Solid state forms of MNK inhibitors

Abstract

The present disclosure relates to solid forms of a compound having the following structure (I) or a tautomer thereof. The present disclosure also relates to methods of making and using the compounds of structure (I).

Description

[0001] Government Interest Statement

[0002] This application was made with government support under Grant No. 1U44NS115692-01 awarded by the National Institutes of Health. The government has certain rights in the application.

[0003] Related Applications

[0004] This application claims the benefit of and priority to U.S. Application No. 63 / 478,409, filed January 4, 2023, the entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0005] Embodiments of the present disclosure generally relate to solid forms of compounds and methods of making the same, and their use as therapeutic or prophylactic agents, for example, for the treatment of various diseases and conditions (e.g., inflammation, neuropathic pain, migraine, etc.). BACKGROUND

[0006] In the United States, inadequate treatment of pain is a devastating health problem. One-third of all Americans suffer from some form of chronic pain, and one-third of these people have pain that is resistant to current medical therapies. The economic impact of pain is equally staggering, costing approximately $100 billion per year. Opioids, or narcotic analgesics, typified by morphine, are the most effective treatments for acute and chronic severe pain. However, their clinical use is often hampered by the development of tolerance to the analgesic, which requires escalating doses to achieve equivalent pain relief. Furthermore, these drugs are often ineffective for neuropathic pain. This complex pathophysiological cycle poses a serious impediment to the quality of life for these patients due to the resultant drug-induced sedation, decreased physical activity, constipation, respiratory depression, high likelihood of addiction, and other side effects.

[0007] Neuropathic pain often develops over time and can benefit from therapies that intervene in pathways involved in its development and / or persistence.

[0008] Diseases or injuries that result in neuropathic pain can affect the central nervous system (CNS), the peripheral nervous system, or both (unlike the etiology of nociceptive pain, which only affects the peripheral nervous system). Common causes of neuropathic pain include spinal cord injury, multiple sclerosis, central nervous system ischemia, spinal nerve disease, diabetes, other metabolic disorders, shingles infection, HIV-related neuropathy, malnutrition, toxins, distal manifestations of malignancy, immune-mediated disorders, physical trauma to the nerve trunk (such as during surgery), peripheral ischemia, peripheral neuropathy, nerve compression, chemotherapy or other drug-induced nerve damage, radiation damage, arthritis, autoimmune diseases, and infection in the area near the affected nerve.

[0009] Neuropathic pain often involves abnormal nociceptor sensitivity. Nociceptors are specialized neurons that detect pain. Nociceptor sensitivity is not fixed; it changes over time. Some etiologies of neuropathic pain affect nociceptor sensitivity by inducing “peripheral sensitization.” Peripheral sensitization includes spontaneous pathological activity, abnormal excitability, enhanced sensitivity to chemical stimuli, enhanced sensitivity to heat stimuli, enhanced sensitivity to mechanical stimuli, and any combination of these.

[0010] Accordingly, neuropathic pain can be treated by disrupting peripheral sensitization, either by first reducing or preventing such peripheral sensitization or by reducing the extent of peripheral sensitization that has already developed. Although the present disclosure is not limited to one mechanism of action, MNK inhibitors as disclosed herein can disrupt peripheral sensitization.

[0011] MNKs phosphorylate eukaryotic translation initiation factor 4E (eIF4E) and factors that bind to AU-rich elements in the 3-untranslated region of certain messenger RNAs (mRNAs). MNKs are a subfamily of Ser / Thr kinases that are phylogenetically considered to be Ca 2+ / calmodulin-dependent kinases (CaMKs). MNKs are activated by phosphorylation via the Ras / extracellular signal-regulated kinase pathway stimulated by growth factors and the p38 pathway induced by stress.

[0012] Nociceptor sensitization can be blocked by inhibiting activity-dependent mRNA translation via the mechanistic target mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway signals to the eukaryotic translation initiation factor (eIF) 4E complex to regulate nociceptor sensitization.

[0013] The compounds can form one or more different pharmaceutically acceptable salts and / or solid forms, including amorphous forms and polymorphic crystalline forms. Individual salts and solid forms of a biologically active compound can have different properties. It is desirable to identify and select appropriate salts and / or solid forms (including appropriate crystalline forms, if applicable) of a biologically active compound for use in developing pharmaceutically acceptable dosage forms for treating various diseases or conditions associated with MNK. SUMMARY

[0014] Briefly, embodiments of the present disclosure provide compounds, including pharmaceutically acceptable salts, solvates, co-crystals, polymorphs, and other solid forms thereof, that are capable of inhibiting the activity of MNK.

[0015] In some embodiments, the present disclosure provides solid forms of the compounds of structure (I), including free base (or “free form”) solid forms, salt forms, and / or solvate forms.

[0016] In one aspect, the present disclosure provides a solid form of a compound having the following structure (I) or a tautomer thereof:

[0017]

[0018] wherein the solid form has an X-ray powder diffraction pattern with at least two peaks at a 2 theta angle selected from the group consisting of 5.6 ± 0.2°, 10.9 ± 0.2°, 18.2 ± 0.2°, and 18.6 ± 0.2°.

[0019] In another aspect, there are also provided pharmaceutical compositions comprising the disclosed solid forms, and methods of using the same for treating, for example, inflammation, neuropathic pain, migraine, lupus, pain from viral infection, COVID-19 related acute respiratory distress syndrome (ARDS), nonalcoholic fatty liver disease (NAFLD), obesity from high-fat diet, Alzheimer’s disease, or Fragile X syndrome. BRIEF DESCRIPTION OF DRAWINGS

[0020] The following patterns refer to the solid form of structure (I), and are for the free form thereof, unless otherwise indicated.

[0021] Figure 1 An XRPD diffractogram of Pattern 3 is shown.

[0022] Figure 2 TGA (top) and DSC (bottom) data for Pattern 3 are shown.

[0023] Figure 3 An XRPD diffractogram of Pattern 11 is shown.

[0024] Figure 4 TGA (top) and DSC (bottom) data for Pattern 11 is shown.

[0025] Figure 5 An overlay of the XRPD diffractograms for Pattern 11 and Pattern 3 is shown.

[0026] Figure 6 A form plot depicting the conditions used to obtain the 11 different polymorphic forms of the free base of Structure (I) is shown.

[0027] Figure 7 is the X-ray powder diffraction pattern of Structure (I) from Batch A.

[0028] Figure 8 is the TGA (top) and DSC (bottom) of Structure (I) from Batch A.

[0029] Figure 9 is an overlay of the XRPD diffractograms of different patterns of the salt of Structure (I) and the free form of Structure (I).

[0030] Figure 10 An overlay of the XRPD diffractograms of Pattern 2 fumarate (from bottom to top) before and after storage for 7 days at 40°C / 75% RH is depicted.

[0031] Figure 11 An overlay of the XRPD diffractograms (from bottom to top) of the free form Pattern 3, the sulfonate Pattern 1, the sulfonate Pattern 2 before storage, and the sulfonate Pattern 2 after storage is shown. The storage conditions were 7 days at 40°C / 75% RH.

[0032] Figure 12 An overlay of the XRPD diffractograms of Pattern 1 before (top) and after (bottom) the double cycle GVS experiment is shown.

[0033] Figure 13 An overlay of the XRPD diffractograms of Pattern 1 (from bottom to top) as a reference material after storage at 25°C / 97% RH for 8 days and at 40°C / 75% RH for 8 days is shown.

[0034] Figure 14 is an overlay of the XRPD diffractograms (from bottom to top) of the free form Pattern 3 (from Batch B), the free form Pattern 2, and the free form Pattern 1 (from Batch A).

[0035] Figure 15 An overlay of the XRPD diffractograms of the free form Pattern 3 before (bottom) and after (top) the GVS is depicted.

[0036] Figure 16An overlay of XRPD diffractograms of Free Form Pattern 3 is shown (bottom), after 7 days of storage at 25°C / 97% RH (middle), and after 7 days of storage at 40°C / 75% RH (top).

[0037] Figure 17 An overlay of XRPD diffractograms of Free Form Pattern 3 is shown under various vacuum and temperature conditions. From bottom to top, the conditions are 25°C + 30 min after release vacuum, 50°C vacuum 3 days, 50°C vacuum, 50°C vacuum, 50°C no vacuum, and 25°C no vacuum.

[0038] Figure 18 An overlay of XRPD diffractograms of Pattern 3 is shown under various temperature conditions. From bottom to top, the temperature conditions are 25°C, 250°C, 175°C, 50°C, and 25°C.

[0039] Figure 19 is an overlay of XRPD diffractograms of the 5 patterns obtained from salt screening various salts using a mixture of 9: 1 THF: water. From bottom to top, the solid forms are Free Form Pattern 1, Tartrate Pattern 1, Fumarate Pattern 1, Citrate Pattern 1, Malate Pattern 1, and Succinate Pattern 1.

[0040] Figure 20 Depicted is an overlay of XRPD diffractograms of solids obtained from the addition of phosphoric acid in a high temperature salt screen. From bottom to top, the diffractograms are Phosphate Pattern 1 (reference), Phosphate Pattern 1 showing additional peaks, Phosphate Pattern 1, Phosphate Pattern 2, and Phosphate Pattern 1 with additional peaks.

[0041] Figure 21 An overlay of XRPD diffractograms of Free Form Pattern 1 (bottom), which is less crystalline, compared to Free Form Pattern 2 (top) is shown.

[0042] Figure 22 An overlay of XRPD diffractograms of (from bottom to top) Free Form Pattern 2 (bottom), Free Form Pattern 1, HBr Salt Pattern 1, and HBr Salt Pattern 2 (top) is shown.

[0043] Figure 23 An overlay of XRPD diffractograms of (from bottom to top) Free Form Pattern 1 (bottom), HC1 Salt Pattern 1, HC1 Salt Pattern 2, HC1 Salt Pattern 3, a combination of HC1 Salt Patterns 1 and 3, and HC1 Salt Pattern 4 (top) is shown.

[0044] Figure 24 is an overlay of XRPD diffractograms of (from bottom to top) Free Form Pattern 2 (bottom), Free Form Pattern 1, Sulfate Pattern 1, and Sulfate Pattern 1 (top).

[0045] Figure 25 XRPD diffractogram overlay of Form 2 free form pattern (bottom), Form 1 free form pattern, p-toluenesulfonate Form 1, and p-toluenesulfonate Form 1 (top) is depicted.

[0046] Figure 26 XRPD diffractogram overlay of Form 2 free form pattern (bottom), Form 1 free form pattern, mesylate Form 1, and mesylate Form 2 (top) is shown.

[0047] Figure 27 XRPD diffractogram overlay of Form 2 free form pattern (bottom), Form 1 free form pattern, besylate Form 1, and besylate Form 1 (top) is shown.

[0048] Figure 28 XRPD diffractogram overlay of Form 2 free form pattern (bottom), Form 1 free form pattern, maleate Form 1, and maleate Form 1 (top) is shown.

[0049] Figure 29 XRPD diffractogram overlay of Form 2 free form pattern (bottom), Form 1 free form pattern, H3PO4 salt Form 1 (top), H3PO4 salt Form 2, and H3PO4 salt Form 1 (top) is shown.

[0050] Figure 30 XRPD diffractogram overlay of Form 2 free form pattern (bottom), Form 1 free form pattern, L-tartrate Form 1, and poorly crystalline material is depicted.

[0051] Figure 31 XRPD diffractogram overlay of Form 2 free form pattern (bottom), Form 1 free form pattern, fumarate Form 1, and poorly crystalline fumarate Form 1 is shown.

[0052] Figure 32 XRPD diffractogram overlay of Form 2 free form pattern (bottom), Form 1 free form pattern, citrate Form 1, and citrate Form 1 (top) is shown.

[0053] Figure 33 XRPD diffractogram overlay of Form 2 free form pattern (bottom), Form 1 free form pattern, L-malate Form 1, and L-malate Form 2 (top) is shown.

[0054] Figure 34is an overlay of XRPD diffractograms (from bottom to top) of Free Form Pattern 2 (bottom), Free Form Pattern 1, Succinate Pattern 1 (re-designated as Free Form Pattern 2), and Succinate Pattern 2 (top - shows some additional peaks).

[0055] Figure 35 An overlay of XRPD diffractograms of HBr Salt Pattern 1 (bottom) and Free Form Pattern 1 (from Batch A) (top) is depicted.

[0056] Figure 36 A DSC thermogram of HBr Salt Pattern 1 is shown.

[0057] Figure 37 An overlay of XRPD diffractograms of HBr Salt Pattern 1 after storage at 40 °C and 75% relative humidity for 7 days (bottom) is shown, with a reference trace of HBr Salt Pattern 1 (top).

[0058] Figure 38 An overlay of XRPD diffractograms (from bottom to top) of HC1 Salt Pattern 1 (bottom), HC1 Salt Pattern 2, HC1 Salt Pattern 3, and Free Form Pattern 1 (from Batch A) is shown. These materials were obtained using a screening process with THF:water in a 9: 1 ratio, as described below.

[0059] Figure 39 is an overlay of XRPD diffractograms (from bottom to top) of Free Form Pattern 1 (from Batch A), HC1 Salt Pattern 1 when stored at 40 °C and 70% relative humidity for 7 days, and HC1 Salt Pattern 1 (top).

[0060] Figure 40 An overlay of XRPD diffractograms (from bottom to top) of Sulfate Pattern 1 (bottom) and Free Form Pattern 1 (from Batch A) is depicted. This material was obtained using a screening process with THF:water in a 9: 1 ratio, as described below.

[0061] Figure 41 An overlay of XRPD diffractograms (from bottom to top) of Sulfate Pattern 1 (bottom) and Sulfate Pattern 1 when stored at 40 °C and 75% relative humidity for 7 days is shown.

[0062] Figure 42 An overlay of XRPD diffractograms (from bottom to top) of Mesylate Pattern 1 and Free Form Pattern 1 (from Batch A) is shown.

[0063] Figure 43 An overlay of XRPD diffractograms of Free Form Pattern 1 and Free Form Pattern 3 (top) (from bottom to top) is shown.

[0064] Figure 44is an overlay of the XRPD diffractograms (from bottom to top) of benzenesulfonate Pattern 1 and Free Form Pattern 1 (from Batch A).

[0065] Figure 45 is an overlay of the XRPD diffractograms (from bottom to top) of benzenesulfonate Pattern 1 and benzenesulfonate Pattern 1 after 7 days at 40 °C and 70% relative humidity.

[0066] Figure 46 is an overlay of the XRPD diffractograms (from bottom to top) of maleate Pattern 1 and Free Form Pattern 1 (from Batch A).

[0067] Figure 47 is an overlay of the XRPD diffractograms (from bottom to top) of maleate Pattern 1 and maleate Pattern 1 after 7 days at 40 °C and 70% relative humidity.

[0068] Figure 48 is an overlay of the XRPD diffractograms (from bottom to top) of phosphate Pattern 1 and Free Form Pattern 1 (from Batch A).

[0069] Figure 49 is an overlay of the XRPD diffractograms (from bottom to top) of phosphate Pattern 1 and phosphate Pattern 1 after 7 days at 40 °C and 70% relative humidity.

[0070] Figure 50 is an overlay of the XRPD diffractograms (from bottom to top) of Free Form Pattern 1 (bottom), citrate Pattern 1, and tartrate Pattern 1.

[0071] Figure 51 is an overlay of the XRPD diffractograms (from bottom to top) of tartrate Pattern 1 and tartrate Pattern 1 after 7 days at 40 °C and 70% relative humidity.

[0072] Figure 52 is an overlay of the XRPD diffractograms (from bottom to top) of fumarate Pattern 1 and Free Form Pattern 1 (from Batch A).

[0073] Figure 53 is an overlay of the XRPD diffractograms (from bottom to top) of fumarate Pattern 1 and fumarate Pattern 1 after 7 days at 40 °C and 70% relative humidity.

[0074] Figure 54 is an overlay of the XRPD diffractograms (from bottom to top) of Free Form Pattern 1, citrate Pattern 1, and tartrate Pattern 1.

[0075] Figure 55XRPD diffractograms of Citrate Pattern 1 and Citrate Pattern 1 after 7 days at 40 °C and 70% relative humidity are depicted (from bottom to top) superimposed.

[0076] Figure 56 XRPD diffractograms of Poorly Crystalline Free Form Pattern 1 and Free Form Pattern 2 are shown (from bottom to top) superimposed.

[0077] Figure 57 XRPD diffractograms of Free Form Pattern 1 (top), HC1 Salt Pattern 1, HC1 Salt Pattern 2, HC1 Salt Pattern 3, a combination of HC1 Salt Pattern 1 and Pattern 3, and HC1 Salt Pattern 4 are shown (from bottom to top) superimposed.

[0078] Figure 58 XRPD diffractograms of HC1 Salt Pattern 4 and HC1 Salt Pattern 4 after 7 days at 40 °C and 70% relative humidity are shown (from bottom to top) superimposed.

[0079] Figure 59 XRPD diffractograms of Free Form Pattern 2, Free Form Pattern 1, Mesylate Pattern 1, and Mesylate Pattern 2 are shown (from bottom to top) superimposed.

[0080] Figure 60 XRPD diffractograms of Free Form Pattern 2, Free Form Pattern 1, L-Malate Pattern 1, and L-Malate Pattern 2 are depicted (from bottom to top) superimposed.

[0081] Figure 61 XRPD diffractograms of Free Form Pattern 3 (input), HC1 Salt Pattern 1 (01), Phosphate Pattern 1 (02), Phosphate Pattern 1 (03), Fumarate Pattern 2 (04), Fumarate Pattern 2 (05), Mesylate Pattern 2 (06), and Mesylate Pattern 2 (07) are shown (from bottom to top) superimposed.

[0082] Figure 62 XRPD diffractograms of Free Form Pattern 3 (input material), Free Form Pattern 2, HC1 Salt Pattern 1, HC1 Salt Pattern 2, HC1 Salt Pattern 3, HC1 Salt Pattern 4, and HC1 Salt Pattern 1 are shown (from bottom to top) superimposed.

[0083] Figure 63 XRPD diffractogram of HC1 Salt Pattern 1 is shown.

[0084] Figure 64 XRPD diffractograms of Free Form Pattern 3 (input material), Free Form Pattern 2, Phosphate Pattern 1, Phosphate Pattern 2, Phosphate Pattern 1, and Phosphate Pattern 1 are shown (from bottom to top) superimposed.

[0085] Figure 65 XRPD diffractogram of the phosphate salt Form 1 is depicted.

[0086] Figure 66 XRPD diffractogram overlay of (from bottom to top) free form Form 3 (input material), free form Form 2, fumarate salt Form 1, fumarate salt Form 2, and fumarate salt Form 2 (top) is shown.

[0087] Figure 67 XRPD diffractogram of fumarate salt Form 2 is shown.

[0088] Figure 68 XRPD diffractogram overlay of (from bottom to top) free form Form 3 (input material), free form Form 2, mesylate salt Form 1, mesylate salt Form 2, mesylate salt Form 2, and mesylate salt Form 2 is shown.

[0089] Figure 69 XRPD diffractogram of mesylate salt Form 2 is shown.

[0090] Figure 70 XRPD diffractogram overlay of (from bottom to top) free form Form 3, sulfate salt Form 1, and HC1 salt Form 1 is depicted.

[0091] Figure 71 XRPD diffractogram overlay of (from bottom to top) Form 1 reference material, sample treated with DMSO / water reverse anti-solvent, sample treated with dry grinding for 30 minutes, sample treated with DMSO / TBME reverse anti-solvent (Form 4), and free form Form 3 (from Batch B) is shown.

[0092] Figure 72 XRPD diffractogram overlay of (from bottom to top) Form 4 after 7 days at 40 °C and 70% relative humidity, Form 4 before storage, and free form Form 3 is shown.

[0093] Figure 73 XRPD diffractogram overlay of (from bottom to top) amorphous material after 7 days at 40 °C and 70% relative humidity, amorphous material before storage, and free form Form 3 is shown.

