Solid Forms of TYK2 Inhibitors and Methods of Use

Abstract

Solid forms of TYK2 inhibitors, pharmaceutical compositions thereof, and methods of treatment are described herein.

Description

[Technical field]

[0001] Claiming priority This application claims priority from U.S. Provisional Patent Application No. 63 / 269,944, filed March 25, 2022, which is incorporated by reference in its entirety.

[0002] Technical Field The present invention relates to solid forms of tyrosine protein kinase 2 (TYK2) inhibitors and methods of making the solid forms. The present invention also provides methods of treating disorders using pharmaceutical compositions comprising the solid forms. [Background technology]

[0003] Protein kinases constitute a large family of structurally related enzymes responsible for the control of various signaling processes within cells. Protein kinases are thought to have evolved from a common ancestral gene because their structure and catalytic function are conserved. Almost all kinases contain a similar 250-300 amino acid catalytic domain. Kinases can be classified into families according to the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine / threonine, lipids, etc.).

[0004] In general, protein kinases mediate intracellular signaling by effecting phosphoryl transfer from a nucleoside triphosphate to a protein acceptor involved in a signaling pathway. These phosphorylation events act as molecular on / off switches that can modulate or regulate the biological function of the target protein. These phosphorylation events are ultimately triggered in response to a variety of extracellular and other stimuli. Examples of such stimuli include environmental and chemical stress signals (e.g., osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, and H2O2), cytokines (e.g., interleukin-1 (IL-1), interleukin-8 (IL-8), and tumor necrosis factor a (TNF-a)), and growth factors (e.g., granulocyte macrophage colony stimulating factor (GM-CSF), and fibroblast growth factor (FGF)). Extracellular stimuli can affect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis, and regulation of the cell cycle.

[0005] Many diseases are associated with abnormal cellular responses triggered by kinase-mediated events, including, but not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone-related diseases. Summary of the Invention

[0006] In one embodiment, Compound 1: [ka] The solid form of may be of Form C.

[0007] In another embodiment, Compound 1: [ka] The solid form of may be of Form A.

[0008] In some embodiments, Compound 1 has an XRPD pattern substantially as shown in FIG. 10 (top trace): [ka] Crystalline form C of the formula is provided.

[0009] In another embodiment, Compound 1: [ka] The solid form of can be of Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, or Form J.

[0010] In some embodiments, Compound 1 has an XRPD pattern substantially as shown in FIG. [ka] In some embodiments, crystalline Form A is provided, in which: In some embodiments, Form A is a hydrate. In some embodiments, Form A is a monohydrate.

[0011] In another embodiment, a method of treating a disorder can include using a crystalline polymorph of Compound 1.

[0012] In another aspect, a pharmaceutical composition can include a solid form described herein and a pharma- ceutically acceptable carrier, excipient, or adjuvant.

[0013] In certain embodiments, the solid form may be substantially free of impurities.

[0014] In certain embodiments, the solid form can be a crystalline solid that is substantially free of amorphous Compound 1.

[0015] In certain embodiments, the solid form may be characterized by having at least 3, 4, 5, or 6 peaks in the X-ray powder diffraction pattern (XRPD) of Figure 16 (bottom trace).

[0016] In certain embodiments, the solid form may be characterized by having at least 3, 4, 5, or 6 peaks in the X-ray powder diffraction pattern (XRPD) of FIG.

[0017] In certain embodiments, the solid form exhibits an X-ray powder diffraction pattern (XRPD) substantially similar to that in FIG. 10 (top trace) or FIG. 16 (bottom trace).

[0018] In certain embodiments, the solid form exhibits a mass loss characterized by TGA analysis between 165°C and 175°C.

[0019] In certain embodiments, the solid form exhibits a DSC characterization that includes a peak onset at about 247°C.

[0020] In certain embodiments, the solid form exhibits a characterization by DSC substantially as shown in FIG.

[0021] In certain embodiments, the solid form may be characterized by a DVS isotherm substantially as shown in FIG.

[0022] In certain embodiments, the solid form may be a hydrate.

[0023] In certain embodiments, the solid form may be a monohydrate.

[0024] In certain embodiments, the solid form may be a dihydrate.

[0025] In certain embodiments, the solid form may be a trihydrate.

[0026] In certain embodiments, the solid form may be characterized by having at least 3, 4, 5, or 6 peaks in the X-ray powder diffraction pattern (XRPD) of FIG. 4 (lower trace) or FIG.

[0027] In certain embodiments, the solid form may be characterized by having an X-ray powder diffraction pattern (XRPD) substantially similar to that in FIG. 4 (lower trace) or FIG.

[0028] In certain embodiments, the solid form may be characterized by having at least 3, 4, or 5 of the highest amplitude peaks in the XRPD of FIG.

[0029] In certain embodiments, the solid form may be characterized by TGA analysis of mass loss between 65°C and 130°C.

[0030] In certain embodiments, the solid form may have a TGA substantially as shown in FIG.

[0031] In certain embodiments, the solid form may be characterized by DSC with peak onsets at about 91° C., 103° C., and 245° C. For example, the peak onset may consist essentially of 245° C.

[0032] In certain embodiments, the solid form may have a DSC substantially as shown in FIG.

[0033] In certain embodiments, the solid form may exhibit peaks or other physical characteristics as shown in any one of Figures 1-42.

[0034] Other aspects, embodiments, and features will become apparent from the following description, the drawings, and the claims. [Brief description of the drawings]

[0035] [Figure 1] The numbering of the non-hydrogen atoms of compound 1 is shown. [Diagram 2] 1 illustrates the XRPD patterns of Forms A through E overlay of Compound 1. [Diagram 3] 1 shows an XRPD overlay of compound 1 from F (top) to J (bottom). [Figure 4] 1 illustrates an XRPD overlay of Form A of Compound 1. [Diagram 5] 1 illustrates the XRPD for Form A of Compound 1. [Figure 6] 1 depicts DSC and TGA thermograms for Compound 1 Form A plus a trace amount of Compound 1 Material B. [Figure 7] 1 shows the DSC and TGA thermograms for Compound 1, Form A. [Figure 8] 1 depicts the DVS isotherm for Compound 1 Form A + trace amount of Material B. [Figure 9] 1 shows an atomic displacement ellipsoid diagram of Compound 1, Form C. [Figure 10] 1 shows experimental and calculated XRPD patterns of Compound 1 Form C. [Figure 11] 1 shows a tentative XRPD indexing solution for Compound 1, Form C. [Figure 12] 1 shows DSC and TGA thermograms for Compound 1 Form C. [Figure 13] 1 shows the DVS isotherm for Compound 1 Form C. [Figure 14] 1 shows a diagram of the void space in the crystal structure of Compound 1 Form C. [Figure 15] 1 shows a cycling DSC thermogram for Form C of Compound 1. [Figure 16] 1 shows an XRPD overlay of the patterns of Material D and Form C of Compound 1. [Figure 17] 1 shows a tentative XRPD indexing solution for Compound 1 Material D. [Figure 18] 1 shows an XRPD overlay of the pattern of material E of compound 1. [Figure 19]1 shows an XRPD overlay of the patterns of Material G and Form A of Compound 1. [Figure 20] 1 shows DSC and TGA thermograms for Compound 1 material G+ trace amount of Form A. [Figure 21] 1 shows DSC and TGA thermograms for Compound 1 Material H. [Figure 22] 1 shows an XRPD overlay of a mixture of Form A, Form C, and Material I of Compound 1. [Diagram 23] 1 shows an XRPD overlay of the pattern of Form J of Compound 1. [Figure 24] 1 shows a tentative XRPD indexing solution for Compound 1 Form J. [Diagram 25] 1 shows a DSC thermogram for Compound 1 Form J. [Figure 26] 1 shows DSC and TGA thermograms for Compound 1 Form J. [Figure 27] 1 shows a TGA thermogram of a heating experiment for Compound 1 Form A. [Figure 28] 1 shows cycling TGA thermograms of heating experiments for Compound 1, Form C. [Figure 29] 1 shows a TGA thermogram of a heating experiment on Compound 1 Material H. [Diagram 30] 1 shows cycling TGA / DSC thermograms of heating experiments for Compound 1 Form C. [Diagram 31] Form A of Compound 1 and trace amounts of material B are shown. [Diagram 32] Form A and trace amounts of material B after DVS of compound 1 are shown. [Diagram 33] 1 shows the XRPD of Form A of Compound 1. [Diagram 34] 1 shows an XRPD of additional Form A of Compound 1. [Diagram 35] 1 shows the XRPD of Form C of Compound 1. [Diagram 36] 1 shows an additional XRPD run of Compound 1 Form C. [Figure 37] 1 shows the XRPD of compound 1 after DVS. [Figure 38] 1 shows material D of the anhydrous, non-solvated form of Compound 1. [Figure 39] 2 shows a disordered version of compound 1, material E. [Diagram 40] 1 shows the XRPD of material F of the disordered form of compound 1. [Diagram 41] Shows form G+ traces of A. [Diagram 42] 1 shows the XRPD of Form A of Compound 1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0036] Detailed Description TYK2 catalyzes the phosphorylation of STAT proteins downstream of several cytokine receptors, including type I interferon receptors and IL-12 and IL-23 receptors. Activation of TYK2-dependent receptors by their cytokine ligands activates STAT-dependent transcriptional and cellular functional responses specific to the receptor and the cell type in which they are expressed. Cytokine signaling pathways regulated by TYK2 play important roles in several immune-mediated disorders. The cytokine IL-12 is essential for the development of type 1 T helper cells (Th1), which produce interferon-gamma, the main effector molecule of systemic autoimmune disorders such as systemic lupus erythematosus. The cytokine IL-23 is essential for the expansion and survival of Th17 cells and innate lymphoid cells, both of which have been shown to play important pathogenic roles in autoimmunity. IL-23 stimulation drives the production of important proinflammatory cytokines by Th17 cells, including IL-17A, IL-17F, and IL-22, all of which are important effector molecules in the pathogenesis of conditions such as psoriasis, psoriatic arthritis, and spondyloarthritis. Inhibition of TYK2 is predicted to impact multiple immune-mediated disorders through its effects on the IL-23 / Th17 / Th22 axis, IL-12-mediated Th1 function, and modulation of diverse immune pathways and cell types by type I interferons.

[0037] Compound 1: [ka] is a TYK2 inhibitor previously disclosed by the applicant. See U.S. Patent No. 11,046,698. Various crystalline polymorphs of a compound (e.g., Compound 1) may change the dissolution, stability, hygroscopicity, and bioavailability of the compound. The present disclosure fulfills the need to elucidate the stable polymorphic form of Compound 1 and provides other related advantages.

[0038] It is desirable to provide a solid form of Compound 1 (e.g., as its free base or a salt thereof) that confers properties such as improved aqueous solubility, stability, and ease of formulation. As described herein, Compound 1 described herein or the compounds described herein may be compounds in the solid form specified herein. Thus, the solid forms described herein include Compound 1: [ka] The compound may include either the free base form or a salt form.

[0039] The free base form of compound 1 In one embodiment, compound 1 as a crystalline solid: [ka] Form C of may have an X-ray powder diffraction pattern (XRPD) substantially similar to that of Figure 16 (bottom trace).

[0040] In one embodiment, Compound 1: [ka] The solid form of can be of Form A. In some embodiments, the solid form exhibits an X-ray powder diffraction pattern (XRPD) substantially similar to that of Figure 4 (lower trace).

[0041] It is contemplated that compound 1 can exist in various physical forms. For example, compound 1 can be in a dissolved state, a suspended state, or a solid form. In certain embodiments, compound 1 is in a solid form. When compound 1 is in a solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0042] In some embodiments, a form of Compound 1 can be substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of foreign matter. Such foreign matter can include various forms of Compound 1, residual solvent, or any other impurities that may result from the preparation and / or isolation of Compound 1. In certain embodiments, at least about 95% by weight of a form of Compound 1 is present. In still other embodiments, at least about 99% by weight of a form of Compound 1 is present.

[0043] According to one embodiment, a form of Compound 1 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 percent by weight, the percentages being based on the total weight of the composition. According to another embodiment, a form of Compound 1 comprises less than about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than about 1.5 HPLC area percent of total organic impurities, relative to the total area of ​​the HPLC chromatogram. In other embodiments, a form of Compound 1 comprises less than about 1.0 HPLC area percent of any single impurity, less than about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than about 0.5 HPLC area percent of any single impurity, relative to the total area of ​​the HPLC chromatogram.

[0044] The structures depicted for one form of Compound 1 are also meant to include all of the tautomeric forms of Compound 1. Additionally, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds may include the replacement of hydrogen with deuterium or tritium, or 13 C- or 14 It may have the structure in question, except for the replacement of a carbon with a C-enriched carbon.

[0045] It has been discovered that Compound 1 can exist in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0046] As used herein, the term "polymorph" refers to the different crystal structures that a compound, or a salt or solvate thereof, may crystallize into.

[0047] In certain embodiments, Compound 1 is a crystalline solid. In other embodiments, Compound 1 is a crystalline solid that is substantially free of amorphous Compound 1. As used herein, the term "substantially free of amorphous Compound 1" means that the compound does not contain a significant amount of amorphous Compound 1. In certain embodiments, at least about 95% by weight of crystalline Compound 1 is present. In yet other embodiments, at least about 99% by weight of crystalline Compound 1 is present.

[0048] It has been found that Compound 1 can exist in different polymorphic forms. In certain embodiments, the polymorphic form of Compound 1 can be referred to herein as Form C. In certain embodiments, the polymorphic form of Compound 1 can be referred to herein as Form A.

[0049] In some embodiments, Compound 1 is amorphous. In some embodiments, Compound 1 is amorphous and substantially free of crystalline Compound 1.

[0050] Form C of Compound 1 As noted above, in one embodiment, Form C of Compound 1 can be a crystalline solid. [ka] In some embodiments, Form C exhibits an X-ray powder diffraction pattern (XRPD) substantially similar to that in Figure 16 (bottom trace).

[0051] In some embodiments, Compound 1 has an XRPD pattern substantially as shown in FIG. 10 (top trace): [ka] Crystalline form C of the formula is provided.

[0052] In another embodiment, Compound 1, which is crystalline: [ka] Form C of has an X-ray powder diffraction pattern (XRPD) characterized by having at least three to five of the most amplitude peaks of the XRPD of Form C substantially similar to that of Figure 16 (bottom trace). In some embodiments, the XRPD has three of the most amplitude peaks of the XRPD of Figure 16 (bottom trace). In some embodiments, the XRPD has four of the most amplitude peaks of the XRPD of Figure 16 (bottom trace). In some embodiments, the XRPD has five of the most amplitude peaks of the XRPD of Figure 16 (bottom trace).

[0053] In another embodiment, Compound 1, which is crystalline: [ka] Form C of has an X-ray powder diffraction pattern (XRPD) characterized by having at least three to five of the maximum amplitude peaks of the XRPD of Form C substantially similar to that of Figure 10 (top trace). In some embodiments, the XRPD has three of the maximum amplitude peaks of the XRPD of Figure 10 (top trace). In some embodiments, the XRPD has four of the maximum amplitude peaks of the XRPD of Figure 10 (top trace). In some embodiments, the XRPD has five of the maximum amplitude peaks of the XRPD of Figure 10 (top trace).

[0054] In one embodiment, Compound 1: [ka] The crystalline polymorph form C of is characterized by TGA analysis of mass loss between 165° C. and 175° C. In some embodiments, the TGA is substantially as shown in FIG.

[0055] In one embodiment, Compound 1: [ka] The crystalline polymorph form C of is characterized by DSC with a peak onset at about 247°C.

[0056] In one embodiment, Compound 1: [ka] The crystalline polymorph form C of is characterized by DSC substantially as shown in FIG.

[0057] In one embodiment, Compound 1: [ka] The crystalline polymorph form C of is characterized by a DVS isotherm substantially as shown in FIG.

[0058] A method for preparing Form C of Compound 1 is described below.

[0059] Form A of Compound 1 As noted above, in one embodiment, Compound 1: [ka] Form A of may be crystalline and comprises an X-ray powder diffraction pattern (XRPD) substantially similar to that of FIG. 4 (lower trace).

[0060] In some embodiments, Compound 1 has an XRPD pattern substantially as shown in FIG. [ka] Provided is a crystalline Form A of the formula: In some embodiments, Form A is a hydrate. In some embodiments, Form A is a monohydrate. In some embodiments, Form A is a dihydrate. In some embodiments, Form A is a trihydrate.

[0061] In another embodiment, Compound 1, which is crystalline: [ka] Form A of has an X-ray powder diffraction pattern (XRPD) characterized by having at least three to five of the most amplitude peaks of the XRPD of Form A substantially similar to that of FIG. 4 (lower trace). In some embodiments, the XRPD has three of the most amplitude peaks of the XRPD of FIG. 4 (lower trace). In some embodiments, the XRPD has four of the most amplitude peaks of the XRPD of FIG. 4 (lower trace). In some embodiments, the XRPD has five of the most amplitude peaks of the XRPD of FIG. 4 (lower trace). In some embodiments, Form A is a hydrate. In some embodiments, Form A is a monohydrate. In some embodiments, Form A is a dihydrate. In some embodiments, Form A is a trihydrate.

[0062] In another embodiment, Compound 1, which is crystalline: [ka] Form A of has an X-ray powder diffraction pattern (XRPD) characterized by having at least three to five of the most amplitude peaks of the XRPD of Form A substantially similar to that of FIG. 5. In some embodiments, the XRPD has three of the most amplitude peaks of the XRPD of FIG. 5. In some embodiments, the XRPD has four of the most amplitude peaks of the XRPD of FIG. 5. In some embodiments, the XRPD has five of the most amplitude peaks of the XRPD of FIG. 5. In some embodiments, Form A is a hydrate. In some embodiments, Form A is a monohydrate. In some embodiments, Form A is a dihydrate. In some embodiments, Form A is a trihydrate.

[0063] In one embodiment, Compound 1: [ka] The crystalline polymorph Form A of is characterized by TGA analysis of mass loss between 65° C. and 130° C. In some embodiments, the TGA is substantially as shown in FIG.

[0064] In one embodiment, Compound 1: [ka] The crystalline polymorph form A of is characterized by DSC with peak onsets at about 91°C, 103°C, and 245°C.

[0065] In one embodiment, Compound 1: [ka] The crystalline polymorph form A of is characterized by DSC substantially as shown in FIG.

[0066] A method for preparing Form A of Compound 1 is described below.

[0067] In some embodiments, Compound 1: [ka] may be crystalline.

[0068] In some embodiments, the solid form of Compound 1 can be substantially free of amorphous Compound 1.

[0069] In some embodiments, the solid form of Compound 1 can be substantially free of impurities.

[0070] In some embodiments, a composition can include Compound 1 and a pharma- ceutically acceptable carrier or excipient.

[0071] In some embodiments, a method of inhibiting or preventing accumulation of A2E in a patient can include administering to the patient Compound 1, or a composition thereof.

[0072] Salt forms of compound 1 In some embodiments, the acid and compound 1 are ionically bonded to form the salt shown below. It is contemplated that the salt may exist in various physical forms. For example, the salt may be in a dissolved state, a suspended state, or in a solid form. In certain embodiments, the salt is in a solid form. When the salt is in a solid form, the compound may be amorphous, crystalline, or a mixture thereof. Exemplary such solid forms of the salt are described in more detail below. In some embodiments, the suitable acid is methanesulfonic acid. In some embodiments, the method may include making a mesylate salt of compound 1. In certain embodiments, the mesylate salt of compound 1 is crystalline.

[0073] In some embodiments, the suitable acid is benzenesulfonic acid. In some embodiments, the method can include making a besylate salt of Compound 1. In certain embodiments, the besylate salt of Compound 1 is crystalline.

[0074] In some embodiments, the suitable acid is sulfuric acid. In some embodiments, the method can include making a sulfate salt of Compound 1. In certain embodiments, the sulfate salt of Compound 1 is crystalline.

[0075] In some embodiments, the suitable acid is p-toluenesulfonic acid. In some embodiments, the method can include making a tosylate salt of Compound 1. In certain embodiments, the tosylate salt of Compound 1 is crystalline.

[0076] In some embodiments, the suitable acid is hydrochloric acid. In some embodiments, the method can include making a hydrochloride salt of Compound 1. In certain embodiments, the hydrochloride salt of Compound 1 is crystalline.

[0077] In some embodiments, the suitable acid is oxalic acid. In some embodiments, the method can include making an oxalate salt of Compound 1. In certain embodiments, the oxalate salt of Compound 1 is crystalline.

[0078] In some embodiments, the suitable acid is phosphoric acid. In some embodiments, the method can include making a phosphate salt of Compound 1. In certain embodiments, the phosphate salt of Compound 1 is crystalline.

[0079] In some embodiments, the suitable acid is tartaric acid. In some embodiments, the method can include making a tartrate salt of Compound 1. In certain embodiments, the tartrate salt of Compound 1 is crystalline.

[0080] In some embodiments, the suitable acid is isethionic acid. In some embodiments, the method can include making an isethionate salt of Compound 1. In certain embodiments, the isethionate salt of Compound 1 is crystalline.

