Solid forms of compounds for modulating kinases - Patents.com

Abstract

Forms of 4-(6-(3,5-dimethylisoxazol-4-yl)-1-[(1S)-1-(2-pyridyl)ethyl]pyrrolo[3,2-b]pyridin-3-yl)benzoic acid (Compound I) have been prepared and characterized in the solid state, (I). Manufacturing processes and methods using forms of Compound I are also provided.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 62 / 572,099, filed October 13, 2017, which is incorporated by reference herein in its entirety.

[0002] The present disclosure generally relates to solid forms of compounds that modulate or inhibit the activity of bromodomain proteins, their pharmaceutical compositions, their therapeutic uses, and the process for making the solid forms.The present disclosure also provides an embodiment for a method of treating myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in a subject in need thereof by administering to the subject an effective amount of any one of the solid forms of compound I in combination with an effective amount of a DNA methylation inhibitor (HMA). [Background technology]

[0003] There is still a need to develop effective treatments for subjects suffering from or at risk of protein kinase mediated diseases or conditions.Suitable compounds for treating such diseases and conditions, including Compound I, are disclosed in US Patent Publication No. 2015 / 0133400, the disclosure of which is incorporated herein by reference in its entirety.

[0004] There also remains a need for highly pure solid forms of Compound I that are effective in treating diseases modulated by bromodomain proteins. Summary of the Invention

[0005] The present disclosure relates to compound I of the formula: [ka] and solid forms of its salts, co-crystals, solvates, and hydrates. Also described herein are processes for producing the solid forms of Compound I, pharmaceutical compositions comprising the solid forms of Compound I, and methods for using such solid forms and pharmaceutical compositions in the treatment of diseases mediated by bromodomain proteins.

[0006] Thus, the present disclosure provides, in one embodiment, a free acid amorphous form of Compound I.

[0007] In some embodiments, the free acid amorphous form of Compound I is characterized by an X-ray powder diffraction pattern substantially as shown in FIG.

[0008] In some embodiments, the free acid amorphous form of Compound I is characterized by a thermogravimetric analysis (TGA) thermogram exhibiting a weight loss of about 17% up to about 250° C. In some embodiments, the free acid amorphous form of Compound I is characterized by a TGA thermogram substantially as shown in FIG.

[0009] In some embodiments, the free acid amorphous form of Compound I is characterized by a differential scanning calorimetry (DSC) curve that includes an exotherm with a maximum peak at about 237° C. In some embodiments, the free acid amorphous form of Compound I of claim 5 is characterized by a DSC curve substantially as shown in FIG.

[0010] In some embodiments, the free acid amorphous form of Compound I is a free acid amorphous salt form of Compound I molecularly dispersed in a polymer matrix. In some embodiments, the polymer matrix comprises hypromellose acetate succinate, hydroxypropyl methylcellulose phthalate, Eudragit®, or a combination thereof.

[0011] The present disclosure provides, in one embodiment, a crystalline form of Compound I.

[0012] In some embodiments, the crystalline form of compound I is compound I crystalline form A, characterized by an X-ray powder diffraction pattern containing peaks at 17.1, 19.4, and 23.5° 2θ (±0.2°) as determined by a diffractometer using Cu-Kα radiation. In some embodiments, compound I crystalline form A is i) one or more peaks at 6.7, 9.7, 10.3, 12.1, 12.5, 15.8, 19.0, and 21.4° 2θ±0.2°; and ii) a differential scanning calorimetry (DSC) thermogram comprising an endotherm with a maximum peak at about 238.0° C.

[0013] In some embodiments, the crystalline form of compound I is compound I crystalline form B, characterized by an X-ray powder diffraction pattern containing peaks at 16.8, 17.4, and 21.1°2θ±0.2°2θ (±0.2°) as determined by a diffractometer using Cu-Kα radiation. In some embodiments, compound I crystalline form B is i) one or more peaks at 13.7, 14.0, 14.2, 15.7, 19.7, 22.4, 23.2, and 24.6° 2θ ± 0.2°, and ii) a differential scanning calorimetry (DSC) thermogram comprising an endotherm with a maximum peak at about 277°C.

[0014] In some embodiments, the crystalline form of compound I is compound I crystalline form C, characterized by an X-ray powder diffraction pattern containing peaks at 13.7, 14.6, and 22.6° 2θ (±0.2°) as determined by a diffractometer using Cu-Kα radiation. In some embodiments, compound I crystalline form C is i) one or more peaks at 10.0, 11.2, 12.4, 13.7, 14.6, 15.6, 18.6, 20.2, 21.3, 21.9, 22.6, and 23.8° 2θ ± 0.2°, and ii) a differential scanning calorimetry (DSC) thermogram comprising an endotherm with a maximum peak at about 235° C.

[0015] In some embodiments, the crystalline form of compound I is compound I crystalline form D, characterized by an X-ray powder diffraction pattern containing peaks at 3.5, 18.0, and 19.1 degrees 2θ (±0.2°) as determined on a diffractometer using Cu-Kα radiation. In some embodiments, compound I crystalline form D is i) peaks at 7.0, 10.8, 11.4, 13.1, 15.5, 17.4, 17.5, 18.5, 19.7, and 21.2° 2θ±0.2°; and ii) a differential scanning calorimetry (DSC) thermogram comprising an endotherm having a maximum peak at about 235.0° C.

[0016] The present disclosure provides, in one embodiment, a pharmaceutical composition comprising one or more pharma- ceutically acceptable carriers and the free acid amorphous form of Compound I described herein.

[0017] The present disclosure, in one embodiment, provides pharmaceutical compositions comprising one or more pharma- ceutically acceptable carriers and one or more compounds selected from compound I crystalline form A, compound I crystalline form B, compound I crystalline form C, and compound I crystalline form D, as described herein.

[0018] In one embodiment, the present disclosure provides a method for modulating a bromodomain in a subject in need thereof, comprising administering to the subject an effective amount of the free acid amorphous form of Compound I described herein.

[0019] The present disclosure provides, in one embodiment, a method for treating a subject suffering from or at risk for a disease or condition mediated by a bromodomain, comprising administering to a subject in need thereof an effective amount of the free acid amorphous form of Compound I described herein.

[0020] In some embodiments, the disease or condition treated by the method described herein is cancer, neurological condition, autoimmune condition, inflammatory condition, metabolic disease, or combination thereof.In some embodiments, the disease or condition is rheumatoid arthritis, uveal melanoma, chronic lymphocytic leukemia, acute myeloid leukemia, synovial sarcoma, osteoarthritis, acute gout, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease (Crohn's disease and ulcerative colitis), asthma, chronic obstructive airway disease, pneumonia, myocarditis, pericarditis, myositis, eczema, dermatitis, alopecia, vitiligo, bullous skin disease, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, depression, retinitis, uveitis, scleritis, hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis, Addison's disease, hypophysitis, thyroiditis, type I diabetes, or acute rejection of transplanted organs.

[0021] The disclosure, in one embodiment, provides a method for treating a subject suffering from or at risk for a disease or condition mediated by a bromodomain, comprising administering to a subject in need thereof an effective amount of the free acid amorphous form of Compound I described herein, wherein the disease or condition is selected from the group consisting of rheumatoid arthritis, uveal melanoma, chronic lymphocytic leukemia, acute myeloid leukemia, synovial sarcoma, osteoarthritis, acute gout, psoriasis, systemic lupus erythematosus, and the like. and / or the like, where the condition is selected from the group consisting of chronic obstructive pulmonary disease, multiple sclerosis, inflammatory bowel disease (Crohn's disease and ulcerative colitis), asthma, chronic obstructive airways disease, pneumonia, myocarditis, pericarditis, myositis, eczema, dermatitis, alopecia, vitiligo, bullous skin diseases, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, depression, retinitis, uveitis, scleritis, hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis, Addison's disease, hypophysitis, thyroiditis, type I diabetes, or acute rejection of a transplanted organ.

[0022] The present disclosure provides, in one embodiment, a method for treating chronic lymphocytic leukemia (CLL) or Richter's syndrome in a subject in need thereof by administering to the subject an effective amount of the free acid amorphous form of compound I described herein. In one embodiment, the subject is also optionally administered a Bruton's tyrosine kinase (BTK) inhibitor. In one embodiment, the BTK inhibitor is ibrutinib.

[0023] The present disclosure provides, in one embodiment, a method of treating myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in a subject in need thereof by administering to the subject an effective amount of the free acid amorphous form of Compound I described herein in combination with an effective amount of a DNA methylation inhibitor (HMA).

[0024] The present disclosure, in one embodiment, provides a method of treating chronic lymphocytic leukemia (CLL) or Richter's syndrome in a subject in need thereof by administering to the subject an effective amount of the free acid amorphous form of Compound I described herein in combination with an effective amount of a Bruton's tyrosine kinase (BTK) inhibitor. In one embodiment, the BTK inhibitor is ibrutinib.

[0025] The present disclosure provides, in one embodiment, a method of treating chronic lymphocytic leukemia (CLL) in a subject in need thereof by administering to the subject an effective amount of the free acid amorphous form of Compound I described herein in combination with an effective amount of a B-cell lymphoma 2 (BCL-2) inhibitor.

[0026] The present disclosure provides, in one embodiment, a method of treating chronic lymphocytic leukemia (CLL) in a subject in need thereof by administering to the subject an effective amount of the free acid amorphous form of Compound I described herein in combination with an effective amount of a phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor.

[0027] The present disclosure provides, in one embodiment, a method of treating uveal melanoma in a subject in need thereof by administering to the subject an effective amount of the free acid amorphous form of Compound I described herein in combination with an effective amount of a CTLA-4 inhibitor or checkpoint inhibitor.

[0028] The present disclosure provides, in one embodiment, a method of treating acute myeloid leukemia in a subject in need thereof by administering to the subject an effective amount of the free acid amorphous form of Compound I described herein in combination with an effective amount of quizartinib. [Brief description of the drawings]

[0029] [Figure 1] FIG. 1 is an X-ray powder diffraction pattern of compound I crystalline form A.

[0030] [Diagram 2] 1 is a thermogravimetric analysis (TGA) of Compound I crystalline form A.

[0031] [Diagram 3] 1 is a differential scanning calorimeter (DSC) curve of compound I crystalline form A.

[0032] [Figure 4] 1 is a dynamic vapor sorption (DVS) curve of compound I crystalline form A.

[0033] [Diagram 5] FIG. 1 is an X-ray powder diffraction pattern of compound I crystalline form B.

[0034] [Figure 6] 1 is a thermogravimetric analysis (TGA) of compound I crystalline form B.

[0035] [Figure 7] 1 is a differential scanning calorimeter (DSC) curve of compound I crystalline form B.

[0036] [Figure 8]FIG. 1 is an X-ray powder diffraction pattern of Compound I crystalline form C.

[0037] [Figure 9] 1 is a thermogravimetric analysis (TGA) of Compound I crystalline form C.

[0038] [Figure 10] 1 is a differential scanning calorimeter (DSC) curve of compound I crystalline form C.

[0039] [Figure 11] FIG. 1 is an X-ray powder diffraction pattern of compound I crystalline form D.

[0040] [Figure 12] 1 is a thermogravimetric analysis (TGA) of Compound I crystalline form D.

[0041] [Figure 13] 1 is a differential scanning calorimeter (DSC) curve of compound I crystalline form D.

[0042] [Figure 14] FIG. 1 shows X-ray powder diffraction patterns of compound I crystalline form A, compound I crystalline form B, compound I crystalline form C, compound I crystalline form D, compound I substance E, compound I substance F, and compound I substance G.

[0043] [Figure 15] FIG. 1 is an X-ray powder diffraction pattern of compound I substance G and compound I crystalline form B.

[0044] [Figure 16] Thermogravimetric analysis (TGA) of compound I substance G.

[0045] [Figure 17] 1 is a differential scanning calorimeter (DSC) curve of compound I substance G.

[0046] [Figure 18] FIG. 2 is an X-ray powder diffraction pattern of Compound I free acid amorphous.

[0047] [Figure 19] 1 is a thermogravimetric analysis (TGA) of Compound I free acid amorphous.

[0048] [Figure 20] 1 is a differential scanning calorimeter (DSC) curve of Compound I free acid amorphous.

[0049] [Figure 21] FIG. 1 is an X-ray powder diffraction pattern of Compound I sodium Substance A and Compound I free acid amorphous.

[0050] [Figure 22] 1 is a thermogravimetric analysis (TGA) of Compound I sodium substance A.

[0051] [Diagram 23] 1 is a differential scanning calorimeter (DSC) curve of compound I sodium substance A.

[0052] Figures 24A to 24H are graphs showing the potent anti-leukemic effects of the free acid amorphous form of Compound I (Compound I free acid amorphous, "Compound I FAA") targeting BRD4 in disease models of aggressive chronic lymphocytic leukemia (CLL) and Richter transformation. ● Figures 24 to 24C show data related to the pharmacodynamic evaluation of the antitumor effect of Compound I free acid amorphous in Eμ-TCL1, an aggressive leukemia. Mice were stratified according to leukemic peripheral blood lymphocytes (PBL) and spleen palpation scores and administered either vehicle or Compound I free acid amorphous (20 mg / kg, qd, oral gavage) for 8 days. Compound I free acid amorphous reduced leukemic cells in the systemic circulation (Figure 24A) and locally in the spleen (Figure 24B), and the red lines in Figures 24A and 24B represent the mean values. Figure 24C is a representative immunoblot analysis of the relative protein levels of cMYC, P21, BTK, IKZF1, IKZF3, and TCL1A proteins at the end of the 8-day study. ● Figures 24D to 24G: Using the adoptive transfer model of Eμ-TCL1, recipient wild-type mice were randomized to receive vehicle (n=12) or compound I free acid amorphous (20 mg / kg, qd, oral gavage, n=10) at the time of leukemia onset, and disease progression was measured as CD19 / CD5 / CD45 positive PBL% by flow cytometry. Treatment was terminated at 150 days. Figure 24D is a Kaplan-Meier curve showing overall survival (OS) (p<0.0001), with median OS of 93 and 34 days for compound I free acid amorphous and vehicle, respectively. Survival comparisons in Figure 24D were performed with the log-rank test, and p values ​​were adjusted for multiple comparisons. Compound I free acid amorphous reduced the percentage of circulating leukemic PBL (Figure 24E) and reduced splenic mass (Figure 24F). FIG. 24G shows HE and Ki67 staining of spleen, lung, and blood from Compound I free acid amorphous treated mice that were lymphocyte depleted with Ki67 staining nearly absent. ● Figure 24H is a Kaplan-Meier curve showing overall survival of C57BL / 6 mice engrafted with Eμ-TCL1 leukemic splenocytes treated with ibrutinib or compound I free acid amorphous (20 mg / kg, qd, oral gavage) at the time of leukemia onset, with median OS of 41 days (compound I free acid amorphous, n=7), 32 days (ibrutinib, n=8), and 21 days (vehicle, n=7). Compound I free acid amorphous significantly increased survival compared to vehicle (p=0.024) and ibrutinib (p=0.049). Survival comparisons in Figure 24H were performed with the log-rank test, and p-values ​​were adjusted for multiple comparisons. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0053] The compound 4-(6-(3,5-dimethylisoxazol-4-yl)-1-[(1S)-1-(2-pyridyl)ethyl]pyrrolo[3,2-b]pyridin-3-yl)benzoic acid, referred to herein as Compound I or Compound I (free acid), has the formula: [ka] Compound I is an inhibitor or modulator of bromodomain proteins. Its synthesis and methods of use are described in U.S. Patent Publication No. 2015 / 0133400, the entire contents of which are incorporated herein by reference.

[0054] The present disclosure relates to various solid forms of Compound I and processes for making such solid forms.

[0055] Additional solid forms of Compound I are also described herein, along with the processes for producing such forms. For example, in some embodiments, the solid form of Compound I may include a salt or cocrystal of Compound I. In some embodiments, the solid form of Compound I may include an amorphous form of Compound I. 1.Definition

[0056] As used herein, the following words and phrases are intended to have the meanings generally set forth below, except to the extent that the context in which they are used indicates otherwise.

[0057] The term "comprise" and variations thereof, such as "comprises" and "comprising," should be construed in an open-ended, inclusive sense, i.e., "including, but not limited to." Further, unless the context clearly dictates otherwise, the singular forms "a," "an," and "the" include plural references. Thus, reference to "the compound" includes a plurality of those compounds, and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0058] Reference herein to "about" a value or parameter includes (and describes) embodiments that relate to the value or parameter itself. In some embodiments, the term "about" includes the indicated amount ±10%. In some embodiments, the term "about" includes the indicated amount ±5%. In some other embodiments, the term "about" includes the indicated amount ±1%. Additionally, the term "about X" includes the description of "X".

[0059] In some embodiments, the term "about" includes ±2% variation in weight loss when applied to a thermogravimetric analysis (TGA) thermogram. In some embodiments, the term "about" includes ±3° C. variation when applied to a differential scanning calorimetry (DSC) curve.

[0060] In some embodiments, the phrase "substantially as shown in the Figures" when applied to DSC curves is intended to include a variation of ±3 degrees Celsius, and when applied to TGA thermograms is intended to include a variation of ±2% in weight loss.

[0061] Recitations of numerical ranges throughout this disclosure are intended to serve as shorthand for referring individually to each separate value falling within the range, inclusive of the values ​​defining that range, and each separate value is incorporated into the specification as if it were individually recited herein.

[0062] Forms of Compound I, or its salts, cocrystals, solvates, or hydrates are provided herein. In one embodiment, a reference to a form of Compound I, or its salts, cocrystals, solvates, or hydrates, means that at least 50%-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 is in the specified form. For example, in one embodiment, a reference to Compound I crystalline form A 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 crystalline form A. Reference to Compound I free acid amorphous 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 the Compound I present in the composition is in the free acid amorphous form as described herein.

[0063] The term "solid form" refers to a type of substance in the solid state, including amorphous forms as well as crystalline forms. The term "crystalline form" refers to polymorphs as well as solvates, hydrates, etc. The term "polymorph" refers to a particular crystal structure that has particular physical properties such as X-ray diffraction and melting point.

[0064] 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 may include a non-ionized form of compound I (e.g., compound I free acid) 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 may 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. In addition, the co-crystals may exist in anhydrous, solvate, or hydrate forms. In some embodiments, the co-crystals may have improved properties compared to the parent form (i.e., the free molecule, zwitterion, etc.) or salt of the parent compound. The improved properties can be increased solubility, increased dissolution, increased bioavailability, increased dose response, decreased hygroscopicity, crystalline forms of normally amorphous compounds, crystalline forms of compounds that are difficult to salt or unstable, decreased polymorphism, more desirable morphology, etc. Methods for making and characterizing cocrystals are known to those of skill in the art.

[0065] The term "co-crystal former" or "coformer" refers to one or more pharma- ceutically acceptable bases or pharma-ceutically acceptable acids, as disclosed herein, in association with compound I, or any other compound disclosed herein.

[0066] The term "solvate" refers to a complex formed by the combination of a solvent molecule with a molecule or ion of a 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 a 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 encompassed within the scope of the present disclosure.

[0067] The term "desolvated" refers to a compound I form that is a solvate as described herein, from which solvent molecules have been partially or completely removed. Desolvation techniques for producing desolvated forms include, but are not limited to, subjecting the compound I form (solvate) to vacuum, subjecting the solvate to high temperature, subjecting the solvate to a gas stream such as air or nitrogen, or any combination thereof. Thus, the desolvated compound I form can be anhydrous, i.e., completely free of solvent molecules, or partially solvated, and solvent molecules can be present in stoichiometric or non-stoichiometric amounts.

[0068] The term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and, depending on temperature, can exhibit the physical properties of a solid or a liquid. Typically, such materials do not give distinct X-ray diffraction patterns and, while exhibiting the properties of a solid, are more clearly described as a liquid. Upon heating, a change from the properties of a solid to that of a liquid occurs, which is characterized by a change of state, typically second order (glass transition).

[0069] The term "solid dispersion" refers to any solid composition having at least two components. In certain embodiments, the solid dispersions disclosed herein preferably contain an active ingredient (e.g., Compound I, or a solid or amorphous form of Compound I) dispersed with at least one other ingredient, e.g., a polymer. In certain embodiments, the solid dispersions disclosed herein are pharmaceutical dispersions containing at least one pharma- ceutical or biologically active ingredient (e.g., Compound I, or a solid or amorphous form of Compound I). In some embodiments, the solid dispersions contain Compound I molecularly dispersed with a polymer. In some embodiments, the solid dispersions contain the free acid amorphous form of Compound I, as described herein, molecularly dispersed with a polymer. In some embodiments, the solid dispersions contain the free acid amorphous salt form of Compound I, as described herein, molecularly dispersed with a polymer. In some embodiments, the solid dispersions are present as a one-phase system.

[0070] The term "molecularly dispersed" as used herein refers to the random distribution of a compound (e.g., compound I, solid or amorphous form of compound I) in a polymer. In certain embodiments, the compound is present in the polymer in the final state of fragmentation. See, for example, MG Vachon et al., J. Microencapsulation, 14:281-301 (1997) and Vandelli et al., J. Microencapsulation, 10:55-65 (1993). In some embodiments, a compound (e.g., compound I) can be dispersed within the matrix formed by the polymer in its solid state, such that the compound is fixed in its amorphous form. Whether a compound is molecularly dispersed in a polymer can be demonstrated in various ways, for example, by the resulting solid molecular complex having a single glass transition temperature.

[0071] The term "immobilize" used herein with respect to the immobilization of active compound in polymer matrix means that the molecules of the compound interact with the molecules of polymer in such a way that the molecules of the compound are held in said matrix and are prevented from crystal nucleation due to lack of mobility.In some embodiments, the polymer can prevent the intermolecular hydrogen bond or weak dispersion force between two or more drug molecules of compound I.See, for example, Matsumoro and Zografi, Pharmaceutical Research, Vol.16, No.11, p1722-1728, 1999.

[0072] Any formula or structure described herein, including compound I, is also intended to represent unlabeled forms of the compound as well as isotopically labeled forms.It is understood that for any given atom, isotopes may be present in proportions according to their natural occurrence in nature, or one or more specific atoms may be enriched with one or more isotopes using synthetic methods known to those skilled in the art.Thus, hydrogen may include, for example, 1 H, 2 H, 3 H, and carbon contains e.g. 11 C. 12 C. 13 C. 14 C, and oxygen includes e.g. 16 O. 17 O. 18 O, and nitrogen includes e.g. 13 N, 14 N, 15 N, and sulfur, e.g. 32 S, 33 S, 34 S, 35 S, 36 S, 37 S, 38 S includes, for example, fluorine. 17 F, 18 F, 19 F, and chlorine contains e.g. 35 Cl, 36 Cl, 37 Cl, 38 Cl, 39 For example, it contains Cl.

