Forms and compositions of inhibitors of plasma kallikrein

Abstract

To provide forms and compositions of inhibitors of plasma kallikrein.SOLUTION: The present invention provides a compound and compositions thereof which are useful as inhibitors of plasma kallikrein (pKal) and which exhibit desirable characteristics as pKal inhibitors. The present disclosure provides novel salts and solid forms useful as inhibitors of plasma kallikrein (pKal). In general, salt forms or free base forms, and pharmaceutically acceptable compositions thereof, are useful for treating or lessening the severity of a variety of diseases or disorders as described in detail herein.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 011,776, filed April 17, 2020, entitled "FORMS AND COMPOSITIONS OF INHIBITORS OF PLASMA KALLIKREIN," the disclosure of which is incorporated herein by reference in its entirety. [Background technology]

[0002] Plasma kallikrein (pKal) is a serine protease zymogen in blood that is converted to its catalytically active form by coagulation factor XIIa and contributes to the innate inflammatory response and the intrinsic blood coagulation cascade. Mechanisms leading to activation of this pathway in vivo include interaction with polyphosphate released from activated platelets and the lack of C1 inhibitor (C1-INH), the main physiological inhibitor of pKal. pKal-mediated cleavage of high-molecular-weight kininogen generates bradykinin (BK), a potent vasodilator and pro-inflammatory nonapeptide, which activates the bradykinin 2 receptor. Subsequent cleavage of BK by carboxypeptidases generates des-Arg9-BK, which activates the B1 receptor. Both B1 and B2 receptors are expressed by vascular, glial, and neuronal cell types, with the highest levels of retinal expression detected in the ganglion cell layer and the inner and outer nuclear layers. Activation of B1 and B2 receptors causes vasodilation and increases vascular permeability.

[0003] pKal is also associated with numerous disorders, such as hereditary angioedema (HAE), an autosomal dominant disease characterized by painful, unpredictable, recurrent attacks of inflammation affecting the hands, feet, face, abdomen, genitourinary tract, and larynx. The prevalence of HAE is uncertain but estimated to be approximately 1 case per 50,000 people, with no known differences between racial groups. HAE is caused by a deficiency (type I) or dysfunction (type II) of C1-INH, which inhibits pKal, bradykinin, and other serine proteases in the blood. Individuals with hereditary angioedema (HAE) lack C1-INH, resulting in excessive bradykinin production, which in turn leads to painful, debilitating, and potentially fatal attacks of swelling. If left untreated, HAE can result in a high mortality rate of 40%, primarily due to upper airway obstruction. Consequently, there is a significant need in the art for effective inhibitors of pKal.

[0004] A compound can form one or more different pharmaceutically acceptable salts and / or solid forms, including amorphous and polymorphic crystalline forms. Individual salts and solid forms of a biologically active compound may have different properties. The development of pharmaceutically acceptable dosage forms for the treatment of various diseases or conditions associated with pKal requires the identification and selection of an appropriate salt and / or solid form (including an appropriate crystalline form, if applicable) of the biologically active compound. Summary of the Invention [Means for solving the problem]

[0005] The present disclosure provides novel salts and solid forms useful as inhibitors of plasma kallikrein (pKal). Generally, the salt forms or free base forms, and pharmaceutically acceptable compositions thereof, are useful for treating or lessening the severity of various diseases or disorders, as described in detail herein. [Brief explanation of the drawings]

[0006] [Figure 1]1 provides an X-ray powder diffraction (XRPD) pattern of Form 1 (free base) of Compound 1.

[0007] [Figure 2] 1 provides the TGA / DSC curve of Form 1 (free base) of Compound 1.

[0008] [Figure 3] 1 provides an X-ray powder diffraction (XRPD) pattern of Form 2 (free base) of Compound 1.

[0009] [Figure 4] 1 provides the TGA / DSC curve of Form 1 (free base) of Compound 1.

[0010] [Figure 5] 1 provides an X-ray powder diffraction (XRPD) pattern of Form 2 (free base) of Compound 1.

[0011] [Figure 6] 1 provides the TGA / DSC curve of Form 3 (free base) of Compound 1.

[0012] [Figure 7] 1 provides an X-ray powder diffraction (XRPD) pattern of Compound 3, Pattern 1 (L-malate salt).

[0013] [Figure 8] 1 provides the TGA / DSC curve of Compound 3, Pattern 1 (L-malate).

[0014] [Figure 9] 1 provides an X-ray powder diffraction (XRPD) pattern of Compound 4, Pattern 1 (succinate salt).

[0015] [Figure 10] 1 provides the TGA / DSC curve of Compound 4, Pattern 1 (succinate salt).

[0016] [Figure 11]1 provides an X-ray powder diffraction (XRPD) pattern of Compound 5, Pattern 1 (phosphate salt).

[0017] [Figure 12] 1 provides the TGA / DSC curve of Compound 5, Pattern 1 (phosphate salt).

[0018] [Figure 13] 1 provides an X-ray powder diffraction (XRPD) pattern of Compound 6, Pattern 1 (oxalate salt).

[0019] [Figure 14] 1 provides the TGA / DSC curve of Compound 6, Pattern 1 (oxalate salt).

[0020] [Figure 15] 1 provides an X-ray powder diffraction (XRPD) pattern of Compound 6, pattern 4 (oxalate salt).

[0021] [Figure 16] 1 provides the TGA / DSC curve of Compound 6, Pattern 4 (oxalate salt).

[0022] [Figure 17] 1 provides an overlay of Form 1 of Compound 1 (free base) and Form 1 of Compound 7 (L-tartrate salt).

[0023] [Figure 18] 1 provides the TGA / DSC curve of Compound 7, Pattern 1 (L-tartrate salt).

[0024] [Figure 19] 1 provides an X-ray powder diffraction (XRPD) pattern of Compound 9, Pattern 1 (fumarate salt).

[0025] [Figure 20] 1 provides the TGA / DSC curve of Compound 9, Pattern 1 (fumarate salt).

[0026] [Figure 21] 1 provides thermodynamic stability diagrams of various forms of Compound 1 (free base).

[0027] [Figure 22] 1 provides an overlay of XRPD patterns of Compound 1 (as-synthesized Compound 1), Form 1 (free base) of Compound 1, and Form 2 (free base) of Compound 1 obtained from the synthetic procedure described in Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0028] General Description of Certain Aspects of the Invention: PCT Patent Application Publication No. WO2019 / 178129 (the "'129 Publication"), filed March 12, 2019, and published September 19, 2019, which is incorporated herein by reference in its entirety, describes certain plasma kallikrein (pKal) inhibitor compounds. Such compounds include N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide: [ka]

[0029] Compound 1, the free base, is one of many compounds identified in the '129 publication as a small molecule inhibitor of pKal. In the '129 publication, compound 1 is identified as compound I-148, the synthesis of which is described in detail in Example 148, which is reproduced herein for ease of reference.

[0030] Compound 1 demonstrated potency against plasma kallikrein in in vitro assays (see, e.g., Table 1 of the '129 publication). For example, the '129 publication reports that Compound 1 exhibited an EC 50Compound 1 is therefore useful for the treatment of one or more disorders associated with the activity of pKal.

[0031] The present disclosure provides various free base solid forms of Compound 1, salt forms of Compound 1 and solid forms thereof, pharmaceutical compositions thereof, and methods for preparing solid forms of Compound 1 and salts and solid forms thereof. Salt forms and solid forms (e.g., crystalline solid forms) impart or may impart properties such as improved water solubility, stability, absorption, bioavailability, and ease of formulation. As used herein, the term "salt" refers to a salt or co-crystal of two or more (e.g., two) component molecules (e.g., Compound 1 and a coformer), unless otherwise indicated. In combining an acid and a base compound to prepare a solid form, the ΔpK a (pK a (base)-pK a A (acid) > 1 generally allows for the formation of a salt compound, in which the two compounds are ionized. If this threshold is not met, non-ionic interactions (such as hydrogen bonding) may occur between the neutral acid and the basic compound, forming a co-crystal or the like. In some embodiments, the provided solid form is a salt. In other embodiments, the provided solid form is a co-crystal.

[0032] I. Free Base Form of Compound 1 1. Compound 1 It is believed that Compound 1 can exist in various physical forms. For example, Compound 1 can be in a solution, a suspension, 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.

[0033] In some embodiments, the present invention provides forms of Compound 1 that are substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may 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 some form of Compound 1 is present. In yet other embodiments of the present invention, at least about 99% by weight of some form of Compound 1 is present.

[0034] According to one embodiment, a form of Compound 1 is present in an amount of at least about 97.0, 97.5, 98.0, 98.5, 99.0, 99.5, or 99.8 weight percent, where the percentages are based on the total weight of the composition. According to another embodiment, a form of Compound 1 contains less than or equal to about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than or equal to about 1.5 HPLC area percent of total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, a form of Compound 1 contains less than or equal to about 1.0 HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0035] Structures depicted for forms of Compound 1 are also meant to include all tautomeric forms of Compound 1. Additionally, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 13 C- or 14 Compounds having the present structures except for the replacement of a carbon with a C-enriched carbon are within the scope of this invention.

[0036] It has been discovered that Compound 1 can exist in various solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0037] In some embodiments, Compound 1 is amorphous. In some embodiments, Compound 1 is amorphous and substantially free of crystalline Compound 1.

[0038] As used herein, the term "polymorph" refers to the different crystalline structures in which a compound, or a salt, co-crystal, or solvate thereof, can crystallize.

[0039] 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 significant amounts of amorphous Compound 1. In certain embodiments, at least about 95% by weight of crystalline Compound 1 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline Compound 1 is present.

[0040] It has been discovered that Compound 1 can exist in at least three different polymorphic forms. In certain embodiments, the present invention provides a polymorph of Compound 1, referred to herein as Form 1. In certain embodiments, the present invention provides a polymorph of Compound 1, referred to herein as Form 2. In certain embodiments, the present invention provides a polymorph of Compound 1, referred to herein as Form 3.

[0041] In some embodiments, Compound 1 is a polymorph that is substantially free of other polymorphs. In some embodiments, Compound 1 is Form 1, which is substantially free of other free base forms of Compound 1. In some embodiments, Compound 1 is Form 2, which is substantially free of other free base forms of Compound 1. In some embodiments, Compound 1 is Form 3, which is substantially free of other free base forms of Compound 1.

[0042] In some embodiments, Compound 1 is an anhydrate. In other embodiments, Compound 1 is a hydrate.

[0043] Compound 1 Form 1 In some embodiments, Form 1 of Compound 1 has at least 1, 2, 3, 4, or 5 X-ray powder diffraction (XRPD) peaks selected from the angles (2 theta ±0.2) listed in Table 1 below. [Table 1]

[0044] In some embodiments, Form 1 of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffractions at the following angles (2 theta ±0.2) and corresponding d-spacings (Angstroms ±0.2): [Table 2]

[0045] In some embodiments, Compound 1 Form 1 is characterized in an X-ray powder diffraction pattern having one or more peaks selected from peaks at about 11.8, 15.0, 17.0, 18.0, 19.4, and 23.5. In some embodiments, Compound 1 Form 1 is characterized in an X-ray powder diffraction pattern having two or more peaks selected from peaks at about 11.8, 15.0, 17.0, 18.0, 19.4, and 23.5. In some embodiments, Compound 1 Form 1 is characterized in an X-ray powder diffraction pattern having three or more peaks selected from peaks at about 11.8, 15.0, 17.0, 18.0, 19.4, and 23.5. In some embodiments, Compound 1 Form 1 is characterized in an X-ray powder diffraction pattern having four or more peaks selected from peaks at about 11.8, 15.0, 17.0, 18.0, 19.4, and 23.5. In some embodiments, Form 1 of Compound 1 is characterized by an X-ray powder diffraction pattern having five or more peaks selected from the peaks at about 11.8, 15.0, 17.0, 18.0, 19.4, and 23.5. In some embodiments, Form 1 of Compound 1 is characterized by an X-ray powder diffraction pattern having all six peaks selected from the peaks at about 11.8, 15.0, 17.0, 18.0, 19.4, and 23.5. In some embodiments, Form 1 of Compound 1 is characterized by an X-ray powder diffraction pattern having all six peaks selected from the peaks at about 11.8, 15.0, 17.0, 18.0, 19.4, and 23.5, corresponding to d-spacings (Angstroms±0.2) of 7.52, 5.92, 5.20, 4.93, 4.58, and 3.79 (respectively). The term "about" when used in reference to a 2-theta degree value refers to the stated value plus or minus 0.2 degrees 2-theta.

[0046] In certain embodiments, the X-ray powder diffraction pattern of Form 1 of Compound 1 is substantially similar to the XRPD provided in FIG.

[0047] A method for preparing Form 1 of Compound 1 is described below.

[0048] Form 2 of Compound 1 In some embodiments, Form 1 of Compound 2 has at least 1, 2, 3, 4, or 5 X-ray powder diffraction (XRPD) peaks selected from the angles (2 theta ±0.2) listed in Table 3 below. [Table 3]

[0049] In some embodiments, Form 2 of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffractions at the following angles (2 theta ±0.2) and corresponding d-spacings (Angstroms ±0.2): [Table 4]

[0050] In some embodiments, Form 2 of Compound 1 is characterized by an X-ray powder diffraction pattern having one or more peaks selected from peaks at about 6.1, 8.0, 13.0, 17.0, 17.8, and 25.6. In some embodiments, Form 2 of Compound 1 is characterized by an X-ray powder diffraction pattern having two or more peaks selected from peaks at about 6.1, 8.0, 13.0, 17.0, 17.8, and 25.6. In some embodiments, Form 2 of Compound 1 is characterized by an X-ray powder diffraction pattern having three or more peaks selected from peaks at about 6.1, 8.0, 13.0, 17.0, 17.8, and 25.6. In some embodiments, Form 2 of Compound 1 is characterized by an X-ray powder diffraction pattern having four or more peaks selected from peaks at about 6.1, 8.0, 13.0, 17.0, 17.8, and 25.6. In some embodiments, Form 2 of Compound 1 is characterized by having five or more peaks in an X-ray powder diffraction pattern selected from the peaks at about 6.1, 8.0, 13.0, 17.0, 17.8, and 25.6. In some embodiments, Form 2 of Compound 1 is characterized by having all six peaks in an X-ray powder diffraction pattern selected from the peaks at about 6.1, 8.0, 13.0, 17.0, 17.8, and 25.6. In some embodiments, Form 2 of Compound 1 is characterized by having all six peaks in an X-ray powder diffraction pattern selected from the peaks at about 6.1, 8.0, 13.0, 17.0, 17.8, and 25.6, corresponding to d-spacings (Angstroms±0.2) of 14.52, 11.04, 6.81, 5.20, 4.98, and 3.48 (respectively).

[0051] In certain embodiments, the X-ray powder diffraction pattern of Form 2 of Compound 1 is substantially similar to the XRPD provided in FIG.

[0052] A method for preparing Form 2 of Compound 1 is described below.

[0053] Form 3 of Compound 1 In some embodiments, Form 3 of Compound 1 has at least 1, 2, 3, 4, or 5 X-ray powder diffraction (XRPD) peaks selected from the angles (2 theta ±0.2) listed in Table 5 below. [Table 5]

[0054] In some embodiments, Form 3 of Compound 1 is characterized by an X-ray powder diffraction (XRPD) pattern having diffractions at the following angles (2 theta ±0.2) and corresponding d-spacings (Angstroms ±0.2): [Table 6]

[0055] In certain embodiments, the X-ray powder diffraction pattern of Form 3 of Compound 1 is substantially similar to the XRPD provided in FIG.

[0056] A method for preparing Form 3 of Compound 1 is described below.

[0057] II. Combination of Coformer and Compound 1 In some embodiments, compound 1 is combined with a coformer (e.g., an acid), as described below, to provide a species in which compound 1 and the coformer, for example, ionically or hydrogen bond, to form one of compounds 2-11. It is believed that compounds 2-11 can exist in a variety of physical forms. For example, compounds 2-11 can be in solution, suspension, or solid form. In certain embodiments, compounds 2-11 are in solid form. When compounds 2-11 are in solid form, the compounds can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms of compounds 2-11 are described in more detail below.

