.1 No Yes MeOH 30.7 12.00 1:1.1 No Yes THF 29.7 12.30 1:1.1 No Yes Fumaric acid MeOH/Water 29.6 12.10 1:1.1 No Yes (50/50) THF/Water ) 30.9 11.90 1:1.1 No Yes MeOH 29.9 15.70 1:1.1 No Yes Gentisic acid THF 30.7 15.80 1:1.1 No Yes (Dihydroxy MeOH/Water 30.4 16.00 1:1.1 No Yes benzoic acid, 2,5-) (50/50) THF/Water (50/50) 30.1 16.10 1:1.1 No Yes MeOH 30.5 11.60 1:1.1 No Yes THF 29.8 11.70 1:1.1 No Yes Succinic acid MeOH/Water 30.1 12.80 1:1.1 No Yes (50/50) THF/Water (50/50) 29.8 12.20 1:1.1 No Yes MeOH 30.5 0.10 1:1.1 No Yes THF 29.7 0.10 1:1.1 No Yes none MeOH/Water 30.2 0.10 1:1.1 No Yes (50/50) THF/Water (50/50) 30.6 0.10 1:1.1 No Yes Volume of solvent is 500 µL. 6.3.4 Grinding experiments 64 single-solvent-drop grinding experiments were performed using 6 coformers and 4 solvents. Moreover 4 control experiments were performed. Compound 1 free base was d into metal ng vials, containing two stainless steel ng balls.

The coformers and solvents were added (see Table 11). The molar ratio of compound 1 free base and the coformer is 1:1.1. The experiments were shaken for 1 hour at a frequency of 30 Hz. After the 1-hour shaking, the samples were analyzed by XRPD and digital imaging.

Subsequently the samples were exposed to accelerated aging conditions (40°C, 75% RH) for 48hr and re- analyzed by XRPD and l imaging.

Table 11. Conditions of grinding experiments Coformer Solvent Mass of Mass of Solids after Cmpd 1 Coformer le (mg) (mg) MeOH 29.9 12.30 Yes THF 30.1 11.70 Yes Maleic acid MeOH/Water (50/50) 30.1 11.60 Yes THF/Water ) 29.8 11.80 Yes MeOH 29.8 12.90 Yes THF 29.6 12.50 Yes Benzoic Acid MeOH/Water (50/50) 30.1 12.70 Yes THF/Water (50/50) 29.9 12.40 Yes MeOH 30.3 12.90 Yes THF 30.0 12.20 Yes Nicotinamide MeOH/Water (50/50) 30.1 12.80 Yes THF/Water (50/50) 29.9 12.60 Yes MeOH 30.3 11.90 Yes THF 29.9 12.10 Yes Fumaric acid MeOH/Water (50/50) 29.9 12.00 Yes THF/Water (50/50) 30.2 11.90 Yes MeOH 29.6 15.40 Yes Gentisic acid THF 29.8 15.40 Yes (Dihydroxy benzoic acid, 2,5-) MeOH/Water (50/50) 29.7 15.30 THF/Water (50/50) 29.9 15.40 Yes Succinic acid MeOH 30.8 11.70 Yes THF 29.7 11.90 Yes MeOH/Water ) 29.6 12.00 Yes THF/Water (50/50) 30.0 11.30 Yes MeOH 30.3 0.10 Yes THF 30.0 0.10 Yes none ater ) 30.0 0.10 Yes THF/Water (50/50) 31.1 0.10 Yes Volume of solvent is 10 µL. 6.3.5 tal Solid Form 1 Form 1 was prepared in grinding experiments when benzoic acid was used as er and the mixture of methanol and water (50/50) was used as solvent. Form 1 is a methanol solvated cocrystal form of Compound 1 and benzoic acid. provides an overlay of XRPD patterns (from bottom to top) of: Compound 1, Form 1 and benzoic acid. A list of X-Ray Diffraction Peaks for Form 1 is provided below in Table 12.