[0081] In some embodiments, the suitable acid is aspartic acid. In some embodiments, the method can include making an aspartic acid salt of Compound 1. In certain embodiments, the aspartic acid salt of Compound 1 is crystalline.

[0082] In some embodiments, the suitable acid is malonic acid. In some embodiments, the method can include making a malonate salt of Compound 1. In certain embodiments, the malonate salt of Compound 1 is crystalline.

[0083] A suitable solvent used as the solvent or in the slurry in the method for preparing a polymorphic crystalline form of Compound 1 can be any solvent system (e.g., a solvent or mixture of solvents) in which Compound 1 and / or the acid are soluble or at least partially soluble.

[0084] Examples of suitable solvents may include, but are not limited to, protic solvents, aprotic solvents, polar aprotic solvents, or mixtures thereof. In certain embodiments, suitable solvents include ethers, esters, alcohols, ketones, or mixtures thereof. In some embodiments, the solvent is one or more organic alcohols. In some embodiments, the solvent is chlorinated. In some embodiments, the solvent is an aromatic solvent.

[0085] In certain embodiments, the suitable solvent is methanol, ethanol, isopropanol, or acetone, which is anhydrous or in combination with water or heptane. In some embodiments, suitable solvents include tetrahydrofuran, dimethylformamide, dimethylsulfoxide, glyme, diglyme, methyl t-butyl ether, t-butanol, n-butanol, and acetonitrile. In some embodiments, the suitable solvent is ethanol. In some embodiments, the suitable solvent is absolute ethanol. In some embodiments, the suitable solvent is MTBE.

[0086] In some embodiments, the suitable solvent is ethyl acetate. In some embodiments, the suitable solvent is a mixture of methanol and methylene chloride. In some embodiments, the suitable solvent is a mixture of acetonitrile and water. In certain embodiments, the suitable solvent is methyl acetate, isopropyl acetate, acetone, or tetrahydrofuran. In certain embodiments, the suitable solvent is diethyl ether. In certain embodiments, the suitable solvent is water. In certain embodiments, the suitable solvent is methyl ethyl ketone. In certain embodiments, the suitable solvent is toluene.

[0087] In some embodiments, the method for preparing a salt compound of general formula X, where formula X constitutes compound 1 in salt form, may include one or more of the steps of removing a solvent and adding a solvent. In some embodiments, the solvent added is the same as the solvent removed. In some embodiments, the solvent added is different from the solvent removed. Means of solvent removal are known in the synthetic and chemical arts, including, but not limited to, any of those described herein and in the Examples.

[0088] In some embodiments, the method for preparing the salt compound of general formula X includes one or more of the steps of heating or cooling the preparation.

[0089] In some embodiments, the method for preparing a salt compound of general formula X includes one or more of the steps of agitating or stirring the preparation.

[0090] In some embodiments, the method for preparing a salt compound of general formula X comprises adding a suitable acid to a solution or slurry of compound 1.

[0091] In some embodiments, the method for preparing a salt compound of general formula X comprises a heating step.

[0092] In certain embodiments, the salt compound of formula X precipitates from the mixture. In other embodiments, the salt compound of formula X crystallizes from the mixture. In other embodiments, the salt compound of formula X crystallizes from the solution after seeding the solution (i.e., adding crystals of the salt compound of formula X to the solution).

[0093] The salt compound of formula X may precipitate from the reaction mixture or may be produced by removing some or all of the solvent by methods such as evaporation, distillation, filtration (e.g., nanofiltration, ultrafiltration), reverse osmosis, absorption and reaction, addition of an anti-solvent such as heptane, cooling, or different combinations of these methods.

[0094] As generally described above, the salt compound of formula X is optionally isolated. Of course, the salt compound of formula X can be isolated by any suitable physical means known to those skilled in the art. In certain embodiments, the precipitated solid salt compound of formula X is separated from the supernatant by filtration. In other embodiments, the precipitated solid salt compound of formula X is separated from the supernatant by decanting the supernatant.

[0095] In certain embodiments, the salt compound of formula X is separated from the supernatant by filtration.

[0096] In certain embodiments, the isolated salt compound of formula X is dried in air. In other embodiments, the isolated salt compound of formula X is dried under reduced pressure, optionally at elevated temperature.

[0097] Uses of the Compounds and Pharmaceutically Acceptable Compositions Thereof Compound 1 of the present invention has selectivity for kinase inhibition as a TYK2 inhibitor.Many diseases are related to abnormal cellular responses caused by kinase-mediated events.These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone-related diseases.

[0098] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset, or inhibiting the progression of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment is administered after one or more symptoms have developed. In other embodiments, treatment is administered in the absence of symptoms. For example, treatment is administered to a susceptible individual prior to the onset of symptoms (e.g., taking into account symptom history and / or taking into account genetic or other susceptibility factors). Treatment is also continued after symptoms have resolved, e.g., to prevent, delay, or reduce the severity of symptoms.

[0099] The crystalline compounds described herein may be used to treat, prevent, and / or reduce the risk of autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone-related diseases. "Compound 1" or "Compound" may be formulated into pharmaceutical formulations as described below for the therapeutic uses described herein.

[0100] TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAK) family of protein kinases. The mammalian JAK family consists of four members: TYK2, JAK1, JAK2, and JAK3. JAK proteins, including TYK2, are essential for cytokine signaling. TYK2 associates with the cytoplasmic domains of type I and type II cytokine receptors, as well as interferon type I and type III receptors, and is activated by these receptors upon cytokine binding. Cytokines involved in TYK2 activation include interferons (e.g., IFN-α, IFN-β, IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, and IFN-ζ (also known as limitin) and interleukins (e.g., IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin-1, cardiotrophin-like cytokine, and LIF).Velasquez et al.,“A protein kinase in the interferon α / β signaling pathway,”Cell(1992)70:313、Stahl et al.,“Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6β receptor components,”Science(1994)263:92、Finbloom et al.,“IL-10 induces the tyrosine phosphorylation of Tyk2 and Jak1 and the differential assembly of Stat1 and Stat3 complexes in human T cells and monocytes,”J.Immunol.(1995)155:1079、Bacon et al.,“Interleukin 12(IL-12)induces tyrosine phosphorylation of Jak2 and Tyk2:differential use of Janus family kinases by IL-2 and IL-12,”J.Exp.Med.(1995)181:399、Welham et al.,“Interleukin-13 signal transduction in lymphohemopoietic cells:similarities and differences in signal transduction with interleukin-4 and insulin,”J.Biol.Chem.(1995)270:12286、Parham et al.,“A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit,IL-23R,”J.Immunol.(2002)168:5699。Activated TYK2 then begins to phosphorylate additional signaling proteins, such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6.

[0101] Activation of TYK2 by IL-23 has been linked to inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis. Duerr et al., "A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene," Science (2006) 314:1461-1463. TYK2, as a downstream effector of IL-23, has also been implicated in psoriasis, ankylosing spondylitis, and Behcet's disease. Cho et al., “Genomics and the multifactorial nature of human auto-immune disease,” N. Engl. J. Med (2011) 365: 1612-1623; Cortes et al., “Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci,” Nat. Genet. (2013) 45(7): 730-738; Remmers et al., “Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet's disease,” Nat. Genet. (2010) 42: 698-702. A genome-wide association study of 2,622 individuals with psoriasis identified an association between disease susceptibility and TYK2. Strange et al., “A genome-wide association study identifies a new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1,” Nat. Genet. (2010) 42:985-992. Knockout of TYK2 or inhibition of tyrphostin significantly reduces both IL-23-induced and IL-22-induced dermatitis.Ishizaki et al., “Tyk2 is a therapeutic target for psoriasis-like skin inflammation,” Intl. Immunol. (2013), doi:10.1093 / intimm / dxt062.

[0102] TYK2 is also involved in respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and cystic fibrosis. Goblet cell hyperplasia (GCH) and mucus hypersecretion are mediated by IL-13-induced TYK2 activation, which in turn activates STAT6. Zhang et al., “Docking protein Gab2 regulates mucin expression and goblet cell hyperplasia through TYK2 / STAT6 pathway,” FASEB J. (2012) 26:1-11.

[0103] Reduction of TYK2 activity leads to protection of joints from collagen antibody-induced arthritis, a model of human rheumatoid arthritis. Mechanistically, reduction of Tyk2 activity reduces T h 1 / T h 17-related cytokines and matrix metalloproteinases, as well as other important inflammatory markers. Ishizaki et al., “Tyk2 deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in mice,” Intl. Immunol. (2011) 23(9):575-582.

[0104] TYK2 knockout mice showed complete resistance to experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS)) with no infiltration of CD4 T cells in the spinal cord compared to controls, suggesting that TYK2 is essential for the development of pathogenic CD4-mediated disease in MS. Oyamada et al., “Tyrosine Kinase 2 Plays Critical Roles in the Pathogenic CD4 T Cell Responses for the Development of Experimental Autoimmune Encephalomyelitis,” J. Immunol. (2009) 183: 7539-7546. This supports previous studies that linked increased TYK2 expression to MS susceptibility. Ban et al., “Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor,” Eur J. Hum. Genet. (2009) 17: 1309-1313. Loss-of-function mutations in TYK2 lead to decreased demyelination and increased remyelination of neurons, further suggesting a role for TYK2 inhibitors in the treatment of MS and other CNS demyelinating disorders.

[0105] TYK2 is the only signaling messenger common to both IL-12 and IL-23. In mice, TYK2 knockout reduced footpad thickness induced by methylated BSA injection, imiquimod-induced psoriasis-like skin inflammation, and dextran sulfate sodium or 2,4,6-trinitrobenzenesulfonic acid-induced colitis.

[0106] Co-linkage and association studies of various type I IFN signaling genes and systemic lupus erythematosus (SLE, an autoimmune disorder) have shown a strong and significant correlation between loss-of-function mutations in TYK2 and reduced prevalence of SLE in affected families. Sigurdsson et al., “Polymorphisms in the Tyrosine Kinase 2 and Interferon Regulatory Factor 5 Genes Are Associated with Systemic Lupus Erythematosus,” Am. J. Hum. Genet. (2005) 76:528-537. Genome-wide association studies of SLE affected and unaffected cohorts have shown a highly significant correlation between the TYK2 locus and SLE. Graham et al., “Association of NCF2,IKZF1,IRF8,IFIH1,and TYK2 with Systemic Lupus Erythematosus,” PLoS Genetics(2011)7(10):e1002341.

[0107] TYK2 has been shown to play a key role in maintaining tumor surveillance, and TYK2 knockout mice showed impaired cytotoxic T cell responses and accelerated tumor development. However, these effects were associated with efficient suppression of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors would be highly suitable for the treatment of autoimmune disorders or transplant rejection. Although other JAK family members such as JAK3 have similar roles in the immune system, TYK2 has been suggested as a superior target because it is involved in fewer and more closely related signaling pathways, thus reducing off-target effects. Simma et al. “Identification of an Indispensable Role for Tyrosine Kinase 2 in CTL-Mediated Tumour Surveillance,” Cancer Res. (2009) 69: 203-211.

[0108] However, contrary to the reduced tumor surveillance observed by Simma et al., studies in T-cell acute lymphoblastic leukemia (T-ALL) have shown that T-ALL is highly dependent on IL-10 via TYK2 through STAT1-mediated signaling to maintain cancer cell survival by upregulation of the anti-apoptotic protein BCL2. Knockdown of TYK2 reduced cell growth, but this was not the case for other JAK family members. Specific activating mutations in TYK2 that promote cancer cell survival include mutations to the FERM domain (G36D, S47N, and R425H), JH2 domain (V731I), and kinase domain (E957D and R1027H). However, it was also identified that the kinase function of TYK2 is required to increase cancer cell survival, since TYK2 enzymes characterized by kinase-dead mutations (M978Y or M978F) in addition to activating mutations (E957D) failed to transform. Sanda et al. “TYK2-STAT1-BCL2 Pathway Dependence in T-Cell Acute Lymphoblastic Leukemia,” Cancer Disc. (2013)3(5):564-577.

[0109] Therefore, selective inhibition of TYK2 has been suggested as a suitable target for patients with IL-10 and / or BCL2-dependent tumors, such as 70% of adult T-cell leukemia cases. Fontan et al. "Discovering What Makes STAT Signaling TYK in T-ALL," Cancer Disc. (2013) 3: 494-496.

[0110] TYK2-mediated STAT3 signaling has also been shown to mediate neuronal cell death caused by amyloid beta (Aβ) peptides. Decreased TYK2 phosphorylation of STAT3 following Aβ administration leads to reduced neuronal cell death, and increased phosphorylation of STAT3 has been observed in postmortem brains of Alzheimer's disease patients. Wan et al. “Tyk / STAT3 Signaling Mediates β-Amyloid-Induced Neuronal Cell Death: Implications in Alzheimer's Disease,” J.Neurosci.(2010)30(20):6873-6881.

[0111] Inhibition of the JAK-STAT signaling pathway has also been implicated in hair growth and reversal of hair loss associated with alopecia areata. Xing et al., “Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition,” Nat. Med. (2014) 20:1043-1049; Harel et al., “Pharmacologic inhibition of JAK-STAT signaling promotes hair growth,” Sci. Adv. (2015) 1(9): e1500973.

[0112] Thus, compounds that inhibit the activity of TYK2, particularly those with selectivity over JAK2, would be beneficial. Such compounds should exert pharmacological responses that successfully treat one or more of the conditions described herein without the side effects associated with inhibition of JAK2.

[0113] Although TYK2 inhibitors are known in the art, there is a continuing need to provide new inhibitors with more effective or advantageous pharmacologic properties. For example, compounds with increased activity, selectivity over other JAK kinases (particularly JAK2), and ADMET (absorption, distribution, metabolism, excretion, and / or toxicity) properties. Thus, in some embodiments, a pharmaceutical composition, formulation, or unit dosage form may include a TYK2 inhibitor compound 1 that exhibits selectivity over JAK2.

[0114] The activity of compound 1, which may be utilized as an inhibitor of TYK2 or its mutants, can be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays that determine the inhibition of either the phosphorylation activity and / or subsequent functional consequences, or the ATPase activity, of activated TYK2 or its mutants. An alternative in vitro assay quantifies the ability of an inhibitor to bind to TYK2. Inhibitor binding can be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / TYK2 complex, and determining the amount of radiolabel binding. Alternatively, inhibitor binding may be determined by performing a competition experiment in which a new inhibitor is incubated with TYK2 bound to a known radioligand. Representative in vitro and in vivo assays that are useful for assaying TYK2 inhibitors include, for example, those described and disclosed in the published literature, each of which is incorporated herein by reference in its entirety.

[0115] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset, or inhibiting the progression of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., taking into account symptom history and / or taking into account genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, e.g., to prevent or delay the recurrence of symptoms.

[0116] Compound 1 is an inhibitor of TYK2 and is therefore useful for treating one or more disorders associated with the activity of TYK2 or its mutants. Thus, in certain embodiments, a method for treating a TYK2-mediated disorder may comprise administering to a patient in need thereof a pharmaceutical composition, formulation, or unit dosage form comprising Compound 1 or a pharma-ceutically acceptable salt or hydrate thereof, as described herein.

[0117] As used herein, the term "TYK2-mediated" disorder, disease, and / or condition refers to a disease or other deleterious condition in which TYK2 or a variant thereof is known to play a role. Accordingly, another embodiment relates to treating or reducing the severity of one or more diseases in which TYK2 or a variant thereof is known to play a role. Such TYK2-mediated disorders include, but are not limited to, autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, and transplant-related disorders.

[0118] In some embodiments, a method for treating one or more disorders, wherein the disorder is selected from an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, and a transplant-related disorder, may comprise administering to a patient in need thereof a pharmaceutical composition comprising an effective amount of a pharmaceutical composition, formulation, or unit dosage form comprising compound 1 as described herein.

[0119] In some embodiments, the disorder is an autoimmune disorder, hi some embodiments, the disorder is selected from type 1 diabetes, cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, psoriasis, Behcet's disease, POEMS syndrome, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0120] In some embodiments, the disorder is an inflammatory disorder, hi some embodiments, the inflammatory disorder is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, inflammatory bowel disease.

[0121] In some embodiments, the disorder is a proliferative disorder. In some embodiments, the proliferative disorder is a hematological cancer. In some embodiments, the proliferative disorder is a leukemia. In some embodiments, the leukemia is a T-cell leukemia. In some embodiments, the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments, the proliferative disorder is polycythemia vera, myelofibrosis, or essential thrombocytosis.

[0122] In some embodiments, the disorder is an endocrine disorder. In some embodiments, the endocrine disorder is polycystic ovary syndrome, Crouzon syndrome, or type 1 diabetes.

[0123] In some embodiments, the disorder is a neurological disorder, hi some embodiments, the neurological disorder is Alzheimer's disease.

[0124] In some embodiments, the proliferative disorder is associated with one or more activating mutations in TYK2. In some embodiments, the activating mutation in TYK2 is a mutation to the FERM domain, the JH2 domain, or the kinase domain. In some embodiments, the activating mutation in TYK2 is selected from G36D, S47N, R425H, V731I, E957D, and R1027H.

[0125] In some embodiments, the disorder is transplant-related, hi some embodiments, the transplant-related disorder is transplant rejection or graft-versus-host disease.

[0126] In some embodiments, the disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling. In some embodiments, the disorder is associated with type I interferon signaling. In some embodiments, the disorder is associated with IL-10 signaling. In some embodiments, the disorder is associated with IL-12 signaling. In some embodiments, the disorder is associated with IL-23 signaling.

[0127] Formulations containing Compound 1 are also useful in the treatment of inflammatory or allergic conditions of the skin, such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, cutaneous lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0128] Formulations containing Compound 1 may also be used to treat other diseases or conditions, such as diseases or conditions that have an inflammatory component, e.g., diseases and conditions of the eye, such as ocular allergies, conjunctivitis, keratoconjunctivitis sicca, and vernal keratoconjunctivitis, diseases affecting the nose, including allergic rhinitis, and inflammatory diseases involving an autoimmune response or having an autoimmune component or etiology, e.g., autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, true erythrocytic anemia, and idiopathic thrombocytopenia), cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulation. inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, pulmonary hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis inflammation, cryopyrin-associated periodic syndromes, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with or without nephrotic syndrome, including e.g. idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous diseases, endometriosis, leptospirosis kidney disease, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndromes, asthma (allergic and Non-allergic, mild, moderate, severe, bronchitis, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, rhinosinusitis, ocular allergies, silica-induced disease, COPD (reduction of damage, airway inflammation, bronchial hyperresponsiveness, remodeling, or disease progression), pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, systemic sclerosis with muscle inflammation, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 or type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergies,Blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibromyalgia, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease The composition may also be used to treat ulcerative colitis, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, ovariitis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0129] In some embodiments, inflammatory diseases that may be treated according to the methods described herein are selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryopyrin-associated periodic syndromes (CAPS), and osteoarthritis.

[0130] In some embodiments, the inflammatory disease that may be treated according to the methods described herein is T h 1 Vector-borne disease or T h 17-mediated disease. In some embodiments, the h The 17-mediated disease is selected from cutaneous lupus erythematosus, systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0131] In some embodiments, inflammatory diseases that may be treated according to the methods described herein are selected from Sjogren's syndrome, psoriasis, psoriatic arthritis, irritable bowel disease, allergic disorders, osteoarthritis, ocular conditions (such as ocular allergies, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis), and diseases affecting the nose, such as allergic rhinitis.

[0132] Furthermore, the formulation may contain compound 1 as defined herein for the preparation of a medicament for the treatment of an autoimmune, inflammatory or proliferative disorder, or a disorder that frequently occurs in association with transplantation.

[0133] Combination therapy Depending on the particular condition, or disease, being treated, additional therapeutic agents that are normally administered to treat that condition may be administered in combination with the formulations containing Compound 1 described herein. As used herein, additional therapeutic agents that are normally administered to treat a particular disease or condition are known as "appropriate for the disease or condition being treated."

[0134] In certain embodiments, the provided combinations, or compositions thereof, are administered in combination with another therapeutic agent.

[0135] Examples of drugs that can be further combined with the combinations described herein include, but are not limited to, drugs to treat Alzheimer's disease, such as Aricept® and Excelon®; drugs to treat HIV, such as ritonavir; drugs to treat Parkinson's disease, such as L-DOPA / carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; drugs to treat multiple sclerosis (MS), such as beta interferons (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; drugs to treat asthma, such as albuterol and Singulair®; drugs to treat schizophrenia, such as Zyprexa, Risperdal, Seroquel, and haloperidol; corticosteroids, TNF blockers, IL-1 Anti-inflammatory agents such as RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators and immunosuppressants such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and antiparkinsonian agents; beta blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers agents for treating cardiovascular disease, such as cyclophosphamide, cyclosporine, and statins; agents for treating liver disease, such as corticosteroids, cholestyramine, interferons, and antivirals; agents for treating blood disorders, such as corticosteroids, anti-leukemia agents, and growth factors; agents that prolong or improve pharmacokinetics, such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic degradation) and CYP3A4 inhibitors (e.g., ketokenozole and ritonavir), and agents for treating immune deficiency disorders, such as gamma globulins.