[0058] 2. Compound 2 (hydrochloric acid x Compound 1) According to one embodiment, the present invention provides Compound 2, a chemical species comprising Compound 1 and hydrochloric acid: [ka] In one embodiment, a solid form of Compound 2 has a stoichiometric ratio of (Compound 1):(hydrochloric acid) that is about 1:1. In one embodiment, a solid form of Compound 2 has a stoichiometric ratio of (Compound 1):(hydrochloric acid) that is about 1:2. When Compound 1 is contacted with 1 or 2 equivalents of HCl in various solvents, the resulting Compound 2 can exist in at least 13 different polymorphs. In some embodiments, the present invention provides a polymorph of Compound 2 referred to herein as Pattern 1. In certain embodiments, the present invention provides a polymorph of Compound 2 referred to herein as Pattern 2. In certain embodiments, the present invention provides a polymorph of Compound 2 referred to herein as Pattern 3. In certain embodiments, the present invention provides a polymorph of Compound 2 referred to herein as Pattern 4. In certain embodiments, the present invention provides a polymorph of Compound 2 referred to herein as Pattern 5. In certain embodiments, the present invention provides a polymorph of Compound 2 referred to herein as Pattern 6. In certain embodiments, the present invention provides a polymorph of Compound 2 referred to herein as Pattern 7. In certain embodiments, the present invention provides a polymorph of Compound 2 referred to herein as Pattern 8. In certain embodiments, the present invention provides a polymorph of Compound 2 referred to herein as Pattern 9. In certain embodiments, the present invention provides a polymorph of Compound 2 referred to herein as Pattern 10. In certain embodiments, the present invention provides a polymorph of Compound 2 referred to herein as Pattern 11. In certain embodiments, the present invention provides a polymorph of Compound 2 referred to herein as Pattern 12. In certain embodiments, the present invention provides a polymorph of Compound 2 referred to herein as Pattern 13.

[0059] All of the HCl patterns provided were found to exhibit complex thermal behavior with an endothermic onset at low temperatures. In three instances of drying, the isolated material of Compound 2, Pattern 4, was observed to transform into Compound 2, Pattern 9.

[0060] 2. Compound 3 (L-Malic acid x Compound 1) According to one embodiment, the present invention provides Compound 3, a chemical species comprising Compound 1 and L-malic acid: [ka]

[0061] It is believed that Compound 3 can exist in various physical forms. For example, Compound 3 can be in a solution, a suspension, or a solid form. In certain embodiments, Compound 3 is in a solid form. When Compound 3 is in a solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0062] In one embodiment, the solid form of Compound 3 has a stoichiometric ratio of (Compound 1):(L-malic acid) that is about 1:1.

[0063] In some embodiments, the present invention provides Compound 3 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess L-malic acid, excess Compound 1, residual solvent, or any other impurities that may result from the preparation and / or isolation of Compound 3. In certain embodiments, at least about 95% by weight of Compound 3 is present. In yet other embodiments of the present invention, at least about 99% by weight of Compound 3 is present.

[0064] According to one embodiment, compound 3 is present in an amount of at least about 97.0, 97.5, 98.0, 98.5, 99.0, 99.5, or 99.8 weight percent, percentages based on the total weight of the composition. According to another embodiment, compound 3 contains less than or equal to about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than or equal to about 1.5 HPLC area percent of total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, compound 3 contains less than or equal to about 1.0 HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0065] The structure depicted for compound 3 is also meant to include all tautomeric forms of compound 3. Additionally, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 13 C- or 14 Compounds having the present structures except for the replacement of a carbon with a C-enriched carbon are within the scope of this invention.

[0066] It has been discovered that Compound 3 can exist in various solid forms. Exemplary such forms include polymorphs such as those described herein.

[0067] In some embodiments, Compound 3 is amorphous. In some embodiments, Compound 3 is amorphous and substantially free of crystalline Compound 3.

[0068] In certain embodiments, Compound 3 is a crystalline solid. In other embodiments, Compound 3 is a crystalline solid and is substantially free of amorphous Compound 3. As used herein, the term "substantially free of amorphous Compound 3" means that the compound does not contain significant amounts of amorphous Compound 3. In certain embodiments, at least about 95% by weight of crystalline Compound 3 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline Compound 3 is present.

[0069] It has been discovered that Compound 3 can exist in at least one polymorphic form. In some embodiments, the present invention provides a polymorph of Compound 3, referred to herein as Pattern 1. Compound 3 Pattern 1

[0070] In some embodiments, Pattern 1 of Compound 3 has at least 1, 2, 3, 4, or 5 X-ray powder diffraction (XRPD) peaks selected from the angles (2 theta ±0.2) listed in Table 7 below. [Table 7]

[0071] In some embodiments, pattern 1 of compound 3 is characterized by an X-ray powder diffraction (XRPD) pattern having diffractions at the following angles (2 theta ±0.2) and corresponding d-spacings (Angstroms ±0.2): [Table 8]

[0072] In some embodiments, Pattern 1 of Compound 3 is characterized by having one or more peaks in an X-ray powder diffraction pattern selected from peaks at about 6.2, 12.7, 17.3, 20.4, 25.3, and 26.4. In some embodiments, Pattern 1 of Compound 3 is characterized by having two or more peaks in an X-ray powder diffraction pattern selected from peaks at about 6.2, 12.7, 17.3, 20.4, 25.3, and 26.4. In some embodiments, Pattern 1 of Compound 3 is characterized by having three or more peaks in an X-ray powder diffraction pattern selected from peaks at about 6.2, 12.7, 17.3, 20.4, 25.3, and 26.4. In some embodiments, Pattern 1 of Compound 3 is characterized by having four or more peaks in an X-ray powder diffraction pattern selected from peaks at about 6.2, 12.7, 17.3, 20.4, 25.3, and 26.4. In some embodiments, Compound 3 has Pattern 1 characterized by an X-ray powder diffraction pattern having five or more peaks selected from peaks at about 6.2, 12.7, 17.3, 20.4, 25.3, and 26.4. In some embodiments, Compound 3 has Pattern 1 characterized by an X-ray powder diffraction pattern having all six peaks selected from peaks at about 6.2, 12.7, 17.3, 20.4, 25.3, and 26.4. In some embodiments, Compound 3 has Pattern 1 characterized by an X-ray powder diffraction pattern having all six peaks selected from peaks at about 6.2, 12.7, 17.3, 20.4, 25.3, and 26.4, corresponding to d-spacings (Angstroms±0.2) of 14.32, 6.97, 5.13, 4.34, 3.52, and 3.37 (respectively).

[0073] In certain embodiments, the X-ray powder diffraction pattern of Pattern 1 of Compound 3 is substantially similar to the XRPD provided in FIG.

[0074] A method for preparing pattern 1 of compound 3 is described below.

[0075] 4. Compound 4 (succinic acid x Compound 1) According to one embodiment, the present invention provides Compound 4, a species comprising Compound 1 and succinic acid: [ka]

[0076] In one embodiment, the solid form of Compound 4 has a stoichiometric ratio of (Compound 1):(succinic acid) that is about 1:1. As used herein, the term "about," when used in reference to a stoichiometric ratio, refers to a ratio of (Compound 1):(coformer, e.g., acid) of 1:(1±0.2), e.g., a ratio of 1:(1±0.2), a ratio of 1:(1±0.1), or a ratio of 1:(1±0.05).

[0077] In some embodiments, the present invention provides compound 4 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess succinic acid, excess compound 1, residual solvent, or any other impurities that may result from the preparation and / or isolation of compound 4. In certain embodiments, at least about 95% by weight of compound 4 is present. In yet other embodiments of the present invention, at least about 99% by weight of compound 4 is present.

[0078] According to one embodiment, compound 4 is present in an amount of at least about 97.0, 97.5, 98.0, 98.5, 99.0, 99.5, or 99.8 weight percent, percentages based on the total weight of the composition. According to another embodiment, compound 4 contains less than or equal to about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than or equal to about 1.5 HPLC area percent of total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, compound 4 contains less than or equal to about 1.0 HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0079] The structure depicted for compound 4 is also meant to include all tautomeric forms of compound 4. Additionally, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 13 C- or 14 Compounds having the present structures except for the replacement of a carbon with a C-enriched carbon are within the scope of this invention.

[0080] Compound 4 has been found to be capable of existing in various solid forms. Exemplary such forms include polymorphs such as those described herein.

[0081] In some embodiments, compound 4 is amorphous. In some embodiments, compound 4 is amorphous and substantially free of crystalline compound 4.

[0082] In certain embodiments, compound 4 is a crystalline solid. In other embodiments, compound 4 is a crystalline solid and is substantially free of amorphous compound 4. As used herein, the term "substantially free of amorphous compound 4" means that the compound does not contain a significant amount of amorphous compound 4. In certain embodiments, at least about 95% by weight of crystalline compound 4 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline compound 4 is present.

[0083] It has been discovered that Compound 4 can exist in at least one polymorphic form. In some embodiments, the present invention provides a polymorph of Compound 4, referred to herein as Pattern 1. Compound 4 Pattern 1

[0084] In some embodiments, Pattern 1 of Compound 4 has at least 1, 2, 3, 4, or 5 X-ray powder diffraction (XRPD) peaks selected from the angles (2 theta ±0.2) listed in Table 9 below. [Table 9]

[0085] In some embodiments, pattern 1 of compound 4 is characterized by an X-ray powder diffraction (XRPD) pattern having diffractions at the following angles (2 theta ±0.2) and corresponding d-spacings (Angstroms ±0.2): [Table 10]

[0086] In some embodiments, Pattern 1 of Compound 4 is characterized by having one or more peaks selected from peaks at about 6.2, 10.2, 12.7, 17.3, 20.4, and 23.8 in an X-ray powder diffraction pattern. In some embodiments, Pattern 1 of Compound 4 is characterized by having two or more peaks selected from peaks at about 6.2, 10.2, 12.7, 17.3, 20.4, and 23.8 in an X-ray powder diffraction pattern. In some embodiments, Pattern 1 of Compound 4 is characterized by having three or more peaks selected from peaks at about 6.2, 10.2, 12.7, 17.3, 20.4, and 23.8 in an X-ray powder diffraction pattern. In some embodiments, Pattern 1 of Compound 4 is characterized by having four or more peaks selected from peaks at about 6.2, 10.2, 12.7, 17.3, 20.4, and 23.8 in an X-ray powder diffraction pattern. In some embodiments, Compound 4 has Pattern 1 characterized by an X-ray powder diffraction pattern having five or more peaks selected from peaks at about 6.2, 10.2, 12.7, 17.3, 20.4, and 23.8. In some embodiments, Compound 4 has Pattern 1 characterized by an X-ray powder diffraction pattern having all six peaks selected from peaks at about 6.2, 10.2, 12.7, 17.3, 20.4, and 23.8. In some embodiments, Compound 4 has Pattern 1 characterized by an X-ray powder diffraction pattern having all six peaks selected from peaks at about 6.2, 10.2, 12.7, 17.3, 20.4, and 23.8, corresponding to d-spacings (Angstroms±0.2) of 14.26, 8.64, 6.95, 5.12, 4.35, and 3.73 (respectively).

[0087] In certain embodiments, the X-ray powder diffraction pattern of Compound 4 is substantially similar to the XRPD pattern provided in FIG.

[0088] A method for preparing pattern 1 of compound 4 is described below.

[0089] 5. Compound 5 (Phosphate x Compound 1) According to one embodiment, the present invention provides Compound 5, a chemical species comprising Compound 1 and phosphate: [ka]

[0090] In one embodiment, the solid form of Compound 5 has a stoichiometric ratio of (Compound 1):(phosphate) that is about 1:1.

[0091] In some embodiments, the present invention provides Compound 5 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess L-malic acid, excess Compound 1, residual solvent, or any other impurities that may result from the preparation and / or isolation of Compound 5. In certain embodiments, at least about 95% by weight of Compound 5 is present. In yet other embodiments of the present invention, at least about 99% by weight of Compound 5 is present.

[0092] According to one embodiment, compound 5 is present in an amount of at least about 97.0, 97.5, 98.0, 98.5, 99.0, 99.5, or 99.8 weight percent, where percentages are based on the total weight of the composition. According to another embodiment, compound 5 contains less than or equal to about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than or equal to about 1.5 HPLC area percent of total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, compound 5 contains less than or equal to about 1.0 HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0093] The structure depicted for compound 5 is also meant to include all tautomeric forms of compound 5. Additionally, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 13 C- or 14 Compounds having the present structures except for the replacement of a carbon with a C-enriched carbon are within the scope of this invention.

[0094] Compound 5 has been found to be capable of existing in various solid forms. Exemplary such forms include polymorphs such as those described herein.

[0095] In some embodiments, Compound 5 is amorphous. In some embodiments, Compound 5 is amorphous and substantially free of crystalline Compound 5.

[0096] In certain embodiments, Compound 5 is a crystalline solid. In other embodiments, Compound 5 is a crystalline solid and is substantially free of amorphous Compound 5. As used herein, the term "substantially free of amorphous Compound 5" means that the compound does not contain significant amounts of amorphous Compound 5. In certain embodiments, at least about 95% by weight of crystalline Compound 5 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline Compound 5 is present.

[0097] It has been discovered that Compound 5 can exist in at least one polymorphic form. In some embodiments, the present invention provides a polymorph of Compound 5, referred to herein as Pattern 1.

[0098] Compound 5 Pattern 1 In some embodiments, Pattern 1 of Compound 5 has at least 1, 2, 3, 4, or 5 X-ray powder diffraction (XRPD) peaks selected from the angles (2 theta ±0.2) listed in Table 11 below. [Table 11]

[0099] In some embodiments, pattern 1 of compound 5 is characterized by an X-ray powder diffraction (XRPD) pattern having diffractions at the following angles (2 theta ±0.2) and corresponding d-spacings (Angstroms ±0.2): [Table 12]

[0100] In some embodiments, Pattern 1 of Compound 5 is characterized by having one or more peaks in an X-ray powder diffraction pattern selected from peaks at about 4.7, 6.1, 17.0, 17.4, 18.1, and 24.6. In some embodiments, Pattern 1 of Compound 5 is characterized by having two or more peaks in an X-ray powder diffraction pattern selected from peaks at about 4.7, 6.1, 17.0, 17.4, 18.1, and 24.6. In some embodiments, Pattern 1 of Compound 5 is characterized by having three or more peaks in an X-ray powder diffraction pattern selected from peaks at about 4.7, 6.1, 17.0, 17.4, 18.1, and 24.6. In some embodiments, Pattern 1 of Compound 5 is characterized by having four or more peaks in an X-ray powder diffraction pattern selected from peaks at about 4.7, 6.1, 17.0, 17.4, 18.1, and 24.6. In some embodiments, Compound 5, Pattern 1, is characterized by having five or more peaks in an X-ray powder diffraction pattern selected from peaks at about 4.7, 6.1, 17.0, 17.4, 18.1, and 24.6. In some embodiments, Compound 5, Pattern 1, is characterized by having all six peaks in an X-ray powder diffraction pattern selected from peaks at about 4.7, 6.1, 17.0, 17.4, 18.1, and 24.6. In some embodiments, Compound 5, Pattern 1, is characterized by having all six peaks in an X-ray powder diffraction pattern selected from peaks at about 4.7, 6.1, 17.0, 17.4, 18.1, and 24.6, corresponding to d-spacings (Angstroms±0.2) of 18.68, 14.45, 5.20, 5.10, 4.91, and 3.62 (respectively).

[0101] In certain embodiments, the X-ray powder diffraction pattern of Pattern 1 of Compound 5 is substantially similar to the XRPD provided in FIG.

[0102] A method for preparing Compound 5, Pattern 1, is described below.

[0103] 6. Compound 6 (Oxalic acid x Compound 1) According to one embodiment, the present invention provides Compound 6, a chemical species comprising Compound 1 and oxalic acid: [ka]

[0104] In one embodiment, the solid form of Compound 6 has a stoichiometric ratio of (Compound 1):(oxalic acid) that is about 1:1.

[0105] In some embodiments, the present invention provides Compound 6 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess oxalic acid, excess Compound 1, residual solvent, or any other impurities that may result from the preparation and / or isolation of Compound 6. In certain embodiments, at least about 95% by weight of Compound 6 is present. In yet other embodiments of the present invention, at least about 99% by weight of Compound 6 is present.

[0106] According to one embodiment, compound 6 is present in an amount of at least about 97.0, 97.5, 98.0, 98.5, 99.0, 99.5, or 99.8 weight percent, where percentages are based on the total weight of the composition. According to another embodiment, compound 6 contains less than or equal to about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than or equal to about 1.5 HPLC area percent of total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, compound 6 contains less than or equal to about 1.0 HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0107] The structure shown for compound 6 is also meant to include all tautomeric forms of compound 6. Additionally, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 13 C- or 14 Compounds having the present structures except for the replacement of a carbon with a C-enriched carbon are within the scope of this invention.

[0108] Compound 6 has been found to be capable of existing in various solid forms. Exemplary such forms include polymorphs such as those described herein.

[0109] In some embodiments, compound 6 is amorphous. In some embodiments, compound 4 is amorphous and substantially free of crystalline compound 6.

[0110] In certain embodiments, Compound 6 is a crystalline solid. In other embodiments, Compound 6 is a crystalline solid and is substantially free of amorphous Compound 6. As used herein, the term "substantially free of amorphous Compound 6" means that the compound does not contain a significant amount of amorphous Compound 6. In certain embodiments, at least about 95% by weight of crystalline Compound 6 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline Compound 6 is present.

[0111] It has been discovered that Compound 6 can exist in at least two polymorphic forms. In some embodiments, the present invention provides a polymorph of Compound 6, referred to herein as Pattern 1. In some embodiments, the present invention provides a polymorph of Compound 6, referred to herein as Pattern 4.

