Solid forms comprising (S)-2-(2,6-dioxopiperidine-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidine-1-yl)methyl)benzyl)amino)isoindolin-1,3-dione and its salts, and compositions comprising the same and uses thereof

Abstract

The present invention provides formulations, methods, solid forms, and methods of use related to the salt of (S)-2-(2,6-dioxopiperidine-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidine-1-yl)methyl)benzyl)amino)isoindolin-1,3-dione and solid forms comprising the free base or salt thereof.

Description

Technology Field

[0001] This application claims priority to U.S. provisional application No. 62 / 923,972 filed on October 21, 2019, the full text of said provisional application incorporated herein by reference.

[0002] 1. Field

[0003] Solid forms comprising the salt of (S)-2-(2,6-dioxopiperidine-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidine-1-yl)methyl)benzyl)amino)isoindolin-1,3-dione and its free base or salt are provided herein. Pharmaceutical compositions comprising such salt and solid forms and methods of using such salt and solid forms for treating, preventing, and managing various disorders are also provided herein. Background Technology

[0004] 2. Background Technology

[0005] Alternative solid forms of pharmaceutical compounds have emerged as a possible approach to modifying or enhancing the physical and chemical properties of drug products. The identification and selection of solid forms of pharmaceutical compounds are complex, considering that changes in solid form can affect various physical and chemical properties and provide benefits or drawbacks, particularly in processing, formulation, stability, bioavailability, storage, and handling (e.g., transport), among other important pharmaceutical characteristics. Useful pharmaceutical solid forms include crystalline solids and amorphous solids, depending on the product and its mode of administration. Amorphous solids are characterized by the absence of long-range structural regularity, whereas crystalline solids are characterized by structural periodicity. The intended class of pharmaceutical solids depends on the specific application; amorphous solids are sometimes selected, for example, based on an improved solubility profile, whereas crystalline solids may be desirable due to properties such as physical or chemical stability (e.g., the literature [SR Vippagunta et al. , Adv. Drug. Deliv. Rev. , (2001) 48:3-26]; [L. Yu, Adv. Drug. Deliv. Rev. , (2001) 48:27-42] see reference).

[0006] In particular, not only is it impossible to successfully manufacture the crystalline form of a compound, but it is also not possible to predict a priori whether they exist (e.g., the literature [Braga and Grepioni, 2005, "Making crystals from crystals: a green route to crystal engineering and polymorphism," Chem. Commun. :3635-3645] (In relation to decision operations, if the guidelines are not very accurate and / or other external factors affect the process, the results cannot be predicted); [Jones et al., 2006, Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement," MRS Bulletin 31 :875-879] (Currently, it is generally not possible to predict the number of observable polymorphs, even for the simplest molecules, using a computer); [Price, 2004, "The computational 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] (See also: Significant learning and performance are still required to state the ability to predict crystal structures with a certain degree of confidence, and even more so for polymorphic forms).

[0007] The type of salt form of a specific active pharmaceutical ingredient can affect specific properties of the active pharmaceutical ingredient. These properties include solubility, stability, and bioavailability.

[0008] Various possible solid forms, including both free base and salt forms, result in potential diversity in the physical and chemical properties of a given pharmaceutical compound. The discovery and selection of solid forms are critical to the development of effective, stable, and marketable pharmaceutical products.

[0009] 3. Overview

[0010] A solid form (e.g., crystalline form, amorphous form, polymorph, or mixture thereof) comprising compound 1 having the chemical name (S)-2-(2,6-dioxopiperidine-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidine-1-yl)methyl)benzyl)amino)isoindolin-1,3-dione is provided herein:

[0011]

[0012] A method for manufacturing, isolating, and characterizing a solid form is also provided herein.

[0013] In one embodiment, the solid form comprises a free base of compound 1. In one embodiment, the solid form is form A or form B of the free base of compound 1 as provided herein.

[0014] In one embodiment, the solid form comprises a salt of compound 1.

[0015] In one embodiment, the solid form comprises a hydrochloride salt of compound 1. In one embodiment, the solid form is form A or form B of the hydrochloride salt of compound 1 as provided herein.

[0016] In one embodiment, the solid form comprises a fumarate salt of compound 1. In one embodiment, the solid form is form A of the fumarate salt of compound 1 as provided herein.

[0017] In one embodiment, the solid form comprises a tosylate salt of compound 1. In one embodiment, the solid form is form A of the tosylate salt of compound 1 as provided herein.

[0018] In one embodiment, the solid form comprises a maleate salt of compound 1. In one embodiment, the solid form is form A of the maleate salt of compound 1 as provided herein.

[0019] In one embodiment, the solid form comprises a besylate salt of compound 1. In one embodiment, the solid form is form A of the besylate salt of compound 1 as provided herein.

[0020] A salt of compound 1 is also provided herein. In one embodiment, the salt is a hydrochloride salt, a fumarate salt, a tosylate salt, a maleate salt, or a besylate salt. In one embodiment, the salt is crystalline. In one embodiment, the salt is amorphous.

[0021] The solid forms provided herein are useful as active pharmaceutical ingredients for the manufacture of formulations for use in animals or humans. Accordingly, embodiments of the present invention encompass the use of these solid forms as final drug substances. Specific embodiments provide solid forms useful for manufacturing final dosage forms having improved properties necessary for the manufacture, processing, formulation, and / or storage of final drug products, e.g., particularly powder flow properties, compression properties, tableting properties, stability properties, and excipient compatibility properties. Specific embodiments of the present invention provide pharmaceutical compositions comprising a single-component crystalline form, a multi-component crystalline form, a single-component amorphous form and / or a multi-component amorphous form of Compound 1, and pharmaceutically acceptable diluents, excipients, or carriers.

[0022] A pharmaceutical composition formulated for administration by an appropriate route and means is also provided, containing an effective concentration in solid form of compound 1 provided herein and optionally comprising at least one pharmaceutical carrier.

[0023] A method of using a solid form comprising Compound 1 provided herein for treating, preventing, or managing a blood malignancy is also provided herein. In one embodiment, the method is intended to treat a blood malignancy. In one embodiment, the method is intended to prevent a blood malignancy. In one embodiment, the method is intended to manage a blood malignancy.

[0024] In one embodiment, the blood malignancy is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), multiple myeloma (MM), non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma (HL), T-cell lymphoma (TCL), Burkitt lymphoma (BL), chronic lymphoblastic leukemia / small lymphoblastic lymphoma (CLL / SLL), marginal zone lymphoma (MZL), or myelodysplastic syndrome (MDS).

[0025] A method of using a solid form comprising Compound 1 provided herein, either alone or in combination with rituximab, to treat, prevent, or manage non-Hodgkin lymphoma (NHL) is also provided herein. In one embodiment, the method is intended to treat NHL. In one embodiment, the method is intended to prevent NHL. In one embodiment, the method is intended to manage NHL.

[0026] In certain embodiments, NHL is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), or primary central nervous system lymphoma (PCNSL).

[0027] A method of using a solid form comprising Compound 1 provided herein, either alone or in combination with obinutuzumab, to treat, prevent, or manage chronic lymphocytic leukemia (CLL) is also provided herein. In one embodiment, the method is intended to treat CLL. In one embodiment, the method is intended to prevent CLL. In one embodiment, the method is intended to manage CLL.

[0028] A method of using a solid form comprising Compound 1 provided herein, either alone or in combination with obinutuzumab, to treat, prevent, or manage small lymphocytic lymphoma (SLL) is also provided herein. In one embodiment, the method is intended to treat SLL. In one embodiment, the method is intended to prevent SLL. In one embodiment, the method is intended to manage SLL.

[0029] A solid form or salt of Compound 1 for use in a method for treating a disease provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 to a patient. A pharmaceutical composition comprising the solid form or salt of Compound 1 for use in a method for treating a disease provided herein is also provided herein.

[0030] These and other aspects of the subject matter described herein will become apparent when referring to the following detailed description. Brief explanation of the drawing

[0031] 4. Brief description of the drawing Fig. 1 It provides a representative X-ray powder diffraction (XRPD) pattern of form A of the free base of compound 1. Fig. 2 It provides representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) temperature records of form A of the free base of compound 1. Fig. 3 It provides a representative XRPD pattern of form B of the free base of compound 1. Fig. 4 It provides representative TGA and DSC temperature records of form B of the free base of compound 1. Fig. 5 It provides a representative XRPD pattern of form A of the hydrochloride salt of compound 1. Fig. 6 This provides representative TGA and DSC temperature records of form A of the hydrochloride salt of compound 1. Fig. 7This provides a representative dynamic vapor adsorption (DVS) isotherm plot of form A of the hydrochloride salt of compound 1. Fig. 8 It provides a representative SEM image of form A of the hydrochloride salt of compound 1. Fig. 9 It provides a representative XRPD pattern of form B of the hydrochloride salt of compound 1. Fig. 10 This provides representative TGA and DSC temperature records of form B of the hydrochloride salt of compound 1. Fig. 11 It provides a representative XRPD pattern of form A of the fumarate salt of compound 1. Fig. 12 It provides representative TGA and DSC temperature records of form A of the fumarate salt of compound 1. Fig. 13 It provides a representative XRPD pattern of form A of the tosylate salt of compound 1. Fig. 14 It provides representative TGA and DSC temperature records of form A of the tosylate salt of compound 1. Fig. 15 It provides a representative XRPD pattern of form A of the maleate salt of compound 1. Fig. 16 This provides representative TGA and DSC temperature records of form A of the maleate salt of compound 1. Fig. 17 It provides a representative XRPD pattern of form A of the besylate salt of compound 1. Fig. 18 It provides a representative TGA temperature record of form A of the besylate salt of compound 1. Fig. 19 It provides a representative DCS temperature record of form A of the besylate salt of compound 1. Fig. 20 It provides a representative XRPD pattern of the amorphous starting material of the free base of compound 1. Fig. 21 It provides a representative XRPD pattern of form C of the hydrochloride salt of compound 1. Fig. 22 It provides overlay plots of forms A, B, C, and D of the tosylate salt of compound 1. Specific details for implementing the invention

[0032] 5. Detailed explanation

[0033] 5.1 Definition

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a person skilled in the art. All patents, applications, publications, and other publications are incorporated by reference in their entirety. Where multiple definitions exist for a term in this document, the definition in this section shall prevail unless otherwise noted.

[0035] As used in this application, and in this specification and the appended claims, the singular form includes not only singular references but also plural references, unless the context otherwise clearly indicates.

[0036] As used herein, the terms “comprising” and “accompanying” may be used interchangeably. The terms “comprising” and “accompanying” should be interpreted as specifying the presence of a mentioned feature or a component as designated, but do not exclude the presence or addition of one or more features or components, or a group thereof. Additionally, the terms “comprising” and “accompanying” are intended to include examples covered by the term “constituted.” Accordingly, the term “constituted” may be used instead of the terms “comprising” and “accompanying” to provide more specific embodiments of the invention.

[0037] The term “constituted” means that the object has at least 90%, 95%, 97%, 98%, or 99% of the mentioned features or components that constitute it. In another embodiment, the term “constituted” excludes any other features or components from the category of any subsequent citation, except those that are not essential to the technical effect to be achieved.

[0038] As used herein, the term "or" shall be interpreted as an inclusive "or" meaning any one or any combination. Accordingly, "A, B or C" means any one of the following: "A; B; C; A and B; A and C; B and C; A, B and C". Exceptions to these definitions shall occur only where the combination of elements, functions, steps or actions is, in any way, mutually exclusive.

[0039] As used herein, and unless otherwise specified, the terms “about” and “about” mean a dose, amount, or weight percentage recognized by a person skilled in the art as providing a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percentage when used with the dose, amount, or weight percentage of a component of the composition or dosage form. In certain embodiments, the terms “about” and “about”, when used in connection therewith, consider a dose, amount, or weight percentage within 30%, 20%, 15%, 10%, or 5% of the specified dose, amount, or weight percentage.

[0040] As used herein, and unless otherwise specified, the terms “about” and “approximately” indicate that, when used with numerical values ​​or ranges of values ​​provided to characterize a particular solid form, e.g., describing a particular temperature or temperature range, e.g., melting, dehydration, desolvation, or glass transition temperature; mass change, e.g., mass change as a function of temperature or humidity; e.g., solvent or water content expressed in mass or percentage; or peak position, e.g., peak position in analysis by IR or Raman spectroscopy or XRPD, the values ​​or ranges of values ​​may vary to an extent that is considered reasonable to a person skilled in the art while still describing the particular solid form. For example, in certain embodiments, the terms “about” and “approximately”, when used in this context, indicate that a numerical value or range of values ​​may vary within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the quoted value or range of values. For example, in some embodiments, the value of the XRPD peak position may vary by up to ±0.2 degrees 2θ while still describing a specific XRPD peak. As used herein, a tilde (i.e., “~”) preceding a numerical value or range of values ​​indicates “about” or “approximately”.

[0041] Unless otherwise specified, the terms "X-ray powder diffraction," "powder X-ray diffraction," "PXRD," and "XRPD" are used interchangeably in this application.

[0042] As used herein, and unless otherwise specified, the terms “solid form” and related terms refer to a physical form that is not predominantly in a liquid or gaseous state. As used herein, the terms “solid form” and “solid forms” encompass semi-solids. A solid form may be crystalline, amorphous, semicrystalline, semi-amorphous, or a mixture of the above forms.

[0043] The solid forms provided herein may have various degrees of crystallinity or lattice regularity. The solid forms provided herein are not limited by any specific degree of crystallinity or lattice regularity and may be 0 to 100% crystalline. A method for determining the degree of crystallinity is described in the literature [Suryanarayanan, R., whose full text is incorporated herein by reference. X-Ray Power Diffractometry It is known to those skilled in the art, as described in [Physical Characterization of Pharmaceutical Salts, HG Brittain, Editor, Mercel Dekkter, Murray Hill, NJ, 1995, pp. 187-199]. In some embodiments, the solid form provided herein is about 0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% crystalline.

[0044] As used herein and unless otherwise specified, the term “crystalline” and related terms used herein, when used to describe a material, component, product, or form, mean that the material, component, product, or form is substantially crystalline when determined, for example, by X-ray diffraction. For example, literature [ Remington: The Science and Practice of Pharmacy , 21 st edition, Lippincott, Williams and Wilkins, Baltimore, MD (2005)]; [ The United States Pharmacopeia, 23 rd See edition, 1843-1844 (1995)].

[0045] As used herein, and unless otherwise specified, the terms “crystalline form,” “crystalline forms,” and related terms herein refer to a crystalline solid form. The crystalline form includes single-component crystalline forms and multi-component crystalline forms, and includes, but is not limited to, polymorphs, solvates, hydrates, and other molecular complexes, as well as salts, solvates of salts, hydrates of salts, co-crystals of salts, other molecular complexes of salts, and polymorphs thereof. In certain embodiments, the crystalline form of a material may not substantially contain an amorphous form and / or other crystalline forms. In certain embodiments, the crystalline form of the material may contain, by weight, about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or less than 50% of one or more amorphous form(s) and / or other crystalline form(s). In certain embodiments, the crystalline form of the material may be physically and / or chemically pure. In certain embodiments, the crystalline form of the material may be physically and / or chemically pure about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90%.

[0046] A "single-component" solid form containing a compound is essentially composed of the compound. A "multi-component" solid form containing a compound contains a substantial amount of one or more additional chemical species, such as ions and / or molecules, within the solid form. For example, in certain embodiments, a crystalline multi-component solid form containing a compound further contains one or more chemical species non-covalently bonded at regular positions within a crystal lattice. As another example, in certain embodiments, an amorphous multi-component solid form containing a compound further contains one or more polymer(s), and the compound is dispersed in a solid matrix containing the polymer(s).

[0047] Crystalline forms of a material can be obtained by a number of methods. These methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, recrystallization in a confined space, e.g., in nanopores or capillaries, recrystallization on a surface or on a template, e.g., on a polymer, recrystallization in the presence of additives, e.g., co-crystallized countermolecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, grinding, and solvent-dropping grinding.

[0048] Unless otherwise specified, the terms “polymorph,” “polymorphic form,” “polymorphs,” “polymorphic forms,” and related terms herein refer to two or more crystalline forms essentially composed of the same molecule, molecules, or ions. Like different crystalline forms, different polymorphs may have different physical properties, e.g., melting temperature, heat of fusion, solubility, dissolution rate, and / or vibrational spectrum, due to different arrangements or stereotypes of molecules or ions within the crystal lattice. Differences in physical properties exhibited by polymorphs may affect pharmaceutical parameters, e.g., storage stability, compressibility, and density (important in formulation and product manufacturing), and dissolution rate (an important factor in bioavailability). Differences in stability may be attributed to changes in chemical reactivity (e.g., differential oxidation causing discoloration more rapidly when the dosage form consists of one polymorph than when it consists of another), kinetic changes (e.g., tablets becoming brittle at storage as a kinetically advantageous polymorph transitions to a thermodynamically more stable polymorph), or both (e.g., tablets of one polymorph are more easily destroyed at high humidity). As a result of differences in solubility / dissolution, in extreme cases, a slight polymorph transition may lead to a lack of efficacy, or in other extreme cases, toxicity. Additionally, the physical properties of the crystals may be important for processing (e.g., one polymorph may be more likely to form solvates or filtration and washing to remove impurities may be difficult, and particle shape and size distribution may differ between polymorphs).

[0049] As used herein, and unless otherwise specified, the terms “amorphous,” “amorphous form,” and related terms used herein mean that a material, component, or product is not substantially crystalline when determined by X-ray diffraction. In particular, the term “amorphous form” describes an irregular solid form, that is, a solid form in which long-range crystalline regularity does not exist. In certain embodiments, the amorphous form of a material may not substantially contain other amorphous forms and / or crystalline forms. In other embodiments, the amorphous form of a material may contain one or more other amorphous forms and / or crystalline forms in an amount of about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or less than 50% by weight. In certain embodiments, the amorphous form of a material may be physically and / or chemically pure. In certain embodiments, the amorphous form of the material may be physically and / or chemically about 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% pure. In certain embodiments, the amorphous form of the material may include additional components or ingredients (e.g., additives, polymers, or excipients that may serve to further stabilize the amorphous form). In certain embodiments, the amorphous form may be a solid solution.

[0050] The amorphous form of a material can be obtained by a number of methods. These methods include, but are not limited to, heating, melt-cooling, rapid melt-cooling, solvent evaporation, rapid solvent evaporation, desolvation, sublimation, grinding, ball-milling, cryogenic grinding, spray drying, and freeze-drying.

[0051] Unless otherwise specified, the terms “solvent” and “solvated” refer to the solid form of a substance containing a solvent, as used herein. The terms “hydrate” and “hydrated” refer to a solvent in which the solvent contains water. “Polymorphs of a solvent” refer to the existence of more than one solid form for a specific solvent composition. Similarly, “Polymorphs of a hydrate” refer to the existence of more than one solid form for a specific hydrate composition. As used herein, the term “desolvated solvent” refers to the solid form of a substance that can be prepared by removing the solvent from a solvent. As used herein, the terms “solvent” and “solvated” may also refer to the solvent of a salt, co-crystal, or molecular complex. As used herein, the terms “hydrate” and “hydrated” may also refer to the hydrate of a salt, co-crystal, or molecular complex.

[0052] Techniques for characterizing crystalline and amorphous forms include, but are not limited to, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), single-crystal X-ray diffraction, vibrational spectroscopy, e.g., infrared (IR) and Raman spectroscopy, solid-state and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, high-temperature stage optical microscopy, scanning electron microscopy (SEM), electronic crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility measurement, dissolution measurement, elemental analysis, and Karl Fischer analysis. Characteristic unit cell parameters may be determined using one or more techniques, such as X-ray diffraction and neutron diffraction, including, but not limited to, single-crystal diffraction and powder diffraction. Techniques useful for analyzing powder diffraction data include, for example, profile refining methods such as Rietveld refining, which can be used to analyze diffraction peaks associated with a single phase within a sample containing more than one solid phase. Another method useful for analyzing powder diffraction data includes unit cell indexing, which allows a person skilled in the art to determine unit cell parameters from a sample containing crystalline powder. In one embodiment, XRPD patterns are acquired using Cu Kα radiation. In one embodiment, the slope rate (heating rate) for DSC is about 10°C per minute. In one embodiment, for more accurate DSC testing, a slower heating rate, such as 0.5–2.0°C per minute, may be used. Sample pans used in DSC testing include, for example, aluminum, platinum, and stainless steel pans. The pans may have various configurations, for example, open, pinhole, or hermetic pans. In one embodiment, the slope rate for TGA is about 10°C per minute.

[0053] In certain embodiments, the solid form provided herein, e.g., crystalline or amorphous form, is substantially pure, i.e., substantially free of other solid forms and / or other chemical compounds, and contains one or more other solid forms and / or other chemical compounds in an amount of about 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.75%, 0.5%, 0.25%, or less than 0.1% by weight.

[0054] As used herein, and unless otherwise indicated, a chemical compound, solid form, or composition that "substantially does not contain" another chemical compound, solid form, or composition means that the compound, solid form, or composition contains, in certain embodiments, about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or less than 0.01% by weight of another compound, solid form, or composition.

[0055] As used herein, and unless otherwise specified, the "physically substantially pure" solid form does not substantially contain other solid forms. In certain embodiments, the physically substantially pure crystalline form contains, by weight, about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or less than 0.01% of one or more other solid forms. Detection of other solid forms may be achieved by any method obvious to a person skilled in the art, e.g.,, non-limitingly, diffraction analysis, thermal analysis, elemental combustion analysis, and / or spectroscopic analysis.

