EA046479B1 - SOLID FORMS CONTAINING (S)-2-(2,6-DIOXOPIPERIDIN-3-YL)-4-((2-FLUORINE-4-((3-MORPHOLINOAZETIDIN-1-YL)METHYL)BENZYL)AMINO)ISOINDOLINE- 1,3-DIONE AND ITS SALTS, COMPOSITIONS CONTAINING THEM AND METHODS OF THEIR APPLICATION - Google Patents

Description

This application claims priority to U.S. Provisional Patent Application No. 62/923972, filed October 21, 2019, the contents of which are incorporated herein by reference in their entirety.

1. Technical field

The present invention provides salts and solid forms containing the free base or salts of ^)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl )methyl)benzyl)amino)isoindoline-1,3-dione. Pharmaceutical compositions containing such salts and solid forms, and methods of using such salts and solid forms for the treatment, prevention and control of various disorders are also provided in the present invention.

2. State of the art

Alternative solid forms of pharmaceutical compounds have emerged as a possible approach to modulate or improve the physical and chemical properties of drugs. Identification and selection of the solid form of a pharmaceutical compound is complex, given that changing the solid form can affect various physical and chemical properties that may provide advantages or disadvantages in processing, formulation, stability, bioavailability, storage, handling (e.g., delivery), among other important pharmaceutical characteristics. Useful pharmaceutical solid forms include crystalline solids and amorphous solids depending on the substance and its route of administration. Amorphous solids are characterized by a lack of long-range structural order, whereas crystalline solids are characterized by structural periodicity. The target class of pharmaceutical solid depends on the specific application; amorphous solids are sometimes selected based on, for example, an improved solubility profile, while crystalline solids may be desirable due to properties such as, for example, physical or chemical stability (see, for example, S. R. Vippagunta et al., Adv. Drug. Deliv. Rev. (2001), 48:3-26; L. Yu, Adv. Drug. Deliv. Rev. (2001), 48:27-42).

Notably, it is impossible to predict a priori whether crystalline forms of a compound even exist, let alone how to successfully obtain them (see, e.g., Braga and Grepioni, 2005, Making crystals from crystals: a green route to crystal engineering and polymorphism, Chem. Commun., 3635-3645 (with respect to crystal construction, if the instructions are not very precise and/or if the process is influenced by other external factors, the result may be unpredictable); Jones et al., 2006, Pharmaceutical Cocrystals: An Emerging Approach to Physical Property Enhancement, MRS Bulletin, 37:875-879 (it is currently generally impossible to computationally predict the number of observed polymorphs of even the simplest molecules); 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 (much still needs to be studied and done before it can be stated with any degree of certainty the ability to predict crystal structure, and even more so polymorphic forms)).

The type of salt form of a particular active pharmaceutical ingredient may influence certain properties of the active pharmaceutical ingredient. These properties include solubility, stability and bioavailability.

The variety of possible solid forms, including both free base and salt forms, creates a potential diversity of physical and chemical properties for a given pharmaceutical compound. Research and selection of solid forms are of great importance for the development of an effective, stable and marketable drug.

3. Essence of the invention

The present invention provides solid forms (eg, crystalline forms, amorphous forms, polymorphs, or mixtures thereof) containing compound 1

having the chemical name ^)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1, 3-dion. The present invention also provides methods for the preparation, isolation and characterization of solid forms.

In one embodiment, the solid form contains the 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 in the present invention.

In one embodiment, the solid form contains a salt of Compound 1.

In one embodiment, the solid form contains the hydrochloride salt of Compound 1.

- 1 046479

In one embodiment, the solid form is Form A or Form B of the hydrochloride salt of Compound 1 as provided in the present invention.

In one embodiment, the solid form contains the fumarate salt of Compound 1. In one embodiment, the solid form is Form A of the fumarate salt of Compound 1, as provided in the present invention.

In one embodiment, the solid form contains the tosylate salt of Compound 1. In one embodiment, the solid form is Form A of the tosylate salt of Compound 1, as provided in the present invention.

In one embodiment, the solid form contains the maleate salt of Compound 1. In one embodiment, the solid form is Form A of the maleate salt of Compound 1, as provided in the present invention.

In one embodiment, the solid form comprises the besylate salt of Compound 1. In one embodiment, the solid form is the besylate salt of Compound 1, Form A, as provided in the present invention.

Also provided herein are salts of Compound 1. 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.

The solid forms provided in the present invention are useful as active pharmaceutical ingredients for the preparation of formulations for use in animals or humans. Thus, embodiments of the present invention include the use of these solid forms as a final drug substance. In some embodiments, solid forms are provided useful for the manufacture of final dosage forms with improved properties, e.g., powder flow properties, compaction properties, tabletting properties, stability properties, and excipient compatibility properties, among others, that are needed for manufacturing, processing, formulation formulation and/or storage of finished dosage forms. In some embodiments, the present invention provides 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 containing Compound 1 and a pharmaceutically acceptable diluent, excipient or carrier.

Also provided are pharmaceutical compositions formulated for administration by an appropriate route and means containing effective concentrations of a solid form containing Compound 1 of the present invention, and optionally containing at least one pharmaceutical carrier. Also provided by the present invention are methods of using a solid form containing Compound 1 of the present invention for the treatment, prevention or control of a hematological malignancy. In one embodiment, the method is for treating a hematologic malignancy. In one embodiment, the method is for the prevention of hematologic malignancy. In one embodiment, the method is for monitoring a hematologic malignancy.

In one embodiment, the hematologic malignancy is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), Hodgkin's lymphoma (HL), T-cell lymphoma (TCL), Burkitt's lymphoma (BL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone lymphoma (MZL) or myelodysplastic syndromes (MDS).

Also provided herein are methods of using a solid form containing Compound 1 of the present invention, alone or in combination with rituximab, for the treatment, prevention or control of non-Hodgkin's lymphoma (NHL). In one embodiment, the method is for treating NHL. In one embodiment, the method is for preventing NHL. In one embodiment, the method is for monitoring NHL. In some embodiments, the NHL is diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), or primary central nervous system lymphoma (PCNSL). The present invention also provides methods of using a solid form containing Compound 1 of the present invention, alone or in combination with obinutuzumab, for the treatment, prevention or control of chronic lymphocytic leukemia (CLL). In one embodiment, the method is for treating CLL. In one embodiment, the method is for preventing CLL. In one embodiment, the method is for monitoring CLL.

The present invention also provides methods of using a solid form containing Compound 1 of the present invention, alone or in combination with obinutuzumab,

- 2 046479 for the treatment, prevention or control of small cell lymphocytic lymphoma (SLL). In one embodiment, the method is for treating SLL. In one embodiment, the method is for preventing SLL. In one embodiment, the method is for monitoring an SLL.

Also provided by the present invention is a solid form or salt of Compound 1 for use in a method of treating a disease of the present invention, wherein the method includes administering to a patient a therapeutically effective amount of a solid form or salt of Compound 1. Also provided by the present invention is a pharmaceutical composition comprising a solid form or a salt of compound 1, for use in the method of treating the disease presented in the present invention. These and other aspects of the subject matter described herein will become apparent upon reference to the following detailed description.

4. Brief description of graphic materials

In fig. Figure 1 shows a typical X-ray powder diffraction (XRPD) pattern of Compound 1 free base Form A.

In fig. Figure 2 shows typical thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of Compound 1 free base Form A.

In fig. Figure 3 shows a typical XRPD of Form B of the free base of compound 1.

In fig. Figure 4 shows typical TGA and DSC thermograms of Form B of the free base of compound 1.

In fig. Figure 5 shows a typical XRPD of Form A of the hydrochloride salt of Compound 1.

In fig. Figure 6 shows typical TGA and DSC thermograms of Form A of the hydrochloride salt of compound 1.

In fig. Figure 7 shows a typical dynamic vapor sorption (DVS) isotherm for Form A of the hydrochloride salt of Compound 1.

In fig. Figure 8 shows a typical SEM image of Form A of the hydrochloride salt of Compound 1.

In fig. Figure 9 shows a typical XRPD of Form B of the hydrochloride salt of Compound 1.

In fig. Figure 10 shows typical TGA and DSC thermograms of Form B of the hydrochloride salt of compound 1.

In fig. 11 shows a typical XRPD of Form A of the fumarate salt of Compound 1.

In fig. 12 shows typical TGA and DSC thermograms of Form A of the fumarate salt of Compound 1.

In fig. 13 shows a typical XRPD of Form A of the tosylate salt of Compound 1.

In fig. 14 shows typical TGA and DSC thermograms of Form A of the tosylate salt of Compound 1.

In fig. 15 shows a typical XRPD of Form A of the maleate salt of Compound 1.

In fig. 16 shows typical TGA and DSC thermograms of Form A of the maleate salt of Compound 1.

In fig. 17 shows a typical XRPD of Form A of the besylate salt of Compound 1.

In fig. 18 shows a typical TGA thermogram of Form A of the besylate salt of Compound 1.

In fig. 19 shows a typical DCS thermogram of Form A of the besylate salt of Compound 1.

In fig. 20 shows a typical XRPD of an amorphous starting material of the free base of compound 1.

In fig. 21 shows a typical XRPD of Form C of the hydrochloride salt of Compound 1.

In fig. Figure 22 shows an overlay of graphs of Forms A, B, C and D of the tosylate salt of Compound 1.

5. Detailed description

5.1. Definitions.

Unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as commonly understood by one skilled in the art. All patents, applications, published applications and other publications are incorporated by reference in their entirety. In the event that there are multiple definitions of a term in the present invention, those given in this section take precedence unless otherwise noted.

As used herein and in the specification and appended claims, the singular form and the plural form include references to both plural and singular entities unless the context clearly indicates otherwise. In the context of this invention, the terms containing and including may be used interchangeably. The terms containing and including should be interpreted as defining the presence of specified distinctive features or components in relation to the stated, but not excluding the presence or addition of one or more features or components, or groups thereof. Additionally, the terms containing and including are intended to include examples covered by the term consisting of. Therefore, the term consisting of may be used in place of the terms containing and including to provide more specific embodiments of the invention.

The term consisting of means that an item has at least 90, 95, 97, 98 or 99% of the stated features or components of which it is composed. In another embodiment, the term

- 3 046479 consisting of excludes from the scope of any subsequent listing any other features or components, except those that are not essential to achieve the technical effect. In the context of this invention, the term or should be interpreted to include or to mean any one or any combination. Therefore, A, B or C means any of the following: A; B; WITH; A and B; A and C; B and C; A, B and C. An exception to this definition will occur only when the combination of elements, functions, stages or actions is somehow by default mutually exclusive. In the context of this invention and unless otherwise indicated, the terms about and approximately, when applied to doses, amounts or weight percentages of the ingredients of a composition or dosage form, mean the dose, amount or weight percentage that is recognized by one skilled in the art to provide pharmacological an effect equivalent to that obtained from a specified dose, amount or percentage by weight. In some embodiments, the terms about and approximately, when used in this context, imply a dose, amount, or percentage by weight within 30%, within 20%, within 15%, within 10%, or within 5% of the specified dose. quantity or mass percentage.

In the context of this invention and unless otherwise indicated, the terms about and approximately when applied to numerical values or ranges of values that are provided to characterize a particular solid form, for example, a specific temperature or temperature range, for example, describing the melting point, dehydration , desolvation or glass transition; changes in mass, such as, for example, changes in mass depending on temperature or humidity; solvent or water content, expressed, for example, by weight or percentage; or peak positions, such as in IR or Raman spectroscopy or XRPD analysis, indicate that a value or range of values may deviate within limits considered reasonable by one skilled in the art while describing a particular solid form. For example, in specific embodiments, the terms about and about when used in this context indicate that the numerical value or range of values may vary within the range of 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2 , 1.5, 1, 0.5 or 0.25% of the specified value or range of values. For example, in some embodiments, the XRPD peak position value may vary by up to ±0.2° 2θ while describing a particular XRPD peak. In the context of the present invention, a tilde (ie ~) preceding a numeric value or range of values means about or approximately.

Unless otherwise noted, the terms X-ray powder diffractometry, X-ray powder diffractometry, PXRD and XRPD are used interchangeably in this application.

In the context of this invention and unless otherwise indicated, the term solid form and related terms refer to a physical form that is not predominantly in a liquid or gaseous state. In the context of this invention, the terms solid form and solid forms cover semi-solids. Solid forms may be crystalline, amorphous, partially crystalline, partially amorphous, or mixtures of forms.

The solid forms presented here may have varying degrees of crystallinity or lattice order. The solid forms presented herein are not limited to any particular degree of crystallinity or lattice order and may be 0-100% crystalline. Methods for determining the degree of crystallinity are known to those skilled in the art, such as those described in Suryanarayanan, R., X-Ray Power Diffractometry, Physical Characterization of Pharmaceutical Salts, H.G. Brittain, editor, Mercel Dekkter, Murray Hill, N.J., 1995, p. 187-199, which is incorporated herein by reference in its entirety. In some embodiments, the solid forms provided in the present invention are about 0.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85. 90, 95 or 100% crystalline. In the context of this invention and unless otherwise indicated, the term crystalline and related terms used in the present invention, when used to describe a substance, component, product or form, mean that the substance, component, product or form is substantially crystalline, for example , as determined by X-ray diffraction. See, for example, Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams and Wilkins, Baltimore, MD (2005); The United States Pharmacopeia, 23rd edition, 1843-1844 (1995). As used herein and unless otherwise indicated, the term crystalline form, crystalline forms and related terms as used herein refer to solid forms that are crystalline. Crystal forms include single-component crystal forms and multi-component crystal forms and include, but are not limited to, polymorphs, solvates, hydrates and other molecular complexes, as well as salts, salt solvates, salt hydrates, salt co-crystals, other molecular salt complexes and polymorphs thereof. In some embodiments, the crystalline form of the substance may be substantially free of amorphous forms and/or other crystalline forms. In some embodiments, the crystalline form of the substance may contain less than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, or 50% of one or more amorphous form(s) and/or other crystalline form(s) by mass. In some embodiments, the crystalline form of the substance may be physically

- 4 046479 and/or chemically pure. In some embodiments, the crystalline form of the substance may be about 99, 98, 97, 96, 95, 94, 93, 92, 91, or 90% pure physically and/or chemically.

The one-component solid form containing the compound essentially consists of the compound. The multicomponent solid form containing the compound contains a significant amount of one or more additional particles, such as ions and/or molecules, in the structure of the solid form. For example, in some embodiments, the crystalline multicomponent solid form containing the compound further comprises one or more particles non-covalently bonded at regular positions in the crystal lattice. As another example, in some embodiments, the amorphous multicomponent solid form containing the compound further contains one or more polymer(s), and the compound is dispersed in a solid matrix containing the polymer(s).

Crystalline forms of a substance can be obtained in a number of ways. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, confined volume recrystallization such as nanopores or capillaries, recrystallization on surfaces or templates such as polymers, recrystallization in the presence of additives such as, for example, opposite molecules of cocrystals, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, grinding and grinding of solvent droplets. Unless otherwise specified, the terms polymorph, polymorphic form, polymorphs, polymorphic forms and related terms as used herein refer to two or more crystalline forms that consist of substantially the same molecule, molecules or ions. Like different crystalline forms, different polymorphs may have different physical properties, such as, for example, melting points, heats of fusion, solubility, dissolution rates, and/or vibrational spectra as a result of different arrangements or conformations of molecules or ions in the crystal lattice. Differences in physical properties exhibited by polymorphs can influence pharmaceutical parameters such as storage stability, compressibility and density (important for product formulation and manufacturing) and dissolution rate (an important factor in bioavailability). Differences in stability may result from changes in chemical reactivity (for example, differential oxidation, where a dosage form discolors faster when it is composed of one polymorph than when it is composed of another polymorph) or mechanical changes (for example, tablets crumble during storage because a kinetically preferred polymorph is converted to a thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to disintegration under high humidity). As a result of differences in solubility/dissolution, at the extreme, some polymorphic transitions may result in a lack of activity or, at the other extreme, toxicity. In addition, the physical properties of the crystal may have important processing implications (e.g., one polymorph may be more likely to form solvates or may be difficult to filter and wash away impurities, and particle shape and size distribution may vary between polymorphs).

As used herein and unless otherwise indicated, the term amorphous, amorphous form and related terms as used herein mean that the substance, component or product in question is not substantially crystalline as determined by x-ray diffraction. In particular, the term amorphous form describes a disordered solid form, i.e. a solid form in which there is no long-range order in the crystal structure. In some embodiments, the amorphous form of the substance may be substantially free of other amorphous forms and/or crystalline forms. In other embodiments, the amorphous form of the substance may contain less than about 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% by weight of one or more other amorphous forms and/ or crystalline forms. In some embodiments, the amorphous form of the substance may be physically and/or chemically pure. In some embodiments, the amorphous form of the substance may be about 99, 98, 97, 96, 95, 94, 93, 92, 91, or 90% physically and/or chemically pure. In some embodiments, the amorphous form of the substance may contain additional components or ingredients (eg, an additive, polymer, or excipient that may provide additional stability to the amorphous form). In some embodiments, the amorphous form may be a solid solution.

Amorphous forms of the substance can be obtained in a number of ways. Such methods include, but are not limited to, heating, melt cooling, flash cooling, solvent evaporation, flash solvent evaporation, desolvation, sublimation, grinding, ball milling, low temperature grinding, spray drying and freeze drying.

Unless otherwise specified, the terms solvate and solvated in the context of this invention refer to the solid form of a substance that contains a solvent.

The terms hydrate and hydrated refer to a solvate in which the solvent contains water. Solvate polymorphs refer to the presence of more than one solid form for a particular solvate composition. Similarly, hydrate polymorphs refer to the presence of more than one

- 5 046479 new solid form for a specific hydrate composition. The term desolvated solvate in the context of this invention refers to the solid form of a substance that can be obtained by removing the solvent from the solvate. In the context of this invention, the terms solvate and solvated can also refer to a solvate of a salt, co-crystal or molecular complex. The terms hydrate and hydrated in the context of this invention can also refer to the hydrate of a salt, cocrystal or molecular complex.

Methods for characterizing crystalline forms and amorphous forms include, but are not limited to, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), single crystal X-ray diffractometry, vibrational spectroscopy, such as infrared (IR) and Raman spectroscopy, nuclear magnetic resonance (NMR) spectroscopy of solid state and solution samples, optical microscopy, high temperature optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size distribution (PSA), surface area analysis, measurements solubility, dissolution measurements, elemental analysis and Karl Fischer analysis. Characteristic unit cell parameters can be determined using one or more methods, such as, but not limited to, x-ray diffraction and neutron diffraction, including single crystal diffraction and powder diffraction. Techniques useful for analyzing powder diffraction data include profile refinement, such as Rietveld refinement, which can be used, for example, to analyze diffraction peaks associated with a single phase in a sample containing more than one solid phase. Other techniques useful for analyzing powder diffraction data include unit cell indexing, which allows one skilled in the art to determine unit cell parameters from a sample containing a crystalline powder. In one embodiment, an XRPD diffraction pattern is obtained using CuKa radiation. In one embodiment, the ramp rate (heating rate) for DSC is about 10°C/min. In one embodiment, a slow heating rate, such as 0.5-2.0°C/min, may be used for more accurate DSC testing. Sample cuvettes used in DSC testing include, for example, aluminum, platinum, and stainless steel cuvettes. The cuvettes can have different configurations, such as open cuvettes, pinhole cuvettes, or sealed cuvettes. In one embodiment, the temperature change rate for the TGA is about 10°C/min. In some embodiments, solid forms, such as crystalline or amorphous forms, provided in the present invention are substantially pure, i.e. substantially free of other solid forms and/or other chemical compounds, while containing less than about 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.75, 0.5, 0.25 or 0.1% by weight of one or more other solid forms and/or other chemical compounds.

In the context of this invention and unless otherwise indicated, a chemical compound, solid form or composition that is substantially free of another chemical compound, solid form or composition means that the compound, solid form or composition contains, in some embodiments, less than 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 0.01% by weight of another compound, solid form or composition. In the context of this invention and unless otherwise indicated, a solid form that is substantially physically pure is substantially free of other solid forms. In some embodiments, the crystalline form, which is substantially physically pure, contains less than 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 0.01% by weight of one or more other solid forms. Detection of other solid forms may be accomplished by any method apparent to one skilled in the art, including, but not limited to, diffraction analysis, thermal analysis, combustion-based elemental analysis, and/or spectral analysis.

In the context of this invention and unless otherwise indicated, a solid form that is substantially chemically pure is substantially free of other chemical compounds (ie, chemical impurities). In some embodiments, the solid form, which is substantially chemically pure, contains less than 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 0.01% by weight of one or more other chemical compounds. Detection of other chemical compounds may be accomplished by any method apparent to one skilled in the art, including, but not limited to, chemical analysis techniques such as, for example, mass spectrometric analysis, spectral analysis, thermal analysis, combustion-based elemental analysis, and/or chromatographic analysis.

Solid forms may exhibit a variety of physical characteristics that are unique to a particular solid form, such as the crystalline forms provided in the present invention. This characterization data can be obtained by a variety of methods known to those skilled in the art, including, for example, X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis, and nuclear magnetic resonance spectroscopy. Data obtained using these methods may

- 6 046479 change to identify a specific solid form. One of ordinary skill in the art can determine whether a solid form is one of the forms presented herein by performing one of these characterization methods and determining whether the data obtained corresponds to the reference data provided herein, which is identified as being characteristic of a particular solid form. Those skilled in the art will understand that these characteristics, which correspond to the characteristics of the reference solid form, correspond to the same solid form as the reference solid form. In assessing whether the data are consistent, one of ordinary skill in the art will recognize that specific data points may vary within the reasonable range of characteristics describing a given solid form, for example, due to experimental error and routine assay variation from sample to sample.

In the context of this invention and unless otherwise indicated, the term pharmaceutically acceptable salts refers to salts derived from pharmaceutically acceptable, relatively non-toxic acids, including inorganic acids and organic acids. In some embodiments, suitable acids include, but are not limited to, acetic, adipic, 4-aminosalicylic, ascorbic, aspartic, benzenesulfonic, benzoic, camphoric, camphorsulfonic, capric, caproic, caprylic, cinnamic, carbonic, citric, cyclamic, dihydrophosphoric, 2 ,5-dihydroxybenzoic (gentisic), 1,2-ethanedisulfonic, ethanesulfonic, fumaric, galacturonic, gluconic, glucuronic, glutamic, glutaric, glycol, hippuric, hydrobromic, hydrochloric, hydroiodic, isobutyric, isethionic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, monohydrocarbonic, monohydrophosphoric, monohydrosulfuric, mucinic, 1,5-naphthalene disulfonic, nicotinic, nitric, oxalic, pamic, pantothenic, phosphoric, phthalic, propionic, pyroglutamic, salicylic, suberic, succinic, sulfuric, tartaric, toluenesulfonic acid, etc. .P. (See, for example, S. M. Berge et at., J. Pharm. Sci., 66:1-19 (1977); and Handbook of Pharmaceutical Salts: Properties, Selection and Use, P. H. Stahl, C. G. Wermuth, eds. (2002 ), Wiley, Weinheim). In some embodiments, suitable acids are strong acids (e.g., with a pKa of less than about 1), including, but not limited to, hydrochloric, hydrobromic, sulfuric, nitric, methanesulfonic, benzenesulfonic, toluenesulfonic, naphthalene sulfonic, naphthalene disulfonic, pyridine sulfonic, or other substituted acids. sulfonic acids. Also included are salts of other relatively non-toxic compounds having acidic properties, including amino acids such as aspartic acid and the like, and other compounds such as aspirin, ibuprofen, saccharin and the like. Acid addition salts can be prepared by reacting the neutral form of the compound with a sufficient amount of the desired acid, either pure or in a suitable solvent. As solids, salts can exist in crystalline or amorphous forms or mixtures thereof. Salts can also exist in polymorphic forms.

It should be noted that if there is a discrepancy between a depicted structure and the name of that structure, the depicted structure takes precedence. In the context of this invention and unless otherwise indicated, the term treatment means alleviation, total or partial, of a disorder, disease or condition, or one or more symptoms associated with a disorder, disease or condition, or slowing or stopping the further progression or worsening of those symptoms. or alleviation or elimination of the cause(s) of the disorder, disease, or condition itself.