[0136] In certain embodiments, the combination therapy described herein, or a pharma- ceutically acceptable composition thereof, is administered in combination with a monoclonal antibody or a siRNA therapeutic agent.

[0137] These additional agents may be administered separately from the combination therapy provided as part of a multiple dose regimen. Alternatively, these agents may be part of a single dosage form, mixed together with the compounds described herein as a single composition. When administered as part of a multiple dose regimen, the two active agents may be provided simultaneously, sequentially, or within a period of each other (usually within 5 hours of each other).

[0138] As used herein, the terms "combination," "in combination," and related terms refer to simultaneous or sequential administration of therapeutic agents as described herein. For example, the combinations described herein may be administered with another therapeutic agent either simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form.

[0139] The amount of additional therapeutic agent present in the compositions described herein will not be greater than the amount that would normally be administered in a composition containing that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions of the present disclosure will range from about 50% to 100% of the amount that would normally be present in a composition containing that agent as the only therapeutically active agent.

[0140] In one embodiment, the composition can include Compound 1 and one or more additional therapeutic agents. The therapeutic agents can be administered together with Compound 1, or can be administered before or after the administration of the additional therapeutic agents. Suitable therapeutic agents are described in more detail below. In certain embodiments, Compound 1 can be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, Compound 1 may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours after the therapeutic agent.

[0141] In another embodiment, the method of treating an inflammatory disease, disorder or condition by administering a formulation to a patient in need of treatment may include Compound 1 as described herein and one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or recombinant biological agents, such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids, such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., probenecid, allopurinol, febuxostat (Uloric®), Sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimi®), ne®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and "anti-TNF" agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®), trademark) and adalimumab (Humira®), "anti-IL-1" agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), canakinumab (Ilaris®), anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab (Rituxan®), "anti-T cell" agents such as abatacept (Orencia®), "anti-IL-6" agents such as tocilizumab (Actemra®), diclofenac,Cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiz®), a®), laxatives such as milk of magnesia, polyethylene glycols (MiraLax®), Dulcolax®, Correctol® and Senokot®, anticholinergics or antispasmodics such as dicyclomine (Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alup®), ent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergics such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), trademark), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), and flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, sodium cromoglycate (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®,Theo-24®) and aminophyllines, IgE antibodies such as omalizumab (Xolair®), nucleoside reverse transcriptase inhibitors such as zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®) and etravirine (Intelence®), nucleoside reverse transcriptase inhibitors such as tenofovir (Viread®), protease inhibitors such as amprenavir (Agenvir®), erase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®); entry inhibitors, e.g. For example, enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), and combinations of dexamethasone (Decadron®) and lenalidomide (Revlimid®), or any combination(s) thereof.

[0142] In another embodiment, the method of treating rheumatoid arthritis comprises administering to a patient in need thereof Compound 1 and nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids, such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, sulfasalazine (Azulfidine®), antimalarials, such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts, such as aurothioglucose (Solganal®), aurothiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), or the like. (Tagmark), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and "anti-TNF" agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab. and one or more additional therapeutic agents selected from mabs (Humira®), "anti-IL-1" agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), antibodies such as rituximab (Rituxan®), "anti-T cell" agents such as abatacept (Orencia®), and "anti-IL-6" agents such as tocilizumab (Actemra®).

[0143] In some embodiments, a method of treating osteoarthritis may include administering to a patient in need thereof a formulation comprising Compound 1 and one or more additional therapeutic agents selected from acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), and monoclonal antibodies, such as tanezumab.

[0144] In some embodiments, a method of treating cutaneous or systemic lupus erythematosus may include administering to a patient in need thereof a formulation comprising Compound 1 and one or more additional therapeutic agents selected from acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids, such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, antimalarials, such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®), and anticoagulants, such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®).

[0145] In some embodiments, a method of treating Crohn's disease, ulcerative colitis, or inflammatory bowel disease may include administering to a patient in need thereof a formulation comprising Compound 1 and one or more additional therapeutic agents selected from mesalamine (Asacol®), sulfasalazine (Azulfidine®), antidiarrheal agents such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, and Senokot®, and anticholinergics or antispasmodics such as dicyclomine (Bentyl®), anti-TNF therapy, steroids, and antibiotics such as Flagyl or ciprofloxacin.

[0146] In some embodiments, the method of treating asthma comprises administering to a patient in need thereof Compound 1 and one or more of the following: Singulair®; beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®); anticholinergics such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®); inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Bec and one or more additional therapeutic agents selected from lovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®, sodium cromoglycate (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, and IgE antibodies such as omalizumab (Xolair®).

[0147] In some embodiments, the method of treating COPD includes administering to a patient in need thereof Compound 1 and a combination of a beta-2 agonist, such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®), an anticholinergic, such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), a methylxanthine, such as theophylline (Theo-D In some embodiments, the method may include administering a formulation comprising an aminophylline, an inhaled corticosteroid such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®.

[0148] In another embodiment, a method of treating a hematological malignancy may include administering to a patient in need thereof a formulation comprising Compound 1 and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[0149] In another embodiment, a method of treating a solid tumor may include administering to a patient in need thereof a formulation comprising Compound 1 and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[0150] In another embodiment, a method of treating a hematological malignancy may include administering to a patient in need thereof a formulation comprising Compound 1 and a hedgehog (Hh) signaling pathway inhibitor. In some embodiments, the hematological malignancy is DLBCL (Ramirez et al "Defining causative factors contributing to the activation of hedgehog signaling in diffuse large B-cell lymphoma" Leuk. Res. (2012), published online July 17, and incorporated herein by reference in its entirety).

[0151] In another embodiment, a method of treating diffuse large B-cell lymphoma (DLBCL) may include administering to a patient in need thereof a formulation comprising Compound 1 and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, and combinations thereof.

[0152] In another embodiment, a method of treating multiple myeloma may include administering to a patient in need thereof a formulation comprising compound 1 and one or more additional therapeutic agents selected from bortezomib (Velcade®), and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a combination of a SYK inhibitor and lenalidomide (Revlimid®).

[0153] In another embodiment, a method of treating or lessening the severity of a disease may comprise administering to a patient in need thereof a formulation comprising Compound 1 and a BTK inhibitor, the disease being inflammatory bowel disease, arthritis, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune thyroiditis, Sjogren's syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis. , Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylosis, antiphospholipid syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, autonomic nervous system dysfunction, membranous glomerular nephropathy, endometriosis, interstitial cystitis, pemphigus vulgaris, water Bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, hyperproliferative disorders, rejection of transplanted organs or tissues, acquired immune deficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplants, transfusions, anaphylaxis, allergies (e.g., allergies to plant pollen, latex, drugs, foods, insect venom, animal hair, animal dander, dust mites, or cockroach umbrellas), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis , cervicitis, cholangitis, cholecystitis, chronic transplant rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis,Sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis, B-cell proliferative disorders such as diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenström hypergammaglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, Mann's lymphoma, Torr cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, or lymphomatoid granulomatosis, breast cancer, prostate cancer, or cancer of the mast cells (e.g., mastocytoma, mast cell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer, colon cancer, pancreatic cancer, bone and joint diseases (including, but not limited to, rheumatoid arthritis, seronegative spondyloarthropathy (including ankylosing spondylitis, psoriatic arthritis, and Reiter's disease), systemic sclerosis, osteoporosis, bone cancer, bone metastases), thromboembolic disorders (e.g., myocardial infarction, angina pectoris, Reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transient ischemia, peripheral arterial occlusive disorder, pulmonary embolism, deep vein thrombosis), inflammatory pelvic disease, urethritis, sunburn, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis (cholocystitus), agammaglobulinemia, psoriasis, allergies, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection, hyperacute rejection of transplanted organs Reactions, Asthma, Allergic Rhinitis, Chronic Obstructive Pulmonary Disease (COPD), Autoimmune Polyglandular Disease (also known as Autoimmune Polyglandular Syndrome), Autoimmune Alopecia, Pernicious Anemia, Glomerulonephritis, Dermatomyositis, Multiple Sclerosis, Scleroderma, Vasculitis, Autoimmune Hemolytic and Thrombocytopenic States, Goodpasture's Syndrome, Atherosclerosis, Addison's Disease, Parkinson's Disease, Alzheimer's Disease, Diabetes, Septic Shock, Cutaneous Lupus Erythematosus, Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis, Psoriatic Arthritis, Juvenile Arthritis, Osteoarthritis, Chronic Idiopathic Thrombocytopenic Purpura, Myasthenia Gravis,Selected from Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, scleroderma, mycosis fungoides, and acute inflammatory responses (such as acute respiratory distress syndrome and ischemia / reperfusion injury).

[0154] In another embodiment, a method of treating or lessening the severity of a disease may comprise administering to a patient in need thereof a formulation comprising compound 1 disclosed herein and a PI3K inhibitor, the disease being selected from cancer, neurodegenerative disorders, angiogenic disorders, viral diseases, autoimmune diseases, inflammatory disorders, hormone-related diseases, conditions associated with organ transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), liver diseases, pathological immune conditions involving T cell activation, cardiovascular disorders, and CNS disorders.

[0155] In another embodiment, a method of treating or lessening the severity of a disease may comprise administering to a patient in need thereof a formulation comprising Compound 1 as disclosed herein and a PI3K inhibitor, the disease being a benign or malignant tumor, carcinoma or solid tumor of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, gastric tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastoma, neuroblastoma, multiple myeloma or gastrointestinal cancer, particularly colon cancer or Diseases including colorectal adenoma, or tumors of the head and neck, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasms, epithelial neoplasms, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma (including, for example, non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (also known as Hodgkin or Hodgkin's disease)), breast carcinoma, follicular carcinoma, anaplastic carcinoma, papillary carcinoma, seminoma, melanoma, or leukemia, Cowden syndrome, Lhermitte-Dudos disease, and Bannayan-Zonana syndrome, or diseases in which the PI3K / PKB pathway is aberrantly activated, intrinsic ( Asthma of any type or origin, including both non-allergic (asthma) and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitis asthma, exercise-induced asthma, occupational asthma, and asthma induced after bacterial infection, chronic obstructive pulmonary, airway or lung disease (COPD, COAD or COLD), including acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic bronchitis or associated dyspnea, emphysema, and exacerbation of airway hyperresponsiveness as a result of other medications, especially other inhaled medications bronchitis of any kind or genesis, including but not limited to acute, arachidic, catarrhal, croupus, chronic or tuberculous (phthinoid) bronchitis, pneumoconiosis of any kind or genesis (an inflammatory, generally occupational, lung disease, frequently associated with airway obstruction, caused by repeated inhalation of dust, whether chronic or acute) (including, for example, aluminum lung disease, anthracosis, asbestosis, stone disease, ptilosis, siderosis, silicosis, tobacco disease and byssinosis), Löffler's syndrome, eosinophilic pneumonia,Parasitic (especially metazoan) infestations (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), drug reactions, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, epidermolysis bullosa acquisita, conjunctivitis, keratoconjunctivitis sicca, and vernal mosquito ulcers. eosinophilic granulomas and eosinophil-related disorders affecting the airways caused by rhinitis, diseases affecting the nose, including allergic rhinitis, and inflammatory diseases involving an autoimmune response or having an autoimmune component or etiology, such as autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, true erythrocytic anemia, and idiopathic thrombocytopenia), cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, polychondritis , scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial The disease is selected from chronic pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with or without nephrotic syndrome, including, for example, idiopathic nephrotic syndrome or minimal change nephropathy), restenosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and cerebral ischemia, as well as neurodegenerative diseases resulting from trauma, glutamate neurotoxicity and hypoxia.

[0156] In some embodiments, the method of treating or reducing the severity of a disease may include administering to a patient in need thereof a formulation comprising compound 1 disclosed herein and a Bcl-2 inhibitor, wherein the disease is an inflammatory disorder, an autoimmune disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disorder. In some embodiments, the disorder is a proliferative disorder, lupus, or lupus nephritis. In some embodiments, the proliferative disorder is chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Hodgkin's disease, small cell lung cancer, non-small cell lung cancer, myelodysplastic syndrome, lymphoma, hematological neoplasm, or solid tumor.

[0157] In some embodiments, a method of treating or reducing the severity of a disease may include administering to a patient in need thereof a TYK2 pseudokinase (JH2) domain binding compound and a TYK2 kinase (JH1) domain binding compound. In some embodiments, the disease is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disorder. In some embodiments, the JH2 domain binds to compound 1. Other suitable JH2 domain binding compounds include those described in WO2014074660A1, WO2014074661A1, WO2015089143A1, each of which is incorporated herein by reference in its entirety. Suitable JH1 domain binding compounds include those described in WO2015131080A1, each of which is incorporated herein by reference in its entirety.

[0158] The composition of Compound 1 may be administered using any amount and any route of administration effective for treating or reducing the severity of an autoimmune, inflammatory, proliferative, endocrine, neurological, or transplant-related disorder. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the specific drug, its mode of administration, and the like. Compound 1 is preferably formulated in a unit dosage form for ease of administration and uniformity of dosage. The expression "unit dosage form" as used herein refers to a physically discrete unit of drug appropriate for the patient being treated. However, it will be understood that the total daily usage of the compounds and compositions described herein will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for a particular patient or organism will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound being used; the specific composition being used; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and excretion rate of the specific compound being used; the duration of treatment; drugs used in combination or simultaneously with the specific compound being used, and similar factors well known in the medical field. The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[0159] The pharma- ceutically acceptable compositions may be administered to humans and other animals orally, rectally, parenterally, intravesically, intravaginally, intraperitoneally, topically (as powders, ointments, or drops), bucally, as oral or nasal sprays, etc., depending on the severity of the infection being treated. In certain embodiments, the compounds may be administered orally or parenterally, one or more times per day, at dosage levels of about 0.01 mg / kg to about 50 mg / kg, preferably about 0.01 mg / kg to about 5 mg / kg of body weight of the subject, per day, to obtain the desired therapeutic effect.

[0160] Liquid dosage forms for oral administration include, but are not limited to, pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. Liquid dosage forms may contain, in addition to the active compound, inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and aromatic agents.

[0161] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution (USP), and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0162] The injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0163] To prolong the effect of Compound 1, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound therefore depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the release rate of Compound 1 can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0164] Compositions for rectal or vaginal administration are preferably suppositories which may be prepared by mixing Compound 1 with a suitable non-irritating excipient or carrier (such as cocoa butter, polyethylene glycol, or a suppository wax) which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectal or vaginal cavity to release the active compound.

[0165] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharma- ceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0166] Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0167] The active compound may also be in microencapsulated form with one or more excipients as described above. In some embodiments, a hydroxypropylmethylcellulose (HMPC) capsule encapsulates the composition or formulation. In some embodiments, the capsule is a size 2 hard Swedish orange HPMC capsule. The solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. According to normal practice, such dosage forms may also contain additional substances other than the inert diluent, for example, tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0168] Dosage forms for topical or transdermal administration of formulations containing Compound 1 include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharma- ceutically acceptable carrier and, if necessary, with any necessary preservatives or buffers. Ophthalmic preparations, ear drops, and eye drops may also be formulated. In addition, transdermal patches may be used, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms may be made by dissolving or dispensing the compound in a suitable medium. Absorption enhancers may also be used to increase the flux of the compound through the skin. The rate may be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0169] According to one embodiment, a method for inhibiting protein kinase activity in a biological sample may comprise contacting the biological sample with a formulation comprising compound 1 as described herein.

[0170] According to another embodiment, a method of inhibiting the activity of TYK2 or a variant thereof in a biological sample may comprise contacting the biological sample with compound 1 as described herein or a composition comprising said compound. In certain embodiments, a method of irreversibly inhibiting the activity of TYK2 or a variant thereof in a biological sample may comprise contacting the biological sample with a formulation comprising compound 1 as described herein.

[0171] In another embodiment, the method may include selectively inhibiting TYK2 over one or more of JAK1, JAK2, and JAK3. In some embodiments, the formulations comprising compound 1 described herein have greater than 2-fold selectivity over JAK1 / 2 / 3. In some embodiments, the compounds described herein have greater than 5-fold selectivity over JAK1 / 2 / 3. In some embodiments, the compounds described herein have greater than 10-fold selectivity over JAK1 / 2 / 3. In some embodiments, the compounds described herein have greater than 50-fold selectivity over JAK1 / 2 / 3. In some embodiments, the compounds described herein have greater than 100-fold selectivity over JAK1 / 2 / 3.

[0172] As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof, biopsies or extracts thereof obtained from mammals, and blood, saliva, urine, feces, sperm, tears, or other bodily fluids or extracts thereof.

[0173] Inhibition of TYK2 (or a variant thereof) activity in a biological sample is useful for a variety of purposes known to those of skill in the art, including, but not limited to, blood transfusions, organ transplants, biological specimen storage, and biological assays.

[0174] Another embodiment relates to a method of inhibiting protein kinase activity in a patient, comprising administering to the patient a formulation comprising Compound 1 as described herein.

[0175] According to another embodiment, a method of inhibiting activity of TYK2 or a mutant thereof in a patient may comprise administering to the patient a formulation comprising compound 1 as described herein. According to certain embodiments, a method of reversibly or irreversibly inhibiting activity of one or more of TYK2 or mutants thereof in a patient may comprise administering to the patient a formulation comprising compound 1 as described herein. In other embodiments, a method of treating a disorder mediated by TYK2 or mutants thereof in a patient in need of such treatment may comprise administering to the patient a formulation comprising compound 1 as described herein. Such disorders are described in detail herein.

[0176] Depending on the particular condition, or disease, being treated, additional therapeutic agents that are normally administered to treat that condition may also be present in the compositions described herein. As used herein, additional therapeutic agents that are normally administered to treat a particular disease or condition are known as "appropriate for the disease or condition being treated."

[0177] The formulations comprising compound 1 described herein can also be used in combination with other therapeutic compounds. In some embodiments, the other therapeutic compounds are antiproliferative compounds. Such antiproliferative compounds include aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antitumor antimetabolites; platin compounds; compounds that target / reduce protein or lipid kinase activity and further antiangiogenic compounds; compounds that target, reduce or inhibit the activity of protein or lipid phosphatases; gonadorelin agonists; antiandrogens; methionine aminopeptidase inhibitors ... metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematological malignancies; compounds that target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors, such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 (Conforma Therapeutics); temozolomide (Temodal®); kinesin spindle protein inhibitors, such as SB715992 or SB743921 (GlaxoSmithKline), or pentamidine / chlorpromazine (CombinatoRx); MEK inhibitors, such as ARRY142886 (Array BioPharma), AZD6244 (AstraZeneca), PD181461 (Pfizer) and leucovorin. The term "aromatase inhibitor" as used herein relates to a compound which inhibits estrogen production, for example the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively.The term includes, but is not limited to, steroids, particularly atamestane, exemestane and formestane, and nonsteroids, particularly aminoglutethimide, rogletimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is commercially available under the trade name Aromasin™. Formestane is commercially available under the trade name Lentaron™. Fadrozole is commercially available under the trade name Afema™. Anastrozole is commercially available under the trade name Arimidex™. Letrozole is commercially available under the trade name Femara™ or Femar™. Aminoglutethimide is commercially available under the trade name Orimeten™. The combinations described herein that include a chemotherapeutic agent that is an aromatase inhibitor are particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors.

[0178] The term "anti-estrogen" as used herein refers to a compound that antagonizes the effect of estrogen at the estrogen receptor level. This term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen is marketed under the trade name Nolvadex™. Raloxifene hydrochloride is marketed under the trade name Evista™. Fulvestrant can be administered under the trade name Faslodex™. The combinations described herein that include chemotherapeutic agents that are anti-estrogen are particularly useful for treating estrogen receptor positive tumors, such as breast tumors.

[0179] The term "antiandrogen" as used herein relates to any substance capable of inhibiting the biological effects of androgenic hormones, including, but not limited to, bicalutamide (Casodex™). The term "gonadorelin agonist" as used herein includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin may be administered under the trade name Zoladex™.

[0180] The term "topoisomerase I inhibitors" as used herein includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin, and the polymeric camptothecin conjugate PNU-166148. Irinotecan can be administered in the form as it is marketed, for example, under the trademark Camptosar™. Topotecan is marketed under the trademark Hycamptin™.

[0181] The term "topoisomerase II inhibitors" as used herein includes, but is not limited to, doxorubicin (including liposomal formulations such as Caelyx™), daunorubicin, epirubicin, anthracyclines such as idarubicin and nemorubicin, the anthraquinones mitoxantrone and rosoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide is commercially available under the trade name Etopophos™. Teniposide is commercially available under the trade name VM 26-Bristol. Doxorubicin is commercially available under the trade name Acriblastin™ or Adriamycin™. Epirubicin is commercially available under the trade name Farmorubicin™. Idarubicin is commercially available under the trade name Zavedos™. Mitoxantrone is commercially available under the trade name Novantron.

