Solid forms of salts of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-ethylpropyl)phenyl]phenyl]-2-fluoro-benzonitrile

Abstract

A form of 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile (referred to herein as Compound I) has been prepared and characterized in the solid state. Also provided are processes for making and methods of using the Compound I form.

Description

[Technical field]

[0001] [CROSS REFERENCE TO RELATED APPLICATIONS] This application claims the benefit under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 63 / 187,125, filed May 11, 2021, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates generally to solid forms of compounds that modulate lysine-specific histone demethylase 1A (LSD1), pharmaceutical compositions thereof, therapeutic uses thereof, and processes for making the solid forms. [Background technology]

[0003] The compound 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile (herein referred to as Compound I) is an effective LSD1 inhibitor and is used as an antitumor agent, or an agent for the prevention and / or treatment of cancer.

[0004] It is desirable that such an LSD1 inhibitor exhibits stability when used in a pharmaceutical preparation.

[0005] It is also desirable to develop an LSD1 inhibitor that can be easily handled. It is known that the hygroscopicity of biologically active compounds affects the handling of the compounds during their incorporation into effective pharmaceutical compositions. Hygroscopic compounds have problems due to moisture absorption, which causes fluctuations in the mass of the compound depending on the amount of water present in the surrounding environment, making it difficult to accurately evaluate the biological effectiveness of the compound and to ensure the uniformity of pharmaceutical compositions containing the compound. Furthermore, hygroscopic compounds are highly sticky and can cause problems during processing. Therefore, solid forms with low hygroscopicity and / or stickiness are desirable. Summary of the Invention

[0006] The present disclosure provides polymorphic and / or amorphous forms of Compound I and its salts, cocrystals, solvates and hydrates. Also described herein are forms of Compound I, processes for making pharmaceutical compositions comprising forms of Compound I, and methods for using such forms and pharmaceutical compositions in the treatment of diseases mediated by LSD1. [Brief description of the drawings]

[0007] [Figure 1] 1 is an X-ray powder diffractogram (XRPD) of Form I of Compound I. [Diagram 2] 1 is an X-ray powder diffractogram of Form II of Compound I. [Diagram 3] Figure 3A is an X-ray powder diffractogram of Form IIIA of Compound I. Figure 3B is a differential scanning calorimeter (DSC) curve of Form III of Compound I. [Figure 4] Figure 4A is an X-ray powder diffractogram of Form IVA of Compound I. Figure 4B is a differential scanning calorimeter (DSC) curve of Form IV of Compound I. [Diagram 5] Figure 5A is an X-ray powder diffractogram of Form V of Compound I. Figure 5B is a differential scanning calorimeter (DSC) curve of Form V of Compound I. [Figure 6] Figure 6A is an X-ray powder diffractogram of Form VI of Compound I. Figure 6B is a polarized light microscopy (PLM) image of Form VII of Compound I. [Figure 7] Figure 7A is a PLM image of Form I of Compound I. Figure 7B is a PLM image of Form II of Compound I. [Figure 8] Figure 8A is an X-ray powder diffractogram of Form IIIB of Compound I. Figure 8B is an X-ray powder diffractogram of Form IIIC of Compound I. [Figure 9] FIG. 9A is an X-ray powder diffractogram of Form IIID of Compound I. [Figure 10]Figure 10A is a differential scanning calorimeter (DSC) curve of Form IVB of Compound I. Figure 10B is an X-ray powder diffractogram of Form IVB of Compound I. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] The compound 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile (referred to herein as Compound I) has the following formula: [ka]

[0009] Compound I is an inhibitor of LSD1. Its synthesis and methods of use are described in PCT International Publication No. WO 2017 / 090756, which is incorporated herein by reference in its entirety.

[0010] 1.Definition As used herein, the following words and phrases are generally intended to have the meanings set forth below, except to the extent that the context in which they are used indicates otherwise.

[0011] The terms "comprise" and variations thereof, such as "comprises" and "comprising," are to be construed in an open and inclusive sense, i.e., including, but not limited to. Furthermore, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, reference to "the compound" includes a plurality of such compounds, and reference to "the assay" includes a reference to one or more assays and equivalents thereof known to those skilled in the art.

[0012] As used herein, reference to "about" with respect to a value or parameter includes (and describes) embodiments directed to the value or parameter itself. In certain embodiments, the term "about" includes the indicated amount ±10%. In other embodiments, the term "about" includes the indicated amount ±5%. In certain other embodiments, the term "about" includes the indicated amount ±2.5%. In certain other embodiments, the term "about" includes the indicated amount ±1%. The term "about X" also includes the description of "X".

[0013] Recitations of numerical ranges throughout this disclosure are intended to serve as a shorthand method of referring individually to each separate value falling within the range, including the values ​​defining that range, and each separate value is incorporated into this specification as if it were individually set forth herein.

[0014] Provided herein are forms of Compound I, or its salts, cocrystals, solvates or hydrates. In one embodiment, a reference to a form of Compound I, or its salts, cocrystals, solvates or hydrates means that at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of Compound I, or its salts, cocrystals, solvates or hydrates present in the composition are in the specified form. For example, in one embodiment, a reference to Form I of Compound I means that at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of Compound I present in the composition is in Form I.

[0015] The term "solid form" refers to a type of substance in the solid state, including amorphous and crystalline forms. The term "crystalline form" refers to polymorphs and solvates, hydrates, etc. The term "polymorph" refers to a particular crystal structure that has particular physical properties, such as x-ray diffraction, melting point, etc.

[0016] The term "cocrystal" refers to a molecular complex of a compound disclosed herein and one or more non-ionized co-crystal formers bound via non-covalent interactions. In some embodiments, the co-crystals disclosed herein can include a non-ionized form of compound I (e.g., a free form of compound I) and one or more non-ionized co-crystal formers, where the non-ionized compound I and the co-crystal former(s) are bound via non-covalent interactions. In some embodiments, the co-crystals disclosed herein can include an ionized form of compound I (e.g., a salt of compound I) and one or more non-ionized co-crystal formers, where the ionized compound I and the co-crystal former(s) are bound via non-covalent interactions. The co-crystals can also exist in anhydrous, solvated, or hydrated forms. In certain cases, the co-crystals can have improved properties compared to the parent form (i.e., the free molecule, the zwitterion, etc.) or the salt of the parent compound. The improved property can be increased solubility, increased dissolution, increased bioavailability, increased dose response, reduced hygroscopicity, increased stability, crystalline forms of normally amorphous compounds, crystalline forms of compounds that are difficult or impossible to salt, reduced form diversity, more desirable morphology, etc. Methods for making and characterizing cocrystals are known to those of skill in the art.

[0017] The term "co-crystal former" or "coformer" refers to one or more pharma- ceutically acceptable bases or pharma-ceutically acceptable acids disclosed herein in association with Compound I or any other compound disclosed herein.

[0018] The term "solvate" refers to a complex formed by the combination of solvent molecules with molecules or ions of the solute. The solvent may be an organic compound, an inorganic compound, or a mixture of both. As used herein, the term "solvate" includes "hydrates" (i.e., complexes formed by the combination of water molecules with molecules or ions of the solute), hemihydrates, channel hydrates, and the like. Some examples of solvents include, but are not limited to, methanol, N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water. In general, solvated forms are equivalent to unsolvated forms and are within the scope of the present disclosure.

[0019] The term "desolvated" refers to a solvate as described herein, a form of Compound I from which the solvent molecules have been partially or completely removed. Desolvation techniques to produce desolvated forms include, but are not limited to, exposing a form of Compound I (solvate) to a vacuum, subjecting the solvate to high temperatures, exposing the solvate to a gas stream such as air or nitrogen, or any combination thereof. Thus, a desolvated Compound I form can be anhydrous, i.e., completely free of solvent molecules, or partially solvated, in which the solvent molecules are present in stoichiometric or non-stoichiometric amounts.

[0020] The term "amorphous" refers to a state in which a material does not have long-range order at the molecular level and can exhibit the physical properties of a solid or a liquid, depending on temperature. Typically, such materials do not exhibit distinctive X-ray diffraction patterns and exhibit the properties of a solid, but are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs that is characterized by a phase change, typically second order (glass transition).

[0021] Any formula or structure herein, including compound I, is also intended to represent unlabeled and isotopically labeled forms of the compound. It is understood that for any given atom, isotopes can essentially be present in proportions according to their natural occurrence, or one or more specific atoms can be enriched with one or more isotopes using synthetic methods known to those skilled in the art. That is, hydrogen can be, for example, 1 H, 2 H, 3 H, and carbon is, for example, 11 C. 12 C. 13 C. 14 C, oxygen is e.g. 16 O. 17 O. 18 O, and nitrogen, e.g. 13 N, 14 N, 15 N, and sulfur, for example, 32 S, 33 S, 34 S, 35 S, 36 S, 37 S, 38 S and fluorine, for example, 17 F, 18 F, 19 F, and chlorine, for example, 35 Cl, 36 Cl, 37 Cl, 38 Cl, 39 Contains Cl, etc.