[0073] 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 or amorphous forms of Compound I described herein, in an amount effective to prevent, alleviate, or ameliorate one or more symptoms, e.g., signs, of a disease or condition, and / or prolong the survival of the subject being treated.

[0074] The term "administering" refers to oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, or implantation of a sustained release device, such as a mini-osmotic pump, into 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, intraarteriolar, 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.

[0075] As used herein, the term "modulating" or "modulating" refers to the effect of modifying biological activity, particularly biological activity associated with a particular biomolecule, such as a protein kinase. For example, an agonist or antagonist of a particular biomolecule modulates the activity of that biomolecule, e.g., an enzyme, by either increasing (e.g., agonist, activator) or decreasing (e.g., antagonist, inhibitor) the activity of the biomolecule, e.g., an enzyme. Such activity is typically measured by the inhibitory concentration (IC) of a compound, e.g., an inhibitor or activator, for an enzyme. 50 ) or irritant concentration (EC 50 ) are shown in terms of

[0076] As used herein, the term "protein kinase-mediated disease or condition" refers to a disease or condition in which the biological function of a protein kinase, including any mutants thereof, influences the onset, course, and / or symptoms of the disease or condition and / or modulation of a protein kinase alters the onset, course, and / or symptoms of the disease or condition. Protein kinase-mediated diseases or conditions include diseases or conditions in which inhibition provides a therapeutic benefit, e.g., treatment with a protein kinase inhibitor(s), including one or more solid or amorphous forms of Compound I described herein, provides a therapeutic benefit to a subject suffering from or at risk for the disease or condition.

[0077] As used herein, the term "composition" refers to a pharmaceutical preparation that contains at least one pharma- ceutically active compound, including any solid or amorphous form thereof, and is suitable for administration to an intended subject for therapeutic purposes.The composition may include at least one pharma- ceutically acceptable component, such as a suitable carrier or excipient, to provide an improved formulation of the compound.

[0078] Other embodiments of the present disclosure include compositions of either crystalline or amorphous forms of Compound I in combination with nanoparticles (such as naturally occurring nanocarriers, e.g., exosomes), and the like. It is known that exosomes can be highly effective drug carriers, and there are various methods by which drugs can be loaded into exosomes, including the techniques described in J Control Release, 2015 December 10;219:396-405, the contents of which are incorporated herein by reference in their entirety.

[0079] As used herein, the term "subject" or "patient" refers to an organism, including, but not limited to, any mammal, such as humans, other primates, sport animals, commercial subject animals, such as cattle, farm animals, such as horses, and pets, such as dogs and cats, that is treated with the compounds described herein.

[0080] The term "pharmaceutical acceptable" indicates that the indicated substance does not possess properties that would cause a reasonably prudent physician to avoid administering the substance to a subject, taking into account the disease or condition to be treated and the respective route of administration. For example, such substances are generally required to be essentially sterile, e.g., for injectables.

[0081] The term "pharmaceutical acceptable salt" refers to a salt that is acceptable for administration to a patient, such as a mammal (e.g., a salt that has mammalian safety tolerable for a given dosing regimen). Such salts can be derived from pharmaceutical acceptable inorganic or organic bases and from pharmaceutical acceptable inorganic or organic acids, depending on the particular substituents found on the compounds described herein. When the compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds, either neat or in a suitable inert solvent, with a sufficient amount of the desired base. Salts synthesized from pharmaceutical acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Salts derived from pharma- ceutically acceptable organic bases include salts of primary, secondary, tertiary, and quaternary amines, including substituted amines, cyclic amines, naturally occurring amines, and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, meglumine (N-methyl-glucamine), and the like. When compounds of the present disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds, either neat or in a suitable inert solvent, with a sufficient amount of the desired acid.Salts prepared from pharma- ceutically acceptable acids include acetic acid, trifluoroacetic acid, propionic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glycolic acid, gluconic acid, glucuronic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, pamoic acid, and pantothenic acid. , phosphoric acid, succinic acid, sulfuric acid, hydroiodic acid, carbonic acid, tartaric acid, p-toluenesulfonic acid, pyruvic acid, aspartic acid, benzoic acid, anthranilic acid, mesylic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, embonic acid (pamoic acid), ethanesulfonic acid, benzenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, stearic acid, cyclohexylaminosulfonic acid, alginic acid, hydroxybutyric acid, galactosaccharic acid, and galacturonic acid.

[0082] Also included are salts of amino acids, such as arginates, and salts of organic acids, such as glucuronic acid or galacturonic acid (see, e.g., Berge, SM et al., "Pharmaceutical Salts", J. Pharmaceutical Science, 1977, 66:1-19).Certain compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0083] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent forms of the compounds differ from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent forms of the compounds for purposes of this disclosure.

[0084] In this context, the term "therapeutically effective" or "effective amount" indicates that a substance or amount of a substance is effective to prevent, alleviate, or relieve one or more symptoms of a disease or medical 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 achieve a beneficial or desired clinical result. An effective amount may be provided all at once in a single administration, or in divided amounts that provide an effective amount in several administrations. The exact determination of the expected effective amount can be made based on individual factors for 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.

[0085] In the context of using, testing, or screening compounds that are or may be modulators, the term "contacting" means that the compound(s) are brought into sufficient proximity with a particular molecule, complex, cell, tissue, organism, or other particular substance that a potential binding interaction and / or chemical reaction between the compound and the other particular substance can occur.

[0086] In addition, the abbreviations used herein have the following respective meanings: [Table 1] 2. Form of Compound I

[0087] Generally as described above, the present disclosure provides the crystalline form of Compound I and its salt, cocrystal, solvate or hydrate.Additional forms (including amorphous forms) are also discussed further herein.It should be noted that the crystalline form of Compound I and its salt, cocrystal, solvate or hydrate, as well as other forms (e.g., amorphous forms) of Compound I and its salt, cocrystal, solvate or hydrate are collectively referred to herein as "form of Compound I" or "solid form of Compound I".

[0088] The crystalline forms of Compound I have been found to have surprisingly low solubility, as shown in Table A below, which provides solubility data for the active pharmaceutical ingredient of Compound I. [Table 2] Thus, in some embodiments disclosed herein, techniques, methods, and compositions are provided for improving the solubility and / or bioavailability of Compound I. In some embodiments, compositions and methods are provided that include Compound I in a composition, form, or formulation that has improved solubility and / or bioavailability compared to a crystalline form of Compound I. Thus, in some embodiments, compositions and methods are provided that include the free acid amorphous form of Compound I or the free acid amorphous salt form of Compound I disclosed herein. In some embodiments, compositions and methods are provided that include the free acid amorphous form of Compound I or the free acid amorphous salt form of Compound I molecularly dispersed within a polymer matrix. a. Compound I Crystal Form A

[0089] The present disclosure provides, in one embodiment, a crystalline form of 4-(6-(3,5-dimethylisoxazol-4-yl)-1-[(1S)-1-(2-pyridyl)ethyl]pyrrolo[3,2-b]pyridin-3-yl)benzoic acid (Compound I crystalline Form A), characterized by an X-ray powder diffractogram containing the following peaks: 17.1, 19.4, and 23.5 °2θ ± 0.2 °2θ as determined on a diffractometer using Cu-Kα radiation. In one embodiment, the diffractogram of Compound I crystalline Form A further contains one or more peaks at 6.7, 9.7, 10.3, 12.1, 12.5, 15.8, 19.0, and 21.4, °2θ ± 0.2 °2θ. In one embodiment, the diffractogram of compound I crystalline form A includes at least two of the following peaks: 6.7, 9.7, 10.3, 12.1, 12.5, 15.8, 17.1, 19.0, 19.4, 21.4, and 23.5°2θ±0.2°2θ. In one embodiment, the diffractogram of compound I crystalline form A includes at least four of the following peaks: 6.7, 9.7, 10.3, 12.1, 12.5, 15.8, 17.1, 19.0, 19.4, 21.4, and 23.5°2θ±0.2°2θ. In one embodiment, the diffractogram of compound I crystalline form A includes at least six of the following peaks: 6.7, 9.7, 10.3, 12.1, 12.5, 15.8, 17.1, 19.0, 19.4, 21.4, and 23.5°2θ±0.2°2θ. In one embodiment, the diffractogram of compound I crystalline form A includes at least eight of the following peaks: 6.7, 9.7, 10.3, 12.1, 12.5, 15.8, 17.1, 19.0, 19.4, 21.4, and 23.5°2θ±0.2°2θ. In one embodiment, the diffractogram of Compound I crystalline Form A contains each of the following peaks: 6.7, 9.7, 10.3, 12.1, 12.5, 15.8, 17.1, 19.0, 19.4, 21.4, and 23.5 °2θ±0.2 °2θ. In one embodiment, Compound I crystalline Form A is characterized by a complete X-ray powder diffractogram substantially as shown in FIG.

[0090] In one embodiment, compound I crystalline form A is characterized by a thermogravimetric analysis (TGA) thermogram exhibiting a weight loss of about 3.0% up to about 250° C. In one embodiment, compound I crystalline form A is characterized by a thermogram substantially as shown in FIG.

[0091] In one embodiment, compound I crystalline form A is characterized by a differential scanning calorimetry (DSC) curve that includes an endotherm with a maximum peak at about 238° C. In one embodiment, the DSC curve of compound I crystalline form A includes an additional endotherm with a maximum peak at about 124° C. In one embodiment, compound I crystalline form A is characterized by a complete DSC curve substantially as shown in FIG.

[0092] In one embodiment, Compound I crystalline Form A is characterized by dynamic vapor sorption (DVS) analysis showing minimal weight loss at equilibrium at about 5% RH and a weight gain of about 0.8% from about 5% to about 95% RH corresponding to about 0.2 moles of water. In one embodiment, Compound I crystalline Form A is characterized by a complete DVS sorption curve substantially as shown in FIG.

[0093] In one embodiment, compound I crystalline form A is characterized as a hydrate. b. Compound I crystal form B

[0094] The present disclosure provides, in one embodiment, a crystalline form of 4-(6-(3,5-dimethylisoxazol-4-yl)-1-[(1S)-1-(2-pyridyl)ethyl]pyrrolo[3,2-b]pyridin-3-yl)benzoic acid (Compound I crystalline Form B), characterized by an X-ray powder diffractogram containing the following peaks: 16.8, 17.4, and 21.1 °2θ±0.2 °2θ as determined on a diffractometer using Cu-Kα radiation. In one embodiment, the diffractogram of Compound I crystalline Form B further contains one or more peaks at 13.7, 14.0, 14.2, 15.7, 19.7, 22.4, 23.2, and 24.6 °2θ±0.2 °2θ. In one embodiment, the diffractogram of compound I crystalline form B includes at least two of the following peaks: 13.7, 14.0, 14.2, 15.7, 19.7, 22.4, 23.2, and 24.6°2θ±0.2°2θ. 13.7, 14.0, 14.2, 15.7, 16.8, 17.4, 19.7, 21.1, 22.4, 23.2, and 24.6°2θ±0.2°2θ. In one embodiment, the diffractogram of compound I crystalline form B includes at least four of the following peaks: 13.7, 14.0, 14.2, 15.7, 19.7, 22.4, 23.2, and 24.6°2θ±0.2°2θ. 13.7, 14.0, 14.2, 15.7, 16.8, 17.4, 19.7, 21.1, 22.4, 23.2, and 24.6°2θ±0.2°2θ. In one embodiment, the diffractogram of Compound I crystalline form B includes at least six of the following peaks: 13.7, 14.0, 14.2, 15.7, 19.7, 22.4, 23.2, and 24.6°2θ±0.2°2θ. 13.7, 14.0, 14.2, 15.7, 16.8, 17.4, 19.7, 21.1, 22.4, 23.2, and 24.6°2θ±0.2°2θ. In one embodiment, the diffractogram of Compound I crystalline form B includes at least eight of the following peaks: 13.7, 14.0, 14.2, 15.7, 19.7, 22.4, 23.2, and 24.6 °2θ±0.2 °2θ. 13.7, 14.0, 14.2, 15.7, 16.8, 17.4, 19.7, 21.1, 22.4, 23.2, and 24.6 °2θ±0.2 °2θ.In one embodiment, the diffractogram of compound I crystalline form B includes each of the following peaks: 13.7, 14.0, 14.2, 15.7, 19.7, 22.4, 23.2, and 24.6 °2θ±0.2 °2θ. 13.7, 14.0, 14.2, 15.7, 16.8, 17.4, 19.7, 21.1, 22.4, 23.2, and 24.6 °2θ±0.2 °2θ. In one embodiment, compound I crystalline form B is characterized by a complete X-ray powder diffractogram substantially as shown in FIG. 5.

[0095] In one embodiment, compound I crystalline form B is characterized by a thermogravimetric analysis (TGA) thermogram exhibiting a weight loss of about 2.9% up to about 275° C. In one embodiment, compound I crystalline form B is characterized by a thermogram substantially as shown in FIG.

[0096] In one embodiment, compound I crystalline form B is characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm having a maximum peak at about 277° C. In one embodiment, the DSC curve of compound I crystalline form B further comprises an exotherm having a maximum peak at about 247° C. In one embodiment, compound I crystalline form B is characterized by a complete DSC curve substantially as shown in FIG.

[0097] In one embodiment, compound I crystalline form B is characterized as a racemic mixture containing approximately equal amounts (50:50) of the R and S enantiomers of 4-(6-(3,5-dimethylisoxazol-4-yl)-1-[1-(2-pyridyl)ethyl]pyrrolo[3,2-b]pyridin-3-yl)benzoic acid. As specified above, compound I is the S enantiomer of 4-(6-(3,5-dimethylisoxazol-4-yl)-1-[1-(2-pyridyl)ethyl]pyrrolo[3,2-b]pyridin-3-yl)benzoic acid.

[0098] In one embodiment, Compound I crystalline form B may exist as a solid solution containing approximately equal amounts (50:50) of the R and S enantiomers of Compound I. c. Compound I crystal form C

[0099] The disclosure provides, in one embodiment, a crystalline form of 4-(6-(3,5-dimethylisoxazol-4-yl)-1-[(1S)-1-(2-pyridyl)ethyl]pyrrolo[3,2-b]pyridin-3-yl)benzoic acid (Compound I crystalline Form C), characterized by an X-ray powder diffractogram containing the following peaks as determined on a diffractometer using Cu-Kα radiation: 13.7, 14.6, and 22.6 °2θ ± 0.2 °2θ. In one embodiment, the diffractogram of Compound I crystalline Form C further contains one or more peaks at 10.0, 11.2, 12.4, 13.7, 14.6, 15.6, 18.6, 20.2, 21.3, 21.9, 22.6, and 23.8 °2θ ± 0.2 °2θ. In one embodiment, the diffractogram of compound I crystalline form C includes at least two of the following peaks: 10.0, 11.2, 12.4, 13.7, 14.6, 15.6, 18.6, 20.2, 21.3, 21.9, 22.6, and 23.8 °2θ±0.2 °2θ. In one embodiment, the diffractogram of compound I crystalline form C includes at least four of the following peaks: 10.0, 11.2, 12.4, 13.7, 14.6, 15.6, 18.6, 20.2, 21.3, 21.9, 22.6, and 23.8 °2θ±0.2 °2θ. In one embodiment, the diffractogram of compound I crystalline form C includes at least six of the following peaks: 10.0, 11.2, 12.4, 13.7, 14.6, 15.6, 18.6, 20.2, 21.3, 21.9, 22.6, and 23.8 °2θ±0.2 °2θ. In one embodiment, the diffractogram of compound I crystalline form C includes at least eight of the following peaks: 10.0, 11.2, 12.4, 13.7, 14.6, 15.6, 18.6, 20.2, 21.3, 21.9, 22.6, and 23.8 °2θ±0.2 °2θ. In one embodiment, the diffractogram of compound I crystalline form C includes each of the following peaks: 10.0, 11.2, 12.4, 13.7, 14.6, 15.6, 18.6, 20.2, 21.3, 21.9, 22.6, and 23.8 °2θ±0.2 °2θ. In one embodiment, compound I crystalline form C is characterized by a complete X-ray powder diffractogram substantially as shown in FIG.

[0100] In one embodiment, compound I crystalline form C is characterized by a thermogravimetric analysis (TGA) thermogram exhibiting a weight loss of about 7.4% up to about 240° C. In one embodiment, compound I crystalline form C is characterized by a thermogram substantially as shown in FIG.

[0101] In one embodiment, compound I crystalline form C is characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm having a maximum peak at about 234.5° C. In one embodiment, the DSC curve of compound I crystalline form C further comprises an exotherm having a maximum peak at about 148° C. In one embodiment, compound I crystalline form C is characterized by a complete DSC curve substantially as shown in FIG.

[0102] In one embodiment, Compound I crystalline form C is characterized as anhydrous. d. Compound I crystal form D

[0103] The disclosure provides, in one embodiment, a crystalline form of 4-(6-(3,5-dimethylisoxazol-4-yl)-1-[(1S)-1-(2-pyridyl)ethyl]pyrrolo[3,2-b]pyridin-3-yl)benzoic acid (Compound I crystalline Form D), characterized by an X-ray powder diffractogram containing the following peaks: 3.5, 18.0, and 19.1 °2θ ± 0.2 °2θ as determined on a diffractometer using Cu-Kα radiation. In one embodiment, the diffractogram of Compound I crystalline Form D further contains one or more peaks at 7.0, 10.8, 11.4, 13.1, 15.5, 17.4, 17.5, 18.5, 19.7, and 21.2 °2θ ± 0.2 °2θ. In one embodiment, the diffractogram of compound I crystalline form D includes at least two of the following peaks: 3.5, 7.0, 10.8, 11.4, 13.1, 15.5, 17.4, 17.5, 18.0, 18.5, 19.1, 19.7, and 21.2 °2θ±0.2 °2θ. In one embodiment, the diffractogram of compound I crystalline form D includes at least four of the following peaks: 3.5, 7.0, 10.8, 11.4, 13.1, 15.5, 17.4, 17.5, 18.0, 18.5, 19.1, 19.7, and 21.2 °2θ±0.2 °2θ. In one embodiment, the diffractogram of compound I crystalline form D includes at least six of the following peaks: 3.5, 7.0, 10.8, 11.4, 13.1, 15.5, 17.4, 17.5, 18.0, 18.5, 19.1, 19.7, and 21.2 °2θ±0.2 °2θ. In one embodiment, the diffractogram of compound I crystalline form D includes at least eight of the following peaks: 3.5, 7.0, 10.8, 11.4, 13.1, 15.5, 17.4, 17.5, 18.0, 18.5, 19.1, 19.7, and 21.2 °2θ±0.2 °2θ. In one embodiment, the diffractogram of compound I crystalline form D contains each of the following peaks: 3.5, 7.0, 10.8, 11.4, 13.1, 15.5, 17.4, 17.5, 18.0, 18.5, 19.1, 19.7, and 21.2 °2θ±0.2 °2θ. In one embodiment, compound I crystalline form D is characterized by a complete X-ray powder diffractogram substantially as shown in FIG.

[0104] In one embodiment, compound I crystalline form D is characterized by a thermogravimetric analysis (TGA) thermogram exhibiting a weight loss of about 0.5% up to about 125° C. In one embodiment, the TGA thermogram of compound I crystalline form D may further exhibit a weight loss of about 11.1% from about 125° C. to about 195° C. In one embodiment, the TGA thermogram of compound I crystalline form D may further exhibit a weight loss of about 1.5% from about 195° C. to about 225° C. In one embodiment, compound I crystalline form D is characterized by a thermogram substantially as depicted in FIG.

[0105] In one embodiment, compound I crystalline form D is characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm having a maximum peak at about 235° C. In one embodiment, compound I crystalline form C further comprises an exotherm having a maximum peak at about 107° C. and 237° C. In one embodiment, compound I crystalline form C is characterized by a complete DSC curve substantially as shown in FIG.

[0106] In one embodiment, compound I crystalline form D is characterized as a solvate. In one embodiment, compound I crystalline form D is characterized as an isopropanol solvate. e.Compound I substance E

[0107] The disclosure provides, in one embodiment, a crystalline form of 4-(6-(3,5-dimethylisoxazol-4-yl)-1-[(1S)-1-(2-pyridyl)ethyl]pyrrolo[3,2-b]pyridin-3-yl)benzoic acid (Compound Substance E), characterized by an X-ray powder diffractogram containing the following peaks: 6.4, 22.4, and 25.1 °2θ±0.2 °2θ as determined on a diffractometer using Cu-Kα radiation. In one embodiment, the diffractogram of Compound I Substance E further contains one or more peaks at 9.2, 10.6, 13.1, 19.0, 22.9, and 23.4 °2θ±0.2 °2θ. In one embodiment, the diffractogram of compound I substance E includes at least two of the following peaks: 6.4, 9.2, 10.6, 13.1, 19.0, 22.4, 22.9, 23.4, and 25.1°2θ±0.2°2θ. In one embodiment, the diffractogram of compound I substance E includes at least four of the following peaks: 6.4, 9.2, 10.6, 13.1, 19.0, 22.4, 22.9, 23.4, and 25.1°2θ±0.2°2θ. In one embodiment, the diffractogram of compound I substance E includes at least six of the following peaks: 6.4, 9.2, 10.6, 13.1, 19.0, 22.4, 22.9, 23.4, and 25.1°2θ±0.2°2θ. In one embodiment, the diffractogram of compound I substance E includes at least eight of the following peaks: 6.4, 9.2, 10.6, 13.1, 19.0, 22.4, 22.9, 23.4, and 25.1 °2θ±0.2 °2θ. In one embodiment, the diffractogram of compound I substance E includes each of the following peaks: 6.4, 9.2, 10.6, 13.1, 19.0, 22.4, 22.9, 23.4, and 25.1 °2θ±0.2 °2θ.