[0094] Figure 74is an XRPD diffractogram overlay showing the diffractograms of samples prepared as a result of a polymorph screen to explore the polymorphic nature of the poorly crystalline Form 3 described herein (Polymorph Screen 1). That is, the diffractogram is (from bottom to top) Free Form Pattern 1, Free Form Pattern 2, Free Form Pattern 3, input material, Free Form Pattern 3, mixture of Pattern 5, Pattern 3, and Pattern 5, Pattern 6, Free Form Pattern 3, Pattern 7, Pattern 3 (with additional peaks at 8.3°), Pattern 8, and Free Form Pattern 3.

[0095] Figure 75 is an XRPD diffractogram overlay showing the diffractograms of samples prepared as a result of a polymorph screen to explore the polymorphic nature of the poorly crystalline Form 3 described herein. That is, the diffractogram is (from bottom to top) Free Form Pattern 1, Free Form Pattern 2, Free Form Pattern 3, input material, Free Form Pattern 3, Free Form Pattern 3, Pattern 9, Free Form Pattern 3, Free Form Pattern 3, Pattern 8, Free Form Pattern 3, Free Form Pattern 3, and Free Form Pattern 3.

[0096] Figure 76 is an XRPD diffractogram overlay showing the diffractograms of samples prepared as a result of a polymorph screen to explore the polymorphic nature of the amorphous material described herein (Polymorph Screen 2). That is, the diffractogram is (from bottom to top) Free Form Pattern 1, Free Form Pattern 2, Free Form Pattern 3, amorphous input material, Free Form Pattern 3, Free Form Pattern 3, Free Form Pattern 3, Free Form Pattern 3, Free Form Pattern 3, Pattern 7, Free Form Pattern 3, Pattern 7, and Free Form Pattern 3.

[0097] Figure 77 is an XRPD diffractogram overlay showing the diffractograms of samples prepared as a result of a polymorph screen to explore the polymorphic nature of the amorphous material described herein (Polymorph Screen 2). That is, the diffractogram is (from bottom to top) Free Form Pattern 1, Free Form Pattern 2, Free Form Pattern 3, amorphous input material, Free Form Pattern 3, Free Form Pattern 3, Pattern 8, Free Form Pattern 3, Free Form Pattern 3, Pattern 8, Free Form Pattern 3, Free Form Pattern 3, and Free Form Pattern 3.

[0098] Figure 78 is an XRPD diffractogram overlay showing the diffractograms of samples prepared as a result of a polymorph screen to explore the polymorphic nature of the amorphous material described herein (Polymorph Screen 2). That is, the diffractogram is (from bottom to top) Free Form Pattern 1, Free Form Pattern 2, Free Form Pattern 3, amorphous input material, Free Form Pattern 3, Free Form Pattern 3, Pattern 8, Free Form Pattern 3, Free Form Pattern 3, Pattern 8, Free Form Pattern 3, Free Form Pattern 3, and Free Form Pattern 3.

[0099] Figure 79 is an XRPD diffractogram overlay showing the diffractograms of samples prepared as a result of a polymorph screen to explore the polymorphic nature of the amorphous material described herein (Polymorph Screen 2). That is, the diffractogram is (from bottom to top) Free Form Pattern 1, Free Form Pattern 2, Free Form Pattern 3, amorphous input material, Free Form Pattern 3, Free Form Pattern 3, Pattern 8, Free Form Pattern 3, Free Form Pattern 3, Pattern 8, Free Form Pattern 3, Free Form Pattern 3, and Free Form Pattern 3.

[0100] Figure 80XRPD diffractogram overlays showing (from bottom to top) XRPD diffractogram of Form 3, Form 8 (wet) and Form 8 (dry) are depicted.

[0101] Figure 81 XRPD diffractogram overlays showing (from bottom to top) XRPD diffractogram of Form 3, Form 9 (wet) and Form 9 (dry) are shown.

[0102] Figure 82 XRPD diffractogram overlays showing the formation of Form 7 (top) from slurried Form 3 (bottom) in methyl ethyl ketone are shown.

[0103] Figure 83 XRPD diffractogram overlays showing the formation of Form 11 are shown. From bottom to top, the diffractograms are Form 11 (after drying for 1 day at ambient temperature), Form 11 (after drying for 1 hour at 250 °C), Forms 10 and 11 as references, and Form 3 (from Batch B).

[0104] Figure 84 are the thermal analysis (TGA (top) and DSC (bottom)) readings for Form 11.

[0105] Figure 85 XRPD diffractogram overlays of Form 11 after 7 days at 40 °C and 70% relative humidity, Form 11 after 3 days at 40 °C and 70% relative humidity, and Form 11 before storage are depicted (from bottom to top).

[0106] Figure 86 XRPD diffractogram overlays of Form 11 of two preparations are shown.

[0107] Figure 87 XRPD diffractogram overlays of Form 11 after GVS and Form 11 before GVS are shown (from bottom to top).

[0108] Figure 88 XRPD diffractogram overlays of Form 11, Form 11 after 10 days at 40 °C and 70% relative humidity, and Form 10 after 10 days at 25 °C and 97% relative humidity are shown (from bottom to top).

[0109] Figure 89 is a ball-and-stick diagram of Form 3 as a hemihydrate.

[0110] Figure 90 depicts a view of Form 3 as a hemihydrate from the single crystal structure showing the atom numbering scheme. Anisotropic atomic displacement ellipsoids of non-hydrogen atoms are shown at the 50% probability level.

[0111] Figure 91The hydrogen bonding network of Form 3 in free form is shown (intermolecular hydrogen bonds are depicted as dashed lines).

[0112] Figure 92 The hydrogen bonding network of Form 3 in free form is shown (intermolecular hydrogen bonds are depicted as dashed lines).

[0113] Figure 93 The crystal packing of Form 3 in free form is shown viewed down the crystallographic a-axis. For clarity, all hydrogen atoms have been removed from the packing diagram.

[0114] Figure 94 The crystal packing of Form 3 in free form is shown viewed down the crystallographic b-axis. For clarity, all hydrogen atoms have been removed from the packing diagram.

[0115] Figure 95 The crystal packing of Form 3 in free form is shown viewed down the crystallographic c-axis. For clarity, all hydrogen atoms have been removed from the packing diagram.

[0116] Figure 96 The simulated XRPD diffractogram of Form 3 in free form is shown at 293 K.

[0117] Figure 97 A comparison between the experimental diffractogram of Form 3 in free form collected at room temperature (bottom) and the pattern simulated from the single crystal data at 293 K (top) is shown. The patterns are consistent, which confirms that the single crystal used for structure determination is representative of the reference material. The slight differences between the simulated and experimental diffractograms can be attributed to preferred orientation.

[0118] Figure 98 is an exemplary XRPD spectrum of material comprising Form 3 of Structure (I) and additional peaks.

[0119] Figure 99 is an overlay of the reference XRPD spectrum of Form 3 and material from Part 2 of Example 22 after slurrying in water for 8 hours. DETAILED DESCRIPTION

[0120] The details described herein are by way of example only and for illustrative discussion of the embodiments of the present disclosure only. The use of any and all examples, or exemplary language (e.g., “such as” or “for instance”) provided herein, is intended merely to better illuminate the present disclosure and does not pose a limitation as to the scope of the present disclosure as claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the present disclosure. Further, all methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.

[0121] The use of the alternative (e.g., “or”) should be understood to mean either one, but not both, of the alternatives. Individual embodiments of the above described can be combined to provide further embodiments. Groupings of alternative elements or embodiments of the disclosure disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. All such combinations are contemplated and are within the scope of the disclosure.

[0122] Each of the embodiments disclosed herein can include, consist essentially of, or consist of the particular recited elements, steps, ingredients, or components as set forth herein. As used herein, the terms “comprises,” “comprising,” “consists essentially of,” or “consisting essentially of’ means “including but not limited to” and allows for the inclusion of unspecified elements, steps, ingredients, or components that do not materially affect the basic and novel characteristics of the disclosure. As used herein, the phrase “consisting of’ excludes any element, step, ingredient, or component not specified. As used herein, the phrase “consisting essentially of’ limits the scope of an embodiment to the specified elements, steps, ingredients, or components and those that do not materially affect the basic and novel characteristics of the claimed disclosure.

[0123] The use of the terms “a,” “an,” “the” and similar referents in the context of describing the disclosure (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, any concentration range, percentage range, ratio range, or integer range is intended to include the individual values, sub-ranges, and fractions thereof, within the range. Additionally, unless otherwise indicated herein, any numerical values recited herein are meant to include every whole number within the range, as well as fractions of the values within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.

[0124] The term "about" when used in connection with a stated numerical value or range means a reasonable assigment by a person of ordinary skill in the art to the stated value or range, i.e., a range of slightly greater or slightly less than the stated value; within ±20% of the stated value; within ±19% of the stated value; within ±18% of the stated value; within ±17% of the stated value; within ±16% of the stated value; within ±15% of the stated value; within ±14% of the stated value; within ±13% of the stated value; within ±12% of the stated value; within ±11% of the stated value; within ±10% of the stated value; within ±9% of the stated value; within ±8% of the stated value; within ±7% of the stated value; within ±6% of the stated value; within ±5% of the stated value; within ±4% of the stated value; within ±3% of the stated value; within ±2% of the stated value; or within ±1% of the stated value.

[0125] Structure (I)

[0126] Compound 6”-((6-aminopyrimidin-4-yl)amino)-8”-methyl-2”H-dispiro[cyclopropane-1,1'- cyclohexane-4',3"-imidazo[1,5-a]pyridine]-1",5"-dione:

[0127]

[0128] is an inhibitor of MNK and is further described in WO 2023 / 278686. Structure (I) has shown efficacy against MNK in various assays (see, e.g., WO 2023 / 278686). Accordingly, Structure (I) can be used to treat a disease, disorder, or symptom associated with MNK, such as neuropathic pain.

[0129] The present disclosure provides various free forms and salt forms of Structure (I), solid forms thereof, and pharmaceutical compositions comprising the same. The salt forms and solid forms (e.g., crystalline solid forms) confer or are likely to confer properties such as improved aqueous solubility, stability, hygroscopicity (e.g., the provided form can be less hygroscopic than another form), absorbability, bioavailability, and ease of formulation.

[0130] It will be appreciated that crystalline solid forms of Structure (I), or salts thereof, can exist in pure (i.e., unsolvated) form, hydrated form, solvated form, and / or cosolvated form. In some embodiments, crystalline solid forms of Structure (I), or salts thereof, do not have any water or other solvent incorporated in the crystal lattice (i.e., are “unsolvated” or “anhydrous”). In some embodiments, crystalline solid forms of Structure (I), or salts thereof, include water and / or other solvent in the crystal lattice (i.e., are hydrates and / or solvates, respectively). It will be appreciated that solvates that include only certain solvents, most notably water, are suitable for development as pharmaceuticals. Solvates that include other solvents can be useful for manufacturing and / or testing, especially even if they can not be suitable for approved therapeutic products.

[0131] Without being bound by any particular theory, the present disclosure recognizes certain challenges in obtaining a pattern 3 of Structure (I) that is substantially free of other forms and / or impurities in a consistent manner, and provides a solution to this problem. As described in Example 22, slurrying a material having an increased water content (e.g., greater than 3% w / w, greater than 3.5% w / w, greater than 4% w / w, or greater than 4.5% w / w) and comprising a pattern 3 of Structure (I) and one or more other forms in water unexpectedly resulted in a pattern 3 of Structure (I) that was free of other forms and had a lower water content (e.g., a water content corresponding to a hemihydrate form of Structure (I), such as less than 3% w / w, less than 2.8% w / w, less than 2.6% w / w, or less than 2.4% w / w).

[0132] Free base pattern 3

[0133] In some embodiments, the present disclosure provides a solid form of Structure (I), referred to herein as pattern 3. In some embodiments, pattern 3 is a hydrate (e.g., a hemihydrate).

[0134] In particular, one embodiment provides a solid form of a compound having the following Structure (I), or a tautomer thereof:

[0135]

[0136] wherein the solid form has an X-ray powder diffraction pattern with at least two peaks at a 2 theta angle selected from the group consisting of 5.6 ± 0.2°, 10.9 ± 0.2°, 18.2 ± 0.2°, and 18.6 ± 0.2°.

[0137] In some embodiments, the solid form has an X-ray powder diffraction pattern with at least three peaks at a 2 theta angle selected from the group consisting of 5.6 ± 0.2°, 10.9 ± 0.2°, 18.2 ± 0.2°, and 18.6 ± 0.2°. In certain embodiments, the solid form has an X-ray powder diffraction pattern with peaks at a 2 theta angle of 5.6 ± 0.2°, 10.9 ± 0.2°, 18.2 ± 0.2°, and 18.6 ± 0.2°. In some particular embodiments, the solid form has an X-ray powder diffraction pattern with at least two peaks at a 2 theta angle selected from the group consisting of 5.6°, 10.9°, 18.2°, and 18.6°.

[0138] In certain particular embodiments, the solid form has an X-ray powder diffraction pattern with at least three peaks at a 2 theta angle selected from the group consisting of 5.6°, 10.9°, 18.2°, and 18.6°. In some embodiments, the solid form has an X-ray powder diffraction pattern with peaks at a 2 theta angle of 5.6°, 10.9°, 18.2°, and 18.6°.

[0139] In some embodiments, the solid form has an X-ray powder diffraction pattern with peaks at 2Q angles of 5.6 ± 0.2°, 8.0 ± 0.2° (e.g., 7.8°, 7.9°, 8.0°, 8.1°, or 8.2°), 8.4 ± 0.2° (e.g., 8.2°, 8.3°, 8.4°, 8.5°, or 8.6°), 9.2 ± 0.2°, 10.9 ± 0.2°, 11.2 ± 0.2°, 13.2 ± 0.2°, 14.3 ± 0.2°, 15.3 ± 0.2°, 16.2 ± 0.2° (e.g., 16.0°, 16.1°, 16.2°, 16.3°, or 16.4°), 16.5 ± 0.2° (e.g., 16.3°, 16.4°, 16.5°, 16.6°, or 16.7°), 16.9 ± 0.2° (e.g., 16.7°, 16.8°, 16.9°, 17.0°, or 17.1°), 17.4 ± 0.2°, 18.2 ± 0.2° (e.g., 18.0°, 18.1°, 18.2°, 18.3°, or 18.4°), 18.6 ± 0.2° (e.g., 18.4°, 18.5°, 18.6°, 18.7°, or 18.8°), 19.9 ± 0.2° (e.g., 19.7°, 19.8°, 19.9°, 20.0°, or 20.1°), 20.2 ± 0.2° (e.g., 20.0°, 20.1°, 20.2°, 20.3°, or 20.4°), 20.5 ± 0.2° (e.g., 20.3°, 20.4°, 20.5°, 20.6°, or 20.7°), 21.9 ± 0.2°, 22.3 ± 0.2° (e.g., 22.1°, 22.2°, 22.3°, 22.4°, or 22.5°), 22.5 ± 0.2° (e.g., 22.3°, 22.4°, 22.5°, 22.6°, or 22.7°), 23.3 ± 0.2°, 23.6 ± 0.2° (e.g., 23.4°, 23.5°, 23.6°, 23.7°, or 23.8°), 24.7 ± 0.2°, 25.2 ± 0.2°, 25.8 ± 0.2°, 26.2 ± 0.2°, 27.0 ± 0.2° (e.g., 26.8°, 26.9°, 27.0°, 27.1°, or 27.2°), 27.3 ± 0.2° (e.g., 27.1°, 27.2°, 27.3°, 27.4°, or 27.5°), 27.8 ± 0.2°, 28.5 ± 0.2° (e.g., 28.3°, 28.4°, 28.5°, 28.6°, or 28.7°), and 28.8 ± 0.2° (e.g., 28.6°, 28.7°, 28.8°, 28.9°, or 29.0°).

[0140] In certain embodiments, the solid form has an X-ray powder diffraction pattern with peaks at 2Θ angles of 5.6°, 8.0°, 8.4°, 9.2°, 10.9°, 11.2°, 13.2°, 14.3°, 15.3°, 16.2°, 16.5°, 16.9°, 17.4°, 18.2°, 18.6°, 19.9°, 20.2°, 20.5°, 21.9°, 22.3°, 22.5°, 23.3°, 23.6°, 24.7°, 25.2°, 25.8°, 26.2°, 27.0°, 27.3°, 27.8°, 28.5°, and 28.8°.

[0141] In some particular embodiments, the solid form is characterized by an XRPD pattern comprising the pattern 3. In certain embodiments, the solid form is characterized by an XRPD pattern consisting essentially of the pattern 3. In some embodiments, a composition comprising the solid form is substantially pure.

[0142] One embodiment provides a solid form of a compound having the following structure (I) or a tautomer thereof:

[0143]

[0144] having an X-ray powder diffraction pattern substantially in accordance with that set forth in Figure 1 .

[0145] In some embodiments, the solid form is characterized by a differential scanning calorimetry thermogram comprising an endothermic peak having an onset temperature of about 89.5 °C. In some more particular embodiments, the endothermic peak has an area under the curve of greater than 60 J / g. In some embodiments, the endothermic peak has an area under the curve of greater than 65 J / g.

[0146] In some particular embodiments, the solid form is characterized by a differential scanning calorimetry thermogram comprising an exothermic peak having an onset temperature of about 213.5 °C. In some embodiments, the exothermic peak has an area under the curve of greater than 30 J / g. In certain embodiments, the exothermic peak has an area under the curve of greater than 35 J / g. In some more particular embodiments, the solid form is characterized by a differential scanning calorimetry thermogram substantially in accordance with that set forth in Figure 2 .

[0147] Free base pattern 11

[0148] In some embodiments, the disclosure provides a solid form of structure (I), referred to herein as pattern 11. In some embodiments, pattern 11 is anhydrous and unsolvated.

[0149] One embodiment provides a solid form of a compound having the following structure (I) or a tautomer thereof:

[0150]

[0151] wherein the solid form has an X-ray powder diffraction pattern with at least two peaks at a 2 theta angle chosen from the group consisting of 19.2±0.2°, 19.5±0.2°, and 21.2±0.2°.

[0152] In some embodiments, the solid form has an X-ray powder diffraction pattern with peaks at 2 theta angles of 19.2±0.2°, 19.5±0.2°, and 21.2±0.2°. In certain embodiments, the solid form has an X-ray powder diffraction pattern with at least two peaks at a 2 theta angle chosen from the group consisting of 19.2°, 19.5°, and 21.2°. In some embodiments, the solid form has an X-ray powder diffraction pattern with peaks at 2 theta angles of 19.2°, 19.5°, and 21.2°.

[0153] In certain embodiments, the solid form has an X-ray powder diffraction pattern with peaks at 2 theta angles of 8.2±0.2°, 9.1±0.2°, 11.4±0.2°, 13.8±0.2°, 14.3±0.2°, 15.0±0.2°, 15.5±0.2°, 16.5±0.2°, 17.0±0.2°, 19.2±0.2° (e.g., 19.0°, 19.1°, 19.2°, 19.3°, 19.4°), 19.5±0.2° (e.g., 19.3°, 19.4°, 19.5°, 19.6°, 19.7°), 19.9±0.2° (e.g., 19.7°, 19.8°, 19.9°, 20.0°, 20.1°), 21.2±0.2°, 22.3±0.2° (e.g., 22.1°, 22.2°, 22.3°, 22.4°, 22.5°), 22.7±0.2° (e.g., 22.5°, 22.6°, 22.7°, 22.8°, 22.9°), 23.3±0.2°, 23.9±0.2°, 24.7±0.2°, 25.3±0.2°, 26.0±0.2°, 26.9±0.2°, 27.7±0.2°, 28.5±0.2°, 28.9±0.2°, and 29.7±0.2°.

[0154] In some embodiments, the solid form has an X-ray powder diffraction pattern with peaks at 2Θ angles of 8.2°, 9.1°, 11.4°, 13.8°, 14.3°, 15.0°, 15.5°, 16.5°, 17.0°, 19.2°, 19.5°, 19.9°, 21.2°, 22.3°, 22.7°, 23.3°, 23.9°, 24.7°, 25.3°, 26.0°, 26.9°, 27.7°, 28.5°, 28.9°, and 29.7°.