[0056] As used herein, and unless otherwise specified, the "chemically substantially pure" solid form contains substantially no other chemical compounds (i.e., chemical impurities). In certain embodiments, the chemically substantially pure solid form contains, by weight, about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.05%, or less than 0.01% of one or more other chemical compounds. The detection of other chemical compounds can be achieved by any method obvious to a person skilled in the art, e.g., but not limited to, chemical analysis methods, e.g., mass spectrometry analysis, spectroscopic analysis, thermal analysis, elemental combustion analysis and / or chromatographic analysis.

[0057] A solid form may represent distinct physical characteristic data unique to a specific solid form, e.g., the crystal form provided herein. This characteristic data may be obtained by various techniques known to a person skilled in the art, such as X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis, and nuclear magnetic resonance spectroscopy. Data provided by these techniques may be used to identify a specific solid form. A person skilled in the art may determine whether a solid form is one of the forms provided herein by performing one of these characteristic techniques and determining whether the data generated thereby "matches" the reference data provided herein, which is identified as a characteristic of a specific solid form. Characteristic data that "matches" the data of the reference solid form is understood by a person skilled in the art to correspond to the same solid form as the reference solid form. When analyzing whether the data "matches," a person skilled in the art understands that a specific characteristic data point may vary to a reasonable degree while still describing a given solid form, for example, due to experimental error and routine analysis variation between samples.

[0058] As used herein, and unless otherwise specified, the term “pharmaceutical acceptable salt” refers to a salt prepared from a pharmaceutically acceptable, relatively non-toxic acid, including inorganic and organic acids. In certain embodiments, suitable acids are acetic acid, adipic acid, 4-aminosalicylic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphor acid, camphorsulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, carbonic acid, citric acid, cyclamic acid, dihydrogenated phosphate, 2,5-dihydroxybenzoic acid (gentisic acid), 1,2-ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, glycolic acid, hippuric acid, hydrobromide, hydrochloric acid, hydroiodonic acid, isobutyric acid, isethionic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, monohydrogenated carbonic acid, monohydrogenated phosphate, Includes, but is not limited to, monohydrogen sulfate, mucinic acid, 1,5-naphthalenedisulfonic acid, nicotinic acid, nitric acid, oxalic acid, paromotic acid, pantothenic acid, phosphoric acid, phthalic acid, propionic acid, pyroglutamic acid, salicylic acid, souveric acid, succinic acid, sulfuric acid, tartaric acid, toluenesulfonic acid, etc. (e.g., literature [SM Berge et al., J. Pharm. Sci., 66:1-19 (1977)]; and [ Handbook of Pharmaceutical Salts: Properties, Selection and Use[Refer to , PH Stahl and CG Wermuth, Eds., (2002), Wiley, Weinheim]). In certain embodiments, suitable acids are strong acids (e.g., having a pKa of less than about 1), e.g., but not limited to, hydrochloric acid, hydrobromide, sulfuric acid, nitric acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, pyridinesulfonic acid, or other substituted sulfonic acids. Other relatively non-toxic compounds possessing acidic characteristics, such as amino acids like aspartic acid, and salts of other compounds like aspirin, ibuprofen, saccharin, etc., are also included. Acid addition salts may be obtained by contacting a neutral form of the compound with a sufficient amount of the desired acid, either in a pure form or in a suitable solvent. The salt as a solid may exist in a crystalline or amorphous form, or as a mixture thereof. The salt may also exist in polymorphic forms.

[0059] It should be noted that if there is a discrepancy between the described structure and its name, greater weight should be given to the described structure.

[0060] As used herein, and unless otherwise indicated, the term “treating” means, wholly or partially, the alleviation of one or more of a disorder, disease or condition, or symptoms associated with a disorder, disease or condition, or the slowing or cessation of further progression or worsening of these symptoms, or the alleviation or eradication of the cause(s) of the disorder, disease or condition itself.

[0061] As used herein, and unless otherwise indicated, the term “preventive” means a method of delaying and / or preventing the onset, recurrence, or spread of a disorder, disease, or condition, wholly or in part; preventing a subject from contracting a disorder, disease, or condition; or reducing the risk of a subject contracting a disorder, disease, or condition.

[0062] As used herein, and unless otherwise indicated, the term “managing” encompasses preventing a relapse of a patient with a particular disease or disorder, extending the time a patient with a disease or disorder maintains remission, reducing the patient’s mortality, and / or maintaining a reduction in or avoidance of the severity of symptoms associated with the managed disease or condition.

[0063] As used herein, and unless otherwise indicated, the term “effective amount” with respect to a compound means an amount capable of treating, preventing, or managing a disorder, disease, or condition, or its symptoms.

[0064] As used herein, and unless otherwise indicated, the terms “subject” or “patient” include, but are not limited to, animals such as cattle, monkeys, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits, or guinea pigs, mammals in one embodiment, and humans in another embodiment.

[0065] As used herein, and unless otherwise indicated, the term “relapsed” refers to a disorder, disease, or condition that has progressed after responding to treatment (e.g., achieving a complete response). Treatment may include one or more regimens. In one embodiment, the disorder, disease, or condition was previously treated with one or more regimens. In another embodiment, the disorder, disease, or condition was previously treated with a first, second, third, or fourth regimen. In some embodiments, the disorder, disease, or condition is a hematological malignancy.

[0066] In one embodiment, "relapsed" DLBCL may refer to DLBCL that has previously been treated with one or more lines of therapy. In one embodiment, relapsed DLBCL is DLBCL that has previously been treated with one, two, three, or four lines of therapy. In one embodiment, relapsed DLBCL is DLBCL that has previously been treated with two or more lines of therapy.

[0067] In one embodiment, "relapsed" FL may refer to FL that has previously been treated with one or more lines of therapy. In one embodiment, relapsed FL is FL that has previously been treated with one, two, three, or four lines of therapy. In one embodiment, relapsed FL is FL that has previously been treated with two or more lines of therapy.

[0068] As used herein, and unless otherwise indicated, the term “refractory” refers to a disorder, disease, or condition that has not responded to prior treatment, which may include one or more regimens. In one embodiment, the disorder, disease, or condition was previously treated with a first, second, third, or fourth regimen. In one embodiment, the disorder, disease, or condition was previously treated with two or more regimens and has a non-complete response (CR) to a regimen including the most recent systemic regimen. In some embodiments, the disorder, disease, or condition is a hematological malignancy.

[0069] In one embodiment, "relapsed or refractory" CLL / SLL may refer to a CLL / SLL that has previously been treated with one or more lines of therapy. In one embodiment, a relapsed or refractory CLL / SLL is a CLL / SLL that has previously been treated with one, two, three, or four lines of therapy. In one embodiment, a relapsed or refractory CLL / SLL is a CLL / SLL that has previously been treated with two or more lines of therapy. In one embodiment, a relapsed or refractory CLL / SLL is a CLL / SLL that has previously been treated with a Bruton's tyrosine kinase (BTK) inhibitor. In one embodiment, a relapsed or refractory CLL / SLL is relapsed or refractory to a BTK inhibitor. In one embodiment, the BTK inhibitor is ibrutinib. In one embodiment, the BTK inhibitor is acalabrutinib. In one embodiment, the BTK inhibitor is zanubrutinib. In one embodiment, the BTK inhibitor is tirabrutinib.

[0070] With respect to cancer, e.g., hematological malignancies, inhibition may be assessed by, in particular, inhibition of disease progression, inhibition of tumor growth, reduction of primary tumor, alleviation of tumor-related symptoms, inhibition of tumor-secreted factors, delayed onset of primary or secondary tumors, slowed onset of primary or secondary tumors, reduced onset of primary or secondary tumors, secondary effects of disease with slowed or reduced severity, arrest of tumor growth and regression of tumors, increased time to progression (TTP), increased progression-free survival (PFS), and increased overall survival (OS). As used herein, OS means the time from the initiation of treatment to death from any cause. As used herein, TTP means the time from the initiation of treatment to tumor progression; TTP does not include death. In one embodiment, PFS means the time from the initiation of treatment to tumor progression or death. In one embodiment, PFS means the time from the initial dose of the compound to the first occurrence of disease progression or death from any cause. In one embodiment, the PFS rate is calculated using Kaplan-Meier estimation analysis. Event-free survival (EFS) refers to the time from the initiation of treatment to any treatment failure, such as disease progression, discontinuation of treatment for any reason, or death. In one embodiment, the overall response rate (ORR) refers to the percentage of patients who achieve a response. In one embodiment, the ORR refers to the sum of the percentages of patients who achieve a complete and partial response. In one embodiment, the ORR refers to the percentage of patients who show an optimal response ≥ partial response (PR). In one embodiment, the duration of response (DoR) is the time from the achievement of a response to relapse or disease progression. In one embodiment, the DoR is the time from the achievement of a response ≥ partial response (PR) to relapse or disease progression. In one embodiment, the DoR is the time from the first recorded response to the first recorded disease progression or death.In one embodiment, DoR is the time from the first recorded response ≥ partial response (PR) to the first recorded response to disease progression or death. In one embodiment, Time to Response (TTR) refers to the time from the first dose of the compound to the first recorded response. In one embodiment, TTR refers to the time from the first dose of the compound to the first recorded response ≥ partial response (PR). In extreme cases, complete inhibition is referred herein as prophylaxis or chemoprevention. In this regard, the term "prophylaxis" includes the complete prevention of the development of clinically evident cancer or the prevention of the initiation of a preclinical stage of cancer. Prevention of transformation into malignant cells or the cessation or reversal of progression from precancerous cells to malignant cells is also intended to be encompassed by this definition. This includes prophylactic treatment of individuals at risk of developing cancer.

[0071] In certain embodiments, the treatment of NHL is based on the International Workshop Criteria for Malignant Lymphoma (Literature [Cheson et al. , J. Clin. Oncol., [Refer to 2014, 32(27):3059-3068] and the Deauville Criteria for Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) Scan Interpretation (Itti et al. , Eur. J. Nucl. Med. Mol. Imaging , 2013, 40(9):1312-20; Meignan et al. , Leuk Lymphoma , According to the 2014, 55(1):31-37) ("Lugano Criteria"), it can be assessed using the response and endpoint definitions presented in Table 1-3.

[0072] Table 1 Criteria for site invasion.

[0073]

[0074] CNS = Central Nervous System; CSF = Cerebrospinal Fluid; CT = Computed Tomography; FDG = Fluorodeoxyglucose; GI = Gastrointestinal Surgery; MRI = Magnetic Resonance Imaging; PET = Positron Emission Tomography; N / A = Not Applicable.

[0075] a PET / CT is suitable for determining bone marrow involvement and can be considered highly suggestive of involvement in sites other than lymph nodes. If necessary, biopsy confirmation of these sites may be considered.

[0076] Table 2 . Lugano response criteria for non-Hodgkin lymphoma.

[0077]

[0078]

[0079] CMR = Complete metabolic response; LDi = Longest transverse diameter of the lesion; PPD = Vector product of LDi and vertical diameter; SDi = Shortest axis perpendicular to LDi; SPD = Sum of the products of vertical diameters for multiple lesions; N / A = Not applicable.

[0080] a If there is baseline bone marrow involvement, CR is required.

[0081] b In the ring of Waldyr or extranodal sites accompanied by high physiological uptake or activation within the spleen or bone marrow; (e.g., by chemotherapy or myeloid colony-stimulating factor), uptake may be greater than that of the normal mediastinum and / or liver. In such situations, CMR can be inferred when uptake at the initial site of involvement is not greater than that of the surrounding normal tissue.

[0082] c FDG-linked lymphoma must have a response assessed by PET-CT. Some diseases can typically be tracked by CT alone (i.e., marginal zone lymphoma).

[0083] d PET must be performed in conjunction with contrast-enhanced diagnostic CT, and can be performed simultaneously or as a separate procedure.

[0084] Table 3 . PET 5-Point Grade (5-PS).

[0085]

[0086] a The Deauville 5-Point Rating (5PS) is an internationally recommended rating for clinical commercial procedures and clinical trials using FDG-PET / CT for initial staging and assessment of treatment response in Hodgkin lymphoma (HL) and certain types of non-Hodgkin lymphoma (NHL).

[0087] In one embodiment, the therapeutic response to CLL / SLL is based on the International Workshop Criteria for Chronic Lymphocytic Leukemia (Literature [Hallek, M, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood It can be assessed by [see , 131(25), 2745-2760 (2018)] (Table 4).

[0088] Table 4. Definition of response after treatment in patients with chronic lymphocytic leukemia.

[0089]

[0090] CR = Complete Remission (all criteria must be met); PD = Progressive Disease (at least one criterion from Group A or Group B must be met); PR = Partial Remission (for PR, at least two parameters from Group A and one parameter from Group B must improve if they were previously abnormal; if only one parameter from both Group A and B was abnormal prior to therapy, only that one needs to improve); SD = Stable Disease (all criteria must be met; PD is not defined by systemic symptoms alone).

[0091] a The sum of the products of six or fewer lymph nodes (evaluated by CT scans and physical examinations in clinical trials or by physical examinations in general practice).

[0092] b Spleen size is considered normal if it is < 13 cm. There is no firmly established international consensus on normal liver size; therefore, liver size should be evaluated by imaging and palpation in clinical trials and recorded according to the definition used in the study protocol.

[0093] In one embodiment, the treatment response of CLL / SLL may be assessed by the Eastern Cooperative Oncology Society (ECOG) performance status (Table 5).

[0094] Table 5. ECOG performance status.

[0095]

[0096] ECOG = Eastern Cooperative Oncology Association, President: Robert Comis, MD.

[0097] Source: Oken M, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol , 5(6):649-655 (1982).

[0098] In certain embodiments, the presence or absence of stable disease may be determined by methods known in the relevant art, such as evaluation of patient symptoms, physical examination, visualization of a tumor imaged using, for example, FDG-PET (fluorodeoxyglucose positron emission tomography), PET / CT (positron emission tomography / computed tomography) scan, MRI (magnetic resonance imaging) of the brain and spine, CSF (cerebrospinal fluid), ophthalmic examination, vitreous fluid sampling, retinal photography, bone marrow evaluation, and other commonly accepted modes of evaluation.

[0099] As used herein, and unless otherwise indicated, the terms “co-administration” and “in combination” involve administering one or more therapeutic agents (e.g., the compound provided herein and another anticancer agent or supportive management agent) simultaneously, jointly, or sequentially without any specific time limit. In one embodiment, the agents are simultaneously present in cells or in the body of the patient, or simultaneously exert their biological or therapeutic effects. In one embodiment, the therapeutic agents exist in the same composition or unit dosage form. In another embodiment, the therapeutic agents exist in separate compositions or unit dosage forms.

[0100] The term "supportive management agent" refers to any substance that treats, prevents, or manages adverse effects from treatment using another therapeutic agent.

[0101] 5.2 Solid forms containing salts and Compound 1

[0102] In certain embodiments, a solid form comprising compound 1 is provided herein:

[0103]

[0104] Compound 1 has the chemical name (S)-2-(2,6-dioxopiperidine-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidine-1-yl)methyl)benzyl)amino)isoindolin-1,3-dione. A method for preparing Compound 1 is described in U.S. Application No. 16 / 390,815, the full text of which is incorporated herein by reference.

[0105] In one embodiment, the solid form comprises a free base of Compound 1. In one embodiment, the solid form comprises a salt of Compound 1. In one embodiment, the solid form comprises a hydrochloride salt of Compound 1. In one embodiment, the solid form comprises a fumarate salt of Compound 1. In one embodiment, the solid form comprises a tosylate salt of Compound 1. In one embodiment, the solid form comprises a maleate salt of Compound 1. In one embodiment, the solid form comprises a besylate salt of Compound 1.

[0106] In one embodiment, the solid form is crystalline. In one embodiment, the solid form is a hydrate. In one embodiment, the solid form is anhydrous. In one embodiment, the solid form is a solvate. In one embodiment, the solid form is non-solvent. In one embodiment, the solid form is amorphous.

[0107] The provided solid form may be characterized using a number of methods known to those skilled in the art, e.g., but not limited to, single-crystal X-ray diffraction, X-ray powder diffraction (PXRD), microscopy (e.g., optical microscopy, scanning electron microscopy (SEM)), thermal analysis (e.g., differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and high-temperature stage microscopy), dynamic vapor deposition (DVS), spectroscopic analysis (e.g., infrared, Raman, and nuclear magnetic resonance), and high-performance liquid chromatography (HPLC). The particle size and size distribution of the solid form provided herein may be determined by conventional methods such as laser light scattering techniques.

[0108] A salt of Compound 1 is also provided herein. In one embodiment, the salt is a hydrochloride salt of Compound 1. In one embodiment, the salt is a fumarate salt of Compound 1. In one embodiment, the salt is a tosylate salt of Compound 1. In one embodiment, the salt is a maleate salt of Compound 1. In one embodiment, the salt is a besylate salt of Compound 1.

[0109] Although not limited by any specific theory, an acid associates with one or more basic nitrogen atoms of compound 1. Although not limited by any specific theory, the pKa of the azetidine nitrogen of compound 1 is estimated to be about 7.7, and the pKa of the morpholine nitrogen of compound 1 is estimated to be about 2.12.

[0110] The purity of the solid form and salt provided herein can be determined by standard analytical methods such as thin-layer chromatography (TLC), gel electrophoresis, gas chromatography, high-performance liquid chromatography (HPLC), and mass spectrometry.

[0111] While not intending to be bound by any specific theory, certain solid forms and salts are characterized by physical properties, e.g., stability, solubility, and dissolution rate, suitable for pharmaceutical and therapeutic dosage forms. Furthermore, while not wishing to be bound by any specific theory, certain solid forms and salts are characterized by physical properties (e.g., density, compressibility, hardness, morphology, cutting, adhesiveness, solubility, water absorption, electrical properties, thermal behavior, solid-state reactivity, physical stability, and chemical stability) that influence specific processes (e.g., obtaining, filtration, washing, drying, milling, mixing, tableting, flow, dissolution, formulation, and freeze-drying) that make certain solid forms and salts suitable for the manufacture of solid dosage forms. These properties may be determined using specific chemical analysis techniques, including solid-state analysis techniques (e.g., X-ray diffraction, microscopy, spectroscopy, and thermal analysis), as described herein and known in the relevant art. Although not intended to be bound by any specific theory, the specific solid forms and salts provided herein possess suitable pharmaceutical properties, e.g., pharmaceutical kinetics, pharmaceutical dynamics, half-life, C max It indicates , and bioavailability. These characteristics can be determined using tests known to a person skilled in the art.

[0112] (a) Free base of compound 1

[0113] In some embodiments, the free base of compound 1 is provided herein. The free base of compound 1 is considered to exist in various solid forms. These solid forms include crystalline solids, such as polymorphs, solvates, and hydrates of the crystalline free base of compound 1, as well as amorphous solids or mixtures thereof.

[0114] In one embodiment, a solid form comprising a free base of Compound 1 is provided herein. In one embodiment, the solid form is a solvate of the free base of Compound 1. In one embodiment, the solid form is a hydrate of the free base of Compound 1. In one embodiment, the solid form is a non-solvented form of the free base of Compound 1. In one embodiment, the solid form is a desolvated form of the free base of Compound 1. In one embodiment, the solid form is an anhydrous form (anhydride) of the free base of Compound 1. In one embodiment, the solid form is a dehydrated form of the free base of Compound 1.

[0115] (i) Form of the free base of compound 1 A

[0116] In certain embodiments, form A of the free base of compound 1 is provided herein.

[0117] In one embodiment, form A is crystalline. In one embodiment, form A is substantially crystalline. In one embodiment, form A is moderately crystalline. In one embodiment, form A is partially crystalline.

[0118] The representative XRPD pattern of type A is Fig. 1 It is provided in.

[0119] In one embodiment, a solid form comprising a free base of compound 1 is provided herein, characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or all of the peaks located approximately at the following positions: 4.5, 11.4, 12.6, 13.3, 15.3, 15.9, 18.1, 19.1, 20.1, 20.9, 21.6, 22.6, 23.9, 25.4, 26.3, 28.1, and 29.0° 2θ. In one embodiment, the solid form is characterized by 3 of the peaks. In one embodiment, the solid form is characterized by 5 of the peaks. In one embodiment, the solid form is characterized by 7 of the peaks. In one embodiment, the solid form is characterized by 9 of the peaks. In one embodiment, the solid form is characterized by 11 of the peaks. In one embodiment, the solid form is characterized by all of the peaks.

[0120] In one embodiment, a solid form comprising a free base of compound 1 is provided herein, characterized by an XRPD pattern comprising peaks at approximately 4.5, 15.3, and 18.1° 2θ. In one embodiment, the XRPD pattern further comprises peaks at approximately 13.3 and 15.9° 2θ. In one embodiment, the XRPD pattern further comprises peaks at approximately 20.1 and 20.9° 2θ. In one embodiment, the XRPD pattern comprises peaks at approximately 4.5, 13.3, 15.3, 15.9, 18.1, 19.1, 20.1, 20.9, 21.6, and 26.3° 2θ.

[0121] In one embodiment, a solid form comprising a free base of compound 1 is provided herein, characterized by an XRPD pattern including a peak at approximately 4.5° 2θ. In one embodiment, the XRPD pattern includes peaks at approximately 4.5, 11.4, and 12.6° 2θ. In one embodiment, the XRPD pattern includes peaks at approximately 4.5, 11.4, 12.6, 13.3, and 15.3° 2θ. In one embodiment, the XRPD pattern includes peaks at approximately 4.5, 11.4, 12.6, 13.3, 15.3, 15.9, and 18.1° 2θ.