[0182] The term "microtubule active agent" refers to microtubule stabilizing compounds, microtubule destabilizing compounds, and microtubule polymerization inhibitors, including but not limited to taxanes such as paclitaxel and docetaxel; vinca alkaloids such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolide; cochicine and epothilones and their derivatives. Paclitaxel is commercially available under the trade name Taxol™. Docetaxel is commercially available under the trade name Taxotere™. Vinblastine sulfate is commercially available under the trade name Vinblastin RP™. Vincristine sulfate is commercially available under the trade name Farmistin™.

[0183] The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is commercially available under the trade name Cyclostin™. Ifosfamide is commercially available under the trade name Holoxan™.

[0184] The term "histone deacetylase inhibitors" or "HDAC inhibitors" relates to compounds which inhibit histone deacetylase and which possess antiproliferative activity, including, but not limited to, suberoylanilide hydroxamic acid (SAHA).

[0185] The term "antineoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds (such as 5-azacytidine and decitabine), methotrexate and edatrexate, and folate antagonists (such as pemetrexed). Capecitabine is marketed under the trade name Xeloda™. Gemcitabine is marketed under the trade name Gemzar™.

[0186] The term "platin compounds" as used herein includes, but is not limited to, carboplatin, cisplatin, cisplatinum and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark Carboplat™. Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark Eloxatin™.

[0187] The term "compounds targeting / reducing protein or lipid kinase activity, or protein or lipid phosphatase activity, or further anti-angiogenic compounds" as used herein includes, but is not limited to, protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, such as: a) compounds that target, reduce or inhibit the activity of platelet derived growth factor receptor (PDGFR), e.g. compounds that target, reduce or inhibit the activity of PDGFR, in particular compounds that inhibit the PDGF receptor, e.g. N-phenyl-2-pyrimidine-amine derivatives, e.g. imatinib, SU101, SU6668 and GFB-111; b) compounds that target, reduce or inhibit the activity of fibroblast growth factor receptor (FGFR); c) compounds that target, reduce or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), e.g. compounds that inhibit the activity of IGF-IR. d) compounds that target, reduce or inhibit the activity of the Trk receptor tyrosine kinase family or ephrinB4 inhibitors; e) compounds that target, reduce or inhibit the activity of the AxI receptor tyrosine kinase family; f) compounds that target, reduce or inhibit the activity of the Ret receptor tyrosine kinase; g) compounds that target, reduce or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, such as imatinib; h) compounds that target, reduce or inhibit the activity of the C-kit receptor tyrosine kinase, which is part of the PDGFR family, such as compounds that target, reduce or inhibit the activity of the c-Kit receptor tyrosine kinase family, in particular compounds that inhibit the c-Kit receptor, such as imatinib;i) Compounds that target, reduce or inhibit the activity of c-Abl family members, their gene fusion products (e.g., BCR-Abl kinase) and mutants, such as compounds that target, reduce or inhibit the activity of c-Abl family members and their gene fusion products, such as N-phenyl-2-pyrimidine-amine derivatives, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 (from ParkeDavis); or dasatinib (BMS-354825); j) compounds which target, decrease or inhibit the activity of members of the protein kinase C (PKC) and Raf families of serine / threonine kinases, MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, BTK and TEC families, and / or members of the cyclin-dependent kinase family (CDK), including staurosporine derivatives such as midostaurin; further exemplary compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521; LY333531 / LY379196; isochinoline compounds; FTI; PD184352 or QAN697 (P13K inhibitors) or AT7519 (CDK inhibitors); k) compounds that target, decrease or inhibit the activity of protein tyrosine kinase inhibitors, such as compounds that target, decrease or inhibit the activity of protein tyrosine kinase inhibitors, such as imatinib mesylate (Gleevec™) or tyrphostin A23 / RG-50810; AG99; tyrphostin AG 213; tyrphostin AG 1748; tyrphostin AG 490; tyrphostin B44; tyrphostin B44(+) enantiomer; tyrphostin AG 555; AG 494; tyrphostin AG 556, AG957 and adahostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adahostin); l) compounds which target, reduce or inhibit the activity of the epidermal growth factor receptor tyrosine kinase family (EGFR1, ErbB2, ErbB3, ErbB4 as homodimers or heterodimers) and variants thereof, for example compounds which target, reduce or inhibit the activity of the epidermal growth factor receptor family, in particular compounds which inhibit members of the EGF receptor tyrosine kinase family such as EGF receptor, ErbB2, ErbB3 and ErbB4, or which inhibit EGF or EGF-related ligands, CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds which target, reduce or inhibit the activity of the c-Met receptor, for example compounds which target, reduce or inhibit the activity of c-Met, in particular compounds which inhibit the kinase activity of the c-Met receptor, or antibodies which target the extracellular domain of c-Met or which bind to HGF, n) PRT-062070, SB- 1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib; o) compounds that target, decrease, or inhibit the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK), including but not limited to ATU-02; 7, compounds that target, decrease, or inhibit the kinase activity of PI3 kinase (PI3K), including but not limited to SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictorelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib;and q) compounds that target, decrease, or inhibit the signaling effects of the Hedgehog protein (Hh) or Smoothened receptor (SMO) pathways, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (salidegib);

[0188] The term "PI3K inhibitor" as used herein includes, but is not limited to, compounds that have inhibitory activity against one or more enzymes of the phosphatidylinositol-3-kinase family, including, but not limited to, PI3K α, PI3K γ, PI3K δ, PI3K β, PI3K-C2 α, PI3K-C2 β, PI3K-C2 γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87. Examples of PI3K inhibitors include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictorelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

[0189] The term "BTK inhibitor" as used herein includes, but is not limited to, compounds that have inhibitory activity against Bruton's tyrosine kinase (BTK), including, but not limited to, AVL-292 and ibrutinib.

[0190] The term "SYK inhibitors" as used herein includes, but is not limited to, compounds that have inhibitory activity against spleen tyrosine kinase (SYK), including, but not limited to, PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0191] The term "Bcl-2 inhibitors" as used herein includes, but is not limited to, compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including, but not limited to, ABT-199, ABT-731, ABT-737, apogossypol, Ascenta's pan-Bcl-2 inhibitors, curcumin (and analogs thereof), dual Bcl-2 / Bcl-xL inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof; see WO2008118802), navitoclax (and analogs thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), and venetoclax. In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic agent. In some embodiments, the Bcl-2 inhibitor is a peptidomimetic.

[0192] Further examples of BTK inhibitory compounds, and conditions treatable by such compounds in combination with the compounds described herein, can be found in WO2008039218 and WO2011090760, which are incorporated herein by reference in their entireties.

[0193] Further examples of SYK inhibitory compounds, and conditions treatable by such compounds in combination with the compounds described herein, can be found in WO2003063794, WO2005007623, and WO2006078846, the entireties of which are incorporated herein by reference.

[0194] Further examples of PI3K inhibitory compounds, and conditions treatable by such compounds in combination with the compounds described herein, can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554, and WO2007044729, the entireties of which are incorporated herein by reference.

[0195] Further examples of JAK inhibitory compounds and conditions treatable by such compounds in combination with the compounds described herein can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514, the entireties of which are incorporated herein by reference.

[0196] Additional anti-angiogenic compounds include, for example, compounds that have another mechanism of their activity unrelated to protein or lipid kinase inhibition, such as thalidomide (Thalomid™) and TNP-470.

[0197] Examples of proteasome inhibitors useful for use in combination with the formulations containing Compound 1 described herein include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0198] Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are, for example, inhibitors of phosphatase 1, phosphatase 2A or CDC25, such as okadaic acid or a derivative thereof.

[0199] Compounds that induce cell differentiation processes include, but are not limited to, retinoic acid, α-γ- or δ-tocopherol, or α-γ- or δ-tocotrienol.

[0200] The term cyclooxygenase inhibitors as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acids and derivatives, such as celecoxib (Celebrex™), etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acids, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid, lumiracoxib.

[0201] The term "bisphosphonate" as used herein includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etridonic acid is commercially available under the trade name Didronel™. Clodronic acid is commercially available under the trade name Bonefos™. Tiludronic acid is commercially available under the trade name Skelid™. Pamidronic acid is commercially available under the trade name Aredia™. Alendronic acid is commercially available under the trade name Fosamax™. Ibandronic acid is commercially available under the trade name Bondranat™. Risedronic acid is commercially available under the trade name Actonel™. Zoledronic acid is commercially available under the trade name Zometa™. The term "mTOR inhibitors" relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and have antiproliferative activity, such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578.

[0202] As used herein, the term "heparanase inhibitor" refers to a compound that targets, reduces, or inhibits the degradation of heparin sulfate. This term includes, but is not limited to, PI-88. As used herein, the term "biological response modifier" refers to lymphokines or interferons.

[0203] The term "inhibitor of Ras oncogenic isoforms" such as H-Ras, K-Ras or N-Ras, as used herein, refers to compounds that target, reduce or inhibit the oncogenic activity of Ras, for example, "farnesyltransferase inhibitors" such as L-744832, DK8G557 or R115777 (Zarnestra™). The term "telomerase inhibitor" as used herein refers to compounds that target, reduce or inhibit the activity of telomerase. Compounds that target, reduce or inhibit the activity of telomerase are in particular compounds that inhibit the telomerase receptor, such as telomestatin.

[0204] The term "methionine aminopeptidase inhibitor" as used herein refers to a compound that targets, reduces or inhibits the activity of methionine peptidase. Compounds that target, reduce or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or its derivatives.

[0205] As used herein, the term "proteasome inhibitor" refers to a compound that targets, decreases, or inhibits the activity of the proteasome. Compounds that target, decrease, or inhibit the activity of the proteasome include, but are not limited to, bortezomib (Velcade™) and MLN 341.

[0206] The term "matrix metalloproteinase inhibitors" or ("MMP" inhibitors) as used herein includes, but is not limited to, collagen peptidomimetic and non-peptidomimetic inhibitors, tetracycline derivatives, such as the hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogs marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

[0207] The term "compounds used in the treatment of hematological malignancies" as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target, decrease or inhibit the activity of FMS-like tyrosine kinase receptor (Flt-3R); interferon, 1-β-D-arabinofuranylcytosine (ara-c) and bisulfan; ALK inhibitors, which are compounds that target, decrease or inhibit anaplastic lymphoma kinase, and Bcl-2 inhibitors.

[0208] Compounds which target, decrease or inhibit the activity of the FLT-3R-like tyrosine kinase receptor are in particular compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248 and MLN518.

[0209] The term "HSP90 inhibitors" as used herein includes, but is not limited to, compounds that target, reduce or inhibit the intrinsic ATPase activity of HSP90 and degrade, target or inhibit HSP90 client proteins via the ubiquitin proteosome pathway. Compounds that target, reduce or inhibit the intrinsic ATPase activity of HSP90 are, in particular, compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG), geldanamycin derivatives; other geldanamycin-related compounds; radicicol and HDAC inhibitors.

[0210] The term "antiproliferative antibody" as used herein includes, but is not limited to, trastuzumab (Herceptin™), trastuzumab-DM1, erbitux, bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40), and 2C4 antibodies. By antibody is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.

[0211] For the treatment of acute myeloid leukemia (AML), the compounds described herein can be used in combination with standard leukemia therapy, particularly in combination with therapy used to treat AML. In particular, the formulations containing compound 1 described herein can be administered in combination with, for example, farnesyltransferase inhibitors and / or other drugs useful for the treatment of AML, such as daunorubicin, Adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatinum and PKC412. In some embodiments, the method of treating AML associated with ITD and / or D835Y mutation can include administering a formulation containing compound 1 described herein together with one or more FLT3 inhibitors. In some embodiments, the FLT3 inhibitor is selected from quizartinib (AC220), staurosporine derivatives (e.g., midostaurin or lestaurtinib), sorafenib, tandutinib, LY-2401401, LS-104, EB-10, famitinib, NOV-110302, NMS-P948, AST-487, G-749, SB-1317, S-209, SC-110219, AKN-028, fedratinib, tozasertib, and sunitinib. In some embodiments, the FLT3 inhibitor is selected from quizartinib, midostaurin, lestaurtinib, sorafenib, and sunitinib.

[0212] Other anti-leukemia compounds include, for example, Ara-C, a pyrimidine analogue, which is a 2'-alpha-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are 6-mercaptopurine (6-MP), a purine analogue of hypoxanthine, and fludarabine phosphate. Compounds that target, decrease or inhibit the activity of histone deacetylase (HDAC) inhibitors, such as sodium butyrate and suberoylanilide hydroxanoic acid (SAHA), inhibit the activity of enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), trichostatin A, and compounds disclosed in US6,552,065, including, but not limited to, N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof, particularly the lactate salt. As used herein, somatostatin receptor antagonist refers to compounds that target, treat, or inhibit somatostatin receptors, such as octreotide and SOM230. A method that damages tumor cells refers to a method such as ionizing radiation. The term "ionizing radiation" referred to above and hereinafter means ionizing radiation that occurs either as electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but is not limited to, radiation therapy, which is known in the art. Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4 th Edition, Vol. 1, pp. 248-275 (1993).

[0213] Also included are EDG binders and ribonucleotide reductase inhibitors. The term "EDG binders" as used herein refers to a class of immunosuppressants that modulate lymphocyte recirculation, such as FTY720. The term "ribonucleotide reductase inhibitors" refers to pyrimidine or purine nucleoside analogs, including but not limited to fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C for ALL) and / or pentostatin. Ribonucleotide reductase inhibitors are in particular hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0214] In particular, compounds, proteins, or monoclonal antibodies of VEGF such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharma- ceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin™; Endostatin™; anthranilamide; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamers, such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, Angiozyme (RPI 4610) and bevacizumab (Avastin™).

[0215] As used herein, photodynamic therapy refers to therapy that uses certain chemicals known as photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include treatment with compounds such as Visudyne™ and porfimer sodium.

[0216] As used herein, angiogenic antisteroids refer to compounds that block or inhibit angiogenesis, such as, for example, anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, and dexamethasone.

[0217] Implants containing corticosteroids refer to compounds such as fluocinolone and dexamethasone.

[0218] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds, or compounds with other or unknown mechanisms of action.

[0219] The formulations comprising compound 1 described herein are also useful as combination therapeutic compounds for use in combination with other drug substances, such as anti-inflammatory, bronchodilatory or antihistamine drug substances, for example, as enhancers of the therapeutic activity of such drugs, or as a means of reducing the required dosage or potential side effects of such drugs, particularly in the treatment of obstructive or inflammatory airway diseases as mentioned herein above. The formulations comprising compound 1 described herein may be mixed with the other drug substances in a given pharmaceutical composition, or may be administered separately before, simultaneously with, or after the other drug substances. Thus, combination formulations can be prepared that comprise compound 1 described herein and anti-inflammatory, bronchodilatory, antihistamine or antitussive drug substances, where the compound described herein and the drug substances are in the same or different pharmaceutical compositions.

[0220] Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate; non-steroidal glucocorticoid receptor agonists; LTB4 antagonists such as LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4 antagonists such as montelukast and zafirlukast; cilomilast (Ariflo® GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), allofilin (Almirall). PDE4 inhibitors such as Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID™ CC-10004 (Celgene), VM554 / UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2a agonists; A2b antagonists; and beta-2 adrenoceptor agonists such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol fenoterol, procaterol, and especially formoterol, and pharma- ceutically acceptable salts thereof. Suitable bronchodilators include anticholinergic or antimuscarinic compounds, in particular ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate.

[0221] Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine.

[0222] Other useful combinations of the compounds described herein with anti-inflammatory agents include, for example, antagonists of chemokine receptors such as CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, and in particular CCR-5 antagonists such as the Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, and Takeda antagonists such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminium chloride (TAK-770).

[0223] The structures of the active compounds, identified by code number, generic name or trade name, can be obtained from the current edition of the standard abstract "The Merck Index" or from databases such as Patents International (eg IMS World Publications).

[0224] Formulations containing compound 1 described herein may be used in combination with known therapeutic processes, such as administration of hormones or radiation. In certain embodiments, provided compounds are used as radiosensitizers, particularly for the treatment of tumors that exhibit insufficient sensitivity to radiation therapy.

[0225] The preparations comprising compound 1 described herein can be administered alone or in combination with one or more other therapeutic compounds, and possible combination therapy is in the form of a fixed combination, or the administration of compound 1 and one or more other therapeutic compounds as a preparation is performed alternately or independently of each other, or the combined administration of a fixed combination with one or more other therapeutic compounds. Compound 1 can be administered in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or combinations thereof, particularly in tumor therapy. In the context of other treatment strategies as mentioned above, long-term therapy is equally possible, as is adjuvant therapy. Other possible treatment methods are therapy to maintain the patient's condition after tumor regression, or even chemopreventive therapy, for example in patients at risk.

[0226] These additional agents may be administered separately from the composition containing the compound of the present invention as part of a multiple dose regimen. Alternatively, these agents may be part of a single dosage form, mixed together with Compound 1 as a single formulation or composition. When administered as part of a multiple dose regimen, the two active agents may be provided simultaneously, sequentially, or within a period of each other (usually within 5 hours of each other).

[0227] As used herein, the terms "combination", "combined" and related terms refer to simultaneous or sequential administration of therapeutic agents according to the present invention. For example, Compound 1 may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or together in a single unit dosage form. Thus, the present invention provides a single unit dosage form that includes Compound 1, an additional therapeutic agent, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle.

[0228] The amounts of both the compounds of the invention and additional therapeutic agents (in compositions containing additional therapeutic agents as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, the compositions should be formulated so that a dosage of 0.01 to 10 mg / kg body weight / day of Compound 1 can be administered.

[0229] In compositions containing an additional therapeutic agent, the additional therapeutic agent and compound 1 may act synergistically. Thus, the amount of the additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions, the additional therapeutic agent may be administered at a dosage of 0.01 to 1,000 μg / kg body weight / day.

[0230] The amount of additional therapeutic agent present in a composition comprising Compound 1 will not be greater than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in a composition of the present disclosure will range from about 50% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0231] Compound 1 and its pharmaceutical compositions may be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices run the risk of clot formation or platelet activation. These undesirable effects can be prevented or mitigated by pre-coating the device with a pharma- ceutical acceptable composition that includes a kinase inhibitor. An implantable device coated with a compound described herein is another embodiment. In some embodiments, the medicament may include at least Compound 1 formulated as described herein.

[0232] Pharmaceutically acceptable compositions The compositions described herein are administered using any amount and any route of administration effective for treating or reducing the severity of the above diseases. The exact amount required will vary from subject to subject depending on the species, age, and general condition of the subject, the severity of the infection, the specific drug, its mode of administration, and the like. Compound 1 is preferably formulated in unit dosage form, e.g., Form C, for ease of administration and uniformity of dosage. The expression "unit dosage form" as used herein refers to a physically discrete unit of drug appropriate for the patient to be treated. However, it will be understood that the total daily usage of the compounds and compositions described herein will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for a particular patient or organism (e.g., cat, dog, cow, horse, pig, or bird) will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination or simultaneously with the specific compound used, and similar factors well known in the medical field.

[0233] The pharma- ceutically acceptable compositions described herein can be administered to humans and other animals orally, rectally, parenterally, intravesically, intrathecally, transdermally, transmucosally, ophthalmically, by inhalation, intravaginally, intraperitoneally, topically (as powders, ointments, or drops), bucally, intranasally, as oral or nasal sprays, etc., depending on the severity of the disease being treated. In certain embodiments, the compounds described herein are administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg, e.g., about 1 mg / kg to about 25 mg / kg of subject body weight, one or more times per day to obtain the desired therapeutic effect.

[0234] The unit dosage forms described herein may be formulated for oral administration. Pharmaceutical compositions / formulations suitable for oral administration may be provided as individual dosage forms, such as, but not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups. In some embodiments, such dosage forms contain a predetermined amount of active ingredient and may be prepared by methods of pharmacy known to those skilled in the art. Remington's Pharmaceutical Sciences, 18 th ed., Mack Publishing, Easton Pa. (1990). As used herein, oral administration also includes buccal, lingual, and sublingual administration.

[0235] In some embodiments, the formulation further comprises one or more pharma- ceutically acceptable excipients or carriers.

[0236] Those of skill in the art will recognize that a pharmaceutical formulation ingredient may serve multiple purposes within a formulation, and therefore, a particular formulation ingredient may be classified according to multiple functions (e.g., an ingredient may be both a filler and a binder).

[0237] In some embodiments, the unit dosage forms provided herein are prepared according to conventional pharmaceutical compounding techniques by combining the active ingredient in an intimate mixture with one or more pharma- ceutically acceptable excipients or carriers, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, dye transfer inhibitors, sweeteners, flavoring agents, emulsifiers, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and carbon dioxide sources. Excipients or carriers can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients or carriers suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and colorants. Examples of excipients or carriers suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants.