[0155] In some embodiments, the solid form is characterized by an XRPD pattern comprising Pattern 11. In some embodiments, the solid form is characterized by an XRPD pattern consisting essentially of Pattern 11. In certain particular embodiments, a composition comprising the solid form is substantially pure.

[0156] One embodiment provides a solid form of a compound having the following structure (I) or a tautomer thereof:

[0157]

[0158] having an X-ray powder diffraction pattern substantially in accordance with that set forth in Figure 3 .

[0159] In some embodiments, the solid form is characterized by a differential scanning calorimetry thermogram that does not include any events prior to 340 °C. In certain embodiments, the solid form is characterized by a differential scanning calorimetry thermogram substantially in accordance with that set forth in Figure 4 .

[0160] Other free base forms

[0161] In some embodiments, the present disclosure provides structure (I) in various free base forms, including amorphous and crystalline forms.

[0162] In some embodiments, the present disclosure provides structure (I) in crystalline solid forms. Exemplary crystalline solid forms of structure (I) and methods of making them are described in the Examples below.

[0163] In some embodiments, the present disclosure provides a Pattern 1 of Structure (I). In some embodiments, the present disclosure provides a Pattern 2 of Structure (I). In some embodiments, the present disclosure provides a Pattern 4 of Structure (I). In some embodiments, the present disclosure provides a Pattern 5 of Structure (I). In some embodiments, the present disclosure provides a Pattern 6 of Structure (I). In some embodiments, the present disclosure provides a Pattern 7 of Structure (I). In some embodiments, the present disclosure provides a Pattern 8 of Structure (I). In some embodiments, the present disclosure provides a Pattern 9 of Structure (I). In some embodiments, the present disclosure provides a Pattern 10 of Structure (I).

[0164] In some embodiments, the present disclosure provides Structure (I) in an amorphous form. Exemplary amorphous forms of Structure (I) and processes for preparing them are described in the Examples below.

[0165] Salt forms of Structure (I)

[0166] In some embodiments, the present disclosure provides a solid form of Structure (I) (i.e., a salt or co-crystal) in which Structure (I) and a co-former are ionically bonded, for example, or are hydrogen bonded to form a provided form described herein. When the salt forms of Structure (I) are in a solid form, they can be amorphous, crystalline, or mixtures thereof. Exemplary salt forms of Structure (I) and processes for preparing them are described in the Examples below.

[0167] In some embodiments, the present disclosure provides a salt form of Structure (I) formed between Structure (I) and a co-former selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, maleic acid, fumaric acid, phosphoric acid, citric acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, tartaric acid, succinic acid, and malic acid.

[0168] In some embodiments, the present disclosure provides a salt form of Structure (I) formed between Structure (I) and hydrochloric acid. In some embodiments, the salt form of Structure (I) is HC1 Pattern 1. In some embodiments, the salt form of Structure (I) is HC1 Pattern 2. In some embodiments, the salt form of Structure (I) is HC1 Pattern 3. In some embodiments, the salt form of Structure (I) is HC1 Pattern 4.

[0169] In some embodiments, the present disclosure provides a salt form of Structure (I) formed between Structure (I) and hydrobromic acid. In some embodiments, the salt form of Structure (I) is HBr Pattern 1.

[0170] In some embodiments, the present disclosure provides a salt form of Structure (I) formed between Structure (I) and sulfuric acid. In some embodiments, the salt form of Structure (I) is sulfate Pattern 1.

[0171] In some embodiments, the present disclosure provides a salt form of Structure (I) formed between Structure (I) and maleic acid. In some embodiments, the salt form of Structure (I) is Maleic Acid Salt Pattern 1.

[0172] In some embodiments, the present disclosure provides a salt form of Structure (I) formed between Structure (I) and fumaric acid. In some embodiments, the salt form of Structure (I) is Fumaric Acid Salt Pattern 1. In some embodiments, the salt form of Structure (I) is Fumaric Acid Salt Pattern 2.

[0173] In some embodiments, the present disclosure provides a salt form of Structure (I) formed between Structure (I) and phosphoric acid. In some embodiments, the salt form of Structure (I) is Phosphoric Acid Salt Pattern 1. In some embodiments, the salt form of Structure (I) is Phosphoric Acid Salt Pattern 2.

[0174] In some embodiments, the present disclosure provides a salt form of Structure (I) formed between Structure (I) and citric acid. In some embodiments, the salt form of Structure (I) is Citric Acid Salt Pattern 1.

[0175] In some embodiments, the present disclosure provides a salt form of Structure (I) formed between Structure (I) and p-toluenesulfonic acid. In some embodiments, the salt form of Structure (I) is p-Toluenesulfonic Acid Salt Pattern 1.

[0176] In some embodiments, the present disclosure provides a salt form of Structure (I) formed between Structure (I) and methanesulfonic acid. In some embodiments, the salt form of Structure (I) is Methanesulfonic Acid Salt Pattern 2.

[0177] In some embodiments, the present disclosure provides a salt form of Structure (I) formed between Structure (I) and benzenesulfonic acid. In some embodiments, the salt form of Structure (I) is Benzenesulfonic Acid Salt Pattern 1.

[0178] In some embodiments, the present disclosure provides a salt form of Structure (I) formed between Structure (I) and tartaric acid. In some embodiments, the salt form of Structure (I) is Tartaric Acid Salt Pattern 1.

[0179] In some embodiments, the solid form comprises, consists essentially of, or consists of Pattern 1. In some embodiments, the solid form is a salt of Pattern 1. In some embodiments, the solid form is a co-crystal, solvate, or free form of Pattern 1. In certain embodiments, the solid form is a pharmaceutically acceptable salt of Pattern 1 (e.g., a chloride salt, a bromide salt, a sulfate salt, an acetate salt, a maleate salt, a fumarate salt, a phosphate salt, a citrate salt, a tosylate salt, a mesylate salt, a besylate salt, a tartrate salt, a succinate salt, or a malate salt).

[0180] In some embodiments, the solid form comprises, consists essentially of, or consists of Pattern 2. In some embodiments, the solid form is a salt of Pattern 2. In some embodiments, the solid form is a co-crystal, solvate, or free form of Pattern 2. In certain embodiments, the solid form is a pharmaceutically acceptable salt of Pattern 2 (e.g., a chloride salt, a bromide salt, a sulfate salt, an acetate salt, a maleate salt, a fumarate salt, a phosphate salt, a citrate salt, a tosylate salt, a mesylate salt, a besylate salt, a tartrate salt, a succinate salt, or a malate salt).

[0181] In some embodiments, the solid form comprises, consists essentially of, or consists of Pattern 3. In some embodiments, the solid form is a salt of Pattern 3. In some embodiments, the solid form is a co-crystal, solvate, or free form of Pattern 3. In certain embodiments, the solid form is a pharmaceutically acceptable salt of Pattern 3 (e.g., a chloride salt, a bromide salt, a sulfate salt, an acetate salt, a maleate salt, a fumarate salt, a phosphate salt, a citrate salt, a tosylate salt, a mesylate salt, a besylate salt, a tartrate salt, a succinate salt, or a malate salt).

[0182] In some embodiments, the solid form comprises, consists essentially of, or consists of Pattern 4. In some embodiments, the solid form is a salt of Pattern 4. In some embodiments, the solid form is a co-crystal, solvate, or free form of Pattern 4. In certain embodiments, the solid form is a pharmaceutically acceptable salt of Pattern 4 (e.g., a chloride salt, a bromide salt, a sulfate salt, an acetate salt, a maleate salt, a fumarate salt, a phosphate salt, a citrate salt, a tosylate salt, a mesylate salt, a besylate salt, a tartrate salt, a succinate salt, or a malate salt).

[0183] In some embodiments, the solid form comprises, consists essentially of, or consists of Pattern 5. In some embodiments, the solid form is a salt of Pattern 5. In some embodiments, the solid form is a co-crystal, solvate, or free form of Pattern 5. In certain embodiments, the solid form is a pharmaceutically acceptable salt of Pattern 5 (e.g., a chloride salt, a bromide salt, a sulfate salt, an acetate salt, a maleate salt, a fumarate salt, a phosphate salt, a citrate salt, a tosylate salt, a mesylate salt, a besylate salt, a tartrate salt, a succinate salt, or a malate salt).

[0184] In some embodiments, the solid form comprises, consists essentially of, or consists of Pattern 6. In some embodiments, the solid form is a salt of Pattern 6. In some embodiments, the solid form is a co-crystal, solvate, or free form of Pattern 6. In certain embodiments, the solid form is a pharmaceutically acceptable salt of Pattern 6 (e.g., a chloride salt, a bromide salt, a sulfate salt, an acetate salt, a maleate salt, a fumarate salt, a phosphate salt, a citrate salt, a tosylate salt, a mesylate salt, a besylate salt, a tartrate salt, a succinate salt, or a malate salt).

[0185] In some embodiments, the solid form comprises, consists essentially of, or consists of Pattern 7. In some embodiments, the solid form is a salt of Pattern 7. In some embodiments, the solid form is a co-crystal, solvate, or free form of Pattern 7. In certain embodiments, the solid form is a pharmaceutically acceptable salt of Pattern 7 (e.g., a chloride salt, a bromide salt, a sulfate salt, an acetate salt, a maleate salt, a fumarate salt, a phosphate salt, a citrate salt, a tosylate salt, a mesylate salt, a besylate salt, a tartrate salt, a succinate salt, or a malate salt).

[0186] In some embodiments, the solid form comprises, consists essentially of, or consists of Pattern 8. In some embodiments, the solid form is a salt of Pattern 8. In some embodiments, the solid form is a co-crystal, solvate, or free form of Pattern 8. In certain embodiments, the solid form is a pharmaceutically acceptable salt of Pattern 8 (e.g., a chloride salt, a bromide salt, a sulfate salt, an acetate salt, a maleate salt, a fumarate salt, a phosphate salt, a citrate salt, a tosylate salt, a mesylate salt, a besylate salt, a tartrate salt, a succinate salt, or a malate salt).

[0187] In some embodiments, the solid form comprises, consists essentially of, or consists of Pattern 9. In some embodiments, the solid form is a salt of Pattern 9. In some embodiments, the solid form is a co-crystal, solvate, or free form of Pattern 9. In certain embodiments, the solid form is a pharmaceutically acceptable salt of Pattern 9 (e.g., a chloride salt, a bromide salt, a sulfate salt, an acetate salt, a maleate salt, a fumarate salt, a phosphate salt, a citrate salt, a tosylate salt, a mesylate salt, a besylate salt, a tartrate salt, a succinate salt, or a malate salt).

[0188] In some embodiments, the solid form comprises, consists essentially of, or consists of Pattern 10. In some embodiments, the solid form is a salt of Pattern 10. In some embodiments, the solid form is a co-crystal, solvate, or free form of Pattern 10. In certain embodiments, the solid form is a pharmaceutically acceptable salt of Pattern 10 (e.g., a chloride salt, a bromide salt, a sulfate salt, an acetate salt, a maleate salt, a fumarate salt, a phosphate salt, a citrate salt, a tosylate salt, a mesylate salt, a besylate salt, a tartrate salt, a succinate salt, or a malate salt).

[0189] In some embodiments, the solid form comprises, consists essentially of, or consists of Pattern 11. In some embodiments, the solid form is a salt of Pattern 11. In some embodiments, the solid form is a co-crystal, solvate, or free form of Pattern 11. In certain embodiments, the solid form is a pharmaceutically acceptable salt of Pattern 11 (e.g., a chloride salt, a bromide salt, a sulfate salt, an acetate salt, a maleate salt, a fumarate salt, a phosphate salt, a citrate salt, a tosylate salt, a mesylate salt, a besylate salt, a tartrate salt, a succinate salt, or a malate salt).

[0190] In some of the above embodiments, the salt is formed from hydrobromic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, maleic acid, phosphoric acid, L-tartaric acid, fumaric acid, citric acid, L-malic acid, or succinic acid.

[0191] Methods of making the provided forms

[0192] The solid forms (e.g., crystalline and amorphous free base and salt forms) can be prepared according to the methods described in the Examples.

[0193] In some embodiments, the present disclosure provides a method for making a form of Structure (I) described herein, the method comprising one or more steps of removing a solvent or adding a 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. Solvent removal methods are known in the synthetic and chemical arts and include, but are not limited to, any of those described herein and in the Examples.

[0194] In some embodiments, the method for making a form of Structure (I) described herein comprises one or more steps of heating or cooling the preparation. In some embodiments, the method for making a form of Structure (I) described herein comprises one or more steps of agitating or stirring the preparation. In some embodiments, the method for making a form of Structure (I) described herein comprises a step of adding a suitable co-former to a solution or slurry of Structure (I). In some embodiments, the method for making a form of Structure (I) described herein comprises a step of adding a suitable acid to a solution or slurry of Structure (I).

[0195] In some embodiments, the solid form of structure (I) described herein is precipitated from a mixture. In another embodiment, the solid form of structure (I) described herein is crystallized from a mixture.

[0196] The solid form of structure (I) described herein can be precipitated from a reaction mixture, or can be generated by removing some or all of the solvent by methods such as evaporation, distillation, filtration (e.g., nanofiltration, ultrafiltration), reverse osmosis, absorption, and reaction, by addition of a suitable antisolvent, by cooling, or by different combinations of these methods.

[0197] As generally described herein, the solid form of structure (I) is optionally isolated. It will be appreciated that the solid form of structure (I) can be isolated by any suitable physical means known to one of ordinary skill in the art. In certain embodiments, the precipitated solid form of structure (I) is separated from the supernatant by filtration. In other embodiments, the precipitated solid form of structure (I) is separated from the supernatant by decanting the supernatant.

[0198] In some embodiments, the solid form of structure (I) is optionally purified. It will be appreciated that the solid form of structure (I) can be purified by any suitable physical means known to one of ordinary skill in the art. In some embodiments, the crude solid form of structure (I) is slurried in a suitable solvent (e.g., water) to provide a higher purity solid form of structure (I).

[0199] Compositions

[0200] One embodiment provides a pharmaceutical composition comprising the solid form of any of the embodiments disclosed herein and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is in the form of a capsule. In some embodiments, the pharmaceutical composition is in the form of a tablet.

[0201] In some embodiments, the pharmaceutical composition is formulated as part of an aqueous solution. In some embodiments, the pharmaceutical composition is formulated for injection. In some embodiments, the pharmaceutical composition is formulated for administration via an intravenous, intramuscular, or subcutaneous route. In some embodiments, the pharmaceutical composition is formulated for a rectal or vaginal route. In some embodiments, the pharmaceutical composition is formulated for inhalation.

[0202] In some embodiments, the present disclosure provides a composition comprising a form of structure (I), wherein the composition is substantially free of impurities. As used herein, the term “substantially free of impurities” means that the composition contains no significant amount of extraneous substances. Such extraneous substances can include different forms of structure (I), residual solvents, or any other impurities that can result from the preparation and / or isolation of structure (I). In certain embodiments, at least about 95% by weight of the form of structure (I) is present. In certain embodiments, at least about 95%, about 96%, about 97%, about 98%, or about 99% by weight of the form of structure (I) is present. In still other embodiments of the present disclosure, at least about 99% by weight of the form of structure (I) is present.

[0203] In some embodiments, the present disclosure provides a composition comprising a crystalline form of structure (I) (e.g., Pattern 3 or Pattern 11), wherein the composition is substantially free of other crystalline or amorphous forms of structure (I). For example, such a composition does not include a significant amount of other crystalline or amorphous forms of structure (I). In certain embodiments, at least about 95% by weight of the crystalline form of structure (I) is present. In certain embodiments, at least about 95%, about 96%, about 97%, about 98%, or about 99% by weight of the crystalline form of structure (I) is present. In still other embodiments of the present disclosure, at least about 99% by weight of the crystalline form of structure (I) is present.

[0204] In some embodiments, the present disclosure provides a composition comprising an amorphous form of structure (I), wherein the composition is substantially free of crystalline forms of structure (I). For example, such a composition does not include a significant amount of crystalline forms of structure (I). In certain embodiments, at least about 95% by weight of the amorphous form of structure (I) is present. In certain embodiments, at least about 95%, about 96%, about 97%, about 98%, or about 99% by weight of the amorphous form of structure (I) is present. In still other embodiments of the present disclosure, at least about 99% by weight of the amorphous form of structure (I) is present.

[0205] Methods of use

[0206] One embodiment provides a method for treating, preventing, or ameliorating the effects of a disease associated with abnormal MNK activity in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a solid form of any of the embodiments disclosed herein, or a pharmaceutical composition thereof.

[0207] One embodiment provides a method for treating, preventing, or ameliorating the effects of a disease associated with abnormal MNK activity in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a solid form of any of the embodiments disclosed herein, or a pharmaceutical composition thereof.

[0208] One embodiment provides a method for treating, preventing, or ameliorating the effects of neuropathic pain, lupus, pain caused by viral infection, COVID-19 related acute respiratory distress syndrome (ARDS), nonalcoholic fatty liver disease (NAFLD), obesity caused by high-fat diet, Alzheimer’s disease, or Fragile X syndrome in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a solid form of any of the embodiments disclosed herein, or a pharmaceutical composition thereof.

[0209] Exemplary embodiments

[0210] The following numbered embodiments, while not limiting, are exemplary embodiments of certain aspects of the present disclosure:

[0211] 1. A solid form of a compound having the following structure (I):

[0212]

[0213] wherein the solid form has an X-ray powder diffraction pattern with at least two peaks at a 2 theta angle selected from the group consisting of 5.6 ± 0.2°, 10.9 ± 0.2°, 18.2 ± 0.2°, and 18.6 ± 0.2°.

[0214] 2. The solid form of embodiment 1, wherein the solid form has an X-ray powder diffraction pattern with at least three peaks at a 2 theta angle selected from the group consisting of 5.6 ± 0.2°, 10.9 ± 0.2°, 18.2 ± 0.2°, and 18.6 ± 0.2°.

[0215] 3. The solid form of embodiment 1, wherein the solid form has an X-ray powder diffraction pattern with peaks at a 2 theta angle of 5.6 ± 0.2°, 10.9 ± 0.2°, 18.2 ± 0.2°, and 18.6 ± 0.2°.

[0216] 4. The solid form of embodiment 1, wherein the solid form has an X-ray powder diffraction pattern with at least two peaks at a 2 theta angle selected from the group consisting of 5.6°, 10.9°, 18.2°, and 18.6°.

[0217] 5. The solid form of embodiment 1, wherein the solid form has an X-ray powder diffraction pattern with at least three peaks at a 2 theta angle selected from the group consisting of 5.6°, 10.9°, 18.2°, and 18.6°.

[0218] 6. The solid form of embodiment 1, wherein the solid form has an X-ray powder diffraction pattern with peaks at 5.6°, 10.9°, 18.2°, and 18.6° in terms of 2Q angle.

[0219] 7. The solid form of embodiment 1, wherein the solid form has an X-ray powder diffraction pattern with peaks at 5.6 ± 0.2°, 8.0 ± 0.2°, 8.4 ± 0.2°, 9.2 ± 0.2°, 10.9 ± 0.2°, 11.2 ± 0.2°, 13.2 ± 0.2°, 14.3 ± 0.2°, 15.3 ± 0.2°, 16.2 ± 0.2°, 16.5 ± 0.2°, 16.9 ± 0.2°, 17.4 ± 0.2°, 18.2 ± 0.2°, 18.6 ± 0.2°, 19.9 ± 0.2°, 20.2 ± 0.2°, 20.5 ± 0.2°, 21.9 ± 0.2°, 22.3 ± 0.2°, 22.5 ± 0.2°, 23.3 ± 0.2°, 23.6 ± 0.2°, 24.7 ± 0.2°, 25.2 ± 0.2°, 25.8 ± 0.2°, 26.2 ± 0.2°, 27.0 ± 0.2°, 27.3 ± 0.2°, 27.8 ± 0.2°, 28.5 ± 0.2°, and 28.8 ± 0.2° in terms of 2Q angle.