Table 12. X-Ray Diffraction Peaks for Form 1 Relative Two-theta angle (°) d Space (Å) Intensity (%) 7.78 11.35 82.06 13.02 6.79 54.62 13.54 6.53 23.54 .62 4.3 10.7 24.26 3.66 21.5 .02 3.55 45.6 26.1 3.41 27.99 ] and provide TGMS data and TA data of Form 1, respectively. A mass loss of 5% corresponding to methanol was observed during an endothermic event with Tpeak 89°C suggesting the solvated nature of the sample. According to the SDTA signal in degradation already starts at 200°C. provides HPLC and MS data of Form 1. The peak retention time is 4.8 minutes. HPLC data indicates that the sample purity is 97.5% (area%). provides an FTIR overlay of the starting material Compound 1 (blue), Form 1 (red) and benzoic acid (green). The overlay indicates that the main shifts take place in the spectra in the region 1800-1500cm-1 and 1600-1400cm-1. provides an FTIR y of the starting al Compound 1 (blue), Form 1 (red) and benzoic acid (green) in the region of 1800-400 cm-1. The overlay emphasizes the area between 1800-1500cm-1 and 1600-1400cm-1 corresponding to tertiary amines shifts where the H-bonding is taking place between the coformer and Compound 1. 6.3.6 tal Solid Form 2 Form 2 was ed in grinding experiments when fumaric acid was used as coformer and the mixture of methanol and water (50/50) was used as solvent. Form 2 is a hydrated cocrystal form of Compound 1 and fumaric acid. provides an overlay of XRPD patterns (from bottom to top) of: Compound 1, Form 2, Form 3 and Fumaric acid. A list of X-Ray Diffraction Peaks for Form 2 of Compound 1 is provided below in Table 13.

Table 13. X-Ray Diffraction Peaks for Form 2 Relative Two-theta angle (°) d Space (Å) Intensity (%) 7.66 11.53 77.32 .42 8.48 37.33 14.02 6.31 23.27 17.46 5.07 16.56 18.38 4.82 14.78 19.3 4.59 16.49 24.06 3.69 27.03 27.02 3.3 85.2 and provide TGMS data and TA data of Form 2. A mass loss of 5.1% between about 35 °C and about 135 °C corresponding to water was observed during an endothermic event with Tpeak 115°C suggesting the solvated nature of the sample. According to the SDTA signal in an endothermic melt event was ed at 177°C, followed by immediate decomposition. provides HPLC and MS data of Form 2. The peak retention time is 4.8 minutes. The HPLC data indicates that the sample purity is 98.0% ). provides an FTIR overlay of the starting material Compound 1 (blue), Form 2 (red) and fumaric acid (green). The overlay indicates that the main shifts take place in the a in the region 1800-1500cm-1 and 1600-1400cm-1. provides an FTIR overlay of the starting material nd 1 (blue), Form 2 (red) and fumaric acid (green) in the region of 1800-400 cm-1. The overlay emphasizes the area between 1800-1500cm-1 and 1600-1400cm-1 corresponding to tertiary amines shifts where the H-bonding is taking place n the er and Compound 1. 6.3.7 Cocrystal Solid Form 3 Form 3 was prepared in cooling evaporative experiments when fumaric acid was used as coformer and methanol was used as solvent. Form 3 is a methanol and water solvated cocrystal form of Compound 1 and c acid. provides an overlay of XRPD patterns (from bottom to top) of: Compound 1, Form 2, Form 3 and Fumaric acid. A list of X-Ray Diffraction Peaks for Form 3 of Compound 1 is provided below in Table 14.

Table 14. X-Ray Diffraction Peaks for Form 3 Relative Two-theta angle (°) d Space (Å) Intensity (%) 9.06 9.75 79.55 13.66 6.47 14.11 17.14 5.17 12.91 22.74 3.91 27.27 24.58 3.62 25.39 26.06 3.42 44.2 26.9 3.31 29.59 28.7 3.11 38.87 and provide TGMS data and TG A/SDTA data of Form 3. A mass loss of 4.2% between about 35 °C and about 105 °C corresponding to water and methanol was ed during an endothermic event with Tpeak 93°C ting the solvated nature of the . According to the SDTA signal in , an endothermic melt event was observed at 178.1°C, followed by immediate decomposition. provides HPLC and MS data of Form 3. The peak retention time is 4.8 minutes. The HPLC data indicates that the sample purity is 100.0% (area%). provides an FTIR overlay of the starting material nd 1 (blue), Form 3 (red) and fumaric acid (green). The overlay indicates that the main shifts take place in the spectra in the region 1800-1500cm-1 and 1600-1400cm-1. provides an FTIR overlay of the ng material Compound 1 (blue), Form 3 (red) and fumaric acid (green) in the region of 1800-400 cm-1. The overlay emphasizes the area between 1800-1500cm-1 and 1600-1400cm-1 corresponding to tertiary amines shifts where the H-bonding is taking place n the er and Compound 1. 6.3.8 Cocrystal Solid Form 4 Form 4 was prepared in cooling evaporative experiments when gentisic acid was used as coformer and the mixture of methanol and water (50/50) was used as solvent.

Form 4 is a hydrated cocrystal form of Compound 1 and ic acid. provides an overlay of XRPD patterns of: Compound 1, Form 4, Form 5 and gentisic acid (from bottom to top). A list of X-Ray Diffraction Peaks for Form 4 of Compound 1 is provided below in Table 15.