In the context of this invention and unless otherwise indicated, the term prevention means a method of delaying and/or preventing the occurrence, recurrence or spread, in whole or in part, of a disorder, disease or condition; preventing the subject from developing a disorder, disease or condition; or reducing the subject's risk of developing a disorder, disease or condition.

In the context of this invention and unless otherwise indicated, the term control includes preventing the recurrence of a particular disease or disorder in a patient suffering from it, increasing the time that a patient suffering from a disease or disorder remains in remission, reducing the mortality rates of patients and/or maintaining reduction in severity or avoidance of a symptom associated with the disease or condition being treated. In the context of this invention and unless otherwise indicated, the term effective amount with respect to a compound means an amount capable of treating, preventing or controlling a disorder, disease or condition or the symptoms thereof. In the context of this invention and unless otherwise indicated, the term subject or patient includes an animal, including, but not limited to, an animal such as a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, a rat, rabbit or guinea pig, in one embodiment a mammal, in another embodiment a human.

In the context of this invention and unless otherwise indicated, the term relapsing refers to a disorder, disease or condition that is treatable (eg, achieved a complete response) and then progressed. Treatment may include one or more lines of therapy. Cook in one

- 7 046479 ante the occurrence of a disorder, disease or condition previously treated by one or more lines of therapy. In another embodiment, the disorder, disease or condition has previously been treated with one, two, three or four lines of therapy. In some embodiments, the disorder, disease, or condition is a hematologic malignancy.

In one embodiment, recurrent DLBCL may refer to DLBCL that was previously treated with one or more lines of therapy. In one embodiment, recurrent DLBCL is DLBCL that was previously treated with one, two, three, or four lines of therapy. In one embodiment, recurrent DLBCL is DLBCL that has previously been treated with two or more lines of therapy.

In one embodiment, recurrent FL may refer to FL that was previously treated with one or more lines of therapy. In one embodiment, recurrent 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 was previously treated with two or more lines of therapy. In the context of this invention 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 lines of therapy. In one embodiment, the disorder, disease or condition has previously been treated with one, two, three or four lines of therapy. In one embodiment, the disorder, disease or condition has previously been treated with two or more lines of therapy and has less than a complete response (CR) to the newer systemic therapy comprising the treatment regimen. In some embodiments, the disorder, disease, or condition is a hematologic malignancy.

In one embodiment, the term relapsed or refractory CLL/SLL may refer to CLL/SLL that has previously been treated with one or more lines of therapy. In one embodiment, relapsed or refractory CLL/SLL is CLL/SLL that has previously been treated with one, two, three, or four lines of therapy. In one embodiment, relapsed or refractory CLL/SLL is CLL/SLL that has previously been treated with two or more lines of therapy. In one embodiment, the relapsed or refractory CLL/SLL is CLL/SLL that was previously treated with a Bruton's tyrosine kinase inhibitor (BTK). In one embodiment, the relapsed or refractory CLL/SLL is relapsed or refractory to BTK inhibitor therapy. 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.

In the aspect of cancer, such as hematologic malignancy, inhibition can be assessed by inhibiting disease progression, inhibiting tumor growth, shrinking the primary tumor, alleviating tumor-related symptoms, inhibiting factors secreted by the tumor, delaying the appearance of primary or secondary tumors, delaying the development of primary or secondary tumors. tumors, reducing the incidence of primary or secondary tumors, slowing or reducing the severity of secondary effects of the disease, stopping tumor growth and regression of tumors, increasing time to tumor progression (TTP), increasing progression-free survival (PFS), increasing overall survival (OS), among other things. OS in the context of this invention means the time from the start of treatment to death from any cause. In the context of this invention, TTP means the time from the start of treatment to tumor progression; TTP does not include deaths. In one embodiment, PFS means the time from the start of treatment to tumor progression or death. In one embodiment, PFS means the time from the first dose of a compound to the first occurrence of disease progression or death from any cause. In one embodiment, PFS scores are calculated using Kaplan-Meier estimates. Event-free survival (EFS) refers to the time from the start of treatment to the time of failure of treatment, including disease progression, discontinuation of treatment for any reason, or death. In one embodiment, the overall response rate (ORR) means the percentage of patients who achieve a response. In one embodiment, ORR means the sum of the percentage of patients achieving a complete response and a partial response. In one embodiment, ORR means the percentage of patients who have best response > partial response (PR). In one embodiment, duration of response (DoR) is the time from achieving response to disease relapse or progression. In one embodiment, DoR is the time from achieving response > partial response (PR) to disease relapse or progression. In one embodiment, DoR is the time from the first laboratory instrumental confirmation of response to the first laboratory instrumental confirmation of progressive disease or death. In one embodiment, DoR is the time from first laboratory confirmation of response > partial response (PR) to first laboratory confirmation of progressive disease or death. In one embodiment, time to response (TTR)

- 8 046479 means the time from the first dose of the compound to the first laboratory instrumental confirmation of the response. In one embodiment, TTR means the time from the first dose of a compound to the first laboratory instrumental confirmation of response > partial response (PR). In exceptional cases, complete inhibition is referred to here as prophylaxis or chemoprevention. In this context, the term prevention includes either preventing the occurrence of clinically apparent cancer in general or preventing the occurrence of a preclinically advanced stage of cancer. This definition is also intended to include preventing transformation into malignant cells or stopping or reversing the progression of precancerous cells to malignant cells. This includes preventive treatment of subjects at risk of developing cancer.

In some embodiments, treatment for NHL may be assessed against the International Workshop Criteria for Malignant Lymphoma (see Cheson et al., J. Clin. Oncol., 2014, 32(27):3059-3068) and Deauville criteria for the interpretation of fluorodeoxyglucose positron emission tomography (FDG-PET) (Itti et al., Eur. J. Nucl. Med. Mol. Imaging, 2013, 40(9):1312-20; Meignan et al., Leuk Lymphoma, 2014, 55(1):31-37) (Lugano criteria), applying the definition of response and endpoint shown in Table. 1-3.

Table 1

Involvement criterion

Localization Clinical signs of involvement FDG avidity Study Positive result The lymph nodes Palpable FDG-avid histologies RET/ST Increased FDG absorption Unlikeable disease ST Enlarged lymph nodes of unknown etiology Spleen Palpable FDG-avid histologies RET/ST Diffuse accumulation, solitary tumor formation, miliary lesions, nodules Unlikeable disease ST Length > 13 cm, formations, nodules Liver Palpable FDG-avid histologies RET/ST Diffuse accumulation, formations Unlikeable disease ST Nodules CNS Signs, symptoms N/A ST Neoplasm(s) MRI Infiltration of the meninges, neoplasms CSF Study Cytosis according to cytological examination, flow cytometry Miscellaneous (eg, skin, lungs, gastrointestinal tract, bones, bone marrow) Depending on location N/A PET/ST ^a , biopsy Lymphoma involvement

CNS=central nervous system;

CSF=cerebrospinal fluid;

CT=computed tomography;

FDG=fluorodeoxyglucose;

- 9 046479

GI=gastrointestinal tract;

MI1=magnetic resonance imaging;

PET=positron emission tomography;

X/A=no data available.

^and PET/CT is valid for bone marrow involvement and can be considered highly predictive of involvement of other extralymphatic sites. If necessary, confirmation of these areas by biopsy may be considered.

table 2

Lugano classification: evaluation criteria for non-Hodgkin's lymphoma

Answer Localization PET/ST (metabolic response) CT (radiological response) Full answer Lymph nodes and extralymphatic lesions 1, 2, 3 points with or without residual mass of 5- PS (Table 3) All of the following criteria: Target nodes/nodal masses must regress to <1.5 cm in LDi Without extralymphatic lesion Unmeasurable hearth N/A None Organ hypertrophy N/A Reduction to normal size New lesions Not detected Not detected Bone marrow No evidence of FDG-like disease in the brain Normal in morphology; if the result is questionable, negative ^1NSa Partial answer Lymph nodes and extralymphatic lesions 4 or 5 points on 5-PS with less accumulation compared to baseline and residual mass(es) of any size In the intermediate restaging, these data indicate the response of the disease to treatment At the end of treatment, these results may indicate residual disease All of the following criteria: >50% reduction in SPD to 6 target measurable nodes and extra alymphatic lesions When the extent of the lesion cannot be assessed on CT due to its small size (approximate size 5x5 mm) Complete absence of lesion, 0 mm x 0 mm; For knots > 5mm x 5mm but smaller than normal, it is recommended to use the actual measurement for calculation Unmeasurable hearth N/A Absent/normal, regressed but no increase Increase in the size of an internal organ N/A Reduction in the size of the spleen by 50% in length, but not reaching normal size New lesions Not detected Not detected Bone marrow Residual uptake is higher than uptake in normal bone marrow but reduced compared to baseline. If there are persistent focal changes in the bone marrow during response, consider further assessment of response with biopsy or interval scanning. N/A

- 10 046479

Stable disease Target nodes/nodules, extranodal lesions 5-PS score 4 or 5 without any significant change in FDG uptake from baseline <50% reduction from baseline to 6 dominant, measurable nodes and extranodal nodes No criteria corresponding to disease progression Unmeasurable hearth N/A There is no increase Organ hypertrophy N/A There is no increase New lesions Not detected Not detected Bone marrow No changes compared to opening values N/A Disease progression Lymph nodes and extralymphatic locations 4 or 5 points on 5-PS With an increase in absorption intensity from the initial level and/or new FDG accumulation foci at mid-study or end of treatment At least one of the following: PPD progression: The individual node/lesion must be abnormal with: LDi > 1.5 cm and >50% increase over PPD minimum and Increasing LDi or SDi from minimum 0.5 cm for lesions < 2 cm 1.0 cm for lesions > 2 cm Splenomegaly: Spleen length should increase to >50% of original values (eg, a 15 cm spleen should increase to > 16 cm). If this is not primary splenomegaly, then the length should increase by at least 2 cm from the original values. New or recurrent splenomegaly Unmeasurable hearth Not detected New lesions or apparent progression of primary existing unmeasurable lesions New lesions New FDG accumulates foci consistent with lymphoma rather than other etiologies (eg, infection, inflammation). If there is uncertainty about the etiology of new lesions, then a biopsy or reconsider the scanning interval is necessary Further growth of primary lesions New node > 1.5 cm in any axis New extranodal lesion > 1.0 cm in any axis; if < 1.0 cm in any axis, then its etiology should be unambiguous and should be attributed to lymphoma. Evaluable disease of any size that is clearly considered to be lymphoma. Bone marrow New or recurrent FDG accumulated foci New or recurrent lesions

CMR=complete metabolic response;

LDi=largest transverse diameter of lesion;

PPD=npou3eegeHue LDi and perpendicular diameter;

SDi=shortest longitudinal dimension perpendicular to LDi;

SPD=sum of products of perpendicular dimensions of multiple changes;

N/A=no data available.

a Required for CR if bone marrow involvement is present at baseline.

^b In Waldeyer's ring or extranodal areas with high physiological uptake or activation in the spleen or bone marrow (eg, chi

- 11 046479 myotherapy or myeloid colony-stimulating factors) accumulation may be higher than normal in the mediastinum and/or liver. In this case, CMR can be suspected if the accumulation in the initial lesions is no greater than in the surrounding normal tissue.

^c FDG-avid lymphomas must have a response assessed by PET-CT. Some diseases can usually be monitored using CT alone (eg, marginal zone lymphoma).

^d PET should be performed in conjunction with diagnostic contrast-enhanced CT and can be performed simultaneously or in separate procedures.

Table 3 _______________________PET five-point scale (5-PS)_______________________

1 No absorption above background 2 Uptake at a source site that is less than or equal to the mediastinum 3 Uptake at an initial site that is greater than the mediastinum but less than or equal to the liver 4 Uptake at the original site, which is moderately increased compared with the liver at any site 5 Uptake is markedly higher than in liver and/or new lesions X New areas of uptake are unlikely to be associated with lymphoma

a The Deauville Five Point Score (5PS) is the internationally recommended scale for clinical routine and clinical studies using FDG-PET/CT in the initial staging and assessment of response to treatment in Hodgkin lymphoma (HL) and some types of non-Hodgkin lymphoma (NHL).

In one embodiment, response to CLL/SLL treatment may be assessed using the International Workshop on Chronic Lymphocytic Leukemia criteria (see Hallek, M. et al., iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL, Blood, 131(25), 2745-2760 (2018)) (Table 4).

Table 4

Determining response after treatment in patients with chronic lymphocytic leukemia

Group Parameter CR PR P.D. SD A The lymph nodes Not detected > 1.5 cm Reduction > 50% (from baseline) ³ Increase >50% from baseline or response Change from 49% to +49% Liver and/or spleen size ^b Spleen size 13 cm; liver size is normal Reduction > 50% (from baseline) Increase >50% from baseline or response Change from 49% to +49% Constitutional symptoms Not detected Any Any Any Number of circulating lymphocytes Normal Reduction > 50% (from baseline) Increase >50% from baseline Change from 49% to +49%

- 12 046479

IN Platelet count > 100 x 10 ⁹ /l > 100 x 10 ⁹ /l increase > 50% from baseline Reduction >50% from baseline due to CLL Change from 49% to +49% Hemoglobin > 11.0 g/dL (non-transfusion and without erythropoietin) > 11.0 g/dL or increase > 50% from baseline Decrease >2 g/dL from baseline due to CLL Increase 11.0 g/dL or < 50% of baseline or decrease < 2 g/dL Bone marrow Normocellular, no CLL cells, no Blymphoid nodules Presence of CLL cells or Blymphoid nodules or not >50% increase in CLL cells on serial biopsies No change in bone marrow infiltrate

CR=complete remission (all criteria must be met);

PD=progressive disease (must meet at least 1 of group A or group B criteria);

PR=partial remission (for PR, at least 2 parameters of group A and 1 parameter of group B must be improved if there were previously abnormalities; if only 1 parameter of both groups A and B is abnormal before therapy, only 1 must be improved);

SD=stable disease (all criteria must be met; constitutional symptoms alone do not define PD).

a The sum of the products of the diameters of 6 or fewer lymph nodes (according to CT and physical examination in clinical trials or physical examination in general practice).

^b Spleen size is considered normal if <13 cm. There is no firmly established international consensus on the size of a normal liver; therefore, liver size should be assessed by imaging and manual palpation in clinical trials and recorded according to the definition used in the study protocol.

In one embodiment, response to CLL/SLL treatment can be assessed by Eastern Cooperative Oncology Group (ECOG) performance status.

Table 5

General condition indicator according to the ECOG scale

Points ECOG 0 Fully active, able to perform all pre-disease functions without limitations. 1 Limited in physical activity, but treated as an outpatient and able to perform light or sedentary work, such as light housework, office work. 2 He is treated as an outpatient and is capable of self-care, but is unable to perform any work. Spends up to or more than 50% of waking time actively in an upright position. 3 Capable of only limited self-care, spends more than 50% of waking time in bed or chair. 4 Completely disabled. Completely incapable of self-care. Completely confined to bed or chair. 5 Death.

ECOG=Eastern Cooperative Oncology Group; Robert Comis, MD, Group Chair. Source: Oken M. et al., Toxicity and response criteria of the Eastern Cooperative Oncology Group, Am. J. Clin. Oncol., 5(6):649-655 (1982).

In some embodiments, stable or no disease may be present

- 13 046479 determined by methods known in the art, such as assessment of the patient's symptoms, physical examination, imaging of the tumor, which has been visualized, for example, using FDGPET (fluorodeoxyglucose positron emission tomography), PET/CT (positron emission tomography) studies tomography/computed tomography), MRI (magnetic resonance imaging) of the brain and spine, CSF (cerebrospinal fluid), ophthalmological examinations, vitreal fluid sampling, retinal photography, bone marrow assessment and other generally accepted assessment methods.

As used herein and unless otherwise indicated, the terms co-administration and in combination with include the administration of one or more therapeutic agents (eg, a compound of the present invention and another anticancer agent or symptomatic therapy agent) either simultaneously, in combination, or sequentially without any specific time limits. In one embodiment, the agents are present in the cell or body of the patient at the same time or exert their biological or therapeutic effects at the same time. In one embodiment, the therapeutic agents are in the same composition or unit dosage form. In another embodiment, the therapeutic agents are in separate compositions or unit dosage forms.

The term symptomatic therapy agent refers to any substance that treats, prevents, and controls the adverse effect of treatment with another therapeutic agent.

5.2. Salts and solid forms containing compound 1.

In some embodiments, the present invention provides a solid form containing Compound 1

ABOUT

Compound 1 has the chemical name ^)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1, 3-dion. Methods for preparing compound 1 are described in US application No. 16/390815, which is incorporated herein by reference in its entirety.

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

In one embodiment, the solid form is crystalline. In one embodiment, the solid form is a hydrate. In one embodiment, the solid form is an anhydride. In one embodiment, the solid form is a solvate. In one embodiment, the solid form is unsolvated. In one embodiment, the solid form is amorphous.

The present solid forms can be characterized using a number of techniques known to one of ordinary skill in the art, including, but not limited to, single crystal X-ray diffraction, powder X-ray 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 microscopy), dynamic vapor sorption (DVS), spectroscopy (e.g. infrared, Raman and nuclear magnetic resonance), high performance liquid chromatography (HPLC). The particle size and size distribution of the solid form proposed in the present invention can be determined by conventional methods, such as laser light scattering techniques.

The present invention also provides salts of Compound 1. 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. 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. Without limiting any particular theory, the acids are bonded to one or more base nitrogens of Compound 1. Without limiting any particular theory, or by a specific theory, the pKa of the azetidine nitrogen of compound 1

- 14046479 is estimated to be about 7.7, and the pKa of the morpholine nitrogen of compound 1 is estimated to be about 2.12.

The purity of the solid forms and salts provided in the present invention can be determined by standard analytical techniques such as thin layer chromatography (TLC), gel electrophoresis, gas chromatography, high performance liquid chromatography (HPLC) and mass spectrometry.

Without being limited by any particular theory, certain solid forms and salts have physical properties, such as stability, solubility, and dissolution rate, suitable for pharmaceutical and therapeutic dosage forms. Moreover, without being limited to any particular theory, certain solid forms and salts are characterized by physical properties (e.g., density, compressibility, hardness, structure, cleavage, adhesiveness, solubility, water absorption, electrical properties, thermal behavior, solid phase reactivity , physical stability, and chemical stability) affecting specific processes (e.g., yield, filtration, washing, drying, grinding, mixing, tableting, flowability, dissolution, formulation, and lyophilization) that make certain solid forms and salts suitable for solid drug formulation forms. Such properties can be determined using specific analytical chemical methods, including solid state analytical methods (eg, X-ray diffraction, microscopy, spectroscopy and thermal analysis), as described in the present invention and known in the art. Without being limited by any particular theory, certain solid forms and salts provided in the present invention exhibit suitable pharmaceutical properties, for example, pharmaceutical kinetics, pharmaceutical dynamics, half-life, C _m , and bioavailability. Such properties can be determined using assays known to those skilled in the art.

(a) Free base of connection 1.

In some embodiments, the present invention provides the free base of Compound 1. It is contemplated that the free base of Compound 1 may exist in a variety of solid forms. Such 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.

In one embodiment, the present invention provides a solid form containing the free base of Compound 1. 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 the form is the unsolvated free base form of Compound 1. In one embodiment, the solid form is the desolvated free base form of Compound 1. In one embodiment, the solid form is the anhydrous form (anhydrate) of the free base of Compound 1. In one embodiment, the solid form is is the dehydrated free base form of compound 1.

(i) Form A of the free base of compound 1.

In some embodiments, the present invention provides Compound 1 free base Form A.

In one embodiment, Form A is crystalline. In one embodiment, Form A is substantially crystalline. In one embodiment, Form A is medium crystalline. In one embodiment, Form A is partially crystalline.

A typical XRPD diffraction pattern of Form A is shown in FIG. 1.

In one embodiment, the present invention provides a solid form containing the free base of Compound 1 characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or all 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 peaks. In one embodiment, the solid form is characterized by 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, the present invention provides a solid form containing the free base of compound 1, characterized by an XRPD diffractogram containing peaks at about 4.5, 15.3 and 18.1° 2θ. In one embodiment, the XRPD diffraction pattern further contains peaks at about 13.3 and 15.9° 2θ. In one embodiment, the XRPD diffraction pattern further contains peaks at about 20.1 and 20.9° 2θ. In one embodiment, the XRPD diffraction pattern contains peaks at about 4.5, 13.3, 15.3, 15.9, 18.1, 19.1, 20.1, 20.9, 21.6 and 26.3° 2θ.

In one embodiment, the present invention provides a solid form containing the free base of compound 1, characterized by an XRPD diffraction pattern containing peaks

- 15 046479 at about 4.5° 2θ. In one embodiment, the XRPD diffraction pattern contains peaks at about 4.5, 11.4 and 12.6° 2θ. In one embodiment, the XRPD diffraction pattern contains peaks at about 4.5, 11.4, 12.6, 13.3 and 15.3° 2θ. In one embodiment, the XRPD diffraction pattern contains peaks at about 4.5, 11.4, 12.6, 13.3, 15.3, 15.9 and 18.1° 2θ.

In one embodiment, the present invention provides a solid form containing the free base of Compound 1 having an XRPD diffraction pattern that corresponds to the XRPD diffraction pattern shown in FIG. 1.

In one embodiment, XRPD diffraction patterns are obtained using Cu Ka radiation.

Typical Form A thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms are shown in FIG. 2. In one embodiment, the present invention provides a solid form containing the free base of Compound 1 that 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, the present invention provides a solid form containing the free base of Compound 1 having a TGA thermogram that corresponds to the TGA thermogram shown in FIG. 2.

In one embodiment, the present invention provides a solid form containing the free base of Compound 1 that exhibits, according to DSC, a first thermal effect (endo) with a peak temperature of about 68° C. and a second thermal effect (endo) with a peak temperature of about 112° WITH. In one embodiment, the present invention provides a solid form containing the free base of Compound 1 having a DSC thermogram that corresponds to the DSC thermogram shown in FIG. 2.

In one embodiment, Compound 1 Free Base Form A is prepared by suspending Compound 1 Free Base in water (eg, about 40° C., about 6 days).

In one embodiment, the present invention provides a solid form containing the free base Form A of Compound 1 and the amorphous free base of Compound 1. In one embodiment, the present invention provides a solid form containing the free base Form A of Compound 1 and one or more other crystalline forms the free base of compound 1 provided in the present invention. In one embodiment, the present invention provides a solid form containing Form A of the free base of Compound 1 and one or more forms (eg, amorphous or crystalline) of a salt of Compound 1 of the present invention.

(ii) Form B of the free base of compound 1.

In some embodiments, the present invention provides Compound 1 free base Form B.

In one embodiment, Form B is crystalline. In one embodiment, Form B is substantially crystalline. In one embodiment, Form B is medium crystalline. In one embodiment, Form B is partially crystalline.

A typical Form B XRPD diffraction pattern is shown in FIG. 3.

In one embodiment, the present invention provides a solid form containing the free base of Compound 1 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 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 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks. In one embodiment, the present invention provides a solid form containing the free base of compound 1, characterized by an XRPD diffractogram containing peaks at about 4.8, 9.6 and 14.9° 2θ. In one embodiment, the XRPD diffraction pattern further contains peaks at about 18.7 and 22.1° 2θ. In one embodiment, the XRPD diffraction pattern further contains peaks at about 20.7 and 21.4° 2θ. In one embodiment, the XRPD diffraction pattern contains peaks at about 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. In one embodiment, the present invention provides a solid form containing the free base of compound 1, characterized by an XRPD diffractogram containing peaks at about 4.5, 4.8 and 9.6° 2θ. In one embodiment, the XRPD diffraction pattern contains peaks at about 4.5, 4.8, 9.6, 10.7 and 11.4° 2θ. In one embodiment, the XRPD diffraction pattern contains peaks at about 4.5, 4.8, 9.6, 10.7, 11.4, 13.3 and 13.7° 2θ. In one embodiment, the XRPD diffraction pattern contains peaks at about 4.5, 4.8, 9.6, 10.7, 11.4, 13.3, 13.7, 14.9 and 15.7° 2θ.

In one embodiment, the present invention provides a solid form containing the free base of Compound 1, characterized by an XRPD diffraction pattern that is

- 16 046479 corresponds to the XRPD diffraction pattern shown in Fig. 3.