[0108] In one embodiment, compound I substance E is present as a mixture with crystalline form C. In one embodiment, compound I substance E is characterized by a complete X-ray powder diffraction pattern substantially as shown in Figure 14. Figure 14 also includes X-ray powder diffraction patterns of compound I crystalline form A, compound I crystalline form B, compound I crystalline form C, compound I crystalline form D, compound I substance F (discussed in detail below), and compound I substance G (discussed in detail below). f. Compound I Substance F

[0109] The disclosure provides, in one embodiment, a crystalline form of 4-(6-(3,5-dimethylisoxazol-4-yl)-1-[(1S)-1-(2-pyridyl)ethyl]pyrrolo[3,2-b]pyridin-3-yl)benzoic acid (Compound Substance F), characterized by an X-ray powder diffraction pattern including the following peaks: 12.8, 18.6, and 21.1 °2θ±0.2 °2θ as determined on a diffractometer using Cu-Kα radiation. In one embodiment, the diffractogram of Compound I Substance F further includes one or more peaks at 5.5, 7.7, 11.6, 16.1, 16.9, 19.0, 20.4, 21.9, and 23.3 °2θ±0.2 °2θ. In one embodiment, the diffractogram of compound I substance F includes at least two of the following peaks: 5.5, 7.7, 11.6, 12.8, 16.1, 16.9, 18.6, 19.0, 20.4, 21.1, 21.9, and 23.3°2θ±0.2°2θ. In one embodiment, the diffractogram of compound I substance F includes at least four of the following peaks: 5.5, 7.7, 11.6, 12.8, 16.1, 16.9, 18.6, 19.0, 20.4, 21.1, 21.9, and 23.3°2θ±0.2°2θ. In one embodiment, the diffractogram of compound I substance F includes at least six of the following peaks: 5.5, 7.7, 11.6, 12.8, 16.1, 16.9, 18.6, 19.0, 20.4, 21.1, 21.9, and 23.3°2θ±0.2°2θ. In one embodiment, the diffractogram of compound I substance F includes at least eight of the following peaks: 5.5, 7.7, 11.6, 12.8, 16.1, 16.9, 18.6, 19.0, 20.4, 21.1, 21.9, and 23.3°2θ±0.2°2θ. In one embodiment, the diffractogram of compound I substance F includes each of the following peaks: 5.5, 7.7, 11.6, 12.8, 16.1, 16.9, 18.6, 19.0, 20.4, 21.1, 21.9, and 23.3° 2θ ± 0.2° 2θ.

[0110] In one embodiment, compound I substance F is present as a mixture with crystalline form C. In one embodiment, compound I substance F is characterized by a complete X-ray powder diffraction pattern substantially as shown in FIG. g. Compound I substance G

[0111] The disclosure provides, in one embodiment, a crystalline form of 4-(6-(3,5-dimethylisoxazol-4-yl)-1-[(1S)-1-(2-pyridyl)ethyl]pyrrolo[3,2-b]pyridin-3-yl)benzoic acid (compound substance G), characterized by an X-ray powder diffraction pattern including the following peaks: 15.3, 17.0, and 23.0 °2θ±0.2 °2θ as determined on a diffractometer using Cu-Kα radiation. In one embodiment, the diffraction pattern of compound I substance G further includes one or more peaks at 15.7, 18.7, 20.2, 21.9, 22.1, and 25.7, °2θ±0.2 °2θ. In one embodiment, the diffractogram of compound I substance G includes at least two of the following peaks: 15.3, 15.7, 17.0, 18.7, 20.2, 21.9, 22.1, 23.0, and 25.7°2θ±0.2°2θ. In one embodiment, the diffractogram of compound I substance G includes at least four of the following peaks: 15.3, 15.7, 17.0, 18.7, 20.2, 21.9, 22.1, 23.0, and 25.7°2θ±0.2°2θ. In one embodiment, the diffractogram of compound I substance G includes at least six of the following peaks: 15.3, 15.7, 17.0, 18.7, 20.2, 21.9, 22.1, 23.0, and 25.7°2θ±0.2°2θ. In one embodiment, the diffractogram of compound I substance G includes at least eight of the following peaks: 15.3, 15.7, 17.0, 18.7, 20.2, 21.9, 22.1, 23.0, and 25.7°2θ±0.2°2θ. In one embodiment, the diffractogram of compound I substance G includes each of the following peaks: 15.3, 15.7, 17.0, 18.7, 20.2, 21.9, 22.1, 23.0, and 25.7°2θ±0.2°2θ.

[0112] In one embodiment, compound I substance G is present as a mixture with crystalline form B. In one embodiment, compound I substance G is characterized by a complete X-ray powder diffraction pattern substantially as shown in Figure 15. Figure 15 also includes the X-ray powder diffraction pattern of compound I crystalline form B for reference.

[0113] In one embodiment, compound I substance G is characterized by a thermogravimetric analysis (TGA) thermogram showing a weight loss of about 5.2% up to about 250° C. In one embodiment, compound I substance G is characterized by a thermogram substantially as shown in FIG. 16. In one embodiment, heating compound I substance G to about 235° C. results in a weight loss of about 4.2% and the formation of compound I crystalline form B. The X-ray powder diffraction diagram of compound I crystalline form B formed via heating substance G to about 235° C. is also shown in FIG.

[0114] In one embodiment, compound I substance G is characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm having a maximum peak at about 278° C. In one embodiment, the DSC curve of compound I substance G comprises an additional endotherm having a maximum peak at about 217° C. In one embodiment, the DSC curve of compound I substance G further comprises an exotherm having a maximum peak at about 219° C. In one embodiment, compound I form G is characterized by a complete DSC curve substantially as shown in FIG. h. Compound I free acid amorphous

[0115] The disclosure provides, in one embodiment, the free acid amorphous form of 4-(6-(3,5-dimethylisoxazol-4-yl)-1-[(1S)-1-(2-pyridyl)ethyl]pyrrolo[3,2-b]pyridin-3-yl)benzoic acid (Compound I free acid amorphous, also referred to herein as the free acid amorphous form of Compound I), characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 18.

[0116] In one embodiment, Compound I free acid amorphous is characterized by a thermogravimetric analysis (TGA) thermogram exhibiting a weight loss of about 17% up to about 250° C. In one embodiment, Compound I free acid amorphous is characterized by a thermogram substantially as shown in FIG.

[0117] In one embodiment, Compound I free acid amorphous is characterized by a differential scanning calorimetry (DSC) curve that includes an exotherm with a maximum peak at about 237° C. In one embodiment, the DSC curve of Compound I free acid amorphous exhibits a potential glass transition at about 57° C. In one embodiment, Compound I free acid amorphous is characterized by a complete DSC curve substantially as shown in FIG. i. Sodium salt of Compound I

[0118] The present disclosure provides, in one embodiment, a crystalline form of the sodium salt of 4-(6-(3,5-dimethylisoxazol-4-yl)-1-[(1S)-1-(2-pyridyl)ethyl]pyrrolo[3,2-b]pyridin-3-yl)benzoic acid (Compound I sodium Substance A), characterized by an X-ray powder diffraction pattern substantially as shown in FIG.

[0119] In one embodiment, compound I sodium substance A is characterized by a thermogravimetric analysis (TGA) thermogram exhibiting a weight loss of about 6.4% up to about 175° C. In one embodiment, compound I sodium substance A is characterized by a thermogram substantially as shown in FIG.

[0120] In one embodiment, compound I sodium substance A is characterized by a differential scanning calorimetry (DSC) curve comprising an endotherm having a maximum peak at about 85° C. In one embodiment, the DSC curve of compound I sodium substance A further comprises an endotherm having a maximum peak at about 294° C. In one embodiment, compound I sodium substance A is characterized by a complete DSC curve substantially as shown in FIG. 3. Pharmaceutical Compositions and Modes of Administration

[0121] Compound I and its forms described herein can be administered in pharmaceutical compositions. Thus, provided herein are pharmaceutical compositions comprising Compound I or its salts, or one or more of the 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 can include, for example, inert solid diluents, as well as fillers, diluents including sterile aqueous solutions and various organic solvents, permeation enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical arts. 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 & C.T. Rhodes, Eds.). Pharmaceutical compositions can be administered alone or in combination with other therapeutic agents.

[0122] Some embodiments relate to pharmaceutical compositions comprising Compound I. Some embodiments relate to pharmaceutical compositions comprising a salt of Compound I.

[0123] Some embodiments relate to pharmaceutical compositions comprising a crystalline form of compound I described herein. In one embodiment, the pharmaceutical composition comprises compound I, wherein at least 95% of compound I is a crystalline form described herein. In one embodiment, the pharmaceutical composition comprises compound I, wherein at least 95% of compound I is crystalline form A. In one embodiment, the pharmaceutical composition comprises compound I, wherein at least 95% of compound I is crystalline form B. In one embodiment, the pharmaceutical composition comprises compound I, wherein at least 95% of compound I is crystalline form C. In one embodiment, the pharmaceutical composition comprises compound I, wherein at least 95% of compound I is crystalline form D. In one embodiment, the pharmaceutical composition comprises compound I, wherein at least 95% of compound I is compound I substance E. In one embodiment, the pharmaceutical composition comprises compound I, wherein at least 95% of compound I is compound I substance F. In one embodiment, the pharmaceutical composition comprises compound I, wherein at least 95% of compound I is compound I substance G.

[0124] In one embodiment, the pharmaceutical composition comprises compound I, wherein at least 97% of compound I is a crystalline form described herein. In one embodiment, the pharmaceutical composition comprises compound I, wherein at least 97% of compound I is crystalline form A. In one embodiment, the pharmaceutical composition comprises compound I, wherein at least 97% of compound I is crystalline form B. In one embodiment, the pharmaceutical composition comprises compound I, wherein at least 97% of compound I is crystalline form C. In one embodiment, the pharmaceutical composition comprises compound I, wherein at least 97% of compound I is crystalline form D. In one embodiment, the pharmaceutical composition comprises compound I, wherein at least 97% of compound I is compound I substance E. In one embodiment, the pharmaceutical composition comprises compound I, wherein at least 97% of compound I is compound I substance F. In one embodiment, the pharmaceutical composition comprises compound I, wherein at least 97% of compound I is compound I substance G.

[0125] In one embodiment, the pharmaceutical composition comprises compound I, wherein at least 99% of compound I is a crystalline form described herein. In one embodiment, the pharmaceutical composition comprises compound I, wherein at least 99% of compound I is crystalline form A. In one embodiment, the pharmaceutical composition comprises compound I, wherein at least 99% of compound I is crystalline form B. In one embodiment, the pharmaceutical composition comprises compound I, wherein at least 99% of compound I is crystalline form C. In one embodiment, the pharmaceutical composition comprises compound I, wherein at least 99% of compound I is crystalline form D. In one embodiment, the pharmaceutical composition comprises compound I, wherein at least 99% of compound I is compound I substance E. In one embodiment, the pharmaceutical composition comprises compound I, wherein at least 99% of compound I is compound I substance F. In one embodiment, the pharmaceutical composition comprises compound I, wherein at least 99% of compound I is compound I substance G.

[0126] In one embodiment, the pharmaceutical composition comprises an amorphous form of Compound I as described herein. In one embodiment, the pharmaceutical composition comprises a free acid amorphous form of Compound I as described herein. In one embodiment, the pharmaceutical composition comprises Compound I, wherein at least 95% of Compound I is Compound I free acid amorphous. In one embodiment, the pharmaceutical composition comprises Compound I, wherein at least 97% of Compound I is Compound I free acid amorphous. In one embodiment, the pharmaceutical composition comprises Compound I, wherein at least 99% of Compound I is Compound I free acid amorphous.

[0127] In one embodiment, the pharmaceutical composition comprises the free acid amorphous salt form of Compound I described herein (amorphous form of a salt of Compound I). In one embodiment, the pharmaceutical composition comprises Compound I, wherein at least 95% of Compound I is the free acid amorphous salt form of Compound I described herein. In one embodiment, the pharmaceutical composition comprises Compound I, wherein at least 97% of Compound I is the free acid amorphous salt form of Compound I described herein. In one embodiment, the pharmaceutical composition comprises Compound I, wherein at least 99% of Compound I is the free acid amorphous salt form of Compound I described herein.

[0128] In some embodiments, the pharmaceutical composition comprises a free acid amorphous form of Compound I molecularly dispersed in a polymer matrix. In some embodiments, the pharmaceutical composition comprises a free acid amorphous salt form of Compound I molecularly dispersed in a polymer matrix. Non-limiting examples of polymer matrices that can be used include, but are not limited to, hypromellose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), and Eudragit®.

[0129] Some embodiments relate to pharmaceutical compositions comprising a salt of compound I in a crystalline form as described herein. In one embodiment, the pharmaceutical composition comprises a sodium salt of compound I, wherein at least 95% of compound I is compound I sodium substance A. In one embodiment, the pharmaceutical composition comprises a sodium salt of compound I, wherein at least 97% of compound I is compound I sodium substance A. In one embodiment, the pharmaceutical composition comprises a sodium salt of compound I, wherein at least 99% of compound I is compound I sodium substance A.

[0130] Some embodiments relate to pharmaceutical compositions comprising a therapeutically effective amount of a compound selected from Compound I or a salt thereof described herein, Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I substance G, Compound I free acid amorphous, the free acid amorphous salt form of Compound I, and Compound I sodium substance A, and one or more pharma- ceutically acceptable carriers.

[0131] 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 the administration of the compound by a specific route. Examples of carriers include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, starch types, cellulose derivatives, gelatin, lipids, liposomes, nanoparticles, etc. Also, physiologically compatible liquids for solvents or suspensions can be included as carriers, such as sterile aqueous solution for injection (WFI), saline, dextrose solution, Hanks' solution, Ringer's solution, vegetable oil, mineral oil, animal oil, polyethylene glycol, liquid paraffin, etc. Also useful as excipients are, for example, 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, stearowet C, magnesium oxide, starch, sodium starch glycolate, glyceryl monostearate, glyceryl dibehenate, glyceryl palmitostearate, hydrogenated vegetable oils, hydrogenated cottonseed oil, Castor oil, mineral oil, polyethylene glycol (e.g., PEG 4000-8000), polyoxyethylene glycol, poloxamer, povidone, crospovidone, croscarmellose sodium, alginic acid, casein, methacrylate divinylbenzene copolymer, docusate sodium, cyclodextrin (e.g., 2-hydroxypropyl-β-cyclodextrin), polysorbate (e.g., polysorbate 80), cetrimide, TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate), magnesium lauryl sulfate, sodium lauryl sulfate, polyethylene glycol ethers, di-fatty acid esters of polyethylene glycol, or polyoxyalkylene sorbitan fatty acid esters (e.g.,Polyoxyethylene sorbitan esters Tween®), polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters, for example sorbitan fatty acid esters from fatty acids such as oleic acid, stearic acid or palmitic acid, mannitol, xylitol, sorbitol, maltose, lactose, lactose monohydrate or spray-dried lactose, sucrose, fructose, calcium phosphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, dextrates, dextran, dextrin, dextrose, cellulose acetate, maltodextrin, simethicone, polydextrose, chitosan, gelatin, HPMC (hydroxypropyl methylcellulose), HPC (hydroxypropyl cellulose), hydroxyethyl cellulose, etc.,

[0132] Pharmaceutical preparations can be provided in unit dose form, containing a predetermined amount of active ingredient per unit dose.Such a unit can contain, for example, 0.5mg to 1g, preferably 1mg to 700mg, more preferably 5mg to 100mg of the compound of the present disclosure (as any form of free acid, solvate (including hydrate), or salt), depending on the condition being treated, the route of administration, and the age, weight, and condition of the patient.Preferred unit dose preparations are those that contain a daily dose, a weekly dose, a monthly dose, a sub-dose, or a suitable fraction thereof, of active ingredient.Furthermore, such pharmaceutical preparations can be prepared by any of the methods well known in the pharmaceutical art.

[0133] The pharmaceutical formulation may be adapted for administration by any suitable route, for example, oral (including capsules, tablets, liquid-filled capsules, disintegrating tablets, immediate release, delayed release and controlled release tablets, oral strips, solutions, syrups, buccal and sublingual), rectal, nasal, inhalation, topical (including transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) routes. Such formulations may be prepared by any method known in the pharmaceutical art, for example, by bringing the active ingredient into association with the carrier(s), excipient(s), or diluent. Generally, the carriers, excipients, or diluents used in pharmaceutical formulations are "non-toxic," meaning that they are considered safe to be ingested in the amounts delivered in the pharmaceutical composition, and are "inert," meaning that they do not appreciably react or produce undesirable effects on the therapeutic activity of the active ingredient.

[0134] In some embodiments, oral administration may be used. Pharmaceutical preparations for oral use may be formulated into conventional oral dosage forms, such as individual unit capsules, tablets, and liquid preparations, such as syrups, elixirs, and concentrated drops. The compounds described herein may be combined with solid excipients, optionally milled after adding suitable auxiliaries if desired, and the resulting mixture may be processed to obtain, for example, tablets, coated tablets, hard capsules, soft capsules, solutions (e.g., aqueous, alcoholic, or oily solutions), and the like. Suitable excipients are, in particular, fillers such as sugars, including lactose, glucose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose (CMC), and / or polyvinylpyrrolidone (PVP: povidone); oily excipients, including vegetable and animal oils, such as sunflower oil, olive oil, or cod liver oil. Oral dosage formulations may also contain disintegrants such as cross-linked polyvinylpyrrolidone, agar, or alginic acid, or salts thereof such as sodium alginate; lubricants such as talc or magnesium stearate; plasticizers such as glycerol or sorbitol; sweeteners such as sucrose, fructose, lactose, or aspartame; natural or artificial flavors such as peppermint, wintergreen oil, cherry flavoring; or dyes or pigments that can be used to identify or characterize different doses or combinations such as unit doses. Sugar-coated cores with suitable coatings are also provided. For this purpose, concentrated sugar solutions may be used, which may optionally contain, for example, gum arabic, talc, poly-vinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Oral fluids such as solutions, syrups, and elixirs may be prepared in unit dosage form so that a given quantity contains a predetermined amount of compound.

[0135] Pharmaceutical preparations that can be used orally include push-fit capsules ("gelcaps") made of gelatin, as well as soft sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Push-fit capsules can contain active ingredients mixed with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, active compounds can be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycols.

[0136] In some embodiments, injections (parenteral administration), for example, intramuscular, intravenous, intraperitoneal, and / or subcutaneous injections, may be used. The compounds for injection described herein may be formulated in sterile liquid solutions, preferably physiologically compatible buffers or solutions, such as physiological saline, Hank's solution, or Ringer's solution. Dispersions may also be prepared in non-aqueous solutions, such as glycerol, propylene glycol, ethanol, liquid polyethylene glycol, triacetin, and vegetable oils. The solutions may also contain preservatives, such as methylparaben, propylparaben, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In addition, the compounds may be formulated in solid form, including, for example, lyophilized forms, and redissolved or suspended prior to use. The formulations may be provided in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example, water for injections, immediately prior to use.

[0137] In some embodiments, transmucosal, topical, or transdermal administration may be used. In such formulations of the compounds described herein, a penetrant appropriate to the barrier to be permeated is used. Such penetrants are generally known in the art and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives. In addition, surfactants may be used to facilitate penetration. Transmucosal administration may be, for example, via nasal sprays or suppositories (rectal or vaginal). Compositions of the compounds described herein for topical administration may be formulated as oils, creams, lotions, ointments, and the like by selecting the appropriate carriers known in the art. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats, and high molecular weight alcohols (C 12 In some embodiments, the carrier is selected so that the active ingredient is soluble. If desired, emulsifiers, stabilizers, humectants and antioxidants, as well as agents that impart color or fragrance, may also be included. Preferably, creams for topical application are formulated from a mixture of mineral oil, self-emulsifying beeswax, and water, into which the active ingredient is mixed, dissolved in a small amount of solvent (e.g., oil). In addition, administration by transdermal means may include a transdermal patch or dressing, such as a bandage, impregnated with the active ingredient and, optionally, one or more carriers or diluents known in the art. To be administered in the form of a transdermal delivery system, the dosage administered will be continuous, rather than intermittent, throughout the entire dosage regimen.

[0138] In some embodiments, the compounds disclosed herein (e.g., Compound I or a salt thereof, or one or more solid or amorphous forms of Compound I) are administered as inhalants. The compounds described herein may be formulated as dry powders, or suitable solutions, suspensions, or aerosols. Powders and solutions may be formulated with suitable additives known in the art. For example, powders may contain suitable powder bases such as lactose or starch, and solutions may contain propylene glycol, sterile water, ethanol, sodium chloride, and other additives such as acids, alkalis, and buffer salts. Such solutions or suspensions may be administered by inhalation via sprays, pumps, atomizers, or nebulizers, etc. The compounds described herein may also be used in combination with other inhalation therapies, for example, corticosteroids such as fluticasone propionate, beclomethasone dipropionate, triamcinolone acetonide, budesonide, and mometasone furoate; beta agonists such as albuterol, salmeterol, and formoterol; anticholinergics such as ipratropium bromide or tiotropium; vasodilators such as treprostinal and iloprost; enzymes such as DNase; therapeutic proteins; immunoglobulin antibodies; oligonucleotides such as single- or double-stranded DNA or RNA, siRNA; antibiotics such as tobramycin; muscarinic receptor antagonists; leukotriene antagonists; cytokine antagonists; protease inhibitors; cromolyn sodium; nedocryl sodium; and sodium cromoglycate.

[0139] The amount of various compounds administered will depend on the compound activity (in vitro, e.g., compound IC 50The dosage can be determined by standard procedures, taking into account factors such as the efficacy of the compound in vivo (e.g., activity against target, or in vivo activity in animal efficacy models), pharmacokinetic results in animal models (e.g., biological half-life or bioavailability), age, size, weight, and related disorders of the subject. The importance of these and other factors is well known to those skilled in the art. In general, dosages will range from about 0.01 to 50 mg / kg, and also from about 0.1 to 20 mg / kg of the subject being treated. Multiple doses can be used.