[0122] In one embodiment, as a solid form comprising a free base of compound 1, Fig. 1 A solid form featuring an XRPD pattern that matches the XRPD pattern presented in [the document] is provided herein.

[0123] In one embodiment, the XRPD pattern is obtained using Cu Kα radiation.

[0124] Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) temperature records of Type A Fig. 2 Provided herein. In one embodiment, a solid form comprising a free base of compound 1 is provided herein, which exhibits a weight loss of about 1.3% when heated from about 25°C to about 50°C and a weight loss of about 1.4% when heated from about 50°C to about 200°C. In one embodiment, as a solid form comprising a free base of compound 1, Fig. 2 A solid form featuring a TGA temperature record that matches the TGA temperature record presented in [the document] is provided herein.

[0125] In one embodiment, a solid form comprising a free base of compound 1 is provided herein, which, when characterized by DSC, exhibits a first thermal event (endothermic) having a peak temperature of about 68°C and a second thermal event (endothermic) having a peak temperature of about 112°C. In one embodiment, as a solid form comprising a free base of compound 1, Fig. 2 A solid form is provided herein featuring a DSC temperature record that matches the DSC temperature record presented in [the document].

[0126] In one embodiment, form A of the free base of compound 1 is prepared by slurrying the free base of compound 1 in water (e.g., about 40°C, about 6 days).

[0127] In one embodiment, a solid form comprising form A of the free base of Compound 1 and an amorphous free base of Compound 1 is provided herein. In one embodiment, a solid form comprising form A of the free base of Compound 1 and one or more other crystalline forms of the free base of Compound 1 provided herein is provided herein. In one embodiment, a solid form comprising form A of the free base of Compound 1 and one or more forms (e.g., amorphous or crystalline) of the salt of Compound 1 provided herein is provided herein.

[0128] (ii) Form of the free base of Compound 1 B

[0129] In certain embodiments, form B of the free base of compound 1 is provided herein.

[0130] In one embodiment, form B is crystalline. In one embodiment, form B is substantially crystalline. In one embodiment, form B is moderately crystalline. In one embodiment, form B is partially crystalline.

[0131] The representative XRPD pattern of type B is Fig. 3 It is provided in.

[0132] In one embodiment, a solid form comprising a free base of compound 1 is provided herein, characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or all of the peaks located approximately at the following positions: 4.5, 4.8, 9.6, 10.7, 11.4, 12.0, 13.3, 13.7, 14.9, 15.7, 17.3, 18.7, 19.0, 20.2, 20.7, 21.3, 21.4, 22.1, 22.9, 23.8, 24.5, 25.4, 26.2, 26.9, and 28.2° 2θ. In one embodiment, the solid form is characterized by three of the peaks. In one embodiment, the solid form is characterized by five of the peaks. In one embodiment, the solid form is characterized by seven of the peaks. In one embodiment, the solid form is characterized by nine of the peaks. In one embodiment, the solid form is characterized by eleven of the peaks. In one embodiment, the solid form is characterized by all of the peaks.

[0133] In one embodiment, a solid form comprising a free base of compound 1 is provided herein, characterized by an XRPD pattern including peaks at approximately 4.8, 9.6, and 14.9° 2θ. In one embodiment, the XRPD pattern further includes peaks at approximately 18.7 and 22.1° 2θ. In one embodiment, the XRPD pattern further includes peaks at approximately 20.7 and 21.4° 2θ. In one embodiment, the XRPD pattern includes peaks at approximately 4.5, 4.8, 9.6, 14.9, 15.7, 17.3, 18.7, 19.0, 20.7, 21.3, 21.4, 22.1, 22.9, and 28.2° 2θ.

[0134] In one embodiment, a solid form comprising a free base of compound 1 is provided herein, characterized by an XRPD pattern comprising peaks at approximately 4.5, 4.8, and 9.6° 2θ. In one embodiment, the XRPD pattern comprises peaks at approximately 4.5, 4.8, 9.6, 10.7, and 11.4° 2θ. In one embodiment, the XRPD pattern comprises peaks at approximately 4.5, 4.8, 9.6, 10.7, 11.4, 13.3, and 13.7° 2θ. In one embodiment, the XRPD pattern comprises peaks at approximately 4.5, 4.8, 9.6, 10.7, 11.4, 13.3, 13.7, 14.9, and 15.7° 2θ.

[0135] In one embodiment, as a solid form comprising a free base of compound 1, Fig. 3 A solid form featuring an XRPD pattern that matches the XRPD pattern presented in [the document] is provided herein.

[0136] In one embodiment, the XRPD pattern is obtained using Cu Kα radiation.

[0137] Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) temperature records of Type B Fig. 4 It is provided in. In one embodiment, a solid form comprising a free base of compound 1 is provided herein, which exhibits a weight loss of about 0.9% when heated from about 25°C to about 225°C. In one embodiment, as a solid form comprising a free base of compound 1, Fig. 4 A solid form featuring a TGA temperature record that matches the TGA temperature record presented in [the document] is provided herein.

[0138] In one embodiment, a solid form comprising a free base of compound 1 is provided herein, which, when characterized by DSC, exhibits a first thermal event (endothermic) having a peak temperature of about 82°C, a second thermal event (endothermic) having a peak temperature of about 107°C, and a third thermal event (endothermic) having a peak temperature of about 138°C. In one embodiment, as a solid form comprising a free base of compound 1, Fig. 4 A solid form is provided herein featuring a DSC temperature record that matches the DSC temperature record presented in [the document].

[0139] In one embodiment, form B of the free base of compound 1 is prepared by crystallizing the free base of compound 1 from a solvent / reverse solvent system (e.g., at room temperature), where the solvent is acetone and the reverse solvent is water.

[0140] In one embodiment, a solid form comprising form B of the free base of Compound 1 and an amorphous free base of Compound 1 is provided herein. In one embodiment, a solid form comprising form B of the free base of Compound 1 and one or more other crystalline forms of the free base of Compound 1 provided herein is provided herein. In one embodiment, a solid form comprising form B of the free base of Compound 1 and one or more forms (e.g., amorphous or crystalline) of the salt of Compound 1 provided herein is provided herein.

[0141] (b) Hydrochloride salt of compound 1

[0142] In some embodiments, a hydrochloride salt of Compound 1 is provided herein. The hydrochloride salt of Compound 1 is considered to exist in various solid forms. These solid forms include crystalline solids, such as polymorphs, solvates, and hydrates of the crystalline hydrochloride salt of Compound 1, as well as amorphous solids or mixtures thereof.

[0143] In one embodiment, a solid form comprising a hydrochloride salt of Compound 1 is provided herein. In one embodiment, the solid form is a solvate of the hydrochloride salt of Compound 1. In one embodiment, the solid form is a hydrate of the hydrochloride salt of Compound 1. In one embodiment, the solid form is a non-solvented form of the hydrochloride salt of Compound 1. In one embodiment, the solid form is a desolvented form of the hydrochloride salt of Compound 1. In one embodiment, the solid form is an anhydrous form (anhydride) of the hydrochloride salt of Compound 1. In one embodiment, the solid form is a dehydrated form of the hydrochloride salt of Compound 1.

[0144] In some embodiments, the molar ratio of compound 1 to hydrochloric acid in solid form ranges from about 1:1 to about 1:2. In one embodiment, the molar ratio is about 1:2 (i.e., bis-hydrochloride salt). In another embodiment, the molar ratio is about 1:1 (i.e., mono-hydrochloride salt).

[0145] (i) Form A of the hydrochloride salt of Compound 1

[0146] In certain embodiments, form A of the hydrochloride salt of compound 1 is provided herein.

[0147] In one embodiment, form A is crystalline. In one embodiment, form A is substantially crystalline. In one embodiment, form A is moderately crystalline. In one embodiment, form A is partially crystalline.

[0148] In one embodiment, the molar ratio of compound 1 to hydrochloric acid in form A is about 1:1. In one embodiment, form A is a mono-hydrochloride salt of compound 1.

[0149] In one embodiment, form A is a hydrate of the hydrochloride salt of compound 1. In one embodiment, form A is a channel hydrate of the hydrochloride salt of compound 1.

[0150] The representative XRPD pattern of form A of the hydrochloride salt of compound 1 is Fig. 5 It is provided in.

[0151] In one embodiment, a solid form comprising a hydrochloride salt of compound 1 is provided herein, characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or all of the peaks located approximately at the following positions: 4.2, 7.8, 11.1, 12.4, 15.1, 15.5, 16.3, 17.1, 17.3, 17.9, 18.2, 18.9, 19.2, 20.1, 20.4, 20.7, 21.7, 22.4, 23.0, 24.4, 24.8, 25.7, 27.5, 28.1, 29.1, 29.8, 30.2, and 30.8° 2θ. In one embodiment, the solid form is characterized by three of the peaks. In one embodiment, the solid form is characterized by five of the peaks. In one embodiment, the solid form is characterized by seven of the peaks. In one embodiment, the solid form is characterized by nine of the peaks. In one embodiment, the solid form is characterized by eleven of the peaks. In one embodiment, the solid form is characterized by all of the peaks.

[0152] In one embodiment, a solid form comprising a hydrochloride salt of compound 1 is provided herein, characterized by an XRPD pattern including peaks at approximately 15.1, 16.3, and 20.7° 2θ. In one embodiment, the XRPD pattern further includes peaks at approximately 7.8 and 22.4° 2θ. In one embodiment, the XRPD pattern further includes peaks at approximately 18.2, 18.9, and 24.8° 2θ. In one embodiment, the XRPD pattern includes peaks at approximately 7.8, 15.1, 16.3, 17.9, 18.2, 18.9, 19.2, 20.4, 20.7, 21.7, 22.4, and 24.8° 2θ.

[0153] In one embodiment, a solid form comprising a hydrochloride salt of compound 1 is provided herein, characterized by an XRPD pattern including peaks at approximately 4.2, 7.8, and 11.1° 2θ. In one embodiment, the XRPD pattern includes peaks at approximately 4.2, 7.8, 11.1, 12.4, and 15.1° 2θ. In one embodiment, the XRPD pattern includes peaks at approximately 4.2, 7.8, 11.1, 12.4, 15.1, 15.5, and 16.3° 2θ. In one embodiment, the XRPD pattern includes peaks at approximately 4.2, 7.8, 11.1, 12.4, 15.1, 15.5, 16.3, 17.1, and 17.3° 2θ.

[0154] In one embodiment, as a solid form comprising a hydrochloride salt of compound 1, Fig. 5 A solid form featuring an XRPD pattern that matches the XRPD pattern presented in [the document] is provided herein.

[0155] In one embodiment, the XRPD pattern is obtained using Cu Kα radiation.

[0156] Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) temperature charts of form A of the hydrochloride salt of Compound 1 Fig. 6 Provided herein. In one embodiment, a solid form comprising a hydrochloride salt of compound 1 is provided herein, which exhibits a weight loss of about 1.5% when heated from about 25°C to about 200°C and a weight loss of about 2.7% when heated from about 200°C to about 230°C. In one embodiment, a solid form comprising a hydrochloride salt of compound 1, Fig. 6 A solid form featuring a TGA temperature record that matches the TGA temperature record presented in [the document] is provided herein.

[0157] In one embodiment, a solid form comprising a hydrochloride salt of compound 1 is provided herein, which, when characterized by DSC, exhibits a first thermal event (endothermic) having a peak temperature of about 218°C and a second thermal event (exothermic) having a peak temperature of about 227°C. In one embodiment, a solid form comprising a hydrochloride salt of compound 1, Fig. 6 A solid form is provided herein featuring a DSC temperature record that matches the DSC temperature record presented in [the document]. The melting point of form A of the hydrochloride salt of compound 1 may vary depending on the degree of crystallization and crystal structure defects.

[0158] Representative dynamic vapor adsorption (DVS) isotherm plot of form A of the hydrochloride salt of Compound 1 Fig. 7 Provided herein. In one embodiment, a solid form comprising a hydrochloride salt of compound 1 is provided herein, which exhibits a mass increase of about 3.0% when applied to an increase in relative humidity (RH) from about 0% to about 95%. In one embodiment, a solid form comprising a hydrochloride salt of compound 1, Fig. 7A solid form is provided herein featuring a DVS isotherm plot that matches the DVS isotherm plot presented in [the document].

[0159] In one embodiment, form A of the hydrochloride salt of Compound 1 has the crystal habit of short rod-shaped primary particles. A representative SEM image of form A of the hydrochloride salt of Compound 1 is Fig. 8 It is presented in.

[0160] In one embodiment, form A of the hydrochloride salt of compound 1 is prepared by slurrying the hydrochloride salt of compound 1 in a solvent. In one embodiment, form A of the hydrochloride salt of compound 1 is prepared by slurrying the free base of compound 1 and hydrochloric acid in a solvent. In one embodiment, the solvent is acetone, acetonitrile, anisole, DCM, DMAc, EtOH, EtOAc, ethyl formate, isopropyl acetate, MeOH, MEK, MTBE, 2-MeTHF, nitromethane, NMP, 2-propanol, tetrahydrofuran, toluene, water, a mixture of acetone and water (e.g., 95 / 5 v / v), a mixture of acetonitrile and water (e.g., 95 / 5 v / v), a mixture of 2-PrOH and water (e.g., 95 / 5 v / v), or a mixture of THF and water (e.g., 95 / 5 v / v). In one embodiment, the solvent is acetonitrile. In one embodiment, slurrying is performed at room temperature. In one embodiment, slurrying is performed at about 50°C. In one embodiment, slurrying is performed for a time period of about 1 day to about 7 days. In one embodiment, slurrying is performed for about 2 days. In one embodiment, slurrying is performed for about 7 days.

[0161] In one embodiment, a solid form is provided herein comprising form A of the hydrochloride salt of Compound 1 and one or more forms of the free base of Compound 1 (e.g., amorphous form and crystalline form). In one embodiment, a solid form is provided herein comprising form A of the hydrochloride salt of Compound 1 and an amorphous hydrochloride salt of Compound 1. In one embodiment, a solid form is provided herein comprising form A of the hydrochloride salt of Compound 1 and one or more other crystalline forms of the hydrochloride salt of Compound 1 provided herein. In one embodiment, a solid form is provided herein comprising form A of the hydrochloride salt of Compound 1 and one or more forms of the salt of Compound 1 provided herein (e.g., amorphous or crystalline).

[0162] (ii) Form B of the hydrochloride salt of Compound 1

[0163] In certain embodiments, form B of the hydrochloride salt of compound 1 is provided herein.

[0164] In one embodiment, form B is crystalline. In one embodiment, form B is substantially crystalline. In one embodiment, form B is moderately crystalline. In one embodiment, form B is partially crystalline.

[0165] The representative XRPD pattern of form B of the hydrochloride salt of compound 1 Fig. 9 It is provided in.

[0166] In one embodiment, a solid form comprising a hydrochloride salt of compound 1 is provided herein, characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or all of the peaks located approximately at the following positions: 6.7, 11.6, 13.5, 14.2, 14.6, 16.5, 17.2, 17.5, 18.1, 18.5, 19.6, 20.3, 21.1, 21.6, 21.9, 22.4, 23.2, 23.7, 24.2, 24.8, 26.1, 26.7, 27.0, 27.7, 28.2, 29.5, and 30.2° 2θ. In one embodiment, the solid form is characterized by three of the peaks. In one embodiment, the solid form is characterized by five of the peaks. In one embodiment, the solid form is characterized by seven of the peaks. In one embodiment, the solid form is characterized by nine of the peaks. In one embodiment, the solid form is characterized by eleven of the peaks. In one embodiment, the solid form is characterized by all of the peaks.

[0167] In one embodiment, a solid form comprising a hydrochloride salt of compound 1 is provided herein, characterized by an XRPD pattern including peaks at approximately 17.5, 21.6, and 24.8° 2θ. In one embodiment, the XRPD pattern further includes peaks at approximately 21.1 and 27.0° 2θ. In one embodiment, the XRPD pattern further includes peaks at approximately 14.6, 17.2, and 20.3° 2θ. In one embodiment, the XRPD pattern includes peaks at approximately 6.7, 14.6, 17.2, 17.5, 19.6, 20.3, 21.1, 21.6, 21.9, 22.4, 24.8, 26.7, 27.0, 27.7, and 29.5° 2θ.

[0168] In one embodiment, a solid form comprising a hydrochloride salt of compound 1 is provided herein, characterized by an XRPD pattern including peaks at approximately 6.7, 11.6, and 13.5° 2θ. In one embodiment, the XRPD pattern includes peaks at approximately 6.7, 11.6, 13.5, 14.2, and 14.6° 2θ. In one embodiment, the XRPD pattern includes peaks at approximately 6.7, 11.6, 13.5, 14.2, 14.6, 16.5, and 17.2° 2θ. In one embodiment, the XRPD pattern includes peaks at approximately 6.7, 11.6, 13.5, 14.2, 14.6, 16.5, 17.2, 17.5, and 18.1° 2θ.

[0169] In one embodiment, as a solid form comprising a hydrochloride salt of compound 1, Fig. 9 A solid form featuring an XRPD pattern that matches the XRPD pattern presented in [the document] is provided herein.

[0170] In one embodiment, the XRPD pattern is obtained using Cu Kα radiation.

[0171] Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) temperature records of form B of the hydrochloride salt of Compound 1 Fig. 10 Provided herein. In one embodiment, a solid form comprising a hydrochloride salt of compound 1 is provided herein, which exhibits a weight loss of about 1.6% when heated from about 25°C to about 175°C and a weight loss of about 5.3% when heated from about 175°C to about 230°C. In one embodiment, a solid form comprising a hydrochloride salt of compound 1, Fig. 10 A solid form featuring a TGA temperature record that matches the TGA temperature record presented in [the document] is provided herein.

[0172] In one embodiment, a solid form comprising a hydrochloride salt of compound 1 is provided herein, which exhibits a thermal event (exothermic) having a peak temperature of about 230°C when characterized by DSC. In one embodiment, a solid form comprising a hydrochloride salt of compound 1, Fig. 10 A solid form is provided herein featuring a DSC temperature record that matches the DSC temperature record presented in [the document].

[0173] In one embodiment, form B of the hydrochloride salt of compound 1 is prepared by slurrying the free base of compound 1 and about 2 equivalents of HCl in acetonitrile (e.g., at room temperature for about 5 days).

[0174] In one embodiment, a solid form is provided herein comprising form B of the hydrochloride salt of compound 1 and one or more forms of the free base of compound 1 (e.g., amorphous form and crystalline form). In one embodiment, a solid form is provided herein comprising form B of the hydrochloride salt of compound 1 and an amorphous hydrochloride salt of compound 1. In one embodiment, a solid form is provided herein comprising form B of the hydrochloride salt of compound 1 and one or more other crystalline forms of the hydrochloride salt of compound 1 provided herein. In one embodiment, a solid form is provided herein comprising form B of the hydrochloride salt of compound 1 and one or more forms of the salt of compound 1 provided herein (e.g., amorphous or crystalline).

[0175] (iii) Form of the hydrochloride salt of Compound 1 C

[0176] In certain embodiments, form C of the hydrochloride salt of Compound 1 is provided herein. A representative XRPD pattern of form C of the hydrochloride salt of Compound 1 is Fig. 21It is provided in. In one embodiment, as a solid form comprising a hydrochloride salt of compound 1, Fig. 21 A solid form featuring an XRPD pattern that matches the XRPD pattern presented in [the document] is provided herein.

[0177] (c) Fumarate salt of Compound 1

[0178] In some embodiments, a fumarate salt of Compound 1 is provided herein. The fumarate salt of Compound 1 is considered to exist in various solid forms. These solid forms include crystalline solids, such as polymorphs, solvates, and hydrates of the crystalline fumarate salt of Compound 1, as well as amorphous solids or mixtures thereof.

[0179] In one embodiment, a solid form comprising a fumarate salt of Compound 1 is provided herein. In one embodiment, the solid form is a solvate of the fumarate salt of Compound 1. In one embodiment, the solid form is a hydrate of the fumarate salt of Compound 1. In one embodiment, the solid form is a non-solvented form of the fumarate salt of Compound 1. In one embodiment, the solid form is a desolvented form of the fumarate salt of Compound 1. In one embodiment, the solid form is an anhydrous form (anhydride) of the fumarate salt of Compound 1. In one embodiment, the solid form is a dehydrated form of the fumarate salt of Compound 1.

[0180] In some embodiments, the molar ratio of compound 1 to fumaric acid in solid form ranges from about 1:1 to about 1:2. In one embodiment, the molar ratio is about 1:2 (i.e., bis-fumarate salt). In another embodiment, the molar ratio is about 1:1 (i.e., mono-fumarate salt).

[0181] (i) Form A of the fumarate salt of Compound 1

[0182] In certain embodiments, form A of the fumarate salt of compound 1 is provided herein.

[0183] In one embodiment, form A is crystalline. In one embodiment, form A is substantially crystalline. In one embodiment, form A is moderately crystalline. In one embodiment, form A is partially crystalline.

[0184] In one embodiment, the molar ratio of compound 1 to fumaric acid in form A is about 1:2. In one embodiment, form A is the bis-fumarate salt of compound 1.

[0185] In one embodiment, form A is a non-solved form of the fumarate salt of compound 1.

[0186] The representative XRPD pattern of form A of the fumarate salt of compound 1 is Fig. 11 It is provided in.