[0022] As used herein, the terms "treat," "treating," "therapy," "therapies," and similar terms refer to the administration of a substance, e.g., any one or more solid, crystalline, or polymorphic forms of Compound I described herein, in an amount effective to prevent, alleviate, or ameliorate one or more symptoms, i.e., signs, of a disease or condition, and / or prolong the survival of the subject being treated.

[0023] The term "administration" refers to oral administration, administration as a suppository, topical contact, intravenous administration, intraperitoneal administration, intramuscular administration, intralesional administration, intranasal administration or subcutaneous administration, or implantation of a sustained release device, such as a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like.

[0024] As used herein, the term "modulation" or "modulating" refers to the effect of changing a biological activity, particularly a biological activity associated with a particular biological molecule, such as LSD1. For example, an agonist or antagonist of a particular biological molecule modulates the activity of that biological molecule, e.g., LSD1, by either increasing (e.g., agonist, activator) or decreasing (e.g., antagonist, inhibitor) the activity of the biological molecule. Such activity is typically measured, e.g., with respect to LSD1, in terms of the inhibitory concentration (IC 50 ) or excitation concentration (EC 50 ) is shown.

[0025] As used herein, the term "LSD1-mediated disease or condition" refers to a disease or condition in which the biological function of LSD1, including any mutations thereof, influences the onset, course and / or symptoms of the disease or condition, and / or a disease or condition in which modulation of LSD1 alters the onset, course and / or symptoms of the disease or condition. LSD1-mediated diseases or conditions include diseases or conditions in which modulation of LSD1 provides a therapeutic benefit, for example, in which treatment with a compound(s) comprising one or more solid, crystalline or polymorphic forms of Compound I described herein provides a therapeutic benefit to a subject suffering from or at risk for the disease or condition.

[0026] As used herein, the term "composition" refers to a pharmaceutical preparation containing at least one pharma- ceutically active compound, including any solid form thereof, suitable for administration to an intended subject for therapeutic purposes. The composition may contain at least one pharma- ceutically acceptable ingredient, such as a suitable carrier or excipient, to provide an improved formulation of the compound.

[0027] As used herein, the term "subject" or "patient" refers to a living organism treated with the compounds described herein, including, but not limited to, any mammal, such as humans, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats.

[0028] The term "pharmaceutical acceptable" indicates that the indicated substance does not possess properties that would prevent a reasonably prudent physician from administering it to a patient, taking into account the disease or condition to be treated and the respective route of administration. For example, for injectables, such substances are generally required to be essentially sterile.

[0029] In the context of this application, the term "therapeutically effective" or "effective amount" indicates that a substance or amount of a substance is effective to prevent, reduce or ameliorate one or more symptoms of a disease or condition and / or to prolong the survival of the subject being treated. The therapeutically effective amount will vary depending on the compound, the disorder or condition and its severity, as well as the age, weight, etc., of the mammal being treated. For example, an effective amount is an amount sufficient to produce an effective or desired clinical result. An effective amount can be provided all at once in a single administration, or in multiple divided amounts that provide an effective amount in several administrations. The exact determination of what will be considered an effective amount can be based on factors individual to each subject, including the subject's size, age, injury, and / or the disease or injury being treated, and the amount of time since the injury occurred or the disease began. One of ordinary skill in the art will be able to determine the effective amount for a given subject based on these considerations, which are routine in the art.

[0030] In some embodiments, the phrase "substantially as shown in the figures" when applied to X-ray powder diffractograms means including a variation of ±0.2°2θ or ±0.1°2θ, when applied to DSC thermograms means including a variation of ±3° C., and when applied to thermogravimetric analysis (TGA) means including a variation of ±2% in weight loss.

[0031] "Substantially pure form (of a polymorph)" means, in some embodiments, that in the referenced substance, at least 99.9% of the substance is the referenced polymorph. "Substantially pure form (of a polymorph)" means, in some embodiments, that in the referenced substance, at least 99.5% of the substance is the referenced polymorph. "Substantially pure form (of a polymorph)" means, in some embodiments, that in the referenced substance, at least 99% of the substance is the referenced polymorph. "Substantially pure form (of a polymorph)" means, in some embodiments, that in the referenced substance, at least 98% of the substance is the referenced polymorph. "Substantially pure form (of a polymorph)" means, in some embodiments, that in the referenced substance, at least 97% of the substance is the referenced polymorph. "Substantially pure form (of a polymorph)" means, in some embodiments, that in the referenced substance, at least 96% of the substance is the referenced polymorph. "Substantially pure form (of a polymorph)" means, in some embodiments, that the referenced substance is at least 95% of the substance in the referenced polymorph. In the context of using, testing, or screening compounds that are or may be modulators, the term "contacting" means bringing the compound(s) into sufficient proximity to a particular molecule, complex, cell, tissue, organ, or other particular substance that an effective binding interaction and / or chemical reaction can occur between the compound and the other particular substance.

[0032] Additionally, the abbreviations used herein have the following respective meanings:

[0033] [Table 1]

[0034] 2. Form of Compound I As outlined above, the present disclosure provides crystalline forms of the compound 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile (hereinafter, "Compound I" or "Compound"). The crystalline forms of Compound I and its salts, co-crystals, solvates or hydrates, and other forms (e.g., amorphous forms) of Compound I and its salts, co-crystals, solvates or hydrates are collectively referred to herein as "forms of Compound I."

[0035] In some embodiments, compound I is a free base. In some embodiments, compound I is a salt or co-crystal. In some embodiments, compound I is a pharma- ceutically acceptable salt or co-crystal. In some embodiments, compound I is a solvate. In some embodiments, compound I is a hydrate. In some embodiments, compound I is anhydrous.

[0036] In some embodiments, Compound I is in an amorphous form.

[0037] Techniques for characterizing crystalline and amorphous forms include, but are not limited to, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), single crystal X-ray diffraction, vibrational spectroscopy, such as infrared (IR) and Raman spectroscopy, solid state and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility measurements, dissolution measurements, elemental analysis, and Karl Fischer analysis. Characteristic unit cell parameters can be determined using one or more techniques, 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, for example, profile refinement, such as Rietveld refinement, which can be used to analyze diffraction peaks associated with a single phase in a sample that contains two or more solid phases. Other methods 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 that contains a crystalline powder.

[0038] Form I of Compound I - Hemi-Fumarate In one embodiment, provided herein is crystalline 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methylpropyl)phenyl]phenyl]-2-fluoro-benzonitrile hemifumarate (Form I of Compound I), characterized by an X-ray powder diffraction pattern containing the following peaks, expressed as 2θ angles determined using Cu K-α (λ=1.5406 Å) radiation: 9.37°±0.2°, 14.63°±0.2°, and 21.27°±0.2°.

[0039] In some embodiments, the diffraction pattern of Form I of Compound I further comprises one or more peaks selected from 4.73°±0.2°, 18.86°±0.2°, and 20.65°±0.2°, expressed as 2θ angles determined using Cu K-α (λ=1.5406 Å) radiation.

[0040] In some embodiments, the diffraction pattern of Form I of Compound I further comprises two or more peaks selected from 4.73°±0.2°, 8.18°±0.2°, 14.79°±0.2°, 18.86°±0.2°, 20.41°±0.2°, and 20.65°±0.2°, expressed as 2θ angles determined using Cu K-α (λ=1.5406 Å) radiation.

[0041] In some embodiments, the diffraction pattern of Form I of Compound I comprises peaks selected from: 4.73°±0.2°, 8.18°±0.2°, 9.37°±0.2°, 14.63°±0.2°, 14.79°±0.2°, 18.86°±0.2°, 20.41°±0.2°, 21.27°±0.2°, and 20.65°±0.2°, expressed as 2θ angles determined using Cu K-α (λ=1.5406 Å) radiation.

[0042] In some embodiments, the diffraction pattern of Form I of Compound I is substantially as shown in FIG.

[0043] In some embodiments, Form I of Compound I is contacting a solution of Compound I in a solvent with a solution of fumaric acid in a solvent at room temperature to obtain a slurry; warming the slurry to a temperature of about 50° C.; Cooling the slurry to room temperature; filtering the solids from the slurry to obtain a filter cake; drying the filter cake to obtain Form I of Compound I; It is prepared by a process comprising:

[0044] In some embodiments, the solvent is selected from acetonitrile, anisole, butanol, isopropanol, methyl tert-butyl ether (MTBE), ethanol, ethyl acetate, heptane, isopropyl acetate, methyl acetate, methyl ethyl ketone (MEK) and toluene. In some embodiments, the solvent is isopropanol. In some embodiments, Form I of Compound I is prepared by the sequence of steps described in the Examples section.

[0045] Form II of Compound I - Monooxalate In one embodiment, provided herein is crystalline 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methylpropyl)phenyl]phenyl]-2-fluoro-benzonitrile monooxalate (Form II of Compound I), characterized by an X-ray powder diffraction pattern containing the following peaks, expressed as 2θ angles determined using Cu K-α (λ=1.5406 Å) radiation: 13.86°±0.2°, 19.05°±0.2°, and 22.94°±0.2.