[0220] 8. The solid form of embodiment 1, wherein the solid form has an X-ray powder diffraction pattern with peaks at 5.6°, 8.0°, 8.4°, 9.2°, 10.9°, 11.2°, 13.2°, 14.3°, 15.3°, 16.2°, 16.5°, 16.9°, 17.4°, 18.2°, 18.6°, 19.9°, 20.2°, 20.5°, 21.9°, 22.3°, 22.5°, 23.3°, 23.6°, 24.7°, 25.2°, 25.8°, 26.2°, 27.0°, 27.3°, 27.8°, 28.5°, and 28.8° in terms of 2Q angle.

[0221] 9. The solid form of embodiment 1, wherein the solid form comprises Pattern 3.

[0222] 10. The solid form of embodiment 1, wherein the solid form consists essentially of Pattern 3.

[0223] 11. The solid form of embodiment 1, wherein the solid form is substantially pure.

[0224] 12. A solid form of a compound having the following structure (I):

[0225]

[0226] having an X-ray powder diffraction pattern substantially in accordance with Figure 1

[0227] 13. The solid form of any one of embodiments 1 to 12 characterized by a differential scanning calorimetry thermogram comprising an endothermic peak with an onset temperature of about 89.5 °C.

[0228] 14. The solid form of embodiment 13, wherein the endothermic peak is greater than 60 J / g.

[0229] 15. The solid form of embodiment 13, wherein the endothermic peak is greater than 65 J / g.

[0230] 16. The solid form of any one of embodiments 1 to 15 characterized by a differential scanning calorimetry thermogram comprising an exothermic peak with an onset temperature of about 213.5 °C.

[0231] 17. The solid form of embodiment 16, wherein the exothermic peak is greater than 30 J / g.

[0232] 18. The solid form of embodiment 16, wherein the endothermic peak is greater than 35 J / g.

[0233] 19. The solid form of any one of embodiments 1 to 18 characterized by a differential scanning calorimetry thermogram substantially in accordance with that shown in Figure 2

[0234] 20. A solid form of a compound having the following structure (I):

[0235]

[0236] wherein the solid form has an X-ray powder diffraction pattern with at least two peaks at a 2 theta angle selected from the group consisting of 19.2 ± 0.2°, 19.5 ± 0.2°, and 21.2 ± 0.2°.

[0237] 21. The solid form of embodiment 20, wherein the solid form has an X-ray powder diffraction pattern with peaks at a 2 theta angle of 19.2 ± 0.2°, 19.5 ± 0.2°, and 21.2 ± 0.2°.

[0238] 22. The solid form of embodiment 20, wherein the solid form has an X-ray powder diffraction pattern with at least two peaks at a 2 theta angle selected from the group consisting of 19.2°, 19.5°, and 21.2°.

[0239] ​​23. The solid form of embodiment 20, wherein the solid form has an X-ray powder diffraction pattern with peaks at 19.2°, 19.5°, and 21.2° 2Θ.

[0240] 24. The solid form of embodiment 20, wherein the solid form has an X-ray powder diffraction pattern with peaks at 8.2 ± 0.2°, 9.1 ± 0.2°, 11.4 ± 0.2°, 13.8 ± 0.2°, 14.3 ± 0.2°, 15.0 ± 0.2°, 15.5 ± 0.2°, 16.5 ± 0.2°, 17.0 ± 0.2°, 19.2 ± 0.2°, 19.5 ± 0.2°, 19.9 ± 0.2°, 21.2 ± 0.2°, 22.3 ± 0.2°, 22.7 ± 0.2°, 23.3 ± 0.2°, 23.9 ± 0.2°, 24.7 ± 0.2°, 25.3 ± 0.2°, 26.0 ± 0.2°, 26.9 ± 0.2°, 27.7 ± 0.2°, 28.5 ± 0.2°, 28.9 ± 0.2°, and 29.7 ± 0.2° 2Θ.

[0241] 25. The solid form of embodiment 20, wherein the solid form has an X-ray powder diffraction pattern with peaks at 8.2°, 9.1°, 11.4°, 13.8°, 14.3°, 15.0°, 15.5°, 16.5°, 17.0°, 19.2°, 19.5°, 19.9°, 21.2°, 22.3°, 22.7°, 23.3°, 23.9°, 24.7°, 25.3°, 26.0°, 26.9°, 27.7°, 28.5°, 28.9°, and 29.7° 2Θ.

[0242] 26. The solid form of embodiment 20, wherein the solid form comprises Pattern 11.

[0243] 27. The solid form of embodiment 20, wherein the solid form consists essentially of Pattern 11.

[0244] 28. The solid form of embodiment 20, wherein the solid form is substantially pure.

[0245] 29. A solid form of a compound having the structure (I):

[0246]

[0247] or a tautomer thereof, having an X-ray powder diffraction pattern substantially in accordance with that set forth in Figure 3 .

[0248] 30. The solid form of any one of embodiments 20-29, characterized by a differential scanning calorimetry thermogram that does not include any event before 340 °C.

[0249] 31. The solid form of any one of embodiments 20-29, characterized by a differential scanning calorimetry thermogram that is substantially in accordance with that shown in FIG. Figure 4

[0250] 32. A pharmaceutical composition comprising a solid form according to any one of embodiments 1-31 and a pharmaceutically acceptable carrier or excipient.

[0251] 33. The pharmaceutical composition of embodiment 32, formulated for oral administration.

[0252] 34. The pharmaceutical composition of embodiment 32, in the form of a capsule.

[0253] 35. The pharmaceutical composition of embodiment 32, in the form of a tablet.

[0254] 36. A method for treating, preventing, or ameliorating the effects of migraine or a symptom associated with migraine, comprising administering a therapeutically effective amount of a solid form according to any one of embodiments 1-31 or a pharmaceutical composition according to any one of embodiments 32-35.

[0255] 37. A method for treating, preventing, or ameliorating the effects of a disease associated with aberrant MNK activity in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a solid form according to any one of embodiments 1-31 or a pharmaceutical composition according to any one of embodiments 32-35.

[0256] 38. A method for treating, preventing, or ameliorating the effects of neuropathic pain, lupus, pain resulting from viral infection, COVID-19 associated acute respiratory distress syndrome (ARDS), nonalcoholic fatty liver disease (NAFLD), obesity resulting from high fat diet, Alzheimer’s disease, or Fragile X syndrome in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a solid form according to any one of embodiments 1-31 or a pharmaceutical composition according to any one of embodiments 32-35.

[0257] Example

[0258] Specific conditions used to prepare and obtain data are given below. Abbreviations / acronyms / initialisms

[0259] 13 C NMR = Carbon Nuclear Magnetic Resonance

[0260] ​1 H NMR = proton nuclear magnetic resonance

[0261] 1-PrOH = 1-propanol

[0262] 2D = two-dimensional

[0263] 2-Me-1-PrOH = 2-methyl-1-propanol

[0264] ACN = acetonitrile

[0265] ADD = additional peak

[0266] API = active pharmaceutical ingredient

[0267] AS = antisolvent

[0268] ASR = analytical service report

[0269] ca. = about

[0270] DMSO = dimethyl sulfoxide

[0271] D-PAS = dip-probe absorption spectroscopy

[0272] DSC = differential scanning calorimetry

[0273] DVS = dynamic vapor sorption

[0274] Eq / Eq. / Equiv. = equivalent

[0275] EtOAc = ethyl acetate

[0276] EtOH = ethanol

[0277] FaSSGF = fasted state simulated gastric fluid

[0278] FaSSIF = fasted state simulated intestinal fluid

[0279] FeSSIF = fed state simulated intestinal fluid

[0280] GVS = gravimetric vapor sorption

[0281] H2O = water

[0282] HBr = hydrobromic acid

[0283] HC1 = hydrochloric acid

[0284] HPLC = high performance liquid chromatography

[0285] Hr or hr = hour

[0286] HSM = hot stage microscopy

[0287] IC = ion chromatography

[0288] ID = identification

[0289] IPA = 2-propanol

[0290] iPrOAc = isopropyl acetate

[0291] IR = infrared spectroscopy

[0292] ISA = ion strength adjustment

[0293] KF = Karl Fischer

[0294] MALe = maleate

[0295] MALi = L-malate

[0296] MDSC = modulated differential scanning calorimetry

[0297] MeCN = acetonitrile

[0298] MEK = methyl ethyl ketone

[0299] MeOH = methanol

[0300] MIBK = methyl isobutyl ketone

[0301] Min or min = minute

[0302] mol = mole

[0303] MS = mass spectrometry

[0304] N / A = not applicable

[0305] NMR = nuclear magnetic resonance

[0306] No. = number

[0307] P = pattern

[0308] PE = polyethylene

[0309] PLM = polarized light microscopy

[0310] PTFE = polytetrafluoroethylene

[0311] RH = relative humidity

[0312] RRT = relative retention time

[0313] RT = room temperature

[0314] SCXRD = single crystal X-ray diffraction

[0315] SGF = simulated gastric fluid

[0316] SIF = simulated intestinal fluid

[0317] SUC = succinate

[0318] TAR = L-tartaric acid (or salt thereof)

[0319] TBME = tert-butyl methyl ether

[0320] Temp = temperature

[0321] TFA = trifluoroacetic acid

[0322] Tg = glass transition temperature

[0323] TGA = thermogravimetric analysis

[0324] THF = tetrahydrofuran

[0325] TRIS = tris(hydroxymethyl)aminomethane

[0326] USP = United States Pharmacopeia

[0327] UV = ultraviolet

[0328] v / v = volume to volume

[0329] vac = vacuum

[0330] Vol = volume

[0331] w / w = weight to weight

[0332] wt = weight

[0333] wt% = weight percent

[0334] XRPD = X-ray powder diffraction

[0335] General methods

[0336] X-ray powder diffraction (XRPD)

[0337] Bruker AXS D8 Advance

[0338] Cu Ka radiation (40 kV, 40 mA, l=1.5406 A) XRPD diffractograms were collected on a Bruker D8 diffractometer equipped with a Ge monochromator on a theta-2 theta goniometer. The incident beam passed through a 2.0 mm divergence slit, followed by a 0.2 mm anti-scatter slit and a Gobel jump. The diffracted beam passed through an 8.0 mm receiving slit with 2.5° Soller slits, followed by a Lynxeye detector. The software used for data collection and analysis were Diffrac Plus XRD Commander and HighScore Plus, respectively.

[0339] The sample was run as a flat plate sample as a powder under ambient conditions. The sample was prepared by gently pressing onto a flat surface or packing into a cut-out cavity on a polished zero background (510) silicon wafer. The sample was allowed to rotate in its own plane.

[0340] Details of the standard Pharmorphix data collection method are as follows:

[0341] Angular range: 2° to 42° 2 theta

[0342] Step size: 0.05° 2 theta

[0343] Collection time: 0.5 seconds / step (total collection time: 6.40 minutes)

[0344] PANalytical Empyrean

[0345] XRPD diffractograms were collected on a PANalytical Empyrean diffractometer using Cu Ka radiation (45 kV, 40 mA, 12 mm divergence slit, 10 mm anti-scatter slit, 0.3 mm receiving slit) in transmission geometry.

[0346] Samples were prepared and analysed in transmission mode in either a metal or Millipore 96 well plate. X-ray transparent film (approximately 1 - 2 mg) was used between the metal sheets on the metal well plate. The Millipore plate was used to isolate and analyse solids from suspensions by adding a small amount of suspension directly into the plate prior to filtration under light vacuum.

[0347] The scan mode for the metal plate used an angular scan axis, whereas for the Millipore plate a 2 theta scan was utilised.

[0348] ​The details of the standard data collection method are as follows:

[0349] Angle range: 2.5° to 32.0°2θ

[0350] Step size: 0.0130°2θ

[0351] Data collection time: 12.75 seconds / step (total data collection time: 2.07 minutes)

[0352] Non-environmental conditions

[0353] Using Cu Kα radiation (45kV, 40mA) in reflection geometry XRPD diffraction patterns were acquired on a PANalytical Empyrean diffractometer. This instrument is equipped with an Anton Paar CHC plus+ stage with a graphite / Kapton window and features either air-cooled coupling or a low-vacuum pump system using an Edwards RV3 pump. A programmable divergence slit (in automatic mode) with a 10mm fixed incident beam mask, a Ni filter, and a 0.04 Radsaller slit was used on the incident beam. A PIXcel was placed on the diffraction beam. 3D The detector is equipped with a programmable anti-scattering slit (in automatic mode) and a 0.04 Radsall slit.

[0354] The software used for data collection was X'Pert Data Collector, and Highscore Plus was used for data analysis and presentation.

[0355] For the Variable Temperature (VT-XRPD) experiment, samples were prepared and analyzed in an Anton Paar chrome-plated sample holder. The sample chamber was exposed to ambient atmosphere, and a heating / cooling rate of 10°C / min was used, followed by isothermal treatment for 2 minutes before the start of the measurement. Measurement parameters conformed to standard screening data acquisition methods (detailed above). Measurements were obtained at the following temperatures: 25°C, 80°C, 170°C, 250°C, and 25°C.

[0356] For XRPD analysis under vacuum, samples were prepared and analyzed in an Anton Paar chrome-plated sample holder. The sample temperature was maintained at 25°C throughout. Measurement parameters conformed to standard screening data acquisition methods (detailed above). Initial measurements were acquired before vacuuming began, followed by measurements at 10-minute intervals. Data acquisition was stopped after three consecutive scans showed no change.

[0357] Nuclear magnetic resonance (NMR)

[0358] Data were collected on a Bruker 400MHz instrument equipped with an autosampler and controlled by a DRX400 console. 1H NMR and / or 13 C NMR spectra. Unless otherwise stated, samples were prepared in DMSO-d6solvent. Automated experiments used ICON-NMR configuration in Topspin software, using standard Bruker loaded experiments 1 H, 13 C{ 1 H}, DEPT135) were acquired. Off-line analysis was performed using ACD Spectro Processor.

[0359] For non-routine spectra (2D NMR and variable temperature NMR), data were acquired only by using Topspin.

[0360] Differential Scanning Calorimetry (DSC)

[0361] TA Instruments Q2000

[0362] DSC data were collected on a TA Instruments Q2000 equipped with a 50 position auto-sampler. Typically, 0.5-3 mg of each sample in an aluminum pan with pinhole was heated from 25 °C to 300 °C at 10 °C / minute. A purge of dry nitrogen at 50 mL / minute was maintained over the sample.

[0363] The instrument control software was Advantage for Q Series and Thermal Advantage, and data were analyzed using Universal Analysis or TRIOS.

[0364] TA Instruments Discovery DSC

[0365] DSC data were collected on a TA Instruments Discovery DSC equipped with a 50 position auto-sampler. Typically, 0.5-3 mg of each sample in an aluminum pan with pinhole was heated from 25 °C to 300 °C at 10 °C / minute. A purge of dry nitrogen at 50 mL / minute was maintained over the sample.

[0366] The instrument control software was TRIOS, and data were analyzed using TRIOS or Universal Analysis.

[0367] Thermogravimetric Analysis (TGA)

[0368] TA Instruments Q500

[0369] TGA data were collected on a TA Instruments Q500 TGA equipped with a 16 position auto-sampler. Typically, 5-10 mg of each sample was loaded onto a pre-prepared aluminum DSC pan and heated from ambient temperature to 350 °C at 10 °C / minute. A purge of nitrogen at 60 mL / minute was maintained over the sample.

[0370] Instrument control software was Advantage for Q Series and Thermal Advantage, and data were analyzed using Universal Analysis or TRIOS.

[0371] TA Instruments Discovery TGA

[0372] TGA data were collected on a TA Instruments Discovery TGA equipped with a 25-position auto-sampler. Typically, 5-10 mg of each sample was loaded onto a pre-prepared aluminum DSC pan and heated from ambient temperature to 350 °C at 10 °C / minute. A nitrogen purge at 25 mL / minute was maintained over the sample.

[0373] Instrument control software was TRIOS, and data were analyzed using TRIOS or Universal Analysis.

[0374] Polarized Light Microscopy (PLM)

[0375] Leica LM / DM Polarized Light Microscope

[0376] Samples were analyzed on a Leica LM / DM Polarized Light Microscope with a digital video camera for image capture. A small amount of each sample was placed on a glass slide with or without an immersion oil and covered with a glass slide. The sample was viewed using the appropriate magnification and partially polarized light in conjunction with a lambda pseudo-color filter. Images were captured using StudioCapture or ImageProPlus software.

[0377] Hot Stage Microscopy (HSM)

[0378] Hot stage microscopy was performed using a Leica LM / DM Polarized Light Microscope in conjunction with a Mettler-Toledo FP82HT hot stage and a digital video camera for image capture. A small amount of each sample was placed onto a glass slide with individual particles separated as much as possible. The sample was viewed using the appropriate magnification and partially polarized light in conjunction with a lambda pseudo-color filter while being heated from ambient temperature at typically 10 °C / minute. Data were collected using StudioCapture.

[0379] Gravimetric Vapor Sorption (GVS)

[0380] SMS DVS Intrinsic

[0381] An SMS DVS Intrinsic moisture sorption analyser controlled using DVS Intrinsic control software was used to obtain sorption isotherms. The sample temperature was maintained at 25 °C by the instrument controller. Humidity was controlled by mixing flows of dry and wet nitrogen gas, with a total flow rate of 200 mL / minute. Relative humidity was measured by a calibrated Rotronic probe (dynamic range 1.0 - 100% RH) located close to the sample. Changes in the weight of the sample (mass relaxation) as a function of %RH were continuously monitored by a microbalance (accuracy ±0.005 mg).

[0382] Typically, 5-30 mg of sample was placed in a deremed netted stainless steel basket under ambient conditions. The sample was loaded and unloaded at 40% RH and 25 °C (typical room conditions). Moisture sorption isotherms were performed as described below (2 scans per complete cycle). Standard isotherms were performed at 25 °C in the range 0-90% RH at 10% RH intervals. Typically, double cycles were performed (4 scans). Data analysis was performed using DVS analysis suite within Microsoft Excel.

[0383] Table 1. Method parameters for SMS DVS Intrinsic experiments

[0384]

[0385]

[0386] Hiden IGASorp

[0387] A Hiden IGASorp moisture sorption analyser controlled by Isochema HISorp software was used to obtain sorption isotherms. The sample temperature was maintained at 25 °C by a Grant LT ecocool 150 recirculating water bath. Humidity was controlled by mixing flows of dry and wet nitrogen gas, with a total flow rate of 250 ml / minute. Relative humidity was measured by a calibrated Vaisala RH probe (dynamic range 0 - 95% RH) located close to the sample. Changes in the weight of the sample (mass relaxation) as a function of %RH were continuously monitored by a microbalance (accuracy ±0.001 mg).

[0388] Typically, 20-30 mg of sample was placed in a tared mesh stainless steel basket under ambient conditions. The sample was loaded and unloaded at 40% RH and 25 °C (typical room conditions). Moisture sorption isotherms were performed as described (2 scans gave one complete cycle). Standard isotherms were performed at 25 °C at 10% RH intervals over the range 0-90% RH. Typically, double cycles were performed (4 scans). Data analysis was performed in Isochema HISorp 2019 software and exported to Microsoft Excel for presentation accordingly.

[0389] Table 2. Method parameters for Hiden IGASorp experiments

[0390]

[0391]

[0392] Chemical purity determination by HPLC

[0393] Purity analysis was performed on an Agilent HP1100 / Infinity II 1260 series system equipped with a diode array detector and using OpenLAB software. Full method details are provided below:

[0394] Table 3. HPLC method for chemical purity determination

[0395]

[0396] Moisture determination by Karl Fischer titration (KF)

[0397] The water content of each sample was measured on a Metrohm 874 oven sample processor at 150 °C with an 851 Titrano coulometer, using Hydranal Coulomat AG oven reagent and a nitrogen purge. Weighed solid samples were introduced into a sealed sample vial. Approximately 10 mg of sample was used for each titration, and duplicate determinations were made. The average of these results is presented unless otherwise stated. Data collection and analysis were performed using Tiamo software.