[0140] The compounds described herein (e.g., Compound I or a salt thereof, or one or more solid or amorphous forms of Compound I) may also be used in combination with other therapies, drugs, medical procedures, etc., for example, to treat the same disease. In some embodiments, such combinations include administering one or more other therapies, drugs, or medical procedures at different times (e.g., within a short time, such as within a few hours (e.g., 1, 2, 3, 4 to 24 hours), or within a long time (e.g., 1 to 2 days, 2 to 4 days, 4 to 7 days, 1 to 4 weeks)) or simultaneously with the compounds described herein. In some embodiments, combinations include use with at least one therapy, drug, or medical procedure, such as surgery, administered once or on an irregular basis, with the compounds described herein administered within a short or longer time period before or after the other therapy, drug, or procedure. In some embodiments, combinations include delivery of the compounds described herein and one or more other medicinal treatments by the same or different routes of administration. In some embodiments, the compounds described herein and one or more other therapeutic agents may be delivered together by the same route of administration in any formulation, including formulations in which the compounds and the other therapeutic agent(s) are chemically linked in such a manner that they maintain their therapeutic activity when administered. In some embodiments, the other therapeutic agent(s) may be co-administered with the compounds described herein. In some embodiments, co-administration includes administration of a co-formulation or formulation of chemically linked compounds, or administration of two or more compounds in separate formulations administered by the same or different routes within a short time of each other (e.g., within 1 hour, 2 hours, 3 hours, up to 24 hours). Co-administration of separate formulations includes co-administration by delivery via one device, e.g., the same inhalation device, the same syringe, etc., or administration from separate devices within a short time of each other.Co-formulation of the compounds disclosed herein with one or more additional therapeutic agents delivered by the same route includes preparation together with such substances that can be administered by one device, including separate compounds combined in one formulation, or compounds that are chemically bound but still adjusted to maintain their biological activity. Such chemically bound compounds may have bonds that are substantially maintained in vivo, or the bonds may degrade in vivo, separating the two active components. In some embodiments, the compounds disclosed herein may be used in adjuvant or neoadjuvant therapy in combination with other therapies or therapeutic agents described herein. In some embodiments related to combinations, the dose may be adjusted for one or more of the compounds disclosed herein or other therapeutic agents used in combination, for example, by reducing the dose compared to the compound or therapy used alone, by methods well known to those skilled in the art. Exemplary combination therapies are discussed below. 4. Disease Manifestations and Regulation of Bromodomains

[0141] Members of the BET (bromodomain and extra terminal) family of bromodomain proteins (BRD2, BRD3, BRD4, and BRDT) have been implicated in a variety of neurological, autoimmune and inflammatory diseases, metabolic disorders (Muller et al. Expert Rev. Mol. Med. 2011, Sep 13;13:e29; Prinjha et al. Trends Pharmacol. Sci. 2012, 33, 146-153; Belkina et al. J. Immunol. 2013, 190, 3670-3678; and Belkina et al. Nature Rev. Cancer 2012, 12, 465-477), and cancer (Alsarraj et al. International Journal of Breast Cancer 2012, 1-7; Barbieri et al. Briefings in Functional Genomics 2013, 1-12; Blobel et al. These proteins have been associated with a variety of disorders, including mitochondrial cell death (Dang Cell 2012,149,22-35; Chemokine 2013,363-370; Chemokine 2013,363-380; Chemokine 2013,363-390; Chemokine 2013,363-391). In addition, some viruses utilize these proteins to tether their genomes to host cell chromatin as part of the process of viral replication (You et al Cell,2004 117,349-60).

[0142] The compounds described herein (e.g., Compound I or a salt thereof, or one or more solid or amorphous forms of Compound I) are useful for treating disorders associated with one or more proteins involved in epigenetic regulation, such as proteins containing an acetyl-lysine recognition motif, i.e., bromodomains (e.g., BET proteins such as BRD2, BRD3, BRD4, and / or BRDT), and diseases associated with aberrant expression of bromodomains, including, for example, cell proliferative disorders, cancer, chronic autoimmune, inflammatory conditions, among others.

[0143] The presence of bromodomains has been linked to many different types of cancer, as well as other diseases and conditions, as described below. Bromodomain inhibitors are useful in treating systemic or tissue inflammation, inflammatory responses to infection or hypoxia, cell activation and proliferation, lipid metabolism, fibrosis, and the prevention and treatment of viral infections.

[0144] Bromodomain inhibitors, such as the compounds described herein (e.g., Compound I or a salt thereof, or one or more solid or amorphous forms of Compound I), are useful in the prevention and treatment of chronic autoimmune and inflammatory conditions, such as rheumatoid arthritis, uveal melanoma, chronic lymphocytic leukemia, acute myeloid leukemia, synovial sarcoma, osteoarthritis, acute gout, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease (Crohn's disease and ulcerative colitis), asthma, chronic obstructive airway disease, pneumonia, myocarditis, pericarditis, myositis, eczema, dermatitis, alopecia, vitiligo, bullous skin diseases, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, depression, retinitis, uveitis, scleritis, hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis, Addison's disease, hypophysitis, thyroiditis, type I diabetes, and acute rejection of transplanted organs.

[0145] Bromodomain inhibitors, such as the compounds described herein (e.g., Compound I or a salt thereof, or one or more solid or amorphous forms of Compound I), are useful in the prevention and treatment of acute inflammatory conditions, including, but not limited to, acute gout, giant cell arteritis, nephritis, including lupus nephritis, vasculitis with organ involvement such as glomerulonephritis, vasculitis, including giant cell arteritis, Wegener's granulomatosis, polyarteritis nodosa, Behcet's disease, Kawasaki disease, Takayasu's arteritis, vasculitis with organ involvement and acute rejection of transplanted organs.

[0146] Bromodomain inhibitors, such as the compounds described herein (e.g., Compound I or a salt thereof, or one or more solid or amorphous forms of Compound I), are useful in the prevention and treatment of autoimmune and inflammatory diseases or conditions involving inflammatory responses to infection with viruses, such as bacteria, herpes viruses, human papilloma viruses, adenoviruses, and pox viruses, as well as other DNA viruses; fungi, parasites, or their toxins, such as sepsis, septic syndrome, septic shock, endotoxemia, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome, toxic shock syndrome, acute lung injury, ARDS (adult respiratory distress syndrome), acute renal failure, fulminant hepatitis, burns, acute pancreatitis, postoperative syndrome, sarcoidosis, Herxheimer reaction, encephalitis, myelitis, meningitis, malaria, and SIRS associated with viral infections, such as influenza, herpes zoster, herpes simplex, and coronaviruses.

[0147] Bromodomain inhibitors, such as the compounds described herein (e.g., Compound I or a salt thereof, or one or more solid or amorphous forms of Compound I), are useful in the prevention and treatment of diseases or conditions associated with ischemia-reperfusion injury, including, but not limited to, myocardial infarction, cerebrovascular ischemia (stroke), acute coronary syndrome, renal reperfusion injury, organ transplantation, coronary artery bypass grafting, cardiopulmonary bypass surgery, pulmonary, renal, hepatic, gastrointestinal, or peripheral limb embolism.

[0148] Bromodomain inhibitors, such as the compounds described herein (e.g., Compound I or a salt thereof, or one or more solid or amorphous forms of Compound I), are useful in the prevention and treatment of hypercholesterolemia, atherosclerosis, and Alzheimer's disease.

[0149] Bromodomain inhibitors, such as the compounds described herein (e.g., Compound I or a salt thereof, or one or more solid or amorphous forms of Compound I), can be used to treat a variety of cancers, including, but not limited to, hematological cancers, epithelial cancers, including lung, breast, and colon cancers, midline carcinomas, mesenchymal tumors, liver tumors, renal tumors, neurological tumors, adrenal gland cancer, acinic cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acral sweat gland adenoma, acute eosinophilic leukemia, acute erythrocytic leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatous odontogenic tumor, adenomatous squamous cell carcinoma, and thyroid cancer. Epithelial carcinoma, adipose tissue neoplasm, adrenal cortical carcinoma, adult T-cell leukemia / lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, brown tumor, Burkitt lymphoma, breast cancer, brain cancer, carcinoma, carcinoma in situ, cancer Sarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, inclusion fetal malformation, fibroma, fibrosarcoma, follicular lymphoma, thyroid follicular carcinoma, posterior mediastinal ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of bone, glioma Alzheimer's tumors, glioblastoma multiforme, glioma, glioma cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, male and female germ cell tumor, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, malignant hematologic tumors, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, Leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer,MALT lymphoma, Malignant fibrous histiocytoma, Malignant peripheral nerve sheath tumor, Malignant Triton tumor, Mantle cell lymphoma, Marginal zone B-cell lymphoma, Mast cell leukemia, Mediastinal germ cell tumor, Medullary carcinoma of the breast, Medullary carcinoma of the thyroid, Medulloblastoma, Melanoma, Meningioma, Merkel cell carcinoma, Mesothelioma, Metastatic urothelial carcinoma, Mixed Müllerian tumor, Mucinous tumor, Multiple myeloma, Muscle tissue neoplasm, Mycosis fungoides, Myxoid liposarcoma, Myxoma, Myxosarcoma, Nasopharyngeal Head cancer, neurilemmoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, eye cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid carcinoma, paraganglioma, pineoblastoma, pineocytoma, pituitary cell tumor, pituitary adenoma, pituitary tumor, plasmacytoma, polyembryoma, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma , primary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma peritonei, renal cell carcinoma, medullary renal carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter transformation (also known as Richter syndrome), rectal cancer, sarcoma, schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small round blue cell tumor, small cell carcinoma, soft tissue sarcoma, somatostatinoma, sooty wart, spinal cord tumor, splenic marginal sarcoma The compounds are useful in the prevention and treatment of cancers, including lymphoma of the ovary, squamous cell carcinoma, synovial sarcoma, Sezary's disease, small intestine cancer, squamous cell carcinoma, gastric cancer, T-cell lymphoma, testicular cancer, thecoma, thyroid cancer, transitional cell carcinoma, laryngeal cancer, urachal carcinoma, genitourinary cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, and Wilms' tumor. 5. Methods for Treating Bromodomain-Mediated Conditions

[0150] The present disclosure provides, in some embodiments, a method for modulating or inhibiting a bromodomain (e.g., BET protein or BRD4 protein) or a variant thereof, in which the modulation or inhibition of the bromodomain plays a role or provides some advantages. For example, in some embodiments, the present disclosure provides a method for modulating or inhibiting a bromodomain or a variant thereof by contacting a cell or a bromodomain protein in vitro or in vivo with any one or more solid or amorphous forms of compound I described herein (e.g., compound I crystalline form A, compound I crystalline form B, compound I crystalline form C, compound I crystalline form D, compound I substance E, compound I substance F, compound I substance G, compound I free acid amorphous, compound I free acid amorphous salt form, or compound I sodium substance A) or a composition comprising any one or more solid or amorphous forms of compound I described herein. In some embodiments, the disclosure provides methods for modulating or inhibiting a bromodomain or a variant thereof by contacting compound I or a salt thereof, or a composition comprising compound I or a salt thereof, with a cell or a bromodomain protein in vitro or in vivo.

[0151] In some embodiments, the disclosure provides a method for treating a subject suffering from or at risk of a bromodomain-mediated disease or condition by administering to the subject an effective amount of any one or more solid or amorphous forms of Compound I described herein (e.g., Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I substance G, Compound I free acid amorphous, Compound I free acid amorphous salt form, or Compound I sodium substance A), or a composition comprising a compound described herein. In some embodiments, the disclosure provides a method for treating a subject suffering from or at risk of a bromodomain-mediated disease or condition by administering to the subject an effective amount of Compound I or a salt thereof, or a composition comprising Compound I or a salt thereof. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal.

[0152] In some embodiments, the present disclosure provides a method for suppressing the unwanted proliferation of tumor cells mediated by bromodomain. The method includes contacting tumor cells with an effective amount of a compound described herein (e.g., compound I or a salt thereof, compound I crystalline form A, compound I crystalline form B, compound I crystalline form C, compound I crystalline form D, compound I substance E, compound I substance F, compound I substance G, compound I free acid amorphous, free acid amorphous salt form of compound I, or compound I sodium substance A), or a composition comprising a compound described herein. In some examples, tumor cells are mediated by BET protein, BRD4 protein, or a variant thereof.

[0153] In some embodiments, the disease or condition treatable with one or more compounds described herein (e.g., Compound I or a salt thereof, Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I substance G, Compound I free acid amorphous, the free acid amorphous salt form of Compound I, or Compound I sodium substance A) comprises cancer, a neurological condition, an autoimmune condition, an inflammatory condition, a metabolic condition, or a combination thereof.

[0154] In some embodiments, a disease or condition treatable with one or more compounds described herein (e.g., Compound I or a salt thereof, Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I substance G, Compound I free acid amorphous, the free acid amorphous salt form of Compound I, or Compound I sodium substance A) includes, but is not limited to, cancer, e.g., hematological cancers, epithelial cancers including lung cancer, breast cancer, and colon cancer, midline carcinoma, mesenchymal tumors, liver tumors, renal tumors, neurological tumors, adrenal cancer, acinar cell carcinoma, acoustic neuroma, acral melanoma, cerebrovascular disease, and pulmonary arterial disease. Melanoma, acrohidrotic adenoma, acute eosinophilic leukemia, acute erythrocytic leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatous odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenal cortical carcinoma, adult T-cell leukemia / lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytic glioma, atypical teratoid rhabdominis Breast tumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, brown tumor, Burkitt lymphoma, breast cancer, brain cancer, carcinoma, intraepithelial carcinoma, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine neoplasm, endodermal sinus tumor tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, inclusion malformation fetus, fibroma, fibrosarcoma, follicular lymphoma, thyroid follicular cancer, posterior mediastinal ganglioneuroma, digestive cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of bone, glial tumor, glioblastoma multiforme, glioma, glioma cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, male and female germ cell tumor, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, malignant blood tumor, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna,Fatal midline carcinoma, leukemia, Leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant Triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary carcinoma of the thorax, medullary thyroid carcinoma, medulloblastoma, melanoma, meningeal tumor, Merkel cell carcinoma, mesothelioma, metastatic urothelial carcinoma, mixed Müllerian tumor, mucinous tumor, multiple myeloma, muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, schwannoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, eye cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid carcinoma, paraganglioma, pineoblastoma, pineocytoma, pituitary cell tumor, pituitary adenoma , pituitary tumor, plasmacytoma, polyembryoma, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, primary peritoneal carcinoma, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma peritonei, renal cell carcinoma, medullary renal carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter transformation (also known as Richter syndrome), rectal cancer, sarcoma, schwannomatosis, seminoma, Sertoli cell tumor, sex cord stromal tumor, signet ring cell carcinoma, skin cancer, small round blue cell tumor, small cell carcinoma , soft tissue sarcoma, somatostatinoma, sooty warts, spinal cord tumors, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sézary disease, small intestine cancer, squamous cell carcinoma, gastric cancer, T-cell lymphoma, testicular cancer, theca cell tumor, thyroid cancer, transitional cell carcinoma, laryngeal cancer, urachal carcinoma, genitourinary cancer, urothelial carcinoma, uveal melanoma, chronic lymphocytic leukemia, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, and Wilms' tumor.

[0155] In some embodiments, the cancer treatable with a compound of the disclosure (e.g., Compound I or a salt thereof, Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I substance G, Compound I free acid amorphous, the free acid amorphous salt form of Compound I, or Compound I sodium substance A) is an adenocarcinoma, adult T-cell leukemia / lymphoma, bladder cancer, blastoma, bone cancer, breast cancer, brain cancer, carcinoma, myeloid sarcoma, cervical cancer, colorectal cancer, esophageal cancer, gastrointestinal cancer, glioblastoma multiforme, The cancer is selected from glioma, gallbladder cancer, gastric cancer, head and neck cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, intestinal cancer, kidney cancer, laryngeal cancer, leukemia, lung cancer, lymphoma, liver cancer, small cell lung cancer, non-small cell lung cancer, mesothelioma, multiple myeloma, eye cancer, optic nerve tumor, oral cancer, ovarian cancer, pituitary tumor, primary central nervous system lymphoma, prostate cancer, pancreatic cancer, pharyngeal cancer, renal cell carcinoma, rectal cancer, sarcoma, skin cancer, spinal tumor, small intestine cancer, gastric cancer, T-cell lymphoma, testicular cancer, thyroid cancer, pharyngeal cancer, genitourinary cancer, uterine cancer, vaginal cancer, or Wilms' tumor.

[0156] In some embodiments, cancers or tumors treatable with a compound of the disclosure (e.g., Compound I or a salt thereof, Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I substance G, Compound I free acid amorphous, the free acid amorphous salt form of Compound I, or Compound I sodium substance A) include benign soft tissue tumors, bone tumors, brain and spinal cord tumors, eyelid and orbit tumors, granulomas, lipomas, meningiomas, multiple endocrine neoplasia, nasal polyps, pituitary tumors, prolactinomas, pseudotumor cerebri, seborrheic keratosis, gastric polyps, thyroid nodules, cystic tumors of the pancreas, hemangiomas, vocal cord nodules, polyps, and cysts, Castleman's disease, chronic pilonidal disease, dermatofibroma, sebaceous cyst, pyogenic granuloma, and juvenile polyposis syndrome.

[0157] In some embodiments, diseases or conditions treatable with a compound of the disclosure (e.g., Compound I or a salt thereof, Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I substance G, Compound I free acid amorphous, the free acid amorphous salt form of Compound I, or Compound I sodium substance A) include non-small cell lung cancer, small cell lung cancer, ovarian cancer, melanoma, midline carcinoma, breast cancer, lymphoma, neuroblastoma, or castration-resistant prostate cancer, myelofibrosis, myelodysplastic syndrome, or acute myeloid leukemia.

[0158] In some embodiments, diseases or conditions treatable with a compound of the disclosure (e.g., Compound I or a salt thereof, Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I substance G, Compound I free acid amorphous, the free acid amorphous salt form of Compound I, or Compound I sodium substance A) include non-small cell lung cancer, small cell lung cancer, ovarian cancer, melanoma, neuroblastoma, and castration-resistant prostate cancer.

[0159] In some embodiments, the disclosure provides a method for treating a subject suffering from or at risk of a disease or condition mediated by a bromodomain, or a variant thereof, by administering to a subject in need thereof an effective amount of any one or more solid or amorphous forms of Compound I described herein (e.g., Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I substance G, Compound I free acid amorphous, Compound I free acid amorphous salt form, or Compound I sodium substance A), or a composition comprising any one or more solid or amorphous forms of Compound I described herein, wherein the disease or condition is chronic lymphocytic leukemia (CLL), Richter's syndrome, uveal melanoma, acute myeloid leukemia (AML), or myelodysplastic syndrome (MDS). In some embodiments, the present disclosure provides a method for treating a subject suffering from or at risk of a disease or condition mediated by a bromodomain or a variant thereof by administering to a subject in need thereof an effective amount of Compound I or a salt thereof, or a composition comprising Compound I or a salt thereof, wherein the disease or condition is chronic lymphocytic leukemia (CLL), Richter's syndrome, uveal melanoma, acute myeloid leukemia (AML), or myelodysplastic syndrome (MDS). In one embodiment, the disease is chronic lymphocytic leukemia (CLL). In one embodiment, the disease or condition is Richter's syndrome. In one embodiment, the disease or condition is uveal carcinoma. In one embodiment, the disease or condition is myeloid leukemia. In one embodiment, the disease or condition is myelodysplastic syndrome (MDS).

[0160] In some embodiments, the disclosure provides a method for treating a subject suffering from or at risk of a disease or condition mediated by a bromodomain, or a variant thereof, by administering to a subject in need thereof an effective amount of any one or more solid or amorphous forms of Compound I described herein (e.g., Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I substance G, Compound I free acid amorphous, free acid amorphous salt form of Compound I, or Compound I sodium substance A), or a composition comprising any one or more solid or amorphous forms of Compound I described herein, wherein the disease or condition is chronic lymphocytic leukemia (CLL) or Richter's syndrome. In some embodiments, the present disclosure provides a method for treating a subject suffering from or at risk of a disease or condition mediated by a bromodomain or a variant thereof by administering to a subject in need thereof an effective amount of Compound I or a salt thereof, or a composition comprising Compound I or a salt thereof, wherein the disease or condition is chronic lymphocytic leukemia (CLL) or Richter's syndrome. In one embodiment, the disease is chronic lymphocytic leukemia (CLL). In one embodiment, the disease or condition is Richter's syndrome.

[0161] In some embodiments, the disclosure provides a method for treating a subject suffering from or at risk of a disease or condition mediated by a bromodomain, or a variant thereof, by administering to a subject in need thereof an effective amount of any one or more solid or amorphous forms of Compound I described herein (e.g., Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I substance G, Compound I free acid amorphous, free acid amorphous salt form of Compound I, or Compound I sodium substance A), or a composition comprising any one or more solid or amorphous forms of Compound I described herein, wherein the disease or condition is acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). In some embodiments, the present disclosure provides a method for treating a subject suffering from or at risk of a disease or condition mediated by a bromodomain or a variant thereof by administering to a subject in need thereof an effective amount of Compound I or a salt thereof, or a composition comprising Compound I or a salt thereof, wherein the disease or condition is acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). In one embodiment, the disease or condition is acute myeloid leukemia (AML). In one embodiment, the disease or condition is myelodysplastic syndrome (MDS).

[0162] In some embodiments, diseases or conditions treatable with one or more compounds disclosed herein (e.g., Compound I or a salt thereof, Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I substance G, Compound I free acid amorphous, the free acid amorphous salt form of Compound I, or Compound I sodium substance A) include autoimmune or inflammatory diseases or conditions, which may be chronic or acute, including, but are not limited to, inflammatory pelvic disease, urethritis, sunburn of the skin, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, pericarditis, nephritis, including lupus nephritis, osteomyelitis, myositis, eczema, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, primary biliary cirrhosis, cholecystitis, sclerosing cholangitis, agammaglobulinemia, psoriasis, allergies, clotting syndrome, inflammatory bowel disease ... Disease, irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue transplant rejection such as acute graft-versus-host disease, hyperacute rejection of transplanted organs, asthma, chronic obstructive airway disease, allergic rhinitis, chronic obstructive pulmonary disease (COPD), polyglandular autoimmune disease (also known as polyglandular autoimmune syndrome), autoimmune alopecia, pernicious anemia, vasculitis, glomerulonephritis, giant cell arteritis, Wegener's granulomatosis, polyarteritis nodosa, dermatomyositis, inflammation, multiple sclerosis, scleroderma, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome, atherosclerosis, Addison's disease, hypophysitis, Parkinson's disease, Alzheimer's disease, Kawasaki disease, Takayasu's arteritis, depression, retinitis, uveitis, scleritis, type I diabetes mellitus, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, gout, chronic idiopathic hematologic These may include thrombocytopenic purpura, Waldenstrom's macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, bullous skin diseases, autoimmune hypopituitarism, Guillain-Barre syndrome, Behcet's disease, scleracierma, mycosis fungoides, acute inflammatory reactions (such as acute respiratory distress syndrome and ischemia / reperfusion injury), and Graves' disease.In some embodiments, autoimmune and inflammatory diseases and conditions may include systemic or tissue inflammation, hypoxemia, cell activation and proliferation, lipid metabolism, fibrosis, inflammatory responses to infection with bacteria, viruses (e.g., herpes viruses, human papilloma viruses, adenoviruses, pox viruses, and other DNA viruses), fungi, parasites, or their toxins, such as sepsis, septic syndrome, septic shock, endotoxemia, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome, toxic shock syndrome, acute lung injury, ARDS (adult respiratory distress syndrome), acute renal failure, fulminant hepatitis, burns, acute pancreatitis, postoperative syndrome, sarcoidosis, Herxheimer reaction, encephalitis, myelitis, meningitis, malaria, and SIRS associated with viral infections such as influenza, herpes zoster, herpes simplex, and coronavirus.