[0046] In some embodiments, the diffraction pattern of Form II of Compound I further comprises one or more peaks selected from 18.50°±0.2°, 22.31°±0.2°, and 28.48°±0.2°, expressed as 2θ angles determined using Cu K-α (λ=1.5406 Å) radiation.

[0047] In some embodiments, the diffraction pattern of Form II of Compound I further comprises two or more peaks selected from 15.83°±0.2°, 16.32°±0.2°, 18.50°±0.2°, 18.79°±0.2°, 22.31°±0.2°, and 28.48°±0.2°, expressed as 2θ angles determined using Cu K-α (λ=1.5406 Å) radiation.

[0048] In some embodiments, the diffraction pattern of Form II of Compound I comprises peaks selected from 13.86°±0.2°, 15.83°±0.2°, 16.32°±0.2°, 18.50°±0.2°, 18.79°±0.2°, 19.05°±0.2°, 22.31°±0.2°, 22.94°±0.2°, and 28.48°±0.2°, expressed as 2θ angles determined using Cu K-α (λ=1.5406 Å) radiation.

[0049] In some embodiments, the diffraction pattern of Form II of Compound I is substantially as shown in FIG.

[0050] In some embodiments, Form II of Compound I is contacting a solution of Compound I in a solvent with a solution of oxalic acid in a solvent at room temperature to obtain a slurry; warming the slurry to a temperature of about 50° C.; Cooling the slurry to room temperature; filtering the solids from the slurry to obtain a filter cake; drying the filter cake to obtain the monooxalate salt of Compound I; recrystallizing the monooxalate salt of Compound I from ethanol to obtain Form II of Compound I; It is prepared by a process comprising:

[0051] In some embodiments, the solvent is selected from acetonitrile, anisole, butanol, isopropanol, methyl tert-butyl ether (MTBE), ethanol, ethyl acetate, heptane, isopropyl acetate, methyl acetate, methyl ethyl ketone (MEK) and toluene. In some embodiments, the solvent is isopropanol. In some embodiments, Form II of Compound I is prepared by the sequence of steps described in the Examples section.

[0052] Forms IIIA-IIID of Compound I - Mesylate Salts In one embodiment, provided herein is crystalline 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methylpropyl)phenyl]phenyl]-2-fluoro-benzonitrile mesylate (Form IIIA of Compound I), characterized by an X-ray powder diffraction pattern comprising the following peaks, expressed as 2θ angles determined using Cu K-α (λ=1.5406 Å) radiation: 6.24°±0.2°, 16.47°±0.2°, and 21.20°±0.2°.

[0053] In some embodiments, the diffraction pattern of Form IIIA of Compound I further comprises one or more peaks selected from 15.39°±0.2°, 16.97°±0.2°, and 21.51°±0.2°, expressed as 2θ angles determined using Cu K-α (λ=1.5406 Å) radiation.

[0054] In some embodiments, the diffraction pattern of Form IIIA of Compound I further comprises two or more peaks selected from 8.52°±0.2°, 15.39°±0.2°, 16.97°±0.2°, 17.95°±0.2°, and 21.51°±0.2°, expressed as 2θ angles determined using Cu K-α (λ=1.5406 Å) radiation.

[0055] In some embodiments, the diffraction pattern of Form IIIA of Compound I comprises peaks selected from 6.24°±0.2°, 8.52°±0.2°, 15.39°±0.2°, 16.47°±0.2°, 16.97°±0.2°, 17.95°±0.2°, 21.20°±0.2°, and 21.51°±0.2°, expressed as 2θ angles determined using Cu K-α (λ=1.5406 Å) radiation.

[0056] In some embodiments, the diffraction pattern of Form IIIA of Compound I is substantially as shown in FIG. 3A.

[0057] In some embodiments, the differential scanning calorimetry (DSC) curve for Form IIIA of Compound I exhibits an endotherm onset at about 169.3°C.

[0058] In some embodiments, the DSC curve of Form IIIA of Compound I is substantially as shown in Figure 3B.

[0059] In some embodiments, Form IIIA of Compound I is contacting a solution of Compound I in a solvent with a solution of methanesulfonic acid in the solvent at room temperature to obtain a slurry; filtering the solids from the slurry to obtain a filter cake; drying the filter cake to obtain Form IIIA of Compound I; It is prepared by a process comprising:

[0060] In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is isopropanol. In some embodiments, Form IIIA of compound I is prepared by the sequence of steps described in the Examples section. In some embodiments, a similar process provided Form IIIB of compound I when the solvent was anisole. In some embodiments, a similar process provided Form IIIC of compound I when the solvent was butanol, 1,4-dioxane, ethyl acetate, methyl ethyl ketone, or toluene. In some embodiments, a similar process provided Form IIID of compound I when the solvent was trifluorotoluene or isopropanol. In some embodiments, Forms IIIB, IIIC, and IIID of compound I are prepared by the sequence of steps described in the Examples section.

[0061] Forms IVA and IVB of Compound I - Esylate Salt In one embodiment, provided herein is crystalline 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methylpropyl)phenyl]phenyl]-2-fluoro-benzonitrile esylate (Form IVA of Compound I), characterized by an X-ray powder diffraction pattern comprising the following peaks, expressed as 2θ angles determined using Cu K-α (λ=1.5406 Å) radiation: 6.17°±0.2°, 16.86°±0.2°, and 20.92°±0.2°.

[0062] In some embodiments, the diffraction pattern of Form IVA of Compound I further comprises one or more peaks selected from 8.42°±0.2°, 18.99°±0.2°, and 21.57°±0.2°, expressed as 2θ angles determined using Cu K-α (λ=1.5406 Å) radiation.

[0063] In some embodiments, the diffraction pattern of Form IVA of Compound I further comprises two or more peaks selected from 8.42°±0.2°, 18.99°±0.2°, 21.57°±0.2°, and 24.26°±0.2°, expressed as 2θ angles determined using Cu K-α (λ=1.5406 Å) radiation.

[0064] In some embodiments, the diffraction pattern of Form IVA of Compound I comprises peaks selected from 6.17°±0.2°, 8.42°±0.2°, 16.86°±0.2°, 18.99°±0.2°, 20.92°±0.2°, 21.57°±0.2°, and 24.26°±0.2°, expressed as 2θ angles determined using Cu K-α (λ=1.5406 Å) radiation.

[0065] In some embodiments, the diffraction pattern of Form IVA of Compound I is substantially as shown in FIG. 4A.

[0066] In some embodiments, the differential scanning calorimetry (DSC) curve for Form IVA of Compound I exhibits an endotherm onset at about 238.5°C.

[0067] In some embodiments, the DSC curve of Form IVA of Compound I is substantially as shown in Figure 4B.

[0068] In some embodiments, Form IVA of Compound I is contacting a solution of Compound I in a solvent with a solution of ethanesulfonic acid in a solvent at room temperature to obtain a slurry; filtering the solids from the slurry to obtain a filter cake; drying the filter cake to obtain Form IVA of Compound I; It is prepared by a process comprising:

[0069] In some embodiments, the solvent is selected from acetonitrile, anisole, butanol, methyl tert-butyl ether (MTBE), ethanol, ethyl acetate, heptane, isopropyl acetate, methyl acetate, methyl ethyl ketone (MEK), and toluene. In some embodiments, Form IVA of Compound I is prepared by the sequence of steps described in the Examples section. In some embodiments, a similar process provided Form IVB of Compound I when the solvent was THF or isopropanol. In some embodiments, Form IVB of Compound I is prepared by the sequence of steps described in the Examples section.

[0070] Form V of Compound I - Maleate Salt In one embodiment, provided herein is crystalline 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methylpropyl)phenyl]phenyl]-2-fluoro-benzonitrile maleate (Form V of Compound I), characterized by an X-ray powder diffraction pattern of Form IIIA of Compound I containing the following peaks, expressed as 2θ angles determined using Cu K-α (λ=1.5406 Å) radiation: 6.18°±0.2°, 17.41°±0.2°, and 19.34°±0.2°.

[0071] In some embodiments, the diffraction pattern of Form V of Compound I further comprises one or more peaks selected from 18.10°±0.2°, 22.20°±0.2°, and 24.14°±0.2°, expressed as 2θ angles determined using Cu K-α (λ=1.5406 Å) radiation.

[0072] In some embodiments, the diffraction pattern of Form V of Compound I further comprises two or more peaks selected from 12.78°±0.2°, 18.10°±0.2°, 22.20°±0.2°, 24.14°±0.2°, and 25.87°±0.2°, expressed as 2θ angles determined using Cu K-α (λ=1.5406 Å) radiation.

[0073] In some embodiments, the diffraction pattern of Form V of Compound I comprises peaks selected from 6.18°±0.2°, 12.78°±0.2°, 17.41°±0.2°, 18.10°±0.2°, 19.34°±0.2°, 22.20°±0.2°, 24.14°±0.2°, and 25.87°±0.2°, expressed as 2θ angles determined using Cu K-α (λ=1.5406 Å) radiation.