] Table 15. X-Ray Diffraction Peaks for Form 4 Relative Two-theta angle (°) d Space (Å) Intensity (%) 6.62 13.34 14.26 7.58 11.65 30.02 8.9 9.92 8.57 9.42 9.38 9.56 12.22 7.23 45.27 12.82 6.9 24.53 13.34 6.63 71.66 13.9 6.36 13.45 14.34 6.17 10.11 16.14 5.49 14.05 18.94 4.68 12.58 .46 4.34 7.7 22.34 3.97 24.96 22.9 3.88 53.61 23.66 3.76 24.65 24.22 3.67 28.84 .18 3.53 73.43 26.62 3.34 19.81 27.46 3.24 23.79 33.02 2.71 20.57 and e TGMS data and TG A/SDTA data of Form 4. A mass loss of 1.7% between approximately 110 °C and approximately 150 °C corresponding to water was observed during an endothermic event with Tpeak 101.3 and 141.6°C, suggesting the solvated nature of the sample, followed by another ermic event with Tpeak 169.4°C.

An exothermic event with Tpeak 175°C suggests re-crystallization to another form. According to the SDTA signal in , an endothermic melt event was observed at 199°C, followed by immediate decomposition. provides HPLC and MS data of Form 4. The peak retention time is 4.8 minutes. The HPLC data indicates that the sample purity is 100.0% (area%). provides an FTIR overlay of the starting material Compound 1 (blue), Form 4 (red) and gentisic acid (green). The overlay indicates that the main shifts take place in the spectra in the region 1800-1500cm-1 and 1600-1400cm-1. es an FTIR overlay of the starting material Compound 1 (blue), Form 4 (red) and gentisic acid (green) in the region of 1800-400 cm-1. The overlay emphasizes the area between 500cm-1 and 1600-1400cm-1 corresponding to tertiary amines shifts where the H-bonding is taking place between the coformer and Compound 1. 6.3.9 Cocrystal Solid Form 5 Form 5 was prepared in cooling evaporative ments when gentisic acid was used as coformer and methanol was used as solvent. Form 5 is a ed cocrystal form of Compound 1 and gentisic acid. es an overlay of XRPD ns of: Compound 1, Form 4, Form 5 and gentisic acid (from bottom to top). A list of X-Ray ction Peaks for Form 5 of Compound 1 is provided below in Table 16.

Table 16. X-Ray Diffraction Peaks for Form 5 Two-theta angle (°) d Space (Å) Intensity (%) .82 8.17 17.72 16.9 5.24 9.12 17.42 5.08 60.71 19.3 4.59 22.22 24.7 3.6 89.63 28.34 3.15 33.09 .86 2.89 29.05 37.58 2.39 14.42 and provide TGMS data and TG A/SDTA data of Form 5. A mass loss of 1.6% between approximately 35 °C and approximately 155 °C corresponding to water was observed during an endothermic event with Tpeak 180°C suggesting the solvated nature of the sample. According to the SDTA signal in , an endothermic melt event was observed at 194°C, followed by immediate decomposition at 236 oC. es HPLC and MS data of Form 5. The peak retention time is 4.8 minutes. The HPLC data indicates that the sample purity is 92.0% (area%). provides an FTIR overlay of the starting material nd 1 (blue), Form 5 (red) and gentisic acid (green). The y indicates that the main shifts take place in the spectra in the region 1800-1500cm-1 and 1600-1400cm-1. ] provides an FTIR overlay of the starting material Compound 1 (blue), Form 5 (red) and gentisic acid (green) in the region of 1800-400 cm-1. The overlay emphasizes the area between 500cm-1 and 1600-1400cm-1 corresponding to tertiary amines shifts where the H-bonding is taking place between the coformer and Compound 1. 6.3.10 Cocrystal Solid Form 6 Form 6 was prepared in grinding experiments when nicotinamide was used as er and the mixture of THF and water (50/50) was used as solvent. Form 6 is a ter solvated cocrystal form of Compound 1 and nicotinamide. es an overlay of XRPD patterns of: Compound 1, Form 6 and nicotinamide (from bottom to top). A list of X-Ray Diffraction Peaks for Form 6 of Compound 1 is provided below in Table 17.