[0163] In some embodiments, the disclosure provides a method for treating a subject suffering from or at risk of ischemia-reperfusion injury by administering to a subject in need thereof an effective amount of a compound described herein (e.g., Compound I or a salt thereof, Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I substance G, Compound I free acid amorphous, Compound I free acid amorphous salt form, or Compound I sodium substance A), or a composition comprising a compound described herein. Ischemia-reperfusion injury includes, but is not limited to, myocardial infarction, cerebrovascular ischemia (stroke), acute coronary syndrome, renal reperfusion injury, organ transplantation, coronary artery bypass graft, cardiopulmonary bypass surgery, pulmonary, renal, hepatic, gastrointestinal, and peripheral lower limb embolism.

[0164] In some embodiments, the disclosure provides a method for treating a subject suffering from or at risk for a disease or condition mediated by a bromodomain, or a variant thereof, comprising administering to a subject in need thereof an effective amount of any one or more solid or amorphous forms of Compound I described herein (e.g., Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I substance G, Compound I free acid amorphous, the free acid amorphous salt form of Compound I, or Compound I sodium substance A), or any one or more solid or amorphous forms of Compound I described herein. and the disease or condition is rheumatoid arthritis, uveal melanoma, chronic lymphocytic leukemia, acute myeloid leukemia, synovial sarcoma, osteoarthritis, acute gout, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease (Crohn's disease and ulcerative colitis), asthma, chronic obstructive airways disease, pneumonia, myocarditis, pericarditis, myositis, eczema, dermatitis, alopecia, vitiligo, bullous skin disease, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, depression, retinitis, uveitis, scleritis, hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis, Addison's disease, hypophysitis, thyroiditis, type I diabetes, or acute rejection of a transplanted organ. In some embodiments, the disclosure provides a method for treating a subject suffering from or at risk of a disease or condition mediated by a bromodomain, or a variant thereof, by administering to a subject in need thereof an effective amount of Compound I or a salt thereof, or a composition comprising Compound I or a salt thereof, the disease or condition being selected from the group consisting of rheumatoid arthritis, uveal melanoma, chronic lymphocytic leukemia, osteoarthritis, acute myeloid leukemia, synovial sarcoma, and the like. , acute gout, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease (Crohn's disease and ulcerative colitis), asthma, chronic obstructive airways disease, pneumonia, myocarditis, pericarditis, myositis, eczema, dermatitis, alopecia, vitiligo, bullous skin diseases, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, depression, retinitis, uveitis, scleritis, hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis, Addison's disease, hypophysitis, thyroiditis, type I diabetes mellitus, or acute rejection of a transplanted organ.In one embodiment, the disease or condition is rheumatoid arthritis. In one embodiment, the disease or condition is osteoarthritis. In one embodiment, the disease or condition is acute gout. In one embodiment, the disease or condition is psoriasis. In one embodiment, the disease or condition is systemic lupus. In one embodiment, the disease or condition is systemic lupus. In one embodiment, the disease or condition is erythematous. In one embodiment, the disease or condition is multiple sclerosis. In one embodiment, the disease or condition is inflammatory bowel disease. In one embodiment, the disease or condition is Crohn's disease. In one embodiment, the disease or condition is ulcerative colitis. In one embodiment, the disease or condition is asthma. In one embodiment, the disease or condition is chronic obstructive airways disease. In one embodiment, the disease or condition is pneumonia. In one embodiment, the disease or condition is myocarditis. In one embodiment, the disease or condition is pericarditis. In one embodiment, the disease or condition is myositis. In one embodiment, the disease or condition is eczema. In one embodiment, the disease or condition is dermatitis. In one embodiment, the disease or condition is alopecia. In one embodiment, the disease or condition is vitiligo. In one embodiment, the disease or condition is a bullous skin disease. In one embodiment, the disease or condition is nephritis. In one embodiment, the disease or condition is vasculitis. In one embodiment, the disease or condition is atherosclerosis. In one embodiment, the disease or condition is Alzheimer's disease. In one embodiment, the disease or condition is depression. In one embodiment, the disease or condition is retinitis. In one embodiment, the disease or condition is uveitis. In one embodiment, the disease or condition is scleritis. In one embodiment, the disease or condition is hepatitis. In one embodiment, the disease or condition is pancreatitis. In one embodiment, the disease or condition is primary biliary cirrhosis. In one embodiment, the disease or condition is sclerosing cholangitis. In one embodiment, the disease or condition is Addison's disease. In one embodiment, the disease or condition is hypophysitis. In one embodiment, the disease or condition is thyroiditis. In one embodiment, the disease or condition is type I diabetes. In one embodiment, the disease or condition is acute rejection of a transplanted organ.

[0165] In some embodiments, the present disclosure provides a method for treating a subject suffering from or at risk of hypercholesterolemia by administering to a subject in need thereof an effective amount of any one or more solid or amorphous forms of Compound I described herein (e.g., Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I substance G, Compound I free acid amorphous, Compound I free acid amorphous salt form, or Compound I sodium substance A), or a composition comprising any one or more solid or amorphous forms of Compound I described herein. In some embodiments, the present disclosure provides a method for treating a subject suffering from or at risk of hypercholesterolemia by administering to a subject in need thereof an effective amount of Compound I or a salt thereof, or a composition comprising Compound I or a salt thereof.

[0166] In some embodiments, the disclosure provides the use of a compound described herein (e.g., Compound I or a salt thereof, Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I substance G, Compound I free acid amorphous, the free acid amorphous salt form of Compound I, or Compound I sodium substance A), or a composition comprising a compound described herein, in the manufacture of a medicament for the treatment of a disease or condition described herein. In some embodiments, the disclosure provides a compound described herein, or a composition comprising a compound described herein, for use in the treatment of a disease or condition described herein.

[0167] As discussed in detail below, the present disclosure provides combination therapies for treating a subject suffering from or at risk for a disease or condition described herein, such combination therapies comprising administering to a subject in need thereof any one or more of the compounds disclosed herein (e.g., Compound I or a salt thereof, Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I substance G, Compound I free acid amorphous, the free acid amorphous salt form of Compound I, or Compound I sodium substance A) or a composition comprising any one or more of the compounds described herein in combination with one or more other therapeutic agents, including, but not limited to, a BCL-2 inhibitor, a PI3K inhibitor, a BTK inhibitor, a CTLA-4 inhibitor, a checkpoint inhibitor, or quizartinib.

[0168] The following literature publications describe just a few examples of these uses of bromodomain inhibitors.

[0169] Since the compounds described herein have been shown to be bromodomain inhibitors, the following publications confirm the utility of the claimed compounds: cancer

[0170] Bromodomain inhibitors have been administered to humans in clinical trials for breast cancer, non-small cell lung cancer, small cell lung cancer, acute myeloid leukemia, myelodysplastic neoplasms, myelodysplastic syndromes, midline carcinoma, castration-resistant prostate cancer, pancreatic cancer, multiple myeloma, colorectal cancer, and neuroblastoma (CA French, Small-Molecule Targeting of BET Proteins in Cancer, Advances in Cancer Research, (2016), 131, 21-58).

[0171] Bromodomain 4 (BRD4) inhibitors inhibit colorectal cancer growth and metastasis (Y. Hu, et al., BRD4 Inhibitor Inhibits Colorectal Cancer Growth and Metastasis, Int. J. Mol. Sci. (2015), 16, 1928-1948).

[0172] Bromodomain inhibitors inhibit castration-resistant prostate cancer (IA Asangani, et al., Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer, Nature (2014), 510, 278-282).

[0173] Treatment of a panel of neuroblastoma cell lines with bromodomain inhibitors resulted in potent growth inhibition and cytotoxicity in most cell lines (A. Wyce, et al., BET Inhibition Silences Expression of MYCN and BCL2 and Induces Cytotoxicity in Neuroblastoma Tumor Models, PLOS ONE (2013), 8, 8, 1-16).

[0174] Bromodomain inhibitors potently reduce survival in acute lymphoblastic leukemia (CJ Ott, et al., BET bromodomain inhibition targets both c-MYC and IL7R in high-risk acute lymphoblastic leukemia, Blood Journal (2012), 1-23).

[0175] Bromodomain inhibitors selectively suppress the proliferation of mouse and human AML cell lines. (AF Hohmann et al., Sensitivity and engineered resistance of myeloid leukemia cells to BRD9 inhibition, Nature Chemical Biology (2016), 12, 672-679).

[0176] Compound I of the present disclosure was found to be a structurally distinct BET inhibitor with novel in vitro and in vivo pharmacological properties that match or exceed the efficacy of B cell receptor (BCR) signaling agents in preclinical models of CLL. (HG Ozer et al., BRD4 profiling identifies critical Chronic Lymphocytic Leukemia oncogenic circuits and reveals sensitivity to PLX51107, a novel structurally distinct BET inhibitor, Cancer Discovery, Published Online March 14, 2018 doi:10.1158 / 2159-8290.CD-17-0902).

[0177] In a mouse xenograft model of uveal melanoma (UM), compound I of the present disclosure significantly inhibited tumor growth. (G. Ambrosini et al., Cytotoxic Effects of a Novel BRD4 Inhibitor in Uveal Melanoma Cells with Gnaq / 11 Mutations, Molecular and Cellular Biology, Genetics, DOI:10.1158 / 1538-7445.AM2016-4462 Published July 2016).

[0178] Several bromodomain inhibitor candidates are progressing into clinical trials for myelodysplastic syndromes, AML, multiple myeloma, and glioblastoma multiforme (GWRhyasen, et al., AZD5153: A Novel Bivalent BET Bromodomain Inhibitor Highly Active against Hematologic Malignancies, Mol. Cancer Ther. (2016), 15, 11, 2563-2574).

[0179] Bromodomain 4 (BRD4) inhibitors have been found to result in selective inhibition of the MYC oncogene in multiple myeloma (J. Loven, et al., Selective Inhibition of Tumor Oncogenes by Disruption of Super-Enhancers, Cell (2013), 153, 320-334).

[0180] Potent antimyeloma activity has been observed with bromodomain inhibitors (A. Chaidos, et al., Potent antimyeloma activity of the novel bromodomain inhibitors I-BET151 and I-BET762, Blood (2014), 123, 5, 697-705).

[0181] Bromodomain inhibitors were found to induce cell cycle arrest in glioblastoma multiforme cells (C. Pastori, et al., The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation, PNAS (2015), 1-6).

[0182] Suppression of BRD4 has been demonstrated to correlate with inhibition of Merkel cell carcinoma xenograft tumor growth (D. Sengupta, et al., Disruption of BRD4 at H3K27Ac-enriched enhancer region correlates with decreased c-Myc expression in Merkel cell carcinoma, Epigenetics (2015), 10, 6, 460-466).

[0183] BRD4 inhibitors suppress breast cancer cell growth (J. Shi, et al., Disrupting the Interaction of BRD4 with Diacetylated Twist Suppresses Tumorigenesis in Basal-like Breast Cancer, Cancer Cell (2014), 25, 210-225).

[0184] Bromodomain inhibition primes NSCLC cells for induction of apoptosis, and BRD inhibitors have been demonstrated to exhibit distinct anti-proliferative activity in a panel of NSCLC cell lines (O. Klingbeil, et al., Inhibition of BET bromodomain-dependent XIAP and FLIP expression sensitizes KRAS-mutated NSCLC to pro-apoptic agents, Cell Death and Disease (2016), 7, e2365, doi:10.1038 / cddis.2016.271, 1-13).

[0185] BRD4 inhibitors significantly inhibit the proliferation and survival of osteosarcoma cells (DH Lee et al., Synergistic Effect of JQ1 2014 and Rapamycin for Treatment of Human Osteosarcoma, Int. J. Cancer (2015), 135, 2055-2064).

[0186] Bromodomain inhibitors demonstrated inhibitory effects on ovarian cancer cell lines (AM Kurimchak, et al., Resistance to BET Bromodomain Inhibitors is Mediated by Kinome Reprogramming in Ovarian Cancer, Cell Reports (2016), 16, 1273-1286).

[0187] Bromodomain inhibitors potently inhibit gastric cancer cell growth (RC Montenegro, et al., BET inhibition as a new strategy for the treatment of gastric cancer, Oncotarget (2016), 7, 28, 43997-44012).

[0188] Certain LAC cell lines are highly sensitive to bromodomain inhibition (WW Lockwood, et al., Sensitivity of human lung adenocarcinoma cell lines to targeted inhibition of BET epigenetic signaling proteins, PNAS (2012), 109, 47, 19408-19413)

[0189] BRD4 is a promising target for midline carcinoma (J. Lu et al., Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4, Chemistry & Biology (2015), 22, 755-763).

[0190] BRD4 inhibitors were found to suppress both the growth and tumorigenesis of malignant peripheral nerve sheath tumors (MPNSTs) (AJ Patel et al., BET Bromodomain Inhibition Triggers Apoptosis of NF1-Associated Malignant Peripheral Nerve Sheath Tumors through Bim Induction, Cell Reports (2014), 6, 1-12).

[0191] Bromodomain inhibitors have been found to induce apoptosis and reduce the growth of melanoma cells (A. Heinemann et al., Combining BET and HDAC inhibitors synergistically induces apoptosis of melanoma and suppresses AKT and YAP signaling, Oncotarget (2015) 6, 25, 21507-21521).

[0192] BRD4 inhibition has been characterized as a novel therapeutic intervention for uveal melanoma (G. Ambrosini et al., BRD4-targeted therapy induces Myc-independent cytotoxicity in Gnaq / 11-mutant uveal melanoma cells, Oncotarget (2015), 6, 32, 33397-33409).

[0193] Mice bearing medulloblastoma xenografts showed extended survival when treated with bromodomain inhibitors (A. Hennsen et al., BET bromodomain protein inhibition is a therapeutic option for medulloblastoma, Oncotarget (2013), 4, 11, 2080-2095). Lymphoma

[0194] Bromodomain inhibitors inhibit the proliferation of lymphoma cell lines of different origins (M. Jung, et al., Targeting BET bromodomains for cancer treatment, Epigenomics (2015), 7(3), 487-501).

[0195] Bromodomain inhibitors have been shown to be effective against Burkitt's lymphoma (S.Wu,et al.,Phospho Switch Triggers Brd4 Chromotin Binding and Activator Recruitment for Gene-Specific Targeting,Molecular Cell (2013),49,1-15;J.Lu et al.,Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4,Chemistry & Biology (2015),22,755-763).

[0196] Bromodomain inhibition induces apoptosis in B-cell lymphoma (SJHogg et al., BET inhibition Induces Apoptosis in Aggressive B-Cell Lymphoma via Epigenetic Regulation of BCL-2 Family Members, Mol Cancer Ther (2016), 15, 9, 2030-2041).

[0197] Inflammatory and autoimmune disorders

[0198] Bromodomain inhibitors have been shown to be effective in treating disease indications such as autoimmune diseases and inflammation (OAKharenko, et al., RVX-297- a novel BD2 selective inhibitor of BET bromodomains, Biochemical and Biophysical Research Communication (2016), 477, 62-67).

[0199] Bromodomain inhibition has been found to provide beneficial activity in autoimmune disease areas (DULee et al., Nonselective inhibition of the epigenetic transcriptional regulator BET induces marked lymphoid and hematopoietic toxicity in mice, Toxicology and Applied Pharmacology (2016), 300, 47-54).

[0200] Bromodomain inhibition was found to ameliorate colitis in mice (K. Cheung et al., BET N-terminal bromodomain inhibition selectively blocks Th17 cell differentiation and ameliorates colitis in mice, PNAS (2017), 114, 11, 2952-2957).

[0201] BRD4 inhibitors reduce IL-1β-induced inflammation in human airway epithelial cells and may be effective in treating chronic obstructive pulmonary disease (YM Khan, et al., Brd4 is Essential for IL-1β-Induced Inflammation in Human Airway Epithelial Cells, PLOS ONE (2014), 9, 4, 1-17).

[0202] Bromodomain inhibition provides beneficial activity against atherosclerosis (DULee et al., Nonselective inhibition of the epigenetic transcriptional regulator BET induces marked lymphoid and hematopoietic toxicity in mice, Toxicology and Applied Pharmacology (2016), 300, 47-54). Arthritis / Joint-related diseases

[0203] Bromodomain inhibitors reduce joint swelling and inflammation and help prevent bone loss, which may be useful in treating rheumatoid arthritis and osteoarthritis (K. Park-Min, et al., Inhibition of osteoclastogenesis and inflammatory bone resorption by targeting BET proteins and epigenetic regulation, Nature Communications (2014), 5:5418, 1-9).

[0204] Bromodomains mediate inflammation-related pathologies such as rheumatoid arthritis (KA Papavassiliou, et al., Bromodomains: pockets with therapeutic potential, Trends in Molecular Medicine (2014), 20, 9, 477-478). 6. Combination Therapy

[0205] Bromodomain modulators may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the cancers described herein, as well as in other diseases and indications. In one embodiment, the composition comprises any one or more compound(s) described herein (e.g., compound I or a salt thereof, or any one or more solid or amorphous forms of compound I) with one or more compounds that are therapeutically effective for the same disease indication, and the compounds have a synergistic effect on the disease indication. In one embodiment, the composition comprises any one or more compound(s) described herein that are effective in treating cancer, and one or more other compounds that are effective in treating the same cancer, and the compounds are synergistically effective in treating cancer.

[0206] In some embodiments, the disclosure provides compositions, e.g., pharmaceutical compositions, comprising any one or more solid or amorphous forms of Compound I described herein (e.g., Compound I or a salt thereof, Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I substance G, Compound I free acid amorphous, the free acid amorphous salt form of Compound I, or Compound I sodium substance A) and one or more other therapeutic agents. In some embodiments, the disclosure provides compositions, e.g., pharmaceutical compositions, comprising Compound I or a salt thereof and one or more other therapeutic agents. In some embodiments, the one or more other therapeutic agents include, but are not limited to, adozelin, altretamine, bendamustine, bizelin, busulfan, carboplatin, carboquone, carmofur, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, etoglucide, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomustine, mannosulfan, mechlorethamine, melphalan, mitobronitol, nedaplatin, nimustine, oxaliplatin, piposulfan, prednimustine, procaine, rifabutin ... Alkylating agents, including rubazine, ranimustine, satraplatin, semustine, streptozocin, temozolomide, thiotepa, treosulfan, triaziquone, triethylenemelamine, triplatin tetranitrate, trofosfamide, and uramustine; antibiotics, including, but not limited to, aclarubicin, amrubicin, bleomycin, dactinomycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, idarubicin, menogaril, mitomycin, neocarzinostatin, pentostatin, pirarubicin, plicamycin, valrubicin, and zorubicin;antimetabolites, including, but not limited to, aminopterin, azacitidine, azathioprine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, tegafur-uracil, thioguanine, trimethoprim, trimetrexate, and vidarabine; Immunotherapy, including but not limited to alemtuzumab, bevacizumab, cetuximab, galiximab, gemtuzumab, panitumumab, pertuzumab, rituximab, brentuximab, tositumomab, trastuzumab, 90Y ibritumab tiuxetan, ipilimumab, tolerimumab, and anti-CTLA-4 antibodies; antibody therapy, including but not limited to anastrozole, androgens, buserelin, diethylstilbestrol, exemestane, furuta hormones or hormone antagonists, including, but not limited to, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, magestrol, raloxifene, tamoxifen, and toremifene; taxanes, including, but not limited to, DJ-927, docetaxel, TPI287, larotaxel, ortataxel, paclitaxel, DHA-paclitaxel, and tesetaxel; retinoids, including tenth, fenretinide, isotretinoin, and tretinoin; alkaloids, including but not limited to demecolcine, homoharringtonine, vinblastine, vincristine, vindesine, vinflunine, and vinorelbine; antiangiogenic agents, including but not limited to AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide;topoisomerase inhibitors, including, but not limited to, amsacrine, belotecan, edotecarin, etoposide, etoposide phosphate, exatecan, irinotecan (as well as the active metabolite SN-38 (7-ethyl-10-hydroxy-camptothecin)), lucantone, mitoxantrone, pixantrone, rubitecan, teniposide, topotecan, and 9-aminocamptothecin; Kinase inhibitors, including sanib (AMG706), nilotinib (AMN107), seliciclib, sorafenib, sunitinib malate, AEE-788, BMS-599626, UCN-01 (7-hydroxystaurosporine), vemurafenib, dabrafenib, selumetinib, LGX818, BGB-283, PLX3397, and vatalanib; targeted signal transduction inhibitors, including but not limited to, bortezomib, geldanamycin, and rapamycin; biological response modifiers, including but not limited to, imiquimod, interferon-alpha, and interleukin-2;and, but are not limited to, 3-AP (3-amino-2-carboxaldehyde thiosemicarbazone), altrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elesclomol, eribulin mesylate (E7389), ixabepilone, lonidamine, masoprocol, mitogen activator, oblimersen, sulindac, testolactone, tiazofurin, mTOR inhibitors (e.g., sirolimus, everolimus, deforolimus), BCL-2 inhibitors (e.g., venetocalx), PI3K inhibitors (e.g., BEZ235, venetocalx, idelalisib, IDH1, ID H2, EZH2, GDC-0941, XL147, XL765), BTK inhibitors (e.g., ibrutinib, alabrutinib), Cdk4 inhibitors (e.g., PD-332991), Akt inhibitors, CTLA-4 inhibitors (ipilimumab), Hsp90 inhibitors (e.g., geldanamycin, radicicol, tanespimycin), checkpoint inhibitors (PD-1 inhibitors such as nivolumab, or PDL-1 inhibitors such as pembrolizumab), farnesyltransferase inhibitors (e.g., tipifarnib), and aromatase inhibitors (anastrozole letrozole exemestane);