[0074] In some embodiments, the diffraction pattern of Form V of Compound I is substantially as shown in FIG. 5A.

[0075] In some embodiments, the differential scanning calorimetry (DSC) curve of Form V of Compound I exhibits an endotherm onset at about 139.9°C.

[0076] In some embodiments, the DSC curve of Form V of Compound I is substantially as shown in Figure 5B.

[0077] In some embodiments, Form V of Compound I is contacting a solution of Compound I in a solvent with a solution of maleic acid in a solvent at room temperature to obtain a slurry; filtering the solids from the slurry to obtain a filter cake; drying the filter cake to obtain Form V of Compound I; It is prepared by a process comprising:

[0078] In some embodiments, the solvent is selected from acetonitrile, anisole, butanol, isopropanol, methyl tert-butyl ether (MTBE), ethanol, ethyl acetate, heptane, isopropyl acetate, methyl acetate, methyl ethyl ketone (MEK) and toluene. In some embodiments, the solvent is isopropanol. In some embodiments, Form V of Compound I is prepared by the sequence of steps described in the Examples section.

[0079] 3. Pharmaceutical Compositions, Kits and Modes of Administration The forms of Compound I described herein can be administered in pharmaceutical compositions. That is, pharmaceutical compositions are provided herein that include one or more forms of Compound I described herein and one or more pharma- ceutically acceptable vehicles, such as carriers, adjuvants, and excipients. Suitable pharma-ceutically acceptable vehicles include, for example, inert solid diluents and bulking agents, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner known in the pharmaceutical art. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985) and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker & CT Rhodes, Eds.). Pharmaceutical compositions can be administered alone or in combination with other therapeutic agents.

[0080] Some embodiments relate to pharmaceutical compositions comprising a therapeutically effective amount of a solid form of Compound I described herein. In some embodiments, the pharmaceutical compositions comprise a solid form selected from Form I of Compound I, Form II of Compound I, Form IIIA of Compound I, Form IVA of Compound I, and / or Form V of Compound I, and one or more pharma- ceutically acceptable carriers.

[0081] Some embodiments relate to pharmaceutical compositions comprising a crystalline or amorphous form of Compound I as described herein and one or more pharma- ceutically acceptable carriers. In one embodiment, the pharmaceutical composition comprises Compound I, where at least 95% of Compound I is in a crystalline form as described herein. In one embodiment, the pharmaceutical composition comprises Compound I, where at least 95% of Compound I is in an amorphous form as described herein. In one embodiment, the pharmaceutical composition comprises Compound I, where at least 95% of Compound I is in Form I. In one embodiment, the pharmaceutical composition comprises Compound I, where at least 95% of Compound I is in Form II. In one embodiment, the pharmaceutical composition comprises Compound I, where at least 95% of Compound I is in Form IIIA. In one embodiment, the pharmaceutical composition comprises Compound I, where at least 95% of Compound I is in Form IVA. In one embodiment, the pharmaceutical composition comprises Compound I, where at least 95% of Compound I is in Form V.

[0082] In one embodiment, the pharmaceutical composition comprises Compound I, wherein 97% or more of Compound I is in a crystalline form described herein. In one embodiment, the pharmaceutical composition comprises Compound I, wherein at least 97% of Compound I is in Form I. In one embodiment, the pharmaceutical composition comprises Compound I, wherein at least 97% of Compound I is in Form II. In one embodiment, the pharmaceutical composition comprises Compound I, wherein at least 97% of Compound I is in Form IIIA. In one embodiment, the pharmaceutical composition comprises Compound I, wherein at least 97% of Compound I is in Form IVA. In one embodiment, the pharmaceutical composition comprises Compound I, wherein at least 97% of Compound I is in Form V.

[0083] In one embodiment, the pharmaceutical composition comprises Compound I, wherein at least 99% of Compound I is in a crystalline form described herein. In one embodiment, the pharmaceutical composition comprises Compound I, wherein at least 99% of Compound I is in Form I. In one embodiment, the pharmaceutical composition comprises Compound I, wherein at least 99% of Compound I is in Form II. In one embodiment, the pharmaceutical composition comprises Compound I, wherein at least 99% of Compound I is in Form IIIA. In one embodiment, the pharmaceutical composition comprises Compound I, wherein at least 99% of Compound I is in Form IVA. In one embodiment, the pharmaceutical composition comprises Compound I, wherein at least 99% of Compound I is in Form V.

[0084] In one embodiment, the pharmaceutical composition comprises Compound I, wherein at least 99.5% of Compound I is in a crystalline form described herein. In one embodiment, the pharmaceutical composition comprises Compound I, wherein at least 99.5% of Compound I is in Form I. In one embodiment, the pharmaceutical composition comprises Compound I, wherein at least 99.5% of Compound I is in Form II. In one embodiment, the pharmaceutical composition comprises Compound I, wherein at least 99.5% of Compound I is in Form IIIA. In one embodiment, the pharmaceutical composition comprises Compound I, wherein at least 99.5% of Compound I is in Form IVA. In one embodiment, the pharmaceutical composition comprises Compound I, wherein at least 99.5% of Compound I is in Form V.

[0085] In one embodiment, the pharmaceutical composition comprises Compound I, wherein at least 99.9% of Compound I is in a crystalline form described herein. In one embodiment, the pharmaceutical composition comprises Compound I, wherein at least 99.9% of Compound I is in Form I. In one embodiment, the pharmaceutical composition comprises Compound I, wherein at least 99.9% of Compound I is in Form II. In one embodiment, the pharmaceutical composition comprises Compound I, wherein at least 99.9% of Compound I is in Form IIIA. In one embodiment, the pharmaceutical composition comprises Compound I, wherein at least 99.9% of Compound I is in Form IVA. In one embodiment, the pharmaceutical composition comprises Compound I, wherein at least 99.9% of Compound I is in Form V.

[0086] Any of the crystalline forms of Compound I described herein can be processed, with or without micronization, into various forms of pharmaceutical compositions, such as tablets, capsules, granules, granules, powdered medicines, dry syrups and similar oral preparations, suppositories, inhalants, nasal drops, ointments, patches, aerosols, etc.

[0087] In some embodiments, the composition includes pharma- ceutically acceptable carriers or excipients, such as fillers, binders, disintegrants, glidants, lubricants, complexing agents, solubilizers, and surfactants, which can be selected to facilitate administration of the compound by a particular route. Examples of carriers include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, starches, cellulose derivatives, gelatin, lipids, liposomes, nanoparticles, and the like. Carriers also include physiologically compatible liquids for use as solvents or suspensions, including, for example, sterile solutions of water for injection (WFI), physiological saline, glucose solutions, Hanks' solution, Ringer's solution, vegetable oils, mineral oils, animal oils, polyethylene glycols, liquid paraffin, and the like. Examples of excipients include colloidal silicon dioxide, silica gel, talc, magnesium silicate, calcium silicate, sodium aluminosilicate, magnesium trisilicate, powdered cellulose, macrocrystalline cellulose, carboxymethylcellulose, crosslinked sodium carboxymethylcellulose, sodium benzoate, calcium carbonate, magnesium carbonate, stearic acid, aluminum stearate, calcium stearate, magnesium stearate, zinc stearate, sodium stearyl fumarate, syloid, stearowetC, magnesium oxide, starch, sodium starch glycolate, glyceryl monostearate, glyceryl dibehenate, glyceryl palmitostearate, hydrogenated vegetable oil, hydrogenated cottonseed oil, castor oil, mineral oil, polyethylene glycol (e.g., PEG4000-8000), polyoxyethylene glycol, poloxamer, povidone, crospovidone, croscarmellose sodium, alginic acid, casein, methacrylate divinylbenzene copolymer, sodium docusate, cyclodextrin (e.g., 2-hydroxypropyl-δ-cyclodextrin), polysorbate (e.g., polysorbate 80), cetrimide, TPGS (d-α-tocopherol polyethylene glycol 1000 succinate), magnesium lauryl sulfate, sodium lauryl sulfate, polyethylene glycol ether, difatty acid ester of polyethylene glycol, or polyoxyalkylene sol. Also included are sorbitan fatty acid esters (e.g., Polyoxyethylene Sorbitan Ester Tween™), polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters, e.g., sorbitan fatty acid esters from fatty acids such as oleic acid, stearic acid or palmitic acid, mannitol, xylitol, sorbitol, maltose, lactose, lactose monohydrate or lactose spray dried, sucrose, fructose, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, dextrates, dextran, dextrin, dextrose, cellulose acetate, maltodextrin, simethicone, polydextrosem, chitosan, gelatin, HPMC (hydroxypropyl methylcellulose), HPC (hydroxypropyl cellulose), hydroxyethyl cellulose, and the like.