[0112] Compound 6 Pattern 1 In some embodiments, Pattern 1 of Compound 6 has at least 1, 2, 3, 4, or 5 X-ray powder diffraction (XRPD) peaks selected from the angles (2 theta ±0.2) listed in Table 13 below. [Table 13]

[0113] In some embodiments, pattern 1 of compound 6 is characterized by an X-ray powder diffraction (XRPD) pattern having diffractions at the following angles (2 theta ±0.2) and corresponding d-spacings (Angstroms ±0.2): [Table 14]

[0114] In some embodiments, Pattern 1 of Compound 6 is characterized by having one or more peaks selected from peaks at about 4.7, 6.1, 18.7, 24.0, 24.2, and 24.6 in an X-ray powder diffraction pattern. In some embodiments, Pattern 1 of Compound 6 is characterized by having two or more peaks selected from peaks at about 4.7, 6.1, 18.7, 24.0, 24.2, and 24.6 in an X-ray powder diffraction pattern. In some embodiments, Pattern 1 of Compound 6 is characterized by having three or more peaks selected from peaks at about 4.7, 6.1, 18.7, 24.0, 24.2, and 24.6 in an X-ray powder diffraction pattern. In some embodiments, Pattern 1 of Compound 6 is characterized by having four or more peaks selected from peaks at about 4.7, 6.1, 18.7, 24.0, 24.2, and 24.6 in an X-ray powder diffraction pattern. In some embodiments, Compound 6 Pattern 1 is characterized by having five or more peaks in an X-ray powder diffraction pattern selected from peaks at about 4.7, 6.1, 18.7, 24.0, 24.2, and 24.6. In some embodiments, Compound 6 Pattern 1 is characterized by having all six peaks in an X-ray powder diffraction pattern selected from peaks at about 4.7, 6.1, 18.7, 24.0, 24.2, and 24.6. In some embodiments, Compound 6 Pattern 1 is characterized by having all six peaks in an X-ray powder diffraction pattern selected from peaks at about 4.7, 6.1, 18.7, 24.0, 24.2, and 24.6, corresponding to d-spacings (Angstroms±0.2) of 18.88, 14.36, 4.73, 3.71, 3.67, and 3.62 (respectively).

[0115] In certain embodiments, the X-ray powder diffraction pattern of Pattern 1 of Compound 6 is substantially similar to the XRPD provided in FIG.

[0116] A method for preparing pattern 1 of compound 6 is described below.

[0117] Compound 6 Pattern 4 In some embodiments, pattern 4 of compound 6 has at least 1, 2, 3, 4, or 5 X-ray powder diffraction (XRPD) peaks selected from the angles (2 theta ±0.2) listed in Table 15 below. [Table 15]

[0118] In some embodiments, pattern 4 of compound 6 is characterized by an X-ray powder diffraction (XRPD) pattern having diffractions at the following angles (2 theta ±0.2) and corresponding d-spacings (Angstroms ±0.2): [Table 16]

[0119] In some embodiments, Pattern 4 of Compound 6 is characterized by having one or more peaks selected from peaks at about 6.4, 11.9, 19.2, 26.1, 26.6, and 27.2 in an X-ray powder diffraction pattern. In some embodiments, Pattern 4 of Compound 6 is characterized by having two or more peaks selected from peaks at about 6.4, 11.9, 19.2, 26.1, 26.6, and 27.2 in an X-ray powder diffraction pattern. In some embodiments, Pattern 4 of Compound 6 is characterized by having three or more peaks selected from peaks at about 6.4, 11.9, 19.2, 26.1, 26.6, and 27.2 in an X-ray powder diffraction pattern. In some embodiments, Pattern 4 of Compound 6 is characterized by having four or more peaks selected from peaks at about 6.4, 11.9, 19.2, 26.1, 26.6, and 27.2 in an X-ray powder diffraction pattern. In some embodiments, Compound 6 has Pattern 4 characterized by an X-ray powder diffraction pattern having five or more peaks selected from peaks at about 6.4, 11.9, 19.2, 26.1, 26.6, and 27.2. In some embodiments, Compound 6 has Pattern 4 characterized by an X-ray powder diffraction pattern having all six peaks selected from peaks at about 6.4, 11.9, 19.2, 26.1, 26.6, and 27.2. In some embodiments, Compound 6 has Pattern 4 characterized by an X-ray powder diffraction pattern having all six peaks selected from peaks at about 6.4, 11.9, 19.2, 26.1, 26.6, and 27.2, corresponding to d-spacings (Angstroms±0.2) of 13.89, 7.43, 4.63, 3.42, 3.35, and 3.27 (respectively).

[0120] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0121] A method for preparing pattern 4 of compound 6 is described below.

[0122] 7. Compound 7 (L-tartaric acid x compound 1) According to one embodiment, the present invention provides Compound 7, a chemical species comprising Compound 1 and L-tartaric acid: [ka]

[0123] In one embodiment, the solid form of Compound 7 has a stoichiometric ratio of (Compound 1):(L-tartaric acid) that is about 1:1.

[0124] In some embodiments, the present invention provides compound 7 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound is free of significant amounts of contaminants. Such contaminants may include excess L-tartaric acid, excess compound 1, residual solvent, or any other impurities that may result from the preparation and / or isolation of compound 7. In certain embodiments, at least about 95% by weight of compound 7 is present. In yet other embodiments of the present invention, at least about 99% by weight of compound 7 is present.

[0125] According to one embodiment, compound 7 is present in an amount of at least about 97.0, 97.5, 98.0, 98.5, 99.0, 99.5, or 99.8 weight percent, where percentages are based on the total weight of the composition. According to another embodiment, compound 7 contains less than or equal to about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than or equal to about 1.5 HPLC area percent of total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, compound 7 contains less than or equal to about 1.0 HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0126] The structure depicted for compound 7 is also meant to include all tautomeric forms of compound 7. Additionally, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of a hydrogen with deuterium or tritium, or 13 C- or 14 Compounds having the present structures except for the replacement of a carbon with a C-enriched carbon are within the scope of this invention.

[0127] Compound 7 has been found to be capable of existing in various solid forms. Exemplary such forms include polymorphs such as those described herein.

[0128] In some embodiments, compound 7 is amorphous. In some embodiments, compound 7 is amorphous and substantially free of crystalline compound 7.

[0129] In certain embodiments, compound 7 is a crystalline solid. In other embodiments, compound 7 is a crystalline solid and is substantially free of amorphous compound 7. As used herein, the term "substantially free of amorphous compound 7" means that the compound does not contain a significant amount of amorphous compound 7. In certain embodiments, at least about 95% by weight of crystalline compound 7 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline compound 7 is present.

[0130] It has been discovered that Compound 7 can exist in at least one polymorphic form. In some embodiments, the present invention provides a polymorph of Compound 7, referred to herein as Pattern 1.

[0131] 8. Compound 8 (methanesulfonic acid x Compound 1) According to one embodiment, the present invention provides compound 8, a chemical species comprising compound 1 and methanesulfonic acid: [ka]

[0132] In one embodiment, the solid form of Compound 8 has a stoichiometric ratio of (Compound 1):(methanesulfonic acid) that is about 1:1.

[0133] In some embodiments, the present invention provides compound 8 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess methanesulfonic acid, excess compound 1, residual solvent, or any other impurities that may result from the preparation and / or isolation of compound 8. In certain embodiments, at least about 95% by weight of compound 8 is present. In yet other embodiments of the present invention, at least about 99% by weight of compound 8 is present.

[0134] According to one embodiment, compound 8 is present in an amount of at least about 97.0, 97.5, 98.0, 98.5, 99.0, 99.5, or 99.8 weight percent, where percentages are based on the total weight of the composition. According to another embodiment, compound 8 contains less than or equal to about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than or equal to about 1.5 HPLC area percent of total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, compound 8 contains less than or equal to about 1.0 HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0135] The structure depicted for compound 8 is also meant to include all tautomeric forms of compound 8. Additionally, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of a hydrogen with deuterium or tritium, or 13 C- or 14 Compounds having the present structures except for the replacement of a carbon with a C-enriched carbon are within the scope of this invention.

[0136] Compound 8 has been found to be capable of existing in various solid forms. Exemplary such forms include polymorphs such as those described herein.

[0137] In some embodiments, Compound 8 is amorphous. In some embodiments, Compound 8 is amorphous and substantially free of crystalline Compound 8.

[0138] In certain embodiments, compound 8 is a crystalline solid. In other embodiments, compound 8 is a crystalline solid and is substantially free of amorphous compound 8. As used herein, the term "substantially free of amorphous compound 8" means that the compound does not contain a significant amount of amorphous compound 8. In certain embodiments, at least about 95% by weight of crystalline compound 8 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline compound 8 is present.

[0139] It has been discovered that Compound 8 can exist in at least one polymorphic form. In some embodiments, the present invention provides a polymorph of Compound 8 referred to herein as Pattern 1. In some embodiments, the present invention provides a polymorph of Compound 8 referred to herein as Pattern 2. In embodiments, the present invention provides a polymorph of Compound 8 referred to herein as Pattern 3.

[0140] 9. Compound 9 (fumaric acid x compound 1) According to one embodiment, the present invention provides compound 9, a chemical species comprising compound 1 and fumaric acid: [ka]

[0141] In one embodiment, the solid form of Compound 9 has a stoichiometric ratio of (Compound 1):(fumaric acid) that is about 1:1.

[0142] In some embodiments, the present invention provides Compound 9 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound is free of significant amounts of contaminants. Such contaminants may include excess fumaric acid, excess Compound 1, residual solvent, or any other impurities that may result from the preparation and / or isolation of Compound 9. In certain embodiments, at least about 95% by weight of Compound 9 is present. In yet other embodiments of the present invention, at least about 99% by weight of Compound 9 is present.

[0143] According to one embodiment, compound 9 is present in an amount of at least about 97.0, 97.5, 98.0, 98.5, 99.0, 99.5, or 99.8 weight percent, where percentages are based on the total weight of the composition. According to another embodiment, compound 9 contains less than or equal to about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than or equal to about 1.5 HPLC area percent of total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, compound 9 contains less than or equal to about 1.0 HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0144] The structure depicted for compound 9 is also meant to include all tautomeric forms of compound 9. Additionally, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of a hydrogen with deuterium or tritium, or 13 C- or 14 Compounds having the present structures except for the replacement of a carbon with a C-enriched carbon are within the scope of this invention.

[0145] Compound 9 has been found to be capable of existing in various solid forms. Exemplary such forms include polymorphs such as those described herein.

[0146] In some embodiments, Compound 9 is amorphous. In some embodiments, Compound 9 is amorphous and substantially free of crystalline Compound 9.

[0147] In certain embodiments, compound 9 is a crystalline solid. In other embodiments, compound 9 is a crystalline solid and is substantially free of amorphous compound 9. As used herein, the term "substantially free of amorphous compound 9" means that the compound does not contain a significant amount of amorphous compound 9. In certain embodiments, at least about 95% by weight of crystalline compound 9 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline compound 9 is present.

[0148] It has been discovered that Compound 9 can exist in at least one polymorphic form. In some embodiments, the present invention provides a polymorph of Compound 9, referred to herein as Pattern 1.

[0149] Compound 9 Pattern 1 In some embodiments, Pattern 1 of Compound 9 has at least 1, 2, 3, 4, or 5 X-ray powder diffraction (XRPD) peaks selected from the angles (2 theta ±0.2) listed in Table 17 below. [Table 17]

[0150] In some embodiments, pattern 1 of compound 9 is characterized by an X-ray powder diffraction (XRPD) pattern having diffractions at the following angles (2 theta ±0.2) and corresponding d-spacings (Angstroms ±0.2): [Table 18]

[0151] In some embodiments, Pattern 1 of Compound 9 is characterized by having one or more peaks in an X-ray powder diffraction pattern selected from peaks at about 6.1, 10.8, 12.7, 20.4, 25.3, and 26.5. In some embodiments, Pattern 1 of Compound 9 is characterized by having two or more peaks in an X-ray powder diffraction pattern selected from peaks at about 6.1, 10.8, 12.7, 20.4, 25.3, and 26.5. In some embodiments, Pattern 1 of Compound 9 is characterized by having three or more peaks in an X-ray powder diffraction pattern selected from peaks at about 6.1, 10.8, 12.7, 20.4, 25.3, and 26.5. In some embodiments, Pattern 1 of Compound 9 is characterized by having four or more peaks in an X-ray powder diffraction pattern selected from peaks at about 6.1, 10.8, 12.7, 20.4, 25.3, and 26.5. In some embodiments, Compound 9's Pattern 1 is characterized by having five or more peaks in an X-ray powder diffraction pattern selected from peaks at about 6.1, 10.8, 12.7, 20.4, 25.3, and 26.5. In some embodiments, Compound 9's Pattern 1 is characterized by having all six peaks in an X-ray powder diffraction pattern selected from peaks at about 6.1, 10.8, 12.7, 20.4, 25.3, and 26.5. In some embodiments, Compound 6's Pattern 4 is characterized by having all six peaks in an X-ray powder diffraction pattern selected from peaks at about 6.1, 10.8, 12.7, 20.4, 25.3, and 26.5, corresponding to d-spacings (Angstroms±0.2) of 14.4, 8.19, 6.96, 4.34, 3.52, and 3.36 (respectively).

[0152] In certain embodiments, the X-ray powder diffraction pattern of Pattern 1 of Compound 9 is substantially similar to the XRPD provided in FIG.

[0153] A method for preparing pattern 1 of compound 9 is described below.

[0154] III. Cocrystal form 10. Compound 10 (Methyl gallate x Compound 1) According to one embodiment, the present invention provides compound 10, a chemical species comprising compound 1 and methyl gallate: [ka]

[0155] In one embodiment, the solid form of Compound 10 has a stoichiometric ratio of (Compound 1):(methyl gallate) that is about 1:1.

[0156] In some embodiments, the present invention provides compound 10 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess methyl gallate, excess compound 1, residual solvent, or any other impurities that may result from the preparation and / or isolation of compound 10. In certain embodiments, at least about 95% by weight of compound 10 is present. In yet other embodiments of the present invention, at least about 99% by weight of compound 10 is present.

[0157] According to one embodiment, compound 10 is present in an amount of at least about 97.0, 97.5, 98.0, 98.5, 99.0, 99.5, or 99.8 weight percent, with percentages based on the total weight of the composition. According to another embodiment, compound 10 contains less than or equal to about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than or equal to about 1.5 HPLC area percent of total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, compound 10 contains less than or equal to about 1.0 HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0158] The structure depicted for compound 10 is also meant to include all tautomeric forms of compound 10. Additionally, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of a hydrogen by deuterium or tritium, or 13 C- or 14 Compounds having the present structures except for the replacement of a carbon with a C-enriched carbon are within the scope of this invention.

[0159] It has been discovered that compound 10 can exist in various solid forms. Exemplary such forms include polymorphs such as those described herein.

[0160] In some embodiments, Compound 10 is amorphous. In some embodiments, Compound 10 is amorphous and substantially free of crystalline Compound 10.

[0161] In certain embodiments, Compound 10 is a crystalline solid. In other embodiments, Compound 10 is a crystalline solid and is substantially free of amorphous Compound 10. As used herein, the term "substantially free of amorphous Compound 10" means that the compound does not contain significant amounts of amorphous Compound 10. In certain embodiments, at least about 95% by weight of crystalline Compound 10 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline Compound 10 is present.

[0162] It has been discovered that Compound 10 can exist in at least one polymorphic form. In some embodiments, the present invention provides a polymorph of Compound 10, referred to herein as Pattern 1.

[0163] 11. Compound 11 (Propyl gallate x Compound 1) According to one embodiment, the present invention provides compound 11, a species comprising compound 1 and propyl gallate: [ka]

[0164] In one embodiment, the solid form of Compound 11 has a stoichiometric ratio of (Compound 1):(propyl gallate) that is about 1:1.

[0165] In some embodiments, the present invention provides compound 11 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include excess propyl gallate, excess compound 1, residual solvent, or any other impurities that may result from the preparation and / or isolation of compound 11. In certain embodiments, at least about 95% by weight of compound 11 is present. In yet other embodiments of the present invention, at least about 99% by weight of compound 11 is present.

[0166] According to one embodiment, compound 11 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 percent by weight, where the percentages are based on the total weight of the composition. According to another embodiment, compound 11 contains less than or equal to about 3.0 HPLC area percent of total organic impurities, and in certain embodiments, less than or equal to about 1.5 HPLC area percent of total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, compound 11 contains less than or equal to about 1.0 HPLC area percent of any single impurity, less than or equal to about 0.6 HPLC area percent of any single impurity, and in certain embodiments, less than or equal to about 0.5 HPLC area percent of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0167] The structure shown for compound 11 is also meant to include all tautomeric forms of compound 11. Additionally, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of a hydrogen by deuterium or tritium, or 13 C- or 14Compounds having the present structures except for the replacement of a carbon with a C-enriched carbon are within the scope of this invention.

[0168] Compound 11 has been found to be capable of existing in various solid forms. Exemplary such forms include polymorphs such as those described herein.