[0398] Ion chromatography (IC)

[0399] Data were collected using IC MagicNet software on a Metrohm 930 Compact IC Flex with an 858 Pro automated sampler and 800 Dosino dosing unit monitor. Accurately weighed samples were prepared as stock solutions in the appropriate solvent. Quantitation was achieved by comparison to standard solutions of known concentration of the ion being analyzed. Analyses were performed in duplicate and the average of the values given unless otherwise stated.

[0400] Table 4. IC Method for Cation Chromatography

[0401]

[0402] Table 5. IC Method for Anion Chromatography

[0403]

[0404] Experimental Crystallization Methods

[0405] The choice of crystallization method will affect which form is produced, and thus various crystallization methods and conditions can produce different polymorphs.

[0406] The crystallization methods used herein and the degrees of freedom available for each method are listed in Table 6.

[0407] Table 6. Crystallization Methods

[0408]

[0409]

[0410] Solvent Mediated Techniques

[0411] Without wishing to be bound by theory, crystallization occurs when the concentration of the compound in the solvent is higher than its solubility product.

[0412] To perform the crystallization screen, solvents with highly diverse properties (e.g., hydrogen bond donor / acceptor propensity, dipole moment, dielectric constant, viscosity, etc.) were selected. Solvent mixtures were also explored to obtain systems with suitable solubility, polarity, etc. The stability of the compound in a given solvent or solvent mixture was also considered.

[0413] Maturation / Slurry Maturation

[0414] Maturation experiments (or slurry maturation) were performed in various solvents or solvent mixtures and subjected to heating-cooling cycles. Without wishing to be bound by theory, repeated heating and cooling cycles can improve crystallinity, or convert metastable (or in the case of amorphous material, unbalanced) states to more thermodynamically stable crystalline forms. The rate and extent of conversion depend on the solubility of the input material.

[0415] Cooling crystallization

[0416] Crystallization is performed by reducing the temperature of the clarified solution. Without wishing to be bound by theory, the solubility of most materials decreases as the temperature is reduced, and thus cooling can be used to create a supersaturated state, allowing crystallization to occur.

[0417] Controlled evaporation

[0418] Crystallization is performed by controlled evaporation of the clarified, particulate-free solution. Without wishing to be bound by theory, controlled evaporation typically works well when the solvent has a relatively high vapor pressure, such that solvent is removed from the system, increasing the solute concentration.

[0419] Precipitation / crystallization by addition of antisolvent

[0420] Antisolvent crystallization (or drowning crystallization) is another method used to precipitate materials from solution. Without wishing to be bound by theory, the addition of a miscible antisolvent to a solute solution decreases the original solubility of the solute, increasing the saturation and causing it to precipitate. Typically, the antisolvent is chosen to be miscible with the solvent in any proportion, and the solute is relatively insoluble in the antisolvent.

[0421] Example 1

[0422] Summary of salt form investigation

[0423] This investigation identified salt forms of Structure (I) that have suitable solid state and physicochemical properties for use in a drug product. At the same time, it also investigated the solid forms of the free form via polymorph evaluation studies in order to identify forms with appropriate properties for end use.

[0424] Measurement of pKa showed that Structure (I) has a basic pKa at 4.73 and an acidic center at 11.49, and thus the compound is considered a suitable candidate to form salts at both ends of the pH scale. Extensive work was performed to identify salt forms of Structure (I). The investigation included solubility and salt formation evaluation and four salt screens. A screen with 12 acids was employed, and the following techniques were used: heat-cool cycle, cool slope, high temperature screen, one and two equivalent target screens, and target screens using high purity input materials.

[0425] During the course of this study, 12 salt forms were identified as well as a number of free base forms, two of which were selected for further development (Free Form Pattern 3 and Pattern 11). Some of the salts formed did not exhibit desirable properties. Several salt forms (e.g. Phosphate Pattern 1, Mesylate Pattern 1) were characterized as hydrates, however, in each case, the associated water molecules were lost at temperatures close to ambient, limiting the potential for use of these forms in a pharmaceutical product. However, it will be appreciated that salts and free base forms with less desirable properties can still be useful in production processes (e.g. as intermediates) and / or for testing purposes, especially even if they can not be suitable for an approved therapeutic product.

[0426] Example 2

[0427] Salt screening

[0428] Acid and base stock solutions used in the screen were prepared as described in Table 7.

[0429] Table 7. Details of counterions / co-formers used in the salt screen

[0430]

[0431]

[0432] Structure (I) from Batch A (Free Form Pattern 1) (20 mg) was charged into a HPLC vial, treated with solvent, 10 volumes at a time until the material was fully dissolved or 50 volumes had been added, whichever was the maximum. Once 50 volumes had been reached without dissolution, the temperature was increased to 50 °C. To each suspension, 1.1 molar equivalents (60 μΐ^) of HC1 (1 M in THF) was added, stirred for 5 minutes and slowly cooled to 5 °C at 0.1 °C / minute and held at this temperature overnight. All solids were then isolated by filtration through a PTFE glass frit and dried under suction for 20 minutes. Samples were analysed by XRPD.

[0433] Free Form Pattern 1 of Structure (I) was soluble in most solvents under each condition. New XRPD patterns were obtained from methanol, ethanol, ethyl acetate, isopropyl acetate, acetonitrile and 90:10 THF:water after addition of HC1. Based on the results for solubility and salt formation, 90:10 THF:water was selected as the solvent for the subsequent salt screen.

[0434] Table 8. Results of initial solubility tests, x indicates where no dissolution was observed, while ± indicates where some dissolution was observed.

[0435]

[0436]

[0437] Example 3

[0438] Salt Screen 1 - THF:Water (9:1)

[0439] Poorly crystalline Structure (I) (from Batch A, Free Form Map 1, 30 mg) was dissolved in 50 volumes of THF:Water 9:1 in 13 vials at 60 °C with stirring at 500 RPM (there was a small amount of chipping). The solution was then treated with 1.1 molar equivalents (90 / 180 pL) of the selected counterion (Table 7). The resulting solution was then cooled to 5 °C at 0.1 °C / min and held at this temperature for 2 days. The suspensions were filtered and dried under suction for 20 minutes. The taped samples were uncapped to facilitate crystallization. All of the obtained solids were initially analyzed by XRPD and stored in glass HPLC vials for subsequent analysis. All solids that showed new XRPD diffraction patterns were further characterized using DSC, HPLC, 1 Some or all of the H NMR were further characterized and stored under elevated moderate humidity.

[0440] Solid material was isolated from all samples, indicating that the compound of Structure (I) readily forms salts. Based on the XRPD analysis of the solids, names were assigned to the forms according to Table 9. Further characterization and analysis of these solids can be found in the disclosure and figures herein.

[0441] Table 9. Observations made during THF:Water 9:1 salt screen

[0442]

[0443]

[0444] Example 4

[0445] Salt Screen 2 - High Temperature Solvent Screen

[0446] Due to the low solubility observed in the experiments of Example 2, a second solubility evaluation of Structure (I) from Batch A was performed using higher temperatures close to the boiling point of the selected solvent systems (Table 10). Once at temperature, phosphoric acid or base was added to promote the formation of the phosphate or Na / K salts.

[0447] Structure (I) (from Batch A, Free Form Map 1, 30 mg) was weighed into 6 HPLC vials and a stir bar was added to each vial. 50 volumes of the different solvents were added to the samples according to Table 10 and the samples were heated stepwise on a Polar Bear heating block with stirring at 400 RPM. Observations were recorded as the temperature was increased, holding at each temperature for 10 minutes.

[0448] All samples were then cooled to 60 °C and 1.1 molar equivalents of 90 pL of phosphoric acid (1 M in THF) was added to samples 10-1 to 10-5. These samples were allowed to equilibrate, cooled to 5 °C at 0.1 °C / min, and held under stirring (400 rpm) for 14 hours. Sample 10-6 was not added acid, but was treated under the same cooling profile. To vials with samples 10-7 and 10-8, 0.8 molar equivalents of NaOH and KOH solutions (1 M in water) were added, then allowed to equilibrate, and treated under the same cooling profile.

[0449] The suspensions were separated using positive pressure and filter cartridges with PE glass frit. The resulting solids were dried under compressed air and analyzed by XRPD.

[0450] All solids that showed new XRPD diffraction patterns were further characterized using DSC, HPLC, and 1 H NMR and are discussed herein.

[0451] Observations made during the solubility assessment are presented in Table 10. All solvent systems did not exhibit complete dissolution despite the temperature increase (some pieces remained in the THF:water 9:1 sample).

[0452] Table 10. Observations during high temperature solubility assessment

[0453]

[0454]

[0455] T = turbid solution

[0456] X = suspension

[0457] The addition of 1.1 molar equivalents of phosphoric acid to samples 10-1 to 10-5 resulted in the isolation of phosphonate (PHO) pattern 1 from ethyl acetate, PHO pattern 1 contained some additional peaks from acetone:water 9:1 and ethanol:water 9:1; and the isolation of a new form of PHO pattern 2 from 1,4-dioxane. Sample 10-6, which was not added a counterion, resulted in the free form pattern 2. The samples where base was added gave brown oily / gummy residue on the vial walls. These results are summarized in Table 11 and further characterization of PHO pattern 2 can be found in the disclosure and figures herein.

[0458] Table 11. Results of high temperature solution testing

[0459]

[0460]

[0461] The characterization of sample 10-6 is summarized in Table 12. The XRPD showed that one new crystalline form was isolated, free form pattern 2. Crystallization resulted in material with a purity of 98.2%, but the material still contained 0.2 molar equivalents of potassium, which were also present in the input material.

[0462] Table 12. Summary of characterization of free form pattern 2 of sample 10-6

[0463]

[0464] Example 5

[0465] Salt screen 3 - double equivalent salt solutions

[0466] To facilitate the formation of different salt forms, another screen was performed, mainly in THF:water 9:1. This screen used an additional equivalent of each selected acid.

[0467] Poorly crystalline Structure (I) (from batch A, free form pattern 1, 20 mg) was dissolved in 50 volumes of solvent system at 60 °C in 13 vials (samples 13-1 to 13-13) and in DMSO in vial 14 (sample 13-14) at 60 °C. The solutions were then treated with 2.1 molar equivalents of selected counterions according to Table 13. The resulting solutions were then cooled to 5 °C at 0.1 °C / min and kept at this temperature for 2 days. Stirring was maintained throughout (500 rpm). The suspensions were isolated using PE glass frits and filter cartridges.

[0468] The addition of 2.1 molar equivalents of acid counterions resulted in the isolation of a large number of solids, three of which were not observed before. These were HC1 pattern 4, mesylate pattern 2 and malate pattern 2, and further characterization of these forms can be found in the disclosure and figures herein. It was also noted that some of the suspensions were poorly filterable, which can be a function of particle size.

[0469] Table 13. Results and observations of double equivalent salt addition experiment

[0470]

[0471]

[0472] Example 6

[0473] Characterization of solids from screen 1-3

[0474] The material generated in screen 1-3 was characterized to determine the properties of the solids.

[0475] Table 14. Characterization summary for HBr Pattern 1 and HC1 Patterns 1 and 3

[0476]

[0477]

[0478] HBr Pattern 1 contains some diffraction peaks that match the input material and the thermal behavior can not be suitable for use as a drug product, containing two broad endothermic peaks and no transparent melt. The sample remains HBr Pattern 1 upon storage and a slight increase in purity is observed.

[0479] Based on the XRPD pattern observed in the salt formation evaluation, HC1 Patterns 1 and 3 appear to be a mixture of forms. The thermal analysis contains two endothermic peaks, a smaller broad endothermic peak followed by a more sharp endothermic peak, which can be a melt. Only 0.8 molar equivalents of chloride are observed in the ion chromatogram. The sample is stable upon storage at 40°C / 75% RH.

[0480] Table 15. Characterization summary for Sulfate (SUL) Pattern 1 and Tosylate (TOS) Pattern 1

[0481]

[0482]

[0483] SUL Pattern 1 contains 1 molar equivalent of sulfate by ion chromatography and 97.4% purity by HPLC. The DSC contains two broad endothermic peaks, the shape of the first endothermic peak suggests that the second event can be occurring simultaneously. No well-defined melting behavior is observed. The solid form is stable upon storage at 40°C / 75% RH, but there is a decrease in the chemical purity observed.

[0484] By 1 H NMR, TOS Pattern 1 contains 1 molar equivalent of tosylate, which also indicates the presence of 0.42 equivalents of THF, which does not rule out the possibility that the solid form is solvated. The DSC contains a large endothermic peak from 40-140°C (165 J / g), which can represent the loss of this solvent. The DSC also contains two exothermic peaks at higher temperatures, with no apparent melting. Upon storage at 40°C / 75% RH, there is a large loss of crystallinity, with some free form Pattern 1 possibly present.

[0485] Table 16. Characterization summary for Free Form Pattern 3 and Benzenesulfonate (BES) Pattern 1

[0486]

[0487] Sample 9-5 was initially assigned as mesylate (MES) Pattern 1, but upon characterization and comparison to other data collected, it was determined to be the free form Pattern 3. Only 0.19 mole equivalents of mesylate and 0.15 equivalents of THF were observed by NMR. After storage at 40 °C / 75% RH, the material remained unchanged by XRPD with a slight decrease in chemical purity.

[0488] By 1 Sample 9-6, denoted as BES Pattern 1, was found by H NMR spectroscopy to contain 1 mole equivalent of benzenesulfonate. The sample contained 0.18 mole equivalents of THF. The residual solvent can have caused the overlapping endothermic peaks seen in DSC between 50-120 °C. DSC also contained two exothermic peaks at high temperature. The solid form was not stable upon storage at 40 °C / 75% RH.

[0489] Table 17. Characterization summary of maleate (MALe) Pattern 1, phosphate (PHO) Pattern 1, and tartrate (TAR) Pattern 1

[0490]

[0491] Maleate Pattern 1 contained by 1 1.2 mole equivalents of maleate and 0.25 mole equivalents of residual THF by H NMR spectroscopy. The salt form had fairly simple thermal data with a small exothermic peak at 126.8 °C and a larger overlapping event with an onset temperature of 226.2 °C. The XRPD after storage at 40 °C / 75% RH for 7 days had very low intensity, which can be due to low sample loading, and the observed reflections were consistent with maleate Pattern 1.

[0492] Phosphate Pattern 1 was obtained with a HPLC purity of 98.0% and the solid contained 0.11 mole equivalents of THF. IC showed that the solid contained 1.27 mole equivalents of phosphate. DSC contained a large broad endothermic peak between 50-150 °C (212.5 J / g) followed by a smaller broad endothermic peak with an onset temperature of 207.6 °C (39.5 J / g). The XRPD after storage at 40 °C / 75% RH for 7 days had low intensity, which can be due to low sample loading, and the observed reflections were consistent with PHO Pattern 1.

[0493] Tartrate Pattern 1 had an XRPD diffractogram consistent with citrate (CIT) Pattern 1 (Table 18). Upon 1One molar equivalent of tartaric acid was observed in the H NMR spectrum, containing trace amounts of THF. The DSC contained a broad endothermic peak from 40-150 °C, and two overlapping exothermic peaks just above 200 °C. This solid form was stable upon storage at elevated height and humidity conditions. Since CIT Pattern 1 (in Table 18 below) did not appear to be a salt, but shared the XRPD pattern with TAR Pattern 1, TAR Pattern 1 was likely the free form.

[0494] Table 18. Characterization summary of Fumarate (FUM) Pattern 1 and Citrate (CIT) Pattern 1

[0495]

[0496]

[0497] FUM Pattern 1 was obtained with a HPLC purity of 98.1%. 1 The H NMR spectrum showed that this material contained 1.83 molar equivalents of fumarate salt, which did not align with a salt having the standard stoichiometry. The material also contained 0.5 molar equivalents of THF, which can indicate that it is a solvated form. The DSC contained a single endothermic peak with an onset temperature of 180.5 °C, but the shape of this event suggested that this can be two overlapping events. This solid form was stable upon storage at 40 °C / 75% RH for 7 days, with a slight increase observed in the HPLC of the sample. One possibility is that a co-crystal was formed, which can or can not contain any charged species.

[0498] Sample 9-11 (designated as CIT Pattern 1) had an XRPD pattern that matched that of TAR Pattern 1 described above, which was designated as a mono-salt. By 1 The H NMR spectrum indicated that Sample 9-11 did not contain any citrate salt, suggesting that it can be the free form.

[0499] Table 19. Characterization summary of Free Form Pattern 2

[0500]

[0501]

[0502] Sample 9-12 was initially designated as MALi Pattern 1, but upon comparison with subsequent data, it was re-designated as Free Form Pattern 2 due to the lack of malate salt observed in the 1 The H NMR observed malate salt resulted in re-designation as Free Form Pattern 2. The XRPD pattern of Sample 9-13 matched Free Form Pattern 2 very well, and was also re-designated on this basis. Both samples had residual THF present at 4.1 and 0.5 molar equivalents, respectively, suggesting that this can be a solvated form.

[0503] Table 20. Summary of characterization of phosphate (PHO) pattern 2 and HC1 pattern 4

[0504]

[0505] PHO pattern 2 was obtained from 1,4-dioxane in salt screen 2. It exhibits complex thermal behavior with a broad endothermic peak between 30 °C - 120 °C followed by a series of other endothermic events. The material has 1.1 equivalents of phosphate by IC and loses a significant amount of crystallinity when stored at 40 °C 75% RH for 7 days.

[0506] HC1 pattern 4 is poorly crystalline with the two largest peaks attributed to contamination from the filter glass frit (21.5° and 24.0° 2Q). The DSC contains one sharp endothermic peak with an onset temperature of 123.7 °C attributed to the polyethylene filter glass frit. By 1 H NMR spectrum, the sample also contains a significant amount of residual THF. The poor crystallinity and instability upon storage at elevated temperature and humidity suggest that this salt form can not be suitable for use in a drug product.

[0507] Table 21. Summary of characterization of mesylate (MES) pattern 2 and malate (MALi) pattern 2

[0508]

[0509] MES pattern 2 was obtained from the double equivalent screen and has a relatively low purity of 93.2%. It has a high residual solvent content, reflected in the large and broad endothermic peak at the onset of the DSC. There are complex endothermic-exothermic peaks at high temperatures > 200 °C.

[0510] MALi pattern 2 was obtained from the double equivalent screen and is likely to be the free form as there are no peaks attributed to L-malic acid in the 1 H NMR spectrum. It has a significant amount of residual THF (0.82 equivalents), which is also seen in the DSC as a large and broad endothermic peak with an onset temperature of 65.6 °C. There are a large number of overlapping events from 180 °C - 260 °C.

[0511] Example 7

[0512] Summary of salt screens 1-3

[0513] Using the compound of pattern 1 of structure (I) (from batch A) as input material, solubility and preliminary salt formation evaluation, as well as three salt screens were performed. Two of the screens were performed in THF:water 9:1 as this was the only solvent system identified to have any appreciable solubility. The third screen attempted to address this issue by increasing the temperature of the selected solvent.

[0514] Through these screens, a total of 11 salt forms have been crystallized and characterized. In addition, two new free form patterns have been identified, Free Form Pattern 2 and Free Form Pattern 3. Three additional samples have been isolated for which the nature of the form is not yet clear (TAR Pattern 1, CIT Pattern 1, and MALi Pattern 2).

[0515] Overall, the solid form properties of the salts isolated from the screens using Structure (I) from Batch A are not desirable for development as a pharmaceutical product (e.g., due to complex or unfavorable thermal behavior or instability under certain storage conditions), but can still have utility as intermediates for manufacturing processes and / or for testing purposes. It is postulated that the 0.2 equivalents of potassium in the input material from Batch A can have influenced the properties of the resulting materials.

[0516] Example 8

[0517] Screen 4 - Target Salt Screen

[0518] An additional target salt screen was performed on the compound of Structure (I) using material from Batch B, which has a lower residual potassium content and is characterized as Free Form Pattern 3 (see Example 20 below). The most promising candidates from the previous screens (hydrochloric acid, methanesulfonic acid, phosphoric acid, fumaric acid, and sulfuric acid) were attempted to form salts using THF:water (9:1) or 1,4-dioxane.