[0088] Pharmaceutical formulations can be in unit dosage forms containing a predetermined amount of active ingredient per unit dosage. Such units can contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound of the present disclosure (in any form, as a free acid, solvate (including hydrate) or salt), depending on the condition to be treated, the route of administration, and the age, weight and condition of the patient. Preferred unit dosage formulations are those containing a daily dose, weekly dose, monthly dose, sub-dose or an appropriate minor fraction thereof of an active ingredient. Moreover, such pharmaceutical formulations can be prepared by any method known in the art of pharmacy.

[0089] Compound I and any one of its forms described herein are usually administered in the form of pharmaceutical compositions.Therefore, also provided herein is a pharmaceutical composition comprising one or more of Compound I, any one of its forms described herein, and one or more pharma-ceutically acceptable vehicles selected from carriers, adjuvants and excipients.Suitable pharma-ceutically acceptable vehicles can include, for example, inert solid diluents and bulking agents, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants.Such compositions are prepared in a manner known in the pharmaceutical art.See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985) and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker & CT Rhodes, Eds.).

[0090] The pharmaceutical composition can be administered in either a single dose or multiple doses. The pharmaceutical composition can be administered by a variety of methods, including, for example, rectal, buccal, intranasal, and transdermal routes. In certain embodiments, the pharmaceutical composition can be administered by intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or inhalant.

[0091] One mode of administration is parenterally, for example, by injection. Forms in which the pharmaceutical compositions described herein can be incorporated for administration by injection include, for example, aqueous or oily suspensions or emulsions using sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0092] When preparing an injection, a pH adjuster, a buffer, a stabilizer, an isotonicity agent, a local anesthetic, etc. can be added to the crystalline form of Compound I as necessary, and the resulting mixture can be formulated into a subcutaneous injection, an intramuscular injection, or an intravenous injection according to a conventional method.

[0093] Examples of usable pH adjusters and buffers include sodium citrate, sodium acetate, sodium phosphate, etc. Examples of usable stabilizers include sodium pyrosulfite, EDTA, thioglycolic acid, and thiolactic acid. Examples of usable local anesthetics include procaine hydrochloride, lidocaine hydrochloride, etc. Examples of usable isotonicity agents include sodium chloride, glucose, D-mannitol, glycerin, etc.

[0094] Oral administration can be another route of administration of the compounds described herein. Administration can be, for example, via capsules or enteric coated tablets. When preparing pharmaceutical compositions containing at least one compound described herein, or its pharma- ceutically acceptable salts, isotopically enriched analogs, stereoisomers, mixtures of stereoisomers, or prodrugs thereof, the active ingredient is usually diluted with an excipient and / or enclosed in a carrier, such as may be in the form of a capsule, sachet, paper, or other container. When an excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which serves as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), ointment, soft and hard gelatin capsules, sterile injectable liquids, and sterile packaged powders.

[0095] Oral solid preparations can be prepared by adding excipients to the crystalline form of Compound I, optionally together with binders, disintegrants, lubricants, colorants, taste-masking or flavoring agents, etc., and then formulating the resulting mixture into tablets, coated tablets, granules, powders, capsules, etc., by methods known in the art.

[0096] Examples of excipients include lactose, sucrose, D-mannitol, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, and anhydrous silicic acid. Examples of binders include water, ethanol, 1-propanol, 2-propanol, simple syrup, liquid glucose, liquid α-starch, liquid gelatin, D-mannitol, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylstarch, methylcellulose, ethylcellulose, shellac, calcium phosphate, and polyvinylpyrrolidone. Examples of disintegrants include dry starch, sodium alginate, powdered agar, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, monoglyceride stearate, and lactose. Examples of lubricants include purified talc, sodium stearate, magnesium stearate, borax, and polyethylene glycol. Examples of colorants include titanium oxide and iron oxide. Examples of taste-masking or flavoring agents include sucrose, bitter orange peel, citric acid, L-tartaric acid, etc. The formulations can further include wetting agents, emulsifying and suspending agents, preservatives such as methyl- and propyl hydroxybenzoates.

[0097] When preparing liquid preparations for oral administration, taste masking agents, buffering agents, stabilizers, flavoring agents, and the like can be added to one of the forms of Compound I described herein, and the resulting mixture can be formulated into oral liquid preparations, syrups, elixirs, and the like in a conventional manner.

[0098] In this case, the same taste masking agent or flavoring agent as above can be used. Examples of buffers include sodium citrate, etc., and examples of stabilizers include tragacanth, gum arabic, gelatin, etc. If necessary, these preparations for oral administration can be coated with enteric coating or other coatings according to the method known in the art, for example, for the purpose of prolonged effect. Examples of such coating agents include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, and Tween 80 (trademark).

[0099] Compositions comprising at least one of the forms of Compound I described herein can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a subject by using procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems comprising polymer-coated reservoirs or drug-polymer matrix formulations. Another formulation used in the methods disclosed herein employs transdermal delivery devices ("patches"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for the delivery of therapeutic agents is known in the art. Such patches can be constructed for continuous, pulsatile, or on-demand delivery of therapeutic agents.

[0100] To prepare solid compositions such as tablets, the principal active ingredient can be mixed with pharmaceutical excipients to form solid preformulation compositions that contain a homogeneous mixture of Compound I and any one of its forms described herein. These preformulation compositions are referred to as homogeneous in that the active ingredient can be evenly dispersed throughout the composition, which allows the composition to be readily subdivided into similarly effective unit dosage forms such as tablets, pills, and capsules.

[0101] The tablet or pill of Compound I and any one of its forms described herein can be coated or otherwise compounded to provide a dosage form that provides the advantage of extended action or to protect against the acidic conditions of the stomach.For example, the tablet or pill can comprise an inner dosage component and an outer dosage component, the latter being in the form of an outer membrane over the former.The two components can be separated by an enteric layer that functions to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or to be delayed in release.For such enteric layer or coating, a variety of materials can be used, including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

[0102] In another aspect, the disclosure provides a kit or container comprising compound I and any one of its forms described herein, or any one of its pharmaceutical compositions described herein. In some embodiments, the compound or composition is packaged, for example, in a vial, bottle, flask, which may be further packaged, for example, in a box, packet, or bag. The compound or composition is approved by the U.S. Food and Drug Administration or a similar regulatory agency for administration to a mammal, for example, a human. The compound or composition is approved for administration to a mammal, for example, a human, for a bromodomain protein-mediated disease or condition. The kit or container disclosed herein may include instructions for use and / or other indications indicating that the compound or composition is suitable or approved for administration to a mammal, for example, a human, for a bromodomain protein-mediated disease or condition. The compound or composition may be packaged in a unit dose or single dose form, for example, a single dose pill, capsule, etc.

[0103] The amount of various compounds administered depends on the activity of the compounds (in vitro, e.g., the IC 50The dosage can be determined by standard procedures, taking into consideration factors such as the efficacy of the drug in the treatment of a subject, the in vivo activity in an animal efficacy model, the pharmacokinetic results in an animal model (e.g., biological half-life or bioavailability), the age, size, weight of the subject, and any disorders associated with the subject. The importance of these and other factors is known to those of skill in the art. In general, a single dose will be in the range of about 0.01 mg / kg to 50 mg / kg, and also about 0.1 mg / kg to 20 mg / kg of the subject being treated. Multiple doses can also be used.

[0104] The amount of any one of the forms of Compound I incorporated into each such unit dosage form depends on the condition of the patient to whom the compound is administered, the dosage form, etc. In general, for oral medications, injections, and suppositories, the amount of the compound of the present disclosure is preferably 0.05 mg to 1000 mg, 0.01 mg to 500 mg, and 1 mg to 1000 mg per unit dosage form, respectively.

[0105] The daily dosage of the drug in such dosage forms depends on the patient's condition, body weight, age, sex, etc. and cannot be generalized. For example, the daily dosage of the salt of Compound I described herein for an adult (body weight: 50 kg to 70 kg) can be 0.05 mg to 5000 mg, or 0.1 mg to 1000 mg, and can be administered in a single dose or in 2 to 4 divided doses per day, or any other suitable administration schedule.

[0106] 4. Administration The specific dosage level of Compound I and any one of its forms described herein for any particular subject will depend on a variety of factors, including the activity of the particular compound used, age, body weight, overall health, sex, diet, time of administration, route of administration, and excretion rate in the subject being treated, drug combinations, and the severity of the particular disease. For example, dosages can be expressed as milligrams of the compound described herein per kilogram of subject body weight (mg / kg). Dosages between about 0.1 mg / kg and 150 mg / kg can be appropriate. In some embodiments, between about 0.1 mg / kg and 100 mg / kg can be appropriate. In other embodiments, dosages of 0.5 mg / kg to 60 mg / kg can be appropriate. In some embodiments, dosages of about 0.0001 mg to about 100 mg of the compound per kg of body weight, about 0.001 mg to about 50 mg of the compound per kg of body weight, or about 0.01 mg to about 10 mg of the compound per kg of body weight per day can be appropriate. Normalization according to subject weight is particularly useful when adjusting dosages between subjects of widely differing sizes, as occurs, for example, when using a pharmaceutical agent in both pediatric and adult subjects, or when converting an effective dosage in a non-human subject, such as a dog, to a dosage appropriate for a human subject.