In one embodiment, XRPD diffraction patterns are obtained using Cu Κα radiation.

Typical Form B thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms are shown in FIG. 4. In one embodiment, the present invention provides a solid form containing the free base of Compound 1 that exhibits a weight loss of about 0.9% when heated from about 25°C to about 225°C. In one embodiment, the present invention provides a solid form containing the free base of Compound 1 having a TGA thermogram that corresponds to the TGA thermogram shown in FIG. 4.

In one embodiment, a solid form containing the free base of Compound 1 is provided that exhibits, according to DSC, a first thermal effect (endo) with a peak temperature of about 82°C, a second thermal effect (endo) with a peak temperature of about 107°C, and a third thermal effect (endo) with a peak temperature of about 138°C. In one embodiment, the present invention provides a solid form containing the free base of Compound 1 having a DSC thermogram that corresponds to the DSC thermogram shown in FIG. 4.

In one embodiment, Compound 1 Free Base Form B is prepared by crystallizing Compound 1 Free Base from a solvent/antisolvent system (eg, at room temperature) where the solvent is acetone and the antisolvent is water. In one embodiment, the present invention provides a solid form containing Free Base Form B of Compound 1 and an amorphous free base of Compound 1. In one embodiment, the present invention provides a solid form containing Free Base Form B of Compound 1 and one or more other crystalline forms free base of compound 1 presented here. In one embodiment, the present invention provides a solid form containing the free base Form B of Compound 1 and one or more salt forms (eg, amorphous or crystalline) of Compound 1 of the present invention.

(b) Hydrochloride salt of compound 1.

In some embodiments, the present invention provides a hydrochloride salt of Compound 1. It is contemplated that the hydrochloride salt of Compound 1 may exist in various solid forms. Such 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.

In one embodiment, the present invention provides a solid form comprising a hydrochloride salt of Compound 1. In one embodiment, the solid form is a hydrochloride salt solvate of Compound 1. In one embodiment, the solid form is a hydrochloride salt hydrate of Compound 1. In one embodiment, the solid form is a hydrochloride salt of Compound 1. the form is the unsolvated form of the hydrochloride salt of Compound 1. In one embodiment, the solid form is the desolvated form of the hydrochloride salt of Compound 1. In one embodiment, the solid form is the anhydrous form (anhydrate) of the hydrochloride salt of Compound 1. In one embodiment, the solid form is is a dehydrated form of the hydrochloride salt of compound 1.

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 (ie, bis-hydrochloride salt). In another embodiment, the molar ratio is about 1:1 (ie, monochloride salt).

(i) Form A of the hydrochloride salt of Compound 1.

In some embodiments, the present invention provides Form A of the hydrochloride salt of Compound 1.

In one embodiment, Form A is crystalline. In one embodiment, Form A is substantially crystalline. In one embodiment, Form A is medium crystalline. In one embodiment, Form A is partially crystalline.

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 the hydrochloride salt of Compound 1. In one embodiment, Form A is the hydrochloride salt hydrate of Compound 1. In one embodiment, Form A is the hydrochloride salt channel hydrate of Compound 1. Representative XRPD diffraction pattern of Form A of the hydrochloride salt of Compound 1 is shown in Fig. 5.

In one embodiment, the present invention provides a solid form containing a hydrochloride salt of Compound 1 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 peaks located approximately in the following

- 17 046479 blowing 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 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, the present invention provides a solid form containing a hydrochloride salt of Compound 1, characterized by an XRPD diffractogram containing peaks at about 15.1, 16.3 and 20.7° 2θ. In one embodiment, the XRPD diffraction pattern further contains peaks at about 7.8 and 22.4° 2θ. In one embodiment, the XRPD diffraction pattern further contains peaks at about 18.2, 18.9 and 24.8° 2θ. In one embodiment, the XRPD diffraction pattern contains peaks at about 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. In one embodiment, the present invention provides a solid form containing a hydrochloride salt of Compound 1, characterized by an XRPD diffractogram containing peaks at about 4.2, 7.8 and 11.1° 2θ. In one embodiment, the XRPD diffraction pattern contains peaks at about 4.2, 7.8, 11.1, 12.4 and 15.1° 2θ.

In one embodiment, the XRPD diffraction pattern contains peaks at about 4.2, 7.8, 11.1, 12.4, 15.1, 15.5 and 16.3° 2θ. In one embodiment, the XRPD diffraction pattern contains peaks at about 4.2, 7.8, 11.1, 12.4, 15.1, 15.5, 16.3, 17.1 and 17.3° 2θ. In one embodiment, the present invention provides a solid form containing a hydrochloride salt of Compound 1 having an XRPD diffraction pattern that corresponds to the XRPD diffraction pattern shown in FIG. 5.

In one embodiment, XRPD diffraction patterns are obtained using Cu Ka radiation.

Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of Compound 1 hydrochloride salt Form A are shown in FIG. 6. In one embodiment, the present invention provides a solid form containing a hydrochloride salt of Compound 1 that 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 25° C. to about 200° C. heating from about 200°C to about 230°C. In one embodiment, the present invention provides a solid form containing a hydrochloride salt of Compound 1 having a TGA thermogram that corresponds to the TGA thermogram shown in FIG. 6.

In one embodiment, the present invention provides a solid form containing a hydrochloride salt of Compound 1 that exhibits, according to DSC, a first thermal effect (endo) with a peak temperature of about 218°C, and a second thermal effect (exo) with a peak temperature of about 227 °C. In one embodiment, the present invention provides a solid form containing a hydrochloride salt of Compound 1 having a DSC thermogram that corresponds to the DSC thermogram shown in FIG. 6. The melting point of Compound 1 hydrochloride salt Form A may vary depending on crystallinity and defects in the crystal structure.

A typical dynamic vapor sorption (DVS) isotherm plot of Form A hydrochloride salt of Compound 1 is shown in FIG. 7. In one embodiment, the present invention provides a solid form containing a hydrochloride salt of Compound 1 that exhibits a weight increase of about 3.0% as relative humidity (RH) increases from about 0% to about 95%. In one embodiment, the present invention provides a solid form containing a hydrochloride salt of Compound 1 having a DVS isotherm plot that corresponds to the DVS isotherm plot shown in FIG. 7. In one embodiment, Form A of the hydrochloride salt of Compound 1 has a crystalline habit of small rod primary particles. A typical SEM image of Compound 1 hydrochloride salt Form A is shown in FIG. 8.

In one embodiment, Form A of the hydrochloride salt of Compound 1 is prepared by suspending the hydrochloride salt of Compound 1 in a solvent. In one embodiment, Compound 1 hydrochloride salt Form A is prepared by suspending 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, mixture acetone and water (for example, 95/5 v/v), a mixture of acetonitrile and water (for example, 95/5 v/v), a mixture of 2-PrOH and water (for example, 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, the suspension is carried out at room temperature. In one embodiment, suspension is carried out at about 50°C. In one embodiment, suspension is carried out for a period of time from about 1 day to about 7 days. In one embodiment, the suspension

- 18 046479 roving is carried out for about 2 days. In one embodiment, suspension is carried out for about 7 days.

In one embodiment, the present invention provides a solid form comprising the hydrochloride salt Form A of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, the present invention provides a solid form comprising hydrochloride salt Form A of Compound 1 and an amorphous hydrochloride salt of Compound 1. In one embodiment, the present invention provides a solid form containing hydrochloride salt Form A of Compound 1 and one or more other crystalline forms hydrochloride salt of compound 1 presented in the present invention. In one embodiment, the present invention provides a solid form containing Form A of the hydrochloride salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of the salt of Compound 1 provided in the present invention.

(ii) Form B of the hydrochloride salt of compound 1.

In some embodiments, the present invention provides Form B of the hydrochloride salt of Compound 1.

In one embodiment, Form B is crystalline. In one embodiment, Form B is substantially crystalline. In one embodiment, Form B is medium crystalline. In one embodiment, Form B is partially crystalline.

A typical XRPD diffraction pattern of Form B of the hydrochloride salt of Compound 1 is shown in FIG. 9.

In one embodiment, the present invention provides a solid form containing a hydrochloride salt of Compound 1 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 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 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, the present invention provides a solid form containing a hydrochloride salt of Compound 1, characterized by an XRPD diffractogram containing peaks at about 17.5, 21.6 and 24.8° 2θ. In one embodiment, the XRPD diffraction pattern further contains peaks at about 21.1 and 27.0° 2θ. In one embodiment, the XRPD diffraction pattern further contains peaks at about 14.6, 17.2 and 20.3° 2θ. In one embodiment, the XRPD diffraction pattern contains peaks at about 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.

In one embodiment, the present invention provides a solid form containing a hydrochloride salt of Compound 1 characterized by an XRPD diffractogram containing peaks at about 6.7, 11.6 and 13.5° 2θ. In one embodiment, the XRPD diffraction pattern contains peaks at about 6.7, 11.6, 13.5, 14.2 and 14.6° 2θ. In one embodiment, the XRPD diffraction pattern contains peaks at about 6.7, 11.6, 13.5, 14.2, 14.6, 16.5 and 17.2° 2θ. In one embodiment, the XRPD diffraction pattern contains peaks at about 6.7, 11.6, 13.5, 14.2, 14.6, 16.5, 17.2, 17.5 and 18.1° 2θ. In one embodiment, the present invention provides a solid form containing a hydrochloride salt of Compound 1 having an XRPD diffractogram that corresponds to the XRPD diffractogram shown in FIG. 9 In one embodiment, XRPD diffraction patterns are obtained using Cu Ka radiation.

Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of Form B hydrochloride salt of Compound 1 are shown in FIG. 10. In one embodiment, the present invention provides a solid form containing a hydrochloride salt of Compound 1 that 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, the present invention provides a solid form containing a hydrochloride salt of Compound 1 having a TGA thermogram that corresponds to the TGA thermogram shown in FIG. 10.

In one embodiment, the present invention provides a solid form containing a hydrochloride salt of Compound 1 that exhibits a thermal effect (exo) according to DSC with a peak temperature of approximately 230°C. In one embodiment, the present invention provides a solid form containing a hydrochloride salt of Compound 1 having a DSC thermogram that corresponds to the DSC thermogram shown in FIG. 10.B

- 19 046479 In one embodiment, Form B of the hydrochloride salt of Compound 1 is prepared by suspending the free base of Compound 1 and about 2 equivalents of HCl in acetonitrile (eg, at room temperature for about 5 days).

In one embodiment, the present invention provides a solid form comprising the hydrochloride salt Form B of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, the present invention provides a solid form comprising hydrochloride salt Form B of Compound 1 and an amorphous hydrochloride salt of Compound 1. In one embodiment, the present invention provides a solid form containing hydrochloride salt Form B of Compound 1 and one or more other crystalline forms hydrochloride salt of compound 1 presented in the present invention. In one embodiment, the present invention provides a solid form containing Form B of the hydrochloride salt of Compound 1 and one or more salt forms (eg, amorphous or crystalline) of Compound 1 of the present invention.

(iii) Form C of the hydrochloride salt of Compound 1.

In some embodiments, the present invention provides the hydrochloride salt Form C of Compound 1. A typical XRPD diffraction pattern of the hydrochloride salt Form C of Compound 1 is shown in FIG. 21. In one embodiment, the present invention provides a solid form containing a hydrochloride salt of Compound 1 having an XRPD diffraction pattern that corresponds to the XRPD diffraction pattern shown in FIG. 21.

(c) Fumarate salt of compound 1.

In some embodiments, the present invention provides a fumarate salt of Compound 1. It is contemplated that the fumarate salt of Compound 1 may exist in various solid forms. Such 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.

In one embodiment, the present invention provides a solid form comprising a fumarate salt of Compound 1. In one embodiment, the solid form is a fumarate salt solvate of Compound 1. In one embodiment, the solid form is a fumarate salt hydrate of Compound 1. In one embodiment, the solid form is a fumarate salt hydrate of Compound 1. the form is the unsolvated form of the fumarate salt of Compound 1. In one embodiment, the solid form is the desolvated form of the fumarate salt of Compound 1. In one embodiment, the solid form is the anhydrous form (anhydrate) of the fumarate salt of Compound 1. In one embodiment, the solid form is is a dehydrated form of the fumarate salt of compound 1.

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 (ie, bis-fumarate salt). In another embodiment, the molar ratio is about 1:1 (ie, monofumarate salt).

(i) Form A of the fumarate salt of Compound 1.

In some embodiments, the present invention provides Form A of the fumarate salt of Compound 1.

In one embodiment, Form A is crystalline. In one embodiment, Form A is substantially crystalline. In one embodiment, Form A is medium crystalline. In one embodiment, Form A is partially crystalline.

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.

In one embodiment, Form A is the unsolvated form of the fumarate salt of Compound 1.

A typical XRPD diffraction pattern of Form A of the fumarate salt of Compound 1 is shown in FIG. eleven.

In one embodiment, the present invention provides a solid form containing a fumarate salt of Compound 1 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, 30 or all 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 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, the present invention provides a solid form containing

- 20 046479 fumarate salt of compound 1, characterized by an XRPD diffractogram containing peaks at about 22.3, 23.2 and 23.4° 2θ. In one embodiment, the XRPD diffraction pattern further contains peaks at about 17.9 and 25.8° 2θ. In one embodiment, the XRPD diffraction pattern further contains peaks at about 11.7 and 18.3° 2θ. In one embodiment, the XRPD diffraction pattern contains peaks at about 11.7, 15.0, 17.9, 18.3, 19.4, 20.1, 22.3, 22.9, 23.2, 23.4, and 25.8° 2θ.

In one embodiment, the present invention provides a solid form containing the fumarate salt of Compound 1, characterized by an XRPD diffractogram containing peaks at about 11.7, 12.2 and 12.8° 2θ. In one embodiment, the XRPD diffraction pattern contains peaks at about 11.7, 12.2, 12.8, 13.8 and 14.5° 2θ. In one embodiment, the XRPD diffraction pattern contains peaks at about 11.7, 12.2, 12.8, 13.8, 14.5, 14.7 and 15.0° 2θ. In one embodiment, the XRPD diffraction pattern contains peaks at about 11.7, 12.2, 12.8, 13.8, 14.5, 14.7, 15.0, 15.2 and 16.6° 2θ.

In one embodiment, the present invention provides a solid form containing the fumarate salt of Compound 1 having an XRPD diffractogram that corresponds to the XRPD diffractogram shown in FIG. 11. In one embodiment, XRPD diffraction patterns are obtained using Cu Ka radiation.

Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of Form A fumarate salt of Compound 1 are shown in FIG. 12. In one embodiment, the present invention provides a solid form containing the fumarate salt of Compound 1, 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 heating from about 150°C to about 205°C. In one embodiment, the present invention provides a solid form containing the fumarate salt of Compound 1 having a TGA thermogram that corresponds to the TGA thermogram shown in FIG. 12.

In one embodiment, the present invention provides a solid form containing the fumarate salt of Compound 1, which exhibits a thermal effect (endo) according to DSC with a peak temperature of approximately 198°C. In one embodiment, without being limited by any particular theory, the thermal effect corresponds to melting. In one embodiment, the present invention provides a solid form containing the fumarate salt of Compound 1 having a DSC thermogram that corresponds to the DSC thermogram shown in FIG. 12.

In one embodiment, Form A of the fumarate salt of Compound 1 is prepared by suspending the fumarate salt of Compound 1 in a solvent. In one embodiment, Form A of the fumarate salt of Compound 1 is prepared by suspending 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 (for example, 95/5 v/v). In one embodiment, the solvent is acetonitrile. In one embodiment, the suspension is carried out at room temperature. In one embodiment, suspension is carried out at about 50°C. In one embodiment, suspension is carried out for a period of time from about 1 day to about 7 days. In one embodiment, suspension is carried out for about 2 days. In one embodiment, suspension is carried out for about 7 days.

In one embodiment, the present invention provides a solid form containing the fumarate salt Form A of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, the present invention provides a solid form containing fumarate salt Form A of Compound 1 and an amorphous fumarate salt of Compound 1. In one embodiment, the present invention provides a solid form containing fumarate salt Form A of Compound 1 and one or more other crystalline forms fumarate salt of Compound 1. In one embodiment, the present invention provides a solid form comprising Form A of the fumarate salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of a salt of Compound 1 of the present invention.

(d) Tosylate salt of compound 1.

In some embodiments, the present invention provides a tosylate salt of Compound 1. It is contemplated that the tosylate salt of Compound 1 may exist in various solid forms. Such 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.

In one embodiment, the present invention provides a solid form containing a tosylate salt of Compound 1. In one embodiment, the solid form is a tosylate salt solvate of Compound 1. In one embodiment, the solid form is

- 21 046479 is the hydrate of the tosylate salt of Compound 1. In one embodiment, the solid form is the unsolvated form of the tosylate salt of Compound 1. In one embodiment, the solid form is the desolvated form of the tosylate salt of Compound 1. In one embodiment, the solid form is the anhydrous form (anhydrate) tosylate salt of Compound 1. In one embodiment, the solid form is a dehydrated form of the tosylate salt of Compound 1.

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 (ie, bis-tosylate salt). In another embodiment, the molar ratio is about 1:1 (ie, monotosylate salt).

(i) Form A of the tosylate salt of Compound 1.

In some embodiments, the present invention provides Form A of the tosylate salt of Compound 1.

In one embodiment, Form A is crystalline. In one embodiment, Form A is substantially crystalline. In one embodiment, Form A is medium crystalline. In one embodiment, Form A is partially crystalline.

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 the monotosylate salt of Compound 1.

In one embodiment, Form A is the unsolvated form of the tosylate salt of Compound 1.

A typical XRPD diffraction pattern of Compound 1 tosylate salt Form A is shown in FIG. 13.

In one embodiment, the present invention provides a solid form containing the tosylate salt of Compound 1, 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 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 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks. In one embodiment, the present invention provides a solid form containing the tosylate salt of Compound 1, characterized by an XRPD diffractogram containing peaks at about 17.6, 18.0 and 23.8° 2θ. In one embodiment, the XRPD diffraction pattern further contains peaks at about 15.7 and 20.6° 2θ. In one embodiment, the XRPD diffraction pattern further contains peaks at about 24.7 and 25.0° 2θ. In one embodiment, the XRPD diffraction pattern contains peaks at about 15.7, 16.4, 17.6, 18.0, 18.6, 20.6, 21.2, 23.4, 23.8, 24.7, and 25.0° 2θ.

In one embodiment, the present invention provides a solid form containing the tosylate salt of compound 1, characterized by an XRPD diffractogram containing peaks at about 3.9, 6.8 and 7.3° 2θ. In one embodiment, the XRPD diffraction pattern contains peaks at about 3.9, 6.8, 7.3, 7.8 and 8.6° 2θ. In one embodiment, the XRPD diffraction pattern contains peaks at about 3.9, 6.8, 7.3, 7.8, 8.6, 10.9 and 11.4° 2θ. In one embodiment, the XRPD diffraction pattern contains peaks at about 3.9, 6.8, 7.3, 7.8, 8.6, 10.9, 11.4, 12.1 and 14.5° 2θ.

In one embodiment, the present invention provides a solid form containing the tosylate salt of Compound 1 having an XRPD diffraction pattern that corresponds to the XRPD diffraction pattern shown in FIG. 13.

In one embodiment, XRPD diffraction patterns are obtained using Cu Ka radiation.

Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of Compound 1 tosylate salt Form A are shown in FIG. 14. In one embodiment, the present invention provides a solid form containing the tosylate salt of Compound 1, which exhibits a weight loss of about 1.0% when heated from about 25°C to about 200°C. In one embodiment, the present invention provides a solid form containing the tosylate salt of Compound 1 having a TGA thermogram that corresponds to the TGA thermogram presented in FIG. 14.

In one embodiment, the present invention provides a solid form containing the tosylate salt of Compound 1, which exhibits a thermal effect (endo) according to DSC data with a peak temperature of about 189°C. In one embodiment, without being limited by any particular theory, the thermal effect corresponds to melting. In one embodiment, the present invention provides a solid form containing the tosylate salt of Compound 1 having a DSC thermogram that corresponds to the DSC thermogram shown in FIG. 14. In one embodiment, Compound 1 tosylate salt Form A is prepared by suc

- 22 046479 soaking the tosylate salt of compound 1 in a solvent. In one embodiment, Compound 1 tosylate salt Form A is prepared by suspending 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 suspension is carried out at room temperature. In one embodiment, suspension is carried out at about 50°C. In one embodiment, suspension is carried out for a period of time from about 1 day to about 7 days. In one embodiment, suspension is carried out for about 2 days. In one embodiment, suspension is carried out for about 7 days.

In one embodiment, the present invention provides a solid form containing the tosylate salt Form A of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, the present invention provides a solid form containing the tosylate salt Form A of Compound 1 and an amorphous tosylate salt of Compound 1. In one embodiment, the present invention provides a solid form containing the tosylate salt Form A of Compound 1 and one or more other crystalline forms tosylate salt of Compound 1. In one embodiment, the present invention provides a solid form containing Form A of the tosylate salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of a salt of Compound 1 of the present invention.

(ii) Additional tosylate salt forms of Compound 1.

In some embodiments, the present invention provides the tosylate salt Form B of Compound 1. A typical XRPD diffraction pattern of the tosylate salt Form B of Compound 1 is shown in FIG. 22 (as part of graph overlay). In one embodiment, the present invention provides a solid form containing the tosylate salt of Compound 1 having an XRPD diffractogram that matches the XRPD diffractogram for Form B shown in FIG. 22. In some embodiments, the present invention provides the tosylate salt Form C of Compound 1. A typical XRPD diffraction pattern of the tosylate salt Form C of Compound 1 is shown in FIG. 22 (as part of graph overlay). In one embodiment, the present invention provides a solid form containing the tosylate salt of Compound 1 having an XRPD diffractogram that matches the XRPD diffractogram for Form C shown in FIG. 22. In some embodiments, the present invention provides the tosylate salt Form D of Compound 1. A typical XRPD diffraction pattern of the tosylate salt Form D of Compound 1 is shown in FIG. 22 (as part of graph overlay). In one embodiment, the present invention provides a solid form containing the tosylate salt of Compound 1 having an XRPD diffractogram that matches the XRPD diffractogram for Form D shown in FIG. 22.

(f) Maleate salt of compound 1.

In some embodiments, the present invention provides a maleate salt of Compound 1. It is contemplated that the maleate salt of Compound 1 may exist in various solid forms. Such 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.

In one embodiment, the present invention provides a solid form comprising a maleate salt of Compound 1. 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 the form is the unsolvated form of the maleate salt of Compound 1. In one embodiment, the solid form is the desolvated form of the maleate salt of Compound 1. In one embodiment, the solid form is the anhydrous form (anhydrate) of the maleate salt of Compound 1. In one embodiment, the solid form is is the dehydrated form of the maleate salt of compound 1.

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 (ie, bis-maleate salt). In another embodiment, the molar ratio is about 1:1 (ie, monomaleate salt).

(i) Form A of the maleate salt of Compound 1.

In some embodiments, the present invention provides Form A of the maleate salt of Compound 1.

In one embodiment, Form A is crystalline. In one embodiment, Form A is substantially crystalline. In one embodiment, Form A is

- 23 046479 medium-crystalline. In one embodiment, Form A is partially crystalline.

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 the monomaleate 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 the bis-maleate salt of Compound 1. In one embodiment, Form A is a mixture of the monomaleate salt and the bis-maleate salt of Compound 1.

In one embodiment, Form A is the unsolvated maleate salt form of Compound 1. In one embodiment, Form A is the maleate salt solvate of Compound 1.

A typical XRPD diffraction pattern of Form A of the maleate salt of Compound 1 is shown in FIG. 15.

In one embodiment, the present invention provides a solid form containing a maleate salt of Compound 1 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 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 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, the present invention provides a solid form containing the maleate salt of Compound 1, characterized by an XRPD diffractogram containing peaks at about 17.6, 24.4 and 26.9° 2θ. In one embodiment, the XRPD diffraction pattern further contains peaks at about 18.0, 18.4 and 19.3° 2θ. In one embodiment, the XRPD diffraction pattern further contains peaks at about 19.8 and 24.0° 2θ. In one embodiment, the XRPD diffraction pattern contains peaks at about 11.9, 17.6, 18.0, 18.4, 19.3, 19.8, 24.0, 24.4, 25.1, 26.0, and 26.9° 2θ.