[0187] In one embodiment, a solid form comprising a fumarate salt of compound 1 is provided herein, characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or all of the peaks located approximately at the following positions: 11.7, 12.2, 12.8, 13.8, 14.5, 14.7, 15.0, 15.2, 16.6, 17.1, 17.3, 17.7, 17.9, 18.3, 19.0, 19.4, 20.1, 20.5, 20.7, 21.4, 22.3, 22.9, 23.2, 23.4, 23.7, 24.3, 24.7, 24.9, 25.8, 26.6, and 27.1° 2θ. In one embodiment, the solid form is characterized by three of the peaks. In one embodiment, the solid form is characterized by five of the peaks. In one embodiment, the solid form is characterized by seven of the peaks. In one embodiment, the solid form is characterized by nine of the peaks. In one embodiment, the solid form is characterized by eleven of the peaks. In one embodiment, the solid form is characterized by all of the peaks.

[0188] In one embodiment, a solid form comprising a fumarate salt of compound 1 is provided herein, characterized by an XRPD pattern including peaks at approximately 22.3, 23.2, and 23.4° 2θ. In one embodiment, the XRPD pattern further includes peaks at approximately 17.9 and 25.8° 2θ. In one embodiment, the XRPD pattern further includes peaks at approximately 11.7 and 18.3° 2θ. In one embodiment, the XRPD pattern includes peaks at approximately 11.7, 15.0, 17.9, 18.3, 19.4, 20.1, 22.3, 22.9, 23.2, 23.4, and 25.8° 2θ.

[0189] In one embodiment, a solid form comprising a fumarate salt of compound 1 is provided herein, characterized by an XRPD pattern including peaks at approximately 11.7, 12.2, and 12.8° 2θ. In one embodiment, the XRPD pattern includes peaks at approximately 11.7, 12.2, 12.8, 13.8, and 14.5° 2θ. In one embodiment, the XRPD pattern includes peaks at approximately 11.7, 12.2, 12.8, 13.8, 14.5, 14.7, and 15.0° 2θ. In one embodiment, the XRPD pattern includes peaks at approximately 11.7, 12.2, 12.8, 13.8, 14.5, 14.7, 15.0, 15.2, and 16.6° 2θ.

[0190] In one embodiment, as a solid form comprising a fumarate salt of compound 1, Fig. 11 A solid form featuring an XRPD pattern that matches the XRPD pattern presented in [the document] is provided herein.

[0191] In one embodiment, the XRPD pattern is obtained using Cu Kα radiation.

[0192] Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) temperature charts of form A of the fumarate salt of Compound 1 Fig. 12 Provided herein. In one embodiment, a solid form comprising a fumarate salt of compound 1 is provided herein, which exhibits a weight loss of about 0.5% when heated from about 25°C to about 150°C and a weight loss of about 7.9% when heated from about 150°C to about 205°C. In one embodiment, a solid form comprising a fumarate salt of compound 1, Fig. 12 A solid form featuring a TGA temperature record that matches the TGA temperature record presented in [the document] is provided herein.

[0193] In one embodiment, a solid form comprising a fumarate salt of Compound 1 is provided herein, which exhibits a thermal event (endothermic) having a peak temperature of about 198°C when characterized by DSC. In one embodiment, the thermal event corresponds to melting, although not limited by any particular theory. In one embodiment, as a solid form comprising a fumarate salt of Compound 1, Fig. 12 A solid form is provided herein featuring a DSC temperature record that matches the DSC temperature record presented in [the document].

[0194] In one embodiment, form A of the fumarate salt of compound 1 is prepared by slurrying the fumarate salt of compound 1 in a solvent. In one embodiment, form A of the fumarate salt of compound 1 is prepared by slurrying the free base of compound 1 and fumaric acid in a solvent. In one embodiment, the solvent is acetone, acetonitrile, anisole, DCM, EtOH, EtOAc, ethyl formate, isopropyl acetate, MeOH, MEK, MTBE, 2-MeTHF, nitromethane, 2-propanol, tetrahydrofuran, toluene, water, a mixture of acetone and water (e.g., 95 / 5 v / v), a mixture of acetonitrile and water (e.g., 95 / 5 v / v), a mixture of 2-PrOH and water (e.g., 95 / 5 v / v), or a mixture of THF and water (e.g., 95 / 5 v / v). In one embodiment, the solvent is acetonitrile. In one embodiment, slurrying is performed at room temperature. In one embodiment, slurrying is performed at about 50°C. In one embodiment, slurrying is performed for a time period of about 1 day to about 7 days. In one embodiment, slurrying is performed for about 2 days. In one embodiment, slurrying is performed for about 7 days.

[0195] In one embodiment, a solid form is provided herein comprising form A of the fumarate salt of Compound 1 and one or more forms of the free base of Compound 1 (e.g., amorphous form and crystalline form). In one embodiment, a solid form is provided herein comprising form A of the fumarate salt of Compound 1 and an amorphous fumarate salt of Compound 1. In one embodiment, a solid form is provided herein comprising form A of the fumarate salt of Compound 1 and one or more other crystalline forms of the fumarate salt of Compound 1. In one embodiment, a solid form is provided herein comprising form A of the fumarate salt of Compound 1 and one or more forms of the salt of Compound 1 provided herein (e.g., amorphous or crystalline).

[0196] (d) Tosylate salt of Compound 1

[0197] In some embodiments, a tosylate salt of compound 1 is provided herein. The tosylate salt of compound 1 is considered to exist in various solid forms. These solid forms include crystalline solids, such as polymorphs, solvates, and hydrates of the crystalline tosylate salt of compound 1, as well as amorphous solids or mixtures thereof.

[0198] In one embodiment, a solid form comprising a tosylate salt of Compound 1 is provided herein. In one embodiment, the solid form is a solvate of the tosylate salt of Compound 1. In one embodiment, the solid form is a hydrate of the tosylate salt of Compound 1. In one embodiment, the solid form is a non-solvented form of the tosylate salt of Compound 1. In one embodiment, the solid form is a desolvented form of the tosylate salt of Compound 1. In one embodiment, the solid form is an anhydrous form (anhydride) of the tosylate salt of Compound 1. In one embodiment, the solid form is a dehydrated form of the tosylate salt of Compound 1.

[0199] In some embodiments, the molar ratio of compound 1 to p-toluenesulfonic acid in solid form ranges from about 1:1 to about 1:2. In one embodiment, the molar ratio is about 1:2 (i.e., bis-tosylate salt). In another embodiment, the molar ratio is about 1:1 (i.e., mono-tosylate salt).

[0200] (i) Form A of the tosylate salt of Compound 1

[0201] In certain embodiments, form A of the tosylate salt of compound 1 is provided herein.

[0202] In one embodiment, form A is crystalline. In one embodiment, form A is substantially crystalline. In one embodiment, form A is moderately crystalline. In one embodiment, form A is partially crystalline.

[0203] In one embodiment, the molar ratio of compound 1 to p-toluenesulfonic acid in form A is about 1:1. In one embodiment, form A is a mono-tosylate salt of compound 1.

[0204] In one embodiment, form A is a non-solvent form of the tosylate salt of compound 1.

[0205] The representative XRPD pattern of form A of the tosylate salt of compound 1 is Fig. 13 It is provided in.

[0206] In one embodiment, a solid form comprising a tosylate salt of compound 1 is provided herein, characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or all of the peaks located approximately at the following positions: 3.9, 6.8, 7.3, 7.8, 8.6, 10.9, 11.4, 12.1, 14.5, 15.4, 15.5, 15.7, 15.9, 16.4, 17.0, 17.6, 18.0, 18.6, 19.3, 19.7, 20.6, 21.2, 22.6, 23.0, 23.4, 23.8, 24.7, and 25.0° 2θ. In one embodiment, the solid form is characterized by three of the peaks. In one embodiment, the solid form is characterized by five of the peaks. In one embodiment, the solid form is characterized by seven of the peaks. In one embodiment, the solid form is characterized by nine of the peaks. In one embodiment, the solid form is characterized by eleven of the peaks. In one embodiment, the solid form is characterized by all of the peaks.

[0207] In one embodiment, a solid form comprising a tosylate salt of compound 1 is provided herein, characterized by an XRPD pattern including peaks at approximately 17.6, 18.0, and 23.8° 2θ. In one embodiment, the XRPD pattern further includes peaks at approximately 15.7 and 20.6° 2θ. In one embodiment, the XRPD pattern further includes peaks at approximately 24.7 and 25.0° 2θ. In one embodiment, the XRPD pattern includes peaks at approximately 15.7, 16.4, 17.6, 18.0, 18.6, 20.6, 21.2, 23.4, 23.8, 24.7, and 25.0° 2θ.

[0208] In one embodiment, a solid form comprising a tosylate salt of compound 1 is provided herein, characterized by an XRPD pattern including peaks at approximately 3.9, 6.8, and 7.3° 2θ. In one embodiment, the XRPD pattern includes peaks at approximately 3.9, 6.8, 7.3, 7.8, and 8.6° 2θ. In one embodiment, the XRPD pattern includes peaks at approximately 3.9, 6.8, 7.3, 7.8, 8.6, 10.9, and 11.4° 2θ. In one embodiment, the XRPD pattern includes peaks at approximately 3.9, 6.8, 7.3, 7.8, 8.6, 10.9, 11.4, 12.1, and 14.5° 2θ.

[0209] In one embodiment, as a solid form comprising a tosylate salt of compound 1, Fig. 13 A solid form featuring an XRPD pattern that matches the XRPD pattern presented in [the document] is provided herein.

[0210] In one embodiment, the XRPD pattern is obtained using Cu Kα radiation.

[0211] Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) temperature records of form A of the tosylate salt of Compound 1 Fig. 14 It is provided in. In one embodiment, a solid form comprising a tosylate salt of compound 1 is provided herein, which exhibits a weight loss of about 1.0% when heated from about 25°C to about 200°C. In one embodiment, a solid form comprising a tosylate salt of compound 1, Fig. 14 A solid form featuring a TGA temperature record that matches the TGA temperature record presented in [the document] is provided herein.

[0212] In one embodiment, a solid form comprising a tosylate salt of Compound 1 is provided herein, which exhibits a thermal event (endothermic) having a peak temperature of about 189°C when characterized by DSC. In one embodiment, the thermal event corresponds to melting, although not limited by any particular theory. In one embodiment, as a solid form comprising a tosylate salt of Compound 1, Fig. 14 A solid form is provided herein featuring a DSC temperature record that matches the DSC temperature record presented in [the document].

[0213] In one embodiment, form A of the tosylate salt of Compound 1 is prepared by slurrying the tosylate salt of Compound 1 in a solvent. In one embodiment, form A of the tosylate salt of Compound 1 is prepared by slurrying the free base of Compound 1 and p-toluenesulfonic acid in a solvent. In one embodiment, the solvent is acetone, acetonitrile, anisole, DCM, EtOH, EtOAc, ethyl formate, isopropyl acetate, MeOH, MEK, MTBE, 2-MeTHF, nitromethane, 2-propanol, tetrahydrofuran, toluene, water, a mixture of acetone and water (e.g., 95 / 5 v / v), or a mixture of 2-PrOH and water (e.g., 95 / 5 v / v). In one embodiment, the solvent is acetonitrile. In one embodiment, the slurrying is performed at room temperature. In one embodiment, slurrying is performed at about 50°C. In one embodiment, slurrying is performed for a time period of about 1 day to about 7 days. In one embodiment, slurrying is performed for about 2 days. In one embodiment, slurrying is performed for about 7 days.

[0214] In one embodiment, a solid form is provided herein comprising form A of the tosylate salt of Compound 1 and one or more forms of the free base of Compound 1 (e.g., amorphous form and crystalline form). In one embodiment, a solid form is provided herein comprising form A of the tosylate salt of Compound 1 and an amorphous tosylate salt of Compound 1. In one embodiment, a solid form is provided herein comprising form A of the tosylate salt of Compound 1 and one or more other crystalline forms of the tosylate salt of Compound 1. In one embodiment, a solid form is provided herein comprising form A of the tosylate salt of Compound 1 and one or more forms of the salt of Compound 1 provided herein (e.g., amorphous or crystalline).

[0215] (ii) Additional form of the tosylate salt of compound 1

[0216] In certain embodiments, form B of the tosylate salt of Compound 1 is provided herein. A representative XRPD pattern of form B of the tosylate salt of Compound 1 is Fig. 22 It is provided in (as part of an overlay plot). In one embodiment, as a solid form comprising a tosylate salt of compound 1, Fig. 22 A solid form is provided herein featuring an XRPD pattern that matches the XRPD pattern for form B as presented in [the document].

[0217] In certain embodiments, form C of the tosylate salt of Compound 1 is provided herein. A representative XRPD pattern of form C of the tosylate salt of Compound 1 is Fig. 22 It is provided in (as part of an overlay plot). In one embodiment, as a solid form comprising a tosylate salt of compound 1, Fig. 22 A solid form is provided herein featuring an XRPD pattern that matches the XRPD pattern for form C as presented in [the document].

[0218] In certain embodiments, form D of the tosylate salt of Compound 1 is provided herein. A representative XRPD pattern of form D of the tosylate salt of Compound 1 is Fig. 22 It is provided in (as part of an overlay plot). In one embodiment, as a solid form comprising a tosylate salt of compound 1, Fig. 22 A solid form is provided herein featuring an XRPD pattern that matches the XRPD pattern for form D as presented in [the document].

[0219] (e) Maleate salt of compound 1

[0220] In some embodiments, a maleate salt of Compound 1 is provided herein. The maleate salt of Compound 1 is considered to exist in various solid forms. These solid forms include crystalline solids, such as polymorphs, solvates, and hydrates of the crystalline maleate salt of Compound 1, as well as amorphous solids or mixtures thereof.

[0221] In one embodiment, a solid form comprising the maleate salt of Compound 1 is provided herein. In one embodiment, the solid form is a solvate of the maleate salt of Compound 1. In one embodiment, the solid form is a hydrate of the maleate salt of Compound 1. In one embodiment, the solid form is a non-solvented form of the maleate salt of Compound 1. In one embodiment, the solid form is a desolvented form of the maleate salt of Compound 1. In one embodiment, the solid form is an anhydrous form (anhydride) of the maleate salt of Compound 1. In one embodiment, the solid form is a dehydrated form of the maleate salt of Compound 1.

[0222] In some embodiments, the molar ratio of compound 1 to maleic acid in solid form ranges from about 1:1 to about 1:2. In one embodiment, the molar ratio is about 1:2 (i.e., bis-maleate salt). In another embodiment, the molar ratio is about 1:1 (i.e., mono-maleate salt).

[0223] (i) Form A of the maleate salt of Compound 1

[0224] In certain embodiments, form A of the maleate salt of compound 1 is provided herein.

[0225] In one embodiment, form A is crystalline. In one embodiment, form A is substantially crystalline. In one embodiment, form A is moderately crystalline. In one embodiment, form A is partially crystalline.

[0226] In one embodiment, the molar ratio of compound 1 to maleic acid in form A is about 1:1. In one embodiment, form A is a mono-maleate salt of compound 1. In one embodiment, the molar ratio of compound 1 to maleic acid in form A is about 1:2. In one embodiment, form A is a bis-maleate salt of compound 1. In one embodiment, form A is a mixture of the mono-maleate salt and the bis-maleate salt of compound 1.

[0227] In one embodiment, form A is a non-solvated form of the maleate salt of compound 1. In one embodiment, form A is a solvate of the maleate salt of compound 1.

[0228] The representative XRPD pattern of form A of the maleate salt of compound 1 is Fig. 15 It is provided in.

[0229] In one embodiment, a solid form comprising a maleate salt of compound 1 is provided herein, characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or all of the peaks located approximately at the following positions: 6.0, 11.6, 11.9, 12.5, 13.3, 13.9, 15.2, 16.2, 17.0, 17.6, 17.7, 18.0, 18.4, 18.9, 19.3, 19.8, 20.0, 22.2, 22.4, 22.7, 23.1, 23.3, 23.6, 24.0, 24.4, 25.1, 25.6, 26.0, and 26.9° 2θ. In one embodiment, the solid form is characterized by three of the peaks. In one embodiment, the solid form is characterized by five of the peaks. In one embodiment, the solid form is characterized by seven of the peaks. In one embodiment, the solid form is characterized by nine of the peaks. In one embodiment, the solid form is characterized by eleven of the peaks. In one embodiment, the solid form is characterized by all of the peaks.

[0230] In one embodiment, a solid form comprising a maleate salt of compound 1 is provided herein, characterized by an XRPD pattern including peaks at approximately 17.6, 24.4, and 26.9° 2θ. In one embodiment, the XRPD pattern further includes peaks at approximately 18.0, 18.4, and 19.3° 2θ. In one embodiment, the XRPD pattern further includes peaks at approximately 19.8 and 24.0° 2θ. In one embodiment, the XRPD pattern includes peaks at approximately 11.9, 17.6, 18.0, 18.4, 19.3, 19.8, 24.0, 24.4, 25.1, 26.0, and 26.9° 2θ.

[0231] In one embodiment, a solid form comprising a maleate salt of compound 1 is provided herein, characterized by an XRPD pattern including peaks at approximately 6.0, 11.6, and 11.9° 2θ. In one embodiment, the XRPD pattern includes peaks at approximately 6.0, 11.6, 11.9, 12.5, and 13.3° 2θ. In one embodiment, the XRPD pattern includes peaks at approximately 6.0, 11.6, 11.9, 12.5, 13.3, 13.9, and 15.2° 2θ. In one embodiment, the XRPD pattern includes peaks at approximately 6.0, 11.6, 11.9, 12.5, 13.3, 13.9, 15.2, 16.2, and 17.0° 2θ.

[0232] In one embodiment, as a solid form comprising a maleate salt of compound 1, Fig. 15 A solid form featuring an XRPD pattern that matches the XRPD pattern presented in [the document] is provided herein.

[0233] In one embodiment, the XRPD pattern is obtained using Cu Kα radiation.

[0234] Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) temperature records of form A of the maleate salt of Compound 1 Fig. 16 Provided herein. In one embodiment, a solid form comprising a maleate salt of compound 1 is provided herein, which exhibits a weight loss of about 0.2% when heated from about 25°C to about 150°C and a weight loss of about 8.8% when heated from about 150°C to about 185°C. In one embodiment, a solid form comprising a maleate salt of compound 1, Fig. 16 A solid form featuring a TGA temperature record that matches the TGA temperature record presented in [the document] is provided herein.

[0235] In one embodiment, a solid form comprising a maleate salt of Compound 1 is provided herein, which exhibits a thermal event (endothermic) having a peak temperature of about 174°C when characterized by DSC. In one embodiment, the thermal event corresponds to melting, although not limited by any particular theory. In one embodiment, as a solid form comprising a maleate salt of Compound 1, Fig. 16 A solid form is provided herein featuring a DSC temperature record that matches the DSC temperature record presented in [the document].

[0236] In one embodiment, form A of the maleate salt of compound 1 is prepared by slurrying the free base of compound 1 and maleic acid in acetonitrile (e.g., at room temperature for about 5 days).

[0237] In one embodiment, a solid form is provided herein comprising form A of the maleate salt of Compound 1 and one or more forms of the free base of Compound 1 (e.g., amorphous form and crystalline form). In one embodiment, a solid form is provided herein comprising form A of the maleate salt of Compound 1 and an amorphous maleate salt of Compound 1. In one embodiment, a solid form is provided herein comprising form A of the maleate salt of Compound 1 and one or more other crystalline forms of the maleate salt of Compound 1. In one embodiment, a solid form is provided herein comprising form A of the maleate salt of Compound 1 and one or more forms of the salt of Compound 1 provided herein (e.g., amorphous or crystalline).

[0238] (f) Besylate salt of compound 1

[0239] In some embodiments, a besylate salt of Compound 1 is provided herein. The besylate salt of Compound 1 is considered to exist in various solid forms. These solid forms include crystalline solids, such as polymorphs, solvates, and hydrates of the crystalline besylate salt of Compound 1, as well as amorphous solids or mixtures thereof.

[0240] In one embodiment, a solid form comprising a besylate salt of Compound 1 is provided herein. In one embodiment, the solid form is a solvate of the besylate salt of Compound 1. In one embodiment, the solid form is a hydrate of the besylate salt of Compound 1. In one embodiment, the solid form is a non-solvented form of the besylate salt of Compound 1. In one embodiment, the solid form is a desolvented form of the besylate salt of Compound 1. In one embodiment, the solid form is an anhydrous form (anhydride) of the besylate salt of Compound 1. In one embodiment, the solid form is a dehydrated form of the besylate salt of Compound 1.

[0241] In some embodiments, the molar ratio of compound 1 to benzenesulfonic acid in solid form ranges from about 1:1 to about 1:2. In one embodiment, the molar ratio is about 1:2 (i.e., bis-besylate salt). In another embodiment, the molar ratio is about 1:1 (i.e., mono-besylate salt).

[0242] (i) Form A of the besylate salt of Compound 1

[0243] In certain embodiments, form A of the besylate salt of compound 1 is provided herein.

[0244] In one embodiment, form A is crystalline. In one embodiment, form A is substantially crystalline. In one embodiment, form A is moderately crystalline. In one embodiment, form A is partially crystalline.

[0245] The representative XRPD pattern of form A of the besylate salt of compound 1 is Fig. 17 It is provided in.