[0107] 5. Disease Indication and Regulation of LSD1 Provided herein is a method for treating a lysine-specific histone demethylase 1A (LSD-1)-associated disease or condition in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a crystalline form of Compound I described herein, or a composition described herein.

[0108] In some embodiments, the LSD-1 related disease or condition is cancer.

[0109] In some embodiments, the cancer is a malignant tumor.

[0110] In some embodiments, the cancer is head and neck cancer, esophageal cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, gallbladder cancer, bile duct cancer, biliary tract cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, kidney cancer, bladder cancer, prostate cancer, testicular cancer, osteosarcoma, soft tissue sarcoma, leukemia, myelodysplastic syndrome, chronic myeloproliferative disorder, malignant lymphoma, multiple myeloma, skin cancer, brain cancer, or mesothelioma.

[0111] In some embodiments, the cancer is non-small cell lung cancer, small cell lung cancer, leukemia, or myelodysplastic syndrome.

[0112] In certain embodiments, the present disclosure provides the use of compound I and any one of its forms described herein, or any one of its pharmaceutical compositions described herein, in the manufacture of a medicament for the treatment of a disease or condition described herein. In other embodiments, the present disclosure provides compound I and any one of its forms described herein, or any one of its pharmaceutical compositions described herein, for use in the treatment of a disease or condition described herein. EXAMPLES

[0113] equipment technology X-ray powder diffraction X-ray powder diffraction (XRPD) analyses were performed using a Bruker D2 Phaser powder diffractometer equipped with a LynxEye detector. Specimens underwent minimal preparation, but were lightly ground in a pestle and mortar prior to acquisition, if necessary. Specimens were placed at the center of a silicon sample holder within a 5 mm pocket (approximately 5 mg to 10 mg). Samples were continuously rotated during data collection and scanned from 4°2θ to 40°2θ using a step size of 0.02°2θ (29). Data were acquired using either a 3 min or 20 min acquisition method. Data were processed using Bruker's Diffrac.Suite.

[0114] Differential Scanning Calorimetry and Thermogravimetry Weight loss was measured as a function of temperature from 30 °C to 600 °C using a Pyris Diamond TG / DTA 6300 from Perkin Elmer. The scan rate was 10 °C per minute and the purge gas was nitrogen. For DSC analysis, a DSC 821 instrument from Mettler Toledo was used and operated with STARe software. Analyses were performed in 40 μL open aluminum pans under nitrogen and sample sizes ranged from 1 mg to 10 mg. A typical analytical method was 20 °C to 250 °C at 10 °C / min.

[0115] Polarized light microscopy The equipment used for digital capture was an Olympus BX41 microscope equipped with a digital camera attachment. Magnifications were 100x and 400x. Samples were viewed under plane and cross polarized light.

[0116] Example 1. Synthesis of Compound I 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methyl-propyl)phenyl]phenyl]-2-fluoro-benzonitrile (Compound I) was prepared according to the procedure described in Example 37 of WO 2017 / 090756.

[0117] Example 2. Salt Screen Compound I free base was dispensed into vials. Stock solutions of various acid counterions were prepared in methanol, containing 1.0 equivalent of counterion, corrected for water content and assay value, and stoichiometric amounts (1.0 equivalent or 0.5 equivalent, as applicable) were filled into vials. The sealed vials were shaken for approximately 1-2 hours to facilitate dissolution of the substrate and salt formation. The vials were then oven dried at 40° C. under reduced pressure for approximately 20 hours to ensure removal of the solvent. The appropriate quench solvent selected for the screen was then added to each vial. The vials were sealed and shaken for approximately 18-20 hours. Each vial was inspected for solid formation. Vials containing the appropriate amount of solids were centrifuged and the supernatant was decanted off. The solid pellets were dried under reduced pressure for approximately 20 hours and analyzed by XRPD.

[0118] Solvents tested include, but are not limited to, acetone, CAN, TBME, MEK, IPA, IPAc, 1-butanol, methanol, ethanol, DCM, toluene, anisole, ethyl acetate, THF, and / or combinations thereof. Acid counterions tested include, but are not limited to, sulfate, phosphate, tartrate, fumarate, malate, succinate, glutarate, oxalate, methanesulfonate, ethanesulfonate, lactate, succinate, and / or other similar counterions.

[0119] Example 3. Form I of Compound I (hemifumarate salt) The hemifumarate salt of Form I of Compound I (2:1 ratio of Compound I:fumaric acid) was prepared as follows: To a solution of the free base of Compound I (475 mg, 1.0 mmol, 1.0 equiv.) in IPA (10 mL) was added fumaric acid (58 mg, 0.5 mmol, 0.5 equiv.) in IPA (5 mL) at room temperature, and the resulting slurry was warmed to 50° C. The resulting cloudy slurry was slowly cooled to room temperature over 2 hours. The slurry was then stirred at room temperature for an additional 4 hours and filtered. The filter cake was washed with IPA (2 mL) and dried under vacuum at 40° C. for 18 hours to obtain 300 mg (53%) of Form I of Compound I. Form I exhibited a packed lath morphology and was highly crystalline. Figure 1A, Figure 1B, and Figure 7A show the XRPD, DSC, and PLM images of Form I of Compound I, respectively.

[0120] Example 4. Form II of Compound I (Monoxalate Salt) The monooxalate salt (1:1 ratio of compound I:oxalic acid) was prepared as follows: To a solution of compound I free base (475 mg, 1.0 mmol, 1.0 equiv) in 2-propanol (10 mL) was added oxalic acid (100 mg, 1.1 mmol, 1.1 equiv) in 2-propanol (4 mL) at room temperature, and the resulting cloudy slurry was warmed to 50° C. The slurry was slowly cooled to room temperature over 2 hours. The slurry was stirred at room temperature for an additional 4 hours and filtered. The filter cake was washed with cold 2-propanol (5 mL) and dried under vacuum at 40° C. for 42 hours to give 280 mg (49.5%) of the monooxalate salt of compound I.

[0121] Recrystallization of monooxalate salt of compound I to provide form II: monooxalate salt of compound I (100 mg, 0.17 mmol) was suspended in ethanol:water (3:2 ratio, 10 mL). The resulting suspension was heated to 80° C. to give a clear solution. The clear solution was cooled to room temperature and kept for 2 days. During this period, the product crystallized as a white solid. The resulting solid was separated by filtration and the filter cake was washed with ethanol:water (3:2 ratio, 2 mL). The compound was dried under vacuum at 40° C. for 18 hours to obtain 80 mg (80% recovery) of form II of compound I. Form II exhibited stacked and plate-like morphology and was highly crystalline. Figure 2A and Figure 7B show the XRPD and PLM images of form II of compound I, respectively.

[0122] Example 5. Forms IIIA-IIID of Compound I (Mesylate Salt) To a solution of compound I free base (250 mg, 0.52 mmol, 1.0 equiv) in IPA (5 mL) (dispensed in a 25 mL round bottom flask) was added a solution of methanesulfonic acid (55.6 mg, 0.57 mmol, 1.1 equiv) in 2-propanol (5 mL) at room temperature. During the addition, the product / salt started to crystallize and the resulting slurry was stirred at room temperature for an additional 4 h. The product was isolated by filtration and the filter cake was washed with cold 2-propanol (5 mL). The resulting wet cake was oven dried under reduced pressure at 40° C. for 72 h. Yield: 246 mg, 82% of Form IIIA of compound I. Form IIIA exhibited a morphology of clustered laths, platelets and globules. Figures 3A and 3B show the XRPD and DSC of Form IIIA of compound I, respectively.

[0123] To investigate the polymorphism of the mesylate salt, amorphous mesylate salt of compound I was prepared by mixing compound I (5 g, 10.4 mmol, 1.0 equiv.) with methanesulfonic acid (1.11 g, 11.4 mmol, 1.1 equiv.) in methanol (50 mL, 10 vol.). The mixture was concentrated to dryness under reduced pressure and further dried at 40° C. under reduced pressure. Amorphous mesylate salt of compound I (approximately 50 mg) was then mixed with an appropriate solvent (1 mL, 20 vol.) and stirred at 40° C. for 7-10 days. The mixture was cooled, isolated by filtration, washed with filtrate and dried at 40° C. under reduced pressure. Form IIIA of compound I was obtained when the solvent was acetonitrile. Form IIIB of compound I was obtained when the solvent was anisole. Form IIIC of compound I was obtained when the solvent was butanol, 1,4-dioxane, ethyl acetate, methyl ethyl ketone and toluene. Under these conditions, when the solvent was trifluorotoluene or isopropanol, Form IIID of Compound I was obtained. Figures 8A, 8B, and 9A show the XRPDs of Form IIIB of Compound I, Form IIIC of Compound I, and Form IIID of Compound I, respectively.