[0169] In certain embodiments, compound 11 is a crystalline solid. In other embodiments, compound 11 is a crystalline solid and is substantially free of amorphous compound 11. As used herein, the term "substantially free of amorphous compound 11" means that the compound does not contain a significant amount of amorphous compound 11. In certain embodiments, at least about 95% by weight of crystalline compound 11 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline compound 11 is present.

[0170] It has been discovered that Compound 11 can exist in at least one polymorphic form. In some embodiments, the present invention provides a polymorph of Compound 11, referred to herein as Pattern 1.

[0171] In some embodiments, compound 11 is amorphous. In some embodiments, compound 11 is amorphous and substantially free of crystalline compound 11.

[0172] General Methods for Providing Compounds Compound 1 is prepared according to the methods detailed in the '129 publication, which is incorporated herein by reference in its entirety.

[0173] Acid addition compounds of general formula A, including, among others, compounds 2-9, and / or specific forms thereof, are prepared from compound 1 according to the following general scheme. [ka]

[0174] In this scheme, "acid" represents, for example, any of the coformers described herein. For example, each of compounds 2-9, and forms thereof, is prepared from compound 1 by combining compound 1 with an appropriate acid to form the product compound. Accordingly, another aspect of the present invention provides a method for preparing compounds 2-9, and forms thereof, by combining compound 1 with an appropriate acid to form the product compound.

[0175] As generally described above, in some embodiments, the present invention provides a method for preparing Compound A, comprising: [ka] [ka] with a suitable coformer (e.g., a suitable acid) and optionally a suitable solvent under conditions suitable to form compound A.

[0176] In some embodiments, compound 1 is treated with a coformer selected from hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, L-malic acid, phosphoric acid, gentisic acid, salicylic acid, L-tartaric acid, fumaric acid, citric acid, 4-aminosalicylic acid, L-maleic acid, benzoic acid, succinic acid, nicotinic acid, sorbic acid, methyl gallate, and propyl gallate.

[0177] In some embodiments, a suitable coformer is hydrochloric acid.

[0178] In some embodiments, a suitable coformer is sulfuric acid.

[0179] In some embodiments, a suitable coformer is p-toluenesulfonic acid.

[0180] In some embodiments, a suitable coformer is methanesulfonic acid.

[0181] In some embodiments, a suitable coformer is oxalic acid.

[0182] In some embodiments, a suitable coformer is L-malic acid.

[0183] In some embodiments, a suitable coformer is phosphoric acid.

[0184] In some embodiments, a suitable coformer is gentisic acid.

[0185] In some embodiments, a suitable coformer is salicylic acid.

[0186] In some embodiments, a suitable coformer is L-tartaric acid.

[0187] In some embodiments, a suitable coformer is fumaric acid.

[0188] In some embodiments, a suitable coformer is citric acid.

[0189] In some embodiments, a suitable coformer is 4-aminosalicylic acid.

[0190] In some embodiments, a suitable coformer is maleic acid.

[0191] In some embodiments, a suitable coformer is benzoic acid.

[0192] In some embodiments, a suitable coformer is succinic acid.

[0193] In some embodiments, a suitable coformer is nicotinic acid.

[0194] In some embodiments, a suitable coformer is sorbic acid.

[0195] In some embodiments, a suitable coformer is methyl gallate.

[0196] In some embodiments, a suitable coformer is propyl gallate.

[0197] A suitable solvent can be any solvent system (eg, one solvent or mixture of solvents) in which Compound 1 and / or the acid are soluble or at least partially soluble.

[0198] Examples of suitable solvents useful in the present invention 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.

[0199] In certain embodiments, the suitable solvent is methanol, ethanol, isopropanol, t-butanol, acetonitrile, tetrahydrofuran (THF), or acetone, wherein the solvent is anhydrous or in combination with water or dichloromethane (DCM). In some embodiments, suitable solvents include n-heptane, ethyl acetate, methyl ethyl ketone (MEK), tert-butyl methyl ether (TBME), isopropyl acetate (IPAC), methyl isobutyl ketone (MIBK), dimethylformamide (DMF), dimethylacetamide (DMAC), dimethyl sulfoxide (DMSO), toluene, trifluorotoluene, anisole, chlorobenzene, cumene, or N-methylpyrrolidone (NMP). In some embodiments, the suitable solvent is acetone. In some embodiments, the suitable solvent is methanol. In some embodiments, the solvent is ethyl acetate. In some embodiments, the suitable solvent is a combination of the above solvents.

[0200] In some embodiments, the present invention provides a method of preparing the free base form of Compound 1 or Compound A, comprising one or more of the steps of removing solvent and adding solvent. In some embodiments, the added solvent is the same as the removed solvent. In some embodiments, the added solvent is different from the removed solvent. Means for solvent removal are known in the synthetic and chemical arts and include, but are not limited to, any of those described herein and in the examples.

[0201] In some embodiments, the method of preparing the free base form of Compound 1 or Compound A includes one or more of heating or cooling the preparation.

[0202] In some embodiments, the method of preparing the free base form of Compound 1 or Compound A includes one or more of the steps of stirring the preparation or stirring the preparation.

[0203] In some embodiments, the method of preparing the free base form of Compound 1 or Compound A comprises adding a suitable coformer to a solution or slurry of Compound 1.

[0204] In some embodiments, the method of preparing the free base form of Compound 1 or Compound A comprises adding a suitable acid to a solution or slurry of Compound 1.

[0205] In some embodiments, the method of preparing the free base form of Compound 1 or Compound A comprises a heating step.

[0206] In certain embodiments, the free base form of Compound 1 or Compound A precipitates from the mixture. In other embodiments, the free base form of Compound 1 or Compound A crystallizes from the mixture. In other aspects, the free base form of Compound 1 or Compound A crystallizes from the solution following seeding of the solution (i.e., adding crystals of the free base form of Compound 1 or Compound A to the solution).

[0207] The free base form of Compound 1 or Compound A 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, or by adding a suitable anti-solvent such as, but not limited to, heptane, cumene, toluene, and TBME, by cooling, or by different combinations of these methods.

[0208] As generally described above, the free base form of Compound 1 or Compound A is optionally isolated. It is understood that the free base form of Compound 1 or Compound A can be isolated by any suitable physical means known to those skilled in the art. In certain embodiments, the precipitated solid free base form of Compound 1 or Compound A is separated from the supernatant by filtration. In other embodiments, the precipitated solid free base form of Compound 1 or Compound A is separated from the supernatant by decanting the supernatant.

[0209] In certain embodiments, the free base form of Compound 1 or Compound A is separated from the supernatant by filtration.

[0210] In certain embodiments, the isolated free base form of Compound 1 or Compound A is dried in air. In other embodiments, the isolated free base form of Compound 1 or Compound A is dried under reduced pressure, optionally at elevated temperature.

[0211] How to use In certain embodiments, a compound of the invention (e.g., any of Compounds 1-11) is for use in medicine. In some embodiments, a compound of the invention is useful as a serine protease zymogen inhibitor. In certain embodiments, a compound of the invention is a selective inhibitor of plasma kallikrein (pKal). In some embodiments, the invention provides methods for reducing pKal activity. Such methods include contacting pKal with an effective amount of a provided compound. Accordingly, the invention further provides methods for inhibiting pKal activity by contacting pKal with a compound of the invention.

[0212] In some embodiments, provided compounds are useful for treating diseases and disorders that can be alleviated by inhibiting (i.e., decreasing) pKal activity. By "disease" is meant a disease or a symptom of a disease. Accordingly, the present invention provides methods for treating a pKal-mediated disorder in a subject in need thereof. Such methods include administering a therapeutically effective amount of a provided compound to the subject.

[0213] Exemplary pKal-mediated disorders include edema, which refers to swelling throughout a subject's entire body or a portion thereof due to inflammation or injury when small blood vessels become leaky and release fluid into surrounding tissues. In some examples, the edema is hereditary angioedema (HAE). In other examples, the edema occurs in the eye (e.g., diabetic macular edema (DME)). The present disclosure provides methods for inhibiting the activity of pKal. In certain embodiments, the present application provides methods for inhibiting the activity of pKal in vitro by contacting any of the compounds described herein with pKal molecules in a sample, e.g., a biological sample. In certain embodiments, the present application provides methods for inhibiting the activity of pKal in vivo by delivering an effective amount of any of the compounds described herein to a subject in need of treatment by a suitable route.

[0214] In certain embodiments, provided methods include administering any of the compounds described herein to a subject in need thereof (e.g., a subject, such as a human patient, having edema). In certain embodiments, the methods include administering a compound of Formulas 1-11, or a pharmaceutically acceptable salt or composition thereof, to a subject in need thereof. In some embodiments, the methods include administering a pharmaceutical composition comprising a compound of Formulas 1-11.

[0215] In certain embodiments, the subject treated by any of the methods described herein is a human patient who has, is suspected to have, or is at risk of having edema, such as HAE or DME.Subjects with edema can be identified by routine medical examination, for example, clinical examination.Subjects suspected to have edema can show one or more symptoms of disease / disorder.Subjects at risk of edema can have one or more of the risk factors related to disease, for example, C1 inhibitor (C1-INH) deficiency for HAE.

[0216] In certain embodiments, provided herein is a method for alleviating one or more symptoms of HAE in a human patient suffering from an HAE attack. Such patients can be identified through routine medical procedures. An effective amount of one or more of the provided compounds can be administered to a human patient by an appropriate route, such as those described herein. The compounds described herein can be used alone or in combination with other anti-HAE drugs, such as C1 esterase inhibitors (e.g., Cinryze® or Berinert®), pKal inhibitors (e.g., ecallantide or lanadelumab), or bradykinin B2 receptor antagonists (e.g., Firazyr®).

[0217] In another embodiment, a method for reducing the risk of HAE attacks in a human HAE patient in a quiescent state is provided herein. Such patients can be identified based on various factors, including a history of HAE attacks. An effective amount of one or more of the compounds can be administered to a human patient by an appropriate route, such as those described herein. The compounds described herein can be used alone or in combination with other anti-HAE agents, such as C1 esterase inhibitors (e.g., Cinryze® or Berinert®), pKal inhibitors (e.g., ecallantide or lanadelumab), or bradykinin B2 receptor antagonists (e.g., Firazyr®).

[0218] In yet another embodiment, provided herein is a preventive treatment of HAE in human patients at risk of HAE attacks using one or more of the compounds described herein.Patients suitable for such preventive treatment may be human subjects with a history of HAE attacks (e.g., human subjects experiencing more than two attacks per month).Alternatively, patients suitable for preventive treatment may be human subjects without a history of HAE attacks but with one or more risk factors for HAE (e.g., family history, genetic defects in the C1-INH gene, etc.).Such preventive treatment may include a compound described herein as the only active agent, or may include an additional anti-HAE agent, such as one described herein.

[0219] In certain embodiments, provided herein are methods for preventing or reducing edema in the eye of a subject (e.g., a human patient). In some examples, the human patient is a diabetic patient who has, is suspected of having, or is at risk for diabetic macular edema (DME). DME is a proliferative form of diabetic retinopathy characterized by swelling of the retinal layers, neovascularization, vascular leakage, and retinal thickening in diabetes due to leakage of fluid from blood vessels in the macula. In certain embodiments of practicing this method, an effective amount of one or more compounds described herein, or a pharmaceutically acceptable salt thereof, can be delivered to the eye of a subject in need of treatment. For example, the compound can be delivered by intraocular or intravitreal injection. The subject can be treated with a compound described herein, either as the sole active agent or in combination with another treatment for DME. Non-limiting examples of treatments for DME include laser photocoagulation, steroids, VEGF pathway targeting agents (e.g., Lucentis® (ranibizumab) or Eylea® (aflibercept)), and / or anti-PDGF agents.

[0220] In certain embodiments, the methods disclosed herein include administering to a subject an effective amount of a compound of Formulas 1-11. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount.

[0221] In certain embodiments, the subject to be treated is an animal. The animal may be of either sex and at any stage of development. In certain embodiments, the subject is a mammal. In certain embodiments, the subject to be treated is a human. In certain embodiments, the subject is a domestic animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In other embodiments, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal.

[0222] Certain methods described herein may include administering one or more additional pharmaceutical agents in combination with a compound described herein. The additional pharmaceutical agent(s) may be administered simultaneously with the compound of Formulas 1-11 or at a different time than the compound of Formulas 1-11. For example, the compound of Formulas 1-11 and any additional pharmaceutical agent(s) may be on the same administration schedule or different administration schedules. All or a portion of the dose of the compound of Formulas 1-11 may be administered before all or a portion of the dose of the additional pharmaceutical agent, after all or a portion of the dose of the additional pharmaceutical agent, within the administration schedule of the additional pharmaceutical agent, or a combination thereof. The timing of administration of the compound of Formulas 1-11 and the additional pharmaceutical agent may vary depending on the additional pharmaceutical agent.

[0223] In certain embodiments, the additional pharmaceutical agent comprises an agent useful in the treatment of edema, e.g., HAE or DME. Examples of such agents are provided herein.

[0224] Assay To develop useful pKal inhibitors, candidate inhibitors capable of reducing pKal activity can be identified in vitro, and the activity of inhibitor compounds can be assayed using methods known in the art and / or those methods provided herein.

[0225] Pharmaceutical Composition In another aspect, the present invention provides a pharmaceutical composition comprising any of the compounds described herein (e.g., any of the compounds of Formulas 1-11), or any of the compounds described herein (e.g., any of the compounds of Formulas 1-11) in combination with a pharmaceutically acceptable excipient (e.g., carrier).

[0226] The pharmaceutical compositions include enantiomers, diastereomers, or pharmaceutically acceptable salts of the inhibitors disclosed herein.

[0227] As used herein, "pharmaceutically acceptable carrier" refers to a pharmaceutical excipient, e.g., a pharmaceutically and physiologically acceptable organic or inorganic carrier substance suitable for enteral or parenteral administration that does not adversely react with the active agent. Suitable pharmaceutically acceptable carriers include water, salt solutions (e.g., Ringer's solution), alcohol, oils, lipids, gelatin, and carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, and polyvinylpyrrolidine. Such preparations may be sterilized and, if necessary, may be mixed with auxiliary substances, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or flavoring agents, which do not adversely react with the compounds of the present invention.

[0228] The compounds of the present invention can be administered alone or co-administered. Co-administration is meant to include administering the compounds individually or in combination (two or more compounds), simultaneously or sequentially. The formulation can also be combined with other active substances, if necessary (for example, to reduce metabolic degradation).

[0229] formulation The compounds of the present invention can be prepared and administered in a wide variety of oral, parenteral, and topical dosage forms. Thus, the compounds of the present invention can be administered by injection (e.g., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally). The compounds described herein can also be administered by inhalation, for example, intranasally. Additionally, the compounds of the present invention can be administered transdermally. It is also contemplated that multiple routes of administration (e.g., intramuscularly, orally, transdermally) can be used to administer the compounds of the present invention. Accordingly, the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and one or more compounds of the present invention.

[0230] For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be solid or liquid.Solid preparations include powder, tablets, pills, capsules, cachets, suppositories and dispersible granules.Solid carriers can be one or more substances that can also function as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents or encapsulating materials.

[0231] In powders, the carrier is a finely divided solid in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0232] Powders and tablets preferably contain 5% to 70% of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting waxes, cocoa butter, and the like. The term "formulation" is intended to include formulations of the active compound with an encapsulating material as a carrier, in which the active ingredient, with or without other carriers, is surrounded by a carrier, thereby providing a capsule in which the carrier is associated with the active ingredient. Cachets and lozenges are also included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0233] For preparing suppositories, a low-melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active ingredient is dispersed homogeneously therein as by stirring, etc. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby solidify.

[0234] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions.For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

[0235] When parenteral administration is required or desired, particularly suitable mixtures for the compounds of the present invention are injectable sterile solutions, preferably oily or aqueous solutions, and suspensions, emulsions, or inserts, including suppositories. In particular, carriers for parenteral administration include aqueous solutions of dextrose, saline, purified water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene block polymers, etc. Ampoules are convenient unit doses. The compounds of the present invention can also be incorporated into liposomes or administered via transdermal pumps or patches. Pharmaceutical mixtures suitable for use in the present invention include, for example, those described in Pharmaceutical Sciences (17th Ed., Mack Pub. Co., Easton, PA) and WO 96 / 05309.

[0236] Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickeners, if desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active ingredient in water with viscous substances, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

[0237] Also included are solid form preparations intended to be converted into liquid form preparations for oral administration immediately before use.Such liquid forms include solutions, suspensions and emulsions.These preparations may contain, in addition to the active ingredient, colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0238] Pharmaceutical preparations are preferably in unit dosage form.In this form, the preparation is subdivided into unit doses containing appropriate amounts of active ingredients.The unit dosage form can be a packaged preparation, and the package contains individual amounts of preparations, for example, packaged tablets, capsules, and powders in vials or ampoules.Alternatively, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be any suitable number of such in package form.

[0239] The quantity of active ingredient in a unit dose preparation may be varied or adjusted according to the particular use and potency of the active ingredient. The composition may also contain other compatible therapeutic agents, if desired. [Example]

[0240] The following examples illustrate certain embodiments of the present invention and are not meant to limit the scope of the invention.