[0246] In one embodiment, a solid form comprising a besylate salt of compound 1 is provided herein, characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or all of the peaks located approximately at the following positions: 6.9, 7.8, 8.5, 10.9, 11.3, 12.1, 13.2, 14.6, 15.1, 15.7, 16.2, 16.5, 16.9, 17.4, 17.9, 18.3, 19.3, 19.8, 20.5, 21.1, 21.9, 22.7, 23.8, 24.9, 25.1, 25.9, 26.7, and 27.4° 2θ. In one embodiment, the solid form is characterized by three of the peaks. In one embodiment, the solid form is characterized by five of the peaks. In one embodiment, the solid form is characterized by seven of the peaks. In one embodiment, the solid form is characterized by nine of the peaks. In one embodiment, the solid form is characterized by eleven of the peaks. In one embodiment, the solid form is characterized by all of the peaks.

[0247] In one embodiment, a solid form comprising a besylate salt of compound 1 is provided herein, characterized by an XRPD pattern including peaks at approximately 17.9, 18.3, and 23.8° 2θ. In one embodiment, the XRPD pattern further includes peaks at approximately 15.7 and 16.2° 2θ. In one embodiment, the XRPD pattern further includes peaks at approximately 8.5 and 16.5° 2θ. In one embodiment, the XRPD pattern includes peaks at approximately 6.9, 8.5, 15.7, 16.2, 16.5, 16.9, 17.9, 18.3, 20.5, 21.1, 23.8, and 25.1° 2θ.

[0248] In one embodiment, a solid form comprising a besylate salt of compound 1 is provided herein, characterized by an XRPD pattern including peaks at approximately 6.9, 7.8, and 8.5° 2θ. In one embodiment, the XRPD pattern includes peaks at approximately 6.9, 7.8, 8.5, 10.9, and 11.3° 2θ. In one embodiment, the XRPD pattern further includes peaks at approximately 6.9, 7.8, 8.5, 10.9, 11.3, 12.1, and 13.2° 2θ. In one embodiment, the XRPD pattern includes peaks at approximately 6.9, 7.8, 8.5, 10.9, 11.3, 12.1, 13.2, 14.6, and 15.1° 2θ.

[0249] In one embodiment, as a solid form comprising a besylate salt of compound 1, Fig. 17 A solid form featuring an XRPD pattern that matches the XRPD pattern presented in [the document] is provided herein.

[0250] In one embodiment, the XRPD pattern is obtained using Cu Kα radiation.

[0251] Representative thermogravimetric analysis (TGA) temperature record of form A of the besylate salt of Compound 1 Fig. 18Provided herein. In one embodiment, a solid form comprising a besylate salt of compound 1, which exhibits a weight loss of about 0.25% upon heating from about 25°C to about 150°C, is provided herein. In one embodiment, a solid form comprising a besylate salt of compound 1, wherein Fig. 18 A solid form featuring a TGA temperature record that matches the TGA temperature record presented in [the document] is provided herein.

[0252] Representative differential scanning calorimetry (DSC) temperature record of form A of the besylate salt of Compound 1 Fig. 19 Provided herein. In one embodiment, a solid form comprising a besylate salt of Compound 1 is provided herein, which exhibits a thermal event (endothermic) having an onset temperature of about 164°C when characterized by DSC. In one embodiment, the thermal event also has a peak temperature of about 175°C. In one embodiment, although not limited by any particular theory, the thermal event corresponds to melting. In one embodiment, as a solid form comprising a besylate salt of Compound 1, Fig. 19 A solid form is provided herein featuring a DSC temperature record that matches the DSC temperature record presented in [the document].

[0253] In one embodiment, form A of the besylate salt of compound 1 is prepared by adding benzenesulfonic acid to a solution of the free base of compound 1 in a solvent, thereby causing the precipitation of form A of the besylate salt of compound 1. In one embodiment, the solvent is acetone. In one embodiment, the solvent is MEK. In one embodiment, benzenesulfonic acid is added as a MEK solution.

[0254] In one embodiment, a solid form is provided herein comprising form A of the besylate salt of Compound 1 and one or more forms of the free base of Compound 1 (e.g., amorphous form and crystalline form). In one embodiment, a solid form is provided herein comprising form A of the besylate salt of Compound 1 and an amorphous besylate salt of Compound 1. In one embodiment, a solid form is provided herein comprising form A of the besylate salt of Compound 1 and one or more other crystalline forms of the besylate salt of Compound 1. In one embodiment, a solid form is provided herein comprising form A of the besylate salt of Compound 1 and one or more forms of the salt of Compound 1 provided herein (e.g., amorphous or crystalline).

[0255] 5.3 How to Use

[0256] In one embodiment, a method for treating a blood malignancy is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a patient.

[0257] In one embodiment, a method for preventing blood malignancies is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a patient.

[0258] In one embodiment, a method for managing a blood malignancy is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a patient.

[0259] In one embodiment, the blood malignancy is leukemia.

[0260] In one embodiment, the blood malignancy is acute myeloid leukemia. In one embodiment, the acute myeloid leukemia is B-cell acute myeloid leukemia.

[0261] In one embodiment, the blood malignancy is acute lymphoblastic leukemia.

[0262] In one embodiment, the blood malignancy is chronic lymphocytic leukemia / small lymphocytic lymphoma.

[0263] In one embodiment, the blood malignancy is a multiple myeloma.

[0264] In one embodiment, the blood malignancy is multiple myeloma. In one embodiment, the multiple myeloma is plasma cell leukemia (PCL).

[0265] In one embodiment, the blood malignancy is lymphoma.

[0266] In one embodiment, the blood malignancy is a non-Hodgkin lymphoma.

[0267] In one embodiment, the blood malignancy is diffuse large B-cell lymphoma.

[0268] In one embodiment, the blood malignancy is a T-cell lymphoma. In one embodiment, the T-cell lymphoma is anaplastic large cell lymphoma (ALCL). In one embodiment, the T-cell lymphoma is Sezary syndrome.

[0269] In one embodiment, the blood malignancy is Burkitt lymphoma.

[0270] In one embodiment, the blood malignancy is marginal zone lymphoma. In one embodiment, the marginal zone lymphoma is splenic marginal zone lymphoma (SMZL).

[0271] In one embodiment, the blood malignancy is Hodgkin lymphoma.

[0272] In one embodiment, the blood malignancy is myelodysplastic syndrome.

[0273] In one embodiment, the blood malignancy is newly diagnosed. In one embodiment, the blood malignancy is recurrent or refractory.

[0274] In one embodiment, AML is newly diagnosed AML. In one embodiment, AML is relapsed or refractory AML. In one embodiment, B-cell AML is newly diagnosed B-cell AML. In one embodiment, B-cell AML is relapsed or refractory B-cell AML.

[0275] In one embodiment, ALL is newly diagnosed ALL. In one embodiment, ALL is relapsed or refractory ALL.

[0276] In one embodiment, MM is newly diagnosed MM. In one embodiment, MM is relapsed or refractory MM. In one embodiment, PCL is newly diagnosed PCL. In one embodiment, PCL is relapsed or refractory PCL.

[0277] In one embodiment, HL is a newly diagnosed HL. In one embodiment, HL is a relapsed or refractory HL.

[0278] In one embodiment, NHL is a newly diagnosed NHL. In one embodiment, NHL is a relapsed or refractory NHL.

[0279] In one embodiment, TCL is newly diagnosed TCL. In one embodiment, TCL is relapsed or refractory TCL. In one embodiment, ALCL is newly diagnosed ALCL. In one embodiment, ALCL is relapsed or refractory ALCL. In one embodiment, three-digit syndrome is newly diagnosed three-digit syndrome. In one embodiment, three-digit syndrome is relapsed or refractory three-digit syndrome.

[0280] In one embodiment, BL is a newly diagnosed BL. In one embodiment, BL is a relapsed or refractory BL.

[0281] In one embodiment, MZL is newly diagnosed MZL. In one embodiment, MZL is relapsed or refractory MZL. In one embodiment, SMZL is newly diagnosed SMZL. In one embodiment, SMZL is relapsed or refractory SMZL.

[0282] In one embodiment, MDS is newly diagnosed MDS. In one embodiment, MDS is recurrent or refractory MDS.

[0283] In one embodiment, a method for achieving a complete response, a partial response, or stable disease in a patient is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a patient having a hematological malignancy provided herein. In one embodiment, a method for achieving an increase in overall survival, progression-free survival, event-free survival, time to progression, or disease-free survival in a patient is provided, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a patient having a hematological malignancy provided herein. In one embodiment, a method for achieving an increase in overall survival in a patient is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a patient having a hematological malignancy provided herein. In one embodiment, a method for achieving an increase in progression-free survival in a patient is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a patient having a hematological malignancy provided herein. In one embodiment, a method for achieving increased event-free survival in a patient is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a patient having a blood malignancy provided herein. In one embodiment, a method for achieving increased time to progression in a patient is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a patient having a blood malignancy provided herein. In one embodiment, a method for achieving increased disease-free survival in a patient is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a patient having a blood malignancy provided herein. In one embodiment, the blood malignancy is AML (e.g., B-cell AML). In one embodiment, the blood malignancy is ALL. In one embodiment, the blood malignancy is CLL / SLL.In one embodiment, the blood malignancy is MM. In one embodiment, the blood malignancy is PCL. In one embodiment, the blood malignancy is NHL. In one embodiment, the blood malignancy is DLBCL. In one embodiment, the blood malignancy is TCL (e.g., ALCL or three-digit syndrome). In one embodiment, the blood malignancy is Burkitt lymphoma. In one embodiment, the blood malignancy is HL. In one embodiment, the blood malignancy is MZL (e.g., SMZL). In one embodiment, the blood malignancy is MDS.

[0284] In one embodiment, a method for treating AML is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring treatment for AML. In one embodiment, the AML is B-cell AML.

[0285] In one embodiment, a method for preventing AML is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring prevention of AML. In one embodiment, AML is B-cell AML.

[0286] In one embodiment, a method for managing AML is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring management of AML. In one embodiment, the AML is B-cell AML.

[0287] In one embodiment, a method for treating ALL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring treatment for ALL.

[0288] In one embodiment, a method for preventing ALL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring prevention of ALL.

[0289] In one embodiment, a method for managing ALL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring management of ALL.

[0290] In one embodiment, a method for treating MM is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring treatment for MM.

[0291] In one embodiment, a method for preventing MM is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring prevention of MM.

[0292] In one embodiment, a method for managing MM is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring management of MM.

[0293] In one embodiment, a method for treating PCL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring treatment for PCL.

[0294] In one embodiment, a method for preventing PCL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring prevention of PCL.

[0295] In one embodiment, a method for administering PCL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring PCL administration.

[0296] In one embodiment, a method for treating TCL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring treatment for TCL. In one embodiment, TCL is ALCL. In one embodiment, TCL is three-digit syndrome.

[0297] In one embodiment, a method for preventing TCL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring prevention of TCL. In one embodiment, TCL is ALCL. In one embodiment, TCL is Sézary syndrome.

[0298] In one embodiment, a method for managing TCL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring management of TCL. In one embodiment, TCL is ALCL. In one embodiment, TCL is three-digit syndrome.

[0299] In one embodiment, a method for treating BL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring treatment for BL.

[0300] In one embodiment, a method for preventing BL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring prevention of BL.

[0301] In one embodiment, a method for managing BL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring management of BL.

[0302] In one embodiment, a method for treating HL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring treatment for HL.

[0303] In one embodiment, a method for preventing HL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring prevention of HL.

[0304] In one embodiment, a method for managing HL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring management of HL.

[0305] In one embodiment, a method for treating MZL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring treatment for MZL. In one embodiment, MZL is SMZL.

[0306] In one embodiment, a method for preventing MZL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring prevention of MZL. In one embodiment, MZL is SMZL.

[0307] In one embodiment, a method for administering MZL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring administration of MZL. In one embodiment, MZL is SMZL.

[0308] In one embodiment, a method for treating MDS is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring treatment for MDS.

[0309] In one embodiment, a method for preventing MDS is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring prevention of MDS.

[0310] In one embodiment, a method for managing MDS is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring management of MDS.

[0311] In one embodiment, a method of using the solid form or salt of Compound 1 provided herein, either alone or in combination with rituximab, to treat, prevent, or manage non-Hodgkin lymphoma (NHL) is provided herein.

[0312] In one embodiment, a method for treating NHL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring treatment for NHL.

[0313] In one embodiment, a method for preventing NHL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring prevention of NHL.

[0314] In one embodiment, a method for managing NHL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring management of NHL.

[0315] In one embodiment, NHL is DLBCL. In one embodiment, DLBCL is primary DLBCL. In one embodiment, DLBCL is activated B-cell type DLBCL (ABC-DLBCL). In one embodiment, DLBCL is germinal center B-cell type DLBCL (GCB-DLBCL). In one embodiment, DLBCL is unclassified DLBCL. In one embodiment, DLBCL is primary mediastinal B-cell type DLBCL (PMBL DLBCL). In one embodiment, DLBCL is a duplicative DLBCL (DHIT DLBCL), also referred to as cMyc / Bcl-2 mutant DLBCL. In one embodiment, DLBCL is a triplicative DLBCL (THIT DLBCL), also referred to as cMyc / Bcl2 / Bcl6 rearrangement DLBCL.

[0316] In one embodiment, NHL is follicular lymphoma (FL).

[0317] In one embodiment, NHL is mantle cell lymphoma (MCL).

[0318] In one embodiment, NHL is primary central nervous system lymphoma (PCNSL).

[0319] In certain embodiments, the NHL is a relapsed or refractory NHL. In one embodiment, the NHL is a relapsed NHL. In one embodiment, the NHL is a refractory NHL.

[0320] In certain embodiments, the NHL subject has radiological evidence of progression after achieving a complete response (CR). In certain embodiments, the NHL subject achieved a non-CR response to the most recent systemic therapy regimen and has radiological evidence of active disease or disease progression or relapse within 12 months of the preceding stem cell transplant (SCT).

[0321] In certain embodiments, the NHL subject has failed one or more regimens and is not a candidate for other regimens. In certain embodiments, the subject has received at least one prior regimen and is not eligible for any regimen other than the treatment methods described herein. In certain embodiments, the subject has relapsed after standard anticancer therapy or was progressing during standard anticancer therapy.

[0322] In certain embodiments, the subject failed at least one prior therapy. In certain embodiments, the subject failed at least two prior therapies.

[0323] In one embodiment, NHL is relapsed or refractory DLBCL. In one embodiment, DLBCL is relapsed DLBCL. In one embodiment, DLBCL is refractory DLBCL. In one embodiment, DLBCL is relapsed / refractory DLBCL. In one embodiment, DLBCL is refractory to doxorubicin. In one embodiment, DLBCL is resistant to doxorubicin. In one embodiment, DLBCL is refractory to one or more of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide, bendamustine, lenalidomide, gemcitabine, dexamethasone, ifosfamide, polatuzumab, or CAR-T.

[0324] In one embodiment, DLBCL is treated with two or more prior treatments.

[0325] In one embodiment, DLBCL is a transformed lymphoma. In another embodiment, DLBCL is (NOS) DLBCL not otherwise specified.

[0326] In one embodiment, NHL is a relapsed or refractory FL. In one embodiment, FL is a relapsed FL. In one embodiment, FL is a refractory FL.

[0327] In one embodiment, FL is treated with one or more prior treatments. In one embodiment, FL is treated with two or more prior treatments.

[0328] In one embodiment, NHL is a relapsed or refractory MCL. In one embodiment, MCL is a relapsed MCL. In one embodiment, MCL is a refractory MCL.

[0329] In one embodiment, MCL is treated with one or more prior treatments. In one embodiment, MCL is treated with two or more prior treatments.

[0330] In one embodiment, NHL is a relapsed or refractory PCNSL. In one embodiment, PCNSL is a relapsed PCNSL. In one embodiment, PCNSL is a refractory PCNSL.

[0331] In certain embodiments, NHL is a newly diagnosed NHL. In certain embodiments, NHL is a newly diagnosed diffuse large B-cell lymphoma. In certain embodiments, NHL is a newly diagnosed follicular lymphoma. In certain embodiments, NHL is a newly diagnosed mantle cell lymphoma. In certain embodiments, NHL is a newly diagnosed primary central nervous system lymphoma.

[0332] In certain embodiments, the method provided herein further comprises administering a therapeutically effective amount of rituximab to a subject.

[0333] In one embodiment, the first therapy provided herein (an agent such as a solid form or salt of Compound 1 provided herein) is administered to the subject prior to the administration of the second therapy (e.g., rituximab) (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks prior).

[0334] In one embodiment, the first therapy provided herein (an agent such as a solid form or salt of Compound 1 provided herein) is administered to the subject in combination with the administration of a second therapy (e.g., rituximab).

[0335] In one embodiment, the first therapy provided herein (an agent such as a solid form or salt of Compound 1 provided herein) is administered to the subject after the administration of the second therapy (e.g., rituximab) (e.g., after 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks).

[0336] In certain embodiments, rituximab is administered according to locally approved labels or pharmaceutical manuals regarding manufacturing, administration, and storage information. In certain embodiments, rituximab is administered intravenously. In certain embodiments, rituximab is administered subcutaneously. In certain embodiments, rituximab is administered via IV injection or IV infusion. In certain embodiments, rituximab is administered via IV infusion.

[0337] In certain embodiments, rituximab is administered in an amount determined by a physician. In certain embodiments, rituximab is administered once or twice daily. In certain embodiments, rituximab is about 50 to about 1000 mg / m² 2 , about 100 to about 750 mg / m² 2 , about 250 to about 500 mg / m² 2 , or about 300 to about 400 mg / m² 2 It is administered in the amount of. In certain embodiments, rituximab is 375 mg / m² per day. 2 It is administered in an amount of .

[0338] In one embodiment, a method for treating DLBCL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring treatment for DLBCL. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the subject.

[0339] In one embodiment, a method for preventing DLBCL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring prevention of DLBCL. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the subject.

[0340] In another embodiment, a method for managing DLBCL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring management of DLBCL. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the subject.

[0341] In one embodiment, a method for treating FL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring treatment for FL. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the subject.

[0342] In one embodiment, a method for preventing FL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring prevention of FL. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the subject.

[0343] In another embodiment, a method for managing FL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring management of FL. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the subject.

[0344] In one embodiment, a method for treating MCL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring treatment for MCL. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the subject.

[0345] In one embodiment, a method for preventing MCL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring prevention of MCL. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the subject.

[0346] In another embodiment, a method for managing MCL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring management of MCL. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the subject.

[0347] In one embodiment, a method for treating PCNSL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring treatment for PCNSL. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the subject.

[0348] In one embodiment, a method for preventing PCNSL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring prevention of PCNSL. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the subject.

[0349] In another embodiment, a method for administering PCNSL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring administration of PCNSL. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the subject.

[0350] In one embodiment, a method for treating relapsed or refractory DLBCL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring treatment for relapsed or refractory DLBCL. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the subject.

[0351] In one embodiment, a method for preventing relapsed or refractory DLBCL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring prevention of relapsed or refractory DLBCL. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the subject.

[0352] In another embodiment, a method for managing relapsed or refractory DLBCL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring management of relapsed or refractory DLBCL. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the subject.

[0353] In one embodiment, a method for treating relapsed or refractory FL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring treatment for relapsed or refractory FL. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the subject.

[0354] In one embodiment, a method for preventing relapsed or refractory FL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring prevention of relapsed or refractory FL. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the subject.

[0355] In another embodiment, a method for managing relapsed or refractory FL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring management of relapsed or refractory FL. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the subject.

[0356] In one embodiment, a method for treating relapsed or refractory MCL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring treatment for relapsed or refractory MCL. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the subject.

[0357] In one embodiment, a method for preventing relapsed or refractory MCL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring prevention of relapsed or refractory MCL. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the subject.

[0358] In another embodiment, a method for managing relapsed or refractory MCL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring management of relapsed or refractory MCL. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the subject.

[0359] In one embodiment, a method for treating relapsed or refractory PCNSL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring treatment for relapsed or refractory PCNSL. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the subject.

[0360] In one embodiment, a method for preventing relapsed or refractory PCNSL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring prevention of relapsed or refractory PCNSL. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the subject.

[0361] In another embodiment, a method for managing relapsed or refractory PCNSL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring management of relapsed or refractory PCNSL. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to the subject.

[0362] In another embodiment, a method for achieving a complete response, partial response, or stable disease as determined by the Lugano response criteria in a patient is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a patient with NHL. In another embodiment, a method for achieving an increase in overall survival, progression-free survival, event-free survival, time to progression, or disease-free survival in a patient is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a patient with NHL. In another embodiment, a method for achieving an increase in overall survival in a patient is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a patient with NHL. In another embodiment, a method for achieving an increase in progression-free survival in a patient is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a patient with NHL. In another embodiment, a method for achieving an increase in event-free survival in a patient is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a patient with NHL. In another embodiment, a method for achieving an increase in time to progression in a patient is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a patient having NHL. In another embodiment, a method for achieving an increase in disease-free survival in a patient is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a patient having NHL. In one embodiment, the method further comprises administering a therapeutically effective amount of rituximab to a subject.

[0363] In one embodiment, a method of using the solid form or salt of Compound 1 provided herein, either alone or in combination with obinutuzumab, to treat, prevent, or manage chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL) is provided herein.

[0364] As used herein, and unless otherwise indicated, “CLL / SLL” or “CLL and / or SLL” means CLL, or SLL, or CLL and SLL. In one embodiment, the method provided herein is for treating, preventing, or managing CLL. In one embodiment, the method provided herein is for treating, preventing, or managing SLL. In one embodiment, the method provided herein is for treating, preventing, or managing CLL and SLL.