[0124] Example 6. Forms IVA and IVB of Compound I (Esylate Salt) To a solution of the free base of compound I (250 mg, 0.52 mmol, 1.0 equiv.) in IPA (5 mL) (dispensed in a 25 mL round bottom flask) was added a solution of ethanesulfonic acid (63.7 mg, 0.57 mmol, 1.1 equiv.) in 2-propanol (5 mL) at room temperature. During the addition, the product / salt began to crystallize and the resulting slurry was stirred at room temperature for an additional 4 hours. The product was isolated by filtration and the filter cake was washed with cold 2-propanol (5 mL). The resulting wet cake was oven dried under reduced pressure at 40° C. for 72 hours. Yield: 240 mg, 78% of compound I form IVA. Form IVA exhibited a needle-like leaf-like, tubule-folded morphology. Figures 4A and 4B show the XRPD and DSC of compound I form IVA, respectively.

[0125] To investigate the polymorphism of the esylate salt, crystallization from various solvents was performed. Approximately 50 mg portions of the esylate salt were loaded into separate scintillation vials. To each vial, the appropriate solvent, as shown in the table below, was added and the suspension was heated until complete dissolution occurred. If dissolution was not achieved, binary solvent (either water or methanol) was added in small portions at 80°C until dissolution was achieved. Stirring was discontinued and the solution was removed from the heat and allowed to cool slowly and settle. Vials that showed crystals were centrifuged, the supernatant was decanted, and the solid pellet was oven dried at 40°C under reduced pressure for approximately 20 hours.

[0126] It was found that using THF as a solvent affords Form IVB of Compound I. Figures 10A and 10B show the DSC and XRPD, respectively, of Form IVB of Compound I. Form IVB of Compound I exhibits an onset of melting event at about 196°C, compared to an onset of melting at about 238°C for Form IVA of Compound I.

[0127] [Table 2]

[0128] Example 7. Form V of Compound I (Maleate Salt) To a solution of compound I free base (250 mg, 0.52 mmol, 1.0 equiv) in IPA (5 mL) (dispensed in a 25 mL round bottom flask) was added a solution of maleic acid (67.2 mg, 0.57 mmol, 1.1 equiv) in 2-propanol (5 mL) at room temperature. During the addition, the product / salt started to crystallize and the resulting slurry was stirred at room temperature for an additional 4 h. The product was isolated by filtration and the filter cake was washed with cold 2-propanol (2 mL). The resulting wet cake was oven dried under reduced pressure at 40° C. for 72 h. Yield: 217 mg (70%) of compound I form V. Form V exhibited a packed lath morphology. Figures 5A and 5B show the XRPD and DSC of compound I form V, respectively.

[0129] Example 8. Form VI of Compound I (Monofumarate Salt) To a solution of the free base of compound I (250 mg, 0.52 mmol, 1.0 equiv) in IPA (5 mL) was added a solution of fumaric acid (67.1 mg, 0.57 mmol, 1.1 equiv) in IPA (5 mL) at room temperature, and the resulting slurry was warmed to 50° C. The resulting cloudy slurry was slowly cooled to room temperature over 2 hours. The slurry was then stirred at room temperature for an additional 4 hours and filtered. The filter cake was washed with IPA (5 mL) and dried under vacuum at 40° C. for 72 hours. Yield: 233 mg, 75% of Form VI of compound I. Form VI exhibited a layered crystalline morphology with highly aggregated packed laths. Figure 6A shows the XRPD of Form VI of compound I.

[0130] Example 9. Form VII of Compound I (hemi-oxalate salt) To a solution of the free base of compound I (475 mg) in 2-propanol or ethanol (10 mL) at room temperature, oxalic acid (0.45 equiv.) in 2-propanol or ethanol was added and the resulting slurry was warmed to 50° C. The slurry was slowly cooled to room temperature over 2 hours, stirred at room temperature for an additional 4 hours, and filtered. The filter cake was washed with cold 2-propanol (5 volumes) and dried under vacuum at 45° C. for 18 hours to obtain Form VII of compound I. Form VII exhibited semi-crystalline morphology. FIG. 6B shows the PLM image for Form VII of compound I.

[0131] Example 10. Stability Test The stability of the different salt forms was tested. The salts were placed in 20 mL scintillation vials, covered with Kimwipes, and the resulting vials were exposed to 40° C. and 75% RH (relative humidity) for 5 days. The samples were analyzed for moisture absorption. The results are shown below.

[0132] [Table 3]

[0133] The monofumarate salt, Form VI, did not absorb any moisture under the conditions tested. The hemifumarate salt (Form I) and monooxalate salt (Form II) were observed to absorb between 1% and 4.5% moisture under the conditions tested.

[0134] Both the mono-fumarate salt (Form VI) and the hemifumarate salt (Form I) of Compound I crystallized from solution. The mono-fumarate salt (Form VI) was a sticky solid and took a long time to filter. The mono-fumarate salt (Form VI) produced plate-like crystals. However, the degree of crystallinity was low by XRPD.

[0135] The hemifumarate salt (Form I) filtered well and produced tightly packed laths or needles with good crystallinity by XRPD.

[0136] Both the monooxalate and the hemixalate salts (Form VII of Compound I) crystallized from solution. The hemixalate salt (Form VII) was sticky and took a long time to filter.

[0137] The monooxalate salt filtered well, however the monooxalate salt obtained from IPA had low crystallinity by XRPD and was a semi-crystalline material.

[0138] The monooxalate salt, when subsequently recrystallized from ethanol (Form II of Compound I), filtered well and was highly crystalline (XRPD). The particles of the monooxalate salt (Form II) appeared to consist of stacked and platelet morphologies.

[0139] In general, Form I of the hemifumarate salt was crystalline (XRPD), had low residual moisture, a particle size distribution (PSD) of d90=143 μm, and was slightly hygroscopic. Form I exhibited densely packed lath or needle morphology. The monooxalate salt (Form II) recrystallized from ethanol was crystalline (XRPD), had a PSD of d90=50 μm, had good water solubility, and was slightly hygroscopic. Form II exhibited layered and plate-like morphology.

[0140] All patents and other references cited in this specification are indicative of the level of skill of those skilled in the art to which this disclosure pertains and are hereby incorporated by reference in their entirety, including any tables and figures, to the same extent as if each reference was individually incorporated by reference in its entirety.

[0141] Those skilled in the art will readily appreciate that the present disclosure is well adapted to obtain the objects and advantages mentioned, as well as those inherent in the present disclosure. The methods, variations, and compositions described herein as representative of the presently preferred embodiments are exemplary and are not intended to limit the scope of the disclosure. Modifications therein and other uses will occur to those skilled in the art, which are encompassed within the spirit of the disclosure and defined by the scope of the claims.

Claims

1. Crystalline 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methylpropyl)phenyl]phenyl]-2-fluoro-benzonitrile hemifumarate (Form I of Compound I), characterized by an X-ray powder diffraction pattern containing the following peaks, expressed as 2θ angles determined using Cu K-alpha (λ=1.5406 Å) radiation: 9.37°±0.2°, 14.63°±0.2°, and 21.27°±0.2°.

2. 2. The crystalline form of claim 1, wherein the diffraction pattern further comprises one or more peaks selected from 4.73°±0.2°, 18.86°±0.2°, and 20.65°±0.2°, expressed as 2θ angles determined using Cu K-α (λ=1.5406 Å) radiation.

3. 2. The crystalline form of claim 1, wherein the diffraction pattern further comprises two or more peaks selected from 4.73°±0.2°, 8.18°±0.2°, 14.79°±0.2°, 18.86°±0.2°, 20.41°±0.2°, and 20.65°±0.2°, expressed as 2θ angles determined using Cu K-α (λ=1.5406 Å) radiation.

4. 2. The crystalline form of claim 1, wherein the diffraction pattern is substantially as shown in FIG. 1A.

5. The crystalline form is contacting a solution of Compound I in a solvent with a solution of fumaric acid in a solvent at room temperature to obtain a slurry; warming the slurry to a temperature of about 50° C.; Cooling the slurry to room temperature; filtering the solids from the slurry to obtain a filter cake; drying the filter cake to obtain Form I of Compound I; 2. The crystalline form of claim 1, prepared by a process comprising:

6. 6. The crystalline form of claim 5, wherein the solvent is selected from acetonitrile, anisole, butanol, isopropanol, methyl tert-butyl ether (MTBE), ethanol, ethyl acetate, heptane, isopropyl acetate, methyl acetate, methyl ethyl ketone (MEK), and toluene.

7. 6. The crystalline form of claim 5, wherein the solvent is isopropanol.

8. Crystalline 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methylpropyl)phenyl]phenyl]-2-fluoro-benzonitrile monooxalate (Form II of Compound I), characterized by an X-ray powder diffraction pattern containing the following peaks, expressed as 2θ angles determined using Cu K-alpha (λ=1.5406 Å) radiation: 13.86°±0.2°, 19.05°±0.2°, and 22.94°±0.

2.