[0241] General Experiment Abbreviation 1 H NMR proton nuclear magnetic resonance API Active Pharmaceutical Ingredient ASR Analytical Services Report ca. approx. CCD charge-coupled detector DCM dichloromethane DMSO dimethyl sulfoxide DSC Differential Scanning Calorimetry DVS Dynamic Vapor Sorption eq equivalent EtOH ethanol GVS Gravimetric Vapor Sorption H2O Water HPLC High Performance Liquid Chromatography IC ion chromatography ID Identification IDR specific dissolution rate IP Intellectual Property IPA 2-propanol IPAC Isopropyl Acetate KF Karl Fischer MDSC Modulated Differential Scanning Calorimetry MeCN acetonitrile MEK Methyl ethyl ketone MeOH Methanol MIBK Methyl isobutyl ketone MSZW metastable region width N / A Not applicable NMP N-methylpyrrolidone NMR nuclear magnetic resonance PLM polarized light microscope Relative humidity Relative humidity RM reaction mixture RT room temperature SCXRD Single Crystal X-ray Diffraction TBME tert-butyl methyl ether t-BuOH tert-butanol TFA trifluoroacetic acid TGA thermogravimetric analysis THF tetrahydrofuran UV ultraviolet VH-XRPD Variable Humidity X-ray Powder Diffraction vol volume VT-XRPD Variable Temperature X-ray Powder Diffraction XRPD X-ray powder diffraction

[0242] Apparatus and method AX-ray powder diffraction (XRPD) The following X-ray powder diffractometer was used for XRPD diffraction: The parameters used are listed in Table 19. Unless otherwise stated, the 2-theta (2θ) values ​​disclosed herein were obtained using a Bruker AXS D8 Advance with the parameters listed in Table 19. [Table 19]

[0243] B. Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC) TGA data was collected using a TA Instruments TA Q500 / Q5000 TGA. DSC was performed using a TA Instruments TA Q200 / Q2000 DSC. The detailed parameters used are listed in Table 20. [Table 20] C. HPLC An Agilent 1100 HPLC was used and the detailed chromatographic conditions are listed in Table 21. [Table 21]

[0244] D. Solution NMR Solution NMR was collected on a Bruker 400M NMR Spectrometer using DMSO-d6 unless otherwise stated.

[0245] E. Intrinsic dissolution rate (IDR) Approximately 40 mg of sample was compressed into a 6 mm disk recess under 100 kg for 2 minutes using greaseproof paper on the compression base to form a non-disintegrating disk. The disk was then capped with a stopper so that only one side was exposed to the media during analysis and transferred to a Sirius inForm dissolution apparatus. Analysis was performed in 40 mL of media (36 mL of ISA water, 4 mL of 0.1 M acetate-phosphate buffer) at 37°C. Dissolution data were collected over four pH sectors (pH 2.0, 5.5, 6.5, and 7.4) for a total of 2 hours (30 minutes per sector), with UV spectra collected every 30 seconds. A stirring speed of 225 rpm was used with a 10 mm pathlength probe. IDR was calculated based on the surface area of ​​the 3 / 6 / 8 mm disk recess used (surface area 28.3 mm2). XRPD analysis was performed on all samples both after compression of the material into the disk recess and after dissolution analysis to observe changes in morphology. XRPD diffractograms were collected on a Bruker C2.

[0246] Example 1: N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (Compound 1) The synthesis of Compound 1 is described in detail in Example 148 of the '897 application and is reproduced here for ease of reference. [ka]

[0247] Synthesis of 5-cyclopropylpyridin-2-amine. [ka] A mixture of 5-bromopyridin-2-amine (100 g, 585 mmol), cyclopropylboronic acid (60 g, 701 mmol), Pd(AcO) (6.5 g, 29 mmol), SPhos (24 g, 58.5 mmol), and KPO (372 g, 1.755 mol) in toluene / HO (1.2 L / 0.12 L) was stirred at 90 °C under N for 14 h. The reaction was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (PE / EA = 1 / 2) to give 5-cyclopropylpyridin-2-amine (61 g, yield: 78%) as a yellow solid. ESI-MS [M+H] + : 135.1.

[0248] Synthesis of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine. [ka] A mixture of 5-cyclopropylpyridin-2-amine (61 g, 455 mmol) and 1,3-dichloropropan-2-one (172 g, 1365 mmol) in EtOH (1 L) was stirred at 95 °C for 13 h. The reaction was concentrated to remove EtOH. The pH of the residue was adjusted to 9 by adding aqueous NaHCO and extracted with EtOAc (1 L × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (EA) to give 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (40 g, yield: 42%) as a yellow solid. ESI-MS [M+H] + : 207.1.

[0249] Synthesis of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-b]pyridazine. [ka] To a solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-a]pyridine (40 g, 193 mmol) in DMF (600 mL) was added NaN (18.8 g, 290 mmol). The resulting reaction was stirred at room temperature for 2 hours. The reaction was diluted with HO (500 mL) and extracted with EtOAc (500 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (PE / EA = 2 / 1) to give 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (35 g, yield: 85%) as a yellow solid. ESI-MS [M+H] + : 214.1.

[0250] Synthesis of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyrimidin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate. [ka] A mixture of 2-(azidomethyl)-6-cyclopropylimidazo[1,2-a]pyridine (35 g, 163.5 mmol), ethyl propiolate (17.6 g, 180 mmol), CuSO (2.6 g, 16.35 mmol), and sodium ascorbate (3.3 g, 16.35 mmol) in HO / t-BuOH (150 mL / 150 mL) was stirred at room temperature for 3 h. After 3 h, a yellow solid precipitated, and the mixture was filtered. The cake was dried to give ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (29 g, 57% yield) as a yellow solid, which was used in the next step without further purification. ESI-MS [M+H] + : 312.1.

[0251] Synthesis of 1-((6-cyclopropylimidazo[1,2-a]pyridazin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid. [ka] A mixture of ethyl 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (29 g, 93.2 mmol) and LiOH (6.7 g, 279.6 mmol, 50 mL of solution in HO) in THF / EtOH (150 mL / 150 mL) was stirred at 50 °C for 2 h. The reaction was concentrated to remove most of the solvent. The pH of the residue was adjusted to 4 with 2 N HCl, resulting in the precipitation of a pink solid. The mixture was filtered, and the filter cake was dried to give 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (20 g, 77%) as a pink solid. ESI-MS [M+H] + : 284.1.

[0252] Synthesis of N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide. [ka] To a suspension of 1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (37 mg, 0.13 mmol) and (7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methanamine hydrochloride (35 mg, 0.15 mmol) in DMF (3 mL) was added HOBT (40 mg, 0.3 mmol) and EDCI (57 mg, 0.3 mmol), followed by DIPEA (65 mg, 0.5 mmol). The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was slowly poured into HO (15 mL). The suspension mixture was stirred for 1 hour and filtered. The filter cake was washed with HO (20 mL) and MeOH (20 mL) and then dried under vacuum to give N-((7-chloro-8-fluoroimidazo[1,5-a]pyridin-1-yl)methyl)-1-((6-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide as a pale solid (30 mg, yield: 50%). ESI-MS [M+H] + : 465.0.Purity: 98.4% (214 nm), 98.5% (254 nm). 1 H NMR (400 MHz, DMSO-d6): 8.70 (t, J = 5.4 Hz, 1H), 8.55 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.35 (s, 1H), 8.21 (d, J = 7.4 Hz, 1H), 7.83 (s, 1H), 7.41 (d, J = 9.3 Hz, 1H), 7.01 (dd, J = 9.4, 1.8 Hz, 1H), 6.76 (dd, J = 7.3, 6.6 Hz, 1H), 5.73 (s, 2H), 4.70 (d, J = 5.5 Hz, 2H), 1.94-1.90 (m, 1H), 0.94-0.89 (m, 2H), 0.69-0.65 (m, 2H).

[0253] Example 2: Solid Form of Compound 1 (Free Base) Studies were conducted to identify various new forms (eg, solid forms) of Compound 1.

[0254] Solubility Test Compound 1, obtained from the synthetic procedure described in Example 1, was found to exhibit limited solubility in most organic solvents evaluated (Table 22). In all solvents evaluated, the material exhibited a solubility of less than 10 mg / mL at 25° C. Solubility of less than 10 mg / mL at 50° C. was only observed in DMSO, NMP, and MeOH:DCM 1:3. [Table 22-1] [Table 22-2]

[0255] Preparation of the amorphous form of Compound 1 Compound 1 (30 mg), obtained from the synthesis procedure described in Example 1, was placed in a 2 mL Retsch milling jar equipped with one stainless steel milling ball. This was milled at 30 Hz for 30 minutes. The amorphous form of Compound 1 was successfully prepared by milling on a 30 mg scale. The XRPD pattern of the as-prepared material was observed to be free of peaks associated with the formation of amorphous material. Initial Experiments

[0256] Polymorph screening experiments were carried out using various solution crystallization or solid-state transformation methods. The methods utilized and the crystalline forms identified are summarized in Table 23. These initial screening experiments resulted in two distinct solid forms. [Table 23]

[0257] Slurry of amorphous material at 50°C Slurry conversion experiments were carried out at 50° C. in various solvent systems. Approximately 15 mg of amorphous Compound 1 was suspended in 100 vol of solvent (50 vol in the case of DMSO) in an HPLC vial. The suspension was stirred at 50° C. for 2 days, after which the remaining solid was isolated for XRPD analysis. The results, summarized in Table 24, indicated that Form 1 of Compound 1 was produced. [Table 24]

[0258] Temperature cycling of amorphous materials in slurries Fifteen milligrams of amorphous Compound 1 were dispensed into HPLC vials, to which aliquots of the selected solvent were added, and the suspension was heated to 50°C with magnetic stirring (350 rpm) using a HEL block. Solvent addition was performed until a maximum of 100 vol (50 vol for the DMSO sample) had been added. The material was slurried at temperatures cycled between 25°C and 50°C for two days (four hours at each temperature, except for the first cycle, which had a 16-hour isothermal hold at 50°C to assess dissolution). After this time, the solid was isolated by filtration and pulled dry. The solid was analyzed by XRPD. The results, summarized in Table 25, indicated that Form 1 of Compound 1 was produced. [Table 25]

[0259] Slurry of amorphous material at 5°C Slurry conversion experiments were carried out at 5°C in various solvent systems. Approximately 15 mg of amorphous Compound 1 was suspended in 100 vol of solvent in an HPLC vial. The suspension was stirred at 5°C for 2 days, after which the remaining solid was isolated for XRPD analysis. The results, summarized in Table 26, indicated that either Form 1 or Form 2 of Compound 1 was produced. [Table 26]

[0260] Antisolvent crystallization 25 mg of the amorphous form of Compound 1 was placed in a 4 mL vial and added to these aliquots of the selected solvent, and the suspension was heated to 50° C. If observations were made, more solvent was added until dissolution was observed. Anti-solvent was then added in 2×1 mL aliquots and observations were made. The solution was then cooled to 25° C. at 1° C. / min and further observations were made. Further anti-solvent (2 mL) was added to the DMSO solution and observations were made. The solid was isolated by filtration, suction dried, and analyzed by XRPD. The results, summarized in Table 27, indicated that Form 1 of Compound 1 was produced. [Table 27]

[0261] Solvent-assisted milling of free forms 20 mg of amorphous Compound 1 was placed in an HPLC vial, to which two stainless steel milling balls were added, along with 20 μL of each selected solvent. The sample was milled for 2 hours at 500 rpm using 2-3 mm ball bearings in a Fritsch planetary mill equipped with an Automaxion adapter. The solid was then isolated and analyzed by XRPD. The results, summarized in Table 28, indicated that either Form 1 or Form 2 of Compound 1 was produced. [Table 28]

[0262] Cooling crystallization 30 mg of the amorphous form of Compound 1 was placed in an HPLC vial and added to these aliquots of selected solvent. The suspension was heated to 100°C and observed. Further solvent was added until dissolution was observed. The solution was then cooled to 25°C at 0.25°C / min. The solid was isolated by filtration, dried under vacuum, and analyzed by XRPD. The results, summarized in Table 29, indicated that Form 1 of Compound 1 was produced. [Table 29]

[0263] 2. Characterization data of polymorphs of compound 1 Compound 1 Form 1 Form 1 of Compound 1 can be prepared from the amorphous form of Compound 1. Acetone (100 vol, 42 mL) was placed in a container and the amorphous form was slurried at 5° C. with magnetic suspension stirring at 500 rpm for 3 days. The solid was then isolated by filtration and dried under suction for 30 minutes. Recovery: 339.33 mg, Yield: 80.2%. [Table 30]

[0264] FIG. 1 provides Form 1 of Compound 1 in XRPD.

[0265] FIG. 2 provides the TGA / DSC curve of Form 1 of Compound 1.

[0266] Form 2 of Compound 1 Form 2 of Compound 1 can be prepared from the amorphous form of Compound 1. 393 mg of the amorphous form of Compound 1 was placed in a 100 mL HEL polyblock vial. Methanol (100 vol, 40 mL) dried over molecular sieves and cooled to 5° C. was added to the vessel, and the material was slurried at 5° C. with suspension magnetic stirring at 500 rpm for 1 hour. After 1 hour, an aliquot of the material was isolated by filtration, partially dried under positive pressure, analyzed by XRPD, and then dried and reanalyzed. The remaining solid was then isolated by filtration and dried under vacuum for 30 minutes. Recovery: 288.74 mg, 73.4% yield [Table 31]

[0267] FIG. 3 provides the XRPD pattern of Form 2 of Compound 1.

[0268] FIG. 4 provides the TGA / DSC curve of Form 2 of Compound 1. Form 3 of Compound 1

[0269] Form 3 of Compound 1 can be prepared from the amorphous form of Compound 1. 502 mg of the amorphous form of Compound 1 was placed in a 20 mL scintillation vial. Acetic acid (5 vol) was added, and the sample was heated to 50°C on a Polar Bear with magnetic stirring at 500 rpm, resulting in a clear, brown solution. The solution was cooled to 20°C at 1°C / min, and acetonitrile (15 vol) was added dropwise, resulting in a white precipitate. The sample was then stirred for an additional 10 minutes before isolation by filtration. The sample was analyzed by XRPD and shown to be an intermediate acetic acid solvate—Pattern 1—and heated to 165°C using a Karl Fischer oven and held isothermal for 15 minutes to yield Form 3 of Compound 1. Recovery: 343.63 mg [Table 32]

[0270] FIG. 5 provides the XRPD pattern of Form 3 of Compound 1.

[0271] FIG. 6 provides the TGA / DSC curve of Form 3 of Compound 1.

[0272] 3. Examination of thermodynamic stability relationships of free base polymorphs of Compound 1 Competitive Slurry Between Form 1 and Form 2 of Compound 1 A 25 mg mixture of Forms 1 and 2 of Compound 1 was placed in an HPLC vial. To this, 40 vol (1 mL) of the selected solvent was added, and the material was slurried on a HEL polyblock at 5°C or 50°C for 72 hours (stirring at 500 rpm). The solid was then isolated by filtration and dried under vacuum before analysis by XRPD. The results of the competitive slurries are shown in Table 33. In all but one experiment, Form 1 was the only phase detectable by XRPD obtained after 72 hours. This therefore demonstrates that Form 1 is thermodynamically more stable than Form 2 in all but one of the solvent mixtures investigated. In the remaining experiment, in which a mixture of Forms 1 and 2 was slurried in methanol at 5°C, the isolated material was shown to be a mixture of the two forms. [Table 33]

[0273] Amorphous forms of Compound 1, Form 1 and Form 2, were successfully scaled up and characterized. Form 2 was shown to form via a tentatively assigned solvated phase (methanol), which converted to Form 2 upon drying. Form 2 was shown to convert to Form 1 during one week of storage at 40°C / 75% relative humidity by GVS analysis. Peaks corresponding to the potential hydrated phase were also observed in the XRPD pattern of Form 2 material after storage at 25°C / 97% relative humidity. Upon heating to 150°C, the amorphous form of Compound 1 was shown to convert to Form 1 after one week of storage at 40°C / 75% relative humidity and 25°C / 97% relative humidity by GVS analysis. Competitive slurries performed on mixtures of Form 1 and Form 2 (Table 33) indicated that Form 1 was the more thermodynamically stable polymorph under the majority of experimental conditions investigated.

[0274] Competitive Slurry Between Forms 1 and 3 of Compound 1 120 mg of both Compound 1 Form 3 and Compound 1 Form 1 were dispensed into 20 mL vials. These were mixed, and then aliquots (20 mg) of this mixture were dispensed into HPLC vials and 90 vol (1.8 mL) of the selected solvent was added. The samples were slurried using a Polar Bear with magnetic stirring at 500 rpm at 5°C and 50°C. After 24 hours, aliquots were removed and analyzed by XRPD. Experiment Numbers: 01-10.