In one embodiment, the present invention provides a solid form containing the maleate salt of Compound 1, characterized by an XRPD diffractogram containing peaks at about 6.0, 11.6 and 11.9° 2θ. In one embodiment, the XRPD diffraction pattern contains peaks at about 6.0, 11.6, 11.9, 12.5 and 13.3° 2θ. In one embodiment, the XRPD diffraction pattern contains peaks at about 6.0, 11.6, 11.9, 12.5, 13.3, 13.9 and 15.2° 2θ. In one embodiment, the XRPD diffraction pattern contains peaks at about 6.0, 11.6, 11.9, 12.5, 13.3, 13.9, 15.2, 16.2 and 17.0° 2θ.

In one embodiment, the present invention provides a solid form containing the maleate salt of Compound 1 having an XRPD diffractogram that corresponds to the XRPD diffractogram shown in FIG. 15. In one embodiment, XRPD diffraction patterns are obtained using Cu Ka radiation.

Representative thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) thermograms of Compound 1 maleate salt Form A are shown in FIG. 16. In one embodiment, the present invention provides a solid form containing the maleate salt of Compound 1, 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 heating from about 150°C to about 185°C. In one embodiment, the present invention provides a solid form containing the maleate salt of Compound 1 having a TGA thermogram that corresponds to the TGA thermogram shown in FIG. 16.

In one embodiment, the present invention provides a solid form containing the maleate salt of Compound 1, which exhibits a thermal effect (endo) according to DSC data with a peak temperature of approximately 174°C. In one embodiment, without being limited by any particular theory, the thermal effect corresponds to melting. In one embodiment, the present invention provides a solid form containing the maleate salt of Compound 1 having a DSC thermogram that corresponds to the DSC thermogram shown in FIG. 16. In one embodiment, Form A of the maleate salt of Compound 1 is prepared by suspending the free base of Compound 1 and maleic acid in acetonitrile (eg, at room temperature for about 5 days). In one embodiment, the present invention provides a solid form containing maleate salt Form A of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, the present invention provides a solid form containing maleate salt Form A of Compound 1 and an amorphous maleate salt of Compound 1. In one embodiment, the present invention provides a solid form containing maleate salt Form A of Compound 1 and one or more other crystalline forms maleate salt of compound 1. In one embodiment, the present invention provides a solid form containing the form

- 24 046479

A maleate salt of compound 1 and one or more forms (eg, amorphous or crystalline) of a salt of compound 1 provided in the present invention.

(f) Besylate salt of compound 1.

In some embodiments, the present invention provides a besylate salt of Compound 1. It is contemplated that the besylate salt of Compound 1 may exist in various solid forms. Such 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.

In one embodiment, the present invention provides a solid form containing a besylate salt of Compound 1. 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 the form is the unsolvated form of the besylate salt of Compound 1. In one embodiment, the solid form is the desolvated form of the besylate salt of Compound 1. In one embodiment, the solid form is the anhydrous form (anhydrate) of the besylate salt of Compound 1. In one embodiment, the solid form is is a dehydrated form of the besylate salt of compound 1.

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 (ie, bis-besylate salt). In another embodiment, the molar ratio is about 1:1 (ie, monobesylate salt).

(i) Form A of the besylate salt of Compound 1.

In some embodiments, the present invention provides Form A of the besylate salt of Compound 1.

In one embodiment, Form A is crystalline. In one embodiment, Form A is substantially crystalline. In one embodiment, Form A is medium crystalline. In one embodiment, Form A is partially crystalline.

A typical XRPD diffraction pattern of Form A of the besylate salt of compound 1 is shown in FIG. 17.

In one embodiment, the present invention provides a solid form containing a besylate salt of Compound 1 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 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 3 peaks. In one embodiment, the solid form has 5 peaks. In one embodiment, the solid form has 7 peaks. In one embodiment, the solid form has 9 peaks. In one embodiment, the solid form has 11 peaks. In one embodiment, the solid form is characterized by all peaks.

In one embodiment, the present invention provides a solid form containing the besylate salt of Compound 1, characterized by an XRPD diffractogram containing peaks at about 17.9, 18.3 and 23.8° 2θ. In one embodiment, the XRPD diffraction pattern further contains peaks at about 15.7 and 16.2° 2θ. In one embodiment, the XRPD diffraction pattern further contains peaks at about 8.5 and 16.5° 2θ. In one embodiment, the XRPD diffraction pattern contains peaks at about 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.

In one embodiment, the present invention provides a solid form containing the besylate salt of Compound 1, characterized by an XRPD diffractogram containing peaks at about 6.9, 7.8 and 8.5° 2θ. In one embodiment, the XRPD diffraction pattern contains peaks at about 6.9, 7.8, 8.5, 10.9 and 11.3° 2θ. In one embodiment, the XRPD diffraction pattern further contains peaks at about 6.9, 7.8, 8.5, 10.9, 11.3, 12.1 and 13.2° 2θ. In one embodiment, the XRPD diffraction pattern contains peaks at about 6.9, 7.8, 8.5, 10.9, 11.3, 12.1, 13.2, 14.6 and 15.1° 2θ.

In one embodiment, the present invention provides a solid form containing the besylate salt of Compound 1 having an XRPD diffraction pattern that corresponds to the XRPD diffraction pattern shown in FIG. 17.

In one embodiment, XRPD diffraction patterns are obtained using Cu Ka radiation.

A typical thermogravimetric analysis (TGA) thermogram of Compound 1 besylate salt Form A is shown in FIG. 18. In one embodiment, the present invention provides a solid form containing a besylate salt of Compound 1 that exhibits a weight loss of about 0.25% when heated from about 25°C to about 150°C. In one embodiment, the present invention provides a solid form containing the besylate salt of Compound 1 having a TGA thermogram that corresponds to the TGA thermogram shown in FIG. 18.

A typical differential scanning calorimetry (DSC) thermogram of Compound 1 besylate salt Form A is shown in FIG. 19. In one embodiment of the present invention

- 25 046479 we present a solid form containing the besylate salt of compound 1, which shows, according to DSC, a thermal effect (endo) with an initial temperature of about 164°C. In one embodiment, the thermal effect also has a peak temperature of about 175°C. In one embodiment, without being limited by any particular theory, the thermal effect corresponds to melting. In one embodiment, the present invention provides a solid form containing the besylate salt of Compound 1 having a DSC thermogram that corresponds to the DSC thermogram shown in FIG. 19.

In one embodiment, Compound 1 Besylate Salt Form A is prepared by adding benzenesulfonic acid to a solution of the free base of Compound 1 in a solvent, resulting in the precipitation of Compound 1 Besylate Salt Form A. In one embodiment, the solvent is acetone. In one embodiment, the solvent is MEK. In one embodiment, benzenesulfonic acid is added as a solution of MEK. In one embodiment, the present invention provides a solid form containing the besylate salt Form A of Compound 1 and one or more free base forms of Compound 1 (eg, an amorphous form and crystalline forms). In one embodiment, the present invention provides a solid form containing the besylate salt Form A of Compound 1 and an amorphous besylate salt of Compound 1. In one embodiment, the present invention provides a solid form containing the besylate salt Form A of Compound 1 and one or more other crystalline forms besylate salt of Compound 1. In one embodiment, the present invention provides a solid form comprising Form A of the besylate salt of Compound 1 and one or more forms (eg, amorphous or crystalline) of a salt of Compound 1 of the present invention.

5.3. Methods of application.

In one embodiment, the present invention provides a method of treating a hematologic malignancy that comprises administering to a patient a therapeutically effective amount of a solid form or salt of Compound 1 of the present invention.

In one embodiment, the present invention provides a method for preventing a hematologic malignancy, which includes administering to a patient a therapeutically effective amount of a solid form or salt of Compound 1 of the present invention.

In one embodiment, the present invention provides a method of regulating a hematologic malignancy, which includes administering to a patient a therapeutically effective amount of a solid form or salt of Compound 1 of the present invention.

In one embodiment, the hematologic malignancy is leukemia.

In one embodiment, the hematologic malignancy is acute myeloid leukemia. In one embodiment, the acute myeloid leukemia is B-cell acute myeloid leukemia.

In one embodiment, the hematologic malignancy is acute lymphoblastic leukemia.

In one embodiment, the hematologic malignancy is chronic lymphocytic leukemia/small cell lymphocytic lymphoma.

In one embodiment, the hematologic malignancy is myeloma.

In one embodiment, the hematologic malignancy is multiple myeloma. In one embodiment, the multiple myeloma is plasma cell leukemia (PCL).

In one embodiment, the hematologic malignancy is lymphoma.

In one embodiment, the hematologic malignancy is non-Hodgkin's lymphoma.

In one embodiment, the hematologic malignancy is diffuse large B-cell lymphoma.

In one embodiment, the hematologic 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 Sézary syndrome.

In one embodiment, the hematologic malignancy is Burkitt's lymphoma.

In one embodiment, the hematologic malignancy is marginal zone lymphoma. In one embodiment, marginal zone lymphoma

- 26 046479 is a splenic marginal zone lymphoma (SMZL).

In one embodiment, the hematologic malignancy is Hodgkin lymphoma.

In one embodiment, the hematologic malignancies are myelodysplastic syndromes.

In one embodiment, the hematologic malignancy is newly diagnosed. In one embodiment, the hematologic malignancy is recurrent or refractory.

In one embodiment, the AML is newly diagnosed AML. In one embodiment, the AML is relapsed or refractory AML. In one embodiment, the AML is newly diagnosed B cell AML. In one embodiment, B cell AML is relapsed or refractory B cell AML.

In one embodiment, the ALL is newly diagnosed ALL. In one embodiment, ALL is relapsed or refractory ALL.

In one embodiment, the MM is newly diagnosed MM. In one embodiment, the MM is relapsed or refractory MM. In one embodiment, the PCL is newly diagnosed PCL. In one embodiment, the PCL is relapsed or refractory PCL.

In one embodiment, the HL is newly diagnosed HL. In one embodiment, the HL is relapsed or refractory HL.

In one embodiment, the NHL is newly diagnosed NHL. In one embodiment, the NHL is relapsed or refractory NHL.

In one embodiment, the TCL is newly diagnosed TCL. In one embodiment, the TCL is relapsed or refractory TCL. In one embodiment, the ALCL is newly diagnosed ALCL. In one embodiment, the ALCL is relapsed or refractory ALCL. In one embodiment, Sezary syndrome is newly diagnosed Sezary syndrome. In one embodiment, Sezary syndrome is relapsed or refractory Sezary syndrome.

In one embodiment, the BL is newly diagnosed BL. In one embodiment, the BL is relapsed or refractory BL.

In one embodiment, the MZL is newly diagnosed MZL. In one embodiment, the MZL is relapsed or refractory MZL. In one embodiment, the SMZL is newly diagnosed SMZL. In one embodiment, the SMZL is relapsed or refractory SMZL.

In one embodiment, the MDS is newly diagnosed MDS. In one embodiment, the MDS is relapsed or refractory MDS.

In one embodiment, the present invention provides methods for achieving a complete response, partial response, or stable disease in a patient, comprising administering to a patient having a hematologic malignancy provided by the present invention a therapeutically effective amount of a solid form or salt of Compound 1 provided by the present invention. In one embodiment, the present invention provides methods for achieving an increase in overall survival, progression-free survival, event-free survival, time to disease progression, or disease-free survival in a patient, comprising administering to a patient having a hematologic malignancy of the present invention a therapeutically effective the amount of solid form or salt of compound 1 presented in the present invention. In one embodiment, the present invention provides methods for achieving an increase in overall survival in a patient, comprising administering to a patient having a hematologic malignancy provided by the present invention a therapeutically effective amount of a solid form or salt of Compound 1 provided by the present invention. In one embodiment, the present invention provides methods for achieving increased progression-free survival in a patient, comprising administering to a patient having a hematologic malignancy provided by the present invention a therapeutically effective amount of a solid form or salt of Compound 1 provided by the present invention. In one embodiment, the present invention provides methods for achieving increased event-free survival in a patient, comprising administering to a patient having a hematologic malignancy provided by the present invention a therapeutically effective amount of a solid form or salt of Compound 1 provided by the present invention. In one embodiment, the present invention provides methods for achieving an increase in time to disease progression in a patient, comprising:

- 27 046479 administering to a patient having a hematological malignancy of the present invention a therapeutically effective amount of a solid form or salt of Compound 1 of the present invention. In one embodiment, the present invention provides methods for achieving increased disease-free survival in a patient, comprising administering to a patient having a hematologic malignancy provided by the present invention a therapeutically effective amount of a solid form or salt of Compound 1 provided by the present invention. In one embodiment, the hematologic malignancy is AML (eg, B cell AML). In one embodiment, the hematologic malignancy is ALL. In one embodiment, the hematologic malignancy is CLL/SLL. In one embodiment, the hematologic malignancy is MM. In one embodiment, the hematologic malignancy is PCL. In one embodiment, the hematologic malignancy is NHL. In one embodiment, the hematologic malignancy is DLBCL. In one embodiment, the hematologic malignancy is a TCL (eg, ALCL or Sezary syndrome). In one embodiment, the hematologic malignancy is Burkitt's lymphoma. In one embodiment, the hematologic malignancy is HL. In one embodiment, the hematologic malignancy is MZL (eg, SMZL). In one embodiment, the hematologic malignancy is MDS. In one embodiment, the present invention provides a method of treating AML, comprising administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, the AML is B cell AML.

In one embodiment, the present invention provides a method for preventing AML, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, the AML is B cell AML.

In one embodiment, the present invention provides a method of regulating AML, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, the AML is B cell AML.

In one embodiment, the present invention provides a method of treating ALL, comprising administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein.

In one embodiment, the present invention provides a method for preventing ALL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein.

In one embodiment, the present invention provides a method of regulating ALL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein.

In one embodiment, the present invention provides a method of treating MM, comprising administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein.

In one embodiment, the present invention provides a method for preventing MM, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein.

In one embodiment, the present invention provides a method of regulating MM, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein.

In one embodiment, the present invention provides a method of treating PCL, comprising administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein.

In one embodiment, the present invention provides a method of preventing PCL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein.

In one embodiment, the present invention provides a method of regulating PCL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein.

In one embodiment, the present invention provides a method of treating TCL, comprising administering to a subject in need thereof a therapeutically effective amount of a solid

- 28 046479 doy form or salt of compound 1 presented in the present invention. In one embodiment, the TCL is ALCL. In one embodiment, TCL is Sézary syndrome. In one embodiment, the present invention provides a method for preventing TCL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, the TCL is ALCL. In one embodiment, TCL is Sézary syndrome. In one embodiment, the present invention provides a method of regulating TCL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, the TCL is ALCL. In one embodiment, TCL is Sézary syndrome. In one embodiment, the present invention provides a method of treating BL, comprising administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein.

In one embodiment, the present invention provides a method for preventing BL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein.

In one embodiment, the present invention provides a method of regulating BL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein.

In one embodiment, the present invention provides a method of treating HL, comprising administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein.

In one embodiment, the present invention provides a method for preventing HL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein.

In one embodiment, the present invention provides a method of regulating HL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein.

In one embodiment, the present invention provides a method of treating MZL, comprising administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, MZL is SMZL.

In one embodiment, the present invention provides a method of preventing MZL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, MZL is SMZL.

In one embodiment, the present invention provides a method of regulating MZL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, MZL is SMZL.

In one embodiment, the present invention provides a method of treating MDS, comprising administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein.

In one embodiment, the present invention provides a method for preventing MDS, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein.

In one embodiment, the present invention provides a method of regulating MDS, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein.

In one embodiment, the present invention provides methods of using a solid form or salt of Compound 1 of the present invention, alone or in combination with rituximab, for the treatment, prevention or management of non-Hodgkin's lymphoma (NHL).

In one embodiment, the present invention provides a method of treating NHL, comprising administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein.

In one embodiment, the present invention provides a method of preventing NHL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein.

In one embodiment, the present invention provides a method of regulating NHL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein.

- 29 046479

In one embodiment, the NHL is a DLBCL. In one embodiment, the DLBCL is a primary DLBCL. In one embodiment, the DLBCL is DLBCL with an activated B cell phenotype (ABC-DLBCL). In one embodiment, the DLBCL is germinal center B cell DLBCL (GCB-DLBCL). In one embodiment, the DLBCL is an unspecified DLBCL. In one embodiment, the DLBCL is primary mediastinal B-cell type DLBCL (PMBL DLBCL). In one embodiment, the DLBCL is double-hit DLBCL (DHIT DLBCL), also referred to as cMyc/Bcl-2 mutant DLBCL. In one embodiment, the DLBCL is triple-hit DLBCL (THIT DLBCL) (with three translocations), also referred to as cMyc/Bc12/Bc16 rearranged DLBCL.

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

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

In one embodiment, the NHL is a primary central nervous system lymphoma (PCNSL).

In some embodiments, the NHL is relapsed or refractory NHL. In one embodiment, the NHL is recurrent NHL. In one embodiment, the NHL is refractory NHL.

In some embodiments, the subject with NHL has radiographic evidence of progression after achieving a complete response (CR). In some embodiments, the subject with NHL has achieved less than a CR on the most recent systemic therapy containing the regimen and has radiographic evidence of active disease or disease progression or relapse 12 months or less prior to stem cell transplantation (SCT).

In some embodiments, the subject with NHL has failed one or more lines of therapy and is not a candidate for another therapy. In some embodiments, the subject has received at least one prior treatment and is not suitable for any therapy other than the methods of treatment described in the present invention. In some embodiments, the subject has relapsed or progressed following standard anticancer therapy.

In some embodiments, the subject has failed at least one prior therapy. In some embodiments, the subject has failed at least two prior therapies.

In one embodiment, NHL is relapsed or refractory DLBCL. In one embodiment, the DLBCL is recurrent DLBCL. In one embodiment, the DLBCL is refractory DLBCL. In one embodiment, the DLBCL is relapsed/refractory DLBCL. In one embodiment, DLBCL is refractory to doxorubicin treatment. In one embodiment, DLBCL is resistant to doxorubicin. In one embodiment, DLBCL is resistant to one or more of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide, bendamustine, lenalidomide, gemcitabine, dexamethasone, ifosfamide, polatuxumab, or CAR-T.

In one embodiment, DLBCL is treated with two or more prior lines of therapy.

In one embodiment, DLBCL is a transformed lymphoma. In another embodiment, the DLBCL is a non-specific (NOS) DLBCL.

In one embodiment, NHL is relapsed or refractory FL. In one embodiment, the FL is recurrent FL. In one embodiment, the FL is refractory FL.

In one embodiment, FL is treated with one or more prior lines of therapy. In one embodiment, FL is treated with two or more prior lines of therapy.

In one embodiment, NHL is relapsed or refractory MCL. In one embodiment, the MCL is recurrent MCL. In one embodiment, the MCL is refractory MCL.

In one embodiment, the MCL is treated with one or more prior lines of therapy. In one embodiment, MCL is treated with two or more prior lines of therapy.

In one embodiment, NHL is relapsed or refractory PCNSL. In one embodiment, the PCNSL is recurrent PCNSL. In one embodiment, the PCNSL is a refractory PCNSL.

In some embodiments, the NHL is newly diagnosed NHL. In some embodiments, NHL is a newly diagnosed diffuse large B cell lymphoma. In some embodiments, the NHL is a newly diagnosed follicular lymphoma. In some embodiments, NHL is a newly diagnosed mantle cell lymphoma. In some embodiments, NHL is a newly diagnosed primary central nervous system lymphoma.

In some embodiments, the methods presented in the present invention additionally

- 30 046479 specifically include administering to a subject a therapeutically effective amount of rituximab.

In one embodiment, the first therapy provided in the present invention (for example, an agent, such as a solid form or salt of Compound 1 provided in the present invention) is administered to the subject before (for example, 5, 15, 30, 45 minutes, 1, 2, 4, 6, 12, 24, 48, 72, 96 hours, 1, 2, 3, 4, 5, 6, 8, or 12 weeks) of second therapy (eg, rituximab).

In one embodiment, the first therapy provided in the present invention (eg, an agent, such as a solid form or salt of Compound 1 provided in the present invention) is administered to a subject simultaneously with the administration of a second therapy (eg, rituximab).

In one embodiment, the first therapy provided in the present invention (for example, an agent such as a solid form or salt of Compound 1 provided in the present invention) is administered to the subject after (for example, 5, 15, 30, 45 minutes, 1, 2, 4, 6, 12, 24, 48, 72, 96 hours, 1, 2, 3, 4, 5, 6, 8, or 12 weeks) of second therapy (eg, rituximab).

In some embodiments, rituximab is administered in accordance with locally approved guidelines for use or pharmaceutical guidelines containing information regarding preparation, administration, and storage. In some embodiments, rituximab is administered intravenously. In some embodiments, rituximab is administered subcutaneously. In some embodiments, rituximab is administered by intravenous injection or intravenous infusion. In some embodiments, rituximab is administered by intravenous infusion. In some embodiments, rituximab is administered in an amount as determined by the physician. In some embodiments, rituximab is administered once or twice daily. In some embodiments, rituximab is administered in an amount of from about 50 mg/ ^m2 to about 1000 mg/ ^m2 , from about 100 mg/ ^m2 to about 750 mg/ ^m2 , from about 250 mg/ ^m2 to about 500 mg/m2. m ² or from about 300 mg/m ² to about 400 mg/m ² . In some embodiments, rituximab is administered in an amount of 375 mg/m ² per day.

In one embodiment, the present invention provides a method of treating DLBCL that includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, the method further includes administering to the subject a therapeutically effective amount of rituximab.

In one embodiment, the present invention provides a method of preventing DLBCL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, the method further includes administering to the subject a therapeutically effective amount of rituximab.

In another embodiment, the present invention provides a method of regulating DLBCL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, the method further includes administering to the subject a therapeutically effective amount of rituximab.

In one embodiment, the present invention provides a method of treating FL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, the method further includes administering to the subject a therapeutically effective amount of rituximab.

In one embodiment, the present invention provides a method for preventing FL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, the method further includes administering to the subject a therapeutically effective amount of rituximab.

In another embodiment, the present invention provides a method of regulating FL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 of the present invention. In one embodiment, the method further includes administering to the subject a therapeutically effective amount of rituximab.

In one embodiment, the present invention provides a method of treating MCL that includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, the method further includes administering to the subject a therapeutically effective amount of rituximab.

In one embodiment, the present invention provides a method for preventing MCL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, the method further includes administering to the subject a therapeutically effective

- 31,046,479 new quantities of rituximab.

In another embodiment, the present invention provides a method of regulating MCL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, the method further includes administering to the subject a therapeutically effective amount of rituximab.

In one embodiment, the present invention provides a method of treating PCNSL that includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, the method further includes administering to the subject a therapeutically effective amount of rituximab.

In one embodiment, the present invention provides a method for preventing PCNSL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, the method further includes administering to the subject a therapeutically effective amount of rituximab.

In another embodiment, the present invention provides a method of regulating PCNSL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 of the present invention. In one embodiment, the method further includes administering to the subject a therapeutically effective amount of rituximab.

In one embodiment, the present invention provides a method of treating relapsed or refractory DLBCL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, the method further includes administering to the subject a therapeutically effective amount of rituximab.

In one embodiment, the present invention provides a method of preventing relapsed or refractory DLBCL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, the method further includes administering to the subject a therapeutically effective amount of rituximab.

In another embodiment, the present invention provides a method of regulating relapsed or refractory DLBCL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, the method further includes administering to the subject a therapeutically effective amount of rituximab.

In one embodiment, the present invention provides a method of treating relapsed or refractory FL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, the method further includes administering to the subject a therapeutically effective amount of rituximab.

In one embodiment, the present invention provides a method of preventing relapsed or refractory FL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, the method further includes administering to the subject a therapeutically effective amount of rituximab.

In another embodiment, the present invention provides a method of regulating relapsed or refractory FL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, the method further includes administering to the subject a therapeutically effective amount of rituximab.

In one embodiment, the present invention provides a method of treating relapsed or refractory MCL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, the method further includes administering to the subject a therapeutically effective amount of rituximab.