Table 17. X-Ray Diffraction Peaks for Form 6 Relative Two-theta angle (°) d Space (Å) Intensity (%) 6.02 14.66 20.63 7.46 11.84 20.21 11.5 7.69 81.85 13.3 6.65 11.43 14.9 5.94 39.22 18.66 4.75 16.2 .38 4.35 18.72 23.42 3.79 82.75 24.18 3.68 47.45 .06 3.55 80.21 26.1 3.41 24.4 26.9 3.31 16.32 27.98 3.19 16.91 28.78 3.1 17.38 provides TGMS data of Form 6. A mass loss of 3.8% corresponding to THF and water was observed during a double endothermic event with Tpeak 115.7°C and 133.8°C, suggesting the solvated nature of the sample. According to the SDTA signal in , an endothermic melt event was observed at the above mentioned temperatures, 115.7°C and 133.8°C, followed by immediate decomposition at 200°C. provides HPLC and MS data of Form 6. The peak retention time is 4.8 minutes. The HPLC data tes that the sample purity is 100.0% (area%). provides an FTIR overlay of the ng material nd 1 (blue), Form 6 (red) and nicotinamide (green). The y indicates that the main shifts take place in the spectra in the region 1800-1500cm-1 and 1600-1400cm-1. provides an FTIR overlay of the ng material Compound 1 (blue), Form 6 (red) and nicotinamide (green) in the region of 1800-400 cm-1. The overlay emphasizes the area between 1800-1500cm-1 and 1600-1400cm-1 corresponding to tertiary amines shifts where the ing is taking place n the coformer and Compound 1. 6.3.11 Cocrystal Solid Form 7 Form 7 was prepared in grinding experiments when ic acid was used as coformer and the mixture of methonal and water (50/50) was used as solvent. Form 7 is a hydrated cocrystal form of Compound 1 and succinic acid. provides an overlay of XRPD patterns of: Compound 1, Form 7 and succinic acid (from bottom to top). A list of X-Ray Diffraction Peaks for Form 7 of Compound 1 is ed below in Table 18.

Table 18. X-Ray Diffraction Peaks for Form 7 Relative Two-theta angle (°) d Space (Å) Intensity (%) 7.62 11.59 72.94 .54 8.38 31.45 13.82 6.4 24.43 17.46 5.07 18.19 17.94 4.94 16.96 19.34 4.58 18.39 24.26 3.66 23.69 26.7 3.33 82.32 27.38 3.25 11.54 provides TGMS data of Form 7. A mass loss of 3.8% corresponding to water was observed during an endothermic event with Tpeak 108.8°C, suggesting the solvated nature of the sample. According to the SDTA signal in , another endothermic melt event was observed at 163.4°C, followed by immediate decomposition. provides HPLC and MS data of Form 7. The peak retention time is 4.8 minutes. The HPLC data indicates that the sample purity is 98.8% (area%). provides an FTIR overlay of the starting material Compound 1 , Form 7 (red) and ic acid (green). The overlay indicates that the main shifts take place in the spectra in the region 1800-1500cm-1 and 1600-1400cm-1. provides an FTIR y of the starting al Compound 1 (blue), Form 7 (red) and succinic acid (green) in the region of 1800-400 cm-1. The overlay emphasizes the area n 1800-1500cm-1 and 1600-1400cm-1 corresponding to tertiary amines shifts where the H-bonding is taking place between the coformer and Compound 1. 6.3.12 Cocrystal Solid Form 8 ] Form 8 was prepared in grinding experiments when maleic acid was used as coformer and the mixture of methonal and water (50/50) was used as solvent. Form 8 is a hydrated cocrystal form of Compound 1 and maleic acid. provides an overlay of XRPD patterns of: Compound 1, Form 8 and succinic acid (from bottom to top). A list of X-Ray ction Peaks for Form 8 of Compound 1 is provided below in Table 19.

Table 19. X-Ray Diffraction Peaks for Form 8 Relative Two-theta angle (°) d Space (Å) Intensity (%) 6.94 12.72 43.53 12.54 7.05 12.02 13.82 6.4 91.12 16.54 5.35 14.71 .82 4.26 7.88 22.18 4 29.97 22.78 3.9 27.37 24.46 3.63 27.58 26.22 3.39 33.82 26.98 3.3 38.32 27.66 3.22 59.4 28.7 3.11 11 Relative Two-theta angle (°) d Space (Å) Intensity (%) 29.66 3.01 12.33 es TGMS data of Form 8. A mass loss of 4.6% corresponding to water was observed during an ermic event with Tpeak C, suggesting the solvated nature of the sample. According to the SDTA signal in , the endothermic event was followed by immediate decomposition. provides HPLC and MS data of Form 8. The peak retention time is 4.8 minutes. The HPLC data indicates that the sample purity is 100.0% (area%). provides an FTIR overlay of the starting material Compound 1 (blue), Form 8 (red) and maleic acid (green). The overlay indicates that the main shifts take place in the spectra in the region 1800-1500cm-1 and 1600-1400cm-1. es an FTIR overlay of the starting material Compound 1 (blue), Form 8 (red) and maleic acid (green) in the region of 00 cm-1. The overlay emphasizes the area between 1800-1500cm-1 and 1600-1400cm-1 corresponding to tertiary amines shifts where the H-bonding is taking place between the coformer and Compound 1. 6.4 BIOLOGICAL EXAMPLES 6.4.1 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 d appropriately for the experiments. Reagents are prepared as s: ] “Simple TOR buffer” (used to dilute high glycerol 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 Cy5-GST Amersham (Cat#PA92002V), 9 ng/mL oc—phospho p70S6 (Thr389) (Cell Signaling Mouse Monoclonal #9206L), 627 ng/mL oc—mouse Lance Eu (Perkin Elmer 0077).