[0365] In one embodiment, a method for treating CLL / SLL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring treatment for CLL / SLL.

[0366] In one embodiment, a method for preventing CLL / SLL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring prevention of CLL / SLL.

[0367] In one embodiment, a method for managing CLL / SLL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring management of CLL / SLL.

[0368] In one embodiment, the CLL / SLL subject has failed one or more lines of therapy. In one embodiment, the subject has failed at least one prior therapy. In one embodiment, the subject has failed at least two prior therapies. In one embodiment, the subject has previously been treated with a Bruton's tyrosine kinase (BTK) inhibitor. In one embodiment, the subject is relapsed or refractory to a BTK inhibitor. In one embodiment, the BTK inhibitor is ibrutinib. In one embodiment, the BTK inhibitor is acalabrutinib. In one embodiment, the BTK inhibitor is zanubrutinib. In one embodiment, the BTK inhibitor is tirabrutinib.

[0369] In one embodiment, CLL / SLL is a newly diagnosed CLL / SLL. In one embodiment, CLL / SLL is a relapsed or refractory CLL / SLL (R / R CLL / SLL).

[0370] In one embodiment, CLL is characterized by a mutated IGHV (immunoglobulin heavy chain gene). In one embodiment, CLL is characterized by an IGHV without mutations.

[0371] In one embodiment, CLL is characterized by one or more mutations in TP53 (tumor protein 53). In one embodiment, CLL is characterized by wild-type TP53.

[0372] In one embodiment, CLL is characterized by one or more cytogenetic abnormalities, e.g., del(13q), del(11q), del(17p), tri12, t(6;17), del(11q22.3), t(11;14), del(18q), and t(14;19). In one embodiment, CLL is characterized by del(17p).

[0373] In one embodiment, CLL is characterized by Richter transformation (also known as Richter syndrome).

[0374] In one embodiment, the method provided herein further comprises administering a therapeutically effective amount of obinutuzumab to a subject.

[0375] In one embodiment, the first therapy provided herein (an agent such as a solid form or salt of Compound 1 provided herein) is administered to the subject prior to the administration of the second therapy (e.g., obinutuzumab) (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks prior).

[0376] In one embodiment, the first therapy provided herein (an agent such as a solid form or salt of Compound 1 provided herein) is administered to the subject in combination with the administration of a second therapy (e.g., obinutuzumab).

[0377] In one embodiment, the first therapy provided herein (an agent such as a solid form or salt of Compound 1 provided herein) is administered to the subject after the administration of the second therapy (e.g., obinutuzumab) (e.g., after 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 144 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks).

[0378] In one embodiment, obinutuzumab is administered according to locally approved labels or pharmaceutical manuals regarding manufacturing, administration, and storage information. In one embodiment, obinutuzumab is administered intravenously. In one embodiment, obinutuzumab is administered subcutaneously. In one embodiment, obinutuzumab is administered via intravenous (IV) injection or IV infusion. In one embodiment, obinutuzumab is administered via IV injection. In one embodiment, obinutuzumab is administered via IV infusion.

[0379] In one embodiment, obinutuzumab is administered in an amount determined by a physician. In one embodiment, obinutuzumab is administered on day 1. In one embodiment, obinutuzumab is administered at a dose of about 75 mg to about 1100 mg on day 1. In one embodiment, obinutuzumab is administered at a dose of about 75 mg to about 125 mg on day 1, about 800 mg to about 1000 mg on day 1, or about 900 mg to about 1100 mg on day 1. In one embodiment, obinutuzumab is administered at a dose of about 100 mg on day 1. In one embodiment, obinutuzumab is administered at a dose of about 900 mg on day 1. In one embodiment, obinutuzumab is administered at a dose of about 1000 mg on day 1. In one embodiment, obinutuzumab is administered at a dose of about 100 mg on day 1 of the first 28-day cycle, about 900 mg on day 2 of the first 28-day cycle, and about 1000 mg on days 8 and 15 of the first 28-day cycle and on day 1 of the second to sixth 28-day cycles, respectively. In one embodiment, obinutuzumab is administered at a dose of about 1000 mg combined on days 1 and 2 of the first 28-day cycle, and about 1000 mg on days 8 and 15 of the first 28-day cycle and on day 1 of the second to sixth 28-day cycles, respectively. Obinutuzumab may be administered for six or more cycles. In one embodiment, obinutuzumab is administered as described herein in a first 28-day cycle and at about 1000 mg on the first day of the second to twelfth 28-day cycles. In one embodiment, obinutuzumab is administered as described herein in a first 28-day cycle and at about 1000 mg on the first day of the second to twenty-fourth 28-day cycles. In one embodiment, obinutuzumab is administered as described herein in a first 28-day cycle and at about 1000 mg on the first day of the 28-day cycles that follow until disease progression.

[0380] In one embodiment, a method for treating newly diagnosed CLL / SLL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring treatment for newly diagnosed CLL / SLL. In one embodiment, the method further comprises administering a therapeutically effective amount of obinutuzumab to the subject.

[0381] In one embodiment, a method for preventing newly diagnosed CLL / SLL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring prevention of newly diagnosed CLL / SLL. In one embodiment, the method further comprises administering a therapeutically effective amount of obinutuzumab to the subject.

[0382] In another embodiment, a method for managing newly diagnosed CLL / SLL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring management of newly diagnosed CLL / SLL. In one embodiment, the method further comprises administering a therapeutically effective amount of obinutuzumab to the subject.

[0383] In one embodiment, a method for treating relapsed or refractory CLL / SLL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring treatment for relapsed or refractory CLL / SLL. In one embodiment, the method further comprises administering a therapeutically effective amount of obinutuzumab to the subject.

[0384] In one embodiment, a method for preventing relapsed or refractory CLL / SLL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring prevention of relapsed or refractory CLL / SLL. In one embodiment, the method further comprises administering a therapeutically effective amount of obinutuzumab to the subject.

[0385] In another embodiment, a method for managing relapsed or refractory CLL / SLL is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a subject requiring management of relapsed or refractory CLL / SLL. In one embodiment, the method further comprises administering a therapeutically effective amount of obinutuzumab to the subject.

[0386] In another embodiment, a method for achieving a complete response, partial response, or stable disease as determined by the International Workshop Criteria for Chronic Lymphocytic Leukemia in a patient is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a patient with CLL / SLL. In one embodiment, detection of minimal residual disease (MRD) may be performed in subjects undergoing a bone marrow evaluation to confirm a complete response (CR). In one embodiment, a method for achieving minimal residual disease (MRD) negativity in a patient is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a patient with CLL / SLL. In one embodiment, MRD negativity is measured in peripheral blood and / or bone marrow. In one embodiment, MRD negativity persists for at least 3 months. In another embodiment, a method for achieving an increase in overall survival, progression-free survival, event-free survival, time to progression, or disease-free survival in a patient is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a patient with CLL / SLL. In another embodiment, a method for achieving increased overall survival in a patient is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a patient having CLL / SLL. In another embodiment, a method for achieving increased progression-free survival in a patient is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a patient having CLL / SLL. In another embodiment, a method for achieving increased event-free survival in a patient is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a patient having CLL / SLL.In another embodiment, a method for achieving an increase in time to progression in a patient is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a patient having CLL / SLL. In another embodiment, a method for achieving an increase in disease-free survival in a patient is provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein to a patient having CLL / SLL. In one embodiment, the method further comprises administering a therapeutically effective amount of obinutuzumab to a subject.

[0387] The methods provided herein encompass treating patients regardless of their age. In some embodiments, the subject is 18 years of age or older. In other embodiments, the subject is 18, 25, 35, 40, 45, 50, 55, 60, 65, or over 70 years of age. In other embodiments, the subject is under 65 years of age. In other embodiments, the subject is over 65 years of age.

[0388] A solid form or salt of Compound 1 for use in a method for treating a disease provided herein, comprising administering a therapeutically effective amount of the solid form or salt of Compound 1 to a patient. A pharmaceutical composition comprising the solid form or salt of Compound 1 for use in a method for treating a disease provided herein is also provided herein.

[0389] 5.4 Pharmaceutical Composition and Route of Administration

[0390] The solid form or salt of Compound 1 provided herein may be administered to a subject orally, topically, or parenterally in the form of conventional formulations, such as capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions. Suitable formulations include conventional organic or inorganic additives, such as diluents (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, or calcium carbonate), binders (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, or starch), disintegrants (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate, or calcium citrate), lubricants (e.g., magnesium stearate, hard anhydrous silica, talc, or sodium lauryl sulfate), flavorings (e.g., citric acid, menthol, glycine, or orange powder), preservatives (e.g., sodium benzoate, sodium bisulfite, methylparaben, or It can be prepared by commonly used methods using propylparaben), a stabilizer (e.g., citric acid, sodium citrate, or acetic acid), a suspending agent (e.g., methylcellulose, polyvinylpyrrolidone, or aluminum stearate), a dispersant (e.g., hydroxypropylmethylcellulose), water, and a base wax (e.g., cocoa butter, white petrolatum, or polyethylene glycol). The effective amount of the compound in the pharmaceutical composition may be at a level that produces the desired effect in both oral and parenteral administration.

[0391] The solid form or salt of Compound 1 provided herein may be administered orally. In one embodiment, when administered orally, the solid form or salt of Compound 1 provided herein is administered with a meal and water. In another embodiment, the solid form or salt of Compound 1 provided herein is dispersed in water or juice (e.g., apple juice or orange juice) and administered orally as a solution or suspension.

[0392] The solid form or salt of Compound 1 provided herein may also be administered intradermally, intramuscularly, intraperitoneally, via the skin, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, vaginally, transdermally, rectally, mucous membranes, by inhalation, or topically to the ears, nose, eyes, or skin. The method of administration is at the discretion of the medical professional and may vary in part depending on the site of the medical condition.

[0393] In one embodiment, a capsule containing the solid form or salt of Compound 1 provided herein without additional excipients is provided herein. In another embodiment, a composition is provided herein comprising an effective amount of the solid form or salt of Compound 1 provided herein and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient may comprise a diluent, a binder, a disintegrant, a lubricant, a lubricant, or a mixture thereof. In one embodiment, the composition is a pharmaceutical composition.

[0394] The composition may be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, troches, suppositories, and suspensions. The composition may be formulated to contain a daily dose or a convenient fraction of a daily dose in a dosage unit, which may be a single tablet or capsule, or in a convenient volume of liquid. In one embodiment, the solution is prepared from a water-soluble salt. Generally, all compositions are prepared according to methods known in pharmaceutical chemistry. Capsules may be prepared by mixing the solid form or salt of Compound 1 provided herein with a suitable excipient and filling a suitable amount of the mixture into a capsule. Conventional excipients include, but are not limited to, inert powdered materials such as many different types of starch, powdered cellulose, particularly crystalline and microcrystalline cellulose, sugars such as fructose, mannitol, and sucrose, grain flour, and similar edible powders. The capsule filling may also be prepared by wet granulation or dry granulation.

[0395] In capsule formulation, a lubricant may be required to prevent the powder from sticking to the pin. The lubricant can be selected from slippery solids such as talc, magnesium stearate and calcium stearate, sodium stearyl fumarate, stearic acid, and hydrogenated vegetable oil. Disintegrators are substances that swell when wetted, destroying the capsule slug and releasing the compound. These include starch, clay, cellulose, crospovidone, sodium croscarmellose, sodium starch glycolate, algin, and gum. More specifically, for example, corn and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resin, alginic acid, guar gum, citrus pulp, and carboxymethyl cellulose, as well as sodium lauryl sulfate, may be used. Lubricants including silicon dioxide, talc, and calcium silicate may also be used.

[0396] Tablets can be manufactured by direct compression, wet granulation, or dry granulation. Their formulation typically incorporates not only the compound but also diluents, binders, lubricants, and disintegrants. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or calcium sulfate, inorganic salts such as sodium chloride, and powdered sugars. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin, and sugars such as lactose, fructose, glucose, etc. Natural and synthetic gums, including acacia, alginate, methylcellulose, polyvinylpyrrolidine, etc., are also convenient. Polyethylene glycol, ethylcellulose, and waxes can also serve as binders.

[0397] In tablet formulation, a lubricant may be required to prevent the tablet and punch from sticking to the die. The lubricant may be selected from slippery solids such as talc, magnesium stearate and calcium stearate, sodium stearyl fumarate, stearic acid, and hydrogenated vegetable oil. Tablet disintegrators are substances that swell when wetted, destroying the tablet and releasing compounds. These include starch, clay, cellulose, crospovidone, sodium croscarmellose, sodium starch glycolate, algin, and gum. More specifically, for example, corn and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resin, alginic acid, guar gum, citrus pulp, and carboxymethyl cellulose, as well as sodium lauryl sulfate, may be used. Lubricants including silicon dioxide, talc, and calcium silicate may also be used. The tablet may be coated with sugars as flavoring agents and sealants, or with film-forming protective agents to modify the solubility properties of the tablet. The composition may also be formulated as a chewable tablet by using a substance such as mannitol, for example, in formulation.

[0398] When it is desirable to administer the solid form or salt of Compound 1 provided herein as a suppository, a typical base may be used. Cocoa butter is a traditional suppository base, which may be modified by the addition of wax to slightly raise its melting point. In particular, water-miscible suppository bases containing polyethylene glycol of various molecular weights are widely used.

[0399] The effect of the solid form or salt of Compound 1 provided herein may be delayed or extended by appropriate formulation. For example, a slowly solubilizing pellet of the solid form or salt of Compound 1 provided herein may be prepared and incorporated into a tablet or capsule, or as a sustained-release implantable device. The technique also includes preparing pellets with several different dissolution rates and filling a mixture of pellets into a capsule. The tablet or capsule may be coated with a film that resists dissolution for a predictable period of time. Even parenteral formulations may be long-acting by dissolving or suspending the solid form or salt of Compound 1 provided herein in an oily or emulsified vehicle that causes it to be slowly dispersed in serum.

[0400] Depending on the condition of the disease to be treated and the condition of the subject, the solid form or salt of Compound 1 provided herein may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intravesical injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration. The solid form or salt of Compound 1 provided herein may be formulated into suitable dosage units, either alone or in combination, with pharmaceutically acceptable excipients, carriers, ajuvants, and vehicles suitable for each route of administration.

[0401] In one embodiment, the solid form or salt of Compound 1 provided herein is administered orally. In another embodiment, the solid form or salt of Compound 1 provided herein is administered parenterally. In another embodiment, the solid form or salt of Compound 1 provided herein is administered intravenously.

[0402] The solid form or salt of Compound 1 provided herein may be delivered as a single dose, e.g., a single bolus injection, or as an oral capsule, tablet, or pill; or over time, e.g., as a continuous infusion over time or as divided bolus doses over time. The solid form or salt of Compound 1 provided herein may be administered repeatedly as needed, e.g., until the patient experiences stable disease or regression, or until the patient experiences disease progression or unacceptable toxicity.

[0403] The solid form or salt of Compound 1 provided herein may be administered once daily (QD) or divided into multiple daily doses, for example, twice daily (BID), three times daily (TID), and four times daily (QID). Additionally, administration may be continuous (i.e., daily or every day for a continuous number of days), intermittent, for example, periodic (i.e., including periods of several days, weeks, or months). As used herein, the term “daily” is intended to mean that the therapeutic compound, for example, the solid form or salt of Compound 1 provided herein, is administered once daily or more than once for a specified period of time. The term “continuous” is intended to mean that the therapeutic compound, for example, the solid form or salt of Compound 1 provided herein, is administered daily for an uninterrupted period of at least 7 days to 52 weeks. As used herein, the term “intermittent” or “intermittently” is intended to mean stopping and starting at regular or irregular intervals. For example, intermittent administration of the solid form or salt of Compound 1 provided herein is administration for 1 to 6 days per week, periodic administration (e.g., daily administration for 2 to 8 consecutive weeks, followed by a rest period of up to 1 week without administration), or administration every other day. As used herein, the term “periodic” is intended to mean that the therapeutic compound, e.g., the solid form or salt of Compound 1 provided herein, is administered daily or consecutively, but with rest periods.

[0404] In some embodiments, the frequency of administration is in the range of about daily doses to about monthly doses. In certain embodiments, administration is once a day, twice a day, three times a day, four times a day, once every other day, twice a week, once a week, once every two weeks, once every three weeks, or once every four weeks. In one embodiment, the solid form or salt of Compound 1 provided herein is administered once a day. In another embodiment, the solid form or salt of Compound 1 provided herein is administered twice a day. In another embodiment, the solid form or salt of Compound 1 provided herein is administered three times a day. In another embodiment, the solid form or salt of Compound 1 provided herein is administered four times a day.

[0405] In a specific embodiment, the method provided herein comprises administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein in one or more 7-day treatment cycles. In another embodiment, the method provided herein comprises administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein on days 1 through 5 of a 7-day cycle. In yet another embodiment, the method provided herein comprises administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein on days 1 through 3 of a 7-day cycle.

[0406] In a specific embodiment, the method provided herein comprises administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein in one or more 14-day treatment cycles. In another embodiment, the method provided herein comprises administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein on days 1 through 7 of a 14-day cycle. In yet another embodiment, the method provided herein comprises administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein on days 1 through 10 of a 14-day cycle.

[0407] In a specific embodiment, the method provided herein comprises administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein in one or more 28-day treatment cycles. In another embodiment, the method provided herein comprises administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein on days 1 through 21 of a 28-day cycle. In another embodiment, the method provided herein comprises administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein on days 1 through 5, days 8 through 12, days 15 through 19, and days 22 through 26 of a 28-day cycle. In another embodiment, the method provided herein comprises administering a therapeutically effective amount of the solid form or salt of Compound 1 provided herein on days 1 through 10 and days 15 through 24 of a 28-day cycle.

[0408] In one embodiment, the solid form or salt of Compound 1 provided herein is administered once daily for 5 days, followed by a 2-day rest. In one embodiment, the solid form or salt of Compound 1 provided herein is administered once daily for 3 days, followed by a 4-day rest. In one embodiment, the solid form or salt of Compound 1 provided herein is administered once daily for 7 days, followed by a 7-day rest. In one embodiment, the solid form or salt of Compound 1 provided herein is administered once daily for 10 days, followed by a 4-day rest. In one embodiment, the solid form or salt of Compound 1 provided herein is administered once daily for 21 days, followed by a 7-day rest.

[0409] In certain embodiments, treatment comprises administering a therapeutically effective amount of rituximab in one or more treatment cycles. In one embodiment, rituximab is administered once every 7 days. In one embodiment, rituximab is administered once every 4 weeks. In one embodiment, rituximab is administered once every 8 weeks. In one embodiment, rituximab is administered on days 1, 8, 15, and 22 of a first 28-day cycle, and on day 1 of a second to sixth 28-day cycle, and then administered once every 8 weeks.

[0410] In one embodiment, treatment comprises administering a therapeutically effective amount of obinutuzumab in one or more treatment cycles. In one embodiment, obinutuzumab is administered twice every 7 days. In one embodiment, obinutuzumab is administered once a week. In one embodiment, obinutuzumab is administered once every 4 weeks. In one embodiment, obinutuzumab is administered on days 1, 2, 8, and 15 of the first 28-day cycle and on day 1 of the second to sixth 28-day cycles. In one embodiment, obinutuzumab is administered on day 1 of the second to twelfth 28-day cycles. In one embodiment, obinutuzumab is administered on day 1 of the second to twenty-fourth 28-day cycles. In one embodiment, obinutuzumab is administered on day 1 of the 28-day cycles following disease progression.

[0411] In one embodiment, obinutuzumab is administered at a dose of about 100 mg on the first day of the first 28-day cycle, about 900 mg on the second day of the first 28-day cycle, and about 1000 mg each on the eighth and fifteenth days of the first 28-day cycle. In one embodiment, obinutuzumab is administered at a dose of about 1000 mg combined on the first and second days of the first 28-day cycle, and about 1000 mg each on the eighth and fifteenth days of the first 28-day cycle. In one embodiment, obinutuzumab is administered at a dose of about 1000 mg on the first day of the second to sixth 28-day cycles. In one embodiment, obinutuzumab is administered at a dose of about 1000 mg on the first day of the second to twelfth 28-day cycles. In one embodiment, obinutuzumab is administered at about 1,000 mg on the first day of the 2nd to 24th 28-day cycle. In one embodiment, obinutuzumab is administered at about 1,000 mg on the first day of the 28-day cycle that follows until disease progression.

[0412] Any treatment cycle described herein may be repeated for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more cycles. In certain cases, a treatment cycle as described herein comprises 1 to about 24 cycles, about 2 to about 16 cycles, or about 2 to about 4 cycles. In certain cases, a treatment cycle as described herein comprises 1 to about 4 cycles. In some embodiments, a therapeutic effective amount of the solid form or salt of Compound 1 provided herein and / or rituximab is administered for 1 to 13 cycles of 28 days (e.g., about 1 year). In some embodiments, a therapeutic effective amount of the solid form or salt of Compound 1 provided herein and / or rituximab is administered for 1 to 24 cycles of 28 days (e.g., about 2 years). In some embodiments, a therapeutic effective amount of the solid form or salt of Compound 1 provided herein and / or obinutuzumab is administered for 1 to 13 cycles of 28 days (e.g., about 1 year). In some embodiments, a therapeutic effective amount of the solid form or salt of Compound 1 provided herein and / or obinutuzumab is administered for 1 to 24 cycles of 28 days (e.g., about 2 years). In certain cases, the cyclic therapy is not limited to the number of cycles and the therapy continues until disease progression. In certain cases, the cycles may include varying durations of the administration period and / or rest period described herein.