[0207] In some embodiments, the disclosure provides compositions, e.g., any one or more solid or amorphous forms of Compound I described herein (e.g., Compound I or a salt thereof, Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I substance G, Compound I free acid amorphous, the free acid amorphous salt form of Compound I, or Compound I sodium substance A), including, but not limited to, adozelesin, altretamine, bendamustine, bizeresin, busulfan, , carboplatin, carboquone, carmofur, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, etoglucide, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomustine, mannosulfan, mechlorethamine, melphalan, mitobronitol, nedaplatin, nimustine, oxaliplatin, piposulfan, prednimustine, procarbazine, ranimustine, satraplatin, semustine, Alkylating agents, including but not limited to streptozocin, temozolomide, thiotepa, treosulfan, triaziquone, triethylenemelamine, triplatin tetranitrate, trofosfamide, and uramustine; including but not limited to aclarubicin, amrubicin, bleomycin, dactinomycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, idarubicin, menogaril, mitomycin, neocarzinostatin, pentostatin, pirarubicin, plicamycin, valrubicin, antibiotics, including but not limited to aminopterin, azacitidine, azathioprine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, tegafur-uracil, thioguanine, trimethoprim, trimetrexate, and vidarabine;Immunotherapy, including but not limited to alemtuzumab, bevacizumab, cetuximab, galiximab, gemtuzumab, panitumumab, pertuzumab, rituximab, brentuximab, tositumomab, trastuzumab, 90Y ibritumab tiuxetan, ipilimumab, tolerimumab, and anti-CTLA-4 antibodies; antibody therapy, including but not limited to anastrozole, androgens, buserelin, diethylstilbestrol, excitobacter, androgen therapy; Hormones or hormone antagonists, including, but not limited to, semestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, magestrol, raloxifene, tamoxifen, and toremifene; taxanes, including, but not limited to, DJ-927, docetaxel, TPI287, larotaxel, ortataxel, paclitaxel, DHA-paclitaxel, and tesetaxel; retinoids, including, but not limited to, alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin; alkaloids, including, but not limited to, demecolcine, homoharringtonine, vinblastine, vincristine, vindesine, vinflunine, and vinorelbine; and steroids, including, but not limited to, AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalid antiangiogenic agents, including but not limited to amsacrine, belotecan, edotecarin, etoposide, etoposide phosphate, exatecan, irinotecan (as well as the active metabolite SN-38 (7-ethyl-10-hydroxy-camptothecin)), lucanthone, mitoxantrone, pixantrone, rubitecan, teniposide, topotecan, and 9-aminocamptothecin;Examples of anti-cancer drugs include, but are not limited to, axitinib (AG013736), dasatinib (BMS354825), erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, motesanib diphosphate (AMG706), nilotinib (AMN107), seliciclib, sorafenib, sunitinib malate, AEE-788, BMS-599626, UCN-01 (7-hydroxystaurosporine), vemurafenib, dabrafenib, selumetinib, paradoxbreaker, kinase inhibitors, including but not limited to, KAR (PLX8394 or PLX7904), LGX818, BGB-283, pexidartinib (PLX3397), and vatalanib; targeted signal transduction inhibitors, including but not limited to, bortezomib, geldanamycin, and rapamycin; biological response modifiers, including but not limited to, imiquimod, interferon-α, and interleukin-2; and 3-AP (3-amino-2-carbazolidinediaminetetraacetate). xylaldehyde thiosemicarbazone), altrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elesclomol, eribulin mesylate (E7389), ixabepilone, lonidamine, masoprocol, mitogen activator, oblimersen, sulindac, testolactone, tiazofurin, mTOR inhibitors (e.g., sirolimus, everolimus, deforolimus, INK28, AZD8055), PI3K inhibitors (e.g., BE and one or more other therapeutic agents selected from other chemotherapeutic agents including: anti-cancer drugs (e.g., Z235, GDC-0941, XL147, XL765, BMK120), Cdk4 inhibitors (e.g., PD-332991), Akt inhibitors, Hsp90 inhibitors (e.g., geldanamycin, radicicol, tanespimycin), farnesyltransferase inhibitors (e.g., tipifarnib), and aromatase inhibitors (anastrozole letrozole exemestane);

[0208] In some embodiments, the disclosure provides compositions, such as, but not limited to, Compound I or a salt thereof, and a combination of Compound I, ... Alkylating agents, including but not limited to, aclarubicin, amrubicin, bleomycin, dactinomycin, daunorubicin, doxorubicin, daun ... Antibiotics, including, but not limited to, aminopterin, azacitidine, azathioprine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, antimetabolites, including rituximab, nelarabine, pemetrexed, raltitrexed, tegafur-uracil, thioguanine, trimethoprim, trimetrexate, and vidarabine; immunotherapies, including, but not limited to, alemtuzumab, bevacizumab, cetuximab, galiximab, gemtuzumab, panitumumab, pertuzumab, rituximab, brentuximab, tositumomab, trastuzumab, 90Y-ibritumab tiuxetan, ipilimumab, tolerimumab, and anti-CTLA-4 antibodies;Hormones or hormone antagonists, including, but not limited to, anastrozole, androgens, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, magestrol, raloxifene, tamoxifen, and toremifene; taxanes, including, but not limited to, DJ-927, docetaxel, TPI287, larotaxel, ortataxel, paclitaxel, DHA-paclitaxel, and tesetaxel; retinoids, including but not limited to alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin; alkaloids, including but not limited to demecolcine, homoharringtonine, vinblastine, vincristine, vindesine, vinflunine, and vinorelbine; antiangiogenic agents, including but not limited to AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide; topoisomerase inhibitors, including, but not limited to, camptothecin, edotecarin, etoposide, etoposide phosphate, exatecan, irinotecan (as well as the active metabolite SN-38 (7-ethyl-10-hydroxy-camptothecin)), lucantone, mitoxantrone, pixantrone, rubitecan, teniposide, topotecan, and 9-aminocamptothecin; kinase inhibitors, including, but not limited to, bortezomib, geldanamycin, and rapamycin;biological response modifiers, including, but not limited to, imiquimod, interferon-α, and interleukin-2; and, but not limited to, 3-AP (3-amino-2-carboxaldehyde thiosemicarbazone), altrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elesclomol, eribulin mesylate (E7389), ixabepilone, lonidamine, masoprocol, mitoguanazone, oblimersen, sulindac, testolactone, tiazofurin, mTOR inhibitors (e.g., sirolimus, and one or more other therapeutic agents selected from other chemotherapeutic agents including: everolimus, deforolimus, INK28, AZD8055), PI3K inhibitors (e.g., BEZ235, GDC-0941, XL147, XL765, BMK120), Cdk4 inhibitors (e.g., PD-332991), Akt inhibitors, Hsp90 inhibitors (e.g., geldanamycin, radicicol, tanespimycin), farnesyltransferase inhibitors (e.g., tipifarnib), and aromatase inhibitors (anastrozole letrozole exemestane);

[0209] In some embodiments, the disclosure provides compositions, e.g., compositions comprising any one or more solid or amorphous forms of Compound I described herein (e.g., Compound I or a salt thereof, Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I substance G, Compound I free acid amorphous, the free acid amorphous salt form of Compound I, or Compound I sodium substance A) in combination with i) adozelesin, altretamine, bizelesin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cytomegalovirus ... an alkylating agent selected from suplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, hepsulfame, ifosfamide, improsulfan, irofulven, lomustine, mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine, streptozocin, temozolomide, thiotepa, and treosulfan; ii) bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone, neosulfan, iii) an antibiotic selected from azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, ftorafur, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine, and trimetrexate; iv) an antimetabolite selected from alemtuzumab, bevacizumab, cetuximab, galiximab. , gemtuzumab, nivolumab, panitumumab, pembrolizumab, pertuzumab, rituximab, tositumomab, trastuzumab, and 90Y-ibritumab tiuxetan; v) a hormone or hormone antagonist selected from anastrozole, androgen, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, magestrol, raloxifene, tamoxifen, and toremifene;vi) taxanes selected from DJ-927, docetaxel, TPI287, paclitaxel, and DHA-paclitaxel; vii) retinoids selected from alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin; viii) alkaloids selected from etoposide, homoharringtonine, teniposide, vinblastine, vincristine, vindesine, and vinorelbine; ix) AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenastat ... x) an antiangiogenic agent selected from amsacrine, edotecan, exatecan, irinotecan, SN-38 (7-ethyl-10-hydroxy-camptothecin), rubitecan, topotecan, and 9-aminocamptothecin; xi) an antiangiogenic agent selected from erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, sorafenib, sunitinib malate, AEE-788, AG-013736, AMG706, AMN107, BMS-354825, BMS-59962 6) kinase inhibitors selected from UCN-01 (7-hydroxystaurosporine), vemurafenib, dabrafenib, trametinib, cobimetinib, selumetinib, and vatalanib; xii) targeted signal transduction inhibitors selected from bortezomib, geldanamycin, and rapamycin; xiii) biological response modifiers selected from imiquimod, interferon-α, and interleukin-2; xiv) IDO inhibitors; and xv) 3-AP (3-amino-2-carboxaldehyde thiosemicarbazone), altracentra. xvi) a chemotherapeutic agent selected from rifapril, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elesclomol, eribulin mesylate (E7389), ixabepilone, lonidamine, masoprocol, mitoguanazone, oblimersen, sulindac, testolactone, tiazofurin, mTOR inhibitors, PI3K inhibitors, Cdk4 inhibitors, Akt inhibitors, Hsp90 inhibitors, farnesyltransferase inhibitors, or aromatase inhibitors (anastrozole, letrozole, exemestane); xvi) a Mek inhibitor;and one or more other therapeutic agents selected from: xvii) a tyrosine kinase inhibitor; xviii) a c-Kit mutant inhibitor; xix) an EGFR inhibitor, or xx an epigenetic modulator. In further embodiments, a bromodomain modulator, particularly a solid or amorphous form of Compound I described herein (e.g., Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I free acid amorphous, Compound I free acid amorphous salt form, or Compound I sodium salt) may be administered in combination with one or more agents described herein, simultaneously, sequentially, or separately;

[0210] In some embodiments, the disclosure provides a composition, e.g., a combination of Compound I or a salt thereof with i) adozelesin, altretamine, bizelesin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomustine, mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine, streptozocin, temozolomide, thiotetracycline, temozolomide ... ii) an alkylating agent selected from bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin, and plicamycin; iii) an antibiotic selected from azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, ftrafur, gemcitabine, hydroxylase, tert-butanol ... antimetabolites selected from cyclothiourea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine, and trimetrexate; iv) antibody therapy selected from alemtuzumab, bevacizumab, cetuximab, galiximab, gemtuzumab, nivolumab, panitumumab, pembrolizumab, pertuzumab, rituximab, tositumomab, trastuzumab, and 90Y-ibritumab tiuxetan; v) anastrozole, androgens, buserelin, and diethylstilbest. vi) hormones or hormone antagonists selected from lorlol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, magestrol, raloxifene, tamoxifen, and toremifene; vi) taxanes selected from DJ-927, docetaxel, TPI287, paclitaxel, and DHA-paclitaxel; vii) retinoids selected from alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin;viii) alkaloids selected from etoposide, homoharringtonine, teniposide, vinblastine, vincristine, vindesine, and vinorelbine; ix) antiangiogenic agents selected from AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide; x) amsacrine, edotecarin, exatecan, irinotecan, SN-38 (7-ethyl-10-hydroxy-camptothecin), rubitecan, topoisomerase inhibitors, and cyclosporine inhibitors. tecan, and 9-aminocamptothecin; xi) a topoisomerase inhibitor selected from erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, sorafenib, sunitinib malate, AEE-788, AG-013736, AMG706, AMN107, BMS-354825, BMS-599626, UCN-01 (7-hydroxystaurosporine), vemurafenib, dabrafenib, trametinib, cobimetinib selumetinib, and vatalanib. , kinase inhibitors; xii) targeted signal transduction inhibitors selected from bortezomib, geldanamycin, and rapamycin; xiii) biological response modifiers selected from imiquimod, interferon-α, and interleukin-2; xiv) IDO inhibitors; and xv) 3-AP (3-amino-2-carboxaldehyde thiosemicarbazone), altrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elesclomol, mesyl. a chemotherapeutic agent selected from eribulin acid (E7389), ixabepilone, lonidamine, masoprocol, mitoguanazone, oblimersen, sulindac, testolactone, tiazofurin, mTOR inhibitors, PI3K inhibitors, Cdk4 inhibitors, Akt inhibitors, Hsp90 inhibitors, farnesyltransferase inhibitors, or aromatase inhibitors (anastrozole, letrozole, exemestane); xvi) a Mek inhibitor; xvii) a tyrosine kinase inhibitor; xviii) a c-Kit mutant inhibitor;xix) one or more other therapeutic agents selected from an EGFR inhibitor, or xx epigenetic modulator. In a further embodiment, the bromodomain modulator, particularly compound I or a salt thereof, may be administered simultaneously, sequentially, or separately in combination with one or more agents described herein;

[0211] Epigenetic modulators include DNA methylating agents, as well as agents that regulate post-translational modifications of histones and / or proteins through the activity of chromatin modifiers. Non-limiting examples of epigenetic modulators include: (a) a DNA methyltransferase (e.g., azacitidine, decitabine, or zebularine), (b) histone and protein methyltransferases, including but not limited to DOT1L inhibitors such as EPZ004777 (7-[5-deoxy-5-[[3-[[[[4-(1,1-dimethylethyl)phenyl]amino]carbonyl]amino]propyl](1-methylethyl)amino]-β-D-ribofuranosyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine), EZH1 inhibitors, EZH2 inhibitors, or EPX5687; (c) histone demethylase, (d) histone deacetylase inhibitors (HDAC inhibitors), including, but not limited to, vorinostat, romidepsin, chidamide, panobinostat, belinostat, valproic acid, mocetinostat, abexinostat, entinostat, resminostat, givinostat, or xinostat; (e) Examples of compounds that may be used include, but are not limited to, C-646, (4-[4-[[5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)]methylene]-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl]benzoic acid a), CPTH2 (cyclopentylidene-[4-(4'-chlorophenyl)thiazol-2-yl]hydrazine), CTPB (N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-6-pentadecyl-benzamide), garcinol ((1R,5R, 7R)-3-(3,4-dihydroxybenzyl)-4-hydroxy-8,8-dimethyl-1,7-bis(3-methyl-2-buten-1-yl)-5-[(2S)-5-methyl-2-(1-methylethenyl)-4-hexen-1-yl]bicyclo[3.3.1]non-3-ene-2,9-dione), anacardic acid, EML425 (5-[(4-hydroxy-2,6-dimethylphenyl)methylene]-1,3-bis(phenylmethyl)-2,4,6(1H,3H,5H)-pyrimidinetrione), ISOX histone acetyltransferase inhibitors (also referred to as HAT inhibitors), including DUAL ([3-[4-[2-[5-(dimethyl-1,2-oxazol-4-yl)])-1-[2-(morpholin-4-yl)ethyl]-1H-1,3-benzodiazol-2-yl]ethyl]phenoxy]propyl]dimethylamine), L002 (4-[O-[(4-methoxyphenyl)]sulfonyl]oxime]-2,6-dimethyl-2,5-cyclohexadiene-1,4-dione), NU9056 (5-(1,2-thiazol-5-yldisulfanyl)-1,2-thiazole), SI-2 hydrochloride (1-(2-pyridinyl)ethanone 2-(1-methyl-1H-benzimidazol-2-yl)hydrazone hydrochloride), or (f) Other chromatin remodelers include:

[0212] In some embodiments, the epigenetic modulator is vorinostat, romidepsin, belinostat, or panobinostat.

[0213] In some embodiments, compositions are provided that include a therapeutically effective amount of any one or more compound(s) described herein (e.g., Compound I or a salt thereof, or any solid or amorphous form of Compound I) and at least one pharma- ceutically acceptable carrier, excipient, and / or diluent. In some embodiments, compositions are provided that include a therapeutically effective amount of any two or more compound(s) described herein (e.g., Compound I or a salt thereof, or a solid or amorphous form of Compound I) and at least one pharma- ceutically acceptable carrier, excipient, and / or diluent. In some embodiments, the compositions can further include a plurality of different pharmacologically active compounds, which can include a plurality of compounds described herein. In some embodiments, the compositions can include any one or more compound(s) described herein together with one or more compounds that are therapeutically effective for the same disease indication. In some embodiments, the compositions can include any one or more compound(s) described herein together with one or more compounds that are therapeutically effective for the same disease indication, and the compounds have a synergistic effect on the disease indication. In one embodiment, the composition comprises any one or more compound(s) described herein effective in treating cancer, and one or more other compounds effective in treating the same cancer, and further, the compounds are synergistically effective in treating cancer. The compounds can be administered simultaneously or sequentially.

[0214] In some embodiments, the disclosure provides compositions, e.g., pharmaceutical compositions, comprising any one or more solid or amorphous forms of Compound I described herein (e.g., Compound I or a salt thereof, Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I substance G, Compound I free acid amorphous, the free acid amorphous salt form of Compound I, or Compound I sodium substance A) in combination with an FMS inhibitor, such as quizartinib or pexidartinib. In some embodiments, the disclosure provides pharmaceutical compositions comprising any one or more solid or amorphous forms of Compound I described herein, a pharma- ceutically acceptable carrier, and quizartinib or pexidartinib.

[0215] In some embodiments, the disclosure provides a composition, e.g., a pharmaceutical composition, comprising the free acid amorphous form of Compound I described herein, or a pharma- ceutically acceptable salt thereof, in combination with an FMS inhibitor, such as quizartinib or pexidartinib. In some embodiments, the disclosure provides a pharmaceutical composition comprising the free acid amorphous form of Compound I described herein, or a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable carrier, and quizartinib or pexidartinib.

[0216] In some embodiments, the disclosure provides a pharmaceutical composition comprising compound I or a salt thereof in combination with an FMS inhibitor, such as quizartinib or pexidartinib. In some embodiments, the disclosure provides a pharmaceutical composition comprising compound I or a salt thereof, a pharma- ceutically acceptable carrier, and quizartinib or pexidartinib.

[0217] In some embodiments, the disclosure provides compositions, e.g., pharmaceutical compositions, comprising any one or more solid or amorphous forms of Compound I described herein (e.g., Compound I or a salt thereof, Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I substance G, Compound I free acid amorphous, the free acid amorphous salt form of Compound I, or Compound I sodium substance A) in combination with quizartinib. In some embodiments, the disclosure provides pharmaceutical compositions comprising any one or more solid or amorphous forms of Compound I described herein, a pharma- ceutically acceptable carrier, and quizartinib.

[0218] In some embodiments, the disclosure provides a composition, e.g., a pharmaceutical composition, comprising the free acid amorphous form of Compound I described herein, or a pharma- ceutically acceptable salt thereof, in combination with quizartinib. In some embodiments, the disclosure provides a pharmaceutical composition comprising the free acid amorphous form of Compound I described herein, or a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable carrier, and quizartinib.

[0219] In some embodiments, the disclosure provides a composition, e.g., a pharmaceutical composition, comprising Compound I or a salt thereof, in combination with Quizartinib. In some embodiments, the disclosure provides a pharmaceutical composition, comprising Compound I or a salt thereof, a pharma- ceutically acceptable carrier, and Quizartinib.

[0220] In some embodiments, the disclosure provides compositions, e.g., pharmaceutical compositions, comprising any one or more solid or amorphous forms of Compound I described herein (e.g., Compound I or a salt thereof, Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I substance G, Compound I free acid amorphous, the free acid amorphous salt form of Compound I, or Compound I sodium substance A) in combination with pexidartinib. In some embodiments, the disclosure provides pharmaceutical compositions comprising any one or more solid or amorphous forms of Compound I described herein, a pharma- ceutically acceptable carrier, and pexidartinib.

[0221] In some embodiments, the disclosure provides a composition, e.g., a pharmaceutical composition, comprising the free acid amorphous form of Compound I described herein, or a pharma- ceutically acceptable salt thereof, in combination with pexidartinib. In some embodiments, the disclosure provides a pharmaceutical composition comprising the free acid amorphous form of Compound I described herein, or a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable carrier, and pexidartinib.

[0222] In some embodiments, the disclosure provides a composition, e.g., a pharmaceutical composition, comprising Compound I or a salt thereof, in combination with pexidartinib. In some embodiments, the disclosure provides a pharmaceutical composition, comprising Compound I or a salt thereof, a pharma- ceutically acceptable carrier, and pexidartinib.

[0223] In some embodiments, the disclosure provides compositions, e.g., pharmaceutical compositions, comprising any one or more solid or amorphous forms of Compound I described herein (e.g., Compound I or a salt thereof, Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I substance G, Compound I free acid amorphous, the free acid amorphous salt form of Compound I, or Compound I sodium substance A) in combination with a DNA methylation inhibitor (HMA). In some embodiments, the disclosure provides pharmaceutical compositions comprising any one or more solid or amorphous forms of Compound I described herein, a pharma- ceutically acceptable carrier, and a DNA methylation inhibitor (HMA).

[0224] In some embodiments, the disclosure provides a composition, e.g., a pharmaceutical composition, comprising the free acid amorphous form of Compound I described herein, or a pharma- ceutically acceptable salt thereof, in combination with a DNA methylation inhibitor (HMA). In some embodiments, the disclosure provides a pharmaceutical composition comprising the free acid amorphous form of Compound I described herein, or a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable carrier, and a DNA methylation inhibitor (HMA).

[0225] In some embodiments, the disclosure provides a composition, e.g., a pharmaceutical composition, comprising Compound I or a salt thereof, in combination with a DNA methylation inhibitor (HMA). In some embodiments, the disclosure provides a pharmaceutical composition, comprising Compound I or a salt thereof, a pharma- ceutical acceptable carrier, and a DNA methylation inhibitor (HMA).

[0226] In some embodiments, the disclosure provides a pharmaceutical composition comprising any one or more solid or amorphous forms of Compound I described herein (e.g., Compound I or a salt thereof, Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I substance G, Compound I free acid amorphous, Compound I free acid amorphous salt form, or Compound I sodium substance A) in combination with a Bruton's tyrosine kinase (BTK) inhibitor. In some embodiments, the disclosure provides a pharmaceutical composition comprising any one or more solid or amorphous forms of Compound I described herein, a pharma- ceutically acceptable carrier, and a Bruton's tyrosine kinase (BTK) inhibitor. In some embodiments, the BTK inhibitor is ibrutinib or alabrutinib. In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, the BTK inhibitor is alabrutinib.

[0227] In some embodiments, the disclosure provides a composition, e.g., a pharmaceutical composition, comprising the free acid amorphous form of compound I described herein, or a pharma- ceutically acceptable salt thereof, in combination with a Bruton's tyrosine kinase (BTK) inhibitor. In some embodiments, the disclosure provides a pharmaceutical composition, comprising the free acid amorphous form of compound I described herein, or a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable carrier, and a Bruton's tyrosine kinase (BTK) inhibitor. In some embodiments, the BTK inhibitor is ibrutinib or alabrutinib. In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, the BTK inhibitor is alabrutinib.