[0275] Results from competitive slurries of Compound 1 Form 1 and Form 3 are shown in Table 34. After 24 hours, XRPD showed that all samples had converted to Compound 1 Form 1, demonstrating that Compound 1 Form 1 is thermodynamically more stable than Compound 1 Form 3 and is the most stable free base form of Compound 1 identified. [Table 34]

[0276] A polymorphic morphology diagram for Compound 1 is shown in Figure 21, illustrating the relationship between the three crystalline forms, the candidate methanol solvate, the unstable acetic acid solvate, and the amorphous material. Notably, conditions for conversion of Form 1 to other forms were not identified. Taken together, this data indicates that Form 1 is the most stable polymorph under typical storage and processing conditions.

[0277] An overlay of the XRPD patterns of Compound 1 obtained from the synthetic procedure described in Example 1 and Forms 1 and 2 of Compound 1 shows that Compound 1 obtained from the synthetic procedure described in Example 1 consists of a mixture of Forms 1 and 2 of Compound 1 (Figure 22 - varying peak magnitudes are attributed to changes in composition and preferred orientation. Data obtained by PANalytical Empyrean with parameters listed in Table 19).

[0278] Example 3: Initial Salts and Cocrystals Compound 1, obtained from the synthetic procedure described in Example 1, was used as the starting material for salt and co-crystal experiments.

[0279] 1. Early HCl Experiments Initial salt formation experiments were performed using HCl as the counterion, and these experiments yielded 13 samples with novel XRPD patterns (Tables 35 and 36). A. Salt formation with 1 equivalent of HCl

[0280] 15 mg of compound 1 in a 1.5 mL HPLC vial was treated with 100 vol of the selected solvent at 50° C. with magnetic stirring (500 rpm). One equivalent of HCl was added at 50° C., except for the sample containing DCM as the solvent, which was cooled to room temperature before the addition of the counterion. The samples were then cooled to 5° C. at 0.1° C. / min, except for the NMP / DMSO sample, which was cooled to 25° C. All solids were then isolated by filtration and suction dried. All solutions were allowed to evaporate at ambient conditions. All isolated solids were analyzed by XRPD. The results of the XRPD studies are summarized in Table 35.

[0281] B. Salt formation with 2 equivalents of HCl 15 mg of compound 1 in a 1.5 mL HPLC vial was treated with 100 vol of the selected solvent at 50° C. with magnetic stirring (500 rpm). To these, 2 equivalents of HCl (1 M in THF) were added, and the samples were stirred and held isothermally for 30 minutes after observation. Except for the DCM sample, which was cooled to room temperature before adding HCl, the samples were then slowly cooled to 5° C. at 0.5° C. / min and then held isothermally for 16 hours, except for the DMSO and NMP samples, which were cooled to 25° C. All solids were then isolated by filtration and suction dried. All solutions were allowed to evaporate at ambient conditions. All isolated solids were analyzed by XRPD. The results of the XRPD studies are summarized in Table 36. [Table 35-1] [Table 35-2] [Table 35-3] [Table 36-1] [Table 36-2] [Table 36-3]

[0282] All of the HCl patterns provided were found to exhibit complex thermal behavior with an endothermic onset at low temperatures. In three instances of drying, the isolated material of Compound 2, Pattern 4, was observed to transform into Compound 2, Pattern 9.

[0283] of the solid obtained from the HCl experiment 1H NMR analysis showed shifts consistent with salt formation in all but one sample. This sample was considered to be a new free base pattern. Of the remaining 12 new patterns, Cl - was shown to be present in all samples by ion chromatography. Thermal analysis of the samples showed that all novel HCl patterns exhibited complex thermal behavior with an endothermic onset at low temperatures. In three instances of drying, the isolated HCl salt-pattern 4 material was observed to transform into HCl salt-pattern 9. The HCl salts isolated in the preliminary salt formation experiments were deemed unsuitable for further investigation due to the extensive polymorphism exhibited by the HCl salts and the complex thermal behavior of all isolated HCl salts. Based on the salt formation results and observations made regarding the introduction of counterions, acetone, methanol, and ethyl acetate were selected as solvents for further salt experiments.

[0284] 2. Salt Form Experiments with Other Acids in Acetone, Methanol, and Ethyl Acetate 25 mg of compound 1 in a 4 mL vial was suspended in 100 vol of acetone, methanol, or ethyl acetate at 50° C. with magnetic stirring at 500 rpm. One or two equivalents of the respective counterion (except for the 1 M stock solution in THF, 0.25 M nicotinic acid in HO, and 0.5 M succinic acid in MeOH) were added, and the sample was slowly cooled to 5° C. at 0.1° C. / min and then held isothermally for 12 hours. All solids were then isolated by filtration and suction dried. All solutions were uncapped and allowed to evaporate at ambient conditions. All isolated solids were analyzed by XRPD. Overall, the salt experiments resulted in the isolation of 13 materials with novel XRPD patterns (Table 37). [Table 37-1] [Table 37-2]

[0285] In the salt experiments using acetone as the solvent, 10 salts were isolated, 8 of which were new for this experiment (2 HCl salts were previously isolated in preliminary experiments). In 10 of the 12 experiments in which no salt was formed, Form 1 of Compound 1 was isolated after cooling. In the remaining two cases, material was isolated with an XRPD pattern corresponding to poorly crystalline material.

[0286] In the salt experiments with methanol, three salt patterns were isolated, one of which was new in this experiment (sulfate salt pattern 2), as both the fumarate salt pattern 1 and the HCl salt pattern 9 were isolated from previous experiments. In experiments in which no salt was formed, poorly crystalline material or a mixture of Compound 1 Form 1 and Compound 1 Form 2 was isolated after cooling to 5 °C.

[0287] From the salt experiments conducted using ethyl acetate as the solvent, 10 salts were isolated, four of which had not been observed previously. The remaining six salts were identified in previously performed experiments. In the remaining experiments in which no salts were isolated in the ethyl acetate experiments, XRPD indicated that Form 1 of Compound 1 was the only material isolated.

[0288] A total of 13 salt forms were identified from 66 experiments. Of these 13 salt forms, seven had properties deemed suitable for further characterization. Specifically, these seven salt forms were identified from experiments with L-malic acid, succinic acid, phosphoric acid, oxalic acid, L-tartaric acid, methanesulfonic acid, and fumaric acid. The remaining salt forms, such as the sulfate salt and HCl salt, exhibited complex thermal behavior, represented by multiple endotherms at low temperatures, or altered XRPD patterns after one week of storage at 40°C / 75% relative humidity, and were deemed unsuitable for further scale-up and characterization.

[0289] Example 4: Compound 3 (L-Malate) [ka] Compound 3 Pattern 1 Form 1 of Compound 3 was isolated from an experiment conducted using ethyl acetate as the solvent. Form 1 of Compound 3 is 1 H-NMR spectroscopy showed it to contain 0.7 molar equivalents of L-malic acid. Little change was observed in the XRPD pattern of the material after one week of storage at 40°C / 75% relative humidity.

[0290] Scale-up: Compound 1, obtained from the synthetic procedure described in Example 1, was placed in a 100 mL HEL polyblock vial. Ethyl acetate (100 vol, 50 mL) was then charged to the vial, and the resulting suspension was heated to 50°C with magnetic suspension stirring at 500 rpm. To this was added 1 equivalent of L-malic acid (1 M in THF). The suspension was kept isothermal with stirring for 16 hours, during which time an aliquot was removed and analyzed by XRPD. After 16 hours, no conversion was observed to have occurred. The suspension was then cooled to 5°C at 0.5°C / min and held isothermal for 72 hours, after which a further aliquot was isolated and analyzed by XRPD. Conversion was observed to have occurred. The resulting solid was isolated by filtration and pulled dry. The material was isolated in 98.2% purity and 78.4% yield. [Table 38]

[0291] FIG. 7 provides the XRPD pattern of Pattern 1 of Compound 3.

[0292] Figure 8 provides the TGA / DSC curve of Pattern 1 for Compound 3. The figure shows an endotherm (likely melting / decomposition) at 187.2°C onset temperature and a weight loss of 1.9% up to 150°C.

[0293] TGA analysis of Compound 3, Pattern 1, indicates the onset of thermal decomposition at approximately 190 °C. The DSC trace of the scaled-up material contained a single endotherm with an onset at 187.2 °C (82.9 J / g). GVS analysis of the material indicated slight hygroscopicity, with a 0.22% mass gain observed from 0 to 90% relative humidity, and no observed changes in the material were evidenced by XRPD after GVS analysis. The material was shown to be unchanged by XRPD after 1 week of storage at 40 °C / 75% relative humidity and 25 °C / 97% relative humidity.

[0294] Example 5: Compound 4 (succinate salt) [ka] Compound 4 Pattern 1 Compound 4 Pattern 1 was isolated from an experiment conducted using acetone and ethyl acetate as solvents. 1 H-NMR showed it contained 0.75 molar equivalents of succinic acid. Pattern 1 of compound 4 was shown to be unchanged by XRPD after 1 week of storage at 40°C / 75% relative humidity.

[0295] Scale-up: Compound 1 obtained from the synthesis procedure described in Example 1 was placed in a 100 mL HEL polyblock vial. Acetone (100 vol, 50 mL) was then added to the vial, and the resulting suspension was heated to 50°C with magnetic stirring at 500 rpm. To this, 1 equivalent of succinic acid (1 M in MeOH) was added to obtain a suspension. The suspension was kept isothermal with stirring for 16 hours, and an aliquot was removed and analyzed by XRPD. After 16 hours, conversion was observed to have occurred. The suspension was then cooled to 5°C at 0.5°C / min, held isothermal for 1 hour, and then isolated by filtration. The material was isolated in 98.2% purity and 80.5% yield. [Table 39]

[0296] FIG. 9 provides the XRPD pattern of Pattern 1 of Compound 4.

[0297] FIG. 10 provides the TGA / DSC curve of Pattern 1 of Compound 4.

[0298] TGA analysis of the material indicates thermal decomposition begins at approximately 200 °C. The DSC trace of the scaled-up material contained a single endotherm (171 J / g) with an onset at 223.4 °C. In contrast, the DSC trace of the material obtained from the screening experiment showed two thermal events. GVS analysis of the material indicated non-hygroscopicity, with a mass gain of 0.16% observed from 0 to 90% relative humidity. No changes were observed in the material by XRPD after GVS analysis. The material was shown to be unchanged by XRPD after one week of storage at 40 °C / 75% relative humidity and 25 °C / 97% relative humidity.

[0299] Example 6: Compound 5 (phosphate salt) [ka] Compound 5 Pattern 1 Compound 5, pattern 1, was isolated from a screening experiment conducted in acetone. This material was shown to contain one equivalent of phosphate by ion chromatography and was shown to be unchanged by XRPD after 1 week of storage at 40°C / 75% relative humidity. Compound 5, pattern 1, showed a DSC thermogram with a small onset of exotherm at 90.3°C, followed by a sharp endotherm at 227.6°C. [Table 40]

[0300] Scale-up: Compound 1, obtained from the synthesis procedure described in Example 1, was placed in a 100 mL HEL polyblock vessel. Acetone (100 vol, 50 mL) was added to the vessel, and the resulting suspension was heated to 50°C with magnetic stirring at 500 rpm. One equivalent of phosphoric acid (1 M in THF) was added to the suspension. The suspension was kept isothermal for 30 minutes with stirring and then cooled to 5°C at 0.1°C / min. The suspension was then kept isothermal for 14 hours, and the resulting material was isolated by filtration and suction dried. The material was isolated in high yield (94.3%) and purity (98.4%).

[0301] FIG. 11 provides the XRPD pattern of Pattern 1 of Compound 5.

[0302] FIG. 12 provides the TGA / DSC curve of Pattern 1 of Compound 5.

[0303] Thermal analysis of the material indicated that thermal decomposition of the material occurred at approximately 225°C, and the DSC trace contained a single endotherm with an onset at 224.7°C (141 J / g). GVS analysis of the material indicated that it was slightly hygroscopic, with a 1.2% mass gain observed from 0 to 90% relative humidity, and no changes were observed in the material by XRPD after analysis. The material was shown to be unchanged by XRPD after one week of storage at 40°C / 75% relative humidity and 25°C / 97% relative humidity.

[0304] Example 7: Compound 6 (Oxalate Salt) [ka] Compound 6 Pattern 1 Pattern 1 of compound 6 was isolated from experiments in both acetone and ethyl acetate. This material was shown to contain one equivalent of oxalic acid by ion chromatography, and its DSC thermogram showed a single melt with an onset at 212.8 °C. After 1 week of storage at 40 °C / 75% relative humidity, the XRPD pattern of the material was slightly altered from that of the material isolated from the screening.

[0305] Scale-up: Compound 1, obtained from the synthesis procedure described in Example 1, was placed in a 100 mL HEL polyblock vessel. Acetone (100 vol, 50 mL) was added to the vessel, and the resulting suspension was heated to 50°C with magnetic stirring at 500 rpm. One equivalent of oxalic acid (1 M in THF) was added to the suspension. The suspension was kept isothermal for 30 minutes with stirring and then cooled to 5°C at 0.1°C / min. The suspension was then kept isothermal for 14 hours, and the resulting material was isolated by filtration and suction dried. The material was isolated in high yield (95%) and purity (98.4%). [Table 41]

[0306] FIG. 13 provides the XRPD pattern of pattern 1 of compound 6.

[0307] FIG. 14 provides the TGA / DSC curve of Pattern 1 of Compound 6.

[0308] Thermal analysis of the material indicated that thermal decomposition of the material occurred at approximately 200°C, and the DSC trace contained a single endotherm with a shoulder (onset 211.3°C, 197 J / g). GVS analysis of the material indicated that it was slightly hygroscopic, with a 0.6% mass gain observed from 0 to 90% relative humidity, and no changes were observed in the material by XRPD after analysis. The material was shown to be unchanged by XRPD after one week of storage at 40°C / 75% relative humidity and 25°C / 97% relative humidity.

[0309] Further experiments on the new form of compound 6 30 mg of compound 1 was placed in a 7 mL vial. To these, 100 vol of the selected solvent (55 vol used for NMP) was added, and the samples were heated to 50 °C (60 °C for DMSO samples, as complete dissolution was not observed at 50 °C). All samples were stirred with a magnetic stirrer at 500 rpm. The samples were stirred for 30 minutes, and then 1 equivalent of oxalic acid (1 M in THF) was added. The samples were then stirred isothermally for 3 hours and cooled to 5 °C at 0.1 °C / min (25 °C for DMSO samples). The samples were held isothermally for 16 hours and then isolated by filtration. Samples containing NMP as the solvent were observed to be clear solutions. To these, 55 vol of TBME was added, and the samples were stirred for an additional 30 minutes before being isolated by filtration. The solids were analyzed by XRPD and then dried overnight in a vacuum oven at 40 °C before a second analysis by XRPD. Experiment No. = 11-20 [Table 42]

[0310] Compound 6 Pattern 4 As described above, Compound 6, Pattern 2, was isolated from a screening experiment in IPA. Approximately 10 mg of Compound 6, Pattern 2, was then heated in a TGA pan at a rate of 10 °C to 175 °C, held isothermal for 5 minutes, and then cooled to ambient temperature to obtain Compound 6, Pattern 4. A TGA thermogram of the material showed no mass loss corresponding to desolvation, indicating the material was in the solvent-free form. The TGA thermogram was found to contain a mass loss between 200 and 260 °C, corresponding to 0.84 molar equivalents of oxalic acid. This mass loss temperature coincides with an endotherm in the DSC trace of the material (onset 223.8 °C, 215 J / g).

[0311] Scale-up: Compound 1, obtained from the synthesis procedure described in Example 1, was placed in a 140 mL HEL polyblock vessel. To this was added 100 vol (50 mL) of IPA, and the sample was heated to 50°C and held isothermal for 30 minutes while stirring at 500 rpm using the HEL polyblock. One equivalent of oxalic acid (1 M in THF) was added, and the sample was stirred for 3 hours, then cooled to 5°C at 0.1°C / min. The sample was then stirred for 3 days, with aliquots removed intermittently and analyzed by XRPD. After 3 days, the sample was deemed fully converted and isolated by filtration and dried under vacuum. This sample was then heated to 175°C for 5 minutes using a Karl Fischer oven and then analyzed by XRPD. [Table 43]

[0312] FIG. 15 provides the XRPD pattern of pattern 4 of compound 6.

[0313] FIG. 16 provides the TGA / DSC curve of pattern 4 of compound 6.

[0314] Pattern 4 of compound 6 was shown by GVS to be slightly hygroscopic, with a mass loss of 0.66% observed from 0 to 90% relative humidity. Analysis of the material after GVS analysis showed it to be unchanged as indicated by XRPD. The material was shown to be unchanged by XRPD after 1 week of storage at 40°C / 75% relative humidity and 25°C / 97% relative humidity.

[0315] Alternatively, Compound 6, Pattern 4, can be prepared according to the following procedure: Compound 1 (500 mg), obtained from the synthetic procedure described in Example 1, was placed in a 100 mL round-bottom flask. 50 vol (25 mL) of MeCN:HO (1:1) was added, and the suspension was heated to 50 °C. Two equivalents of oxalic acid (1 M in THF) were added, and the suspension was observed to clarify. The solution was stirred isothermally for 30 minutes and cooled to 5 °C at 0.1 °C / min. The resulting suspension was held isothermally for 12 hours, then isolated by filtration and suction dried. 523.19 mg of material was recovered in 87.6% yield. This material was shown to have an XRPD pattern consistent with the oxalate salt—Pattern 4. Ion chromatography indicated that this material contained 1.0 equivalent of oxalic acid, indicating that the material was a simple salt, even though two equivalents of oxalic acid were used.