9. 9. The crystalline form of claim 8, wherein the diffraction pattern further comprises one or more peaks selected from 18.50°±0.2°, 22.31°±0.2°, and 28.48°±0.2°, expressed as 2θ angles determined using Cu K-α (λ=1.5406 Å) radiation.

10. 9. The crystalline form of claim 8, wherein the diffraction pattern further comprises two or more peaks selected from 15.83°±0.2°, 16.32°±0.2°, 18.50°±0.2°, 18.79°±0.2°, 22.31°±0.2°, and 28.48°±0.2°, expressed as 2θ angles determined using Cu K-α (λ=1.5406 Å) radiation.

11. 9. The crystalline form of claim 8, wherein the diffraction pattern is substantially as shown in FIG.

12. The crystalline form is contacting a solution of Compound I in a solvent with a solution of oxalic acid in a solvent at room temperature to obtain a slurry; warming the slurry to a temperature of about 50° C.; Cooling the slurry to room temperature; filtering the solids from the slurry to obtain a filter cake; drying the filter cake to obtain the monooxalate salt of Compound I; recrystallizing the monooxalate salt of Compound I from ethanol to obtain Form II of Compound I; 9. The crystalline form of claim 8, prepared by a process comprising:

13. 13. The crystalline form of claim 12, wherein the solvent is selected from acetonitrile, anisole, butanol, isopropanol, methyl tert-butyl ether (MTBE), ethanol, ethyl acetate, heptane, isopropyl acetate, methyl acetate, methyl ethyl ketone (MEK), and toluene.

14. 13. The crystalline form of claim 12, wherein the solvent is isopropanol.

15. Crystalline 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methylpropyl)phenyl]phenyl]-2-fluoro-benzonitrile mesylate (Form IIIA of Compound I), characterized by an X-ray powder diffraction pattern containing the following peaks, expressed as 2θ angles determined using Cu K-alpha (λ=1.5406 Å) radiation: 6.24°±0.2°, 16.47°±0.2°, and 21.20°±0.2°.

16. 16. The crystalline form of claim 15, wherein the diffraction pattern further comprises one or more peaks selected from 15.39°±0.2°, 16.97°±0.2°, and 21.51°±0.2°, expressed as 2θ angles determined using Cu K-α (λ=1.5406 Å) radiation.

17. 17. The crystalline form of claim 16, wherein the diffraction pattern further comprises two or more peaks selected from 8.52°±0.2°, 15.39°±0.2°, 16.97°±0.2°, 17.95°±0.2°, and 21.51°±0.2°, expressed as 2θ angles determined using Cu K-α (λ=1.5406 Å) radiation.

18. 16. The crystalline form of claim 15, wherein the diffraction pattern is substantially as shown in FIG. 3A.

19. 16. The crystalline form of claim 15, characterized by a differential scanning calorimetry (DSC) curve exhibiting an endothermic onset at about 169.3°C.

20. 20. The crystalline form of claim 19, wherein the DSC curve is substantially as shown in Figure 3B.

21. The crystalline form is contacting a solution of Compound I in a solvent with a solution of methanesulfonic acid in a solvent at room temperature to obtain a slurry; filtering the solids from the slurry to obtain a filter cake; drying the filter cake to obtain Form IIIA of Compound I; 16. The crystalline form of claim 15, prepared by a process comprising:

22. 22. The crystalline form of claim 21 , wherein the solvent is acetonitrile or isopropanol.

23. 22. The crystalline form of claim 21 , wherein the solvent is isopropanol.

24. Crystalline 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methylpropyl)phenyl]phenyl]-2-fluoro-benzonitrile esylate (Form IVA of Compound I), characterized by an X-ray powder diffraction pattern containing the following peaks, expressed as 2θ angles determined using Cu K-alpha (λ=1.5406 Å) radiation: 6.17°±0.2°, 16.86°±0.2°, and 20.92°±0.2°.

25. 25. The crystalline form of claim 24, wherein the diffraction pattern further comprises one or more peaks selected from 8.42°±0.2°, 18.99°±0.2°, and 21.57°±0.2°, expressed as 2θ angles determined using Cu K-α (λ=1.5406 Å) radiation.

26. 25. The crystalline form of claim 24, wherein the diffraction pattern further comprises two or more peaks selected from 8.42°±0.2°, 18.99°±0.2°, 21.57°±0.2°, and 24.26°±0.2°, expressed as 2θ angles determined using Cu K-α (λ=1.5406 Å) radiation.

27. 25. The crystalline form of claim 24, wherein the diffraction pattern is substantially as shown in Figure 4A.

28. 25. The crystalline form of claim 24, characterized by a differential scanning calorimetry (DSC) curve exhibiting an endothermic onset at about 238.5°C.

29. 29. The crystalline form of claim 28, wherein the DSC curve is substantially as shown in Figure 4B.

30. The crystalline form is contacting a solution of Compound I in a solvent with a solution of ethanesulfonic acid in a solvent at room temperature to obtain a slurry; filtering the solids from the slurry to obtain a filter cake; drying the filter cake to obtain Form IVA of Compound I; 25. The crystalline form of claim 24, prepared by a process comprising:

31. 31. The crystalline form of claim 30, wherein the solvent is selected from acetonitrile, anisole, butanol, methyl tert-butyl ether (MTBE), ethanol, ethyl acetate, heptane, isopropyl acetate, methyl acetate, methyl ethyl ketone (MEK), and toluene.

32. 31. The crystalline form of claim 30, wherein the solvent is isopropanol.

33. Crystalline 4-[5-[(3S)-3-aminopyrrolidine-1-carbonyl]-2-[2-fluoro-4-(2-hydroxy-2-methylpropyl)phenyl]phenyl]-2-fluoro-benzonitrile maleate (Form V of Compound I), characterized by an X-ray powder diffraction pattern of Form IIIA of Compound I containing the following peaks, expressed as 2θ angles determined using Cu K-alpha (λ=1.5406 Å) radiation: 6.18°±0.2°, 17.41°±0.2°, and 19.34°±0.2°.

34. 34. The crystalline form of claim 33, wherein the diffraction pattern further comprises one or more peaks selected from 18.10°±0.2°, 22.20°±0.2°, and 24.14°±0.2°, expressed as 2θ angles determined using Cu K-α (λ=1.5406 Å) radiation.

35. 34. The crystalline form of claim 33, wherein the diffraction pattern further comprises two or more peaks selected from 12.78°±0.2°, 18.10°±0.2°, 22.20°±0.2°, 24.14°±0.2°, and 25.87°±0.2°, expressed as 2θ angles determined using Cu K-α (λ=1.5406 Å) radiation.

36. 34. The crystalline form of claim 33, wherein the diffraction pattern is substantially as shown in Figure 5A.

37. 34. The crystalline form of claim 33, characterized by a differential scanning calorimetry (DSC) curve exhibiting an endothermic onset at about 139.9°C.

38. 38. The crystalline form of claim 37, wherein the DSC curve is substantially as shown in Figure 5B.

39. The crystalline form is contacting a solution of Compound I in a solvent with a solution of maleic acid in a solvent at room temperature to obtain a slurry; filtering the solids from the slurry to obtain a filter cake; drying the filter cake to obtain Form V of Compound I; 34. The crystalline form of claim 33, prepared by a process comprising:

40. 40. The crystalline form of claim 39, wherein the solvent is selected from acetonitrile, anisole, butanol, isopropanol, methyl tert-butyl ether (MTBE), ethanol, ethyl acetate, heptane, isopropyl acetate, methyl acetate, methyl ethyl ketone (MEK), and toluene.

41. 40. The crystalline form of claim 39, wherein the solvent is isopropanol.

42. 42. The crystalline form of any one of claims 1 to 41, wherein the crystalline form is in substantially pure form.

43. A pharmaceutical composition for treating a lysine-specific histone demethylase 1A (LSD-1) associated disease or condition in a mammal, comprising a crystalline form of Compound I according to any one of claims 1 to 41 and one or more pharma- ceutically acceptable carriers.

44. 44. The pharmaceutical composition of claim 43, wherein at least 99% of Compound I is in a crystalline form.

45. 44. The pharmaceutical composition of claim 43, wherein at least 95% of Compound I is in a crystalline form.

46. 44. The pharmaceutical composition of claim 43, wherein the LSD-1 related disease or condition is cancer.

47. 47. The pharmaceutical composition of claim 46, wherein the cancer is head and neck cancer, esophageal cancer, gastric cancer, colon cancer, rectal cancer, liver cancer, gallbladder cancer, bile duct cancer, biliary tract cancer, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, kidney cancer, bladder cancer, prostate cancer, testicular tumor, osteosarcoma, soft tissue sarcoma, leukemia, myelodysplastic syndrome, chronic myeloproliferative disorder, malignant lymphoma, multiple myeloma, skin cancer, brain tumor, or mesothelioma.

48. 47. The pharmaceutical composition of claim 46, wherein the cancer is non-small cell lung cancer, small cell lung cancer, leukemia, or myelodysplastic syndrome.

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