In one embodiment, the present invention provides a method for preventing relapsed or refractory MCL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, the method further includes administering to the subject a therapeutically effective amount of rituximab.

In another embodiment, the present invention provides a method for controlling

- 32046479 recurrent or refractory MCL, which comprises administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 of the present invention. In one embodiment, the method further includes administering to the subject a therapeutically effective amount of rituximab.

In one embodiment, the present invention provides a method of treating relapsed or refractory PCNSL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, the method further includes administering to the subject a therapeutically effective amount of rituximab.

In one embodiment, the present invention provides a method of preventing relapsed or refractory PCNSL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, the method further includes administering to the subject a therapeutically effective amount of rituximab.

In another embodiment, the present invention provides a method of managing relapsed or refractory PCNSL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, the method further includes administering to the subject a therapeutically effective amount of rituximab.

In another embodiment, the present invention provides methods for achieving a complete response, partial response, or stable disease, as determined by a Lugano response criterion in a patient, comprising administering a therapeutically effective amount of a solid form or salt of Compound 1 of the present invention to a patient with NHL . In another embodiment, the present invention provides methods for achieving an increase in overall survival, progression-free survival, event-free survival, time to disease progression, or disease-free survival in a patient, comprising administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein , a patient with NHL. In another embodiment, the present invention provides methods for achieving an increase in overall survival in a patient, comprising administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein to a patient with NHL. In another embodiment, the present invention provides methods for achieving increased progression-free survival in a patient, comprising administering a therapeutically effective amount of a solid form or salt of Compound 1 of the present invention to a patient with NHL. In another embodiment, the present invention provides methods for achieving increased event-free survival in a patient, comprising administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein to a patient with NHL. In another embodiment, the present invention provides methods for achieving an increase in time to disease progression in a patient, comprising administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein to a patient with NHL. In another embodiment, the present invention provides methods for achieving increased disease-free survival in a patient, comprising administering a therapeutically effective amount of a solid form or salt of Compound 1 of the present invention to a patient with NHL. In one embodiment, the methods further comprise administering to the subject a therapeutically effective amount of rituximab. In one embodiment, the present invention provides methods of using a solid form or salt of Compound 1 of the present invention, alone or in combination with obinutuzumab, for the treatment, prevention or management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

In the context of this invention and unless otherwise indicated, CLL/SLL or CLL and/or SLL means CLL or SLL or CLL and SLL. In one embodiment, the methods presented herein are for treating, preventing, or regulating CLL. In one embodiment, the methods presented herein are for treating, preventing, or regulating SLL. In one embodiment, the methods presented herein are for treating, preventing, or regulating CLL and CLL.

In one embodiment, the present invention provides a method of treating CLL/SLL, comprising administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 of the present invention.

In one embodiment, the present invention provides a method for preventing CLL/SLL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein.

In one embodiment, the present invention provides a method for controlling

- 33 046479

CLL/SLL, which comprises administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 of the present invention.

In one embodiment, a subject with CLL/SLL 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 inhibitor (BTK). 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.

In one embodiment, the CLL/SLL is newly diagnosed CLL/SLL. In one embodiment, the CLL/SLL is relapsed or refractory CLL/SLL (R/R CLL/SLL).

In one embodiment, CLL is characterized by an IGHV (immunoglobulin heavy chain gene) mutation. In one embodiment, CLL is characterized by unmutated IGHV status.

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.

In one embodiment, CLL is characterized by one or more cytogenetic abnormalities, for example, 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).

In one embodiment, CLL is characterized by Richter's transformation (also known as Richter's syndrome).

In one embodiment, the methods provided herein further comprise administering to a subject a therapeutically effective amount of obinutuzumab.

In one embodiment, the first therapy (e.g., an agent such as a solid form or salt of Compound 1 of the present invention) provided herein is administered to the subject before (e.g., 5, 15, 30, 45 minutes, 1, 2, 4, 6, 12, 24, 48, 72, 96, 120, 144 hours, 1, 2, 3, 4, 5, 6, 8, or 12 weeks) by introducing a second therapy (eg, obinutuzumab).

In one embodiment, the first therapy (eg, an agent such as a solid form or salt of Compound 1 of the present invention) provided in the present invention is administered to a subject simultaneously with the administration of a second therapy (eg, obinutuzumab).

In one embodiment, the first therapy (e.g., an agent such as a solid form or salt of Compound 1 of the present invention) provided herein is administered to a subject sequentially (e.g., 5, 15, 30, 45 minutes, 1, 2, 4, 6, 12, 24, 48, 72, 96, 120, 144 hours, 1, 2, 3, 4, 5, 6, 8, or 12 weeks) with the introduction of a second therapy (eg, obinutuzumab).

In one embodiment, administer in accordance with locally approved recommendations for use or pharmaceutical guidelines containing information regarding preparation, administration, and storage. In some embodiments, obinutuzumab is administered intravenously. In some embodiments, obinutuzumab is administered subcutaneously. In some embodiments, obinutuzumab is administered by intravenous injection or intravenous infusion. In some embodiments, obinutuzumab is administered by intravenous injection. In some embodiments, obinutuzumab is administered by intravenous infusion.

In one embodiment, obinutuzumab is administered in an amount as determined by the physician. In one embodiment, obinutuzumab is administered once daily. In one embodiment, obinutuzumab is administered at a dose of about 75 mg to about 1100 mg per day. In one embodiment, obinutuzumab is administered at a dose of about 75 mg to about 125 mg per day, about 800 mg to about 1000 mg per day, or about 900 mg to about 1100 mg per day. In one embodiment, obinutuzumab is administered at a dose of about 100 mg per day. In one embodiment, obinutuzumab is administered at a dose of about 900 mg per day. In one embodiment, obinutuzumab is administered at a dose of about 1000 mg per day. 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 each of days 8 and 15 of the first 28 days. -day cycle and on day 1 from the second to the sixth 28-day cycle. In one embodiment, obinutuzumab is administered at a dose of about 1000 mg on days 1 and 2 of the first 28-day cycle and about 1000 mg on each of the 8th and 15th days of the first 28-day cycle and 1 day on the second to sixth 28-day cycle . Obinutuzumab may be administered in more than six cycles. In one embodiment, obinutuzumab is administered in the first 28-day cycle as described herein, and is administered at a dose of about 1000 mg on day 1 of the second to twelfth 28-day cycle. In one embodiment, obinutuzumab is administered in the first 28-day cycle as described herein, and is administered at a dose of about 1000 mg on day 1 of the second to twenty-fourth 28-day cycle. In one embodiment, obinutuzumab is administered in the first 28-day cycle as described herein, and is administered at a dose of about 1000 mg on Day 1 of subsequent 28-day cycles until disease progression.

- 34 046479

In one embodiment, the present invention provides a method of treating newly diagnosed CLL/SLL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, the method further includes administering to the subject a therapeutically effective amount of obinutuzumab.

In one embodiment, the present invention provides a method of preventing newly diagnosed CLL/SLL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, the method further includes administering to the subject a therapeutically effective amount of obinutuzumab.

In another embodiment, the present invention provides a method of regulating newly diagnosed CLL/SLL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 of the present invention. In one embodiment, the method further includes administering to the subject a therapeutically effective amount of obinutuzumab.

In one embodiment, the present invention provides a method of treating relapsed or refractory CLL/SLL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, the method further includes administering to the subject a therapeutically effective amount of obinutuzumab.

In one embodiment, the present invention provides a method for preventing relapsed or refractory CLL/SLL, which includes administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 provided herein. In one embodiment, the method further includes administering to the subject a therapeutically effective amount of obinutuzumab.

In another embodiment, the present invention provides a method of regulating relapsed or refractory CLL/SLL, which comprises administering to a subject in need thereof a therapeutically effective amount of a solid form or salt of Compound 1 of the present invention. In one embodiment, the method further includes administering to the subject a therapeutically effective amount of obinutuzumab.

In another embodiment, the present invention provides methods for achieving a complete response, partial response, or stable disease, as defined by the International Workshop on Criteria for Chronic Lymphocytic Leukemia in a patient, comprising administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein to a patient with CLL/SLL. In one embodiment, minimal residual disease (MRD) determination may be performed in subjects who have undergone bone marrow evaluation to confirm complete response (CR). In one embodiment, the present invention provides methods for achieving minimal residual disease (MRD) negativity in a patient, comprising administering a therapeutically effective amount of a 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 lasts for at least 3 months. In another embodiment, the present invention provides methods for achieving an increase in overall survival, progression-free survival, event-free survival, time to disease progression, or disease-free survival in a patient, comprising administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein , a patient with CLL/SLL. In another embodiment, the present invention provides methods for achieving an increase in overall survival in a patient, comprising administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein to a patient with CLL/SLL. In another embodiment, the present invention provides methods for achieving increased progression-free survival in a patient, comprising administering a therapeutically effective amount of a solid form or salt of Compound 1 of the present invention to a patient with CLL/SLL. In another embodiment, the present invention provides methods for achieving increased event-free survival in a patient, comprising administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein to a patient with CLL/SLL. In another embodiment, the present invention provides methods for achieving an increase in time to disease progression in a patient, comprising administering a therapeutically effective amount of a solid form or salt of Compound 1 of the present invention to a patient with CLL/SLL. In another embodiment, the present invention provides methods for achieving increased disease-free survival in a patient, comprising administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein

- 35 046479 invention, for a patient with CLL/SLL. In one embodiment, the methods further comprise administering to the subject a therapeutically effective amount of obinutuzumab.

The methods presented in the present invention cover the treatment of a patient regardless of the age of the patient. In some embodiments, the subject is 18 years of age or older. In other embodiments, the subject is over 18, 25, 35, 40, 45, 50, 55, 60, 65, or 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.

Also provided by the present invention is a solid form or salt of Compound 1 for use in a method of treating a disease of the present invention, wherein the method includes administering to a patient a therapeutically effective amount of a solid form or salt of Compound 1. Also provided by the present invention is a pharmaceutical composition comprising a solid form or a salt of compound 1, for use in the method of treating the disease presented in the present invention.

5.4. Pharmaceutical compositions and routes of administration.

The solid forms or salts of Compound 1 provided in the present invention can be administered to a subject orally, topically or parenterally in conventional dosage forms such as capsules, microcapsules, tablets, granules, powder, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions. Suitable formulations can be prepared by conventional methods using conventional organic or inorganic additives such as a diluent (for example, sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), a binder (for example, cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose or starch), disintegrant (e.g. starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate or calcium citrate), lubricant (e.g. stearate magnesium, light anhydrous silicic acid, talc or sodium lauryl sulfate), flavoring (such as citric acid, menthol, glycine or orange powder), preservative (such as sodium benzoate, sodium bisulfite, methylparaben or propylparaben), stabilizer (such as citric acid , sodium citrate or acetic acid), a suspending agent (for example, methylcellulose, polyvinylpyrrolidone or aluminum stearate), a dispersing agent (for example, hydroxypropyl methylcellulose), water and a base wax (for example, cocoa butter, white petrolatum or polyethylene glycol). The effective amount of the compounds in the pharmaceutical composition may be at a level that will produce the desired effect when administered either orally or parenterally.

The solid form or salt of Compound 1 provided in the present invention can be administered orally. In one embodiment, when administered orally, the solid form or salt of Compound 1 of the present invention is administered with food and water. In another embodiment, the solid form or salt of Compound 1 of the present invention is dispersed in water or juice (eg, apple or orange juice) and administered orally as a solution or suspension.

The solid form or salt of Compound 1 of the present invention may also be administered intradermally, intramuscularly, intraperitoneally, transdermally, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, transmucosally, by inhalation or topically. in the ears, nose, eyes or on the skin. The route of administration is at the discretion of the attending physician and may depend in part on the medical indication. In one embodiment, the present invention provides capsules containing a solid form or salt of Compound 1 of the present invention, without additional excipient. In another embodiment, the present invention provides compositions comprising an effective amount of a solid form or salt of Compound 1 of the present invention and a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient may include a diluent, a binder, a disintegrant, a glidant, a lubricant or a mixture of them. In one embodiment, the composition is a pharmaceutical composition.

The compositions may be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, troches, suppositories and suspensions, and the like. The compositions may be formulated to contain a daily dose or a convenient portion of a daily dose in a dosage unit, which may be a single tablet or capsule or a convenient volume of liquid. In one embodiment, solutions are prepared from water-soluble salts. Typically, all compositions are prepared in accordance with techniques known in pharmaceutical chemistry. Capsules can be prepared by mixing the solid form or salt of Compound 1 of the present invention with a suitable excipient and filling the capsules with an appropriate amount of the mixture. Common excipients include, but are not limited to, inert

- 36 046479 powdered substances such as starch of many different types, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, cereal flour and similar food powders. Capsule filling can also be obtained by wet granulation or dry granulation.

A lubricant may be necessary in the capsule formulation to prevent the powder from sticking to the packing pin. The lubricant may be selected from such lubricant solids as talc, magnesium calcium stearate, sodium stearyl fumarate, stearic acid and hydrogenated vegetable oils. Disintegrants are substances that swell when wetted to break the capsule and release the compound. These include starches, clays, celluloses, crospovidone, croscarmellose sodium, sodium starch glycolate, algins and gums. More specifically, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose, as well as sodium lauryl sulfate can be used. Glidants may also be used, including silica, talc and calcium silicate. Tablets can be prepared by direct compression, wet granulation or dry granulation. Their formulations typically include diluents, binders, lubricants and disintegrants, as well as a compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also suitable. Typical tablet binders are starch, gelatin and sugars such as lactose, fructose, glucose, etc. Natural and synthetic gums are also suitable, including gum acacia, alginates, methylcellulose, polyvinylpyrrolidine, and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

A lubricant may be necessary in the tablet formulation to prevent the tablet and punches from getting stuck in the die. The lubricant may be selected from such lubricant solids as talc, magnesium calcium stearate, sodium stearyl fumarate, stearic acid and hydrogenated vegetable oils. Tablet disintegrants are substances that swell when wetted, breaking the tablet and releasing the compound. These include starches, clays, celluloses, crospovidone, croscarmellose sodium, sodium starch glycolate, algins and gums. More specifically, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose, as well as sodium lauryl sulfate can be used. Glidants may also be used, including silica, talc and calcium silicate. Tablets may be coated with sugar as a flavoring and sealant or with film-forming protective agents to modify the dissolution properties of the tablet. The compositions may also be formulated as chewable tablets, for example containing substances such as mannitol.

When it is desired to administer the solid form or salt of Compound 1 of the present invention as a suppository, typical bases may be used. Cocoa butter is a traditional suppository base that can be modified by adding waxes to slightly increase its melting point. Water-miscible suppository bases containing, in particular, polyethylene glycols with different molecular weights are widely used. The effect of the solid form or salt of Compound 1 of the present invention can be delayed or prolonged by suitable formulation. For example, a slowly dissolving solid form or salt granule of Compound 1 of the present invention may be prepared and contained in a tablet or capsule, or may be in the form of a sustained release implantable device. The technique also involves making granules with several different dissolution rates and filling capsules with a mixture of granules. Tablets or capsules may be coated with a film to prevent dissolution for a predictable period of time. Even parenteral drugs can be formulated with sustained release by dissolving or suspending the solid or salt form of Compound 1 of the present invention in oily or emulsified vehicles that allow it to be slowly dispersed in serum.

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 in the present invention may be administered orally, parenterally (eg, intramuscularly, intraperitoneally, intravenously, CIV, by intracisternal injection or infusion, subcutaneous injection or implant), inhalation, nasal, vaginal, rectal, sublingual, or external (eg, transdermal or topical) routes of administration. The solid form or salt of Compound 1 of the present invention may be formulated separately or together in a suitable dosage unit with pharmaceutically acceptable excipients, carriers, adjuvants and media suitable for each route of administration.

In one embodiment, a solid form or salt of Compound 1 presented in an infusion

- 37 046479 according to the invention, administered orally. In another embodiment, the solid form or salt of Compound 1 of the present invention is administered parenterally. In yet another embodiment, the solid form or salt of Compound 1 of the present invention is administered intravenously. The solid form or salt of Compound 1 of the present invention may be delivered in a single dose, such as, for example, a single bolus injection or oral capsules, tablets or pills; or over time, for example, as a continuous infusion over time or divided bolus doses over time. The solid form or salt of Compound 1 of the present invention may be re-administered as needed, for example, until the patient experiences disease stabilization or regression, or until the patient experiences disease progression or unacceptable toxicity. The solid form or salt of Compound 1 of the present invention may be administered once daily (QD) or may be divided into multiple daily doses such as twice daily (BID), three times daily (TID), and four once a day (QID). In addition, administration may be continuous (ie, daily for consecutive days or every day), intermittent, such as in cycles (ie, including days, weeks or months of rest without drug). In the context of the present invention, the term daily is intended to mean that a therapeutic compound, such as a solid form or salt of Compound 1 provided in the present invention, is administered once or more per day, for example, over a period of time. The term continuous is intended to mean that a therapeutic compound, such as a solid form or salt of Compound 1 of the present invention, is administered daily for a continuous period of at least 7 days to 52 weeks. The term periodic or periodic, in the context of this invention, is intended to mean stopping and starting at either regular or irregular intervals. For example, periodic administration of the solid form or salt of Compound 1 of the present invention is administration for one to six days per week, administration in cycles (e.g., daily administration for two to eight consecutive weeks, then a rest period without administration up to one week), or administration every other day. The term intravenous administration, in the context of this invention, is intended to mean that a therapeutic compound, such as a solid form or salt of Compound 1 of the present invention, is administered daily or continuously, but with a rest period.

In some embodiments, the frequency of administration ranges from about a daily dose to about a monthly dose. In some embodiments, administration is once daily, twice daily, three times daily, four times daily, once every other day, twice weekly, once weekly, once every two weeks, once every three weeks or once every four weeks. In one embodiment, the solid form or salt of Compound 1 of the present invention is administered once daily. In another embodiment, the solid form or salt of Compound 1 of the present invention is administered twice daily. In yet another embodiment, the solid form or salt of Compound 1 of the present invention is administered three times daily. In yet another embodiment, the solid form or salt of Compound 1 of the present invention is administered four times daily.

In some embodiments, the methods provided herein include administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein in one or more 7-day treatment cycles. In another embodiment, the methods provided herein include administering a therapeutically effective amount of a solid form or salt of Compound 1 of the present invention on days 1 to 5 of a 7-day cycle. In another embodiment, the methods provided herein include administering a therapeutically effective amount of a solid form or salt of Compound 1 of the present invention on days 1 to 3 of a 7-day cycle. In some embodiments, the methods provided herein include administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein in one or more 14-day treatment cycles. In another embodiment, the methods provided in the present invention include administering a therapeutically effective amount of a solid form or invention, on days 1 to 7 of a 14-day cycle. In another embodiment, the methods provided herein include administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein on days 1 through 10 of a 14-day salt form of Compound 1 provided herein. In some embodiments, the methods provided herein include administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein in one or more 28-day treatment cycles. In another embodiment, the methods provided herein include administering a therapeutically effective amount of a solid form or salt of Compound 1 of the present invention on days 1 to 21 of a 28-day cycle. In another embodiment, the methods provided in the present invention include administering a therapeutically effective amount of solid

- 38 046479 form or salt of compound 1 presented in the present invention, on days 1 to 5, days 8 to 12, days 15 to 19 and days 22 to the 26th of a 28-day cycle. In another embodiment, the methods provided herein include administering a therapeutically effective amount of a solid form or salt of Compound 1 provided herein on days 1 through 10 and days 15 through 24. daily cycle.

In one embodiment, the solid form or salt of Compound 1 of the present invention is administered once daily for 5 days followed by 2 days of rest. In one embodiment, the solid form or salt of Compound 1 of the present invention is administered once daily for 3 days followed by 4 days of rest. In one embodiment, the solid form or salt of Compound 1 of the present invention is administered once daily for 7 days followed by 7 days of rest. In one embodiment, the solid form or salt of Compound 1 of the present invention is administered once daily for 10 days followed by 4 days of rest. In one embodiment, the solid form or salt of Compound 1 of the present invention is administered once daily for 21 days followed by 7 days of rest.

In some 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 the first 28-day cycle, administered on day 1 of the second to sixth 28-day cycles, and then administered once every 8 weeks. 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 every 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 is administered on day 1 of the second through sixth 28-day cycles. In one embodiment, obinutuzumab is administered on day 1 of 2 to 12 of a 28-day cycle. In one embodiment, obinutuzumab is administered on day 1 of days 2 to 24 of 28-day cycles. In one embodiment, obinutuzumab is administered on day 1 of subsequent 28-day cycles until disease progression.

In one embodiment, obnutinuzumab 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 each of days 8 and 15 of the first 28-day cycle. cycle. In one embodiment, obinutuzumab is administered at a dose of about 1000 mg on days 1 and 2 of the first 28-day cycle and about 1000 mg on each of days 8 and 15 of the first 28-day cycle. In one embodiment, obinutuzumab is administered at a dose of about 1000 mg on day 1 of the second to sixth 28-day cycles. In one embodiment, obinutuzumab is administered at about 1000 mg on day 1 of the second through 12th 28-day cycles. In one embodiment, obinutuzumab is administered at about 1000 mg on day 1 of the second to 24th 28-day cycle. In one embodiment, obinutuzumab is administered at about 1000 mg on day 1 of subsequent 28-day cycles until disease progression.

Any treatment cycle described in the present invention can 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 some cases, the treatment cycle described herein includes from 1 to about 24 cycles, from about 2 cycles to about 16 cycles, or from about 2 cycles to about 4 cycles. In some cases, the treatment cycle described herein ranges from 1 cycle to about 4 cycles. In some embodiments, a therapeutically effective amount of a solid form or salt of Compound 1 of the present invention and/or rituximab is administered over 1 to 13 cycles of 28 days (eg, about 1 year). In some embodiments, a therapeutically effective amount of a solid form or salt of Compound 1 of the present invention and/or rituximab is administered over 1 to 24 cycles of 28 days (eg, about 2 years). In some embodiments, a therapeutically effective amount of a solid form or salt of Compound 1 of the present invention and/or obinutuzumab is administered over 1 to 13 cycles of 28 days (eg, about 1 year). In some embodiments, a therapeutically effective amount of a solid form or salt of Compound 1 of the present invention and/or obinutuzumab is administered over 1 to 24 cycles of 28 days (eg, about 2 years). In some cases, cyclic therapy is not limited to the number of cycles and continues until the disease progresses. Cycles may in some cases include varying the length of the administration periods and/or rest periods described in the present invention.

6. Examples

Some embodiments of the invention are illustrated by the following non-limiting examples.

- 39 046479

Abbreviations used

ACN Acetonitrile API Active Pharmaceutical Ingredient DCM Dichloromethane DIEA N,N-diisopropylethylamine DMAc Dimethylacetamide DMSO Dimethyl sulfoxide ESI Electrospray ionization Et ₂ O Diethyl ether EtOAc Ethyl acetate EtOH Ethanol HOPE High Density Polyethylene LCMS Liquid chromatography-mass spectrometry LDPE Low density polyethylene MEK Methyl ethyl ketone MeOH Methanol 2-MeTHF 2-Methyltetrahydrofuran MS Mass spectrometry MTBE Methyl tert-butyl ether NMP N-methylpyrrolidone NMR Nuclear magnetic resonance 2-PrOH 2-Propanol RH Relative humidity THF T ethrahydrofuran

6.1. Synthesis of ^)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1, 3-diones (compound 1)

^)-2-(2,6-Dioxopiperidin-3-yl)-4-((2-fluoro-4-(hydroxymethyl)benzyl)amino)isoindoline-1,3-dione.

Suspension of ^)-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 2:1 dioxane-MeOH (75 ml) was cooled to 0°C and B ₁₀ H ₁₄ (4.92 g, 40.3 mmol) was added in small portions over 5 min. The reaction flask was equipped with a membrane and needle valve (pressure) and stirred vigorously for 10 min. The mixture was allowed to warm to 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 give ^)-2-(2,6-dioxopiperidine-3- yl)-4-((2-fluoro-4-(hydroxymethyl)benzyl)amino)isoindoline1,3-dione as a yellow solid (4.23 g, 56%).

LC-MS (ESI) m/z 411.8 [M+H]+.

^)-4-((4-(Chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione.