To 20 [IL ofthe Simple TOR buffer is added 0.5 uL of test solid form in DMSO. To initiate the reaction 5 uL Substrate solution is added to 20 uL ofthe Simple TOR buffer solution (control) and to the compound solution prepared above. The assay is d after 60 minutes by adding 5 uL of a 60 mM EDTA solution; 10 [LL 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 TR- FRET (excitation at 320 nm and emission at 495/520 11111).

DNA—PK assay. DNA-PK assay is med using the ures supplied in the Promega DNA—PK assay kit (catalog # V7870). DNA-PK enzyme can be purchased from Promega (Promega cat#V5811). 6.5 FORMULATION EXAMPLES Certain formulations comprising solid forms ofCompound 1 are prepared and tested for a number ofphysical and al properties. Modifications are made and subsequent formulations are also tested, until formulations possessing desirable physical and chemical properties are found. The following example describes these formulations and their testing. '1 study evaluates the effect of diluents, disintegrant and drug M A 23 loading on tablet physical properties and chemical stability. Examples of formulation compositions are shown in Table 20. Initial tablet pment is carried out in normal room UV light.

Table 20: Exemplary Formulation Composition OfVarious Tablet Formulations Solid Form of Comound l m. 0.5 Microcrystalline Cellulose (mg) 63.75 83.75 59.25 79.25 lly atinized corn starch Lactose drate, spray dried Crosovidone m Croscannellose Na m Silicon dioxide m ' __m-mm ”___.- M A study is conducted to evaluate the effect of antioxidant (e.g., butylated hydroxyl toluene, BHT) and chelating agent (e.g., disodium edentate, Nag-EDTA) on the stability of solid forms of Compound 1 in formulated product. The impact of dosage form (tablet vs capsule) on the stability of solid forms of Compound 1 is evaluated. ] es of formulation compositions are shown in Table 21. All of the processes are carried out in dark.

Table 21: ary Formulation ition % w/w Ingredients Capsule Capsule Capsule Capsule Tablet Capsule Solid Form of Co" ound l 0.5 0.5 0.5 0.5 0.5 0.5 ”___-_-anno- em EZ 84 94.1 93.6 83.6 ___—___— Sodium starch - l colate 3 3 3 3 3 3 stearic acid ------ Butylated hydroxy- toluene 0.4 0.4 0.4 0.4 0.4 ___—___ ___-nun— —mmmmmm M Further study can be conducted to study the influence of coating and desiccant on the stability of nd 1 tablets. All processes can be canied out under yellow light to prevent any UV light exposure to the Compound 1 formulations.

An exemplary formulation composition is provided in Table 22.

Table 22: Exemplary Formulation Composition Of Tablet Solid form of - Comound 1 0.5 MCC PH112 n Sodium starch glycolate Butylated hydroxy - toluene 0.4 Naz-EDTA Table 23: Exemplary Tablet Formulations Batch # In u edients Solid form ofCompound 1 active in edient Mannitol Manno - em EZ Microcrystalline Cellulose PH 112 Sodium Starch Gl colate Silicon dioxide Stearic acid um EDTA Ma u: esium Stearate Preparation of Tablets: The blends according to Table 24 to Table 29 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 ofCompound 1) is added and blended for 10 s at 46 rpm using a Turbula mixer. The blend is passed through a 25 mesh screen and blended again for 10 minutes at 46 rpm using a Turbula mixer. The resulting blend is passed through a 35 mesh screen. Remaining excipients are added, except for lubricant sium stearate). The resulting mixture is d 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 1pm using a Turbula mixer. For low strength tablet formulations, 140 mg tablets are prepared using a 7.14 mm punch and die. For high th tablet formulations, 400 mg tablets are prepared using a 10.3 mm punch and die.