[0413] 6. Examples

[0414] Specific embodiments of the present invention are illustrated by the following non-limiting embodiments.

[0415] Abbreviations used:

[0416]

[0417] 6.1 Synthesis of (S)-2-(2,6-dioxopiperidine-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidine-1-yl)methyl)benzyl)amino)isoindolin-1,3-dione (Compound 1)

[0418]

[0419] (S)-2-(2,6-dioxopiperidine-3-yl)-4-((2-fluoro-4-(hydroxymethyl)benzyl)amino)isoindolin-1,3-dione : A suspension of (S)-4-amino-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (5.00 g, 18.3 mmol) and 2-fluoro-4-(hydroxymethyl)benzaldehyde (2.82 g, 18.30 mmol) in a 2:1 dioxane-MeOH (75 mL) was cooled to 0°C, and B 10 H 14 (4.92 g, 40.3 mmol) was added gradually over 5 minutes. The reaction flask was fitted with a diaphragm and a needle vent (pressure), and vigorously stirred for 10 minutes. The mixture was allowed to reach ambient temperature and stirred for 3 hours. The mixture was concentrated, and the residue was purified by silica gel chromatography (0-10% MeOH-DCM) to provide (S)-2-(2,6-dioxopiperidine-3-yl)-4-((2-fluoro-4-(hydroxymethyl)benzyl)amino)isoindolin-1,3-dione as a yellow solid (4.23 g, 56%). LCMS (ESI) m / z 411.8 [M+H] + .

[0420] (S)-4-((4-(chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindolin-1,3-dioneA solution of (S)-2-(2,6-dioxopiperidine-3-yl)-4-((2-fluoro-4-(hydroxymethyl)benzyl)amino)isoindolin-1,3-dione (0.727 g, 1.77 mmol) in dry NMP (6 mL) was cooled to 0°C, and methanesulfonyl chloride (0.275 mL, 3.35 mmol) and DIEA (0.617 mL, 3.53 mmol) were added sequentially. The reaction mixture was allowed to reach ambient temperature and stirred for 18 hours. The reaction mixture was slowly added to H2O (60 mL) cooled to 0°C while mixing vigorously. The resulting suspension was filtered, and the collected solid was washed with H2O and Et2O. The solid was dissolved in EtOAc, the solution was dried with MgSO4, filtered, and concentrated to provide (S)-4-((4-(chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione as a yellow solid (0.600 g, 79%). LCMS (ESI) m / z 430.0 [M+H] + .

[0421] (S)-2-(2,6-dioxopiperidine-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidine-1-yl)methyl)benzyl)amino)isoindolin-1,3-dione : 4-(azetidine-3-yl)morpholine hydrochloride (125 mg, 0.698 mmol) and DIEA (0.122 mL, 0.698 mmol) were added to a solution of (S)-4-((4-(chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-dioxopiperidine-3-yl)isoindolin-1,3-dione (300 mg, 0.698 mmol) in dry DMSO (1.0 mL). The reaction mixture was stirred at ambient temperature for 18 hours and diluted with DMSO (1 mL). The solution was purified by chiral reverse-phase chromatography to provide (S)-2-(2,6-dioxopiperidine-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidine-1-yl)methyl)benzyl)amino)isoindolin-1,3-dione (89 mg, 24%, 97% ee). LCMS (ESI) m / z 536.2 [M+H] + .

[0422] 6.2 Cell-based assay using Compound 1

[0423] The following is an example of a cell-based assay that can be used to determine the antiproliferative activity and apoptotic effect of compound 1 using an exemplary non-Hodgkin lymphoma (NHL) cell line.

[0424] Cell proliferation and viability assay using SU-DHL-4 cell line: The following exemplary assay uses DLBCL cell lines 120 hours after treatment, e.g., SU-DHL-4 cell line (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH [DSMZ]: catalog number ACC-495). The seeding density of SU-DHL-4 can be optimized to ensure assay linearity in a 1536-well plate.

[0425] Compound 1 at increasing concentrations (0.5 nM to 10 μM) was spotted into empty 1536-well plates using an acoustic splitter (EDC ATS-100) via a 20-point dilution method (unevenly spaced data points). The DMSO concentration was maintained constant at a final assay concentration of 0.1% DMSO. Prior to the test, SU-DHL-4 cells were grown in RPMI-1640 (Roswell Park Memorial Institute-1640) medium containing 10% FBS (fetal bovine serum: HyClone) and proliferated in culture flasks to provide a sufficient amount of starting material. Subsequently, the cells were diluted to 500 cells per well in a 5 μL volume and added directly to the compound-spotted 1536-well plates. The cells were allowed to grow for 120 hours at 37°C under 5% CO2. At the time point (t0) when cell exposure to the compound began, the initial number of viable cells was assessed by quantifying the level of luminescence produced by adenosine-5'-triphosphate (ATP) present in viable cells using the Cell Titer-Glo® luminescence cell viability assay at a 1 vol:2 vol ratio according to the manufacturer's (Promega Corporation, Madison, Wisconsin) instructions. After 120 hours, the cell viability of the treated cells was assessed using Cell Titer-Glo® and luminescence readings. All growth inhibition curves were processed and evaluated using Activity Base (IDBS, Alameda, California). Cell viability IC50 50 The values ​​were calculated using a 4-parameter logistic model (S-shaped dose-response model):

[0426] y = (A+ ((BA) / (1 + ((C / x)^D))))

[0427] Here:

[0428] A = YMin

[0429] B = Y Max

[0430] C = EC 50

[0431] D = Hill slope

[0432] IC 50 = Y = Concentration of the compound at 50% of the DMSO control

[0433] Y = cell viability measured as luminescence units, and

[0434] x = concentration of the compound.

[0435] Compound 1 has an IC50 in the SU-DHL-4 cell proliferation assay. 50 It was found to have an activity of < 0.2 μM.

[0436] Cell proliferation and viability assay using hematological cell lines: The following exemplary antiproliferative assay uses the following exemplary hematological cell lines. The in vitro growth inhibitory activity of Compound 1 described herein was evaluated using a 384-well flow cytometry assay.

[0437] Table 6 . Hematological cell line

[0438]

[0439]

[0440] ABC = Activated B-cell type; FBS = Fetal bovine serum; GCB = Germ center B-cell; IMDM = Iscov modified Dulbecco medium; NEAA = Non-essential amino acids; RPMI = RPMI1640.

[0441] Cell lines were plated on 384-well flat-bottom plates and evaluated using increasing concentrations of the compound or a dimethyl sulfoxide (DMSO) control ranging from 0.00015 to 10 μM. The final concentration of DMSO was 0.1% (v / v). After the addition of Compound 1 or DMSO and 120 hours of incubation, cell number and apoptosis were analyzed by flow cytometry (Attune®, Thermo Fisher) using Annexin V and the live cell-impermeable DNA dye DRAQ7. Phosphatidylserine translocates from the inner layer of the cell membrane to the outer layer during the early stages of apoptosis, and Annexin V binds to the exposed phosphatidylserine found on the surface of apoptotic cells. The bio-dye DRAQ7 is blocked by intact live cells and stains only cells that have died as a result of apoptosis or necrosis.

[0442] Next, flow cytometry data analysis was performed using Flow Jo_v10 software to determine the number of viable cells (Annexin V and DRAQ7 double-negative stained cells) and the percentage of apoptotic cells (Annexin V-positive cells) for each condition. The number of live cells at all concentrations was normalized to the DMSO control (considered 100%) to calculate the percentage of viable cells remaining after treatment, and this was graphed using GraphPad Prism 7.03. Subsequently, IC was determined by performing non-linear regression curve fitting using log(inhibitor) versus normalized response – variable slope analysis on GraphPad Prism 7.03. 50 (50% inhibition concentration) and E maxThe (maximum achieved efficacy) value was calculated. The area under the curve (AUC) was calculated by performing an area under the curve analysis on GraphPad Prism 7.03. Similarly, for the apoptosis analysis, the percentage of apoptosis—combining both "early" (Annexin V positive and DRAQ7 negative) and "late" (Annexin V and DRAQ7 positive) cell gates relative to DMSO—was graphed using GraphPad Prism 7.03. AUC and EC values ​​were derived from the apoptosis curve by performing nonlinear regression curve fitting and area under the curve analysis using log(agonist) versus normalized response—variable slope analysis on GraphPad Prism 7.03. 50 (Concentration of the compound that triggers the half-maximum apoptosis reaction) and Y max The value of (maximum percentage of achieved apoptosis) was calculated.

[0443] IC for % viable cells using dose-response proliferation curves and non-linear curve-fit regression for a panel of hematological cell lines 50 , AUC, and E max (E for survival rate max Determine (which varies between 100 at low dose and 0 at high dose, corresponding to the inhibition of all surviving cells), and use the dose-response apoptosis curve to determine the EC for % apoptosis. 50 , AUC, and Y max (Y for apoptosis maxThe value was determined to vary from 0 at low doses to 100 at high doses (corresponding to the death of all cells). Tumor cells were exposed to serial dilutions of Compound 1 (0.00015 to 10 μM) or a dimethyl sulfoxide (DMSO) control for 5 days. Viability and apoptosis were determined for all cell lines by Annexin V / 7-aminoactinomycin D (7-AAD) flow cytometry. Compound 1 was found to have antiproliferative activity and / or apoptotic effects in almost all hematological cell lines tested, as shown in the table below.

[0444] Table 7 . Antiproliferative activity and apoptotic effect of Compound 1 in hematological cell lines

[0445]

[0446]

[0447] AUC = Area under the curve; IC 50 = 50% inhibition concentration (μM); E max = Maximum tumor cell removal efficacy achieved, expressed as the percentage of remaining tumor cells; EC 50 = Compound concentration (μM) that triggers the half-maximum apoptosis reaction; Y max = Percentage of the control group calculated at the highest concentration of compound 1.

[0448] 6.3 Analysis Method

[0449] Typical measurement conditions are provided below:

[0450] X-ray powder diffraction (XRPD)

[0451] The Rigaku Smart-Lab X-ray diffraction system is configured with a reflective Bragg-Brentano geometry using a line source X-ray beam. The X-ray source is a Cu long-type precision focusing tube operating at 40 kV and 44 mA. This source provides an incident beam profile that changes from a narrow line at large angles to a wide rectangle at small angles from the sample. A beam conditioning slit is used on the line X-ray source to ensure that the maximum beam size is less than 10 mm both along the line and perpendicular to the line. The Bragg-Brentano geometry is a para-focusing geometry controlled by passive divergence and receiving slits, where the sample itself acts as the focusing component for the optics. The intrinsic resolution of the Bragg-Brentano geometry is partially determined by the diffractometer radius and the width of the receiving slit used. Typically, the Rigaku Smart-Lab is operated to provide a peak width of 0.1° 2θ or less. The axial divergence of the X-ray beam is controlled by a 5.0-degree solar slit in both the incident and diffracted beam paths.

[0452] Powder samples were prepared in a low-background Si holder using light manual pressure to keep the sample surface flat and horizontal with respect to the reference surface of the sample holder. Each sample was analyzed at 2 to 40° 2θ using a continuous scan of 6° 2θ per minute with an effective step size of 0.02° 2θ.

[0453] Differential Scanning Calorimetry (DSC)

[0454] DSC analysis was performed using a TA Instruments Q2000 instrument. Indium was used for instrument temperature calibration. The DSC cell was maintained under nitrogen purging at ~50 mL / min during each analysis. Samples were placed in standard crimped aluminum pans and heated from 25°C to 350°C at a rate of 10°C / min.

[0455] Thermogravimetric (TG) analysis

[0456] TG analysis was performed using a TA Instruments Q50 instrument. The instrument balance was calibrated using M-grade weights, and temperature calibration was performed using an Alumel. Nitrogen purging was ~40 mL / min on the balance and ~60 mL / min in the furnace. Each sample was placed in a pre-weighted platinum pan and heated from 20°C to 350°C at a rate of 10°C / min.

[0457] Infrared (IR) Spectroscopic Analysis

[0458] IR spectra were acquired using a Nicolet 6700 FT-IR system. Samples were analyzed using a Nicolet Smart iTR attenuated total reflection device.

[0459] Raman spectroscopy

[0460] Fourier transform (FT) Raman spectra were collected using a Nicolet Model 6700 spectrometer connected to a Nexus Raman accessory module. This instrument consists of an Nd:YAG laser operating at 1024 nm, a CaF2 beam splitter, and an indium gallium arsenide detector. OMNIC software was used to control the data acquisition and processing of the spectra. Samples were packed into 3-inch glass NMR tubes for analysis.

[0461] Nuclear Magnetic Resonance (NMR) Spectroscopy

[0462] 1 H NMR spectra were collected using a Bruker DRX-500 spectrometer located in the Department of Chemistry at Purdue University. Samples were prepared by dissolving the material in DMSO-d6. For subsequent spectrum collection, the solution was filtered and placed into individual 5-mm NMR tubes. Temperature-controlled (298K) collected with the DRX-500 1 The 1H NMR spectrum was obtained using a 5-mm cryoprobe operating at an observation frequency of 499.89 MHz.

[0463] DVS analysis

[0464] Dynamic Vapor Adsorption (DVS) was measured using the DVS Advantage (Surface Measurement Systems Ltd). Samples were tested isothermally (25°C) over a full cycle of targeted RH in stepwise increments from 0 to 95%. For the isothermal test, the chamber temperature was maintained constant at 25.0 ± 1.0°C by a water bath. Relative humidity within the sample chamber was generated by combining different flows of wet and dry nitrogen at varying flow rates. The analysis was performed in 10% RH increments. The sampling rate was 1 sec, and the data storage rate was 20 sec. The dm / dt (%) value was set to 0.001 with a dm / dt window of 5 min, a minimum stability duration of 10 min, and a maximum stage time of 180 min. The equilibrium weight of the sample corresponding to each RH was recorded. An adsorption isotherm is obtained by plotting the equilibrium moisture content against RH.

[0465] 6.4 Free Base Polymorphism Screening

[0466] The batch of the Compound 1 free base starting material was characterized. XRPD indicated that it is amorphous. TGA showed a weight loss of 7.3% below 200°C. DSC showed several slight endothermic reactions below 150°C. The representative XRPD pattern of the amorphous Compound 1 free base is Fig. 20 It is presented in.

[0467] Compound 1, a free base starting material, was mixed with various solvents under various conditions in an attempt to produce a crystalline material. The results are listed in the table below.

[0468] Table 8. Polymorph screen of free bases of Compound 1

[0469]

[0470]

[0471]

[0472] a. AS = Inverse solvent; E = Evaporation; NC = No crystallization; RT = Room temperature

[0473] b. NC = Amorphous, LC = Low crystallinity, pk = Peak

[0474] Two distinct XRPD patterns were identified, designated as Form A and Form B of the free base of Compound 1, respectively. The two forms were analyzed by XRPD, DSC, TG, and NMR. The data are summarized in the table below.

[0475] Table 9 Characterization of Forms A and B of the free base of Compound 1

[0476]

[0477] 6.5 First Salt Screening

[0478] Compound 1 free base starting material was mixed with various counterions under various conditions in an attempt to produce crystalline salts. Approximately 15 different counterions were used in the salt screen, and the results are listed in the table below.

[0479] Table 10 Salt screening of Compound 1

[0480]

[0481]

[0482]

[0483] a. AS = Inverse solvent; P = Precipitation; RT = Room temperature; S / AS = Solvent / Inverse solvent; SL = Slurry; G = Grinding; C = Cooling; E = Evaporation

[0484] b. NC = amorphous, LC = low crystallinity; pk = peak; A, B, etc. = shape

[0485] Several substances were identified, exhibiting XRPD patterns suggesting the formation of a new phase. That is, the patterns contain peaks that did not originate from the free base of compound 1 or the acid used. The acids used in these experiments were fumaric acid, hydrochloric acid, maleic acid, and p-toluenesulfonic acid.

[0486] All samples with XRPD patterns suggesting new phase formation were analyzed by DSC, TG, and NMR. The results are summarized in the table below.

[0487] Table 11 Characterization of the crystalline salt of Compound 1

[0488]

[0489] 6.6 Second Salt Screening

[0490] The batch of Compound 1 free base was characterized by XRPD, TGA, DSC, and DVS. XRPD confirmed that it is amorphous. TGA indicated that there were several stages of weight loss below 200°C prior to decomposition. Results from dynamic vapor adsorption (DVS) studies demonstrated that the amorphous Compound 1 free base exhibited relatively high hygroscopicity below 75% RH. The free base slowly and continuously absorbed moisture (~6.0% wt) from the dry state up to 90% RH. During desorption, the water content was slowly released from 90% RH down to the dry state (0% RH). Adsorption / desorption was nearly reversible over two full cycles.

[0491] HCl salt

[0492] To search for the crystalline HCl salt of compound 1, several experiments were performed using hydrochloric acid added to different solvents.

[0493] In one experiment, 49.2 mg of the free base of Compound 1 was weighed into a 4-mL glass vial, and 1.0 mL of EtOAc was added. The mixture became a nearly clear solution, and then 0.1 N HCl was added to 0.8 mL of EtOAc. A turbid suspension was observed, and then 0.1 N HCl was added to 0.2 mL of water. The suspension was placed in a fume hood for slow evaporation. The solid was sticky to the walls. The solid particles were examined by XRPD and determined to be a crystalline material, namely Form A of the hydrochloride salt of Compound 1.

[0494] In one experiment, 10.5 mg of free base of Compound 1 was weighed into a 4-mL glass vial, 1 mL of EtOAc was added, followed by the addition of 0.1 N HCl in 0.2 mL of EtOAc. The mixture became turbid. The suspension was placed in a fume hood for slow evaporation. The solid particles were examined by XRPD and determined to be a crystalline material, namely form A of the hydrochloride salt of Compound 1.

[0495] In one experiment, 16.6 mg of free base of Compound 1 was weighed into a 4-mL glass vial, 1 mL of EtOAc was added, followed by 0.05 mL of water and 0.1 N HCl in 0.345 mL of EtOAc. The mixture became turbid. The suspension was placed in a fume hood for slow evaporation, and crystalline aggregates were formed. The solid particles were examined by XRPD and determined to be a crystalline material, namely form A of the hydrochloride salt of Compound 1.

[0496] In one experiment, 25.6 mg of free base of Compound 1 was weighed into a 4-mL glass vial, 1 mL of acetone was added, followed by the addition of 0.1 N HCl in 0.45 mL of acetone, and the mixture became turbid. Additionally, 0.1 N HCl in 0.07 mL of water was added. The mixture became a clear solution. The solution was placed in a fume hood for slow evaporation. A seed suspension was introduced, and precipitation was observed. The solid particles were examined by XRPD and determined to be a crystalline material, namely Form A of the hydrochloride salt of Compound 1.

[0497] In one experiment, 26.1 mg of the free base of Compound 1 was weighed into a 4-mL glass vial, 0.1 N HCl in 1 mL of acetone and 0.07 mL of water was added, followed by the addition of 0.1 N HCl in 0.45 mL of acetone. The mixture was a clear solution. The solution was placed in a fume hood for slow evaporation, and crystals grew around the vial wall just above the liquid / air interface between the wall and the liquid. The solid particles were examined by XRPD and determined to be a crystalline material, namely Form A of the hydrochloride salt of Compound 1.

[0498] In one experiment, 44.2 mg of the free base of Compound 1 was weighed into a 4-mL glass vial, 2 mL of EtOAc was added, followed by the addition of 0.1 N HCl in 0.9 mL of EtOAc. The mixture became turbid. The suspension was placed in a fume hood for slow evaporation, and crystalline aggregates were formed. The solid particles were examined by XRPD and determined to be a crystalline material, namely Form A of the hydrochloride salt of Compound 1, which was further characterized by TGA and DSC. The TGA profile presented multiple stages of weight loss upon heating, prior to decomposition: 1.8% below 100°C, 2.1% from 100 to 200°C, and 1.5% near the melting temperature. The DSC spectrum presented a broad endothermic peak at relatively low temperatures (<100°C) due to the melting of the solid, followed by a small endothermic peak with onset and peak temperatures of 204.9°C and 213.0°C, respectively, and an exothermic peak likely due to decomposition. The dynamic vapor adsorption (DVS) profile indicated that the solid was moderately hygroscopic below 90% RH. The HCl salt slowly and continuously adsorbed moisture (~2.9% wt) from the dry state up to 90% RH. During desorption, the water content was slowly released from 90% to the dry state down to 0% RH. Adsorption / desorption was nearly reversible over two full cycles. NMR revealed chemical shifts due to salt formation and trace amounts of residual solvent.

[0499] In one experiment, 53.9 mg of free base of Compound 1 was weighed into a 4-mL glass vial, 2 mL of EtOAc was added, followed by the addition of 0.1 N HCl in 100 μL of water and 0.1 N HCl in 1.0 mL of EtOAc. The mixture was a viscous suspension. The suspension was placed in a fume hood for slow evaporation, and crystalline aggregates were formed. The solid particles were examined by XRPD and determined to be a crystalline material, namely form A of the hydrochloride salt of Compound 1.

[0500] In one experiment, 26.5 mg of the free base of Compound 1 was weighed into a 4-mL glass vial, followed by 1 mL of acetone and then 0.1 N HCl in 0.52 mL of acetone. The mixture remained a clear solution. The solution was placed in a fume hood for slow evaporation, and crystals grew in the solution and at the bottom. The solid particles were irradiated by XRPD and determined to be a crystalline material, namely Form A of the hydrochloride salt of Compound 1.