A solution of ^)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro-4-(hydroxymethyl)benzyl)amino)isoindoline1,3-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 mixture was allowed to warm to ambient temperature and stirred for 18 hours. The reaction mixture was slowly added to H2O (60 ml), cooled to 0°C, with vigorous stirring. The resulting suspension was filtered and the collected solid was washed with H2O and Et ₂ O. The solid was dissolved in EtOAc and the solution was dried over MgSO ₄ , filtered and concentrated to give ^)-4-((4-(chloromethyl)-2- fluorobenzyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione as a yellow solid (0.600 g, 79%).

LC-MS (ESI) m/z 430.0 [M+H] ⁺ .

- 40 046479

^)-2-(2,6-Dioxopiperidin-3-yl)-4-((2-fluoro-4-((3-morpholinoazetidin-1-yl)methyl)benzyl)amino)isoindoline-1,3-dione .

To a solution of ^)-4-((4-(chloromethyl)-2-fluorobenzyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline1,3-dione (300 mg, 0.698 mmol) in dry DMSO (1.0 ml) 4-(azetidin-3-yl)morpholine hydrochloride (125 mg, 0.698 mmol) and DIEA (0.122 ml, 0.698 mmol) were added. 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 give ^)-2-(2,6-dioxopiperidin-3-yl)-4-((2-fluoro4-((3-morpholinoazetidin-1-yl)methyl)benzyl) amino)isoindoline-1,3-dione (89 mg, 24%, 97% e.i.).

LC-MS (ESI) m/z 536.2 [M+H]+.

6.2. Cellular assay using compound 1.

The following are examples of cellular assays that can be used to determine the antiproliferative activity and apoptotic effects of Compound 1 using typical non-Hodgkin's lymphoma (NHL) cell lines.

Cell proliferation and viability assay using the SU-DHL-4 cell line.

The following exemplary assay used a DLBCL cell line, for example the SU-DHL-4 cell line (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH [DSMZ]: catalog number ACC-495) 120 hours after treatment. The seeding density for SU-DHL-4 can be optimized to ensure linearity in 1536-well plates.

Increasing concentrations (from 0.5 nM to 10 μM) of compound 1 were applied using a 20-point dilution method (unevenly spaced data points) using an acoustic pipette (EDC ATS-100) into an empty 1536-well plate. The DMSO concentration was kept constant for a final assay concentration of 0.1% DMSO. Before testing, SU-DHL-4 cells were grown in RPMI-1640 medium (Roswell Park Memorial Institute - 1640) with 10% FBS (fetal bovine serum: HyClone) and expanded in culture flasks to obtain sufficient starting material. Cells were then diluted to 500 cells per well in a volume of 5 μl and added directly to 1536-well plates spot-coated with compound. Cells were allowed to grow for 120 h in an atmosphere of 5% CO2 at 37°C. At the onset of cell exposure to the compound (t0), the initial number of viable cells was assessed using the Cell Titer-Glo® Luminescent Cell Viability Assay at a 1:2 vol ratio. according to the manufacturer's instructions (Promega Corporation, Madison, WI) by quantifying the level of luminescence caused by adenosine 5'-triphosphate (ATP) present in viable cells. After 120 h, the viability of the treated cells was assessed using Cell Titer-Glo® and luminescence was read. All growth inhibition curves were processed and evaluated using Activity Base (IDBS, Alameda, CA). Cell viability _IC50 values were calculated using a four-parameter logistic model (sigmoidal dose-response model):

y=(A+((B-A)/(1+((C/x)%)), where A=Ym _ln ;

B=Ymax;

c=eC5o;

D=Hill coefficient;

^^compound concentration at Y=50% DMSO control;

Y=cell viability measured as luminescence unit; and x=compound concentration.

Compound 1 was found to be active in the SU-DHL-4 cell proliferation assay with an IC ₅₀ <0.2 μM.

Analysis of cell proliferation and viability using hematological cell lines.

The following exemplary antiproliferative assay used exemplary hematological cell lines. The in vitro growth inhibitory activity of Compound 1 described herein was assessed using 384-well flow cytometry.

- 41 046479

Table 6

Hematological cell lines

Cell line Tumor type Tumor subtype Cultivation conditions ULA DLBCL no specifications RPMI + 10% FBS, IX NEAA, 2 mM Lglutamine SU-DHL-5 DLBCL no specifications OCI-LY18 DLBCL no specifications TMD8 DLBCL ABC SU-DHL-2 DLBCL ABC Farage DLBCL PMBL SU-DHL-10 DLBCL GCB NU-DHL-1 DLBCL GCB VAL DLBCL no specifications WILL-2 DLBCL no specifications SU-DHL-6 DLBCL GCB KARPAS-422 DLBCL GCB NU-DUL-1 DLBCL ABC KARPAS-1106P DLBCL PMBL OCI-LY1 DLBCL GCB SU-DHL-1 DLBCL no specifications WSU-DLCL2 DLBCL GCB STR428 DLBCL no specifications U-2946 DLBCL no specifications U-2940 DLBCL PMBL OCI-LY-19 DLBCL GCB CARNAVAL DLBCL no specifications Toledo DLBCL GCB RC-K8 DLBCL ABC SU-DHL-8 DLBCL GCB OCLLYIO DLBCL ABC SU-DHL-16 DLBCL GCB U-2932 DLBCL ABC WILL-1 DLBCL no specifications SU-DHL-4 DLBCL GCB Pfeiffer DLBCL GCB U-2904 DLBCL no specifications WSU-DLCL DLBCL GCB HT DLBCL GCB RIVA DLBCL ABC ROS-50 DLBCL no specifications GCBDB DLBCL GCB OCI-LY-7 DLBCL GCB IMDM + 20% human plasma OCI-LY-3 DLBCL ABC DOHH2 FL no specifications RPMI + 10% FBS, IX NEAA, 2 mM Lglutamine R.L. FL no specifications Mino MCL no specifications RPMU 640 + 15% FBS + 2 mM Lglutamine + 10 mM Hepes + 1 mM sodium pyruvate + 4.5 g/l glucose Rec-1 MCL no specifications RPMI + 10% FBS + 2 mM L-glutamine EHEB CLL no specifications RPMI + 10% FBS, IX NEAA, 2 mM Lglutamine WA-C3-CD5+ CLL no specifications WA-OSEL CLL no specifications PGA1 CLL no specifications HG3 CLL no specifications I83-E95 CLL no specifications RPMI + 20% FBS, IX NEAA, 2 mM Lglutamine JV CLL no specifications C.I. CLL no specifications Mec2 CLL no specifications IMDM + 10% FBS Mecl CLL no specifications

- 42 046479

SVSL/VL51 MZL SMZL RPMI + 10% FBS, IX NEAA, 2 mM Lglutamine Daudi B.L. no specifications RPMI + 10% FBS + 2 mM L-glutamine BL-41 B.L. no specifications RPMI1640 + 10% FBS + 1 mM sodium pyruvate + 50 µM 2-mercaptoethanol MDS-L M.D.S. no specifications RPMI + 10% FBS + 50 µM 2mercaptoethanol + 50 µM/ml + rhIL-3 HNT-34 AML no specifications RPMI + 10% FBS + 2 mM L-glutamine GDM-1 AML no specifications RPMI + 10% FBS NCI-H929 MM no specifications RPMI + 10% FBS + GlutaMax ORM-2 MM no specifications RPMI + 10% FBS NiT-102 TCL no specifications Karpas-299 TCL no specifications JJN-3 MM PCL L-363 MM PCL SK-MM-1 MM PCL 40% IMDM + 40% DMEM + 20% FBS Karpas-231 ALL no specifications RPMI + 10% FBS KOPN-8 ALL no specifications L-428 H.L. no specifications L-591 H.L. no specifications RPMI+20% FBS

ABC=activated B cells;

FBS=fetal bovine serum;

GCB germinal center B cell;

IMDM Dulbecco's environment as modified by Iskov;

NEAA=nonessential amino acid;

RPMI=RPMI1640.

Cell lines were seeded in 384-well flat-bottom plates and distributed with increasing compound concentrations ranging from 0.00015 to 10 μM or dimethyl sulfoxide (DMSO) as a control. The final DMSO concentration was 0.1% (v/v). After addition of Compound 1 or DMSO and incubation for 120 h, cell number and cell death were analyzed by flow cytometry (Attune®, Thermo Fisher) using Annexin V and the cell-incapable DNA dye DRAQ7. Phosphatidylserine moved from the inner layer to the outer layer of the cell membrane during the early stage of apoptosis, and annexin V bound to exposed phosphatidylserine found on the surface of the apoptotic cell. The vital dye DRAQ7 was excluded from intact living cells and stained only cells that died as a result of apoptosis or necrosis. Flow cytometry data analysis was then performed using Flow Jov10 software to determine the number of viable cells (cells double negatively stained with Annexin V and DRAQ7) and the percentage of apoptotic cells (cells positively stained with Annexin V) for each condition. The number of viable cells for each concentration was normalized to the DMSO control (set as 100%) to calculate the percentage of viable cells remaining after treatment and plotted graphically using GraphPad Prism 7.03. IC ₅₀ (50% inhibitory concentration) and E _max (maximal efficacy achieved) values were then calculated by fitting a nonlinear regression curve using logarithm (inhibitor) versus normalized response - variable slope analysis on GraphPad Prism 7.03. Area under the curve (AUC) was calculated by performing area under the curve analysis on GraphPad Prism 7.03. Similarly, for the apoptosis assay, the percentage of apoptosis combining both early (annexin V positive and DRAQ7 negative) and late apoptotic (annexin V positive and DRAQ7 positive) cells against DMSO was plotted using GraphPad Prism 7.03 . AUC, EC ₅₀ (concentration of compound that induces half-maximal apoptotic response) and Y _max (maximum percentage of apoptosis achieved) values from apoptosis curves were calculated by performing area under the curve analysis and nonlinear regression curve fitting using logarithm (agonist) versus normalized response - Variable slope analysis on GraphPad Prism 7.03.

Proliferation dose-response curves for a panel of hematological cell lines and nonlinear regression curve fitting were used to determine the _IC50 , AUC, and _Emax for % viable cells (Emax for viability ranges from 100 at low doses to 0 at high doses, corresponding to inhibition of all viable cells). cells), and apoptosis dose-response curves were used to determine EC ₅₀ , AUC and Y _max for % apoptosis (Y _max for apoptosis varies from 0 at low doses to 100 at higher doses, corresponding to the death of all cells). Tumor cells were exposed to serial dilutions (0.00015 to 10 μM) of compound 1 or dimethyl sulfoxide (DMSO) as a control for 5 days. Viability and apoptosis for all cell lines were determined by annexin V/7-aminoactinomycin D (7-AAD) flow cytometry. Compound 1 was found to have antiproliferative activity and/or apoptotic effect in kidneys.

- 43 046479 ti in all hematological cell lines tested, as shown in the following table. Table 7

Antiproliferative activity and apoptotic effect of compound 1 in hematological cell lines

Cell line Viable cells, % Apoptosis AUC IC ₅₀ Emax AUC ec ₅₀ Ymax ULA 0.5518 0.00099 0.02523 995.3 0.00179 99.76 SU-DHL-5 1.873 0.002389 0.1398 934.1 0.003603 95.23 OCI-LY18 1.965 0.0009441 0.05973 965.2 0.002976 97.44 TMD8 4,187 0.002459 0.245 963.3 0.006172 97.2 SU-DHL-2 5,586 0.001263 0.2145 928.4 0.006242 95.98 Farage 10.16 0.002375 0.7936 728.7 0.03017 84.17 SU-DHL-10 10.36 0.006101 0.6716 903.0 0.03942 92.27 NU-DHL-1 12.37 0.001073 0.4919 981.8 0.001267 99.17 VAL 14.62 0.0005703 0.9632 936.7 0.0006045 95.68 WILL-2 17.1 0.002359 0.03115 916.9 0.08971 99.43 SU-DHL-6 19.94 0.03248 0.2469 920.7 0.1045 95.92 KARPAS-422 19.97 0.01313 0.8721 911.9 0.0461 93.99 NU-DUL-1 22.12 0.03527 0.0228 962.8 0.06304 99.84 KARPAS-1106P 22.22 0.01748 0.1698 885.2 0.09182 97.08 OCLLY1 22.77 0.006002 1.037 852.3 0.03338 90.09 SU-DHL-1 31.14 0.0005495 2.485 690.1 0.001105 73.83 WSU-DLCL2 36.7 0.01691 1,387 858.9 0.08473 92.1 STR428 43.48 0.09471 1.227 905.9 0.1016 95.17 U-2946 45.47 0.004604 0.4821 762.6 0.1922 93.34 U-2940 70.43 0.006313 5,192 792.5 0.0314 82.19 OCLLY19 72.49 0.02944 3.228 706.2 0.2829 80.91 CARNAVAL 110.6 0.009122 7,134 708.7 0.1516 77.84 Toledo 112.3 0.002002 8.56 231.4 0.2231 27.5 RC-K8 115.7 0.003371 10.06 349.2 0.07435 26.31 SU-DHL-8 119.5 0.4857 2,081 363.2 0.6025 85.44 OCLLYIO 125.3 0.01417 10.16 188.9 0.3202 22.31 SU-DHL-16 149.7 0.1545 7.137 492.6 0.6619 60.79 U-2932 163.7 0.03595 12.8 212.8 0.5669 25.81 WILL-1 233.7 0.8166 4.216 549.4 2.515 79.51 SU-DHL-4 296.2 0.2777 23.44 209.0 0.7823 25.33 Pfeiffer 313.5 0.04768 24.49 493.3 0.0136 51.82 U-2904 334.1 0.2006 7,609 456.1 3,294 77.39 WSU-DLCL 341.9 0.142 27.83 565.1 0.01804 59.91 HT 396.7 0.3192 30.39 225.3 0.06622 25.16 RIVA 452.6 0.1135 36.65 242.8 0.01774 27.92 ROS-50 762.1 10 65.57 87.92 0.3347 10.9 U-2973 853.4 6,776 19.45 391.9 2,161 60.8

- 44 046479

D.B. 941.4 10 89.46 80.31 0.06883 11.62 OCI-LY7 48.18 0.006477 4,191 682.7 0.01627 71.18 OCI-LY3 965.1 10 85.63 24.63 0.000263 4,493 DOHH2 6,902 0.002801 0.2066 923.9 0.01753 95.1 R.L. 234.8 0.008755 21.55 115.9 0.1566 13.93 Mino 62.67 0.005782 5.638 968.2 0.002051 97.04 Rec-1 281.8 0.03199 21.04 508.5 0.009258 57.27 ENEV 319.3 0.0303 28.68 65.03 0.5062 8.42 WA-C3-CD5+ 474.8 0.53 44.2 162.9 0.05244 17.47 WA-OSEL 616.1 10 54.42 69.39 0.112 7.38 PGA1 736.7 10 69.21 48.94 0.1219 5.075 HG3 676.2 10 59.58 131.5 0.1107 14.28 I83-E95 259.2 0.01728 21.6 358.4 0.06111 40.69 JV 926.1 10 78.23 238.1 0.145 26.11 C.I. 603.9 9,701 53.58 123.2 0.02294 13.01 Mec2 312.5 0.07552 25.55 339.8 0.01331 35.28 Mecl 866.5 10 83.45 302.4 0.2097 36.61 SVSL 368.4 0.09517 34.07 340.2 0.002836 35.5 Daudi 196.4 0.0006 0 274 2,320 84.0 BL-41 270.2 6,065 96.65 288.2 6,919 79.5 MDS-L 182.6 0.0513 146.7 425.4 1.557 100 HNT-34 353 0.026 20.47 130.1 0.8756 44.33 GDM-1 1455 6.8e-22 388.4 696.9 l,625e20 265 NCI-H929 215.5 0.0007 6.1 16.86 11.27 7.00 OPM-2 210.5 0.0003 6.65 212.6 1.316 63.00 HuT-102 395.4 0.0065 36.34 42.75 23.36 18.50 Karpas-299 283.7 0.012 8.43 14.51 167.6 8.0 JJN-3 278.2 0.0004 21.6 57.97 5.14e22 26 SK-MM-1 202.2 0.0008 3 90.99 86.36 44.5 L-363 309.1 0.001 27.6 2.954 7,950 2 Karpas-231 449.4 0.484 0 5,720 895.5 5.00 KOPN-8 490.2 0.0418 38.3 14.95 726.5 5.00 L-428 450.4 0.252 47.3 63.35 64.50 27.50 L-591 334.2 0.0003 34.6 45.59 1.521 20.0

АiС=area under the curve;

IC50=50% inhibitory concentration (µM);

E _max = the maximum efficiency of tumor cell elimination achieved, expressed as the percentage of remaining tumor cells;

EC ₅₀ = concentration of compound causing half-maximal apoptotic response (µM);

Y _max = calculated percentage of control at the highest concentration of compound 1.

6.3. Analytical techniques.

Typical measurement conditions are shown below.

X-ray powder diffraction (XRPD).

The Rigaku Smart-Lab X-ray diffraction system was designed to reflect Bragg-Brentano geometry using a line source X-ray beam. The X-ray source is a Cu Long Fine Focus tube operating at 40 kV and 44 mA. This source provides a beam profile incident on the sample that varies from a narrow line at high angles to a wide rectangle at low angles. Beam shaping slits are used on a line x-ray source to ensure that the maximum beam size is less than 10 mm both along the line and normal to the line. The Bragg-Brentano geometry is a parafocusing geometry defined by passive divergence and receiving slits, with the sample itself acting as the focusing component for the optics. The intrinsic resolution of the Bragg-Brentano geometry is determined in part by the radius of the diffractometer and the width of the reception slit used. Typically, Rigaku Smart-Lab operates with a peak width of 0.1° 2Θ or less. The axial divergence of the X-ray beam is controlled by 5.0° Soller slits in both the incident and diffracted beam paths.

Powder samples were prepared in a low background silicon holder using light manual pressure to keep the sample surfaces flat and flush with the reference surface of the sample holder. Each sample was analyzed from 2 to 40° 2θ using a continuous scan rate of 6° 2θ/min with an effective step size of 0.02° 2θ.

- 45 046479

Differential scanning calorimetry (DSC).

DSC analyzes were performed using a TA Instruments Q2000 instrument.

The temperature calibration of the device was carried out using indium. The DSC cell was maintained under nitrogen purging at ∼50 mL/min during each run. The sample was placed in a standard corrugated aluminum tray and heated from 25 to 350°C at a rate of 10°C/min.

Thermogravimetric (TG) analysis.

TG analysis was performed using a TA Instruments Q50 instrument. The instrument scales were calibrated using class M weights, and temperature calibration was carried out using alumel. Nitrogen purge was ~40 mL/min on the balance and ~60 mL/min in the oven.

Each sample was placed in a pre-tared platinum cuvette and heated from 20 to 350°C at a rate of 10°C/min.

Infrared (IR) spectroscopy.

IR spectra were obtained using a Nicolet 6700 FT-IR system. Samples were analyzed using a Nicolet SMART iTR instrument with attenuated total internal reflection.

Raman spectroscopy.

Fourier Raman (FT) spectra were obtained on a Nicolet model 6700 spectrometer connected to a Nexus Raman auxiliary module. This device is equipped with a Nd:YAG laser operating at a wavelength of 1024 nm, a CaF ₂ beam splitter and an indium gallium arsenide detector.

OMNIC software was used to control data acquisition and spectra processing. Samples were placed in a 3-inch glass NMR tube for analysis.

Nuclear Magnetic Resonance (NMR) Spectroscopy.

1H NMR spectra were obtained on a Bruker DRX-500 spectrometer located in the Department of Chemistry at Purdue University. Samples were prepared by dissolving the material in DMSO-d6. The solutions were filtered and placed in separate 5 mm NMR tubes for subsequent acquisition of spectra. A 5 mm cryoprobe operating at an observation frequency of 499.89 MHz was used for temperature-controlled 1H NMR spectra (298 K) acquired on the DRX-500.

DVS analysis.

Dynamic vapor sorption (DVS) was measured using Advantage DVS (Surface Measurement Systems Ltd). The samples were tested under isothermal conditions (25°C) at a given relative humidity from 0 to 95% of the full cycle in a stepwise mode. To conduct isothermal tests, the temperature in the chamber was maintained in a water bath at a constant level of 25.0±1.0°C. Relative humidity in the sample chamber was created by combining different flows of wet and dry nitrogen at variable flow rates. The analysis was carried out in increments of 10% relative humidity. The sampling rate was 1 s and the data rate was 20 s. 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. The sorption isotherm was obtained by plotting the equilibrium moisture content versus relative humidity RH.

6.4. Free base polymorphism screening.

A batch of Compound 1 free base starting material was characterized. XRPD showed it to be amorphous. TGA showed a mass loss of 7.3% below 200°C. DSC showed several small endotherms below 150°C. A typical XRPD diffraction pattern of the amorphous free base of compound 1 is shown in FIG. 20.

The free base starting material of compound 1 was mixed with various solvents under various conditions to obtain a crystalline material. The results are shown in the following table.

- 46 046479

Table 8

Screening for Compound 1 Free Base Polymorphs

Way Solvent Conditions ³ XRPD diffraction pattern ^b cooling acetone hexanes AS, 60°С —> -15°С; E NC ACN water AS, 60°С —►-15°С; E B+NC anisole MTBE AS, 60°С -15°С; E NC DCM hexanes AS, 60°С —> -15°С; E NC DMAc MTBE AS, 60°С -15°С; E NC EtOH 60°С—>--15 ^о С NC EtOAc hexanes AS, 60°С —> -15°С; E NC ethyl formate MTBE AS, 60°С -15°С; E NC isopropyl acetate 60°С—>--15 ^о С NC MeOH 60°С—>--15 ^о С NC MEK MTBE AS, 60°С -15°С; E NC 2-MeTHF hexanes AS, 60°С -15°С NC nitromethane MTBE AS, 60°С -15°С; E NC NMP water AS, 60°С —►-15°С; E NC 2-RgON 40°С—>-15 ^o C NC THF water AS, 60°С^ -15°С A+NC toluene 60°С—>--15 ^о С NC 2-PgOH/water (95:5) 60°С—>--15 ^о С NC slow evaporation acetone foil with 3 micro holes, RT NC ACN foil with 3 micro holes, RT NC anisole foil with 3 micro holes, RT NC DCM foil with 3 micro holes, RT NC DMAc foil with 3 micro holes, RT NC EtOH foil with 3 micro holes, RT NC EtOAc foil with 3 micro holes, RT NC ethyl formate foil with 3 micro holes, RT NC isopropyl acetate foil with 3 micro holes, RT NC MeOH foil with 3 micro holes, RT NC MEK foil with 3 micro holes, RT NC 2-MeTHF foil with 3 micro holes, RT NC nitromethane foil with 3 micro holes, RT NC NMP foil with 3 micro holes, RT A (LC) THF foil with 3 micro holes, RT NC toluene foil with 3 micro holes, RT NC acetone/water (95:5) foil with 3 micro holes, RT NC ACN/water (95:5) foil with 3 micro holes, RT NC 2-PgOH/water (95:5) foil with 3 micro holes, RT NC THF/water (95:5) foil with 3 micro holes, RT NC

- 47 046479

solvent/antisolvent acetone EtOH AS, RT NC hexanes AS, RT NC 2-PrOH AS, RT NC water AS, RT IN ACN MTBE AS, RT NC 2-PrOH AS, RT NC water AS, RT A anisole MTBE AS, RT NC 2-PrOH AS, RT NC DCM EtOH AS, RT NC hexanes AS, RT NC MTBE AS, RT NC 2-PrOH AS, RT NC DMAc hexanes AS, RT NC MTBE AS, RT NC 2-PrOH AS, RT NC EtOAc EtOH AS, RT NC hexanes AS, RT NC MTBE AS, RT NC+pk 2-PrOH AS, RT NC ethyl formate MTBE AS, RT NC 2-PrOH AS, RT NC nitromethane MTBE AS, RT NC 2-PrOH AS, RT NC suspension load Vapor diffusion NMP THF EtOH isopropyl acetate MeOH MTBE toluene water 95:5 2-RgOH/water No acetone ACN DCM MTBE AS, RT 2-PrOH AS, RT water AS, RT EtOH AS, RT hexanes AS, RT 2-PrOH AS, RT water AS, RT RT, 7 days RT, 7 days RT, 7 days 40°C, 7 days RT, 7 days 40°C, 6 days RT, 7 days 40°C, 75% RH 70°C, closed vial Et ₂ O AS; RT^5°C hexanes AS; RT->5°C MTBE AS; solids MTBE AS; RT^5°C 2-PrOH AS; RT->5°C water AS; RT^5°C Et ₂ O AS; solids NC NC NC NC L.C. NC A (displaced) A A+NC NC NC NC + pk LC A IN NC NC NC NC NC NC NC NC B NC hexanes AS; solids NC EtOAc hexanes AS; solids NC MTBE AS; solids NC NMP water AS; RT^5°C NC THF hexanes AS; solids NC MTBE AS; solids NC water AS; RT^5°C A+B(LC)

a) AS=antisolvent;

E=evaporation;

NC=no crystallization;

- 48 046479

RT=room temperature

b) CS=non-crystalline;

LC low crystallinity;

pk=peak.