Table 24: Exemplary Low Strength Tablet Formulation #1 Ingredient Source Amount (weight %) Solid form of 0.7 Compound 1 microcrystalline FMC 38.1 cellulose ymer Mannitol Roquette 57.2 sodium FMC 3.0 carboxymethylcellulose Biopolymer magnesium stearate Nitika 1.0 Chemicals Table 25: Exemplary Low th Tablet Formulation #2 Ingredient Source Amount (weight %) Solid form of 0.7 Compound 1 microcrystalline FMC 75.3 cellulose Biopolymer pregelatinized starch Colorcon 20.0 sodium FMC 3.0 carboxymethylcellulose Biopolymer magnesium stearate Nitika 1.0 Chemicals Table 26: Exemplary Low Strength Tablet ation #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 ium stearate Nitika 1.0 Chemicals Table 27: Exemplary High Strength Tablet Formulation #1 Ingredient Source Amount (weight %) Solid form of 25.0 Compound 1 microcrystalline FMC 28.4 cellulose ymer Mannitol Roquette 42.6 sodium FMC 3.0 carboxymethylcellulose Biopolymer magnesium stearate Nitika 1.0 Chemicals Table 28: Exemplary High Strength Tablet Formulation #2 Ingredient Source Amount (weight %) Solid form of 25.0 nd 1 microcrystalline FMC 51.0 cellulose Biopolymer pregelatinized starch Colorcon 20.0 sodium FMC 3.0 carboxymethylcellulose Biopolymer magnesium te Nitika 1.0 Chemicals Table 29: ary High Strength Tablet Formulation #3 Ingredient Source Amount (weight %) Solid form of 25.0 Compound 1 microcrystalline FMC 28.4 cellulose Biopolymer e monohydrate Meggle 42.6 Pharma sodium FMC 3.0 ymethylcellulose Biopolymer magnesium stearate Nitika 1.0 Chemicals The above ations are subjected to a 6 week stability study.

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

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

Claims (92)

What is claimed is:

1. A solid form comprising (a) 1-ethyl(2-methyl(1H-1,2,4-triazol idinyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one; and (b) a coformer.

2. The solid form of claim 1, wherein the coformer is c acid, fumaric acid, gentisic acid, nicotinamide, succinic acid or mandelic acid.

3. The solid form of claim 2, wherein the coformer is c acid

4. The solid form of claim 2, wherein the coformer is fumaric acid.

5. The solid form of claim 2, wherein the coformer is gentisic acid

6. The solid form of claim 2, wherein the coformer is nicotinamide.

7. The solid form of claim 2, wherein the coformer is succinic acid.

8. The solid form of claim 2, wherein the coformer is mandelic acid.

9. The solid form of any one of claims 1–8, which is substantially crystalline.

10. The solid form of any one of claims 1–9, which is substantially a cocrystal.

11. The solid form of any one of claims 1–10, which is greater than 80% by weight, r than 90% by weight, greater than 95% by weight, greater than 97% by weight, or greater than 99% by weight of a cocrystal.

12. The solid form of any one of claims 1–11, which is substantially physically pure.

13. The solid form of any one of claims 1–12, which is substantially free of other solid forms of 1-ethyl(2-methyl(1H-1,2,4-triazolyl)pyridinyl)-3,4- dihydropyrazino[2,3-b]pyrazin-2(1H)-one.

14. The solid form of any one of claims 1–12, further comprising amorphous 1- ethyl(2-methyl(1H-1,2,4-triazolyl)pyridinyl)-3,4-dihydropyrazino[2,3-b]pyrazin- one.

15. The solid form of any one of claims 1–13, which is substantially crystalline.

16. A pharmaceutical composition comprising the solid form of any one of claims 1—15.

17. The pharmaceutical composition of claim 16, r comprising a pharmaceutically acceptable excipient or carrier.

18. The pharmaceutical composition of claim 17, which is a single unit dosage form.

19. The pharmaceutical composition of claim 18, which is a tablet.

20. The ceutical composition of claim 18, which is a capsule.

21. A crystal form sing the compound of formula (I): (MNN‘ N / H NI\ N NKO which has an X-ray powder diffraction pattern comprising peaks at approximately 7.78, 13.02 and 25.02 °20.

22. The crystal form of claim 21 which has an X-ray powder diffraction pattern further comprising peaks at approximately 13.54, 24.26 and 26.1 °20.

23. The crystal form of claim 21 which has a thermogravimetric analysis gram comprising a total mass loss of approximately 5% of the total mass of the crystal form when heated from about 25 °C to about 300 °C.

24. The crystal form of claim 21 which has a single ential thermal analysis thermogram comprising an endotherm between about 35 °C and about 105 °C with a maximum at approximately 89 °C when heated from about 25 °C to about 300 °C.