[0238] In some embodiments, the active ingredient, such as a solid form of Compound 1 or a pharma- ceutically acceptable salt thereof, is incorporated into the pharmaceutical composition as a spray-dried powder or granules. The use of spray drying to produce powders from fluid feedstocks is well known, with applications ranging from milk powder to bulk chemicals and pharmaceuticals. See U.S. Pat. No. 4,187,617 and Mujumbar et al., 91 Drying, pages 56-73 (1991). The use of spray drying to form solid amorphous dispersions of drugs and concentration-enhancing polymers is also known. See commonly owned European Patent Applications Nos. 0901786, 1027886, 1027887, 1027888, and commonly owned PCT Applications Nos. WO00 / 168092 and WO00 / 168055, each of which is incorporated herein by reference. A typical spray drying apparatus comprises a drying chamber, an atomizing means for atomizing a solvent-containing liquid fed to the drying chamber, a source of heated drying gas directed into the drying chamber, and a dried product collection means for separating the dried product from the cooled drying gas and vaporized solvent stream after it exits the drying chamber. Examples of such apparatus include Niro models PSD-1, PSD-2, and PSD-4 (Niro A / S, Soeborg, Denmark).

[0239] Spray-dried powders or granules generally contain active compounds in combination with polymers, such as concentration-enhancing polymers.One class of polymers suitable for use herein includes non-ionizable (neutral) non-cellulosic polymers.Exemplary polymers include vinyl polymers and copolymers having at least one substituent selected from the group consisting of hydroxyl, alkylacyloxy, and cyclic amide; polyvinyl alcohol having at least a portion of the repeating units in non-hydrolyzed (vinyl acetate) form; polyvinyl alcohol polyvinyl acetate copolymers; polyvinylpyrrolidone; and polyethylene polyvinyl alcohol copolymers; and polyoxyethylene-polyoxypropylene copolymers.

[0240] An exemplary neutral non-cellulosic polymer is composed of a vinyl copolymer of at least one hydrophilic, hydroxyl-containing repeat unit and at least one hydrophobic, alkyl- or aryl-containing repeat unit. Such neutral vinyl copolymers are referred to as "amphiphilic hydroxyl-functional vinyl copolymers". It is believed that amphiphilic hydroxyl-functional vinyl copolymers provide high concentration enhancement because their amphiphilicity provides both sufficient hydrophobic groups to interact with hydrophobic low-solubility drugs and sufficient hydrophilic groups to have sufficient water solubility for good dissolution. The copolymer structure of amphiphilic hydroxyl-functional vinyl copolymers also allows them to adjust their hydrophilicity and hydrophobicity to maximize the performance of certain low-solubility drugs.

[0241] Another class of polymers suitable for use herein includes ionizable non-cellulosic polymers. Exemplary polymers include carboxylic acid functionalized vinyl polymers such as carboxylic acid functionalized polymethacrylates and polyacrylates, such as the EUDRAGIT™ series manufactured by Rohm Tech Inc., Malden, Mass.; amine functionalized polyacrylates and polymethacrylates; proteins such as gelatin and albumin; and carboxylic acid functionalized starches, such as starch glycolate.

[0242] Amphiphilic non-cellulosic polymers are copolymers of relatively hydrophilic and relatively hydrophobic monomers. Examples include acrylate and methacrylate copolymers. Exemplary commercial grades of such copolymers include the EUDRAGIT™ series, which are copolymers of methacrylates and acrylates.

[0243] An additional class of polymers includes ionizable and neutral (or non-ionizable) cellulosic polymers having at least one ester-linked and / or ether-linked substituent, the polymer having a degree of substitution of at least 0.05 for each substituent. Note that in the polymer nomenclature used herein, the ether-linked substituent is described before "cellulose" as a moiety attached to an ether group. For example, "cellulose ethyl benzoate" has an ethoxybenzoic acid substituent. Similarly, the ester-linked substituent is described after "cellulose" as a carboxylate. For example, "cellulose phthalate" has one carboxylic acid of each phthalic acid moiety ester-linked to the polymer and the other carboxylic acid is unreacted.

[0244] It should also be noted that a polymer name such as "cellulose acetate phthalate" (CAP) refers to any of a family of cellulosic polymers that have acetate and phthalate groups attached via ester bonds to the majority of the hydroxyl groups of the cellulosic polymer. In general, the degree of substitution of each substituent can range from 0.05 to 2.9, so long as the other criteria of the polymer are met. "Degree of substitution" refers to the average number of three hydroxyls per saccharide repeat unit on the cellulose chain that is substituted. For example, if all hydroxyls on the cellulose chain are phthalate substituted, the degree of phthalate substitution is 3. Each polymer family type also includes cellulosic polymers to which relatively small amounts of additional substituents have been added that do not substantially change the performance of the polymer.

[0245] Amphiphilic cellulose includes polymers in which the parent cellulosic polymer is substituted with at least one relatively hydrophobic substituent at any or all of the three hydroxyl groups present on each saccharide repeat unit. The hydrophobic substituent can be essentially any substituent that can render the cellulosic polymer essentially water insoluble when substituted to a sufficiently high level or degree of substitution. Examples of hydrophobic substituents include ether-linked alkyl groups such as methyl, ethyl, propyl, butyl, etc.; or ester-linked alkyl groups such as acetate, propionate, butyrate; and ether-linked and / or ester-linked aryl groups such as phenyl, benzoate, or phenylate. The hydrophilic regions of the polymer can be either the portions that are relatively unsubstituted because the unsubstituted hydroxyls themselves are relatively hydrophilic, or the regions that are substituted with hydrophilic substituents. Hydrophilic substituents include ether-linked or ester-linked non-ionizable groups, such as hydroxyalkyl substituents hydroxyethyl, hydroxypropyl, and alkyl ether groups such as ethoxyethoxy or methoxyethoxy. Particularly preferred hydrophilic substituents are those that are ether- or ester-linked ionizable groups, such as carboxylic acids, thiocarboxylic acids, substituted phenoxy groups, amines, phosphates, or sulfonates.

[0246] One class of cellulosic polymers includes neutral polymers, meaning that the polymer is substantially non-ionizable in aqueous solution. Such polymers contain non-ionizable substituents, which may be either ether- or ester-linked. Exemplary ether-linked non-ionizable substituents include alkyl groups such as methyl, ethyl, propyl, butyl, hydroxyalkyl groups such as hydroxymethyl, hydroxyethyl, hydroxypropyl, and aryl groups such as phenyl. Exemplary ester-linked non-ionizable substituents include alkyl groups such as acetate, propionate, butyrate, and aryl groups such as phenylate. However, when aryl groups are included, it may be necessary for the polymer to include a sufficient amount of hydrophilic substituents so that the polymer has at least some aqueous solubility at any of the physiologically relevant pHs from 1 to 8.

[0247] Exemplary non-ionizable cellulosic polymers that can be used as the polymer include hydroxypropyl methylcellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate, and hydroxyethyl ethyl cellulose.

[0248] An exemplary class of neutral cellulosic polymers are those that are amphiphilic, such as hydroxypropyl methylcellulose and hydroxypropyl cellulose acetate, in which cellulose repeat units having a relatively large number of methyl or acetate substituents compared to the unsubstituted hydroxyl or hydroxypropyl substituents constitute hydrophobic regions compared to other repeat units on the polymer.

[0249] A particular class of cellulosic polymers includes polymers that are at least partially ionizable at physiologically relevant pH and contain at least one ionizable substituent that can be either ether- or ester-linked.Exemplary ether-linked ionizable substituents include carboxylic acids, such as acetic acid, propionic acid, benzoic acid, salicylic acid, alkoxybenzoic acids such as ethoxybenzoic acid or propoxybenzoic acid, various isomers of alkoxyphthalic acids such as ethoxyphthalic acid and ethoxyisophthalic acid, various isomers of alkoxynicotinic acids such as ethoxynicotinic acid, and various isomers of picolinic acid such as ethoxypicolinic acid; thiocarboxylic acids such as thioacetic acid; substituted phenoxy groups such as hydroxyphenoxy; amines such as aminoethoxy, diethylaminoethoxy, trimethylaminoethoxy; phosphates such as phosphateethoxy; and sulfonates such as sulfonateethoxy. Exemplary ester-linked ionizable substituents include carboxylic acids, such as succinate, citrate, phthalate, terephthalate, isophthalate, trimellitate, and various isomers of pyridine dicarboxylic acid; thiocarboxylic acids, such as thiosuccinate; substituted phenoxy groups, such as aminosalicylic acid; amines, such as natural or synthetic amino acids, such as alanine or phenylalanine; phosphates, such as acetyl phosphate; and sulfonates, such as acetyl sulfonate.To provide the aromatic substituted polymer with the required water solubility, it is also desirable to attach sufficient hydrophilic groups, such as hydroxypropyl or carboxylic acid functional groups, to the polymer to make it water-soluble, at least at the pH value at which the ionizable group is ionized.In some cases, the aromatic substituent may itself be ionizable, such as a phthalate or trimellitate substituent.

[0250] Exemplary cellulosic polymers that are at least partially ionized at physiologically relevant pH include hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methylcellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxyethyl methylcellulose acetate succinate, hydroxyethyl methylcellulose acetate phthalate, carboxyethyl cellulose, carboxymethyl cellulose, carboxymethyl ethyl cellulose, ethyl carboxymethyl cellulose, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, hydroxypropyl methylcellulose acetate acetate succinate, hydroxypropyl methylcellulose acetate succinate cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate phthalate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitate, methylcellulose acetate trimellitate, ethyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate succinate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridine dicarboxylate, salicylic acid cellulose acetate, hydroxypropyl salicylic acid cellulose acetate, ethyl benzoic acid cellulose acetate, hydroxypropyl ethyl benzoic acid cellulose acetate, ethyl phthalic acid cellulose acetate, ethyl nicotinic acid cellulose acetate, and ethyl picolinic acid cellulose acetate.

[0251] Exemplary cellulosic polymers that meet the definition of amphiphilic, having hydrophilic and hydrophobic regions, include polymers such as cellulose acetate phthalate and cellulose acetate trimellitate, in which cellulose repeat units having one or more acetate substituents are hydrophobic relative to those having no acetate substituents or having one or more ionized phthalate or trimellitate substituents.

[0252] A further subset of cellulosic ionizable polymers are those that have both carboxylic acid functional aromatic and alkylate substituents and are therefore amphiphilic. Exemplary polymers include cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxylpropyl methyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitate, methyl cellulose acetate trimellitate, ethyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxyl cellulose acetate trimellitate, hydroxypropyl ... cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate trimellitate succinate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridine dicarboxylate, cellulose acetate salicylate, hydroxypropyl salicylate cellulose acetate, ethyl benzoate cellulose acetate, hydroxypropyl ethyl benzoate cellulose acetate, ethyl phthalate cellulose acetate, ethyl nicotinate cellulose acetate, and ethyl picolinate cellulose acetate.

[0253] Another subset of ionizable cellulose-based polymers is one that has a non-aromatic carboxylate substituent. Exemplary polymers include hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyethyl methylcellulose acetate succinate, hydroxyethyl methylcellulose acetate succinate, and carboxymethyl ethylcellulose. These cellulose-based polymers that are at least partially ionized at physiologically relevant pH include, for example, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, and carboxymethyl ethylcellulose. In some embodiments, the polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0254] Another class of polymers consists of neutralized acidic polymers. By "neutralized acidic polymer" is meant any acidic polymer in which the majority of the "acidic moieties" or "acidic substituents" are "neutralized", i.e., present in their deprotonated form. By "neutralized acidic cellulosic polymer" is meant any cellulosic "acidic polymer" in which the majority of the "acidic moieties" or "acidic substituents" are "neutralized". By "acidic polymer" is meant any polymer having a significant number of acidic moieties. Generally, a significant number of acidic moieties is about 0.1 milliequivalents of acidic moieties per gram of polymer or more. An "acidic moiety" includes any functional group that is sufficiently acidic that, upon contact with or dissolution in water, it is capable of increasing the hydrogen ion concentration by at least partially donating hydrogen cations to the water. This definition includes any functional group or functional groups having a pK of less than about 10. aThe term "substituent" includes when a functional group is covalently attached to a polymer having the formula: Exemplary classes of functional groups included in the above description include carboxylic acids, thiocarboxylic acids, phosphates, phenolic groups, and sulfonates. Such functional groups may form the primary structure of a polymer such as polyacrylic acid, but are more commonly covalently attached to the backbone of the parent polymer and are therefore referred to as "substituents."

[0255] The amount of concentration-enhancing polymer relative to the amount of drug (compound 1) present in the spray-dried dispersion depends on the drug and the concentration-enhancing polymer, and can vary widely between drug-to-polymer weight ratios of 0.01 to 5. In most cases, however, unless the drug dose is very low, such as 25 mg or less, it is preferred that the drug-to-polymer ratio be greater than 0.05 and less than 2.5, and in many cases, improvements in drug concentration or relative bioavailability are observed at drug-to-polymer ratios of 1 or less, and even 0.2 or less for some drugs. When the drug dose is about 25 mg or less, the drug-to-polymer weight ratio can be significantly less than 0.05. In general, regardless of dose, improvements in drug concentration or relative bioavailability increase as the drug-to-polymer weight ratio decreases. However, because there are practical limits to keeping the total mass of a tablet, capsule, or suspension low, it is often desirable to use a relatively high drug-to-polymer ratio as long as satisfactory results are obtained. The maximum drug:polymer ratio that will give satisfactory results will vary from drug to drug and is best determined by dissolution testing, as described below.

[0256] The spray-dried solid described herein can be a solid dispersion containing the compound described herein and pharma-ceutically acceptable polymer.The specific compounds described herein generally have low water solubility, and their absorption in vivo is limited by dissolution rate.The solid dispersion containing the compound can improve the bioavailability of the compound by increasing the solubility / dissolution of the compound.

[0257] The term "solid dispersion" as used herein refers to a dispersion of a pharma- ceutical active ingredient, such as a compound described herein, in a solid-state inert polymer matrix. A solid dispersion can be prepared by methods well known in the art, such as spray drying or hot melt extrusion. The matrix can be crystalline or amorphous. A solid dispersion contains a co-precipitate of a pharma- ceutical active ingredient with one or more water-soluble polymers, in which the pharma- ceutical active ingredient is uniformly dispersed within the polymer matrix formed from the polymer. The pharma- ceutical active ingredient can be present in an amorphous state, a crystalline dispersion form, or a combination thereof. It can also be finely dispersed or dissolved as a single molecule in the polymer matrix. A solid dispersion is typically prepared by spray drying or hot melt extrusion.

[0258] The method for preparing the solid dispersion includes (i) mixing the compound described herein with a polymer in an organic solvent to provide a feeder solution, and (ii) spray-drying the feeder solution as a fine spray through a nozzle into a chamber, where the solvent evaporates quickly to produce particles containing the compound and the polymer. Following the formation of the solid dispersion, the resulting spray-dried particles may be subjected to a secondary drying step to remove residual solvent. The secondary drying step may be carried out in a static or agitated dryer. Gas, humidified gas, vacuum may be applied to the secondary drying step, which is useful for more quickly removing residual solvent remaining in the spray-dried particles.

[0259] Any organic solvent may be used as long as it can easily dissolve or disperse the above-mentioned compounds and polymers. Examples of organic solvents include low carbon number alcohols such as methanol, ethanol, propanol, and isopropanol; ketones such as methyl ethyl ketone and butanone; and combinations thereof.

[0260] In some embodiments, the pharma- ceutically acceptable excipients and carriers are selected from fillers, binders, diluents, disintegrants, glidants, and lubricants.

[0261] In some embodiments, a capsule or tablet may contain the provided pharmaceutical composition in the form of a solid dosage form. In some embodiments, the composition may be in a capsule. In some embodiments, the composition may be in a tablet.

[0262] In certain embodiments, the dosage form is a tablet, and the tablet is manufactured using standard tablet processing procedures and equipment recognized in the art. In certain embodiments, the method of forming the tablet is direct compression of a powdered, crystalline and / or granular composition that includes the solid form provided herein alone or in combination with one or more excipients or carriers, such as carriers, additives, polymers, etc. In certain embodiments, instead of direct compression, the tablet may be prepared using a wet granulation or dry granulation process. In certain embodiments, the tablet is formed, rather than compressed, starting from a moist or otherwise easy-to-handle material. In certain embodiments, compression and granulation techniques are used.

[0263] In certain embodiments, the dosage form is a capsule, and the capsule may be manufactured using standard capsule processing procedures and equipment recognized in the art. In certain embodiments, soft gelatin capsules may be prepared, in which the capsule contains a mixture comprising the solid forms provided herein and a vegetable oil or a non-aqueous water-miscible material, such as, for example, polyethylene glycol. In certain embodiments, hard gelatin capsules may be prepared, containing granules of the solid forms provided herein in combination with a solid powdered carrier, such as, for example, lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives, or gelatin. In certain embodiments, hard gelatin capsule shells may be prepared from capsule compositions comprising gelatin and small amounts of plasticizers, such as glycerol. In certain embodiments, the capsule shells may be made from carbohydrate materials instead of gelatin. In certain embodiments, the capsule compositions may further comprise polymers, colorants, flavorings, and opacifiers, as required. In certain embodiments, the capsules comprise HPMC.

[0264] In some embodiments, the pharmaceutical composition comprises one or more fillers. In certain embodiments, the filler is selected from ammonium alginate, calcium carbonate, calcium lactate, calcium phosphate, calcium silicate, calcium sulfate, cellulose acetate, compressible sugars (e.g., lactose, glucose, and sucrose), corn starch, dextrates, erythritol, ethylcellulose, glyceryl palmitostearate, isomalt, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, medium chain triglycerides, microcrystalline cellulose, pregelatinized starch, polydextrose, polymethacrylate, silicic acid, simethicone, sodium alginate, sodium chloride, sorbitol, starch, sugar spheres, sulfobutyl ether beta-cyclodextrin, talc, tragacanth, trehalose, and xylitol, or combinations thereof.

[0265] In some embodiments, the filler is selected from talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrate, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0266] In some embodiments, the filler is microcrystalline cellulose. In some embodiments, the filler is lactose. In some embodiments, the filler is starch. In some embodiments, the filler is a combination of starch and lactose. In some embodiments, the filler is a combination of lactose and microcrystalline cellulose. In some embodiments, the filler is a combination of two or three of the above components. In some embodiments, the filler comprises at least microcrystalline cellulose, lactose, and mannitol.

[0267] In certain embodiments, the dosage forms provided herein include one or more diluents. Diluents can be used, for example, to increase the volume so that a tablet or capsule of practical size is finally obtained. Suitable diluents include, among others, dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, microcrystalline cellulose (e.g., AVICEL), microfine cellulose, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrate, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylate (e.g., EUDRAGIT), potassium chloride, sodium chloride, sorbitol, and talc. Diluents also include, for example, ammonium alginate, calcium carbonate, calcium phosphate, calcium sulfate, cellulose acetate, compressible sugar, powdered sugar, dextrate, dextrin, dextrose, erythritol, ethylcellulose, fructose, fumaric acid, glyceryl palmitostearate, isomalt, kaolin, lacitol, lactose, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, polydextrose, polymethylacrylate, simethicone, sodium alginate, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, sulfobutylether-β-cyclodextrin, talc, tragacanth, trehalose, and xylitol.

[0268] In some embodiments, the pharmaceutical composition includes one or more binders. Binders can be used, for example, to provide cohesion to tablets or capsules, ensuring that the formulation remains intact after compression. In some embodiments, the binder is selected from the group consisting of acacia gum, agar, alginic acid, calcium carbonate, calcium lactate, carbomer (e.g., acrylic acid polymers, carboxypolymethylene, polyacrylic acid, carboxyvinyl polymers), sodium carboxymethylcellulose, carrageenan, cellulose acetate phthalate, ceratonia, chitosan, copovidone, corn starch, cottonseed oil, dextrates, dextrin, dextrose, ethylcellulose, gelatin, glyceryl behenate, guar gum, hydrogenated vegetable oil type I, hydroxyethylcellulose ... The polysaccharide extract is selected from methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hypromellose, inulin, lactose, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, microcrystalline cellulose, pectin, poloxamer, polycarbohyl, polydextrose, polyethylene oxide, polymethacrylate, polyvinylpyrrolidone, pregelatinized starch, povidone, sodium alginate, starch, stearic acid, sucrose, tricaprylin, vitamin E polyethylene glycol succinate, and zein.

[0269] Suitable binders include, but are not limited to, starches (including potato starch, corn starch, and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, and lactose), polyethylene glycol, propylene glycol, waxes, and natural and synthetic gums such as acacia, sodium alginate, polyvinylpyrrolidone (PVP), cellulosic polymers (including hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), methylcellulose, ethylcellulose, hydroxyethylcellulose (HEC), carboxymethylcellulose, and the like), veegum, carbomers (e.g., Carbopol), sodium, dextrin, guar gum, hydrogenated vegetable oils, magnesium aluminum silicate, maltodextrin, polymethacrylates, povidone (e.g., KOLLIDON, PLASDONE), microcrystalline cellulose, among others. Binders also include, for example, acacia, agar, alginic acid, cabomer, carrageenan, cellulose acetate phthalate, ceratonia, chitosan, powdered sugar, copovidone, dextrate, dextrin, dextrose, ethylcellulose, gelatin, glyceryl behenate, guar gum, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylstarch, hypromellose, inulin, lactose, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethylacrylate, povidone, sodium alginate, sodium carboxymethylcellulose, starch, pregelatinized starch, stearic acid, sucrose, and zein.