Two characteristic XRPD diffraction patterns were identified, designated 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 is presented in the following table.

Table 9

Characterization of Form A and Form B of the free base of compound 1

Form Methodology Fig. No. Result Form A XRPD Fig. 1 crystalline DSC Fig. 2 endo 67.6, 112.0°C TGA 1.3% start to 50°C, and 1.4% 50 to 200°C NMR not shown in accordance with the structure of the impurity: 1.16 (t), 1.98 (s), 4.01 (q) Form B XRPD Fig. 3 crystalline DSC Fig. 4 endo 82.5, 107.0, 138.1 °C TGA 0.9% start up to 225°C NMR not shown according to the structure

6.5. Salt screening no. 1.

The free base starting material of compound 1 was mixed with various counterions under various conditions to obtain crystalline salts.

Approximately 15 different counterions were used to prepare the salts, and the results are shown in the following table.

Table 10

Compound 1 Salt Screening

Acid Conditions ³ XRPD diffraction pattern ^b L-aspartic G, 1:1 acetone:water, ~20 minutes NC + acid SL, 1:1 MeOH:water, 70°C NC C, 1:2 ASKwater, RT^-15°C NC lemon C, acetone, -15°C, 2 days; hexane AS E NC С, THF, -15°С, 2 days; hexane AS; E NC E, MeOH, RT NC G, MEK, ~20 minutes NC + acid SL, ACN, RT, 5 days NC fumaric C, acetone, -15°C, 2 days NC С, THF, -15°С, 2 days; hexane AS; solids NC E, MeOH, RT NC G, MEK, ~20 minutes NC SL, ACN, RT, 5 days A

- 49 046479

galactar (mucin) C, acetone, -15°C, 2 days; hexane AS; E NC + acid С, THF, -15°С, 2 days; hexane AS; E NC + acid E, MeOH, RT NC + acid G, MEK, ~20 minutes NC + acid SL, ACN, RT, 5 days acid D-gluconic R, acetone, RT, 4 days NC С, THF, -15°С, 2 days; hexane AS; E NC E, MeOH, RT NC G, MEK, ~20 minutes NC SL, ACN, RT, 5 days NC glutamine C, acetone, -15°C, 2 days; hexane AS; E NC С, THF, -15°С, 2 days; hexane AS; E NC E, MeOH, RT NC G, MEK, ~20 minutes NC + acid SL, ACN, RT, 5 days acid glycolic C, acetone, -15°C, 2 days; hexane AS; E NC С, THF, -15°С, 2 days; hexane AS; solids NC E, MeOH, RT NC G, MEK, ~20 minutes NC SL, ACN, RT, 5 days NC HC1 (1 equivalent) R, acetone, RT, 4 days A R, THF, RT, 4 days E, MeOH, RT NC G, MEK, ~20 minutes A SL, ACN, RT, 5 days A + B HC1 (2 equivalents) R, acetone, RT, 4 days A + B R, THF, RT, 4 days A + B (offset) E, MeOH, RT NC G, MEK, ~20 minutes IN SL, ACN, RT, 5 days maleic C, acetone, -15°C, 2 days NC С, THF, -15°С, 2 days A+NC E, MeOH, RT NC

- 50 046479

G, MEK, ~20 minutes NC+pk SL, ACN, RT, 5 days A methanesulfonic R, acetone, RT, 4 days NC R, THF, RT, 4 days L.C. E, MeON, RT NC G, MEK, ~20 minutes NC SL, ACN, RT, 5 days NC phosphorus R, acetone, RT, 4 days NC+pk R, THF, RT, 4 days NC E, MeOH, RT NC G, MEK, ~20 minutes NC SL, ACN, RT, 5 days NC amber C, acetone, -15°C, 2 days; hexane AS; E NC С, THF, -15°С, 2 days; hexane AS; E NC+pk E, MeOH, RT NC G, MEK, ~20 minutes NC + acid SL, ACN, RT, 5 days NC sulfuric R, acetone, RT, 4 days L.C. R, THF, RT, 4 days NC E, MeON, RT NC G, MEK, ~20 minutes NC SL, ACN, RT, 5 days NC L-wine C, acetone, -15°C, 2 days; hexane AS; E NC С, THF, -15°С, 2 days; hexane AS; E NC E, MeOH, RT NC G, MEK, ~20 minutes NC + acid SL, ACN, RT, 5 days NC rtoluenesulfonic C, acetone, -15°C, 2 days; hexane AS; solids A С, THF, -15°С, 2 days; hexane AS; solids NC E, MeON, RT NC G, MEK, ~20 minutes B + acid SL, ACN, RT, 5 days WITH

a) AS=antisolvent;

P=sediment;

RT=room temperature;

S/AS=solvent/antisolvent;

SL=cycneHgupoeaHue;

G=grinding;

C=cooling;

E=evaporation

b) NC=non-crystalline;

LC=low crystallinity;

pk=peak;

A, B, etc.=shape.

Several substances were identified that exhibited an XRPD diffraction pattern indicating the formation of a new phase. Those. The diffraction patterns contained peaks that were not due to the free base of compound 1 or the acid used. The acids used in these experiments were fumaric, hydrochloric, maleic and p-toluenesulfonic acids.

All samples having an XRPD diffractogram indicating the formation of a new phase were analyzed by DSC, TG and NMR. The results are presented in the following table.

- 51 046479

Table 11

Characteristics of crystalline salts of compound 1________

Salt/Sample ID Methodology Fig. No. Result fumarate Form A XRPD crystalline DSC endo 201.7°C TGA 0.5% start up to 150°C 10.2% 150 to 215°C NMR according to salt formation stoichiometry 1:2 API: acid hydrochloric Form A XRPD crystalline DSC endo 217.2°C, exo 226.5°C TGA 0.9% start up to 200°C 3.2% 200 to 235°C NMR according to salt formation hydrochloric Form B XRPD Fig. 9 crystalline DSC Fig. 10 exo 230.4°C TGA 1.6% start up to 175°C 5.3% 175 to 230°C NMR not shown according to salt formation maleate Form A XRPD Fig. 15 crystalline DSC Fig. 16 endo 174.2°C TGA 0.2% start up to 150°C 8.8% 150 to 185°C NMR not shown according to salt formation 1.7 mol acid per mole API, possibly 1:1 salt with excess acid or a mixture of 1:1 and 1:2 ART salt acid tosylate Form A XRPD crystalline DSC endo 189.4°C TGA 0.7% start up to 225°C NMR according to salt formation stoichiometry 1:1 API: acid

6.6. Salt screening no. 2.

The free base batch of Compound 1 was characterized by XRRD, TGA, DSC and DVS. XRPD confirmed that it is amorphous. TGA showed that there were several stages of mass loss at temperatures below 200°C before degradation. The results of a dynamic vapor sorption (DVS) study showed that the amorphous free base of compound 1 exhibits relatively high hygroscopicity at relative humidity below 75%. The free base slowly and continuously absorbed moisture (~6.0 wt%) from the dry state to 90% relative humidity. During desorption, the water content decreased slowly from 90% RH to a dry state (0% RH). Sorption/desorption was practically reversible for two complete cycles.

HCl salt.

Several experiments were carried out to search for crystalline HCl salts of compound 1 using hydrochloric acid added to various solvents.

In one experiment, 49.2 mg of Compound 1 free base was weighed into a 4 mL glass vial and 1.0 mL of EtOAc was added. The mixture became close to a clear solution, then 0.8 ml of 0.1 N was added. HCl in EtOAc. A cloudy suspension was observed and then 0.2 ml of 0.1 N was added. HCl in water. The suspension was placed in a fume hood for slow evaporation. Solids stuck to the wall. The solid particles were examined by XRPD and were determined to be a crystalline substance, namely Form A hydrochloride salt of Compound 1.

In one experiment, 10.5 mg of Compound 1 free base was weighed into a 4 mL glass vial and 1 mL of EtOAc was added, followed by 0.2 mL of 0.1 N. HCl in EtOAc. The mixture became cloudy. The suspension was placed in a fume hood for slow evaporation. The solid particles were examined by XRPD and were determined to be crystalline

- 52 046479 natural substance, namely form A of the hydrochloride salt of compound 1.

In one experiment, 16.6 mg of compound 1 free base was weighed into a 4 mL glass vial and 1 mL of EtOAc was added, followed by 0.05 mL of water and 0.345 mL of 0.1 N. HCl in EtOAc. The mixture became cloudy. The suspension was placed in a fume hood to slowly evaporate and form crystalline aggregates. The solid particles were examined by XRPD and were determined to be a crystalline substance, namely Form A hydrochloride salt of Compound 1.

In one experiment, 25.6 mg of the free base of compound 1 was weighed into a 4 ml glass vial and 1 ml of acetone was added, followed by the addition of 0.45 ml of 0.1 N. a solution of HCl in acetone, and the mixture became cloudy. Additionally, 0.07 ml of 0.1 N was added. HCl in water. The mixture turned into a clear solution. The solution was placed in a fume hood for slow evaporation. A seed suspension was added and a precipitate was observed. The solids were examined by XRPD and determined to be a crystalline substance, namely the hydrochloride salt Form A of Compound 1.

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

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 0.9 ml of 0.1 N. HCl in EtOAc. The mixture became cloudy. The suspension was placed in a fume hood to slowly evaporate and form crystalline aggregates. The solids were examined by XRPD and determined to be a crystalline substance, namely Form A hydrochloride salt of Compound 1, and further characterized by TGA and DSC. The TGA profile showed several stages of mass loss upon heating before decomposition: 1.8% below 100°C, 2.1% from 100 to 200°C and 1.5% around the melting point. The DSC spectrum showed a broad endothermic peak at a relatively low temperature (<100°C) and a small endothermic peak with an initial and peak temperature of 204.9 and 213.0°C, respectively, due to melting of the solid, followed by an exothermic peak, probably due to for decomposition. The dynamic vapor sorption (DVS) profile showed that the solid was moderately hygroscopic at a relative humidity below 90%. The HCl salt slowly and steadily gained moisture (~2.9 wt%) from dry to 90% relative humidity. During desorption, the water content slowly decreased from 90 to 0% dry relative humidity. Sorption/desorption was practically reversible for two complete cycles. NMR showed chemical shifts due to the formation of salts and minor residual solvents.

In one experiment, 53.9 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 100 μL of 0.1 N. HCl in water and 1.0 ml 0.1 N. HCl in EtOAc. The mixture was a sticky suspension. The suspension was placed in a fume hood to slowly evaporate and form crystalline aggregates. The solids were examined by XRPD and determined to be a crystalline substance, namely the hydrochloride salt Form A of Compound 1.

In one experiment, 26.5 mg of the free base of compound 1 was weighed into a 4 ml glass vial, 1 ml of acetone was added, and then 0.52 ml of 0.1 N. HCl in 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 solids were examined by XRPD and determined to be a crystalline substance, namely the hydrochloride salt Form A of Compound 1.

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 first added, then 0.02 ml of water was added, followed by the addition of 0.52 ml of 0.1 N. HCl in EtOAc. The mixture became cloudy.

The solid particles were examined by XRPD and determined to be a crystalline substance, namely Form A of the hydrochloride salt of compound 1. After drying in a vacuum oven at 35° C., the crystalline form remained the same. In one experiment, solid particles obtained from several experiments described above were placed together in a 4 ml glass vial, and then 1 ml of water was added. The suspension was covered and placed at room temperature to equilibrate for a week. The solid form remained Form A after suspension and was then characterized by TGA, DSC and DVS. The TGA profile showed several stages of mass loss upon heating before decomposition, 0.7% below 100°C and 3.9% at the melting point. The DSC spectrum showed a broad endothermic peak with an initial and peak temperature of 196.4 and 212.6 °C, respectively, due to the melting of the solid followed by

- 53 046479 exothermic peak, probably due to decomposition. The DVS profile was similar to the sample from the earlier experiment (44.2 mg scale) discussed above.

In one experiment, 26.2 mg of Compound 1 free base was weighed into a 4 mL glass vial, 1 mL of MEK was added, and then 0.02 mL of 0.1 N was added. HCl in water. The mixture became a clear solution, after which 0.49 ml of 0.105 N was added. HCl in MEK. The mixture immediately became cloudy. The solid particles were examined by XRPD and the solid sample was also examined by TGA and DSC and determined to be a crystalline substance, namely the hydrochloride salt Form A of Compound 1.

In one experiment, 26.2 mg of Compound 1 free base was weighed into a 4 mL glass vial, 1 mL of MEK was added, and then 0.49 mL of 0.105 N was added. HCl in MEK. The mixture became a clear solution, and then 0.02 ml of 0.1 N was added. HCl in water. The mixture immediately became cloudy. The solids were examined by XRPD and the solid sample was also examined by TGA and DSC and determined to be a crystalline substance, namely Form A of the hydrochloride salt of Compound 1. The TGA profile showed several stages of weight loss upon heating prior to decomposition, 0.8 % below 100°C and 3.7% near the melting point. The DSC spectrum showed a broad endothermic peak with an initial and peak temperature of 219.7 and 233.8 °C, respectively, due to melting of the solid, followed by an exothermic peak, probably due to decomposition.

In one experiment, 1.07 g of Compound 1 free base was weighed into a glass beaker, 25 mL of EtOAc was added, followed by 20 mL of 0.1 N. HCl in EtOAc. The mixture was cloudy. The suspension was placed in a fume hood for slow evaporation. The starting solid was amorphous by XRPD, it was suspended for another hour and the substance became the hydrochloride salt Form A crystalline of compound 1. The sample was dried in a vacuum oven overnight, then resuspended in water, and the final product was hydrochloride Form A salts of compound 1.

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 9.0 mL of 0.1 N. HCl in MEK. The mixture was cloudy. The suspension was placed in a fume hood for slow evaporation. The starting solid was crystalline Form A by XRPD.

Without being limited to any particular theory, the variation in initial and peak melting temperatures observed for Form A in these experiments is due to factors such as crystallinity, crystal defects, and the degree of amorphous particles.

Salt 2XHCl.

In one experiment, 45.5 mg of the free base of compound 1 was weighed into a 4 ml glass vial and 0.9 ml of acetone was added. The mixture became clear, and then 1.8 ml of 0.1 N was introduced. HCl in 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 XRPD (FIG. 21) of the solid obtained in this experiment was different in shape from the hydrochloride salt of Form A, and was designated Form C hydrochloride salt of Compound 1. The solid also exhibited a different TGA, DSC and DVS profile. The TGA profile showed several stages of mass loss upon heating before decomposition: 3.8% below 100°C and a further 4.0% from 100 to 200°C. The DSC spectrum showed a broad endothermic effect at relatively low temperature (<125°C) and another endothermic peak with an initial and peak temperature of 138.0 and 151.6°C, respectively, due to solid melting, followed by an exothermic peak, probably due to decomposition. The dynamic vapor sorption (DVS) profile showed that the solid was highly hygroscopic at relative humidity below 90%. The solid sample slowly and steadily gained moisture (~8.0 wt%) from dry to 80% RH, followed by a rapid increase (~6.7%) from 80 to 90% RH. During desorption, the water content decreased rapidly (~7.0%) from 90 to 80% RH, and then the remaining amount of water was gradually released while the RH decreased to a dry state (0% RH).

Besylate salt.

In one experiment, 24.3 mg of Compound 1 free base was weighed into a 4 mL glass vial and 1 mL of MEK was added. The mixture became a clear solution and 0.5 ml of 0.1 N was added. benzenesulfonic acid in MEK. A precipitate immediately formed. A crystalline substance was observed under the microscope and its form was confirmed by XRPD, namely Form A of the besylate salt of Compound 1. In one experiment, 255.3 mg of the free base of Compound 1 was weighed into a 4 ml glass vial and 5 ml of acetone was added. The mixture turned into a clear solution, to which 5.0 ml of 0.1 N was then added. benzenesulfonic acid in MEK. A precipitate immediately formed. A crystalline substance was observed under a microscope and confirmed by XRPD (Fig. 17). The solid was also characterized by thermal analysis using both TGA and DSC. The TGA profile (Fig. 18) showed very little weight loss (0.25%) when heated to 150°C. The DSC spectrum (Fig. 19) showed an endothermic peak with an initial and peak

- 54 046479 temperatures of 164.5 and 175.4 ° C, respectively, due to the melting of the solid substance.

6.7. Preparation and screening of polymorphism of the hydrochloride salt of compound 1.

The hydrochloride salt of compound 1 was prepared from the free base of compound 1 in three experiments. Initially, two small (0.1 g) experiments were performed (suspension in acetone for 1 day and suspension in THF for 1 day). The substances from both experiments were confirmed to be a polymorphic form of the hydrochloride salt of Form A. To determine stoichiometry, both samples were tested for carbon, hydrogen, nitrogen and chloride content. Elemental data (not shown) are consistent with a 1:1 AP1:acid salt ratio. The hydrochloride salt was then prepared on a 10 g scale (suspension in acetone for 2 days) and further characterized. These characteristics are shown in the following table.

Table 12

Characterization of the HCl salt of compound 1 on a large scale

XRPD Fig. 5 XRPD result Form A, HC1 salt DSC/TGA Fig. 6 DSC Result endo 217.7°C, exo 227.0°C TGA result 1.5% start up to 200°C 2.7% 200 to 230°C NMR result according to the structure Result of elemental analysis — %WITH %N %N %С1 theo ^a 58.8 5.5 12.3 6.2 result 57.9 5.4 11.8 5.8

^a Theoretical values for salt 1:1.

The solid HCl salt of compound 1 was mixed with various solvents under various conditions to obtain polymorphs. The results are shown in the following table. In this study, only one polymorph (hydrochloride salt form A of compound 1) was identified.

Table 13

Screening for polymorphism of the hydrochloride salt of compound 1_______

Way Solvent Conditions ³ XRPD diffraction pattern ^b cooling DMAc 200°C -> -15°C;E A DMSO acetone AS, 60°CA-15°C; E A+NC ACN AS, 60°С->-15°С; E NC anisole AS, 60°С-^-15°С; E A+NC EtOH AS, 60°CA-15°C;E A+NC EY Ac AS, 60°С^-15°С; E A+NC IP Ac AS, 60°С->-15°С; E A+NC MTBE AS, 60°С->-15°С; E A+NC 2-PrOH AS, 60°С->-15°С; E NC THFAS, 60°С->-15°С; E A+NC toluene AS, 60°С-^-15°С; E A+NC MeOH 65°С ->-15°С;E A NMP 165°C -E -15°C;E A+NC water 100°C -E -15°C;E NC ACN/water (95/5) 100°C-15°C; E A THF/water (95/5) 100°С -> -15°С A

- 55 046479

evaporation DMAc open vial, RT A (LC) DMSO open vial, RT A MeOH open vial, RT A NMP open vial, RT A water open vial, RT A ACN/water (95/5) open vial, RT A THF/water (95/5) open vial, RT NC deposition DMAc acetone AS, 60°CA-15°C; E A+NC DCM AS, 60°С->-15°С; E A+NC EtOAc AS, 60°С->-15°С; E A+NC 2-PrOH AS, 60°С->-15°С; E A+NC THF AS, 60°С->-15°С; E A+NC toluene AS, 60°С->-15°С; E A MeOH acetone AS, 60°CA-15°C; E A+NC DCM AS, 60°С^-15°С; E A+NC EtOAc AS, 60°С->-15°С; E A Et ₂ O AS, 60°CA-15°C;E A toluene AS, 60°С->-15°С; E A NMP acetone AS, 60°CA-15°C; E. triturated with Et ₂ O A+NC ACN AS, 60°CA-15°C; E. triturated with Et ₂ O A+NC DCM AS, 60°С->-15°С; E A+NC EtOAc AS, 60°С->-15°С; E. triturated with Et ₂ O A+NC 2-PrOH AS, 60°С->-15°С; E A+NC THF AS, 60°С->-15°С; E. triturated with Et ₂ O NC water acetone AS, 60°CA-15°C;E NC 2-PrOH AS, 60°С->-15°С; E NC THF AS, 60°С->-15°С; E NC ACN/water (95/5) acetone AS, 60°С^-15°С; E A 2-PrOH AS, 60°С->-15°С; E A THF AS, 60°С->-15°С; E A suspending acetone RT, 7 days A 50° C, 2 days A acetonitrile RT, 7 days A 50° C, 2 days A anisole RT, 7 days A 50° C, 2 days A

- 56 046479

DCM RT, 7 days A 50° C, 2 days A DMAc RT, 7 days A 50° C, 2 days A EtOH RT, 7 days A 50° C, 2 days A EtOAc RT, 7 days A 50° C, 2 days A ethyl formate RT, 7 days A 50° C, 2 days A isopropyl acetate RT, 7 days A 50° C, 2 days A MeOH RT, 7 days A 50° C, 2 days A MEK RT, 7 days A 50° C, 2 days A MTBE RT, 7 days A 50° C, 2 days A 2-MeTHF RT, 7 days A 50° C, 2 days A nitromethane RT, 7 days A 50° C, 2 days A NMP RT, 7 days A 50° C, 2 days A 2-propanol RT, 7 days A 50° C, 2 days A tetrahydrofuran RT, 7 days A 50° C, 2 days A toluene RT, 7 days A 50° C, 2 days A water RT, 7 days A 50° C, 2 days A acetone/water (95/5) RT, 7 days A 50° C, 2 days A ACN/water (95/5) RT, 7 days A 50° C, 2 days A 2-PgOH/water (95/5) RT, 7 days A 50° C, 2 days A THF/water (95/5) RT, 7 days A 50° C, 2 days A heating/relative humidity water vapor RT, 59% RH A RT, 75% RH A RT, 97% RH A 40°C, 75% RH A absent RT, 0% RH A

a) AS=antisolvent;

NC=no crystallization;

RH relative humidity;

IH=room temperature;

E=evaporation

b) NC=non-crystalline;

pks=nuKu;

A, B, etc.=shape.

6.8. Preparation and screening of polymorphism of the fumarate salt of compound 1.

In one study, the fumarate salt form A of compound 1 was obtained from a precipitation experiment using acetone and hexane. The solids crystallized within 5 hours and were left stirring at room temperature for 2 days.

In another study, the fumarate salt of compound 1 was prepared from the free base of compound 1 in several experiments. Initially, several experiments were carried out in small

- 57 046479 scale. The weakly crystalline material was prepared from suspensions prepared at ambient temperature (250 mg scale, suspended in acetonitrile at room temperature for 1 day, or suspended in acetonitrile at room temperature for 6 days). A highly crystalline substance was obtained by increasing the suspension temperature, and the substance was confirmed to be a fumarate salt form A polymorph (30 mg scale, suspended in acetonitrile at 50°C for 1 day). The experiment was repeated on a larger scale (mass 3.2 g, suspended in acetonitrile at 50°C for 3 days) and the resulting material was further characterized. These characteristics are shown in the following table.

Table 14

Large-scale characterization of the fumarate salt of Compound 1_____

XRPD Fig. eleven XRPD result fumarate Form A DSC/TGA Fig. 12 DSC Result endo 198.3°C TGA result 0.5% start up to 150°C 7.9% 150 to 205°C NMR result according to the structure 1:2 API:acid salt

The solid fumarate salt of compound 1 was mixed with various solvents under various conditions to obtain polymorphs. The results are shown in the following table. In this study, only one polymorph (form A of the fumarate salt of compound 1) was identified.