[0501] In one experiment, 26.2 mg of the free base of Compound 1 was weighed into a 4-mL glass vial, 1 mL of EtOAc was added first, followed by 0.02 mL of water, and then 0.1 N HCl was added to 0.52 mL of EtOAc. The mixture became turbid. The solid particles were examined by XRPD and determined to be a crystalline substance, namely Form A of the hydrochloride salt of Compound 1. This maintained the same crystalline form even after drying in a vacuum oven at 35°C.

[0502] In one experiment, solid particles generated from the aforementioned experiments were placed together in a 4-mL glass vial, and then 1 mL of water was added. The suspension was covered and left at room temperature for one week to equilibrate. After slurrying, the solid form remained as Form A and was subsequently characterized by TGA, DSC, and DVS. The TGA profile presented multiple stages of weight loss upon heating, prior to decomposition: 0.7% below 100°C, and 3.9% near the melting temperature. The DSC spectrum presented a broad endothermic peak with onset and peak temperatures of 196.4°C and 212.6°C, respectively, due to the melting of the solid, followed by an exothermic peak likely due to decomposition. The DVS profile was similar to the sample from the preceding experiment (44.2 mg scale) discussed above.

[0503] In one experiment, 26.2 mg of free base of Compound 1 was weighed into a 4-mL glass vial, 1 mL of MEK was added, and then 0.1 N HCl in 0.02 mL of water was added. The mixture became a clear solution, and then 0.105 N HCl in 0.49 mL of MEK was added. The mixture immediately became turbid. The solid particles were examined by XRPD, and the solid samples were also examined by TGA and DSC, and it was determined to be a crystalline material, namely form A of the hydrochloride salt of Compound 1.

[0504] In one experiment, 26.2 mg of the free base of Compound 1 was weighed into a 4-mL glass vial, 1 mL of MEK was added, followed by the addition of 0.105 N HCl in 0.49 mL of MEK. The mixture became a clear solution, and then 0.1 N HCl in 0.02 mL of water was added. The mixture immediately became turbid. The solid particles were examined by XRPD, and the solid samples were also examined by TGA and DSC, and it was determined to be a crystalline material, namely form A of the hydrochloride salt of Compound 1. The TGA profile presented multiple stages of weight loss upon heating, prior to decomposition: 0.8% below 100°C and 3.7% near the melting temperature. The DSC spectrum presented a broad endothermic peak with onset and peak temperatures of 219.7°C and 233.8°C, respectively, due to the melting of the solid, followed by an exothermic peak likely due to decomposition.

[0505] In one experiment, 1.07 g of the free base of Compound 1 was weighed into a glass beaker, 25 mL of EtOAc was added, and then 0.1 N HCl was added to 20 mL of EtOAc. The mixture became turbid. The suspension was placed in a fume hood for slow evaporation. The initial solid was amorphous by XRPD, and slurrying for an additional hour resulted in crystalline form A of the hydrochloride salt of Compound 1. The sample was dried overnight in a vacuum oven and then re-slurried in water, and the final product was form A of the hydrochloride salt of Compound 1.

[0506] In one experiment, 0.455 g of Compound 1 free base was weighed into a glass beaker, 5 mL of MEK was added, followed by the addition of 0.1 N HCl in 9.0 mL of MEK. The mixture became turbid. The suspension was placed in a fume hood for slow evaporation. The initial solid was crystalline form A by XRPD.

[0507] Although not limited by any specific theory, the fluctuations in the onset of melting point and peak temperature observed for Form A in these experiments are due to factors such as the degree of crystallinity, crystal defects, and the content of amorphous material.

[0508] 2XHCl salt

[0509] In one experiment, 45.5 mg of Compound 1 free base was weighed into a 4-mL glass vial, and 0.9 mL of acetone was added. The mixture became clear, and then 0.1 N HCl was introduced into 1.8 mL of acetone. The mixture remained a clear solution. The solution was placed in a fume hood for slow evaporation, and crystals grew in the solution and at the bottom. The solid form of XRPD obtained from this experiment ( Fig. 21 It differed from mono-hydrochloride salt form A and is designated as form C of the hydrochloride salt of Compound 1. The solid also exhibited different profiles of TGA, DSC, and DVS. The TGA profile presented multiple stages of weight loss upon heating, prior to decomposition: 3.8% below 100°C, and an additional 4.0% from 100 to 200°C. The DSC spectrum presented a broad endothermic event at relatively low temperatures (<125°C) due to the melting of the solid, followed by another endothermic peak with onset and peak temperatures of 138.0°C and 151.6°C, respectively, and an exothermic peak likely due to decomposition. The dynamic vapor adsorption (DVS) profile indicated that the solid was highly hygroscopic at less than 90% RH. The solid sample absorbed moisture (~8.0% wt) slowly and continuously from dry to 80% RH, followed by a rapid increase (~6.7%) from 80% RH to 90% RH. During desorption, the water content was rapidly released from 90% to 80% RH (~7.0%), followed by the continuous removal of the remaining water content as the relative humidity decreased to dry (0% RH).

[0510] Besylate salt

[0511] In one experiment, 24.3 mg of the free base of Compound 1 was weighed into a 4-mL glass vial, and 1 mL of MEK was added. The mixture became a clear solution, and 0.1 N benzenesulfonic acid in 0.5 mL of MEK was added. Precipitation occurred immediately. A crystalline substance was observed under a microscope and was confirmed by XRPD to be a crystalline substance, namely form A of the besylate salt of Compound 1.

[0512] In one experiment, 255.3 mg of Compound 1 free base was weighed into a 4-mL glass vial, and 5 mL of acetone was added. The mixture became a clear solution, and then 0.1 N benzenesulfonic acid in 5.0 mL of MEK was added. Precipitation occurred immediately. A crystalline substance was observed under a microscope and confirmed by XRPD ( Fig. 17 The solid was also characterized by both thermal analysis using TGA and DSC. TGA profile ( Fig. 18 ) indicated that when heated, the weight loss is very negligible (0.25%) at 150℃ or below. DSC spectrum ( Fig. 19 ) presented endothermic peaks with onset and peak temperatures of 164.5°C and 175.4°C, respectively, due to the melting of the solid.

[0513] 6.7 Preparation of Hydrochloride Salt of Compound 1 and Polymorphism Screening

[0514] The hydrochloride salt of Compound 1 was prepared from the free base of Compound 1 in three experiments. First, two small-scale (0.1 g scale) experiments were performed (slurrying in acetone for 1 day and slurrying in THF for 1 day). The products from these experiments were both confirmed to be hydrochloride salt polymorph form A. To determine stoichiometry, both samples were tested for carbon, hydrogen, nitrogen, and chloride content. The elemental data (not presented) were consistent with a 1:1 API:acid salt. Subsequently, the hydrochloride salt was prepared on a 10 g scale (slurrying in acetone for 2 days) and further characterized. The characterization data are summarized in the table below.

[0515] Table 12 Characterization of large-scale compounds 1 HCl salts

[0516]

[0517] a. Theoretical value for 1:1 salt

[0518] In an attempt to generate polymorphs of the solid compound 1 HCl salt, the mixture was mixed with various solvents under various conditions. The results are listed in the table below. Only one polymorph (Form A of compound 1 HCl salt) was identified in this study.

[0519] Table 13 . Polymorph Screening of Compound 1 Hydrochloride Salts

[0520]

[0521]

[0522]

[0523] a. AS = Inverse solvent; NC = No crystallization; RH = Relative humidity; RT = Room temperature; E = Evaporation

[0524] b. NC = amorphous; pks ​​= peaks; A, B, etc. = shape

[0525] 6.8 Preparation of Fumarate Salt of Compound 1 and Polymorphism Screening

[0526] In one study, form A of the fumarate salt of compound 1 was prepared from a precipitation experiment involving acetone and hexane. The solid was crystallized within 5 hours and stirred at room temperature for 2 days.

[0527] In another study, the fumarate salt of Compound 1 was prepared from the free base of Compound 1 through several experiments. First, several small-scale experiments were conducted. A low-molecular-weight crystalline material was obtained from slurrying performed at ambient temperature (250 mg scale, slurrying in acetonitrile at room temperature for 1 day, or slurrying in acetonitrile at room temperature for 6 days). A high-molecular-weight crystalline material was obtained by increasing the slurrying temperature, and the product was confirmed to be fumarate salt polymorph form A (30 mg scale, slurrying in acetonitrile at 50°C for 1 day). The experiment was repeated on a larger scale (3.2 g scale, slurrying in acetonitrile at 50°C for 3 days), and the resulting material was further characterized. The characterization data are summarized in the table below.

[0528] Table 14 Characterization of large-scale compound 1 fumarate salts

[0529]

[0530] In an attempt to generate polymorphs, the solid compound 1 fumarate salt was mixed with various solvents under various conditions. The results are listed in the table below. Only one polymorph (Form A of compound 1 fumarate salt) was identified in this study.

[0531] Table 15 Polymorph screening of Compound 1 fumarate salts

[0532]

[0533]

[0534]

[0535] a. AS = Inverse solvent; E = Evaporation; NC = No crystallization; RH = Relative humidity; RT = Room temperature

[0536] b. NC = amorphous; pks ​​= peaks; A, B, etc. = shape

[0537] 6.9 Preparation of Tosylate Salts of Compound 1 and Polymorphism Screening

[0538] In one study, form A of the tosylate salt of compound 1 was prepared from a precipitation experiment involving acetone and hexane. The solid was crystallized within 5 hours and stirred at room temperature for 2 days.

[0539] In another study, the tosylate salt of Compound 1 was prepared from the free base of Compound 1 through several experiments. First, one small-scale experiment was performed (250 mg scale, slurrying in acetonitrile at room temperature for 1 day). The product was confirmed to be tosylate salt polymorph form A. The experiment was repeated on a larger scale (3.4 g scale, slurrying in acetonitrile at room temperature for 3 days), and the resulting substance was further characterized. The characterization data are summarized in the table below.

[0540] Table 16 Characterization of large-scale compound 1 tosylate salts

[0541]

[0542] The solid tosylate salt of Compound 1 was mixed with various solvents under various conditions in an attempt to generate polymorphs. The results are listed in the table below. Two polymorphs were identified in this study: Form A of the tosylate salt of Compound 1 (identical to the form from the first salt screening) and a novel Form D of the tosylate salt of Compound 1. Form D was obtained in only one experiment as a mixture with amorphous material. Overlay plots of tosylate salt polymorphs Forms A, B, C, and D Fig. 22 It is presented in.

[0543] Table 17 Polymorph screening of Compound 1 tosylate salts

[0544]

[0545]

[0546]

[0547] a. AS = Inverse solvent; NC = No crystallization; RH = Relative humidity; RT = Room temperature; E = Evaporation

[0548] b. NC = amorphous; pks ​​= peaks; A, B, etc. = shape

[0549] 6.10 type evaluation

[0550] (a) Evaluation of form A of the hydrochloride salt of compound 1

[0551] hygroscopic : Form A of the hydrochloride salt of compound 1 was characterized by DVS ( Fig. 7 It began absorbing water at very low humidity. Water adsorption occurred continuously (almost linearly) at all humidity levels, with an absorption of approximately 3.0% w / w, corresponding to about 1 mol of water. The adsorbed water was released in the desorption phase, and slight hysteresis was observed in the dry phase. The solid form remained as form A after DVS.

[0552] Shear sensitivity : Form A of the hydrochloride salt of Compound 1 was compressed under 700 and 1100 lb for 1 minute and analyzed by XRPD. The solid form remained the same and had a slight broad diffraction peak.

[0553] Solid state stability The solid-state stability of Form A of the hydrochloride salt of Compound 1 was evaluated using the Accelerated Stability Assessment Program (ASAP). Forced decomposition storage conditions at 60–80°C and 0–80% RH were used for up to 2 weeks. Photostress studies under 2x ICH conditions were also performed in the solid state. Solid samples were analyzed for both chemical and chiral stability. At the end of the study, the crystalline form of the compound was verified by XRPD. No change in crystalline form was observed compared to the control group after 10 days under the most stringent conditions of 80°C / 70% RH. The results of the stability studies are summarized in the table below.

[0554] Table 18 . Solid-state stability of form A of the hydrochloride salt of Compound 1 under different storage conditions

[0555]

[0556] In the assay, insignificant changes (<5%) were observed, except after 1 and 2 weeks under 80°C / 0% RH conditions. The loss in the assay at 80°C / 0% RH was attributed to the growth of degradation products with molecular weights corresponding to free base + HCl. Compound 1 hydrochloride salt remained stable in relation to the assay and degradation products under other conditions. The change in the assay under photostability conditions was <4%. Additionally, insignificant changes were observed in chiral purity across all conditions, with a maximum change of 0.2% under high humidity conditions. These ASAP stability results confirmed that Form A of the hydrochloride salt of Compound 1 can be considered stable.

[0557] Decision habits : SEM images of form A of the hydrochloride salt of compound 1 show not only short rod-shaped primary particles but also aggregates ( Fig. 8 ).

[0558] Long-term solid-state stability : Form A of the hydrochloride salt of Compound 1 (packaged in double LDPE bags inside HDPE containers) was stored for up to 3 months under storage conditions of 25°C / 60% RH, 30°C / 65% RH, and 40°C / 75% RH. The stability data listed in the table below demonstrates the stability of Form A of the hydrochloride salt of Compound 1 stored for 3 months under conditions of 25°C / 60% RH, 30°C / 65% RH, and 40°C / 75% RH. Therefore, a retest period of 12 months is suggested when stored at or below 25°C.

[0559] Table 19 . Stability results of Form A of the hydrochloride salt of Compound 1 contained in a double LDPE bag inside an HDPE container

[0560]

[0561] 1. Yellow powder

[0562] 2. Matches form A

[0563] (b) Evaluation of other forms of Compound 1

[0564] The solid-state stability of Compound 1 in its free base amorphous, tosylate form A, besylate form A, and fumarate form A (as well as HCl form A) was evaluated under stress storage conditions. Solid samples were analyzed for both chemical and chiral stability. At the end of the study, the crystalline form of Compound 1 was verified by XRPD. The results of the stability study are summarized in the table below.

[0565] Table 20 . Solid-state stability in the form of free bases and salts

[0566]

[0567] The solubility of Compound 1 free base amorphous, HCl form A, fumarate form A, and tosylate form A in various solvents was estimated. The experiment was performed by adding a fraction of the test solvent to a weighed amount of solid. Whether dissolution occurred was determined by visual inspection after the addition of each solvent fraction. The solubility value was calculated by dividing the total amount of solvent used to dissolve the sample by the weight of the sample. The actual solubility may be greater than the calculated value, due to the use of an excessively large solvent fraction or a slow dissolution rate. If no dissolution occurred during the experiment, the solubility value is indicated as "less than". If dissolution occurred upon the addition of the first solvent fraction, the solubility value is indicated as "greater than". The results are listed in the table below.

[0568] Table 21 Estimated solubility in free base and salt forms

[0569]

[0570] The embodiments provided herein should not be limited in scope by specific embodiments provided in the embodiments intended as examples of some aspects of the provided embodiments, and all functionally equivalent embodiments are encompassed by this disclosure. In fact, various variations of the embodiments provided herein other than those presented and described herein will be apparent to those skilled in the art and are intended to be included within the scope of the appended claims.

[0571] Numerous references are cited, the full text of which is incorporated herein by reference.

Claims

Claim 1 It is a solid form containing compound 1: , where the free base of Compound 1 is characterized by an XRPD pattern including peaks at 4.5, 15.3, and 18.1° 2θ ± 0.2° 2θ; the free base of Compound 1 is characterized by an XRPD pattern including peaks at 4.8, 9.6, and 14.9° 2θ ± 0.2° 2θ; the hydrochloride salt of Compound 1 is characterized by an XRPD pattern including peaks at 15.1, 16.3, and 20.7° 2θ ± 0.2° 2θ; the hydrochloride salt of Compound 1 is characterized by an XRPD pattern including peaks at 17.5, 21.6, and 24.8° 2θ ± 0.2° 2θ; the fumarate salt of Compound 1 is characterized by an XRPD pattern including peaks at 22.3, 23.2, and 23.4° 2θ ± 0.2° 2θ; 17.6, A solid form of a tosylate salt of compound 1 characterized by an XRPD pattern including peaks at 18.0 and 23.8° 2θ ± 0.2° 2θ; a maleate salt of compound 1 characterized by an XRPD pattern including peaks at 17.6, 24.4 and 26.9° 2θ ± 0.2° 2θ; or a besylate salt of compound 1 characterized by an XRPD pattern including peaks at 17.9, 18.3 and 23.8° 2θ ± 0.2° 2θ. Claim 2 A solid form of the free base of compound 1, characterized in that, in claim 1, an XRPD pattern including peaks at 4.5, 15.3, and 18.1° 2θ ± 0.2° 2θ. Claim 3 A solid form according to claim 2, wherein the XRPD pattern additionally includes peaks at 13.3 and 15.9° 2θ ± 0.2° 2θ. Claim 4 A solid form according to claim 3, wherein the XRPD pattern additionally includes peaks at 20.1 and 20.9° 2θ ± 0.2° 2θ. Claim 5 A solid form of the free base of compound 1, characterized in that, in claim 1, an XRPD pattern including peaks at 4.8, 9.6, and 14.9° 2θ ± 0.2° 2θ. Claim 6 In claim 5, a solid form in which the XRPD pattern additionally includes peaks at 18.7 and 22.1° 2θ ± 0.2° 2θ. Claim 7 In claim 6, a solid form in which the XRPD pattern additionally includes peaks at 20.7 and 21.4° 2θ ± 0.2° 2θ. Claim 8 A solid form of the hydrochloride salt of compound 1, characterized in that, in claim 1, an XRPD pattern including peaks at 15.1, 16.3, and 20.7° 2θ ± 0.2° 2θ. Claim 9 A solid form according to claim 8, wherein the XRPD pattern additionally includes peaks at 7.8 and 22.4° 2θ ± 0.2° 2θ. Claim 10 A solid form according to claim 9, wherein the XRPD pattern further comprises peaks at 18.2, 18.9, and 24.8° 2θ ± 0.2° 2θ. Claim 11 A solid form of the hydrochloride salt of compound 1, characterized in that, in claim 1, an XRPD pattern including peaks at 17.5, 21.6, and 24.8° 2θ ± 0.2° 2θ. Claim 12 A solid form according to claim 11, wherein the XRPD pattern additionally includes peaks at 21.1 and 27.0° 2θ ± 0.2° 2θ. Claim 13 A solid form according to claim 12, wherein the XRPD pattern additionally includes peaks at 14.6, 17.2, and 20.3° 2θ ± 0.2° 2θ. Claim 14 A solid form of the fumarate salt of compound 1, characterized in that, in claim 1, an XRPD pattern including peaks at 22.3, 23.2, and 23.4° 2θ ± 0.2° 2θ. Claim 15 In claim 14, a solid form in which the XRPD pattern additionally includes peaks at 17.9 and 25.8° 2θ ± 0.2° 2θ. Claim 16 In claim 15, a solid form in which the XRPD pattern additionally includes peaks at 11.7 and 18.3° 2θ ± 0.2° 2θ. Claim 17 A solid form of the tosylate salt of compound 1, characterized in that, in claim 1, an XRPD pattern including peaks at 17.6, 18.0, and 23.8° 2θ ± 0.2° 2θ. Claim 18 In claim 17, a solid form in which the XRPD pattern additionally includes peaks at 15.7 and 20.6° 2θ ± 0.2° 2θ. Claim 19 In claim 18, a solid form in which the XRPD pattern additionally includes peaks at 24.7 and 25.0° 2θ ± 0.2° 2θ. Claim 20 A solid form of the maleate salt of compound 1, characterized in that, in claim 1, an XRPD pattern including peaks at 17.6, 24.4, and 26.9° 2θ ± 0.2° 2θ. Claim 21 A solid form according to claim 20, wherein the XRPD pattern further comprises peaks at 18.0, 18.4, and 19.3° 2θ ± 0.2° 2θ. Claim 22 A solid form according to claim 21, wherein the XRPD pattern additionally includes peaks at 19.8 and 24.0° 2θ ± 0.2° 2θ. Claim 23 A solid form of the besylate salt of compound 1, characterized in that, in claim 1, an XRPD pattern including peaks at 17.9, 18.3, and 23.8° 2θ ± 0.2° 2θ. Claim 24 In claim 23, a solid form in which the XRPD pattern additionally includes peaks at 15.7 and 16.2° 2θ ± 0.2° 2θ. Claim 25 A solid form according to claim 24, wherein the XRPD pattern additionally includes peaks at 8.5 and 16.5° 2θ ± 0.2° 2θ. Claim 26 A pharmaceutical composition for treating a blood malignancy comprising a solid form according to any one of claims 1 to 25, wherein the blood malignancy is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), multiple myeloma (MM), non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma (HL), T-cell lymphoma (TCL), Burkitt lymphoma (BL), chronic lymphoblastic leukemia / small lymphoblastic lymphoma (CLL / SLL), marginal zone lymphoma (MZL), myelodysplastic syndrome (MDS), or follicular lymphoma (FL). Claim 27 delete Claim 28 delete Claim 29 delete Claim 30 delete Claim 31 delete Claim 32 delete Claim 33 delete Claim 34 delete Claim 35 delete Claim 36 delete Claim 37 delete Claim 38 delete Claim 39 delete Claim 40 delete Claim 41 delete Claim 42 delete Claim 43 delete Claim 44 delete Claim 45 delete Claim 46 delete Claim 47 delete

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