[0270] Suitable forms of microcrystalline cellulose include, but are not limited to, materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (FMC Corporation, Marcus Hook, Pa.), and mixtures thereof. In some embodiments, a specific binder is a mixture of microcrystalline cellulose sold as AVICEL RC-581 and sodium carboxymethylcellulose. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103™ and Starch 1500 LM.

[0271] In some embodiments, the pharmaceutical composition comprises one or more disintegrants. In certain embodiments, the disintegrants are selected from alginic acid, calcium alginate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, cellulose, chitosan, colloidal silicon dioxide, corn starch, croscarmellose sodium, crospovidone, docusate sodium, glycine, guar gum, hydroxypropylcellulose, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, pregelatinized starch, polacrilin potassium, povidone, silicates, sodium alginate, sodium carbonate, and sodium starch glycolate.

[0272] Suitable disintegrants include, but are not limited to, agar-agar; bentonite; celluloses such as methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins; alginic acid; gums such as guar gum and Veegum HV; citrus pulp; crosslinked celluloses such as croscarmelose; crosslinked polymers such as crospovidone; crosslinked starches; calcium carbonate; microcrystalline celluloses such as sodium starch glycolate; polacrilin potassium; starches such as corn starch, potato starch, tapioca starch, and pregelatinized starch; clays; algins; and mixtures thereof.

[0273] In some embodiments, the pharmaceutical composition comprises one or more surfactants, hi some embodiments, the surfactants are selected from polyoxyethylene (20) sorbitan monolaurate (e.g., Tween-20), polyoxyethylene (20) sorbitan monooleate (e.g., Tween-80), sodium lauryl sulfate, and sodium dodecyl sulfate.

[0274] In some embodiments, the pharmaceutical composition comprises one or more pore-forming agents. In some embodiments, the pore-forming agent is selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, poloaxamer 188, povidone (e.g., Kollidon K25 / K30), or sugar (e.g., glucose, mannose, fructose, and sucrose).

[0275] In some embodiments, the pharmaceutical composition comprises one or more glidants. In some embodiments, the glidant is selected from calcium phosphate, cellulose, colloidal silicon dioxide, fumed silica, magnesium oxide, magnesium silicate, magnesium stearate, magnesium trisilicate, and talc. Suitable glidants include, but are not limited to, colloidal silicon dioxide, CAB-O-SIL™ (Cabot Co., Boston, MA), and asbestos-free talc.

[0276] In some embodiments, the pharmaceutical composition comprises one or more lubricants, hi some embodiments, the lubricant is selected from calcium stearate, glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, myristic acid, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulfate, sodium stearyl fumarate, solid polyethylene glycol, stearic acid, and talc.

[0277] Lubricants that may be used in pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, for example, syloid silica gel (AEROSIL 200, manufactured by W. R. Grace Co., Baltimore, Md.), coagulated aerosol of synthetic silica (marketed by Degussa Co., Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co., Boston, Mass.), and mixtures thereof.

[0278] In some embodiments, the pharmaceutical composition comprises one or more film coating agents. In some embodiments, the film coating comprises a poly(vinyl alcohol) base. In some embodiments, the film coating comprises a colorant or pigment. In some embodiments, the film coating is Opadry II®, such as Opadry II® yellow.

[0279] Suitable coloring agents include, but are not limited to, any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof. A color lake is a combination of a water soluble dye adsorbed onto a hydrous oxide of a heavy metal resulting in an insoluble form of the dye.

[0280] Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate.

[0281] Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame.

[0282] Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate (Tween-20), polyoxyethylene sorbitan 80 monooleate (Tween-80), and triethanolamine oleate.

[0283] Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.

[0284] Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic acid, sodium benzoate, and alcohol.

[0285] Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.

[0286] Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup.

[0287] Suitable non-aqueous liquids utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil.

[0288] Suitable organic acids include, but are not limited to, citric acid and tartaric acid.

[0289] Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.

[0290] The pharmaceutical compositions for oral administration provided herein may be provided as compressed tablets, tablet triturates, chewable lozenges, fast dissolving tablets, multiple compressed tablets, or enteric coated tablets, sugar coated tablets, or film coated tablets. Enteric coated tablets are compressed tablets coated with a substance that resists the action of stomach acid but protects the active ingredient from the acidic environment of the stomach as it dissolves or disintegrates in the intestine. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylates, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar coated tablets are compressed tablets that are encased in a sugar coating that may help to mask unpleasant tastes or odors and protect the tablet from oxidation. Film coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings impart the same general properties as sugar coatings. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets and press- or dry-coated tablets.

[0291] Tablet dosage forms may be prepared from the active ingredient in powdered, crystalline, or granular form, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents, and / or colorants.

[0292] The tablets of the present disclosure may be formulated for immediate, sustained, extended, or modified release.

[0293] In some embodiments, the unit dosage form comprises one or more pharma- ceutically acceptable excipients selected from microcrystalline cellulose, lactose monohydrate (modified), croscarmellose sodium, hydroxypropyl cellulose, and magnesium stearate.

[0294] Liquid dosage forms for oral administration include, but are not limited to, pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. Liquid dosage forms may contain, in addition to the active compound, inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and aromatic agents.

[0295] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution (USP), and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0296] The injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0297] In order to prolong the effect of the compounds described herein, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound thus depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0298] Compositions for rectal or vaginal administration are preferably suppositories which may be prepared by mixing a compound described herein with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol, or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectal or vaginal cavity releasing the active compound.

[0299] The active compound may also be in microencapsulated form with one or more excipients as described above. The solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. According to normal practice, such dosage forms may also contain additional substances other than inert diluents, for example, tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents, and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes.

[0300] Dosage forms for topical or transdermal administration of the compounds described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharma- ceutically acceptable carrier and, if necessary, with any necessary preservatives or buffers. Ophthalmic preparations, ear drops, and eye drops can also be prepared. In addition, transdermal patches can be used, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0301] In some embodiments, the compositions described herein may include a prodrug of Compound 1. As used herein, the term "prodrug" means a compound that is convertible in vivo by metabolic means (e.g., hydrolysis) to the compound. Various general forms of prodrugs are known in the art, such as those described in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed.). Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, 9 9=., Journal of Drug Delivery Reviews, 8:1-38 (1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); and Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975), each of which is incorporated herein by reference in its entirety.

[0302] For oral administration in the form of tablets or capsules (e.g., gelatin capsules), the active drug components can be combined with oral non-toxic pharma- ceutically acceptable inert carriers, such as ethanol, glycerol, water, etc. Furthermore, if desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone, natural sugars, such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums, such as acacia, tragacanth, or sodium alginate, polyethylene glycol, wax, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, silica, talc, stearic acid, its magnesium or calcium salts, and / or polyethylene glycol, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, starch, agar, alginic acid or its sodium salt, or effervescent mixture, croscarmellose or its sodium salt, etc. Diluents include, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine.

[0303] Tablets contain the active ingredient in a mixture with non-toxic pharma- ceutically acceptable excipients suitable for tablet manufacture.These excipients can be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch, or alginic acid; binders such as starch, gelatin, or acacia, and lubricants such as magnesium stearate, stearic acid, or talc.Tablets can be uncoated or can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time.

[0304] The therapeutically effective dose of the compounds described herein in oral formulations may vary from 0.15 mg / kg to 20 mg / kg of patient body weight per day, more specifically 0.015 to 1.0 mg / kg, and may be administered in one or multiple doses per day. For oral administration, the drug may be delivered in the form of a tablet or capsule containing 1 mg to 100 mg, specifically 1 mg, 5 mg, 10 mg, 20 mg, 50 mg, or 100 mg of active ingredient, or at least 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50% (w / w) of active ingredient. For example, a capsule may contain 50 mg of active ingredient, or 5 to 10% (w / w) of active ingredient. For example, a tablet may contain 100 mg of active ingredient, or 20 to 50% (w / w) of active ingredient. For example, tablets may contain, in addition to the active ingredient, disintegrants or emollients (e.g., croscarmellose or its sodium salt and methylcellulose), diluents (e.g., microcrystalline cellulose), and lubricants (e.g., sodium stearate and magnesium stearate). Drugs may be administered daily, either once, twice or more times a day.

[0305] For administration by inhalation, the compounds can be delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, such as a gas like carbon dioxide, or a nebulizer.

[0306] For transmucosal or transdermal administration, a penetrant appropriate for the barrier to be permeated is used in the formulation. Such penetrants are widely known in the art and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be achieved through the use of nasal sprays or suppositories. For transdermal administration, the active compound is formulated into an ointment, salve, gel, or cream, as is widely known in the art. Penetration enhancers promote the penetration of drugs through the corneal barrier and alter the integrity of the epithelial cell layer. Penetration enhancers frequently used in ophthalmic formulations include cyclodextrin, dimethyl sulfoxide (DMSO), ethylenediaminetetraacetic acid (EDTA), sodium glycocholate and related cholates, Tween 20 (nonionic polysorbate surfactant), Brij 35 (polyoxyethylene lauryl ether), saponin, and bile salts. In general, penetration enhancers such as EDTA and cholates temporarily loosen the tight junctions between adjacent cells of the corneal epithelium. Thus, permeation enhancers when applied topically to the eye have been successfully applied to the delivery of proteins and peptides across the corneal epithelium. In some embodiments, the formulations described herein include a penetration enhancer such as polyoxyethylene-9-lauryl ether, sodium deoxycholate, sodium glycocholate, or sodium taurocholate.

[0307] Parenteral formulations containing the compounds described herein can be prepared as isotonic aqueous solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. The preparations may be sterilized and / or contain adjuvants such as preservatives, stabilizing agents, wetting agents or emulsifying agents, dissolution promoters, salts for regulating osmotic pressure and / or buffers. In addition, they may contain other therapeutically valuable substances. The compositions are prepared according to conventional methods and may contain about 0.1-75%, preferably about 1-50%, of the compounds described herein.

[0308] The phrases "parenteral administration" and "administered parenterally" are art-recognized terms and include modes of administration other than enteral and topical administration, such as by injection, including, but not limited to, intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0309] Formulations for topical administration to the skin can include, for example, ointments, creams, gels, and pastes that contain the primary amine compound in a pharma- ceutically acceptable carrier. Formulations of the primary amine compound for topical use include the preparation of oily or water-soluble ointment bases, as is well known to those skilled in the art. For example, these formulations can include vegetable oils, animal fats, and semi-solid hydrocarbons obtained, for example, from petroleum. Specific ingredients used can include white ointment, yellow ointment, cetyl esters wax, oleic acid, olive oil, paraffin, petrolatum, white petrolatum, spermaceti, starch glycerite, white wax, yellow wax, lanolin, anhydrous lanolin, and glyceryl monostearate. A variety of water-soluble ointment bases can also be used, including glycol ethers and derivatives, polyethylene glycol, polyoxyl 40 stearate, and polysorbates.

[0310] Formulations for topical administration may contain the compounds used in the present application in the range of 0.001-10%, 0.05-10%, 0.1-10%, 0.2-10%, 0.5-10%, 1-10%, 2-10%, 3-10%, 4-10%, 5-10%, or 7-10% (weight / volume), or in the range of 0.001-2.0%, 0.001-1.5%, or 0.001-1.0% (weight / volume), or in the range of 0.05-2.0%, 0. The compound may be contained in a concentration ranging from 0.05 to 1.5%, or 0.05 to 1.0% (weight / volume), or from 0.1 to 5.0%, 0.1 to 2.0%, 0.1 to 1.5%, or 0.1 to 1.0% (weight / volume), or from 0.5 to 5.0%, 0.5 to 2.0%, 0.5 to 1.5%, or 0.5 to 1.0% (weight / volume), or from 1 to 5.0%, 1 to 2.0%, or 1 to 1.5% (weight / volume). Formulations for topical administration may also contain the compounds used in the present application in concentrations ranging from 0.001-2.5%, 0.01-2.5%, 0.05-2.0%, 0.1-2.0%, 0.2-2.0%, 0.5-2.0%, or 1-2.0% (weight / weight), or from 0.001-2.0%, 0.001-1.5%, 0.001-1.0%, or 0.001-5% (weight / weight).

[0311] In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered systemically. In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered orally as part of a solid pharmaceutical composition. In some embodiments, the pharmaceutical composition is a liquid. In some embodiments, the pharmaceutical composition is administered as a liquid via a nasogastric tube.

[0312] In some embodiments, the compound or its pharmaceutically acceptable salt is administered once, twice, three times, or four times a day. In some embodiments, the compound or its pharmaceutically acceptable salt is administered twice a day. In some embodiments, the dose of the compound or its pharmaceutically acceptable salt is about 1 mg BID (i.e., twice a day) to about 20 mg BID.

[0313] In some embodiments, the pharmaceutical composition is administered in one or more divided doses daily. In some embodiments, the composition is administered once a day (qua diem, QD). In some embodiments, the composition is administered twice a day (bis in die, BID). In some embodiments, the composition is administered three times a day (ter in die, TID). In some embodiments, the composition is administered four times a day (quater in die, QID). In some embodiments, the composition is administered every four hours (quaque four hours, q4h).

[0314] In some embodiments, the solid form of Compound 1 is substantially amorphous or crystalline, or a mixture thereof. In some embodiments, the solid form is substantially free of impurities.

[0315] In certain embodiments, Compound 1 is a crystalline solid. In some embodiments, Compound 1 is a crystalline solid and is substantially free of amorphous Compound 1. As used herein, the term "substantially free of amorphous Compound 1" means that the compound does not contain a significant amount of amorphous Compound 1. In some embodiments, at least about 95% by weight of crystalline Compound 1 is present. In still other embodiments, at least about 99% by weight of crystalline Compound 1 is present.

[0316] The compound may be formulated as an SDD formulation. As used herein, "SDD" refers to a pharmaceutical formulation (e.g., of Compound 1 or a pharma- ceutically acceptable salt thereof) that is a spray-dried formulation. In some embodiments, the formulation comprises a compound of the present disclosure (e.g., Compound 1 or a pharma- ceutically acceptable salt thereof) and hypromellose acetate succinate (HPMCAS). In one embodiment, the HMPCAS is HPMCAS-M, where "M" indicates (acetyl content 7.0%-11.0%, succinoyl content 10%-14%). The use of spray drying to produce powders from fluid feedstocks is well known, with applications ranging from milk powder to bulk chemicals and pharmaceuticals. See U.S. Pat. No. 4,187,617 and Mujumbar et al., 91 Drying, pages 56-73 (1991). The use of spray drying to form solid amorphous dispersions of drugs and concentration-enhancing polymers is also known. See European Patent Application Nos. 0901786, 1027886, 1027887, 1027888, and PCT Application Nos. WO00 / 168092 and WO00 / 168055, each of which is incorporated herein by reference. A typical spray drying apparatus comprises a drying chamber, an atomizing means for atomizing the solvent-containing liquid fed into the drying chamber, a source of heated drying gas directed into the drying chamber, and a dried product collecting means for separating the dried product from the cooled drying gas and the vaporized solvent stream after exiting the drying chamber. Examples of such apparatus include Niro models PSD-1, PSD-2, and PSD-4 (Niro A / S, Soeborg, Denmark).

[0317] As used herein, "TPGS" or "vitamin E TPGS" as a descriptor for a pharmaceutical formulation of a compound of the present disclosure refers to a pharmaceutical formulation (e.g., of compound 1 or a pharma- ceutically acceptable salt thereof) that includes the following components: (a) an active compound (e.g., compound 1 or a pharma- ceutically acceptable salt thereof), (b) one or more diluents (e.g., microcrystalline cellulose), (c) one or more solubilizers (e.g., D-α-tocopherol polyethylene glycol succinate [vitamin E TPGS]), and (d) one or more binders (e.g., povidone). The formulation may be prepared using a granulation process (e.g., wet granulation). As used herein, "granulation" refers to a process that produces larger or smaller granules or particles of a substance or mixture of substances. This process may also remove fine granules and improve flowability within the formulation. Both wet granulation and / or dry granulation may be used. Dry granulation is achieved using only a combination of granules without the need for a liquid thereon. Slugging uses a tablet press to form large tablets of variable weight due to the poor flowability of the formulation. The resulting slugs are then run through a granulator to break them into granules, which are then compressed again to produce the final granular product.

[0318] All publications, patents, patent applications, and other documents cited in this application are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, or other document was individually indicated to be incorporated by reference for all purposes.

[0319] All features of each aspect of the invention apply mutatis mutandis to all other aspects.

[0320] In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner. EXAMPLES

[0321] As shown in the Examples below, in certain exemplary embodiments, compounds are prepared according to the general procedures below. Although the general methods show the synthesis of specific compounds described herein, it will be understood that the general methods below, as well as other methods known to those of skill in the art, can be applied to all compounds described herein, and each subclass and species of these compounds.

[0322] Example 1: Polymorph Screening The as-received materials used to initiate the polymorph screening are summarized in Table 1. [Table 1]

[0323] Eight materials were discovered during screening and designated materials / forms C through J (Figures 2 and 3). Important information about each material is summarized in Table 13 and described in detail above.

[0324] Of the forms discovered during screening, two were confirmed to be anhydrous / nonsolvated: Form C and Material D. Form A and Form J are hydrated. All other named materials were only observed in solvated, disordered, or mixtures.

[0325] Early in the study, slurries were prepared for stable form screening at RT (Table 5, below). In these experiments, the solids of an unprocessed mixture of Form A plus traces of material B were combined with a given solvent system at a solid loading that allowed for undissolved solids to remain, and the mixture was stirred at ambient conditions. After two days, the slurries were observed to change color to shades of green, blue, or gray, which was considered an indication of light sensitivity of either the API or impurities present in the unprocessed material. At that point, two slurries were selected for isolation to confirm the solid form and chemical composition, and the remaining slurries were covered in foil as a precaution. The slurry in THF, observed as a green suspension (darker than many of the other slurries), caused conversion to a new crystalline form designated Form C. The other isolated slurry from 80:20 acetone / water produced Form A as a single phase. Proton NMR spectra of both materials were consistent with the chemical structure of Compound 1 and indicated that the color change did not correspond to significant degradation of the API solid (Table 2). [Table 2-1] [Table 2-2] [Table 2-3]

[0326] Based on these results, the remaining RT slurries were allowed to stir for approximately 2 weeks (Table 5). Additional slurries were also prepared at elevated temperatures (approximately 60°C and approximately 80°C) and subambient temperatures (2-8°C). The elevated temperature slurries were stirred for a much shorter period to avoid possible decomposition upon prolonged heating. No significant color change was observed for these slurries, likely because they were protected from light throughout the period. All slurries performed in organic solvents at all temperatures resulted in complete conversion to Form C, indicating that it is likely the most stable anhydrous / nonsolvated form between 2°C and 80°C. Slurries in aqueous / organic mixtures with water activity (aw) 0.82 or greater resulted in Form A (hydrate) at RT and 2-8°C, while those with aw 0.69 or less resulted in complete or partial conversion to Form C. This suggests that the critical water activity between these forms is between 0.69 and 0.82 at RT.

[0327] Polymorph screening using more kinetically controlled techniques yielded a variety of new materials (Table 6, below). The specific conditions that yielded a given form are described and tabulated below. Overall, the results indicate that compound 1 tends to exist in a variety of solid forms, particularly as a solvate or hydrate.

[0328] Attempts to prepare amorphous material by melting / quenching or rotary evaporation from chloroform were unsuccessful (Table 7).

[0329] Thus, the amorphous material was not produced in sufficient quantities to be used as an alternative starting material for polymorph screening. However, cycling DSC experiments successfully melted and quenched the solid without crystallization, allowing the observation of a glass transition event at 110° C., as described in more detail below (Table 2). This experiment also allowed the discovery of a new metastable anhydrous / nonsolvated form of material D, which crystallized when the amorphous material was heated above 160° C. (FIG. 15).

[0330] Selected materials were stressed at approximately 90% RH, slurried in an appropriate solvent system, desolvated by heating, and reproduced for further studies or competitively slurried at conditions of interest (Tables 8-12). These results are described in detail below.

[0331] Description of named materials and known forms of Compound 1: Form A: Form A is a hydrate (up to 3 moles of water) of compound 1 that was obtained from numerous form screening experiments, particularly those at water activity conditions of 0.82 or higher. Three samples containing form A were utilized for various characterization techniques: untreated form A + traces of material B, form A from a slurry in 80:20 acetone / water, and form A stressed at approximately 90% RH (Table 2).

[0332] Characterization was performed by XRPD, OM, proton NMR, DSC, TGA, DVS, and KF (Table 2). By optical microscopy, the material was observed to consist of birefringent granules and aggregates.

[0333] The XRPD pattern for Lot 5 is shown in Figure 4 (top). The pattern was not indexable and was determined to consist of a mixture of primarily Form A with trace amounts of material B components due to the observation of Form A as a single phase from the slurry experiment. A comparison of the XRPD patterns shown in Figure 4 indicates additional peaks attributable to material B, indicated by blue asterisks.

[0334] The XRPD pattern for Form A as a single phase, obtained by slurrying the untreated mixture in acetone / water 80:20 (aw 0.82) for 2 days, was successfully indexed (Figure 5). The unit cell volume obtained from the indexing solution could accommodate compound 1 with up to 3 moles of water based on molecular size.