Table 15

Screening for fumarate salt polymorphism of compound 1

Way Solvent Conditions ³ XRPD diffraction pattern ^b cooling DMSO acetone AS, 60°C^-15°C;E NC+pks ACNAS, 60°C^-15°C;E NC+pks anisole AS, 60°C^-15°C;E NC+pks EtOH AS, 60°С^-15°С; E NC EtOAc AS, 60°С->-15°С; E NC+pks IP Ac AS, 60°С->-15°С; E NC+pks MTBE AS, 60°С->-15°С; E NC+pks 2-MeTHF AS, 60°SE·- ! 5°C; E NC+pks 2-PrOH AS, 60°С->-15°С; E NC+pks toluene AS, 60°С->-15°С; E NC+pks MeOH 65°C -15°C;E A (LC) THF 65°C -E -15°C;E NC+pks water 100°C -E -15°C;E NC acetone/water (95/5) 100°C -15°C;E NC ACN/water (95/5) 100°C -15°C;E NC+pks THF/water (95/5) 100°C -E -15°C;E NC+pks evaporation DMAc open vial, RT NC DMSO open vial, RT NC+pks MeOH open vial, RT NC NMP open vial, RT NC THF open vial, RT NC+pk water open vial, RT NC+pk acetone/water (95/5) open vial, RT NC+pk ACN/water (95/5) open vial, RT NC+pk 2-PgOH/water (95/5) open vial, RT NC+pk THF/water (95/5) open vial, RT NC+pk deposition DMAc acetone AS, 60°С^-15°С; E NC DCM AS, 60°С^-15°С; E NC+pks EtOAc AS, 60°С->-15°С; E NC+pks

- 58 046479

MTBE AS, 60°SE-15°C; E NC+pks 2-PrOH AS, 60°SE-15°C; E NC toluene AS, 60°SE-15°C; E NC+pks MeOH acetone AS, 60°SE-15°C; E A+NC DCMAS, 60°SE-15°C;E NC EtOAc AS, 60°SE-15°C; E NC+pk Et ₂ O AS, 60°SE-15°C;E NC toluene AS, 60°SE-15°C; E A+NC NMP acetone AS, 60°SE-15°C; E. triturated with Et ₂ O NC+pks ACN AS, 60°SE-15°C; E. triturated with Et ₂ O NC+pks DCMAS, 60°SE-15°C; E. triturated with Et ₂ O NC+pks EtOAc AS, 60°SE-15°C; E. triturated with Et ₂ O NC+pks MTBE AS, 60°SE-15°C; E NC+pks 2-PrOH AS, 60°SE-15°C; E. triturated with Et ₂ O NC+pks toluene AS, 60°SE-15°C; E NC+pks water 2-PrOH AS, 60°SE-15°C; E NC THF/water (95/5) acetone AS, 60°SE-15°C; E NC+pk 2-PrOH AS, 60°SE-15°C; E NC+pk suspending acetone RT, 7 days A 50°C, 2 days A acetonitrile RT, 7 days A 50°C, 2 days A anisole RT, 7 days A 50°C, 2 days A DCM RT, 7 days A 50°C, 2 days A EtOH RT, 7 days A 50°C, 2 days A EtOAc RT, 7 days A 50°C, 2 days A ethyl formate RT, 7 days A 50°C, 2 days A isopropyl acetate RT, 7 days A 50°C, 2 days A MeOH RT, 7 days A

- 59 046479

50°C, 2 days A MEK RT, 7 days A 50°C, 2 days A MTBE RT, 7 days A 50°C, 2 days A 2-MeTHF RT, 7 days NC+pk 50°C, 2 days A nitromethane RT, 7 days A 50°C, 2 days A 2-propanol RT, 7 days A 50°C, 2 days A tetrahydrofuran RT, 7 days A 50°C, 2 days A toluene RT, 7 days A 50°C, 2 days A water RT, 7 days A 50°C, 2 days A acetone/water (95/5) RT, 7 days A 50°C, 2 days A ACN/water (95/5) RT, 7 days A 50°C, 2 days A 2-PgOH/water (95/5) RT, 7 days A 50°C, 2 days A THF/water (95/5) RT, 7 days A 50°C, 2 days A(LC) Heating/Relative Humidity water vapor RT, 59% RH A RT, 75% RH A RT, 97% RH A 40°C, 75% RH A absent RT, 0% RH A

a) AS=antisolvent;

E=evaporation;

NC=no crystallization;

RH relative humidity;

RT=room temperature.

b) NC=non-crystalline;

pks=nuKu;

A, B, etc.=shape.

6.9. Preparation and screening of polymorphism of the tosylate salt of compound 1.

In one study, the form A tosylate salt of compound 1 was obtained from a precipitation experiment using acetone and hexane. The solids crystallized within 5 hours and were left to stir at room temperature for 2 days.

In another study, the tosylate salt of compound 1 was prepared from the free base of compound 1 in several experiments. Initially, one small experiment was performed (250 mg scale, suspended in acetonitrile at room temperature for 1 day). The substance was confirmed to be the tosylate salt of polymorph Form A. The experiment was repeated on a larger scale (3.4 g, suspended in acetonitrile at room temperature for 3 days) and the resulting substance was further characterized. These characteristics are shown in the following table.

- 60 046479

Table 16

Large scale characterization of the tosylate salt of compound 1

XRPD Fig. 13 XRPD result tosylate Form A DSC/TGA Fig. 14 DSC Result endo 188.8°C TGA result 1.0% start up to 200°C NMR result according to the structure 1:1 API: acid salt

The solid tosylate salt of compound 1 was mixed with various solvents under various conditions to obtain polymorphs. The results are presented in the following table. In this study, two polymorphs were identified: the tosylate salt form A of compound 1 (the same form from salt screen no. 1) and the new tosylate salt form D of compound 1. Form D was obtained in only one experiment as a mixture with a non-crystalline substance. A plot of the tosylate salts of polymorphs A, B, C, and D overlay is shown in FIG. 22.

Table 17

Screening for tosylate salt polymorphism of compound 1

Way Solvent Conditions ³ XRPD diffraction pattern ^b cooling ACN 80°C -E -15°C; E A DCM 40°С -15°С; E A DMSO acetone AS, 60°С->-15°С; E NC anisole AS, 60°С->-15°С; E NC EtOH AS, 60°С->-15°С; E NC EtOAc AS, 60°С->-15°С NC ethyl formate AS, 60°С->-15°С NC isopropyl acetate AS, 60°С->15°С NC MTBE AS, 60°С->-15°С NC 2-PrOH AS, 60°С->-15°С NC THF AS, 60°С->-15°С NC toluene AS, 60°С->-15°С NC MeOH 65°C -15°C; E NC nitromethane 100°С ->-15°С;E A water 100°С ->-15°С;E A acetone/water (95/5) 100°С ->-15°С;E NC evaporation ACN open vial, RT A+NC DCM open vial, RT NC+pks NC+pk NC DMAc open vial, RT NC DMSO open vial, RT NC MeOH open vial, RT NC nitromethane open vial, RT NC NMP open vial, RT NC water open vial, RT NC+pks acetone/water (95/5) open vial, RT NC ACN/water (95/5) open vial, RT NC THF/water (95/5) open vial, RT NC

- 61 046479

deposition DMAc acetone AS, 60°C^-15°C;E NC anisole AS, 60°С->-15°С; E D+NC sample above, under load, 80°C, 2 days D+NC EtOAc AS, 60°С->-15°С; E NC MTBE AS, 60°С->-15°С NC 2-РгОН AS, 60°С->-15°С; E NC toluene AS, 60°С->-15°С; E NC MeOH acetone AS, 60°С^-15°С; E NC EtOAc AS, 60°С->-15°С; E A Et ₂ O AS, 60°С->-15°С; E A (LC) toluene AS, 60°С->-15°С; E NC nitromethane acetone AS, 60°С^-15°С; E NC Et ₂ O AS, 60°С->-15°С; E NC 2-РгОН AS, 60°С->-15°С; E NC NMP acetone AS, 60°C^-15°C;E NC ACN AS, 60°С->-15°С; E NC EtOAc AS, 60°С->-15°С; E. triturated with Et ₂ O NC+pk MTBE AS, 60°С->-15°С; E. triturated with Et ₂ O NC+pk 2-PrOH AS, 60°С->-15°С; E NC toluene AS, 60°С->-15°С; E NC water 2-PrOH AS, 60°С->-15°С; E NC+pks ACN/water (95/5) 2-PrOH AS, 60°С->-15°С; E A THF/water (95/5) 2-PrOH AS, 60°С->-15°С; E A+NC suspending acetone RT, 7 days A 50°C, 2 days A acetonitrile RT, 7 days A 50°C, 2 days A anisole RT, 7 days A 50°C, 2 days A DCM RT, 7 days A 50°C, 2 days A EUN RT, 7 days A 50°C, 2 days A EtOAc RT, 7 days A 50°C, 2 days A ethyl formate RT, 7 days A 50°C, 2 days A isopropyl acetate RT, 7 days A 50°C, 2 days A MeOH RT, 7 days A 50°C, 2 days A MEK RT, 7 days A 50°C, 2 days A MTBE RT, 7 days A 50°C, 2 days A 2-MeTHF RT, 7 days A 50°C, 2 days A nitromethane RT, 7 days A 50°C, 2 days A 2-propanol RT, 7 days A

- 62 046479

50°C, 2 days A tetrahydrofuran RT, 7 days A 50°C, 2 days A toluene RT, 7 days A 50°C, 2 days A water RT, 7 days A 50°C, 2 days A acetone/water (95/5) RT, 7 days A 50°C, 2 days A 2-PgOH/water (95/5) RT, 7 days NC+pks 50°C, 2 days A heating/relative humidity water vapor RT, 59% RH A RT, 75% RH A RT, 97% RH A 40°C, 75% RH A absent RT, 0% RH A

a) AS=antisolvent;

NC crystallization is absent;

RH=relative humidity;

RT=room temperature;

E=evaporation.

b) NC=non-crystalline; pks=peaks;

A, B, etc.=shape.

6.10. Evaluation form.

(a) Evaluation of Form A of the hydrochloride salt of compound 1.

Hygroscopicity. Form A of the hydrochloride salt of compound 1 was characterized using DVS (Fig. 7). Form A absorbed water starting at very low humidity. Water sorption continued to occur at all humidity levels continuously (almost linearly) with an uptake of about 3.0% w/w, which corresponds to about 1 mol of water. Adsorbed water was released during the desorption phase with slight hysteresis observed during the drying phase. The solid form was maintained as form A after DVS.

Sensitivity to shear force. Compound 1 hydrochloride salt Form A was compressed at 700 and 1100 lb for 1 minute and analyzed by XRPD. The solid form remained the same, with slightly wider diffraction peaks.

Stability in solid state. The solid state stability of Compound 1 hydrochloride salt Form A was assessed using the Accelerated Stability Assessment Program (ASAP). Forced degradation storage conditions were applied at 60-80°C and 0-80% relative humidity for up to 2 weeks. A light stress study was also conducted under 2x ICH conditions in the solid state. Solid samples were analyzed for both chemical and nachiral stability. At the end of the study, the crystalline form of the compound was confirmed by XRPD. No changes in crystalline form were observed under the most stringent conditions of 80°C/70% relative humidity after 10 days compared to the control. The results of stability studies are shown in the following table.

- 63 046479

Table 18

Stability of Form A of the hydrochloride salt of compound 1 in the solid state under various storage conditions

Sample name Time point (days) Pace. (°C) RH (%) LC purity (%) R-isomer % area Heat/Relative Humidity Control N.A. N.A. N.A. 98.44 1.26 60°C, 50% RH, 7 days 7 60.01 49.01 98.51 1.26 60°C, 50% RH, 14 days 14 60.01 49.01 98.47 1.28 70°C, 20% RH, 7 days 7 70.17 19.08 98.28 1.26 70°C, 20% RH, 14 days 14 70.17 19.08 98.50 1.26 70°C, 75% RH, 7 days 7 70.09 75.67 98.48 1.34 70°C, 75% RH, 14 days 14 70.09 75.67 98.24 1.49 80°C, 0% RH, 7 days 7 80.19 0.15 91.18 1.27 80°C, 0% RH, 14 days 14 80.19 0.15 86.98 1.28 80°C, 40% RH, 7 days 7 79.84 41.16 98.32 1.27 80°C, 40% RH, 14 days 14 79.84 41.16 98.29 1.30 80°C, 70% RH, 7 days 7 79.56 69.13 98.43 1.36 80°C, 70% RH, 14 days 14 79.56 69.13 98.21 1.45 Photostress control N.A. N.A. N.A. 98.45 1.27 Photostress 2x ICH N.A. N.A. N.A. 94.80 1.17

No significant changes (<5%) were observed in the assay except for the 80°C/0% RH conditions at 1 week and 2 weeks. Loss of analysis at 80°C/0% RH was due to the growth of a degradation product with a molecular weight corresponding to the free base+HCl. The hydrochloride salt of compound 1 remained stable with respect to the products of analysis and decomposition under other conditions. Changes in the analysis according to photostability conditions were <4%. Additionally, no significant change in chiral purity was observed under all conditions, with a maximum change of 0.2% under high humidity conditions. These ASAP stability results confirmed that Compound 1 hydrochloride salt Form A can be considered stable.

Crystal habit. SEM imaging of Form A of the hydrochloride salt of Compound 1 showed small rod-like primary particles as well as agglomerates (Figure 8).

Long-term solid state stability: Compound 1 hydrochloride salt Form A (packaged in double low-density polyethylene (LDPE) bags in a high-density polyethylene (HDPE) container) was stored for up to 3 months at storage conditions of 25°C/60% RH, 30 °C/65% RH and 40°C/75% RH. The stability data shown in the table below demonstrates the stability of Compound 1 hydrochloride salt Form A when stored at 25°C/60% RH, 30°C/65% RH and 40°C/75% RH for 3 months. As a result, a retest period of 12 months is assumed when stored at 25°C or lower.

Table 19

Stability results for form A hydrochloride

compound 1 salts in double LDPE bags in a container re HDPE 25°C/60% RH 0 months 1 month 3 months Appearance ¹ Compliant Compliant Compliant Solid forms (XRPD) ² Compliant Compliant Compliant Chromatographic purity (%) 98.6 98.5 98.5 Chiral purity (%) 96.0 95.7 95.7 Water (%) 1.4 1.7 1.9 Amount of related impurities (%) 1.41 1.50 1.55 30°C/65% RH 0 months 1 month 3 months Appearance ¹ Compliant Compliant Compliant Solid forms (XRPD) ² NT NT NT Chromatographic purity (%) 98.6 98.4 98.4 Chiral purity (%) 96.0 94.5 95.8 Water (%) 1.4 1.9 2.0 Amount of related impurities (%) 1.41 1.56 1.63 40°C/75% RH 0 months 1 month 3 months Appearance ¹ Compliant Compliant Compliant Solid forms (XRPD) ² Compliant Compliant Compliant

- 64 046479

Chromatographic purity (%) 98.6 98.5 98.4 Chiral purity (%) 96.0 96.0 96.1 Water (%) 1.4 1.8 2.0 Amount of related impurities (%) 1.41 1.52 1.60

¹ Yellow powder.

² In accordance with form A.

(b) Evaluation of other forms of compound 1.

The stability of the amorphous free base of compound 1 in the solid state, tosylate form A, besylate form A and fumarate form A (as well as the HCl salt of form A) was assessed during storage under stress conditions. Solid samples were analyzed for both chemical and chiral stability. At the end of the study, the crystalline form of compound 1 was confirmed by XRPD. The results of stability studies are shown in the following table.

Table 20

Stability of the free base and salt forms in the solid state____

Conditions Free base Besilat Physical Chemical (%) Chiral (%) Physical Chemical (%) Chiral (%) Environment 98.95 99.16 Stable 98.64 98.70 40°C 98.44 99.03 Stable 98.56 98.71 40°C/80% RH 98.56 99.02 Unstable 97.69 98.66 60°C Unstable 95.80 98.69 Stable 98.58 98.62 60°C/75% RH Unstable 98.10 83.04 Unstable 96.77 96.36 70°C Unstable 85.68 95.57 Stable 97.76 98.64 70°C/80% RH Unstable 93.29 52.01 Unstable 96.93 95.11 Conditions Tosylate Fumarate Physical Chemical (%) Chiral (%) Physical Chemical (%) Chiral 1(%) Environment 99.19 98.49 98.77 95.82 40°C Stable 99.18 98.52 Stable 98.64 95.39 40°C/80% RH Stable 98.84 98.48 Stable 98.69 94.55 60°C Stable 99.01 98.46 Stable 97.43 95.54 60°C/75% RH Stable 96.76 98.10 Stable 98.19 93.14 70°C Stable 98.58 98.43 Stable 95.94 95.11 70°C/80% RH Stable 95.73 97.64 Stable 93.79 91.52 Conditions HC1 salt Physical Chemical (%) Chiral (%) Environment 99.08 99.26 40°C Stable 99.13 99.29 40°C/80% RH Stable 99.56 99.22 60°C Stable 99.35 99.02 60°C/75% RH Stable 99.56 98.70 70°C Stable 99.32 99.13 70°C/80% RH Stable 99.43 98.91

The solubility of the amorphous free base of compound 1, HCl form A, fumarate form A and tosylate form A was assessed in several solvents. Experiments were carried out by adding the test solvent in aliquots to weighed portions of the solid. Whether dissolution had occurred was determined visually after adding each aliquot of solvent. Solubility indices were 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 calculated due to the use of too large aliquots of solvent or due to a low dissolution rate. The solubility index is expressed as less than if dissolution did not occur during the experiment. The solubility index is expressed as greater than or equal to if dissolution occurred when the first aliquot of solvent was added. The results are shown in the following table.

-

Claims (28)

Table 21 Calculated solubility of free base and salt forms______ Solvent Free base Salt HC1 Fumarate Tosylate Solubility (mg/ml) Solubility (mg/ml) Solubility (mg/ml) Solubility (mg/ml) acetone 52 <1 <1 <1 acetonitrile 33 <1 <1 1 anisole 26 <1 <1 <1 dichloromethane 59 <1 <1 1 dimethylacetamide 34 1 23 30 dimethyl sulfoxide Ν/Τ 38 36 34 ethanol 1 <1 <1 <1 ethyl acetate 33 <1 <1 <1 ethyl formate thirty <1 <1 <1 isopropylacetate 6 <1 <1 <1 methanol 2 2 3 3 methyl ethyl ketone 29 <1 <1 <1 methyl tert-butyl ether <1 <1 <1 <1 2-methyltetrahydrofuran thirty <1 <1 <1 nitromethane 34 <1 <1 4 N-methylpyrrolidone 31 1 17 17 2-propanol <1 <1 <1 <1 tetrahydrofuran 28 <1 1 <1 toluene 3 <1 <1 <1 water <1 2 2 2 95:5 acetone/water 31 <1 2 3 95:5 ACN/water 27 3 2 17 95:5 2-RgOH/water 2 <1 1 <1 95:5 THF/water 20 1 8 16 The embodiments presented in the present invention are not intended to be limited in scope to the specific embodiments presented in the examples, which are intended to illustrate several aspects of the presented embodiments, and any embodiments that are functionally equivalent are covered by the present disclosure. Indeed, various modifications to the embodiments presented in the present invention, in addition to those shown and described herein, will become apparent to those skilled in the art, and are intended to be included within the scope of the appended claims. A number of references have been cited, the description of which is incorporated herein by reference in their entirety. CLAIM 1. Solid form of the free base or salt of compound 1 representing the free base of compound 1, characterized by an XRPD diffractogram containing peaks at about 4.5, 15.3 and 18.1° 2θ; the free base of compound 1, characterized by an XRPD diffractogram containing peaks at about 4.8, 9.6 and 14.9° 2θ; the hydrochloride salt of compound 1, characterized by an XRPD diffractogram containing peaks at about 15.1, 16.3 and 20.7° 2θ; the hydrochloride salt of compound 1, characterized by an XRPD diffractogram containing peaks at about 17.5, 21.6 and 24.8° 2θ; fumarate salt of compound 1, characterized by an XRPD diffraction pattern containing peaks - 66 046479 at about 22.3, 23.2 and 23.4° 2θ; the tosylate salt of compound 1, characterized by an XRPD diffractogram containing peaks at about 17.6, 18.0 and 23.8° 2θ; the maleate salt of compound 1, characterized by an XRPD diffractogram containing peaks at about 17.6, 24.4 and 26.9° 2θ; or the besylate salt of compound 1, characterized by an XRPD diffractogram containing peaks at about 17.9, 18.3 and 23.8° 2θ. 2. The solid form of claim 1, which is the free base of compound 1, characterized by an XRPD diffractogram containing peaks at about 4.5, 15.3 and 18.1° 2θ. 3. The solid form of claim 2, wherein the XRPD diffraction pattern further contains peaks at about 13.3 and 15.9° 2θ. 4. The solid form of claim 3, wherein the XRPD diffraction pattern further contains peaks at about 20.1 and 20.9° 2θ. 5. The solid form according to claim 2, which is characterized by an XRPD diffraction pattern corresponding to the XRPD diffraction pattern shown in FIG. 1. 6. The solid form of claim 1, which is the free base of compound 1, characterized by an XRPD diffractogram containing peaks at about 4.8, 9.6 and 14.9° 2θ. 7. The solid form of claim 6, wherein the XRPD diffraction pattern further contains peaks at about 18.7 and 22.1° 2θ. 8. The solid form of claim 7, wherein the XRPD diffraction pattern further contains peaks at about 20.7 and 21.4° 2θ. 9. The solid form of claim 6, which is characterized by an XRPD diffraction pattern corresponding to the XRPD diffraction pattern shown in FIG. 3. 10. The solid form of claim 1, which is the hydrochloride salt of compound 1, characterized by an XRPD diffractogram containing peaks at about 15.1, 16.3 and 20.7° 2θ. 11. The solid form of claim 10, wherein the XRPD diffraction pattern further contains peaks at about 7.8 and 22.4° 2θ. 12. The solid form of claim 11, wherein the XRPD diffraction pattern further contains peaks at about 18.2, 18.9 and 24.8° 2θ. 13. The solid form of claim 10, which is characterized by an XRPD diffraction pattern corresponding to the XRPD diffraction pattern shown in FIG. 5. 14. The solid form of claim 1, which is the hydrochloride salt of compound 1, characterized by an XRPD diffractogram containing peaks at about 17.5, 21.6 and 24.8° 2θ. 15. The solid form of claim 14, wherein the XRPD diffraction pattern further contains peaks at about 21.1 and 27.0° 2θ. 16. The solid form of claim 15, wherein the XRPD diffraction pattern further contains peaks at about 14.6, 17.2 and 20.3° 2θ. 17. The solid form of claim 14, which is characterized by an XRPD diffraction pattern corresponding to the XRPD diffraction pattern shown in FIG. 9. 18. The solid form of claim 1, which is the fumarate salt of compound 1, characterized by an XRPD diffractogram containing peaks at about 22.3, 23.2 and 23.4° 2θ. 19. The solid form of claim 18, wherein the XRPD diffraction pattern further contains peaks at about 17.9 and 25.8° 2θ. 20. The solid form of claim 19, wherein the XRPD diffraction pattern further contains peaks at about 11.7 and 18.3° 2θ. 21. The solid form of claim 18, which is characterized by an XRPD diffraction pattern corresponding to the XRPD diffraction pattern shown in FIG. eleven. 22. The solid form of claim 1, which is the tosylate salt of compound 1, characterized by an XRPD diffractogram containing peaks at about 17.6, 18.0 and 23.8° 2θ. 23. The solid form of claim 22, wherein the XRPD diffraction pattern further contains peaks at about 15.7 and 20.6° 2θ. 24. The solid form of claim 23, wherein the XRPD diffraction pattern further contains peaks at about 24.7 and 25.0° 2θ. 25. The solid form of claim 22, which is characterized by an XRPD diffraction pattern corresponding to the XRPD diffraction pattern shown in FIG. 13. 26. The solid form of claim 1, which is the maleate salt of compound 1, characterized by an XRPD diffractogram containing peaks at about 17.6, 24.4 and 26.9° 2θ. 27. The solid form of claim 26, wherein the XRPD diffraction pattern further contains peaks at about 18.0, 18.4 and 19.3° 2θ. 28. Solid form according to claim 27, wherein the XRPD diffraction pattern additionally contains peaks at about -