25. The crystal form of claim 21 which is methanol solvated.

26. The crystal form of claim 21 which is substantially pure.

27. A crystal form comprising the compound of formula 0): <’ \ IZ \ _\ which has an X-ray powder diffraction pattern comprising peaks at approximately 7.66, 10.42 and 27.02 °20.

28. The crystal form of claim 27 which has an X—ray powder diffraction pattern further sing peaks at approximately 14.02, 17.46 and 24.06 °20.

29. The crystal form of claim 27 which has a thermogravimetric analysis thermogram comprising a total mass loss of approximately 5.1% of the total mass ofthe crystal form when heated fiom about 25 °C to about 300 °C.

30. The crystal form of claim 27 which has a single differential thermal analysis thermogram comprising an endotherm between about 35 °C and about 135 °C with a maximum at approximately 115 °C when heated from about 25 °C to about 300 °C.

31. The crystal form of claim 30 n the single ential thermal is thermogram further comprises an endotherm with a maximum at approximately 177 °C.

32. The crystal form of claim 27 which is methanol and water solvated.

33. The crystal form of claim 27 which is substantially pure.

34. A crystal form comprising the compound of formula (I): which has an X-ray powder diffraction pattern comprising peaks at approximately 9.06, 26.06 and 28.7 °20.

35. The crystal form of claim 34 which has an X—ray powder diffraction pattern further comprising peaks at approximately 22.74, 24.58 and 26.9 °20.

36. The crystal form of claim 34 which has a gravimetric analysis gram comprising a total mass loss of approximately 4.2% of the total mass ofthe l form when heated fiom about 25 °C to about 300 °C.

37. The crystal form of claim 34 which has a single difl'erential thermal analysis thermogram comprising an endothenn between about 35 °C and about 105 °C with a maximum at approximately 93 °C when heated from about 25 °C to about 300 °C.

38. The crystal form of claim 37 wherein the single differential l analysis thermogram further comprises an endothenn with a maximum at approximately 178.1 °C.

39. The crystal form of claim 34 which is methanol solvated.

40. The crystal form of claim 34 which is substantially pure.

41. A crystal form comprising the compound of formula 0): which has an X-ray powder diffraction pattern comprising peaks at approximately 13.34, 22.9 and 25.18 °20.

42. The l form of claim 41 which has an X-ray powder diffraction pattern further comprising peaks at approximately 7.58, 12.22 and 24.22 °20.

43. The crystal form of claim 41 which has a thermogravimetric analysis thermogram comprising a total mass loss of approximately 1.7% of the total mass ofthe crystal form when heated from about 25 °C to about 300 °C.

44. The crystal form of claim 41 which has a single ential thermal analysis thermogram comprising an endotherm between about 110 °C and about 150 °C with a maximum at approximately 101.3 °C when heated from about 25 °C to about 300 °C.

45. The crystal form of claim 44 wherein the single differential thermal analysis gram further comprises an endotherm with a maximum at approximately 141.6 °C.

46. The crystal form of claim 41 which is water solvated.

47. The l form of claim 41 which is substantially pure.

48. A crystal form comprising the compound of formula (I): (MNN\ N / HN|\ NNKO which has an X—ray powder ction pattern comprising peaks at approximately 17.42, 24.7 and 28.34 °20.

49. The crystal form of claim 48 which has an X-ray powder diffraction pattern fiirther comprising peaks at approximately 10.82, 19.3 and 30.86 °20.

50. The crystal form of claim 48 which has a thermogravimetric analysis thermogram comprising a total mass loss of approximately 1.6% of the total mass ofthe crystal form when heated from about 25 °C to about 300 °C.

51. The crystal form of claim 48 which has a single differential l analysis thermogram comprising an endotherm between about 35 °C and about 155 °C with a maximum at imately 180 °C when heated from about 25 °C to about 300 °C.

52. The crystal form of claim 51 wherein the single differential thermal analysis thermogram further comprises an endotherm with a maximum at approximately 236 °C.

53. The crystal form of claim 48 which is water solvated.

54. The crystal form of claim 48 which is substantially pure.

55. A crystal form sing the compound of formula (I): (MNN\ N / HNI\ NNKO which has an X-ray powder diffraction pattern comprising peaks at approximately 11.5, 23.42 and 25.06 °20.

56. The crystal form of claim 55 which has an X-ray powder diffraction pattern further comprising peaks at approximately 14.9, 24.18 and 26.1 °26.

57. The l form of claim 55 which has a thermogravimetric analysis thermogram sing a total mass loss of approximately 3.8% of the total mass ofthe crystal form when heated from about 25 °C to about 300 °C.

58. The l form of claim 55 which has a single difierential thermal analysis thermogram comprising an endotherm between about 35 °C and about 145 °C with a maximum at approximately 89 °C when heated from about 25 °C to about 300 °C.