[0335] Proton NMR spectra were obtained for the untreated mixture and for Form A as a single phase in deuterated DMSO. Both spectra were consistent with the chemical structure of Compound 1 and showed a trace amount of an unknown impurity at 1.2 ppm (which was observed in both spectra and therefore is likely not due to material B). Traces of residual acetone were present in the Form A spectrum.

[0336] DSC and TGA thermograms for the untreated mixture and Form A as a single phase are shown in Figures 6 and 7, respectively. Both data sets show a large weight loss step by TGA, corresponding to a broad endotherm by DSC to approximately 140°C, consistent with dehydration. The magnitude of the weight loss step shows a large variability between samples. This is likely due to the presence of residual solvent in the produced Form A material. The small melting endotherm at 0°C in the DSC thermogram of Form A confirms the presence of residual (unbound) water in the sample. The 6.3% weight loss observed in the mixture of Form A + traces of material B corresponds to 1.7 moles of water, assuming water is the only volatile. For the mixture of Form A + traces of material B, an exotherm is noticeable immediately after the dehydration endotherm, likely indicating crystallization to the dehydrated form. A similar crystallization event may have occurred for the Form A sample, but the exothermic component is likely buried in a larger endothermic event corresponding to the loss of a larger amount of water. The dehydrated crystalline material in both thermograms shows a melting endotherm at 242-244°C (onset).

[0337] Based on the thermal data, a sample of Form A was dehydrated by heating to 150° C. by TGA, the solid was collected and analyzed by XRPD (Table 10). Complete conversion to Form C (anhydrous / nonsolvated stable form) was observed.

[0338] The DVS isotherm of the untreated mixture is shown in Figure 8. This material exhibited significant hygroscopicity, with a water uptake of 4.6 wt% (equivalent to 1.2 moles of water) between 5% and 95% RH. Nearly all of the sorbed water was lost upon desorption between RH 95% and 5%, with less than 0.7 wt% being retained. XRPD of the solid after DVS was consistent with a mixture of Form A and traces of Material B.

[0339] Three samples containing Form A were analyzed by Karl Fischer for comparison of water content (Table 2). An untreated mixture of Form A plus traces of material B contained 1.6 moles of water. A sample of Form A from a slurry experiment (previously found by DSC and TGA to contain significant residual solvent, but analyzed by KF approximately one month later) contained 3.4 moles of water. A sample of Form A equilibrated at approximately 90% RH for 6 days (still consisting of Form A by XRPD, Table 8 below) contained 2.0 moles of water. The latter value is believed to be the best representative of the true bound water content, indicating a dihydrate at approximately 90% RH. As the DVS isotherm shows, the water content is variable and dependent on the ambient RH. Form A likely contains 3 moles or less of water based on the unit cell volume and the sum of weight loss by TGA (1.7 moles) and sorption by DVS (1.2 moles).

[0340] The critical water activity between Form A and Form C (anhydrous / non-solvated) is believed to be between 0.69 and 0.82 at RT, as described in more detail below.

[0341] Material B: Material B is a trace crystalline impurity of unknown composition observed in unprocessed Lot 5 as a mixture with Form A. This material was not observed in the XRPD patterns of any of the stable forms or polymorph screening experiments. This material did not occur as a single phase and therefore could not be further characterized. The XRPD overlay in Figure 4 shows peaks attributed to Material B. An insoluble impurity was observed when using the unprocessed lot to determine a solubility estimate that may correspond to Material B, but additional testing will be required to confirm this (Table 4 below).

[0342] Form C: Form C consists of anhydrous / nonsolvated Compound 1 and is a nonsolvated form that is likely stable between 2° C. and 80° C. Form C was obtained from slurries of all stable forms screened in organic solvent systems between 2° C. and 80° C., slurries in aqueous mixtures at RT with aw ≦0.69, as well as numerous polymorph screening and desolvation / dehydration experiments (Tables 5, 6, 7, and 10). Details of the slurry procedure selected to convert Form A+trace amounts of material B to Form C are disclosed therein. A single crystal structure of Form C was obtained and this form was further characterized by XRPD indexing, proton NMR, DSC, TGA, and DVS (Table 2).

[0343] Single crystals of Form C were obtained from a slurry experiment in MEK at about 60 °C (Table 5). The crystal system is monoclinic and the space group is P21. The cell parameters and calculated volume are: a = 12.46390(16) Å, b = 15.55789(14) Å, c = 12.69650(15) Å, α = 90°, β = 110.2065(14)°, γ = 90°, V = 2310.47(5) Å3. The molecular weight is 460.50 g mol-1 with Z = 4 and the calculated density is 1.324 g cm -3 Further details of the crystal data and crystallographic data collection parameters are summarized in Table 3. [Table 3] [Table 4] [Table 5-1] [Table 5-2] [Table 6-1] [Table 6-2] [Table 7] [Table 8] [Table 9]

[0344] The quality of the obtained structure is high, as indicated by the fit residual R of 0.0445 (4.45%). R factors in the range of 2%-6% are estimated to be the most confidently determined structures. The atomic displacement ellipsoid diagram of Form C is shown in Figure 9. The asymmetric unit shown in Figure 9 contains two molecules of compound 1. The XRPD pattern was calculated from the SCXRD data and is in good agreement with the experimentally measured pattern (Figure 10).

[0345] The XRPD pattern of Form C was successfully indexed (FIG. 11). The unit cell parameters are in good agreement with those obtained by SCXRD and are consistent with the anhydrous / nonsolvated form of Compound 1.

[0346] The proton NMR spectrum of Form C was consistent with the chemical structure of Compound 1 with no detectable organic solvent (Table 2).

[0347] The DSC and TGA thermograms are shown in Figure 12. Negligible weight loss was observed up to 300°C, which is consistent with an anhydrous / nonsolvated material. The sharp endotherm at 245°C (onset) likely corresponds to melting.

[0348] The DVS isotherm for Form C is shown in Figure 13 (Table 2). Limited hygroscopicity was observed with this material sorbing 1.75% water (equivalent to approximately 0.5 moles) between 5% and 95% RH. All of this weight was lost upon desorption without hysteresis. The XRPD of the material after DVS was consistent with Form C.

[0349] The single crystal structure of Form C showed an anhydrous form containing void spaces (shown as yellow spaces in FIG. 14) throughout the structure. These void spaces are large enough to accommodate up to 0.5 moles of water, with the amount of water sorbed depending on the surrounding relative humidity. The lack of hysteresis in the DVS isotherm suggests that this material equilibrates quickly and that water can easily enter and exit.

[0350] To further study the behavior at high RH, a sample of Form C was stressed at approximately 90% RH for 11 days (Table 8). The XRPD of the resulting solid was consistent with Form C, confirming that no morphological change occurred upon water sorption over this period. However, since a crystalline hydrate has been found to exist at conditions above a water activity of 0.82 (i.e., RH above 82%), Form C is expected to convert to a hydrated Form A upon longer exposure to water activity conditions above the critical aw.

[0351] Slurries of Form C at high water activity conditions and interconverted slurries containing Form C are described below with respect to the relative thermodynamic stability of the forms.

[0352] Material D: Material D consists of an anhydrous / nonsolvated form of Compound 1 that is metastable at RT and 2-8°C. This material was obtained from a cycling DSC experiment starting from Form C (Figure 15, Table 2). This experiment was first performed to target the amorphous material for observation of the glass transition event. In this experiment, the solid was heated above the melting point (observed as a sharp endotherm with an onset of 245°C in the first step), then cooled back to -25°C in a second step, and reheated in a third step. The final heating step likely showed a glass transition at 110°C, followed by a crystallization exotherm at 171°C (presumably to Material D) and melting at 238°C (onset).

[0353] Based on this data, a sample of Form C was heated by TGA above its melting point (to 270° C.), quenched to 40° C., and then reheated to 200° C. (Table 10). [Table 10]

[0354] The solid was recovered and confirmed by XRPD to consist of material D (Figure 16). This experiment was repeated to obtain additional material, but in order to preserve the solid, it was not characterized by XRPD (Table 11). Of note, material D had previously been observed as a minor component in a mixture containing Form C and material E from a polymorph screening experiment in chloroform (Tables 6 and 7 above). [Table 11]

[0355] The XRPD pattern of material D was successfully indexed (FIG. 17). The unit cell volume is consistent with the anhydrous / nonsolvated form of compound 1, and the density is higher than that of form C (1.390 g / cm). 3 1.324g / cm 3 ). A discussion of how this information relates to the relative thermodynamic stabilities of these forms is provided below.

[0356] Material limitations did not allow further characterization of Material D. This material was only produced in small quantities by the techniques described above, with all solids utilized in the interconversion slurry.

[0357] Material E: Material E was only observed as a disordered material from a fast evaporation experiment in chloroform (Figure 18, top; Table 6). This material was also produced in a mixture containing Form C and Material D by rotary evaporation from chloroform (Figure 18, second from top; Table 7). Due to the disorder, the XRPD pattern could not be indexed. The proton NMR spectrum of this material indicated the absence of organic solvents at the time of analysis, although desolvation prior to analysis could have been possible, especially for materials lacking a highly crystalline structure (Table 2).

[0358] Material F: Material F was only observed as a disordered material from the fast evaporation experiment in TFE (Figure 3, top; Table 6). Due to the disorder, the XRPD pattern could not be indexed. The proton NMR spectrum showed negligible TFE present at the time of analysis, although desolvation prior to analysis could have been possible for material E (Table 2). Due to the disorder, further characterization of this material was not performed.

[0359] Material G: Material G is the HFIPA solvate (1.9 molar) or mixed solvate / hydrate of compound 1, which was only observed as a mixture with trace amounts of Form A (hydrate, FIG. 19). This mixture arose from an attempted crash precipitation experiment in HFIPA / water and was initially obtained as a cloudy liquid containing a yellow oil, which crystallized to an off-white solid after 16 days in the refrigerator. Due to the nature of the mixture, the XRPD pattern could not be indexed.

[0360] Proton NMR of a mixture of material G plus a trace of Form A showed 1.9 moles of HFIPA per mole of API, suggesting a solvate (Table 2).

[0361] DSC and TGA thermograms of the mixture are shown in Figure 20. The endotherm at about 0°C likely corresponds to the melting of residual water. The large weight loss of 49% up to 159°C corresponds to a series of broad endotherms and is consistent with loss of solvent. Overlapping endothermic events at 241°C and 245°C (maxima) are observed, likely corresponding to the melting of a mixture of crystalline forms. Based on the peak maxima, the higher melting form is likely Form C, and the lower melting form may be Material D.

[0362] Material H: Material H is a TFE solvate (0.5 moles TFE) or mixed solvate / hydrate obtained from vapor diffusion experiments in TFE / water (Figure 3, third pattern; Table 6). The XRPD pattern was not indexable, possibly suggesting a mixture of materials.

[0363] Proton NMR of material H indicated the presence of 0.5 moles of TFE, which is consistent with a likely solvated form (Table 2).

[0364] DSC and TGA thermograms are shown in Figure 21. The gradual weight loss of 32% by TGA up to 136°C corresponds to a broad endotherm by DSC and is consistent with loss of solvent. The amount of weight loss corresponds to more than 2 moles of TFE. Since much less TFE was present (0.5 moles) by proton NMR, this weight loss is likely due to loss of both TFE and water. It is unclear whether the water present is bound within the crystal lattice, but at least some of the water remains based on the endotherm at 0°C indicating melting of unbound water. The sharp endotherm at 244°C (onset) likely corresponds to melting of desolvated material.

[0365] To study the desolvation behavior, material H was heated to 150° C. by TGA and the solid was collected and analyzed by XRPD (Table 10). Complete conversion to Form C was observed.

[0366] Material I: Material I was observed only as a minor component of a mixture containing Forms A and C from a crash precipitation experiment in chloroform / heptane (Figure 22, Table 6). Due to the nature of the mixture, further characterization of this material was not performed and the composition remains unknown.

[0367] Form J: Form J is a hydrate of compound 1 (1-2 moles of water) that was initially produced in small quantities from crash-cooling experiments in MeOH (Table 6). Form J was successfully reproduced by adding seeding and repeating the cooling procedure at a lower cooling rate (Table 11). The XRPD pattern of the first preparation showed a preferred orientation effect, which occurs when particles with anisotropic morphology (such as needles) align in the sample holder, causing signal amplification at some angles and suppression at other angles (Figure 23, top). Due to the lack of prominent peaks, it was not possible to index this pattern. However, the reprepared sample showed peaks suitable for indexing (Figure 23, bottom). The unit cell volume could accommodate up to 2 moles of water (Figure 24).

[0368] Proton NMR spectra of both samples showed the presence of negligible MeOH (Table 2).

[0369] The DSC thermogram of the first preparation shows a broad endotherm at 46° C., likely indicating loss of water (FIG. 25). The overlapping endothermic and exothermic events at approximately 135-146° C. likely correspond to recrystallization. The sharp endotherm at 243° C. (onset) is consistent with melting of the recrystallized material, which is likely Form C based on the onset temperature. Since insufficient solids remained from the first preparation for TGA analysis, the reprepared material was analyzed by DSC and TGA (FIG. 26). The DSC thermogram is very similar to that of the first preparation. The 5.8% weight loss by TGA up to 143° C. corresponds to the loss of 0.16 moles MeOH and 1.3 moles water detected by proton NMR.

[0370] Karl Fischer analysis of the material indicated the presence of 1.4 moles of water, consistent with the TGA data (Table 2). Based on the KF, TGA, and indexing results, Form J is recorded as a hydrate containing 1-2 moles of water.

[0371] Amorphous: All attempts to prepare amorphous Compound 1 on bench scale by melting / quenching and rotary evaporation failed, resulting in crystalline material (Table 7). Therefore, the above-mentioned cycling DSC experiment was performed in an attempt to observe the glass transition event by melting / quenching / reheating in situ (Figure 15, Table 2). The observation of a glass transition (Tg) may be characteristic of the amorphous nature of the material. Form C solid was chosen as the starting material due to its anhydrous / nonsolvated nature that would prevent interference from solvent or water loss upon heating. During the second heating step (blue) of the experiment in Figure 15, this material exhibits a Tg at approximately 110°C (ΔCp: 0.2 J / (g * K). This Tg is relatively high and may be an indication of good physical stability of the amorphous solid at ambient temperatures. Of note, differences in solvent and / or water content within the sample may shift the temperature at which the glass transition occurs.

[0372] Relative thermodynamic stability of selected / anhydrous / nonsolvated forms During form screening, two anhydrous / nonsolvated forms were discovered: Form C and Material D. To assess their relative thermodynamic stability, interconversion slurries were performed at RT and 2-8° C. Density values, onset melting temperatures, and heat of fusion were also considered in determining whether these forms convert reversibly at a particular transition temperature (enantiotropic relationships) or whether the forms are not interconvertible (monotropic relationships).

[0373] To prepare the interconversion slurries, THF was pre-saturated with Form C at a specified temperature and a portion of the liquid phase was filtered and poured into a mixture of solids containing seeds of both Form C and Material D (Table 12). The pre-saturated liquid phase is utilized to minimize the effects of kinetic dissolution, dissolve the less stable (and more soluble) form, and precipitate the most stable (and least soluble) form. The slurries were allowed to stir for 7 days at RT and 2-8°C, respectively. Both slurries yielded Form C as a single phase, indicating that it is more stable than Material D between 2°C and RT. [Table 12] [Table 13-1] [Table 13-2]

[0374] Density rules based on Kitaigorodskii's principle of close packing of molecular crystals dictate that for non-hydrogen bonded systems at absolute zero, the most stable polymorph has the highest density due to stronger intermolecular van der Waals interactions. As mentioned above, material D has a density higher than that of form C (1.324 g / cm3). 3 , from SCXRD) has a higher density (1.390 g / cm 3 , from XRPD indexing). If density rules are applicable to this system, these values ​​would indicate that material D is more thermodynamically stable than form C between absolute zero and a yet to be determined transition temperature below 2° C. (enantiotropic relationship).

[0375] In addition to density values, the melting onset temperature and heat of fusion measured by DSC can be compared between the anhydrous / nonsolvated materials to further understand their thermodynamic relationship (monotropic vs. enantiotropic). According to the heat of fusion rule, if the higher melting form has a lower heat of fusion, the two forms are enantiotropic. Otherwise, they are monotropic. The cycling DSC thermograms shown in FIG. 15 show melting endotherms for both Form C (first step of the experiment, black) and the putative Material D (third step of the experiment, blue). In this data, the melting onset and heat of fusion of Form C (245° C., 67 J / g) are both higher than those of Material D (238° C., 65 J / g), which would indicate a monotropic relationship in which Form C is more thermodynamically stable than Material D at all temperatures. However, one must consider the unknown crystallinity of Material D in this experiment and how it may affect the heat of fusion values. Overall, Form C was shown to be more stable than material D between 2° C. and RT.

[0376] Anhydrous vs. hydrated forms To study the relationship between the anhydrous / nonsolvated form C and the hydrated form A at RT, slurry experiments were performed at various water activities. From the stable form slurries in selected acetone / water, MeOH / water, and THF / water mixtures, form A was found to fully or partially convert to form C below aw 0.69 (Table 5). Form A remained unchanged above aw 0.82, likely indicating that the critical water activity between forms A and C falls between 0.69 and 0.82 at RT. Of note, the RT slurry with aw 0.82 was stirred for only 2 days before isolation (to investigate visible color change). This slurry started as a solid that was predominantly form A, resulting in form A, which may have allowed insufficient time for the form conversion. All other slurries of form A at various water activities were stirred for at least 10 days, which is likely to have allowed sufficient time for the form conversion.

[0377] In addition to the slurry starting with Form A, two slurries of Form C were prepared at high water activity conditions to study the possibility of conversion to a hydrate (Table 9, supra). THF / water 50:50 (aw approx. 1) and neat water (aw 1) were used. Complete conversion to Form A was observed after 1 day in THF / water 50:50, whereas no form conversion was observed after 1 day in neat water, likely due to insufficient solubility.

[0378] Overall, the data indicates that Form C is likely to be the thermodynamically stable form below aw 0.69, with Form A likely to be preferred above aw 0.82. Although Form C did not readily convert to a solid-state hydrate at RH of approximately 90% (stressed for 11 days, see above, Table 8), Form C can be converted relatively quickly to Form A when slurried above the critical water activity (as long as suitable solubility for form conversion is achieved).

[0379] Due to material limitations, hydrate form J was not included in the study of relative thermodynamic stability at various water activities.

[0380] Conclusion and Summary A mixture of compound 1 (designated as a mixture of Form A + traces of Material B) was obtained for use in polymorph screening. Approximately 50 screening experiments were set up using various crystallization techniques and solvent systems. The compound showed a relatively high propensity to exist in various solid forms, and eight new materials were discovered during screening (Materials / Forms C-J). Forms of interest included anhydrous / nonsolvated forms C and Material D, as well as hydrated forms A and J. All other named materials were observed only in solvated, disordered, or mixtures.

[0381] Form C is an anhydrous / non-solvated form that is likely thermodynamically stable between 2° C. and 80° C., while material D is metastable within that temperature range.

[0382] The critical water activity between hydrate form A and anhydrous form C likely falls between 0.69 and 0.82. Due to material limitations, hydrate form J was not included in any water activity studies.

[0383] Based on the body of work performed, Form C is recommended for further exploration. Form A can be readily converted to Form C by slurrying below the critical water activity, but care must be taken to provide suitable conditions (solubility, temperature, water activity, seeding, etc.) for complete conversion to the desired form. Crystallization process development studies will help optimize experimental parameters for a robust procedure to reproducibly crystallize Form C.

[0384] Experimental procedure Procedure for Compound 1 Form C: THF Slurry, solids from Compound 1 (Form A + traces of material B, 62.2 mg) were combined with THF (1 mL). The resulting slurry was allowed to stir at RT for 2 days, resulting in an opaque green suspension (experiment performed prior to discovery of potential light sensitivity of the compound). The solids were collected by positive pressure filtration onto a 0.2 μm nylon filter, flushed 10 times with approximately 20 mL of air, and transferred to a clean vial. EtOAc Slurry at approximately 60° C. Solids from Compound 1 (Form A + traces of material B, 67.5 mg) were combined with EtOAc (2 mL). The resulting slurry was allowed to stir in a metal heater block on a hot plate at approximately 60° C. for 3 days, resulting in an opaque off-white suspension. While warm, solids were collected by positive pressure filtration onto a 0.2 μm nylon filter, flushed 10 times with approximately 20 mL of air, and transferred to a clean vial.

[0385] Experimental Technique If a color change (typically to green) is observed within a few days in the first set of slurry experiments, all subsequent samples are treated as light-sensitive. This involves primarily handling the samples in a fume hood with the lights turned off, or otherwise protecting the experiments from long-term light exposure by covering them with foil, etc.

[0386] Isolation Technique Generally, isolation of solids was performed immediately after removing non-ambient samples from their respective temperature controlled devices to minimize equilibration to ambient temperature.

[0387] Decanting the liquid phase For some heterogeneous slurries, the solids were isolated by centrifuging the suspension (if necessary) and discarding the liquid phase, leaving the wet solids. Solids were dried briefly (e.g., air-dried or under nitrogen) unless specified as "analyzed wet" in the data tables below.