[0519] The compound of Structure (I) (from Batch B, approximately 30 mg, Free Form Pattern 3) was treated with aliquots of increasing THF:water (9:1) or 1,4-dioxane up to 70 volumes (2.1 mL) or until dissolution was achieved at 50 °C, 500 rpm. Observations were recorded after each addition of solvent. The undissolved sample was heated to 70 °C, 500 rpm, and further observations were made at 70 °C.

[0520] Each sample was then subjected to 1.1, 2.1, or 3.1 molar equivalents of the selected free acid (Table 22) according to the target stoichiometry. Observations were made.

[0521] The samples were then cooled from 70 °C to 5 °C at 0.1 °C / min and held at 5 °C overnight, 500 rpm. Further observations were made and the solid material was isolated after 24 hours using a SPE syringe barrel and glass wool under positive pressure.

[0522] After 7 days of storage at 40 °C / 75% RH, the samples were analyzed by XRPD, 1Any solids obtained were analyzed by H NMR, HPLC, TGA, DSC, XRPD, and if necessary, by IC. Where appropriate, additional analytical techniques (PLM and HSM) were used to supplement the above analyses.

[0523] Table 22. List of counterions and target salt forms

[0524]

[0525]

[0526] P = Pattern

[0527] Results and Discussion

[0528] Results from the target salt screening are listed in Table 23.

[0529] Table 23. Observations and results of target salt addition screening

[0530]

[0531] As can be seen from Table 23, at 70°C at 70 volumes, no samples dissolved.

[0532] This is in contrast to the previous screening where the material batch used (i.e., where the material from batch A was characterized as a poorly crystalline free form Pattern 1), where dissolution was achieved. The higher crystallinity of the input material used in these experiments and the different solid forms can have had an impact on the results. Due to the insolubility, complete dissolution of the API was not achieved prior to the addition of the counterion. Therefore, the salt formation from this screening was the result of a slurry conversion.

[0533] From the previous screening, the chloride Pattern 1 and Pattern 3, the phosphate Pattern 1 and Pattern 2, the fumarate Pattern 1 and the mesylate Pattern 2 were targeted. These salts were considered to have promising solid form properties. Therefore, the conditions used for salt formation were replicated for these systems. Some color changes from white to yellow of the suspensions were observed upon addition of fumaric acid, methanesulfonic acid and sulfuric acid.

[0534] The solid material was analyzed by XRPD after 24 hours. From the target salt screening, the following patterns were obtained: HC1 Pattern 1, PHO Pattern 1, MES Pattern 2 and a new FUM form (Pattern 2).

[0535] After 7 days of storage at 40°C / 75%RH, samples were analyzed by XRPD, 1 H NMR, HPLC, TGA, DSC, XRPD and IC. Where appropriate, additional analytical techniques (PLM and HSM) were used to supplement the above analyses.

[0536] The results of Chloride Profile 1 and Phosphate Profile 1 are summarized in Table 24.

[0537] Table 24. Characterization of Chloride Profile 1 and Phosphate Profile 1

[0538]

[0539]

[0540] Based on the table, sample 22-1 (Chloride Profile 1) shows an XRPD pattern consistent with previous samples, however, the thermal behavior is not consistent with previous samples (sample 9-2, PI + P3), showing a large broad endotherm followed by an exotherm. The initial endotherm is similar to that observed from the free form provided. The HPLC data indicates that the purity of the material is still high.

[0541] The weight loss in TGA is consistent with the large broad endotherm in DSC, which suggests possible hydrate behavior. There was not enough material available to correlate the mass loss in TGA with residual THF content by NMR. After 7 days of storage at 40 °C / 75% RH, Chloride Profile 1 remained stable by XRPD and HPLC. The IC results indicate that Chloride Profile 1 contains 0.5 molar equivalents of counterion, indicating incomplete salt formation. Based on the data available, the sample can be a mixture of chloride salt and free form.

[0542] Sample 22-2 shows an XRPD pattern consistent with Phosphate Profile 1. The sample shows high purity, 1 The H NMR is consistent with the expected structure, with <0.1 molar equivalents of residual THF present. The TGA shows a 7% weight loss, equivalent to 1.9 moles of water. A large broad endotherm (82.1 °C onset) can be seen in DSC, followed by a second endotherm at 207 °C.

[0543] The weight loss in TGA is consistent with the large broad endotherm in DSC, which suggests possible hydrate behavior. After 7 days of storage at 40 °C / 75% RH, Phosphate Profile 1 remained stable by XRPD and HPLC. The IC results indicate that PHO Profile 1 contains 1 molar equivalents of counterion. Further analysis of PHO Profile 1 by PLM and HSM indicates that the sample is composed of fine needles, which remain stable up to 260 °C, after which the sample begins to melt.

[0544] Based on the data available, the sample can be a monophosphate hydrate. This salt form has reasonable properties, but has a large endotherm and mass loss at relatively low temperature, which can make it difficult to define the occupancy of the hydrate at ambient conditions.

[0545] The results of the targeted screening of FUM Pattern 1 and MES Pattern 2 are summarized in Table 25.

[0546] Table 25. Characterization of Fumarate Pattern 2 and Mesylate Pattern 2

[0547]

[0548]

[0549] Sample 22-3 showed an XRPD pattern that was not consistent with the previously obtained Fumarate Pattern 1 and was therefore assigned as a new pattern (Fumarate Pattern 2). In addition, it should be noted that upon drying, the sample showed additional peaks (FUM P2+ADD) that were not observed previously upon wetting of the sample, suggesting that this form can not be stable. This also suggests that there can be another fumarate form that can be obtained by drying Fumarate Pattern 2.

[0550] By 1 Analysis by H NMR indicated that Fumarate Pattern 2 had a lower than expected stoichiometry, suggesting the formation of a hemi-salt. A small amount (0.2 mole equivalents) of residual THF was also observed. The sample still maintained a high purity.

[0551] TGA showed a large weight loss of 14 wt% corresponding to 3.5 moles of water and 0.2 moles of THF. A large broad endothermic peak (onset temperature 41.3 °C) was visible in DSC followed by an exothermic peak with an onset temperature of 147 °C. The weight loss in TGA was consistent with the large broad endothermic peak in DSC, suggesting a possible hydrate.

[0552] Storage of the sample at 40 °C / 75% RH for 7 days resulted in the disappearance of the additional peaks observed upon drying of the material, suggesting that Fumarate Pattern 2 can be a variable occupancy hydrate.

[0553] Due to the complex thermal behavior, combined with the apparent (partial) change in form, this salt form can not display ideal properties for a drug product.

[0554] Sample 22-6 showed an XRPD pattern that was consistent with the previously obtained Mesylate Pattern 2.

[0555] By 1 Analysis by H NMR indicated that the sample contained 1.1 mole equivalents of mesylate counterion with no residual solvent detected. HPLC indicated that the sample still maintained a high purity.

[0556] TGA indicated a weight loss of 8% by weight prior to decomposition (approximately 300°C), equivalent to 2.2 moles of water. However, the data quality was poor and repeat measurements can be required. The DSC thermogram showed a large broad endothermic peak (onset temperature 65.0°C) followed by a double exothermic peak with onset temperatures of 196°C.

[0557] The sample stored at 40°C / 75% RH for 7 days showed no change in the material by XRPD or HPLC.

[0558] Based on the available data, it is likely that the sample is a monomesylate hydrate. As the dehydration of this material occurs close to ambient conditions, the solid form can not be suitable for further development as a pharmaceutical product.

[0559] The results of the characterisation of the material from the target screening on SUL profile 1 are summarised in Table 26.

[0560] Table 26. Characterisation of sulphate profile 1

[0561]

[0562] Sample 22-8 showed an XRPD pattern broadly consistent with the previously obtained sulphate profile 1, however, additional peaks were observed.

[0563] HPLC showed the sample purity remained above 99%, IC analysis indicated the sample contained 0.7 molar equivalents of sulphate counterions. PLM of the sample showed the particle size was <25 μm and was generally agglomerated. The sample was re-suspended in water and the particle size was reduced to <2 μm. 1 Analysis by H NMR indicated the sample was consistent with the structure provided, with a large amount of residual solvent detected (1.9 molar equivalents of THF). TGA analysis indicated a weight loss of 7% by weight prior to decomposition (approximately 250°C), equivalent to 1.9 moles of water or 0.5 moles of THF. The discrepancy in the NMR and TGA data can indicate that the sample was still moist at the time of analysis by NMR. The DSC thermogram showed a poorly defined asymmetric endothermic peak with a large range (35°C to 190°C) (onset temperature 36°C). No transparent melt was observed.

[0564] The sample stored at 40°C / 75% RH for 7 days showed the material was unstable and had converted to a new pattern, denoted as sulphate profile 2. This new form shared many peaks with sulphate profile 1, but appeared to be more crystalline. The sample purity remained high under storage.

[0565] In summary, batch B of structure (I) was used to complete the target salt screening. Conditions favouring the formation of chloride, mesylate, phosphate, fumarate and sulphate salts were tested.

[0566] From the screening, chloride profile 1, phosphate profile 1, mesylate profile 2, sulfate profile 1 (with additional peaks), and a new fumarate profile 2 were obtained. All profiles obtained were analyzed using a range of techniques. From the data obtained, the samples generally appear to be hydrated salts, possibly with the exception of chloride profile 1 and sulfate profile 1, which appear to be mixtures of free and salt forms. All hydrated forms readily lose water at near ambient conditions.

[0567] Based on these results, none of the salts showed promise for further development as a pharmaceutical product.

[0568] Example 9

[0569] Salt screening conclusions

[0570] Several experiments were performed to isolate salt forms of the compound of structure (I). This took the form of solubility and salt formation assessments and four salt screens (standard screen with 12 common acids, high temperature screen, double equivalent screen, and targeted screen using high purity input materials).

[0571] During the course of this study, 12 salt forms were identified, as well as two free base forms and some forms that were not explicitly assigned. Some of the salts formed exhibited undesirable properties for use as a pharmaceutical product. Some of the most promising candidates (e.g., PHO profile 1, MES profile 1) were characterized as hydrates, however, the water in these solids was lost at temperatures near ambient conditions, which can result in lower than expected stability.

[0572] A large quantity of isolated solid was also observed that contained a stoichiometric amount of counterion (HCI profile 1), as well as a number of free form profiles. Ultimately, two new free base forms were identified, free form profile 2 and free form profile 3. The polymorphic behavior of the free base was investigated and is presented in the examples disclosed herein.

[0573] Example 10

[0574] Polymorphic screening of free form of structure (I)

[0575] Since none of the identified salt forms were optimal, further investigation of the free form of structure (I) was performed. This investigation aimed to identify polymorphs of structure (I), characterize them, and determine their suitability for use in a pharmaceutical product.

[0576] To facilitate the formation and identification of multiple forms, amorphous material was used as input for the screening. Several different methods for generating amorphous material were tested, as described further below.

[0577] Structure (I) (from batch B, 30 mg, Pattern 3 free form) was treated with increasing aliquots of THF:water (7:3 v / v) or MeCN:water (1 :2 v / v) to 100 volumes (3 mL) at 50 °C. After 100 volumes, the sample was left to stand at 50 °C for 1 hour.

[0578] Both samples did not dissolve, so freeze-drying was not completed and no amorphous material was generated using this method.

[0579] Reverse anti-solvent addition (DMSO / TBME)

[0580] The compound of structure (I) (from batch B, 30 mg) was treated with aliquots of DMSO (5 volumes, 150 μί) and stirred at 50 °C until dissolved (total 40 volumes, 1.2 mL). TBME (12 mL, 1 :10 solvent:anti-solvent volume ratio) was stirred at RT and the warm DMSO solution was added dropwise to the TBME. The resulting suspension was filtered (sample 27-1 ).

[0581] The suspension was characterised and the summary of data is presented in Table 27. The solid was a DMSO solvate as evidenced by a large mass loss in TGA and a solvent content in H NMR spectra. It converted to Pattern 3 free form when stored at 40 °C / 75% RH for 7 days. 1 H NMR spectra. It converted to Pattern 3 free form when stored at 40 °C / 75% RH for 7 days.

[0582] Table 27. Characteristics of Pattern 4

[0583]

[0584] Reverse anti-solvent addition (DMSO / water)

[0585] The compound of structure (I) (from batch B, 30 mg) was dissolved in DMSO (40 volumes, 1.2 mL). Water (12 mL, 1 :10 solvent:anti-solvent volume ratio) was stirred at RT and the warm DMSO solution was added dropwise to the water. The resulting suspension was filtered. XRPD analysis of the sample indicated it was Pattern 1 free form.

[0586] Ball milling test

[0587] Structure (I) (from batch B, 30 mg) was added to a stainless steel milling jar with milling balls. The sample was milled at 30 Hz for 60 minutes. Sample ID: 28-1

[0588] XRPD analysis of the material indicated that it was amorphous except for two small peaks attributed to residual potassium chloride. The chemical purity was not deteriorated during the amorphization. The Tg was not determined by mDSC as it appeared to be hidden under a larger endothermic peak, indicating a possible water loss. Two endothermic events attributed to crystallization were observed in mDSC at 149.9 °C and 196.8 °C. The amorphous material was converted to the free form Pattern 3 after 7 days storage at 40 °C / 75% RH.

[0589] Table 28. Characterization of amorphous Structure (I)

[0590]

[0591] WD = weakly diffracting

[0592] Ball milling for screening 1

[0593] Structure (I) (from batch B, 700 mg) was added to a 5 mL stainless steel milling jar with 9 mm milling balls. The sample was milled for 60 minutes at 30 Hz. The sample was milled for an additional 90 minutes. XRPD analysis of the material indicated that while the crystallinity had been reduced, complete amorphization had not been achieved. This material (sample 28-2) was used as input for the first screening.

[0594] Ball milling for screening 2

[0595] Compound of Structure (I) (from batch B, 1 g) was added to a 10 mL stainless steel milling jar with 9 mm milling balls. The sample was milled for 90 minutes at 30 Hz. The sample was milled for an additional 2 x 90 minutes. Sample ID: 29-1

[0596] Increased milling duration and refined parameters allowed to obtain a completely amorphous material. The characterization was consistent with that collected for small scale sample 28-1 and is summarized in Table 29. This sample was used as input material for the second screening.

[0597] Table 29. Characterization of amorphous material used in the second screening

[0598]

[0599] Example 11

[0600] Polymorph screening 1 - poor crystalline Pattern 3 input

[0601] According to Table 30, Structure (I) (sample 28-2, 30 mg, poorly crystalline Pattern 3) was wetted with solvent (300 μL, 10 volumes) and placed in a shaker at 50 °C for 6 days. The suspension was isolated using a filter cartridge and positive pressure. XRPD patterns were collected for each sample. Samples that exhibited new patterns were further characterized, including reanalysis by XRPD after the samples were allowed to dry at ambient conditions overnight. This characterization method is described and discussed in the Examples detailed herein. (See, e.g., Figure 75 ).

[0602] The use of poorly crystalline Pattern 3 (sample 28-2) as input material did not preclude the formation of 4 new patterns. Patterns 5-9 all have similar XRPD patterns, but with some peaks slightly shifted, indicating that they are structurally related forms, possibly solvates. Patterns 8 and 9 are not stable at ambient conditions, converting to Pattern 8, where the peaks of Pattern 3 appear.

[0603] Table 30. Results of polymorph screening using poorly crystalline Pattern 3

[0604]

[0605]

[0606] WD = weakly diffracting

[0607] Example 12

[0608] Polymorph screening 2 - amorphous input

[0609] According to Table 31, amorphous Structure (I) (sample 29-1, 30 mg) was wetted with solvent (300 μL, 10 volumes) and placed in a shaker at 50 °C for 3 days. The samples were isolated using a filter cartridge and glass frit, and XRPD patterns were collected. See, e.g. Figure 77 .

[0610] When amorphous material was used as input for the screening, less variability was obtained, with all but 4 samples producing Pattern 3. Pattern 7 was isolated from MEK and ethanol, while these solvents produced Pattern 7 and Pattern 8, respectively, in the first screening. Pattern 8 was isolated from MeOH and ACN, while these solvents produced Pattern 9 (which converted to P8+P3 upon drying) and Pattern 8, respectively, in the first screening.

[0611] Table 31. Results of polymorph screening using amorphous material

[0612]

[0613]

[0614] The new forms identified in the polymorph screen were characterized to determine the properties of the solid forms.

[0615] Table 32. Characterization of new forms, Pattern 5+3 and Pattern 6

[0616]

[0617]

[0618] Sample 30-2 was originally isolated as Pattern 5, but upon mild drying at ambient conditions it began to convert to Pattern 3. After 7 days of storage at 40°C / 75% RH, the transition was complete. NMR showed 0.2 mole equivalents of ethyl acetate present in the sample, which was consistent with the TGA. DSC contained an endotherm after the mass loss beginning at approximately 180°C in addition to the endotherm associated with solvent loss.

[0619] Sample 30-4 was isolated as Pattern 6, which was maintained upon mild drying, however it converted to Pattern 3 when stored at 40°C / 75% RH for 7 days. Both NMR and TGA indicated 0.5 mole equivalents of MIBK present in the sample, indicating that this sample was a MIBK solvate.

[0620] Table 33. Characterization of new forms, Pattern 7 and Pattern 8+3

[0621]

[0622] Sample 30-6 was isolated from MEK, and the XRPD showed Pattern 7. TGA and 1 H NMR was consistent with 0.4 mole equivalents of solvent content. This material was unstable upon static storage at 40°C / 75% RH for 7 days, converting to Pattern 3.

[0623] Sample 30-15 was represented as Pattern 8+3, which converted from Pattern 9 upon ambient drying for 1 day. Interestingly, NMR showed no residual solvent, but TGA contained a 3.6% mass loss between 40°C - 145°C, which indicated 0.8 mole equivalents of water present in the material.

[0624] Example 13

[0625] Pattern 7 was generated from crystalline Pattern 3

[0626] In two screens, Pattern 7, the solvate form, was obtained from MEK. The input for these screens was amorphous Pattern 3. The first screen was run at 40°C / 75% RH for 7 days, and the second screen was run at 40°C / 75% RH for 14 days.

[0627] Form of Structure (I) or a poorly crystalline Structure (I). This experiment was performed to determine if it was possible to form a solvate under the same conditions using crystalline Pattern 3 as the input material.

[0628] Structure (I) (from Batch B, 30 mg) was wetted with MEK (300 μΐ^, 10 volumes) and placed in a shaker at 50 °C for 3 days. The sample was split for XRPD.

[0629] The XRPD of the sample indicated that Pattern 3 had been converted to Pattern 7. This indicates that even using a more stable crystalline material as input, there is a propensity for solvate formation.

[0630] Example 14A

[0631] Generation of Pattern 11 - Method A

[0632] Pattern 11 was first identified in the VT-XRPD of Pattern 3 (from Batch B) and formed after dehydrating Pattern 3 to Pattern 10 and then high temperature conversion (at 250 °C) to Pattern 11. In the VT experiment, Pattern 11 was obtained as a mixture with Pattern 3. This experiment was performed to determine if this form could be isolated as a pure phase material and if it was stable at ambient conditions.

[0633] Structure (I) (from Batch B, 100 mg) was heated in an oven at 250 °C for 1 hour. After 1 hour, the oven was turned off but the sample was left to cool inside. After 1 hour cooling, the sample was removed from the oven and analysed by XRPD (Sample 34-1).

[0634] The sample was found to be Pattern 11 with no other forms present. It was also found to be stable at ambient conditions, indicating that it can be a form suitable for further development.