[0316] Competitive slurry between Compound 6 Pattern 1 and Compound 6 Pattern 1 120 mg of both Compound 6 Pattern 1 and Compound 6 Pattern 4 were dispensed into 20 mL vials. They were mixed, and then aliquots (20 mg) of this mixture were dispensed into HPLC vials and 90 vol of the selected solvent was added. The samples were slurried using a Polar Bear with magnetic stirring at 500 rpm. After 4 days, aliquots were removed and analyzed by XRPD.

[0317] The results of the competitive slurry of Compound 6 Pattern 1 and Compound 6 Pattern 4 are shown in Table 44. In all but one experiment (Experiment 1), after 4 days of slurrying, Compound 6 Pattern 4 was the only phase detectable by XRPD. In the remaining experiments, in which ethanol was used as the solvent and the material was slurried at 5°C, the XRPD pattern of the isolated material showed to be a mixture of Compound 6 Pattern 4 and a new pattern hypothesized to be the ethanol solvate. Taken together, the competitive slurry data indicate that Compound 6 Pattern 4 is the thermodynamically more stable of the two solvent-free oxalate salts. [Table 44]

[0318] Example 8: Compound 7 (L-tartrate salt) [ka] Compound 7 Pattern 1 Form 1 of Compound 7 was isolated from experiments performed using acetone or ethyl acetate as solvents. 1 H-NMR spectroscopy showed that the material contained 0.87 molar equivalents of L-tartaric acid. The material was shown to be unchanged by XRPD after 1 week of storage at 40°C / 75% relative humidity.

[0319] Scale-up: Compound 1, obtained from the synthesis procedure described in Example 1, was placed in a 100 mL HEL polyblock vessel. Acetone (100 vol, 50 mL) was added to the vessel, and the resulting suspension was heated to 50°C with magnetic stirring at 500 rpm. One equivalent of L-tartaric acid (1 M in THF) was added to the suspension. The suspension was kept isothermal for 30 minutes with stirring and then cooled to 5°C at 0.1°C / min. The suspension was then kept isothermal for 14 hours, and the resulting material was isolated by filtration and suction dried. The material was isolated in high yield (93.7%) and purity (98.3%). [Table 45]

[0320] FIG. 17 provides an XRPD overlay of Form 1 of Compound 1 and Pattern 1 of Compound 7.

[0321] FIG. 18 provides the TGA / DSC curve of Pattern 1 of Compound 7.

[0322] This XRPD pattern indicated that Compound 7, Pattern 1, was poorly crystalline. Analysis of the material showed a 0.6% mass loss between 25 °C, which is believed to correspond to water, and the onset of thermal decomposition at approximately 190 °C. The DSC trace contained a single endotherm with an onset at 199.0 °C (99 J / g). GVS analysis of the material indicated it was hygroscopic, with a 3.4% mass gain observed from 0 to 90% relative humidity, with no hysteresis. This mass gain was consistent with 1.0 molar equivalent of water, indicating possible hydrate formation. XRPD following GVS analysis did not confirm any observed changes to the material. The material was shown to be unchanged by XRPD after one week of storage at 40 °C / 75% relative humidity and 25 °C / 97% relative humidity.

[0323] Example 9: Compound 8 (mesylate salt) [ka] Patterns 1, 2, and 3 of compound 8 A total of three mesylate salts were isolated from the experiments performed. Mesylate salt - Pattern 1 was isolated from the acetone experiment after adding 1 equivalent of methanesulfonic acid. This material was shown to contain 0.93 molar equivalents of methanesulfonic acid and contained two broad endotherms in the DSC trace. Storage of the material for one week at 40°C / 75% relative humidity conditions resulted in a change in its XRPD pattern, with the presence of peaks corresponding to Form 1 of Compound 1. Therefore, the material was deemed unstable and unsuitable for scale-up and further characterization.

[0324] Mesylate - Pattern 2 was isolated from experiments in which two equivalents of methanesulfonic acid were added as a counterion and either acetone or ethyl acetate was used as the solvent. 1It was shown to contain 1.76 molar equivalents of methanesulfonic acid by H-NMR spectroscopy and remained unchanged as evidenced by XRPD after one week of storage at 40°C / 75% relative humidity. The thermal behavior of the material was shown to be complex by DSC, with multiple thermal events observed in the DSC trace. Therefore, the material was deemed unsuitable for scale-up and further characterization.

[0325] Mesylate salt - Pattern 3 was isolated from a screening experiment using 1 equivalent of methanesulfonic acid as the counterion and ethyl acetate as the solvent. 1 H-NMR spectroscopy showed it contained 0.93 molar equivalents of methanesulfonic acid, its DSC trace had a single endotherm (onset at 175.6 °C) and was unchanged as evidenced by XRPD after 1 week of storage at 40 °C / 75% relative humidity. Therefore, this material was deemed suitable for further scale-up and characterization.

[0326] Example 10: Compound 9 (Fumarate Salt) [ka] Compound 9 Pattern 1 Compound 9, pattern 1, was isolated from all three solvent screening runs. 1 It was shown to contain 0.4 molar equivalents of fumaric acid by H-NMR spectroscopy and was unchanged after 1 week of storage at 40°C / 75% relative humidity as evidenced by XRPD.

[0327] Scale-up: Compound 1, obtained from the synthesis procedure described in Example 1, was placed in a 100 mL HEL polyblock vessel. Acetone (100 vol, 50 mL) was added to the vessel, and the resulting suspension was heated to 50°C with magnetic stirring at 500 rpm. One equivalent of fumaric acid (0.5 M in 1:1 THF:methanol) was added to the suspension. The suspension was kept isothermal for 30 minutes with stirring and then cooled to 5°C at 0.1°C / min. The suspension was then kept isothermal for 14 hours, and the resulting material was isolated by filtration and suction dried. The material was isolated in high yield (96.7%) and purity (98.4%). [Table 46]

[0328] FIG. 19 provides the XRPD pattern of pattern 1 of compound 9.

[0329] FIG. 20 provides the TGA / DSC curve of pattern 1 of compound 9.

[0330] TGA analysis of the material showed thermal decomposition to begin at approximately 210°C. The DSC trace contained a single endotherm with an onset at 251.9°C (154 J / g). The material isolated from the screening experiment was 1 It was shown to contain 0.4 molar equivalents of fumaric acid by 1 H-NMR, and the only endotherm in the DSC thermogram had a shoulder. 1 The increase in fumaric acid equivalent weight evidenced by H-NMR and the single peak in the DSC thermogram indicate that the isolated material is more phase-pure than that obtained from screening. GVS analysis of the material revealed slight hygroscopicity, with a 0.6% mass increase observed from 0 to 90% relative humidity. No changes were observed in the material by XRPD after GVS analysis. The material was shown to be unchanged by XRPD after 1 week of storage at 40°C / 75% relative humidity and 25°C / 97% relative humidity. Example 11: Solubility and Scalability of Solid Forms

[0331] Seven of the eight solid forms selected for scale-up were successfully isolated from the experiments performed, with only the mesylate salt—Pattern 3—not being obtained at the 500 mg scale. Of the seven solid forms successfully scaled up, only the L-tartrate salt was shown to be poorly crystalline and hygroscopic. The remaining solid forms, L-malate, succinate, phosphate, oxalate, and fumarate, were observed to be stable under storage, exhibiting a single endotherm in their respective DSC traces and demonstrating reduced hygroscopicity in GVS analysis. The tabulated IDR Sector 1 average values ​​for the resulting solid forms and the stable free base Compound 1 Form 1 are shown in Table 47. The IDR data reveal that the four isolated stable solid forms (oxalate, Patterns 1 and 4 of Compound 6; phosphate, Pattern 1 of Compound 5; succinate, Pattern 1 of Compound 4; and L-malate, Pattern 1 of Compound 3) exhibit increased Sector 1 IDR compared to the free base form of Compound 1, Form 1. From these data, it can be seen that the L-malate solid form (Form 1 of Compound 3) has the highest IDR. However, the solid material of the L-malate, Pattern 1, could not be separated during solution-based scale-up experiments. Furthermore, further solution-based scale-up experiments with the succinate salt showed that external HCl was required for solution clarification (dissolution of all material), making it a less attractive candidate for scale-up production.

[0332] Compound 6 pattern 4 is thermodynamically more stable than compound 6 pattern 1 in competitive slurry experiments. A scalable, solution-based, and easy-to-operate crystallization procedure was identified to isolate phase-pure compound 6 pattern 4 in high yield, high purity, and low residual solvent content. [Table 47]

[0333] Example 12: Compound 10 (Methyl Gallate Cocrystal) [ka] Form 1 of Compound 10 50 mg of compound 1 was dispensed into a 2 mL stainless steel milling jar containing one stainless steel milling ball and 1 molar equivalent of methyl gallate. THF (35 μL) was added to the vial and milled in a Retsch mill at 30 Hz for 30 minutes. An aliquot was isolated and analyzed by XRPD.

[0334] The DSC trace of the material showed a single endotherm at 190.7°C, and the material remained unchanged by XRPD after 1 week of storage at 40°C / 75% relative humidity conditions.

[0335] Example 13: Compound 11 (Propyl Gallate Co-Crystal) [ka] Form 1 of Compound 11 50 mg of compound 1 was dispensed into a 2 mL stainless steel milling jar containing one stainless steel milling ball and 1 molar equivalent of propyl gallate. THF (35 μL) was added to the vial, which was then milled in a Retsch mill at 30 Hz for 30 minutes. Aliquots were isolated and analyzed by XRPD.

[0336] The DSC trace of the material contained a broad endotherm with an onset at 148°C and a second endotherm with an onset at 189°C, including multiple shoulders typical of materials with complex thermal behavior. After storing the material at 40°C / 75% relative humidity for 1 week, the material remained unchanged by XRPD.