[0388] Positive Pressure Filtration Solids were collected on 0.2 μm nylon or PTFE filters by squeezing the slurry through a syringe and Swinnex filter holder assembly. In general, solids were briefly dried by blowing a 20 mL syringe of air onto the filter several times. Where specified below as "analyzed wet," solids were left wet with mother liquor. Some samples were briefly dried under a gentle stream of nitrogen gas prior to analysis.

[0389] vacuum filtration The solids were collected on a paper or nylon filter by vacuum filtration and briefly air-dried on the filter under reduced pressure before being transferred to a vial.

[0390] Crash Cooling (CC) Concentrated solutions were prepared in various solvents at elevated temperatures and typically filtered warm through 0.2 μm nylon or PTFE filters into warm vials. Each solution was capped and then immediately cooled to below ambient temperature, such as by placing in a freezer or immersion in a bath of dry ice and isopropanol. The solutions were held at below ambient temperature for the specified time and any solids present were isolated as described above. If no solids were observed or an oily material occurred, additional techniques were used if specified.

[0391] Crush Precipitation (CP) Solutions were prepared in various solvents and typically filtered through 0.2 μm nylon or PTFE filters. Aliquots of various anti-solvents were dispensed with stirring until precipitation occurred. If necessary, samples were placed at sub-ambient temperature to facilitate precipitation or crystallization. Solids were isolated as above. If no solids were observed or an oily material occurred, additional techniques were used if specified.

[0392] Fast Evaporation (FE) Solutions were prepared in various solvents and typically filtered through 0.2 μm nylon or PTFE filters. Each solution was evaporated from an open vial at ambient conditions unless otherwise noted. Solutions were evaporated to dryness unless indicated as partial evaporation (solids with small amounts of solvent remaining), in which case the solids were isolated as described above.

[0393] Interconversion slurry Saturated solutions were prepared by adding enough solid of a given morphology to a given solvent system at the specified conditions such that undissolved solids were present. The mixture was then agitated or allowed to stand at a specified temperature for an extended period of time to ensure saturation. Seed crystals of the desired morphology were added to an aliquot of the saturated solution (filtered through a 0.2 μm nylon or PTFE filter) such that undissolved solids were present. The mixture was then agitated in a sealed vial at a specified temperature for an extended period of time. The solids were isolated as described above.

[0394] Relative humidity stress load The selected material was transferred to a vial, which was then uncapped and placed in a jar containing a saturated aqueous solution of barium chloride such that the RH in the headspace was approximately 90% (Nyqvist, H.E., Saturated Salt Solutions for Maintaining Specified Relative Humidities, Int. J. Pharm. Technol. Prod. Manuf. 1983, 4, 47-48, which is incorporated by reference in its entirety.) The jar was stored at the specified temperature.

[0395] Rotary evaporation (RE) Solutions were prepared in the specified solvents and typically filtered through 0.2 μm nylon or PTFE filters. The solutions were evaporated to dryness using a rotary evaporator at the specified temperature. The resulting solids were stored under the specified conditions.

[0396] Slow cooling (SC) Concentrated solutions were prepared in various solvents at elevated temperatures and typically filtered warm through 0.2 μm nylon or PTFE filters into warm vials. Each solution was capped and placed on a hot plate, the hot plate was turned off, and the samples were allowed to cool slowly to ambient temperature. If no solids were present after cooling to ambient temperature, the samples were further cooled below ambient temperature. Any solids present after cooling were isolated as described above.

[0397] Slow Evaporation (SE) Solutions were prepared in various solvents and typically filtered through 0.2 μm nylon or PTFE filters. Each solution was allowed to evaporate from a covered vial (e.g., loosely capped or covered with aluminum foil with holes) at ambient conditions. Solutions were allowed to evaporate to dryness unless indicated as partial evaporation (solids with small amounts of solvent remaining), in which case the solids were isolated as described above.

[0398] Slurry Experiments A suspension was prepared by adding enough solid to a given solvent at the specified conditions such that there was undissolved solid. The mixture was then agitated (typically by stirring or shaking) in a closed vial at a given temperature for an extended period of time. The solid was isolated as described above.

[0399] Solubility Estimation Various aliquots of solvent were added to measured amounts of Compound 1 and rocked (typically sonicated) at a specified temperature until complete dissolution was achieved as judged by visual observation. If dissolution occurred after the addition of the first aliquot, the value is recorded as ">". If dissolution did not occur, the value is recorded as "<". If most of the solid dissolved but a few undissolved particles remained (possibly due to trace impurities in the unprocessed lot), the solubility value is recorded as an estimate ("approximate").

[0400] Vapor Diffusion (VD) Concentrated solutions were prepared in various solvents and typically filtered through 0.2 μm nylon or PTFE filters. The filtered solutions were dispensed into small vials, which were then placed into a larger vial containing the antisolvent. The small vial was left uncapped and the larger vial was capped to allow vapor diffusion to occur. Any solids present were isolated as described above.

[0401] calculation techniques XRPD Indexing Indexing and structure refinement are computational studies. In the figures referenced for a given indexed XRPD pattern, a match between the accepted peak positions marked with red bars and the observed peaks indicates a consistent unit cell determination. Successful indexing of a pattern indicates that the sample is composed primarily of a single crystalline phase, unless otherwise noted. The space group, unit cell parameters, and derived quantities consistent with a given annihilation symbol are shown in tabular form at the bottom of the figure. To confirm the tentative indexing solution, the molecular packing motifs within the crystallographic unit cell must be determined. No attempt at molecular packing was made.

[0402] Proprietary SSCI software was used to index the patterns of Form A, Form C, Form D, and Form J (TRIADS™ is covered by U.S. Pat. No. 8,576,985, which is incorporated by reference in its entirety).

[0403] Measurement Technique Differential Scanning Calorimetry (DSC) DSC was performed using a Mettler-Toledo DSC3+ or DSC 822e Differential Scanning Calorimeter. Temperature calibration was performed using octane, phenyl salicylate, indium, tin, and zinc. Samples were placed into hermetically sealed aluminum DSC pans, the weights accurately recorded, holes drilled in the lid, and the samples inserted into the DSC cell. A weighed aluminum pan configured as the sample pan was placed into the reference side of the cell. Samples were analyzed from -30°C to 350°C at 10°C / min.

[0404] Dynamic Vapor Sorption (DVS) Moisture sorption / desorption data were collected with a Surface Measurement System DVS Intrinsic instrument. Samples were not dried prior to analysis. Sorption and desorption data were collected at 10% RH increments over the range 5%-95% RH under a nitrogen purge. The equilibration criteria used for the analysis was a weight change of 0.001 dm / dt in 5 min with a minimum step time of 30 min and a maximum equilibration time of 180 min, with a data logging interval of 3 min. Data were not corrected for the initial moisture content of the samples.

[0405] Karl Fischer titration (KF) Karl Fischer coulometry for water determination was performed using a Mettler Toledo DL39 Karl Fischer titrator equipped with a Stromboli oven attachment. A NIST traceable water standard (Hydranal Water Standard 1.0) was analyzed to check the operation of the coulometer. Additionally, a qualified standard (Apura Water Standard Oven 1%) was analyzed to check the operation of the coulometer / oven system. Approximately 5-40 mg of sample was weighed into a pre-dried Stromboli vial and sealed. Two samples were weighed and placed in a drying oven set at approximately 160 °C (only one replicate was performed for LIMS 502283 due to sample limitations). The drying oven was purged with dry nitrogen and placed into the titration vessel. The sample was then titrated by a generator electrode producing iodine by electrochemical oxidation: 2I- → I2+2e-.

[0406] optical microscopy Samples were viewed under a Motic or Wolfe optical microscope equipped with crossed polarizers or a Leica stereomicroscope equipped with a primary red corrector and crossed polarizers.

[0407] Solution 1 H NMR spectroscopy The solution was developed by Spectral Data Services, Champaign, IL. 1 H NMR spectra were acquired. Samples were dissolved in DMSO-d6. Data acquisition parameters are listed on the first page of each spectrum in the data section of this report.

[0408] Thermogravimetric analysis (TGA) TG analyses were performed using a Mettler-Toledo TGA / DSC3+ analyzer. Temperature calibration was performed using calcium, indium, tin, and zinc oxalate. Samples were placed in aluminum pans. The pans were hermetically sealed, the lids pierced, and then inserted into the TG furnace. A weighed aluminum pan configured as the sample pan was placed on the reference platform. The furnace was heated under nitrogen. Samples were analyzed from 25° C. to 350° C. at 10° C. / min. The TGA / DSC3+ instrument was also used for selected heating / desolvation experiments, in which solids were heated to a given temperature as previously reported, then collected and analyzed by XRPD.

[0409] X-ray powder diffraction (XRPD) XRPD patterns were collected using a PANalytical X'Pert PRO MPD or PANalytical Empyrean diffractometer with an incident beam of Cu radiation generated using a long microfocus source. An elliptically graded multilayer mirror was used to focus the Cu Kα X-rays through the specimen to strike the detector. Prior to analysis, a silicon specimen (NIST SRM 640e) was analyzed to verify that the observed position of the Si 111 peak matched the NIST certified position. Sample specimens were sandwiched between 3 μm thick films and analyzed in transmission geometry. Beam stops, short anti-scatter extensions, and anti-scatter knife edges were used to minimize background generated by air. Soller slits were used on the incident and diffracted beams to minimize spread and asymmetry from axial divergence. Diffraction patterns were collected using a scanning position sensitive detector (X'Celerator) located 240 mm from the specimen and Data Collector software v.2.2b or 5.5. Data acquisition parameters are listed in the figures.

[0410] Single Crystal X-Ray Diffraction (SCXRD) Standard uncertainties in this report are stated in crystallographic brackets notation, e.g., 0.123(4) corresponds to 0.123 ± 0.004.

[0411] Single crystal sample preparation: The solid from untreated Compound 1 (64.6 mg) was combined with MEK (2 mL) and the resulting slurry was allowed to stir in a metal heater block on a hot plate at approximately 60° C. for 3 days. The sample consisted primarily of an opaque off-white suspension with a few amber and light green solids on the top wall. The wall solids were observed to be rectangular plates by optical microscopy. A suitable single crystal was selected and analyzed.

[0412] Data collection 0.6×0.26×0.07mm 3 A light yellow block with approximate dimensions of was mounted in a random orientation on a polymer loop. Preliminary examination and data collection were performed on a Rigaku SuperNova diffractometer equipped with a copper anode microfocus sealed X-ray tube (Cu θ=1.54184 Å) and a Dectris Pilatus3 R 200K hybrid pixel array detector.

[0413] The cell constant and orientation matrix for data collection were obtained from least-squares refinement using set angles of 16314 reflections in the range 3.6920°<θ<77.3870°. The space group was determined to be P21 (international tables no. 4) by the program CRYSALISPRO (CrysAlisPro 1.171.38.41r (Rigaku Oxford Diffraction, 2015)). Data were collected at room temperature up to a maximum diffraction angle (2θ) of 155.234°.

[0414] Data reduction Frames were integrated by CRYSALISPRO. A total of 25050 reflections were collected, of which 9477 were unique. Lorentzian and polarization corrections were applied to the data. The linear absorption coefficient was 0.758 mm for Cu Kα radiation. -1An empirical absorption correction using CRYSALISPRO was applied. Transmission coefficients ranged from 0.863 to 1.000. A second-order extinction correction was applied. The final coefficient, refined by least squares, was 0.0016(3) (absolute units). The intensities of the equivalent reflections were averaged. The agreement factor for the averaging was 2.37% based on the intensity.

[0415] Structure solution and refinement The structure was solved by charge flipping using OLEX2 (Bourhis, LJ, Dolomanov, OV, Gildea, RJ, Howard, JAK, Puschmann, H. Acta Cryst., 2015, A71, 59-75, which is incorporated by reference in its entirety). The remaining atoms were located in a subsequent difference Fourier synthesis. The structure was refined using SHELXL-2014 (Sheldrick, G M Acta Cryst., 2008, A64, 112-122 and Sheldrick, G M Acta Cryst. 2015, A71, 3-8, each of which is incorporated by reference in its entirety). The hydrogen atoms present on the nitrogens were refined independently. The hydrogen atoms present on the carbons were included in the refinement but were constrained to ride on the atoms to which they are bonded. The structure was refined with full matrix least squares by minimizing the following function:

number

[0416] Scattering factors were taken from the "International Tables for Crystallography" (International Tables for Crystallography, Vol. C, Kluwer Academic Publishers: Dordrecht, The Netherlands, 1992, Tables 4.2.6.8 and 6.1.1.4, which is incorporated by reference in its entirety). Of the 9477 reflections used in refinement, only 8578 reflections with intensities greater than twice the uncertainty [I>2σ(I)] were used to calculate the fit residuals R. The final cycle of refinement included 642 variable parameters, one constraint, and converged to the following respective unweighted and weighted sign coefficients:

number

[0417] Calculated X-ray powder diffraction (XRPD) patterns Calculated XRPD patterns were generated using MERCURY (Macrae, CF Edgington, PR MacCabe, P. Pidcock, E. Shields, GP Taylor, R. Towler M. and van de Streek, JJ Appl. Cryst., 2006, 39, 453-457, which is incorporated by reference in its entirety) for Cu radiation, and the atomic coordinates, space group, and unit cell parameters from the single crystal structure.

[0418] Atomic displacement ellipsoid diagram and packing diagram Atomic displacement ellipsoid diagrams were generated using MERCURY, where atoms are represented by anisotropic thermal ellipsoids with a probability of 50%.

[0419] Although several embodiments have been described, it is clear that our basic examples can be modified to provide other embodiments that utilize the compounds and methods described herein. It will therefore be appreciated that the scope of the invention is to be defined by the appended claims, rather than by the specific embodiments that have been represented by way of example.

[0420] References, each of which is incorporated by reference in its entirety: 1. Hofmann,DWMActa Crystallographica Section B:Structural Science.2002,B57,489-493. 2. Glusker,Jenny Pickworth;Trueblood,Kenneth N.Crystal Structure Analysis:A Primer,2 nd ed.;Oxford University press:New York,1985;p.87. 3. Kitaigorodskii, AIMolecular Crystals and Molecules; Academic Press: New York, 1973. 4. Burger, A.; Ramberger, R. On the polymorphism of pharmaceuticals and other organic molecular crystals. I: Theory of thermodynamic rules. Mikrochim. Acta[Wein] 1979 II, 259-271. 5. SSCI internal report,Water Activity Calculations using UNIFAC Calculator,SR-20150515.01,dated 07 / 23 / 2015. 6. Nyqvist, HE, Saturated Salt Solutions for Maintaining Specified Relative Humidities, Int. J. Pharm. Technol. Prod. Manuf. 1983, 4, 47-48. 7. Goldberg,RN;Nuttall,RL,Evaluated Activity and Osmotic Coefficients for Aqueous Solutions:The Alkaline Earth Metal Halides,J.Phys.Chem.Ref.Data,1978,7(1),263-310. 8. TRIADS™ is covered by U.S. Patent No. 8,576,985. 9. CrysAlisPro 1.171.38.41r(Rigaku Oxford Diffraction,2015). 10. Bourhis, LJ, Dolomanov, OV, Gildea, RJ, Howard, JAK, Puschmann, H. Acta Cryst., 2015, A71, 59-75. 11. Sheldrick,GMActa Cryst.,2008,A64,112-122. 12. Sheldrick,GMActa Cryst.2015,A71,3-8. 13. International Tables for Crystallography,Vol.C,Kluwer Academic Publishers:Dordrecht,The Netherlands,1992,Tables 4.2.6.8 and 6.1.1.4. 14. Macrae, CCFedgington, PRMcCabe, P. Pidcock, E. Shields, GPTaylor, R. Towler M. and van de Streek, JJAppl.Cryst., 2006, 39, 453-457. 15. The term and definition of hygroscopicity developed by the SSCI is based in part on concepts presented in Newman, AW; Reutzel-Edens, SM; Zografi, G. Characterization of the “Hygroscopic” Properties of Active Pharmaceutical Ingredients, J. Pharm. Sci. 2008, 97, 1047-1059.

[0421] The details of one or more embodiments are set forth in the accompanying drawings and specification. Other features, objects, and advantages will become apparent from the description, drawings, and claims. Although several embodiments of the invention have been described, it will be understood that various modifications can be made without departing from the spirit and scope of the invention. It will also be understood that the accompanying drawings are not necessarily to scale, and that they depict various features and underlying principles of the invention in a somewhat simplified manner.

Claims

1. Compound 1: 【Chemistry 1】 A solid form of which the solid form is of form C.

2. The solid form according to claim 1, wherein the solid form is substantially free of impurities.

3. The solid form according to claim 1, wherein the solid form is a crystalline solid that substantially does not contain amorphous compound 1.

4. The solid form according to claim 1, further characterized by having at least 3, 4, 5, or 6 peaks in the X-ray powder diffraction pattern (XRPD) shown in Figure 16 (bottom trace).

5. The solid form according to claim 4, further characterized by having at least three of the maximum amplitude peaks of the XRPD shown in Figure 16 (bottom trace).

6. The solid form according to claim 4, further characterized by having at least four of the maximum amplitude peaks of the XRPD shown in Figure 16 (bottom trace).

7. The solid form according to claim 4, further characterized by having at least five of the maximum amplitude peaks of the XRPD shown in Figure 16 (bottom trace).

8. The solid form according to claim 1, further characterized by having at least 3, 4, 5, or 6 peaks in the X-ray powder diffraction pattern (XRPD) shown in Figure 10.

9. The solid form according to claim 8, further characterized by having at least three of the maximum amplitude peaks of the XRPD in Figure 10 (upper trace).

10. The solid form according to claim 8, further characterized by having at least four of the maximum amplitude peaks of the XRPD shown in Figure 10 (upper trace).

11. The solid form according to claim 8, further characterized by having at least five of the maximum amplitude peaks of the XRPD in Figure 10 (upper trace).

12. The solid form according to claim 1, wherein the solid form exhibits an X-ray powder diffraction pattern (XRPD) substantially similar to that of Figure 10 (top trace) or Figure 16 (bottom trace).

13. The solid form according to claim 1, further characterized by TGA analysis of mass loss between 165°C and 175°C.

14. The solid form according to claim 1, further characterized by DSC including a peak initiation point at approximately 247°C.

15. The solid form according to claim 1, further characterized substantially by DSC as shown in Figure 12.

16. The solid form according to claim 1, further characterized by DVS isotherms as substantially shown in Figure 13.

17. Compound 1: 【Chemistry 2】 A solid form of which the solid form is of form A.

18. The solid form according to claim 17, wherein the solid form is substantially free of impurities.

19. The solid form according to claim 17, wherein the solid form is a crystalline solid that substantially does not contain amorphous compound 1.

20. The solid form according to claim 17, wherein the solid form is a hydrate.

21. The solid form according to claim 20, wherein the solid form is a monohydrate.

22. The solid form according to claim 20, wherein the solid form is a dihydrate.

23. The solid form according to claim 20, wherein the solid form is a trihydrate.

24. The solid form according to claim 17, further characterized by having at least 3, 4, 5, or 6 peaks in the X-ray powder diffraction pattern (XRPD) shown in Figure 4 (trace below) or Figure 5.

25. The solid form according to claim 24, further characterized by having at least three of the maximum amplitude peaks of the XRPD in Figure 4 (below trace) or Figure 5.

26. The solid form according to claim 24, further characterized by having at least four of the maximum amplitude peaks of the XRPD in Figure 4 (below trace) or Figure 5.

27. The solid form according to claim 24, further characterized by having at least five of the maximum amplitude peaks of the XRPD in Figure 4 (below trace) or Figure 5.

28. The solid form according to claim 17, characterized by having an X-ray powder diffraction pattern (XRPD) substantially similar to that of Figure 4 (trace below) or Figure 5.

29. The solid form according to claim 24, further characterized by having at least three of the maximum amplitude peaks of the XRPD shown in Figure 5.

30. The solid form according to claim 24, further characterized by having at least four of the maximum amplitude peaks of the XRPD shown in Figure 5.

31. The solid form according to claim 24, further characterized by having at least five of the maximum amplitude peaks of the XRPD shown in Figure 5.

32. The solid form according to claim 17, further characterized by TGA analysis of mass loss between 65°C and 130°C.

33. The solid form according to claim 32, wherein TGA is substantially as shown in Figure 7.

34. The solid form according to claim 17, characterized by DSC including peak initiation points at approximately 91°C, 103°C, and 245°C.

35. The solid form according to claim 34, wherein the peak initiation point is essentially at 245°C.

36. The solid form according to claim 34, characterized substantially by the DSC as shown in Figure 7.

37. Compound 1: 【Transformation 3】 A solid form characterized in that the solid form is of form A, form B, form C, form D, form E, form F, form G, form H, form I, or form J.

38. The solid form according to claim 37, wherein the solid form exhibits peaks or other physical properties as shown in any one of Figures 1 to 42.

39. A pharmaceutical composition comprising a solid form according to any one of claims 1 to 38 and a pharmaceutically acceptable carrier, excipient, or adjuvant.

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