[0635] Table 34. Characteristics of Pattern 11

[0636]

[0637] Example 14B

[0638] Formation of Pattern 11 - Method B

[0639] Polymorph studies of Structure (I) were performed at 75 °C, 100 °C, 175 °C, and 250 °C. Approximately 500 mg of Form 3 of Structure (I) was heated in a vacuum tray dryer (VTD) at 75 °C under reduced pressure for 24 hours. The purity of the material obtained after heating at 75 °C was analyzed by HPLC and XPRD analysis. The results indicated that the sample remained Form 3 by XRPD and there was no change in HPLC purity. Additionally, approximately 500 mg of Structure (I) was heated in a VTD at 75 °C under reduced pressure for 24 hours. After 24 hours, the material was cooled under inert atmosphere to 25-30 °C and its purity was analyzed by HPLC and XRPD.

[0640] Approximately 500 mg of Structure (I) was heated in a VTD at 100 °C under reduced pressure for 24 hours. The purity of the material obtained after heating at 100 °C was analyzed by HPLC and XPRD. The results of the analysis indicated that the sample remained Form 3 by XRPD and showed no change in HPLC purity. Additionally, approximately 500 mg of Structure (I) was heated in a VTD at 100 °C under reduced pressure for 24 hours. After 24 hours, the material was cooled under inert atmosphere to 25-30 °C. The purity of the material obtained was analyzed by HPLC and XPRD.

[0641] Approximately 500 mg of Structure (I) was heated in a VTD at 175 °C under reduced pressure for 24 hours. The purity of the material obtained after heating at 175 °C was analyzed by HPLC and XPRD. The results of the analysis indicated that the sample was converted to Form 11 as confirmed by XRPD; no change in HPLC purity was detected. Additionally, approximately 500 mg of Structure (I) was heated in a VTD at 175 °C under reduced pressure for 24 hours. After 24 hours, the material was cooled under inert atmosphere to 25-30 °C. The purity of the material obtained was analyzed by HPLC and XPRD.

[0642] Approximately 500 mg of Structure (I) was heated in a VTD at 250 °C for 24 hours. The purity of the material obtained after heating at 250 °C was analyzed by HPLC and XPRD. The results of the analysis indicated that the sample was converted to Form 11 as confirmed by XRPD. During sample preparation for HPLC analysis, the sample showed turbidity in the diluent used for sample preparation (10% DMSO in MeOH).

[0643] Prior to the heating experiment at 250 °C, the material was tested for DSC study. The DSC results indicated that no major safety issues were observed prior to a temperature of 400 °C.

[0644] Approximately 500 mg of Structure (I) was heated in VTD at 250 °C for 24 hours. After 24 hours, the sample was cooled to 25-30 °C under inert atmosphere. The purity of the obtained material was analyzed by HPLC and XPRD analysis.

[0645] Based on the results obtained from 175 °C and 250 °C (i.e., where Pattern 11 was obtained and confirmed by XPRD analysis), the polymorphic study was repeated on a 2 g scale to generate seed material of Pattern 11 at 175 °C.

[0646] Example 15

[0647] Formation of Pattern 1 - Ion content analysis

[0648] Formation of Pattern 1 has been observed during solubility analysis in pH 2 buffer and also in pH 1.6 FaSSGF simulated fluid. It is postulated that the formation of Pattern 1 can indicate the formation of an HC1 salt. Pattern 1 was generated by slurring Pattern 3 in pH 2 buffer.

[0649] Structure (I) (from Batch B, 30 mg) was suspended in pH 2.0 buffer (chloride buffer, 3 mL) and placed on a shaker at RT. After 1 day, the sample was filtered and analyzed by XRPD. The sample was re-suspended in pH 2.0 buffer (2 mL) and continued to be shaken at RT for 4 days. The sample was aliquoted and analyzed by XRPD, then filtered and dried under suction. After 5 days, the sample was found to be Pattern 1.

[0650] Ion chromatography showed the presence of 0.49 molar equivalents of chloride. The sub-stoichiometric amount of chloride indicates that only partial salt formation has occurred.

[0651] Pattern 1 was previously obtained by reverse anti-solvent addition of DMSO to water in the absence of chloride and was also the form of the input material from Batch A, which contained no chloride. Therefore, if a chloride salt was produced in the solubility measurement, it can have been amorphous and not detected by XRPD. If this is the case, it can be concluded that the resulting solid is a mixture of free base Pattern 1 and amorphous HC1 salt.

[0652] Example 16

[0653] Summary of polymorphic evaluation

[0654] Two polymorph screens were performed on the free base of compound of structure (I), one using poorly crystalline pattern 3 (sample 28-2) as input material and a second using amorphous compound of structure (I) as input material. During these screens, patterns 5-9 were identified and patterns 5-8 were characterized (pattern 9 was unstable at ambient conditions). Pattern 4 was also identified during an attempt to generate amorphous material by reverse anti-solvent addition (DMSO into TBME). Finally, pattern 11, which was identified during a VT-XRPD of pattern 3, was generated by heating pattern 3 in an oven to 250 °C.

[0655] Pattern 4 was determined to be a DMSO solvate. Patterns 5-9 have similar XRPD diffractograms and are likely structurally related. Patterns 5, 6, and 7 were shown to be solvates of ethyl acetate / isopropyl acetate, MIBK, and MEK, respectively, suggesting that they are likely a family of structurally similar solvates. Although having similar diffractograms, pattern 8 appears to be free of any solvent, so the void in these structure family can also be occupied by water. Due to this structure’s propensity to contain solvent and its conversion to pattern 3 at high temperature and high humidity, these forms can not be ideal for development as a pharmaceutical product.

[0656] Pattern 11 appeared to be an anhydrous form with reasonable stability at 40 °C / 75% RH, so a study was performed to further characterize the form.

[0657] Example 17

[0658] Formation and characterization of new crystalline forms

[0659] Structure (I) (from batch B, 750 mg) was heated in an oven at 250 °C for 1.5 hours. After 1.5 hours, the oven was turned off, but the sample was left to cool inside. After 1 hour of cooling, the sample was removed from the oven and analyzed by XRPD.

[0660] Sample 35-1 was characterized using a variety of techniques to investigate the solid form properties of pattern 11 of structure (I). A summary of the results is presented in Table 35.

[0661] Table 35. Characterization summary of pattern 11

[0662]

[0663] Upon generation in an oven at 250 °C, the sample was found by XRPD to be pattern 11. 1H NMR was consistent with the structure and showed no evidence of residual solvent. The purity of the material measured was found to be 97.9%, indicating that no significant degradation had occurred despite the high temperature involved in the formation of this form (input material purity = 98.1%). PLM of this material showed that it consisted of soft agglomerates of plate-like crystals up to 120 μιη in length. The crystals were broken and not suitable for analysis by single crystal X-ray diffraction.

[0664] TGA showed no loss of mass before decomposition started at >300°C, indicating that it was an anhydrous form. DSC had no clear events other than a possible change in baseline at 290°C, with no melting observed before 350°C. GVS showed Pattern 11 to be slightly hygroscopic, exhibiting very slight hysteresis in the isotherm. After a two-cycle experiment, the sample remained Pattern 11, with an additional peak observed at 7.7° 2Θ. The sample was stored at elevated temperature and / or humidity for 10 days, and the form and purity were found to be stable.

[0665] The thermodynamic solubility of Pattern 11 was determined in 3 simulated media and two buffers. Pattern 11 was found to be practically insoluble in the media, showing the highest solubility in the low pH medium.

[0666] The characterization data for Pattern 11 of Structure (I) indicated that it was a solid form that would be suitable for use in a pharmaceutical product. It was an anhydrous form, stable under high humidity conditions and only slightly hygroscopic.

[0667] Example 18

[0668] Competitive slurries and stability relationship

[0669] A mixture of solids of Pattern 3 of Structure (I) (from Batch B, 300 mg) and Pattern 11 (sample 35-1, 300 mg) was mixed using a vortex mixer for 3 hours.

[0670] The solid mixture (30 mg) was suspended in solvent (dried over molecular sieves, 600 μί, 20 volumes) and agitated in a refrigerator, shaking at RT or 55°C. After 7 days, an aliquot of each suspension was analysed by XRPD. The sample which was still a mixture of forms was returned to the refrigerator / shaker for a further 10 days and analysed again (results shown in Table 36).

[0671] The results of the competitive slurry were inconclusive, as in all solvent systems, one form was not more persistent than the other. In pure THF and IPA, patterns 11 were obtained after 7 days of slurry at all temperatures, however, in the case of IPA, there were additional peaks in the XRPD that matched those associated with the solvate group represented by patterns 5-9, indicating that the transformation can be via solvated forms and thus cannot inform the relative stability of pattern 3 and pattern 11. Where transformation was observed, pattern 3 transformed to pattern 11, but no transformation of pattern 11 to pattern 3 was observed.

[0672] Table 36. Results and observations from competitive slurry experiments

[0673]

[0674]

[0675] * Additional peaks matched pattern 9

[0676] To determine that pattern 3 was not simply dissolving in the solvent system when solids were introduced, gravimetric solubility measurements were performed using the samples at room temperature. These values are presented in Table 37. It can be seen that solubility was highest in THF:water 9:1 at 8.1 mg / mL. The amount of pattern 3 introduced into the solid mixture in each competitive slurry (0.6 mL) was 15 mg, so 25 mg / mL solubility is required to dissolve all of pattern 3. The solubility at room temperature was not sufficient to dissolve the pattern 3 present in the competitive slurry experiments.

[0677] Table 37. Gravimetric solubility measurements from competitive slurry samples

[0678] Sample ID Solvent XRPD after 17 days Gravimetric solubility (mg / mL) 36-6 IPA - * not determined 36-7 THF - * not determined 36-8 Toluene Patterns 3 and 11 2.3 36-9 IPA / water (95:5) Patterns 3 and 11 3.8 36-10 THF / water (9:1) Patterns 3 and 11 8.1

[0679] * Uncertain values due to low mass of solids in vials (negative mass recorded)

[0680] Measurements were performed at room temperature

[0681] The competitive slurry experiments at 55 °C were repeated using saturated solutions as the solvent mixture as well as the competitive slurry experiments at 5 °C to minimize dissolution that can occur at temperatures other than room temperature.

[0682] A saturated solution of THF / water (9:1) (5 mL) with structure (I) (from batch B) was equilibrated in a shaker at 55 °C overnight. The solution was filtered using a 0.45 pm nylon filter prior to use.

[0683] The solid mixture of Pattern 3 and Pattern 11 (30 mg) was suspended in a saturated solution (600 μL, 20 volumes) and stirred in a refrigerator (5 °C) or shaken at 55 °C. After 1 day, an aliquot of the suspension was analyzed by XRPD. Both samples were returned to the refrigerator / shaker. After a total of 11 days, the samples were removed from the refrigerator / shaker. Sample 38-2 was filtered prior to XRPD, sample 38-1 was pipetted onto the XRPD holder and allowed to dry prior to analysis (solids passed through the filter).

[0684] The results of the experiments using saturated solutions as the slurry medium are summarized in Table 38. Both experiments produced a mixture of Pattern 3 and 11 without significant changes in intensity. This is in contrast to the first competitive slurry experiment, in which both samples produced Pattern 11. The difference in the results of the experiments at 55 °C can be due to the dissolution of Pattern 3 in the first experiment (sample 36-15), which did not occur in this experiment (sample 38-2). In summary, the series of competitive slurries did not definitively show that Pattern 3 and Pattern 11 interconverted, or that one form was more stable than the other.

[0685] Table 38. Results of additional competitive slurry experiments

[0686]

[0687] The origin of the additional peaks seen at the one day time point is unknown, as these peaks are not related to any previously observed form.

[0688] Example 19

[0689] Summary of conditions used to obtain solid forms of Pattern 1-11

[0690] The polymorphic evaluation was performed on the free form of the compound of Structure (I). The evaluation involved a study of amorphous material preparation followed by two screenings. The first screening used Pattern 3, a less crystalline form of the compound of Structure (I), as the input material, while the second screening used amorphous compound of Structure (I).

[0691] During the course of this study, 11 free forms of the compound of structure (I) were identified. Pattern 1 is a poorly crystalline form. Pattern 2 was observed in three experiments using salt screening with material having potassium impurities as input, with high solvent content in one sample suggesting it can be a THF solvate. Pattern 3 is a hemihydrate and was the predominant form obtained in two polymorph screens. Pattern 4 was obtained by reverse anti-solvent using dimethyl sulfoxide (DMSO) and tert-butyl methyl ether (TBME) and was determined to be a DMSO solvate. Patterns 5-9 isolated from two polymorph screens are a series of structurally related solvates. Pattern 10 is a dehydrated form of Pattern 3, observed only during VT-XRPD and VAC-XRPD using in situ measurements, which converts back to Pattern 3 at ambient conditions. Pattern 11 was formed by heating Pattern 3 (via Pattern 10) at temperatures approaching 250 °C. Pattern 11 is an anhydrous form and is stable at room temperature. The relationships between the observed solid forms are summarized in Table 1, where each condition for the transitions is shown below: Figure 6

[0692] 1. Cooling with tetrahydrofuran (THF):water in a ratio of 9:1

[0693] 2. Reverse anti-solvent DMSO / water

[0694] 3. Reverse anti-solvent DMSO / TBME

[0695] 4. 7 days at 40 °C at 75% relative humidity

[0696] 5. Ambient conditions (follows condition 4 above)

[0697] 6. Heating under vacuum at 50 °C and at 175 °C

[0698] 7. Heating at 250 °C

[0699] 8. Slurry in fasted state simulated gastric fluid (FaSSGF) and pH 2.0 buffer

[0700] 9. Dry milling

[0701] 10. Slurry in various solvents at 50 °C for 7 days at 40 °C / 70% relative humidity

[0702] 11. Slurry in ethyl acetate and isopropyl acetate at 50 °C

[0703] 12. Slurry in methyl isobutyl ketone (MIBK) at 50 °C

[0704] 13. Slurry in methanol at 50 °C

[0705] ​14. Slurry in ethanol and acetone at 50 °C

[0706] 15. Slurry in methyl ethyl ketone (MEK) at 50 °C

[0707] 16. Slurry in methanol and acetonitrile at 50 °C

[0708] 17. Slurry in MEK and ethanol at 50 °C

[0709] 18. Ambient conditions

[0710] Of the identified forms of the compound of structure (I), Pattern 3 and Pattern 11 have suitable solid state properties for a drug product. Pattern 3 is a hemihydrate with good storage stability under elevated temperature and humidity conditions. Although hygroscopic (8.4 wt% change at 0-90% RH), the solid form is retained upon double cycle GVS testing. Pattern 11 is an anhydrous form and has good stability, but unlike Pattern 3, it has only slight hygroscopicity (0.3 wt% at 0-90% RH). Since Pattern 11 was formed by conversion from a high temperature form, it will be necessary to investigate whether it can be obtained via a more scalable solution-based process. Measurements of the thermodynamic solubility of both forms in simulated media and buffers at 25 °C did not show any clear advantage of one form over the other. The comparison of XRPD patterns is shown in Figure 5

[0711] Competitive slurries using mixtures of Pattern 3 and Pattern 11 were performed to determine the stability relationship between the two forms. The results were inconclusive, with some slurries remaining mixtures. The complex relationship between these forms can be the result of both temperature and water activity dependence. In addition, this project was aimed at determining salt forms of the compound of structure (I), as well as suitable solid state and physicochemical properties for a drug product. It also investigated solid forms of the free form via polymorph evaluation, with the goal of identifying those forms with appropriate properties for an end-use product.

[0712] Two batches of material were used in these experiments. Batch A was identified as the free form Pattern 1, which is poorly crystalline, highly hygroscopic, and has a 0.2 molar equivalent of potassium content. Batch B was characterized as Pattern 3, and is a hemihydrate, which, although hygroscopic, was found to be crystalline and stable. The single crystal structure of Pattern 3 was collected and is shown in Figures 89 to 92

[0713] pKa measurements on this molecule indicate that it has a basic pKa at 4.73 and an acidic center at 11.49, and thus can form salts at both ends of the pH scale.

[0714] ​​Experiments were performed to isolate salt forms of the compound of structure (I). This took the form of solubility and salt formation evaluations and four salt screens. The standard screen containing 12 common acids, a high temperature screen, a double equivalent screen, and a targeted screen using high purity input materials.

[0715] During the course of this study, 12 salt forms were identified, as well as two free base forms and some forms that were not explicitly assigned. Some of the formed salts had properties that were not suitable for use as a drug product. Several of the most promising candidates (e.g. PHO Pattern 1, MES Pattern 1) were characterized as hydrates, however, in each case the water was lost at temperatures close to ambient conditions, which can result in lower than expected stability.

[0716] A polymorph evaluation was performed on the free form of structure (I). This consisted of two screens with 18 solvents, one screen was performed using poorly crystalline Pattern 3 as input material and the second screen used amorphous compound of structure (I) as input material.

[0717] During the course of the examples described herein, 11 free form patterns of the compound of structure (I) were identified. Pattern 1 was the poorly crystalline form observed first in the original material. Pattern 2 was observed only during the salt screen. Pattern 3 was a hemihydrate and also the predominant form obtained during the two polymorph screens. Pattern 4 was obtained by reverse anti-solvent using DMSO and TBME and was determined to be a DMSO solvate. Patterns 5-9 isolated from the two polymorph screens were a series of structurally related solvates. Pattern 10 was a dehydrated form of Pattern 3, observed only during VT-XRPD and VAC-XRPD using in situ measurements, which converted back to Pattern 3 at ambient conditions. Pattern 11 was formed by heating Pattern 3 (via Pattern 10) to temperatures close to 250°C. Pattern 11 was an anhydrous form and was stable at room temperature.

[0718] Patterns 3 and 11 were free forms with properties suitable for scale-up and further characterization. Pattern 3 was hygroscopic, although this did not affect the solid form, which was retained upon return from high humidity levels to ambient conditions. Pattern 11 was only slightly hygroscopic. Pattern 11 was not obtained via a solution-based method, while Pattern 3 was the product of many screening experiments. Thermodynamic solubility data in simulated fluids and buffers was collected for both forms, the results were similar for both forms and therefore could not be used as a discriminator. Competitive slurry experiments were performed in five solvents at three temperatures, these experiments were ultimately inconclusive. However, it should be noted that during the cross-seeding experiments, not one experiment gave pure Pattern 3, all experiments produced mixtures or Pattern 11.

[0719] Example 20

[0720] Preparation and characterization of Batch A and Batch B of Structure (I)

[0721] Two batches of Structure (I) were used in the screening experiments described herein. They were prepared generally as described in WO 2023 / 278686. The final step to generate Structure (I) was carried out as follows:

[0722]

[0723] To a suspension of Int-A (1 eq) in EtOH / THF / H2O (2:1:1, v / v / v, 25 vol) at 25-35 °C was added potassium hydroxide (7.5 eq in 1 vol of water) dropwise. The reaction mixture was heated to 50-60 °C and stirred for 12-16 hours. The reaction mixture was then cooled to 25-35 °C. To the reaction mixture was added activated charcoal (20%) and it was stirred for 1 hour. The reaction mixture was then filtered through a Celite® bed and washed with a mixture of EtOH / THF / H2O (2 vol). Silathane (20% w / w) was added to the filtrate and stirred for 1 hour. The suspension was filtered, the filtrate was passed through a 0.2 micron filter paper, and the pH was adjusted to 7.5-8 with 1.5 N aqueous HC1. The mixture was stirred at 0-5 °C for 1 hour, and the precipitate was collected by filtration and washed with water. The isolated solid was slurred with purified water (10 vol x 2) at 25-30 °C for 30 minutes. The solid was collected by filtration and washed with water (2 vol). The solid was collected and dried at 45-50 °C for 3 hours to give Structure (I). Characterization of Batch A of Structure (I)

[0724] Batch A was prepared as described above in a batch size of 6.4 grams.

[0725] Batch A was characterized using various techniques, as summarized in Table 39.

[0726] Table 39. Characterization of Batch A

[0727]

[0728]

[0729] ​Batch A was identified as having poor crystallinity, with the XRPD pattern matching Pattern 1. Purity was shown to be 97.6% by HPLC, but IC showed 0.2 molar equivalents of potassium present in the sample. Batch A was highly hygroscopic, with a maximum mass change of 23.8% measured from 0-90% RH during GVS experiments. The form by XRPD did not change during the experiment, nor did it change when stored at elevated temperature and / or humidity conditions for 8 days. Pattern 1 of Structure (I) is slightly soluble in SGF (0.13 mg / mL) and almost insoluble in FaSSIF (0.006 mg / mL) and FeSSIF (0.02 mg / mL) according to USP guidelines.