[0228] In some embodiments, the disclosure provides a composition, e.g., a pharmaceutical composition, comprising Compound I or a salt thereof, in combination with a Bruton's tyrosine kinase (BTK) inhibitor. In some embodiments, the disclosure provides a pharmaceutical composition, comprising Compound I or a salt thereof, a pharma- ceutically acceptable carrier, and a Bruton's tyrosine kinase (BTK) inhibitor. In some embodiments, the BTK inhibitor is ibrutinib or alabrutinib. In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, the BTK inhibitor is alabrutinib.

[0229] In some embodiments, the disclosure provides compositions, e.g., pharmaceutical compositions, comprising any one or more solid or amorphous forms of Compound I described herein (e.g., Compound I or a salt thereof, Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I substance G, Compound I free acid amorphous, the free acid amorphous salt form of Compound I, or Compound I sodium substance A) in combination with a B-cell lymphoma 2 (BCL-2) inhibitor. In some embodiments, the disclosure provides pharmaceutical compositions comprising any one or more solid or amorphous forms of Compound I described herein, a pharma- ceutically acceptable carrier, and a B-cell lymphoma 2 (BCL-2) inhibitor. In some embodiments, the BCL-2 inhibitor is venetoclax.

[0230] In some embodiments, the disclosure provides a composition, e.g., a pharmaceutical composition, comprising the free acid amorphous form of Compound I described herein, or a pharma- ceutically acceptable salt thereof, in combination with a B-cell lymphoma 2 (BCL-2) inhibitor. In some embodiments, the disclosure provides a pharmaceutical composition, comprising the free acid amorphous form of Compound I described herein, or a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable carrier, and a B-cell lymphoma 2 (BCL-2) inhibitor. In some embodiments, the BCL-2 inhibitor is venetocalx.

[0231] In some embodiments, the disclosure provides a composition, e.g., a pharmaceutical composition, comprising Compound I or a salt thereof, in combination with a B-cell lymphoma 2 (BCL-2) inhibitor. In some embodiments, the disclosure provides a pharmaceutical composition, comprising the free acid amorphous form of Compound I described herein, or a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable carrier, and a B-cell lymphoma 2 (BCL-2) inhibitor. In some embodiments, the BCL-2 inhibitor is venetocalx.

[0232] In some embodiments, the disclosure provides a pharmaceutical composition comprising any one or more solid or amorphous forms of compound I described herein (e.g., compound I or a salt thereof, compound I crystalline form A, compound I crystalline form B, compound I crystalline form C, compound I crystalline form D, compound I substance E, compound I substance F, compound I substance G, compound I free acid amorphous, free acid amorphous salt form of compound I, or compound I sodium substance A) in combination with a phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor. In some embodiments, the disclosure provides a pharmaceutical composition comprising any one or more solid or amorphous forms of compound I described herein and a phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor. In some embodiments, the PI3K inhibitor is venetocalx, idelalisib, IDH1, IDH2, or EZH2.

[0233] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a composition, for example, a free acid amorphous form of compound I described herein, or a pharma- ceutically acceptable salt thereof, in combination with a phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a free acid amorphous form of compound I described herein, or a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable carrier, and a phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor. In some embodiments, the PI3K inhibitor is venetocalx, idelalisib, IDH1, IDH2, or EZH2.

[0234] In some embodiments, the disclosure provides a pharmaceutical composition comprising compound I or a salt thereof in combination with a phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor. In some embodiments, the disclosure provides a pharmaceutical composition comprising compound I or a salt thereof, a pharma- ceutically acceptable carrier, and a phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor. In some embodiments, the PI3K inhibitor is venetocalx, idelalisib, IDH1, IDH2, or EZH2.

[0235] In some embodiments, the disclosure provides compositions, e.g., pharmaceutical compositions, comprising any one or more solid or amorphous forms of Compound I described herein (e.g., Compound I or a salt thereof, Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I substance G, Compound I free acid amorphous, Compound I free acid amorphous salt form, or Compound I sodium substance A) in combination with a CTLA-4 inhibitor or checkpoint inhibitor. In some embodiments, the disclosure provides pharmaceutical compositions comprising any one or more solid or amorphous forms of Compound I described herein and a CTLA-4 inhibitor or checkpoint inhibitor. In some embodiments, the CTLA-4 inhibitor is ipilimumab. In some embodiments, the checkpoint inhibitor is a PD-1 or PDL-1 inhibitor. In some embodiments, the PD-1 inhibitor is nivolumab. In some embodiments, the PDL-1 inhibitor is pembrolizumab.

[0236] In some embodiments, the disclosure provides a composition, e.g., a pharmaceutical composition, comprising the free acid amorphous form of compound I described herein, or a pharma- ceutically acceptable salt thereof, in combination with a CTLA-4 inhibitor or checkpoint inhibitor. In some embodiments, the disclosure provides a pharmaceutical composition, comprising the free acid amorphous form of compound I described herein, or a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable carrier, and a CTLA-4 inhibitor or checkpoint inhibitor. In some embodiments, the CTLA-4 inhibitor is ipilimumab. In some embodiments, the checkpoint inhibitor is a PD-1 or PDL-1 inhibitor. In some embodiments, the PD-1 inhibitor is nivolumab. In some embodiments, the PDL-1 inhibitor is pembrolizumab.

[0237] In some embodiments, the disclosure provides a pharmaceutical composition comprising compound I or a salt thereof in combination with a CTLA-4 inhibitor or checkpoint inhibitor. In some embodiments, the disclosure provides a pharmaceutical composition comprising compound I or a salt thereof, a pharma- ceutically acceptable carrier, and a CTLA-4 inhibitor or checkpoint inhibitor. In some embodiments, the CTLA-4 inhibitor is ipilimumab. In some embodiments, the PD-1 inhibitor is nivolumab. In some embodiments, the PDL-1 inhibitor is pembrolizumab.

[0238] In some embodiments, the present disclosure provides a method for treating a bromodomain-mediated or mutant bromodomain-mediated disease or condition in a subject in need of treatment, comprising administering to the subject an effective amount of any one or more compounds described herein (e.g., Compound I or a salt thereof, or any one or more solid or amorphous forms of Compound I), or a composition comprising any one or more compounds described herein, in combination with one or more other therapeutic agents described herein. In some embodiments, the bromodomain modulator, particularly the compounds described herein (e.g., Compound I or a salt thereof, or any one or more solid or amorphous forms of Compound I), may be administered simultaneously, sequentially, or separately in combination with one or more other therapeutic agents described above.

[0239] In some embodiments, the disclosure provides a method for treating a bromodomain-mediated or mutant bromodomain-mediated disease or condition in a subject in need of treatment, comprising administering to the subject an effective amount of any one or more solid or amorphous forms of Compound I described herein (e.g., Compound I or a salt thereof, Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I substance G, Compound I free acid amorphous, Compound I free acid amorphous salt form, or Compound I sodium substance A), or a composition comprising any one or more solid or amorphous forms of Compound I described herein, in combination with one or more other therapeutic agents described herein, wherein the disease or condition is cancer, a neurological condition, an autoimmune condition, an inflammatory condition, a metabolic disease, or a combination thereof. In some embodiments, the bromodomain modulator, particularly the solid or amorphous forms of Compound I described herein, may be administered in combination with one or more other therapeutic agents described herein, simultaneously, sequentially, or separately.

[0240] In some embodiments, the present disclosure provides a method for treating a bromodomain-mediated or mutant bromodomain-mediated disease or condition in a subject in need of treatment, comprising administering to the subject an effective amount of Compound I or a salt thereof, or a composition comprising Compound I or a salt thereof, in combination with one or more other therapeutic agents described herein, wherein the disease or condition is cancer, a neurological condition, an autoimmune condition, an inflammatory condition, a metabolic disease, or a combination thereof. In some embodiments, the bromodomain modulator, particularly Compound I or a salt thereof, may be administered simultaneously, sequentially, or separately in combination with one or more other therapeutic agents described above.

[0241] In some embodiments, the disclosure provides a method for treating a bromodomain-mediated or mutant bromodomain-mediated disease or condition in a subject in need of treatment, comprising administering to the subject an effective amount of any one or more solid or amorphous forms of Compound I described herein (e.g., Compound I or a salt thereof, Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I substance G, Compound I free acid amorphous, the free acid amorphous salt form of Compound I, or Compound I sodium substance A), or a composition comprising any one or more solid or amorphous forms of Compound I described herein, and administering in combination with one or more other therapeutic agents selected from the group consisting of rheumatoid arthritis, uveal melanoma, chronic lymphocytic leukemia, acute myeloid leukemia, synovial sarcoma, osteoarthritis, acute gout, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease (Crohn's disease and ulcerative colitis), asthma, chronic obstructive airways disease, pneumonia, myocarditis, pericarditis, myositis, eczema, dermatitis, alopecia, vitiligo, bullous skin diseases, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, depression, retinitis, uveitis, scleritis, hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis, Addison's disease, hypophysitis, thyroiditis, type I diabetes, or acute rejection of a transplanted organ. In some embodiments, bromodomain modulators, particularly compounds described herein (e.g., any one or more solid or amorphous forms of Compound I), may be administered in combination with one or more other therapeutic agents described above, either simultaneously, sequentially, or separately.

[0242] In some embodiments, the disclosure provides a method for treating a bromodomain-mediated or mutant bromodomain-mediated disease or condition in a subject in need of treatment, comprising administering to the subject an effective amount of Compound I or a salt thereof, or a composition comprising Compound I or a salt thereof, in combination with one or more other therapeutic agents described herein, wherein the disease or condition is selected from the group consisting of rheumatoid arthritis, uveal melanoma, chronic lymphocytic leukemia, acute myeloid leukemia, synovial fibrosis, and the like. In some embodiments, the bromodomain modulators, particularly the compounds described herein (e.g., any one or more solid or amorphous forms of Compound I) may be administered in combination with one or more other therapeutic agents, either simultaneously, sequentially, or separately.

[0243] In one embodiment, the disclosure provides a method for treating a cancer mediated by a bromodomain or mutant bromodomain in a subject in need of treatment by administering to the subject an effective amount of any one or more compounds described herein (e.g., compound I or a salt thereof, or any one or more solid or amorphous forms of compound I), or a composition comprising any one or more compound(s) described herein. In some embodiments, a bromodomain modulator, particularly a compound described herein (e.g., compound I or a salt thereof, or any one or more solid or amorphous forms of compound I), may be administered in combination with one or more of the above agents, simultaneously, sequentially, or separately.

[0244] In one embodiment, the disclosure provides a method for treating a bromodomain-mediated cancer in a subject in need of treatment by administering to the subject an effective amount of any one or more compounds described herein (e.g., Compound I or a salt thereof, or any one or more solid or amorphous forms of Compound I), or a composition comprising any one or more compound(s) described herein, in combination with one or more appropriate anti-cancer therapies, such as one or more chemotherapeutic agents or drugs described herein.

[0245] In one embodiment, the disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of any one or more solid or amorphous forms of Compound I described herein (e.g., Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I free acid amorphous, the free acid amorphous salt form of Compound I, or the sodium salt of Compound I), or a composition comprising any one or more solid or amorphous forms of Compound I described herein, in combination with a chemotherapeutic agent selected from capecitabine, 5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin, paclitaxel, SN-38, temozolomide, vinblastine, bevacizumab, cetuximab, interferon-alpha, interleukin-2, or erlotinib. In one embodiment, the present disclosure provides a method of treating cancer in a subject in need of treatment, comprising administering to the subject an effective amount of compound I or a salt thereof, or a composition comprising compound I or a salt thereof, in combination with a chemotherapeutic agent selected from capecitabine, 5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin, paclitaxel, SN-38, temozolomide, vinblastine, bevacizumab, cetuximab, interferon-α, interleukin-2, or erlotinib. In some embodiments, the bromodomain modulator, particularly the compounds described herein (e.g., compound I or a salt thereof, or any one or more solid or amorphous forms of compound I), may be administered simultaneously, sequentially, or separately in combination with one or more of the above agents.

[0246] In one embodiment, the chemotherapeutic agent is a Mek inhibitor.Exemplary Mek inhibitors include, but are not limited to, AS703026, AZD6244 (selumetinib), AZD8330, BIX02188, CI-1040 (PD184352), GSK1120212 (also known as trametinib or JTP-74057), cobimetinib, PD0325901, PD318088, PD98059, RDEA119 (BAY869766), TAK-733, and U0126-EtOH.

[0247] In one embodiment, the chemotherapeutic agent is a tyrosine kinase inhibitor. Exemplary tyrosine kinase inhibitors include, but are not limited to, AEE788, AG-1478 (tyrphostin AG-1478), AG-490, apatinib (YN968D1), AV-412, AV-951 (tivozanib), axitinib, AZD8931, BIBF1120 (bergatev), BIBW2992 (afatinib), BMS794833, BMS-599626, brivanib (BMS-540215), brivanib alaninate (BMS-582664), cedira. Nib (AZD2171), chrysophanic acid (chrysophanol), crenolanib (CP-868569), CUDC-101, CYC116, dovitinib dilactate (TKI258 dilactate), E7080, erlotinib hydrochloride (Tarceva, CP-358774, OSI-774, NSC-718781), foretinib (GSK1363089, XL880), gefitinib (ZD-1839 or Iressa), imatinib (Gleevec), imatinib mesylate, Ki8751, KRN 633, lapatinib (Tykerb), linifanib (ABT-869), masitinib (Masibet, AB1010), MGCD-265, motesanib (AMG-706), MP-470, mubritinib (TAK165), neratinib (HKI-272), NVP-BHG712, OSI-420 (desmethylerlotinib, CP-473420), OSI-930, pazopanib HCl, PD-153035 hydrochloride, PD173074, pelitinib (EKB-569), PF2998 04, ponatinib (AP24534), PP121, RAF265 (CHIR-265), Raf265 derivative, regorafenib (BAY73-4506), sorafenib tosylate (Nexavar), sunitinib malate (Sutent), telatinib (BAY57-9352), TSU-68 (SU6668), vandetanib (Zactima), vatalanib dihydrochloride (PTK787), WZ3146, WZ4002, WZ8040, quizartinib, cabozantinib, XL647, EGFR siRNA, FLT4 siRNA, KDRThese include siRNAs, antidiabetic agents such as metformin, PPAR agonists (rosiglitazone, pioglitazone, bezafibrate, ciprofibrate, clofibrate, gemfibrozil, fenofibrate, indeglitazar), and DPP4 inhibitors (sitagliptin, vildagliptin, tagliptin, saxagliptin, dutogliptin, gemigliptin, alogliptin).

[0248] In one embodiment, the drug is an EGFR inhibitor.Exemplary EGFR inhibitors include but are not limited to AEE-788, AP-26113, BIBW-2992 (Tobok), CI-1033, GW-572016, Iressa, LY2874455, RO-5323441, Tarceva (Erlotinib, OSI-774), CUDC-101 and WZ4002.

[0249] In one embodiment, the therapeutic agent for the combination is a c-Fms and / or c-Kit inhibitor as described in U.S. Patent Application Publication Nos. 2009 / 0076046 and 2011 / 0112127, which are incorporated by reference in their entireties for all purposes.

[0250] In one embodiment, the disclosure provides a method for treating a disease or condition mediated by a bromodomain or mutant bromodomain protein in a subject in need of treatment by administering to the subject an effective amount of any one or more solid or amorphous forms of Compound I described herein (e.g., Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I free acid amorphous, the free acid amorphous salt form of Compound I, or Compound I sodium salt) in combination with quizartinib to treat the disease or condition.

[0251] In one embodiment, the disclosure provides a method for treating a disease or condition mediated by a bromodomain or mutant bromodomain protein in a subject in need of treatment by administering to the subject an effective amount of Compound I, or a salt thereof, in combination with quizartinib to treat the disease or condition.

[0252] In some embodiments, the disclosure provides a method of treating a subject suffering from a disease or condition described in the disclosure, the method comprising administering to the subject an effective amount of any one or more solid or amorphous forms of Compound I described herein (e.g., Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I free acid amorphous, the free acid amorphous salt form of Compound I, or Compound I sodium salt) in combination with a mutant c-Kit protein kinase inhibitor. In some embodiments, the disclosure provides a method of treating a subject suffering from a disease or condition described in the disclosure, the method comprising administering to the subject an effective amount of Compound I or a salt thereof in combination with a mutant c-Kit protein kinase inhibitor. In some embodiments, the mutant c-Kit protein kinase inhibitor is (2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-(3-pyridyl)methanol, (2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-(3-pyridyl)methanone, N-(3-carbamoylphenyl)-2-phenyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide, 2-phenyl-N-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide, 4-bromo-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide, ethyl 3-[(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)carbamoylamino]propanoate, 3,4-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide, 4-methyl-3-phenyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)- 1H-Pyrazole-5-carboxamide, 3-cyclopropyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-5-carboxamide, 5-fluoro-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-indazole-3-carboxamide, N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrimidine-4-carboxamide, 3-fluoro-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridine-2-carboxamide, 3,5-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isoxazole-4-carboxamide, N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridazine-3-carboxamide, N-(2-phenyl-1H-pyrrolo[2 In some embodiments, the compound described herein is selected from the group consisting of N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2H-triazole-4-carboxamide, 3-methyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridine-2-carboxamide, 4,5-dimethyl-N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isoxazole-3-carboxamide, or N-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazole-4-sulfonamide. In some embodiments, the compound described herein is combined with any of the mutant c-Kit mutant inhibitors described herein for treating GIST, including but not limited to first-line, second-line, and neoadjuvant GIST.

[0253] In some embodiments, the disclosure provides a method for treating a subject suffering from or at risk for a disease or condition mediated by a bromodomain, the method comprising administering to a subject in need thereof an effective amount of any one or more solid or amorphous forms of Compound I described herein (e.g., Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I free acid amorphous, the free acid amorphous salt form of Compound I, or Compound I sodium salt) in combination with quizartinib and a pharma- ceutically acceptable excipient or carrier.

[0254] In some embodiments, the disclosure provides a method for treating a subject suffering from or at risk for a disease or condition mediated by a bromodomain, the method comprising administering to a subject in need thereof an effective amount of the free acid amorphous form of Compound I described herein, in combination with quizartinib, and a pharma- ceutically acceptable excipient or carrier.

[0255] In some embodiments, the disclosure provides a method for treating a subject suffering from or at risk of a disease or condition mediated by a bromodomain, the method comprising administering to a subject in need thereof an effective amount of Compound I, or a salt thereof, and a pharma- ceutically acceptable excipient or carrier, in combination with quizartinib.

[0256] In some embodiments, the disclosure provides a method for treating a subject suffering from or at risk for a disease or condition mediated by a bromodomain, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising any one or more solid or amorphous forms of Compound I described herein (e.g., Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I free acid amorphous, the free acid amorphous salt form of Compound I, or Compound I sodium salt), at least one pharma- ceutically acceptable excipient or carrier, and quizartinib.

[0257] In some embodiments, the disclosure provides a method for treating a subject suffering from or at risk of a disease or condition mediated by a bromodomain, the method comprising administering to a subject in need thereof a composition comprising an effective amount of the free acid amorphous form of Compound I described herein, or a pharma- ceutically acceptable salt form thereof, at least one pharma- ceutically acceptable excipient or carrier, and quizartinib.

[0258] In some embodiments, the disclosure provides a method for treating a subject suffering from or at risk of a disease or condition mediated by a bromodomain, the method comprising administering to a subject in need thereof a composition comprising an effective amount of Compound I or a salt thereof, at least one pharma- ceutically acceptable excipient or carrier, and quizartinib.

[0259] In some embodiments, the present disclosure provides a method of treating myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in a subject in need of treatment by administering to the subject an effective amount of the free acid amorphous form of Compound I described herein in combination with an effective amount of a DNA methylation inhibitor (HMA).

[0260] In some embodiments, the disclosure provides a method of treating myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in a subject in need of treatment by administering to the subject an effective amount of any one or more solid or amorphous forms of Compound I described herein (e.g., Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I free acid amorphous, the free acid amorphous salt form of Compound I, or the sodium salt of Compound I) in combination with an effective amount of a DNA methylation inhibitor (HMA).

[0261] In some embodiments, the present disclosure provides a method of treating myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in a subject in need of such treatment by administering to the subject an effective amount of Compound I, or a salt thereof, in combination with an effective amount of a DNA methylation inhibitor (HMA).

[0262] In some embodiments, the present disclosure provides a method of treating chronic lymphocytic leukemia (CLL) or Richter's syndrome in a subject in need of treatment by administering to the subject an effective amount of the free acid amorphous form of compound I described herein, or a pharma- ceutically acceptable salt thereof, optionally in combination with an effective amount of a Bruton's tyrosine kinase (BTK) inhibitor. In some embodiments, the BTK inhibitor is ibrutinib or alabrutinib. In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, the BTK inhibitor is alabrutinib.

[0263] In some embodiments, the disclosure provides a method of treating chronic lymphocytic leukemia (CLL) or Richter's syndrome in a subject in need of treatment by administering to the subject an effective amount of any one or more solid or amorphous forms of Compound I described herein (Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I free acid amorphous, or the sodium salt of Compound I), optionally in combination with an effective amount of a Bruton's tyrosine kinase (BTK) inhibitor. In some embodiments, the BTK inhibitor is ibrutinib or alabrutinib. In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, the BTK inhibitor is alabrutinib.

[0264] In some embodiments, the present disclosure provides a method of treating chronic lymphocytic leukemia (CLL) or Richter's syndrome in a subject in need of treatment by administering to the subject an effective amount of Compound I or a salt thereof, optionally in combination with an effective amount of a Bruton's tyrosine kinase (BTK) inhibitor. In some embodiments, the BTK inhibitor is ibrutinib or alabrutinib. In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, the BTK inhibitor is alabrutinib.

[0265] In some embodiments, the present disclosure provides a method of treating chronic lymphocytic leukemia (CLL) in a subject in need of treatment by administering to the subject an effective amount of the free acid amorphous form of Compound I described herein, or a pharma- ceutically acceptable salt thereof, in combination with an effective amount of a B-cell lymphoma 2 (BCL-2) inhibitor. In some embodiments, the BCL-2 inhibitor is venetocalx.

[0266] In some embodiments, the disclosure provides a method of treating chronic lymphocytic leukemia (CLL) in a subject in need thereof by administering to the subject an effective amount of any one or more solid or amorphous forms of Compound I described herein (Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I free acid amorphous, or the sodium salt of Compound I) in combination with an effective amount of a (BCL-2) inhibitor. In some embodiments, the BCL-2 inhibitor is venetocalx.