[0337] Illustrative Embodiments The following numbered embodiments are non-limiting examples of certain aspects of the present disclosure. Embodiment 1. A solid form of Compound 2, comprising Compound 1 and hydrochloric acid: [ka] Embodiment 2. The solid form of embodiment 1, wherein said solid form is Pattern 2 of Compound 2. Embodiment 3. The solid form of embodiment 1, wherein said solid form is Pattern 4 of Compound 2. Embodiment 4. The solid form of embodiment 1, wherein the solid form is Compound 2 Pattern 9. Embodiment 5. A solid form of Compound 7, comprising Compound 1 and L-tartaric acid: [ka] Embodiment 6. The solid form of embodiment 5, wherein the solid form is Compound 7 Pattern 1 and is characterized by a differential scanning calorimetry (DSC) endotherm having a minimum at about 199.0°C. Embodiment 7. The solid form of any one of embodiments 5 and 6, characterized by a mass gain of about 0.6% at 0-90% relative humidity by gravimetric vapor sorption (GVS) analysis. Embodiment 8. A solid form of Compound 8 comprising Compound 1 and methanesulfonic acid: [ka] Embodiment 9. The solid form of embodiment 8, wherein the solid form is Pattern 1 of Compound 8. Embodiment 10. The solid form of embodiment 8, wherein the solid form is Compound 8 Pattern 2. Embodiment 11. The solid form of embodiment 8, wherein the solid form is Pattern 3 of Compound 8. Embodiment 12. A solid form of Compound 9, comprising Compound 1 and fumaric acid: [ka] Embodiment 13. The solid form of embodiment 12, wherein the solid form is Pattern 1 of Compound 9, characterized by an X-ray powder diffraction (XRPD) pattern having three or more diffractions at angles of 6.1, 10.8, 12.7, 20.4, 25.3, and 26.5 (2-theta ± 0.2). Embodiment 14. The solid form of embodiment 12, wherein the solid form is Pattern 1 of Compound 9, characterized by an X-ray powder diffraction (XRPD) pattern having four or more diffractions at angles of 6.1, 10.8, 12.7, 20.4, 25.3, and 26.5 (2-theta ±0.2). Embodiment 15. The solid form of embodiment 12, wherein the solid form is Compound 9 Pattern 1, characterized by an X-ray powder diffraction (XRPD) pattern having five or more diffractions at angles (2 theta ± 0.2) of 6.1, 10.8, 12.7, 20.4, 25.3, and 26.5. Embodiment 16. The solid form of embodiment 12, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern of Compound 9, Pattern 1, having diffractions at angles of 6.1, 10.8, 12.7, 20.4, 25.3, and 26.5 (2-theta ±0.2). Embodiment 17. The solid form of embodiment 12, wherein the solid form is Pattern 1 of Compound 9, characterized by an X-ray powder diffraction (XRPD) pattern with diffractions at angles (2-theta ±0.2) of 6.1, 10.8, 12.7, 20.4, 25.3, and 26.5, corresponding to d-spacings (Angstroms ±0.2) of 14.4, 8.19, 6.96, 4.34, 3.52, and 3.36 (respectively). Embodiment 18. The solid form of embodiment 12, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern of Compound 9, pattern 1, having diffraction at the following angles (2 theta ±0.2): [Table 48] Embodiment 19. The solid form of embodiment 12, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern of Compound 9, Pattern 1, having diffraction at angles (2 theta ±0.2) corresponding to the following d-spacings (Angstroms ±0.2): [Table 49] Embodiment 20. The solid form of any one of embodiments 12 to 19, characterized by a differential scanning calorimetry (DSC) endotherm having a minimum at about 251.9°C. Embodiment 21. The solid form of any one of embodiments 12 to 20, characterized by a mass gain of about 0.6% at 0-90% relative humidity by gravimetric vapor sorption (GVS) analysis. Embodiment 22. A solid form of Compound 10 comprising Compound 1 and methyl gallate: [ka] Embodiment 23. A solid form of Compound 11 comprising Compound 1 and propyl gallate: [ka] In one embodiment, for example, the following items are provided: (Item 1) A solid form of Compound 1, comprising: [ka] The solid form is selected from the group consisting of salts or co-crystalline forms of Compound 1 with L-malic acid, oxalic acid, phosphoric acid, succinic acid, and L-tartaric acid. (Item 2) 2. The solid form of claim 1, wherein the solid form is an oxalate salt of Compound 1. (Item 3) A solid form of Compound 3, comprising Compound 1 and L-malic acid. [ka] (Item 4) 4. The solid form of claim 3, wherein the solid form is Compound 3 Pattern 1 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising three or more diffractions at angles of 6.2, 12.7, 17.3, 20.4, 25.3, and 26.4 (2 theta ± 0.2). (Item 5) 4. The solid form of claim 3, wherein the solid form is Compound 3 Pattern 1 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising four or more diffractions at angles of 6.2, 12.7, 17.3, 20.4, 25.3, and 26.4 (2 theta ± 0.2). (Item 6) 4. The solid form of claim 3, wherein the solid form is Compound 3 Pattern 1 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more diffractions at angles of 6.2, 12.7, 17.3, 20.4, 25.3, and 26.4 (2 theta ± 0.2). (Item 7) 4. The solid form of claim 3, wherein the solid form is Compound 3 Pattern 1 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffractions at angles of 6.2, 12.7, 17.3, 20.4, 25.3, and 26.4 (2 theta ± 0.2). (Item 8) 4. The solid form of item 3, wherein the solid form is Compound 3 Pattern 1 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffractions at angles (2-theta ±0.2) of 6.2, 12.7, 17.3, 20.4, 25.3, and 26.4, corresponding to d-spacings (Angstroms ±0.2) of 14.32, 6.97, 5.13, 4.34, 3.52, and 3.37 (respectively). (Item 9) 4. The solid form of claim 3, wherein the solid form is Compound 3 Pattern 1 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffractions at the following angles (2 theta ± 0.2): [Table 1] (Item 10) 4. The solid form of item 3, wherein the solid form is Compound 3 Pattern 1 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffractions at angles (2 theta ± 0.2) corresponding to the following d-spacings (Angstroms ± 0.2): [Table 2] (Item 11) 11. The solid form of any one of items 3 to 10, characterized by a differential scanning calorimetry (DSC) endotherm having a minimum at about 187.2 °C. (Item 12) 12. The solid form of any one of items 3 to 11, characterized by a mass gain of about 0.22% at 0-90% relative humidity by gravimetric vapor sorption (GVS) analysis. (Item 13) A solid form of Compound 4, comprising Compound 1 and succinic acid. [ka] (Item 14) 14. The solid form of item 13, wherein the solid form is Compound 4 Pattern 1 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising three or more diffractions at angles of 6.2, 10.2, 12.7, 17.3, 20.4, and 23.8 (2 theta ± 0.2). (Item 15) 14. The solid form of item 13, wherein the solid form is Compound 4 Pattern 1 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising four or more diffractions at angles of 6.2, 10.2, 12.7, 17.3, 20.4, and 23.8 (2 theta ± 0.2). (Item 16) 14. The solid form of item 13, wherein the solid form is Compound 4 Pattern 1, characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more diffractions at angles of 6.2, 10.2, 12.7, 17.3, 20.4, and 23.8 (2 theta ± 0.2). (Item 17) 4. The solid form of claim 3, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern of Compound 4, Pattern 1, comprising diffractions at angles of 6.2, 10.2, 12.7, 17.3, 20.4, and 23.8 (2 theta ± 0.2). (Item 18) 14. The solid form of item 13, wherein the solid form is Compound 4 Pattern 1 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffractions at angles (2-theta ±0.2) of 6.2, 10.2, 12.7, 17.3, 20.4, and 23.8, corresponding to d-spacings (Angstroms ±0.2) of 14.26, 8.64, 6.95, 5.12, 4.35, and 3.73 (respectively). (Item 19) 14. The solid form of item 13, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern of Compound 4, pattern 1, comprising diffractions at the following angles (2 theta ± 0.2): [Table 3] (Item 20) 14. The solid form of item 13, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern of Compound 4, pattern 1, comprising diffractions at angles (2 theta ± 0.2) corresponding to the following d-spacings (Angstroms ± 0.2): [Table 4] (Item 21) 21. The solid form of any one of items 13 to 20, characterized by a differential scanning calorimetry (DSC) endotherm having a minimum at about 223.4°C. (Item 22) 22. The solid form of any one of items 13 to 21, characterized by a mass gain of about 0.16% at 0-90% relative humidity by gravimetric vapor sorption (GVS) analysis. (Item 23) A solid form of Compound 5, comprising Compound 1 and phosphoric acid. [ka] (Item 24) 24. The solid form of item 23, wherein the solid form is Compound 5 Pattern 1 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising three or more diffractions at angles of 4.7, 6.1, 17.0, 17.4, 18.1, and 24.6 (2 theta ± 0.2). (Item 25) 24. The solid form of item 23, wherein the solid form is Compound 5 Pattern 1 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising four or more diffractions at angles of 4.7, 6.1, 17.0, 17.4, 18.1, and 24.6 (2 theta ± 0.2). (Item 26) 24. The solid form of item 23, wherein the solid form is Compound 5 Pattern 1, characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more diffractions at angles of 4.7, 6.1, 17.0, 17.4, 18.1, and 24.6 (2 theta ± 0.2). (Item 27) 24. The solid form of item 23, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern of Compound 5, Pattern 1, comprising diffractions at angles of 4.7, 6.1, 17.0, 17.4, 18.1, and 24.6 (2 theta ± 0.2). (Item 28) 14. The solid form of item 13, wherein the solid form is Pattern 1 of Compound 5 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffractions at angles (2-theta ±0.2) of 4.7, 6.1, 17.0, 17.4, 18.1, and 24.6, corresponding to d-spacings (Angstroms ±0.2) of 18.68, 14.45, 5.20, 5.10, 4.91, and 3.62 (respectively). (Item 29) 24. The solid form of item 23, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern of Compound 5, pattern 1, comprising diffractions at the following angles (2 theta ± 0.2): [Table 5] (Item 30) 24. The solid form of item 23, wherein the solid form is Pattern 1 of Compound 5 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffractions at angles (2 theta ± 0.2) corresponding to the following d-spacings (Angstroms ± 0.2): [Table 6] (Item 31) 31. The solid form of any one of items 23 to 30, characterized by a differential scanning calorimetry (DSC) endotherm having a minimum at about 224.7°C. (Item 32) 32. The solid form of any one of items 23 to 31, characterized by a mass gain of about 1.2% at 0-90% relative humidity by gravimetric vapor sorption (GVS) analysis. (Item 33) A solid form of Compound 6, comprising Compound 1 and oxalic acid. [ka] (Item 34) 34. The solid form of item 33, wherein the solid form is Pattern 1 of Compound 6 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising three or more diffractions at angles of 4.7, 6.1, 18.7, 24.0, 24.2, and 24.6 (2 theta ± 0.2). (Item 35) 34. The solid form of item 33, wherein the solid form is Compound 6 Pattern 1, characterized by an X-ray powder diffraction (XRPD) pattern comprising four or more diffractions at angles of 4.7, 6.1, 18.7, 24.0, 24.2, and 24.6 (2 theta ± 0.2). (Item 36) 34. The solid form of item 33, wherein the solid form is Compound 6 Pattern 1, characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more diffractions at angles of 4.7, 6.1, 18.7, 24.0, 24.2, and 24.6 (2 theta ± 0.2). (Item 37) 34. The solid form of item 33, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern of Compound 6, Pattern 1, comprising diffractions at angles of 4.7, 6.1, 18.7, 24.0, 24.2, and 24.6 (2 theta ± 0.2). (Item 38) 34. The solid form of item 33, wherein the solid form is Pattern 1 of Compound 6 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffractions at angles (2 theta ± 0.2) of 4.7, 6.1, 18.7, 24.0, 24.2, and 24.6, corresponding to d-spacings (Angstroms ± 0.2) of 18.88, 14.36, 4.73, 3.71, 3.67, and 3.62 (respectively). (Item 39) 34. The solid form of item 33, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern of Compound 6, pattern 1, comprising diffractions at the following angles (2 theta ± 0.2): [Table 7] (Item 40) 34. The solid form of item 33, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern of Compound 6, pattern 1, comprising diffractions at angles (2 theta ± 0.2) corresponding to the following d-spacings (Angstroms ± 0.2): [Table 8] (Item 41) 41. The solid form of any one of items 33 to 40, characterized by a differential scanning calorimetry (DSC) endotherm having a minimum at about 211.3 °C. (Item 42) 42. The solid form of any one of items 33 to 41, characterized by a mass gain of about 0.6% at 0-90% relative humidity by gravimetric vapor sorption (GVS) analysis. (Item 43) 34. The solid form of item 33, wherein the solid form is pattern 4 of Compound 6, characterized by an X-ray powder diffraction (XRPD) pattern comprising three or more diffractions at angles of 6.4, 11.9, 19.2, 26.1, 26.6, and 27.2 (2 theta ± 0.2). (Item 44) 34. The solid form of item 33, wherein the solid form is pattern 4 of Compound 6, characterized by an X-ray powder diffraction (XRPD) pattern comprising four or more diffractions at angles of 6.4, 11.9, 19.2, 26.1, 26.6, and 27.2 (2 theta ± 0.2). (Item 45) 34. The solid form of item 33, wherein the solid form is pattern 4 of Compound 6, characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more diffractions at angles of 6.4, 11.9, 19.2, 26.1, 26.6, and 27.2 (2 theta ± 0.2). (Item 46) 34. The solid form of item 33, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern of Compound 6, pattern 4, comprising diffractions at angles of 6.4, 11.9, 19.2, 26.1, 26.6, and 27.2 (2 theta ± 0.2). (Item 47) 34. The solid form of item 33, wherein the solid form is Pattern 4 of Compound 6 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffractions at angles (2-theta ±0.2) of 6.4, 11.9, 19.2, 26.1, 26.6, and 27.2, corresponding to d-spacings (Angstroms ±0.2) of 13.89, 7.43, 4.63, 3.42, 3.35, and 3.27 (respectively). (Item 48) 34. The solid form of item 33, wherein the solid form is characterized by an X-ray powder diffraction (XRPD) pattern of Compound 6, pattern 4, comprising diffractions at the following angles (2 theta ± 0.2): [Table 9] (Item 49) 34. The solid form of item 33, wherein the solid form is pattern 4 of Compound 6 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffractions at angles (2 theta ± 0.2) corresponding to the following d-spacings (Angstroms ± 0.2): [Table 10] (Item 50) 50. The solid form of any one of items 33 and 43-49, characterized by a differential scanning calorimetry (DSC) endotherm having a minimum at about 222.9°C. (Item 51) 51. The solid form of any one of items 33 and 43-50, characterized by a mass gain of about 0.66% at 0-90% relative humidity by gravimetric vapor sorption (GVS) analysis. (Item 52) A solid form of free base Compound 1. [ka] (Item 53) 53. The solid form of item 52, wherein the solid form is Form 1 of Compound 1 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising three or more diffractions at angles of 11.8, 15.0, 17.0, 18.0, 19.4, and 23.5 (2-theta ± 0.2). (Item 54) 53. The solid form of item 52, wherein the solid form is Form 1 of Compound 1 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising four or more diffractions at angles of 11.8, 15.0, 17.0, 18.0, 19.4, and 23.5 (2 theta ± 0.2). (Item 55) 53. The solid form of item 52, wherein the solid form is Form 1 of Compound 1 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising five or more diffractions at angles of 11.8, 15.0, 17.0, 18.0, 19.4, and 23.5 (2 theta ± 0.2). (Item 56) 53. The solid form of item 52, wherein the solid form is Form 1 of Compound 1 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffractions at angles of 11.8, 15.0, 17.0, 18.0, 19.4, and 23.5 (2 theta ± 0.2). (Item 57) 54. The solid form of item 53, wherein the solid form is Form 1 of Compound 1 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffractions at angles (2-theta ± 0.2) of 11.8, 15.0, 17.0, 18.0, 19.4, and 23.5, corresponding to d-spacings (Angstroms ± 0.2) of 7.52, 5.92, 5.20, 4.93, 4.58, and 3.79 (respectively). (Item 58) 54. The solid form of item 53, wherein the solid form is Form 1 of Compound 1 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffractions at the following angles (2 theta ± 0.2): [Table 11] (Item 59) 54. The solid form of item 53, wherein the solid form is Form 1 of Compound 1 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffractions at angles (2 theta ± 0.2) corresponding to the following d-spacings (Angstroms ± 0.2): [Table 12] (Item 60) 60. The solid form of any one of items 53 to 59, characterized by a differential scanning calorimetry (DSC) endotherm having a minimum at about 239.6°C. (Item 61) 61. The solid form of any one of items 53 to 60, characterized by a mass gain of about 0.5% at 0-90% relative humidity by gravimetric vapor sorption (GVS) analysis. (Item 62) 53. The solid form of item 52, wherein the solid form is Form 2 of Compound 1 and is characterized by an X-ray powder diffraction (XRPD) pattern containing three or more diffractions at angles of 6.1, 8.0, 13.0, 17.0, 17.8, and 25.6 (2 theta ± 0.2). (Item 63) 53. The solid form of item 52, wherein the solid form is Form 2 of Compound 1 and is characterized by an X-ray powder diffraction (XRPD) pattern containing four or more diffractions at angles of 6.1, 8.0, 13.0, 17.0, 17.8, and 25.6 (2 theta ± 0.2). (Item 64) 53. The solid form of item 52, wherein the solid form is Form 2 of Compound 1 and is characterized by an X-ray powder diffraction (XRPD) pattern containing five or more diffractions at angles of 6.1, 8.0, 13.0, 17.0, 17.8, and 25.6 (2 theta ± 0.2). (Item 65) 53. The solid form of item 52, wherein the solid form is Form 2 of Compound 1 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffractions at angles of 6.1, 8.0, 13.0, 17.0, 17.8, and 25.6 (2 theta ± 0.2). (Item 66) 54. The solid form of item 53, wherein the solid form is Form 2 of Compound 1 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffractions at angles (2-theta ± 0.2) of 6.1, 8.0, 13.0, 17.0, 17.8, and 25.6, corresponding to d-spacings (Angstroms ± 0.2) of 14.52, 11.04, 6.81, 5.20, 4.98, and 3.48 (respectively). (Item 67) 54. The solid form of item 53, wherein the solid form is Form 2 of Compound 1 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffractions at the following angles (2 theta ± 0.2): [Table 13] (Item 68) 54. The solid form of item 53, wherein the solid form is Form 2 of Compound 1 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffractions at angles (2 theta ± 0.2) corresponding to the following d-spacings (Angstroms ± 0.2): [Table 14] (Item 69) 69. The solid form of any one of items 62 to 68, characterized by a differential scanning calorimetry (DSC) endotherm having a minimum at about 238.2°C. (Item 70) 70. The solid form of any one of items 62 to 69, characterized by a mass gain of about 4% at 0-90% relative humidity by gravimetric vapor sorption (GVS) analysis. (Item 71) 53. The solid form of item 52, wherein the solid form is Form 3 of Compound 1 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising three or more diffractions at angles of 5.8, 8.3, 12.7, 19.3, 24.1, and 29.1 (2 theta ± 0.2). (Item 72) 53. The solid form of item 52, wherein the solid form is Form 3 of Compound 1 and is characterized by an X-ray powder diffraction (XRPD) pattern containing four or more diffractions at angles of 5.8, 8.3, 12.7, 19.3, 24.1, and 29.1 (2 theta ± 0.2). (Item 73) 53. The solid form of item 52, wherein the solid form is Form 3 of Compound 1 and is characterized by an X-ray powder diffraction (XRPD) pattern containing five or more diffractions at angles of 5.8, 8.3, 12.7, 19.3, 24.1, and 29.1 (2 theta ± 0.2). (Item 74) 53. The solid form of item 52, wherein the solid form is Form 3 of Compound 1 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffractions at angles of 5.8, 8.3, 12.7, 19.3, 24.1, and 29.1 (2 theta ± 0.2). (Item 75) 54. The solid form of item 53, wherein the solid form is Form 3 of Compound 1 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffractions at angles (2-theta ± 0.2) of 5.8, 8.3, 12.7, 19.3, 24.1, and 29.1, corresponding to d-spacings (Angstroms ± 0.2) of 15.21, 10.58, 6.98, 4.59, 3.68, and 3.07 (respectively). (Item 76) 54. The solid form of item 53, wherein the solid form is Form 3 of Compound 1 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffractions at the following angles (2 theta ± 0.2): [Table 15] (Item 77) 54. The solid form of item 53, wherein the solid form is Form 3 of Compound 1 and is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffractions at angles (2 theta ± 0.2) corresponding to the following d-spacings (Angstroms ± 0.2): [Table 16] (Item 78) 78. The solid form of any one of items 71 to 77, characterized by a differential scanning calorimetry (DSC) endotherm having a minimum at about 240.5°C. (Item 79) 79. The solid form of any one of items 71 to 78, characterized by a mass gain of about 0.5% at 0-90% relative humidity by gravimetric vapor sorption (GVS) analysis. (Item 80) 52. The solid form of any one of items 1 to 51, wherein the solid form of the compound has an acid:base ratio of about 1:1. (Item 81) 81. The solid form according to any one of items 1 to 80, wherein the solid form is crystalline. (Item 82) 81. The solid form according to any one of items 1 to 80, wherein the solid form is amorphous. (Item 83) 83. The solid form of any one of items 1 to 82, wherein the solid form is substantially free of amorphous forms of the compound. (Item 84) 83. The solid form according to any one of items 1 to 82, wherein the solid form is substantially free of impurities. (Item 85) A solid form of Compound 6, [ka] The solid form prepared by a process comprising mixing Compound 1 and oxalic acid in IPA and then removing the solvent to provide a solid form of Compound 6. (Item 86) 86. The solid form of item 85, prepared by a process comprising adding a solution of oxalic acid in THF to a solution of compound 1 in IPA and then removing the solvent to provide a solid form of compound 6. (Item 87) i) adding a solution of oxalic acid in THF to a solution of compound 1 in IPA at 50°C; ii) cooling the combined solution of step i) to 5°C; iii) stirring the cooled solution for a time sufficient to form a solid form of compound 6; iv) filtering the combined solution to remove the solvent. (Item 88) A solid form of Compound 6, [ka] The solid form prepared by a process comprising mixing Compound 1 and oxalic acid in acetone and then removing the solvent to provide a solid form of Compound 6. (Item 89) 89. The solid form of item 88, prepared by a process comprising adding a solution of oxalic acid in THF to a solution of compound 1 in acetone and then removing the solvent to provide a solid form of compound 6. (Item 90) v) adding a solution of oxalic acid in THF to a solution of compound 1 in acetone at 50°C; vi) cooling the combined solution of step i) to 5°C; vii) stirring the cooled solution for a time sufficient to form a solid form of compound 6; viii) filtering the combined solution to remove the solvent. (Item 91) 91. A pharmaceutical composition comprising the solid form according to any one of items 1 to 90 and a pharmaceutically acceptable carrier or excipient. (Item 92) 1. A method for preparing a solid form of Compound 6, comprising: [ka] The method comprises forming a pattern 1 of compound 6. (Item 93) 1. A method for preparing a solid form of Compound 6, comprising: [ka] The method comprises forming a pattern 4 of a compound 6. (Item 94) 1. A method for preparing a solid form of Compound 6, comprising: [ka] The method, wherein the method does not include forming Pattern 1 of Compound 6 or Pattern 4 of Compound 6. (Item 95) A method of treating a disease or disorder mediated by plasma kallikrein using the solid form or composition of any one of the preceding items. (Item 96) 10. A method of treating hereditary angioedema or diabetic macular edema, comprising administering to a patient in need thereof the solid form or composition of any one of the preceding items.

Claims

[Claim 1] The invention described in the specification.

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