[0730] Characterization of Batch B of Structure (I)

[0731] Batch B was prepared in a batch size of 11.8 grams as described above, except that the pH was adjusted to 8-9 using 1.5 N aqueous HC1.

[0732] Batch B was characterized using various techniques, as summarized in Table 40.

[0733] Table 40. Characterization of Batch B

[0734]

[0735]

[0736] ND = not determined

[0737] Two samples from Batch B were identified as Pattern 3. IC analysis showed that there were fewer ions present in these batches than in Batch A, specifically Sample 2 of Batch B had only 0.01 molar equivalents of chloride present. The solid form and chemical purity remained unchanged when the samples were stored at elevated temperature and humidity.

[0738] Water content analysis by KF showed that the material contained 3.4 wt% water (0.72 molar equivalents of water). This is consistent with the TGA data, which showed a total mass loss of 3.6 wt% from ambient temperature to 265 °C. During GVS experiments, a mass loss of 0.8 wt% was observed as the humidity was decreased to 0%, which suggests that at least some of the water (2.6% remaining based on KF results) is tightly bound and can be part of the crystal structure, rather than surface bound. Based on these data, the material was identified as a hemihydrate.

[0739] The properties of the hydrate were further investigated by vacuum XRPD and variable temperature XRPD. When placed under vacuum, batch B (pattern 3) transformed to pattern 10, which is postulated to be a dehydrated form of the material. When pattern 10 was exposed to ambient conditions for 30 minutes, it transformed back to pattern 3. When pattern 3 was heated to 175 °C, pattern 10 was again observed; this is consistent with the temperature at which the 3.0% mass loss observed in the TGA occurred. When the material was further heated to 250 °C, pattern 10 partially converted to pattern 11. Pattern 10 in this physical mixture transformed to pattern 3 when returned to ambient conditions, while pattern 11 remained unchanged. These experiments suggest that pattern 3 is a hemihydrate, which can be dehydrated to give pattern 10, which will readily rehydrate under ambient conditions. Pattern 11 is formed by heating pattern 10 to around 250 °C, which is seen as an exothermic peak in the DSC, and appears to be stable under ambient conditions.

[0740] The solubility of pattern 3 of structure (I) was determined to be poor in simulated fluids and buffers, with the highest solubility observed in FaSSGF (0.026 mg / mL).

[0741] Example 21

[0742] Single crystal X-ray diffraction analysis of pattern 3 of structure (I) in free form

[0743] Crystals of pattern 3 of structure (I) were obtained by evaporation of a THF:water 9:1 solution. Crystals of pattern 3 of structure (I) of sufficient size and mass for analysis by single crystal X-ray diffraction were isolated from a sample of dimensions ca. 0.15 x 0.05 x 0.02 mm.

[0744] The single crystal X-ray structure of pattern 3 of structure (I) was determined at 293(2) K and a summary of the structure data can be found in Table 41. The crystal structure of pattern 3 of structure (I) was solved in the triclinic space group P-1 with a final R1 [I > 2s(I)] = 4.36%. The structure is illustrated in Figure 89 and Figure 90 was identified and found to contain two molecules of structure (I) in the asymmetric unit.

[0745] Figure 91 and Figure 92 The hydrogen bonding network of pattern 3 of structure (I) is illustrated, with intermolecular hydrogen bonds shown as dashed lines. Figures 93 to 95 Views of part of the crystal packing in the unit cell, looking down the crystallographic a-, b- and c-axes respectively, are shown. For clarity, all hydrogen atoms have been removed from the packing diagrams.

[0746] The simulated XRPD plot of the structure (I) at (293(2)K) is shown in plot 3. Figure 96 middle. Figure 97 The overlay in the image shows a comparison between experimental diffraction patterns collected at RT and simulated patterns from single-crystal data at 293 K. These patterns are consistent, confirming that the single crystal used for structure determination is representative of the reference material. Subtle differences between the simulated and experimental diffraction patterns can be attributed to preferred orientations.

[0747] Table 41. Sample and crystal data for structure (I) 3.

[0748]

[0749]

[0750] Example 22

[0751] Water slurry experiment with free form spectrum 3

[0752] In the spectrum 3 of certain batches of structure (I), additional peaks were observed in the XRPD spectrum (see, for example, Figure 98 Furthermore, a higher water content than expected for the hemihydrate was measured. For consistency purposes, studies were conducted to determine the conditions under which the mixtures of various forms were converted only into structure (I) as shown in Spectrum 3.

[0753] As described below, approximately 10 g of material containing structure (I) with additional peaks and increased water content was tested under post-processing conditions to obtain spectrum 3 (e.g., as...). Figure 98 As shown), an aliquot of approximately 10 g of material was dissolved in a mixture of EtOH / THF / H₂O (2:1:1 / V:V:V, 25V) and KOH (7.0 equivalent). The reaction mixture was stirred for 10 minutes to obtain a clear solution. The pH of the reaction was then adjusted to 7.5-8 using 1.5 N aqueous HCl. The precipitated solid was stirred at 0-5°C for 1 hour, and then collected by filtration and washed with purified water.

[0754] The separated solids were then divided into two fractions (fraction 1 and fraction 2). Fraction 1 was dried in a VTD at 50°C under reduced pressure for 48 hours. Fraction 2 was subjected to an aqueous slurry at 25°C–30°C for 1 hour, followed by drying in a VTD at 50°C under reduced pressure for 48 hours. The water content of the samples from fractions 1 and 2 was analyzed using XPRD. The material of fraction 1 partially conformed to Spectrum 3 and had a water content of 3.1% w / w, while the material of fraction 2 was similar to the material before reprocessing and had a water content of 4.8% w / w.

[0755] About 2 g of the material of Part 2 was subjected to further aqueous slurry using a stir bar at 25-30 °C for 8 hours, followed by drying in a VTD at 50 °C under reduced pressure for 48 hours. The obtained material was analyzed for water content using XRPD and was found to match Pattern 3 Figure 99 ) and to have a water content of 2.3% w / w.

[0756] To confirm the reproducibility of these results, an additional experiment was performed with the same material comprising Pattern 3 of Structure (I) with additional peaks and increased water content. This material was not subjected to reprocessing as described above, but was slurried in water at 25-30 °C for 8 hours. One aliquot (5 g) was slurried in water using a stir bar and another aliquot (5 g) was slurried in water using an overhead stirrer. After slurring, both aliquots were dried in a VTD at 50 °C for 48 hours and then analyzed for XRPD and water content. The material obtained by slurring with a stir bar matched Pattern 3 and had a water content of 2.8% w / w. The material obtained by slurring with an overhead stirrer partially matched Pattern 3 and had a water content of 3.6% w / w. The material was subjected to additional slurring in water at 25-30 °C for 16 hours using an overhead stirrer, resulting in a material that fully matched Pattern 3 and had a water content of 2.6% w / w.

[0757] Example 23

[0758] Characterization studies of Pattern 3 in free form

[0759] A batch of Pattern 3 of Structure (I) with additional peaks (e.g., as described in Example 22) was further characterized.

[0760] Material comprising Pattern 3 of Structure (I) with additional peaks (e.g., such as Figure 98 in Example 22) was micronized using an air jet mill targeting D90 < 20 microns. The following conditions were used: primary nitrogen pressure of 6 kg / cm 2 ; secondary nitrogen pressure of 6 kg / cm 2 ; nitrogen atmosphere; room temperature; input of 75 g; and output after micronization of 62 g. The micronized material was analyzed using XRPD. Only slight changes were observed in the XRPD spectrum and the additional peaks were still present. After micronization, the particle size target of D90 < 20 microns was achieved. Attempts to dry the sample after micronization for 24 hours at 50 °C did not result in a change in water content.

[0761] The input material from Example 22 and the jet-milled batch were analyzed using variable temperature XRPD:

[0762]

[0763] The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications referred to in this specification are incorporated herein by reference, to the extent not inconsistent with this specification. Aspects of the embodiments can be modified, if necessary, to employ various patent, application, and publication concepts to provide yet further embodiments.

[0764] These and other changes can be made to the embodiments in light of the above Detailed Description. The terms used in the following claims should not be construed to limit the claims to the specific embodiments disclosed in the Specification and the Claims. Such limitations are only for the convenience of the Patent Office and for the Applicant's sake.

Claims

1. A solid form of a compound having the following structure (I): or a tautomer thereof: wherein the solid form has an X-ray powder diffraction pattern with at least two peaks at a 2 theta angle selected from the group consisting of 5.6 ± 0.2°, 10.9 ± 0.2°, 18.2 ± 0.2°, and 18.6 ± 0.2°.

2. The solid form of claim 1, wherein the solid form has an X-ray powder diffraction pattern with at least three peaks at a 2 theta angle selected from the group consisting of 5.6 ± 0.2°, 10.9 ± 0.2°, 18.2 ± 0.2°, and 18.6 ± 0.2°.

3. The solid form of claim 1, wherein the solid form has an X-ray powder diffraction pattern with peaks at a 2 theta angle of 5.6 ± 0.2°, 10.9 ± 0.2°, 18.2 ± 0.2°, and 18.6 ± 0.2°.

4. The solid form of claim 1, wherein the solid form has an X-ray powder diffraction pattern with peaks at a 2 theta angle of 5.6 ± 0.2°, 8.0 ± 0.2°, 8.4 ± 0.2°, 9.2 ± 0.2°, 10.9 ± 0.2°, 11.2 ± 0.2°, 13.2 ± 0.2°, 14.3 ± 0.2°, 15.3 ± 0.2°, 16.2 ± 0.2°, 16.5 ± 0.2°, 16.9 ± 0.2°, 17.4 ± 0.2°, 18.2 ± 0.2°, 18.6 ± 0.2°, 19.9 ± 0.2°, 20.2 ± 0.2°, 20.5 ± 0.2°, 21.9 ± 0.2°, 22.3 ± 0.2°, 22.5 ± 0.2°, 23.3 ± 0.2°, 23.6 ± 0.2°, 24.7 ± 0.2°, 25.2 ± 0.2°, 25.8 ± 0.2°, 26.2 ± 0.2°, 27.0 ± 0.2°, 27.3 ± 0.2°, 27.8 ± 0.2°, 28.5 ± 0.2°, and 28.8 ± 0.2°.

5. A solid form of a compound having the following structure (I): or a tautomer thereof: having an X-ray powder diffraction pattern substantially in accordance with that shown in Figure 1.

6. The solid form of any one of claims 1-5, wherein the differential scanning calorimetry thermogram comprises an endothermic peak with an onset temperature of about 89.5 °C.

7. The solid form of any one of claims 1-6, wherein the differential scanning calorimetry thermogram comprises an exothermic peak with an onset temperature of about 213.5 °C.

8. The solid form of any one of claims 1-7, wherein the differential scanning calorimetry thermogram is substantially in accordance with that shown in Figure 2.

9. A solid form of a compound having the following structure (I): or a tautomer thereof: wherein the solid form is prepared by a method comprising: (i) providing N-(6-((8"-methyl-l",5"-dioxo-l",5"-dihydro-2"H-dispiro[cyclopropane-l,r- cyclohexane-4',3"-imidazo[l,5-a]pyridin]-6"-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (Int-A); (ii) contacting Int-A with a hydroxide base (e.g., potassium hydroxide) in a suitable solvent (e.g., ethanol, tetrahydrofuran, and water, or a mixture thereof); and (iii) isolating the solid form. (iii) isolating the solid form of the compound having structure (I).

10. The solid form of claim 9, further comprising the step of slurrying the solid form of the compound having structure (I) in a suitable solvent (e.g., water).

11. The solid form of any one of claims 1 to 10, wherein the solid form is a hemihydrate.

12. A solid form of a compound having the following structure (I) or a tautomer thereof: wherein the solid form has an X-ray powder diffraction pattern with at least two peaks at a 2 theta angle selected from the group consisting of 19.2 ± 0.2°, 19.5 ± 0.2°, and 21.2 ± 0.2°.

13. The solid form of claim 12, wherein the solid form has an X-ray powder diffraction pattern with peaks at 2 theta angles of 19.2 ± 0.2°, 19.5 ± 0.2°, and 21.2 ± 0.2°.

14. The solid form of claim 12, wherein the solid form has an X-ray powder diffraction pattern with peaks at 2 theta angles of 8.2 ± 0.2°, 9.1 ± 0.2°, 11.4 ± 0.2°, 13.8 ± 0.2°, 14.3 ± 0.2°, 15.0 ± 0.2°, 15.5 ± 0.2°, 16.5 ± 0.2°, 17.0 ± 0.2°, 19.2 ± 0.2°, 19.5 ± 0.2°, 19.9 ± 0.2°, 21.2 ± 0.2°, 22.3 ± 0.2°, 22.7 ± 0.2°, 23.3 ± 0.2°, 23.9 ± 0.2°, 24.7 ± 0.2°, 25.3 ± 0.2°, 26.0 ± 0.2°, 26.9 ± 0.2°, 27.7 ± 0.2°, 28.5 ± 0.2°, 28.9 ± 0.2°, and 29.7 ± 0.2°.

15. A solid form of a compound having the following structure (I) or a tautomer thereof: having an X-ray powder diffraction pattern substantially in accordance with that set forth in FIG.

3.

16. The solid form of any one of claims 12-15, wherein The differential scanning calorimetry thermogram does not include any event prior to about 340 °C.

17. The solid form of any one of claims 12-15, characterized by The differential scanning calorimetry thermogram is substantially in accordance with that set forth in FIG.

4.

18. A solid form of a compound having the following structure (I) or a tautomer thereof: wherein the solid form is prepared by a process comprising the steps of: (i) providing structure (I) Pattern 3; (ii) heating structure (I) Pattern 3 to about 250 °C under vacuum; and (iii) isolating the solid form of the compound having structure (I).

19. The solid form of any one of claims 12 to 18, wherein the solid form is unsolvated.

20. An amorphous solid form of a compound having the following structure (I) or a tautomer thereof:

21. An amorphous solid form of a compound having the following structure (I) or a tautomer thereof: wherein the amorphous form is prepared by a process comprising the steps of: (i) providing structure (I) Pattern 3; (ii) subjecting Structure (I) Pattern 3 to ball milling at a suitable frequency (e.g., 30 Hz) for a suitable amount of time (e.g., 3 times, 90 minutes each); and (iii) isolating the amorphous form of the compound having Structure (I).

22. A crystalline solid form of a compound having the following Structure (I) or a tautomer thereof: wherein the crystalline solid form is described in the Examples herein.

23. A crystalline solid form of a compound having the following Structure (I) or a tautomer thereof: wherein the crystalline solid form is prepared by a method comprising the steps of: (i) providing Structure (I); (ii) contacting Structure (I) with one or more suitable solvents (e.g., n-heptane, ethyl acetate, isopropyl acetate, methyl isobutyl ketone, 2-propanol, methylethyl ketone, acetone, ethanol, t-butyl methyl ether, 2-methyl-l-propanol, cyclohexane, methanol, toluene, tetrahydrofuran, acetonitrile, water, dimethyl sulfoxide, or a combination thereof); and (iii) isolating the crystalline solid form, the method optionally including a step of heating or cooling the mixture of Structure (I) in a suitable solvent or the solid precipitate isolated therefrom.

24. A salt form of a compound having the following Structure (I) or a tautomer thereof: wherein the salt form is formed between Structure (I) and a co-forming agent selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, maleic acid, fumaric acid, phosphoric acid, citric acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, tartaric acid, succinic acid, and malic acid.

25. The salt form of claim 24, wherein the salt form is described in the Examples herein.

26. The salt form of claim 24 or 25, wherein the salt form is crystalline.

27. A salt form of a compound having the following Structure (I) or a tautomer thereof: wherein the salt form is prepared by a method comprising the steps of: (i) providing Structure (I); (ii) contacting Structure (I) with a co-forming agent selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, maleic acid, fumaric acid, phosphoric acid, citric acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, tartaric acid, succinic acid, and malic acid; and (iii) isolating the salt form.

28. A solid form (e.g., crystalline or amorphous form of a free base or salt form) of a compound having the following Structure (I) or a tautomer thereof: wherein the solid form is prepared by a method described in the Examples herein.

29. A pharmaceutical composition comprising a solid form according to any one of claims 1 to 28 and a pharmaceutically acceptable carrier or excipient.

30. The pharmaceutical composition of claim 29, which is formulated for oral administration.

31. The pharmaceutical composition of claim 29, which is in the form of a capsule.

32. The pharmaceutical composition of claim 29, which is in the form of a tablet.

33. A method of preparing a solid form of a compound having the following Structure (I) or a tautomer thereof: the method comprising the steps of: (i) providing Structure (I); (i) providing N-(6-((8"-methyl-l",5"-dioxo-l",5"-dihydro-2"H-dispiro[cyclopropane-l,1'- cyclohexane-4',3"-imidazo[l,5-a]pyridin]-6"-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (Int-A); (ii) contacting Int-A with a hydroxide base (e.g., potassium hydroxide) in a suitable solvent (e.g., ethanol, tetrahydrofuran, and water, or a mixture thereof); and (iii) isolating the solid form of the compound having structure (I).

34. The method of claim 33, further comprising the step of slurring the solid form of the compound having structure (I) in a suitable solvent (e.g., water).

35. A method of preparing a solid form of a compound having the following structure (I) or a tautomer thereof: the method comprising the steps of: (i) providing structure (I) Pattern 3; (ii) heating structure (I) Pattern 3 to about 250 °C under vacuum; and (iii) isolating the solid form of the compound having structure (I).

36. A method of preparing an amorphous form of a compound having the following structure (I) or a tautomer thereof: the method comprising the steps of: (i) providing structure (I) Pattern 3; (ii) ball milling structure (I) Pattern 3 at a suitable frequency (e.g., 30 Hz) for a suitable amount of time (e.g., 3 times, 90 minutes each); and (iii) isolating the amorphous form of the compound having structure (I).

37. A method of preparing a crystalline solid form of a compound having the following structure (I) or a tautomer thereof: the method comprising the steps of: (i) providing structure (I); (ii) contacting structure (I) with one or more suitable solvents (e.g., n-heptane, ethyl acetate, isopropyl acetate, methyl isobutyl ketone, 2-propanol, methylethyl ketone, acetone, ethanol, t-butyl methyl ether, 2-methyl-l-propanol, cyclohexane, methanol, toluene, tetrahydrofuran, acetonitrile, water, dimethyl sulfoxide, or a combination thereof); and (iii) isolating the crystalline solid form, the method optionally comprising the step of heating or cooling a mixture of structure (I) in a suitable solvent or a solid precipitate isolated therefrom.

38. A method of preparing a salt form of a compound having the following structure (I) or a tautomer thereof: the method comprising the steps of: (i) providing structure (I); (ii) contacting structure (I) with a co-former selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, maleic acid, fumaric acid, phosphoric acid, citric acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, tartaric acid, succinic acid, and malic acid; and (iii) isolating the salt form.

39. A method for treating, preventing, or ameliorating the effects of migraine or a symptom associated with migraine, the method comprising administering a therapeutically effective amount of a solid form according to any one of claims 1 to 28 or a pharmaceutical composition according to any one of claims 29 to 32.

40. A method for treating, preventing, or ameliorating the effects of a disease associated with aberrant MNK activity in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a solid form of any one of claims 1-28 or a pharmaceutical composition of any one of claims 29-32.

41. A method for treating, preventing, or ameliorating the effects of neuropathic pain, lupus, pain caused by viral infection, COVID-19 related acute respiratory distress syndrome (ARDS), nonalcoholic fatty liver disease (NAFLD), obesity caused by high-fat diet, Alzheimer’s disease, or fragile X syndrome in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a solid form of any one of claims 1-28 or a pharmaceutical composition of any one of claims 29-32.

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