[0267] In some embodiments, the present disclosure provides a method of treating chronic lymphocytic leukemia (CLL) in a subject in need of treatment by administering to the subject an effective amount of Compound I or a salt thereof in combination with an effective amount of a B-cell lymphoma 2 (BCL-2) inhibitor. In some embodiments, the BCL-2 inhibitor is venetocalx.

[0268] In some embodiments, the present disclosure provides a method for treating chronic lymphocytic leukemia (CLL) in a subject in need of treatment, by administering to the subject an effective amount of the free acid amorphous form of compound I described herein, or a pharma- ceutically acceptable salt thereof, in combination with an effective amount of a phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor. In some embodiments, the PI3K inhibitor is venetocalx, idelalisib, IDH1, IDH2, or EZH2.

[0269] In some embodiments, the disclosure provides a method of treating chronic lymphocytic leukemia (CLL) in a subject in need thereof by administering to the subject an effective amount of any one or more solid or amorphous forms of Compound I described herein (Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I free acid amorphous, or the sodium salt of Compound I) in combination with an effective amount of a (PI3K) inhibitor. In some embodiments, the PI3K inhibitor is venetocalx, idelalisib, IDH1, IDH2, or EZH2.

[0270] In some embodiments, the present disclosure provides a method for treating chronic lymphocytic leukemia (CLL) in a subject in need of treatment, by administering to the subject an effective amount of compound I or a salt thereof in combination with an effective amount of a phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor. In some embodiments, the PI3K inhibitor is venetocalx, idelalisib, IDH1, IDH2, or EZH2.

[0271] In some embodiments, the present disclosure provides a method for treating uveal melanoma in a subject in need of treatment, by administering to the subject an effective amount of the free acid amorphous form of compound I described herein, or a pharma- ceutically acceptable salt thereof, in combination with an effective amount of a CTLA-4 inhibitor or a checkpoint inhibitor. In some embodiments, the CTLA-4 inhibitor is ipilimumab. In some embodiments, the checkpoint inhibitor is a PD-1 or PDL-1 inhibitor. In some embodiments, the PD-1 inhibitor is nivolumab. In some embodiments, the PDL-1 inhibitor is pembrolizumab.

[0272] In some embodiments, the disclosure provides a method of treating uveal melanoma in a subject in need of treatment by administering to the subject an effective amount of any one or more solid or amorphous forms of Compound I described herein (e.g., Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I free acid amorphous, Compound I free acid amorphous salt form, or Compound I sodium salt) in combination with an effective amount of a CTLA-4 inhibitor or checkpoint inhibitor. In some embodiments, the CTLA-4 inhibitor is ipilimumab. In some embodiments, the checkpoint inhibitor is a PD-1 or PDL-1 inhibitor. In some embodiments, the PD-1 inhibitor is nivolumab. In some embodiments, the PDL-1 inhibitor is pembrolizumab.

[0273] In some embodiments, the present disclosure provides a method for treating uveal melanoma in a subject in need of treatment, by administering to the subject an effective amount of Compound I or a salt thereof in combination with an effective amount of a CTLA-4 inhibitor or a checkpoint inhibitor. In some embodiments, the CTLA-4 inhibitor is ipilimumab. In some embodiments, the checkpoint inhibitor is a PD-1 or PDL-1 inhibitor. In some embodiments, the PD-1 inhibitor is nivolumab. In some embodiments, the PDL-1 inhibitor is pembrolizumab.

[0274] In some embodiments, the present disclosure provides a method of treating acute myeloid leukemia (AML) in a subject in need of treatment by administering to the subject an effective amount of the free acid amorphous form of Compound I described herein in combination with an effective amount of a flt3 inhibitor, such as quizartinib.

[0275] In some embodiments, the disclosure provides a method of treating AML in a subject in need of treatment by administering to the subject an effective amount of any one or more solid or amorphous forms of Compound I described herein (e.g., Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I free acid amorphous, the free acid amorphous salt form of Compound I, or the sodium salt of Compound I) in combination with an effective amount of a flt3 inhibitor, such as quizartinib.

[0276] In some embodiments, the present disclosure provides a method of treating acute myeloid leukemia (AML) in a subject in need of treatment by administering to the subject an effective amount of compound I, or a salt thereof, in combination with an effective amount of a flt3 inhibitor, such as quizartinib.

[0277] In some embodiments, the present disclosure provides a method for treating a bromodomain or mutant bromodomain-mediated disease or condition in a subject in need of treatment, comprising administering to the subject any one or more compounds described herein (e.g., Compound I or a salt thereof, or any one or more solid or amorphous forms of Compound I), or a composition comprising any one or more compounds described herein, in combination with one or more other suitable therapies to treat the disease or condition. In some embodiments, the bromodomain modulator, particularly the compounds described herein (e.g., Compound I or a salt thereof, or any one or more solid or amorphous forms of Compound I), may be administered simultaneously, sequentially, or separately in combination with one or more other suitable therapies.

[0278] In one embodiment, the disclosure provides a method for treating a cancer mediated by a bromodomain or mutant bromodomain by administering to a subject a composition comprising an effective amount of any one or more compound(s) described herein. In one embodiment, the disclosure provides a method for treating a cancer mediated by a bromodomain by administering to a subject a composition comprising an effective amount of any one or more compound(s) described herein in combination with one or more suitable anti-cancer therapies, such as one or more chemotherapeutic agents or drugs described herein.

[0279] In some embodiments, the disclosure provides a method of treating a cancer described herein in a subject in need of treatment by administering to the subject an effective amount of any one or more solid or amorphous forms of Compound I described herein (Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I free acid amorphous, Compound I free acid amorphous salt form, or Compound I sodium salt), or a composition comprising any one or more solid or amorphous forms of Compound I described herein, in combination with one or more other therapies or medical treatments effective in treating cancer. In some embodiments, the disclosure provides a method of treating a cancer described herein in a subject in need of treatment by administering to the subject an effective amount of Compound I or a salt thereof in combination with one or more other therapies or medical treatments effective in treating cancer. Other therapies or medical procedures include suitable anti-cancer therapies (e.g., drug therapy, vaccine therapy, gene therapy, photodynamic therapy) or medical procedures (e.g., surgery, radiation therapy, hyperthermia, bone marrow or stem cell transplantation). In one embodiment, the one or more suitable anti-cancer therapies or medical procedures are selected from treatment with chemotherapeutic agents (e.g., chemotherapy drugs), radiation therapy (e.g., x-rays, gamma rays, or electron, proton, neutron, or alpha particle radiation), hyperthermia (e.g., microwave, ultrasound, radiofrequency ablation), vaccine therapy (e.g., AFP gene hepatocellular carcinoma vaccine, AFP adenovirus vector vaccine, AG-858, allogeneic GM-CSF-secreting breast cancer vaccine, dendritic cell peptide vaccine), gene therapy (e.g., Ad5CMV-p53 vector, adenovector encoding MDA7, adenovirus 5-tumor necrosis factor alpha), photodynamic therapy (e.g., aminolevulinic acid, motexafin lutetium), oncolytic virus or bacteria therapy, surgery, or bone marrow and stem cell transplantation. In some embodiments, the present disclosure provides a method of treating cancer in a subject in need of treatment, by administering to the subject an effective amount of a compound described herein and separately or simultaneously administering radiation therapy described herein.

[0280] In one embodiment, the disclosure provides a method for treating cancer in a subject in need of treatment by administering to the subject an effective amount of any one or more solid or amorphous forms of Compound I described herein (e.g., Compound I crystalline form A, Compound I crystalline form B, Compound I crystalline form C, Compound I crystalline form D, Compound I substance E, Compound I substance F, Compound I free acid amorphous, the free acid amorphous salt form of Compound I, or the sodium salt of Compound I), followed by radiation therapy (e.g., X-rays, gamma rays, or electron, proton, neutron, or alpha particle radiation). In one embodiment, the disclosure provides a method for treating cancer in a subject in need of treatment by administering to the subject an effective amount of Compound I or a salt thereof, followed by radiation therapy (e.g., X-rays, gamma rays, or electron, proton, neutron, or alpha particle radiation).

[0281] In some embodiments, the disclosure provides a method for treating cancer in a subject in need of treatment by administering radiation therapy (e.g., X-rays, gamma rays, or electron, proton, neutron, or alpha particle radiation) to the subject, followed by administering to the subject an effective amount of a compound described herein. In yet another embodiment, the disclosure provides a method for treating cancer in a subject in need of treatment by simultaneously administering to the subject a compound described herein and radiation therapy (e.g., X-rays, gamma rays, or electron, proton, neutron, or alpha particle radiation).

[0282] In some embodiments, the disclosure provides a kit or container comprising a compound described herein (e.g., Compound I or a salt thereof, or any one or more solid or amorphous forms of Compound I), or a composition thereof 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, envelope, 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 indication 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; and the compound or composition may be packaged in a unit dose or single dose form, for example, a single dose pill, capsule, etc. EXAMPLES

[0283] A. Experimental Method Solubility Estimation Various portions of solvent were added to a measured amount of Compound I or a form of Compound I described herein with stirring (typically sonication) at ambient temperature until complete dissolution was achieved as judged by visual observation. The solubility was calculated based on the total solvent used to obtain the solution, and the actual solubility may be greater due to the volume of the solvent portion used or slow dissolution rate. If dissolution did not occur as determined by visual evaluation, the value was reported as "<". If dissolution occurred in the first portion, the value was reported as ">". Antisolvent addition

[0284] A solution containing Compound I or a form of Compound I described herein was contacted with an anti-solvent for Compound I to induce crystallization. cooling

[0285] Solutions containing Compound I or a form of Compound I described herein were cooled below room temperature for various times to induce nucleation, after which the presence or absence of solids was recorded. Solids were isolated as wet or dry powders for analysis. Crystallization from solution

[0286] Saturated solutions containing Compound I or a form of Compound I described herein were prepared at room temperature and capped. Nucleation was observed to occur in such systems. Fast evaporation

[0287] A solution containing Compound I or a form of Compound I described herein was prepared in a selected solvent, with stirring between portion additions to aid dissolution. When the mixture was completely dissolved, as determined by visual observation, the solution was allowed to evaporate at ambient temperature in an open vial or under nitrogen. The solid formed was isolated for evaluation. slurry

[0288] Solutions of Compound I or forms of Compound I described herein are prepared by adding sufficient solid to a given solvent or solvent system at ambient conditions so that undissolved solid is present.The mixture is then stirred in a closed vial at ambient or elevated temperature for an extended period of time.Solids are collected by vacuum filtration and analyzed. Temperature and Relative Humidity (RH) Stress

[0289] Compound I or a solid form of Compound I described herein was placed in a RH chamber containing a saturated aqueous solution of sodium chloride in the presence of excess salt at about 75% RH. The chamber was sealed and left at ambient temperature or placed in a high temperature oven. vacuum

[0290] The selected material was dried under reduced pressure for a set period of time, with the drying occurring at pressures below 500 mTorr, typically between 30 and 50 mTorr (0.030 to 0.05 mmHg) absolute. B. Equipment Techniques Differential Scanning Calorimetry (DSC)

[0291] DSC was performed using a TA Instruments Q2000 Differential Scanning Calorimeter. Temperature calibration was performed using NIST traceable indium metal. Samples were placed into aluminum DSC pans, covered with lids, and weights were accurately recorded. A weighing aluminum pan configured as the sample pan was placed on the reference side of the cell. Data acquisition parameters and pan configurations for each thermogram are displayed in the images in the data section of this report. Thermogram method codes are abbreviations for the start and end temperatures, and heating rates, e.g., -30-250-10 means "-30°C to 250°C at 10°C / min." The abbreviation used in each image of the pan configuration, TOC, means "T-zero crimped pan." Dynamic Vapor Dissolution

[0292] DVS data were collected on a VTI SGA-100 Vapor Sorption Analyzer. Sodium chloride and PVP were used as calibration standards. Samples were not dried prior to analysis. Adsorption and desorption data were collected in the range of 5 to 95% RH in 10% RH increments under nitrogen atmosphere. The equilibration criteria used for analysis was less than 0.0100% weight change in 5 minutes with a maximum equilibration time of 3 hours. Data were not corrected for the initial moisture content of the samples. Proton solution nuclear magnetic resonance spectroscopy ( 1 H NMR)

[0293] Samples were prepared for NMR spectroscopy as approximately 5 to 50 mg solutions in deuterated DMSO. Specific acquisition parameters are listed on the plot of the first full spectrum of each sample in the data section for samples run on the SSCI. The chemical shift observed at approximately 2.5 ppm is assigned to residual protons in the NMR solvent (DMSO-d6), and the chemical shift observed at approximately 3.3 ppm is due to water. Thermogravimetric analysis (TGA)

[0294] TG analyses were performed using a TA Instruments 2050 Thermogravimetric Analyzer. Temperature calibration was performed using nickel and Alumel™. Each sample was placed in an aluminum pan and inserted into the TG furnace. The furnace was heated under a nitrogen atmosphere. Data acquisition parameters are displayed above each thermogram in the data section of this report. Thermogram method codes are abbreviations for the start and end temperatures, and heating rate, e.g., 25-350-10 means "25°C to 350°C at 10°C / min." 00 used as the initial temperature indicates the sample analysis started from ambient temperature. X-ray powder diffraction (XRPD)

[0295] (i) Inel: XRPD patterns were collected on an Inel XRG-3000 diffractometer. The incident beam of CuKα radiation was generated using a microfocus tube and a parabolic multilayer mirror. Prior to analysis, a silicon standard (NIST SRM 640d) was analyzed to verify the Si 111 peak position. Sample specimens were packed into thin-walled glass capillaries and a beam stop was used to minimize background from air. Diffraction patterns were collected in transmission geometry using Windif v.6.6 software and a curved position-sensitive Equinox detector with a 2θ range of 120°. Data acquisition parameters for each pattern are displayed above the images in the data section of this report.

[0296] (ii) PANalytical: XRPD patterns were collected on a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation generated using an Optix long microfocus source. An ellipsoidal multilayer mirror was used to focus the Cu Kα X-rays through the specimen onto the detector. Prior to analysis, a silicon specimen (NIST SRM 640d) was analyzed to verify the Si 111 peak position. Sample specimens were sandwiched between 3 μm thick films and analyzed in transmission geometry. A beam stop, a short anti-scatter extension, and an anti-scatter knife edge were used to minimize background generated by air. Soller slits of the incident and diffracted beams were used to minimize spread from axial divergence. Diffraction patterns were collected using a scanning position sensitive detector (X'Celerator) positioned 240 mm from the specimen and Data Collector software version 2.2b. Data acquisition parameters for each pattern are displayed above the images in the data section of this report, including the divergence slit (DS) in front of the mirror and the incident beam anti-scatter slit (SS). Supercritical Fluid Chromatography

[0297] Supercritical fluid chromatography (SFC) was used to purify certain compounds disclosed herein. Purification by SFC used the following materials and conditions: [Table 3] C. Preparation and Characterization of Solid Forms of Compound I

[0298] Several solid form screening experiments were carried out using compound I crystalline form A or compound I crystalline form D as starting materials. Compound I crystalline form A and crystalline form D were prepared according to the following scheme. [ka]

[0299] 4-(3-iodo-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole (1) was synthesized as described in WO2017 / 053243. Triphenyl phosphate (TPP) and diisopropyl azodicarboxylate (DIAD) were added to (1) under Mitsunobu reaction conditions to synthesize (S)-4-(3-iodo-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole (2). 2,6-difluorophenylboronic acid, (Pd(dppf)Cl2, and HCl were added to (2) under Suzuki coupling reaction conditions to obtain compound I crystalline form A. Compound I crystalline form A was purified by supercritical fluid chromatography (SFC) to obtain compound I crystalline form D.

[0300] All forms discussed below in Table 1 were obtained starting from Compound I crystalline Form A using a wide range of solvents and solvent mixtures under kinetic and thermodynamic conditions. [Table 4-1] [Table 4-2]

[0301] All forms discussed below in Table 2 were obtained starting from Compound I crystalline form D using a wide range of solvents and solvent mixtures under kinetic and thermodynamic conditions. [Table 5] D. Solubility Estimates Compound I Crystal Form A

[0302] The solubility estimates of Compound I crystalline Form A in various solvents are shown below in Table 3. It should be noted that the presence of impurities observed in some of the samples of Compound I crystalline Form A, and precipitates of Compound I crystalline Form B, may affect the solubility estimates. [Table 6] Compound I crystal form D

[0303] Solubility estimates of Compound I crystalline Form D in various solvents are provided below in Table 4. Note that such solubility estimates may be affected due to the solvate nature of Compound I crystalline Form D. [Table 7] E. Preparation and Characterization of Compound I Sodium Substance A

[0304] The sodium salt forms of Compound I discussed below in Table 5 were obtained starting from Compound I crystalline Form A using a variety of solvents and solvent mixtures under kinetic and thermodynamic conditions. [Table 8] F. Compound I Free Acid Amorphous

[0305] Targeting BRD4 with Compound I free acid amorphous ("Compound I FAA") shows potent anti-leukemic effects in disease models of aggressive CLL and Richter transformation. Figures 24 to 24C show the results of a pharmacodynamic evaluation of the antitumor effect of Compound I free acid amorphous in Eμ-TCL1 with progressive leukemia. Mice were stratified according to leukemic peripheral blood lymphocytes (PBL) and spleen palpation scores and administered either vehicle or Compound I free acid amorphous (20 mg / kg, qd, oral gavage) for 8 days. Compound I free acid amorphous reduced leukemic cells in the systemic circulation (Figure 24A) and locally in the spleen (Figure 24B). The red lines in Figures 24A and 24B represent the mean values. FIG. 24C is a representative immunoblot analysis of relative protein levels of cMYC, P21, BTK, IKZF1, IKZF3, and TCL1A proteins at the end of the 8-day study.

[0306] Using the adoptive transfer model of Eμ-TCL1, recipient wild-type mice were randomized to receive vehicle (n=12) or compound I free acid amorphous (20 mg / kg, qd, oral gavage, n=10) at the time of leukemia onset, and disease progression was measured as CD19 / CD5 / CD45 positive PBL% by flow cytometry. Treatment was terminated at 150 days. Figure 24D is a Kaplan-Meier curve showing overall survival (OS) (p<0.0001), with median OS of 93 and 34 days for compound I free acid amorphous and vehicle, respectively. Survival comparisons in Figure 24D were performed with the log-rank test, and p values ​​were adjusted for multiple comparisons. Compound I free acid amorphous reduced the percentage of circulating leukemic PBL (Figure 24E) and reduced splenic mass (Figure 24F). FIG. 24G shows HE and Ki67 staining of spleen, lung, and blood from Compound I free acid amorphous treated mice that were lymphocyte depleted with Ki67 staining nearly absent. G. Comparative Data Compound I free acid vs. Ibrutinib

[0307] Figure 24H is a Kaplan-Meier curve showing overall survival (OS) of C57BL / 6 mice transplanted with Eμ-TCL1 leukemic splenocytes treated with ibrutinib or Compound I free acid amorphous (Compound I FAA) (20 mg / kg, qd, oral gavage) at the time of leukemia onset. Survival comparisons in Figure 24H were performed with the log-rank test, and p values ​​were adjusted for multiple comparisons.

[0308] Ibrutinib is currently the standard of care (first-line treatment). Surprisingly, the median OS was 41 days for compound I free acid amorphous compared to 32 days for ibrutinib and 21 days for vehicle. Compound I free acid amorphous significantly increased survival compared to vehicle (p=0.024) and ibrutinib (p=0.049).

[0309] 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 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.

[0310] Those skilled in the art will readily recognize that the present disclosure is well adapted to obtain the objects and advantages mentioned, as well as those inherent therein. The methods, variations, and compositions described herein as currently representative of preferred embodiments are exemplary and are not intended to limit the scope of the present disclosure. Modifications therein and other uses will occur to those skilled in the art, which are encompassed within the spirit of the present disclosure and are defined by the scope of the claims.

Claims

1. A free acid amorphous form of Compound I, characterized by a thermogravimetric analysis (TGA) thermogram showing a weight loss of about 17% up to about 250°C, and a differential scanning calorimetry (DSC) curve including an exotherm with a maximum peak at about 237°C. 【Chemistry 1】

2. The free acid amorphous of Compound I as described in claim 1, wherein the free acid amorphous of Compound I is an amorphous salt form of the free acid of Compound I molecularly dispersed in a polymer matrix.

3. 3. The free acid amorphous of Compound I of claim 2, wherein the polymer matrix comprises hypromellose acetate succinate, hydroxypropylmethylcellulose phthalate, or a combination thereof.

4. 4. A pharmaceutical composition comprising one or more pharma- ceutically acceptable carriers and an amorphous free acid of Compound I according to any one of claims 1 to 3.

5. A pharmaceutical composition for treating a subject suffering from or at risk of a disease or condition mediated by a bromodomain, comprising an effective amount of the amorphous free acid of Compound I according to any one of claims 1 to 3, wherein the disease or condition is selected from the group consisting of rheumatoid arthritis, uveal melanoma, chronic lymphocytic leukemia, acute myeloid leukemia, synovial sarcoma, osteoarthritis, acute gout, psoriasis, systemic lupus erythematosus, multiple sclerosis, and the like. , inflammatory bowel disease (Crohn's disease and ulcerative colitis), asthma, chronic obstructive airways disease, pneumonia, myocarditis, pericarditis, myositis, eczema, dermatitis, alopecia, vitiligo, bullous skin diseases, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, depression, retinitis, uveitis, scleritis, hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis, Addison's disease, hypophysitis, thyroiditis, type I diabetes, or acute rejection of transplanted organs.

6. A pharmaceutical composition for treating chronic lymphocytic leukemia (CLL) or Richter's syndrome comprising an effective amount of the free acid amorphous of Compound I according to any one of claims 1 to 3 in combination with an effective amount of a Bruton's tyrosine kinase (BTK) inhibitor.

7. 7. The pharmaceutical composition of claim 6, wherein the BTK inhibitor is ibrutinib.

8. 10. A pharmaceutical composition for treating chronic lymphocytic leukemia (CLL) comprising an effective amount of the amorphous free acid of Compound I of any one of claims 1 or 3 in combination with an effective amount of a B-cell lymphoma 2 (BCL-2) inhibitor.

9. 11. A pharmaceutical composition for treating uveal melanoma comprising an effective amount of the amorphous free acid of Compound I according to any one of claims 1 to 3 in combination with an effective amount of a CTLA-4 inhibitor or checkpoint inhibitor.

10. 11. A pharmaceutical composition for treating acute myeloid leukemia comprising an effective amount of the amorphous free acid of Compound I according to any one of claims 1 to 3 in combination with an effective amount of quizartinib.

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