59. The crystal form of claim 58 wherein the single ential thermal analysis thermogram further comprises an endotherm with a maximum at approximately 200 °C.

60. The crystal form of claim 55 which is THF solvated.

61. The crystal form of claim 55 which is water solvated.

62. The crystal form of claim 55 which is substantially pure.

63. A crystal form comprising the compound of formula 0): <’ \ IZ \ _\ which has an X-ray powder ction pattern comprising peaks at approximately 7.62, 10.54 and 26.7 °29.

64. The crystal form of claim 63 which has an X—ray powder diffraction pattern further comprising peaks at approximately 13.82, 19.34 and 24.26 °29.

65. The crystal form of claim 63 which has a thermogravimetric analysis thermogram comprising a total mass loss of approximately 3.8% of the total mass ofthe crystal form when heated fiom about 25 °C to about 300 °C.

66. The crystal form of claim 63 which has a single differential l analysis gram comprising an endotherm between about 35 °C and about 145 °C with a maximum at approximately 108.8 °C when heated from about 25 °C to about 300 °C.

67. The crystal form of claim 66 wherein the single ential thermal analysis thermogram further comprises an endotherm with a maximum at approximately 164.3 °C.

68. The l form of claim 63 which is waterl solvated.

69. The crystal form of claim 63 which is substantially pure.

70. A crystal form comprising the compound of a (I): <\”N\ N / HNI\ NNKO which has an X—ray powder diffraction pattern comprising peaks at approximately 6.94, 13.82 and 27.66 °20.

71. The crystal form of claim 70 which has an X-ray powder diffraction pattern fiirther comprising peaks at approximately 22.18, 26.22 and 26.98 °20.

72. The crystal form of claim 70 which has a gravimetric analysis thermogram comprising a total mass loss of approximately 4.2% of the total mass ofthe crystal form when heated from about 25 °C to about 300 °C.

73. The crystal form of claim 70 which has a single difl'erential l analysis thermogram sing an endotherm between about 35 °C and about 145 °C with a maximum at approximately 118.7 °C when heated from about 25 °C to about 300 °C.

74. The crystal form of claim 70 which is water solvated.

75. The crystal form of claim 70 which is substantially pure.

76. Use of a solid form of claim 1 or a pharmaceutical composition thereof in the manufacture of a medicament for for treating or ting cancer, an atory condition, an immunological condition, a neurodegenerative disease, diabete, obesity, a neurological disorder, an age-related disease, a cardiovascular condition, or a ions treatable or preventable by inhibition of a kinase pathway.

77. The use of claim 76, wherein the kinase pathway is the TOR kinase pathway.

78. Use of a solid form of claim 1 or a pharmaceutical composition thereof in the manufacture of a medicament for for achieving a Response Evaluation Criteria in Solid Tumors (RECIST 1.1) of complete response, partial response or stable disease in a subject having a solid tumor.

79. Use of a solid form of claim 1 or a pharmaceutical composition thereof in the manufacture of a medicament for for improving International Workshop Criteria (IWC) for NHL, International Uniform Response Criteria for Multiple Myeloma (IURC), n Cooperative Oncology Group Performance Status (ECOG) or Response Assessment for Neuro-Oncology (RANO) Working Group for GBM.

80. A solid form according to claim 1, substantially as herein described or exemplified.

81. A pharmaceutical composition according to claim 16, substantially as herein described or exemplified.

82. A crystal form according to claim 21, ntially as herein bed or exemplified.

83. A crystal form according to claim 27, substantially as herein described or ified.

84. A crystal form according to claim 34, substantially as herein described or exemplified.

85. A crystal form ing to claim 41, substantially as herein bed or exemplified.

86. A crystal form ing to claim 48, substantially as herein described or exemplified.

87. A crystal form according to claim 55, substantially as herein described or exemplified.

88. A crystal form according to claim 63, substantially as herein described or exemplified.

89. A l form according to claim 70, substantially as herein described or exemplified.

90. A use according to claim 76, substantially as herein described or exemplified.

91. A use according to claim 78, substantially as herein described or exemplified.

92. A use according to claim 79, ntially as herein described or exemplified. SIGNAL PHARMACEUTICALS, LLC By Their Attorneys HENRY HUGHES Per: 3] D 220 Benzoic acid 21 0 _/LH_A_/L_/¥_A_.__/\AJ\_A__ 1 30 1 80 Intensuly _. .._.O 1 50 Helallve 1 50 1 4D 1 3D 1 20 W Fol 1 1 0 1 DD 1 D M Compound 1 S 1 8 20 22 24 28 23 3E! 32 34 3B 38 4D 28 ['1