Solid forms of MNK inhibitors

Abstract

The present disclosure relates to solid forms of compounds having the following structure (I), or tautomers thereof. The present disclosure also relates to methods of making and using compounds of structure (I). Briefly, embodiments of the present disclosure provide compounds, including pharmaceutically acceptable salts, solvates, cocrystals, polymorphs, and other solid forms thereof, that can inhibit the activity of MNK. In some embodiments, the present disclosure provides solid forms, including free base (or "free form") solid forms, salt forms, and / or solvate forms of compounds of structure (I). TIFF2026506321000073.tif3058

Description

[Technical Field]

[0001] Statement of Government Interests This invention was made with government support under Grant No. 1U44NS115692-01 awarded by the National Institutes of Health. The government has certain rights in this invention.

[0002] Related Applications This application claims the benefit of and priority to U.S. Patent Application No. 63 / 478,409, filed January 4, 2023, the entire contents of which are incorporated herein by reference.

[0003] Embodiments of the present disclosure are generally directed to solid forms of compounds and methods for their preparation and use as therapeutic or prophylactic agents, for example, for the treatment of various diseases and disorders (e.g., inflammation, neuropathic pain, migraine, etc.). [Background technology]

[0004] Undertreated pain is a devastating health problem in the United States. One-third of all Americans suffer from some form of chronic pain, and one-third of those suffer from pain that is resistant to current medical therapies. The economic impact of pain is equally significant, amounting to approximately $100 billion annually. Opioid, or narcotic, analgesics, such as morphine, are the most effective treatment for acute and chronic severe pain. However, their clinical utility is often hindered when analgesic tolerance develops, requiring increasingly escalating doses to achieve equivalent pain relief. Furthermore, these drugs are often ineffective in treating neuropathic pain. This complex pathophysiological cycle poses a significant barrier to the quality of life for these patients due to the resulting drug-induced sedation, decreased physical activity, constipation, respiratory depression, high addiction potential, and other side effects.

[0005] Neuropathic pain typically develops over time and may benefit from therapies that interfere with pathways involved in its development and / or maintenance.

[0006] Diseases or injuries that cause neuropathic pain can affect the central nervous system (CNS), the peripheral nervous system, or both (as opposed to causes of nociceptive pain that affect only 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, herpes zoster infection, HIV-associated neuropathy, nutritional deficiencies, toxins, remote manifestations of malignancy, immune-mediated disorders, physical trauma to the nerve trunk, such as during surgery, peripheral ischemia, peripheral nerve lesions, nerve compression, chemotherapy or other drug-induced nerve damage, radiation injury, arthritis, autoimmune diseases, and infections in the vicinity of the affected nerve.

[0007] Neuropathic pain is often associated with abnormal nociceptor sensitivity. Nociceptors are specialized neurons that detect pain. Nociceptor sensitivity is not fixed and can change over time. Some causes of neuropathic pain affect nociceptor sensitivity by inducing "peripheral sensitization." Peripheral sensitization can include spontaneous pathological activity, abnormal excitability, increased sensitivity to chemical stimuli, increased sensitivity to heat stimuli, increased sensitivity to mechanical stimuli, and any combination of these.

[0008] Therefore, disrupting peripheral sensitization can treat neuropathic pain by either reducing or preventing such peripheral sensitization in the first place, or by reducing the degree of peripheral sensitization that has already developed. Although the present disclosure is not limited to one mechanism of action, the MNK inhibitors disclosed herein can interfere with peripheral sensitization.

[0009] 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, phylogenetically related to Ca 2+MNK is thought to be a calmodulin-dependent kinase (CaMK). MNK is activated through phosphorylation by the growth factor-stimulated Ras / extracellular signal-regulated kinase pathway and the stress-induced p38 pathway.

[0010] Nociceptor sensitization can be blocked by inhibiting activity-dependent mRNA translation through mechanistic targeting of the mitogen-activated protein kinase (MAPK) pathway, which signals to the eukaryotic translation initiation factor (eIF)4E complex to regulate nociceptor sensitization.

[0011] A chemical compound can form one or more different pharmaceutically acceptable salts and / or solid forms, including amorphous and polycrystalline crystalline forms. Individual salts and solid forms of the bioactive compound can have different properties. For the development of pharmaceutically acceptable dosage forms for the treatment of various MNK-related diseases or conditions, it is necessary to identify and select appropriate salts and / or solid forms of the bioactive compound (including appropriate crystalline forms, if applicable). Summary of the Invention [Means for solving the problem]

[0012] In brief, 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.

[0013] In some embodiments, the present disclosure provides solid forms, including free base (or "free form") solid forms, salt forms, and / or solvate forms of the compound of structure (I).

[0014] In one aspect, the present disclosure provides a compound having the following structure (I): [ka] or a tautomer thereof, wherein the solid form has an X-ray powder diffraction pattern with at least two peaks at 2θ angles selected from the group consisting of 5.6±0.2°, 10.9±0.2°, 18.2±0.2°, and 18.6±0.2°.

[0015] In another aspect, pharmaceutical compositions comprising the disclosed solid forms and methods of use thereof for the treatment of, e.g., inflammation, neuropathic pain, migraine, lupus, viral infection-induced pain, COVID-19-associated acute respiratory distress syndrome (ARDS), non-alcoholic fatty liver disease (NAFLD), high-fat diet-induced obesity, Alzheimer's disease, or fragile X syndrome are also provided.

[0016] The following patterns refer to solid forms of structure (I), which, unless otherwise indicated, are in their free form. [Brief explanation of the drawings]

[0017] [Figure 1] The XRPD diffractogram of pattern 3 is shown. [Figure 2] TGA (top) and DSC (bottom) data for pattern 3 are shown. [Figure 3] The XRPD diffractogram of pattern 11 is shown. [Figure 4] TGA (top) and DSC (bottom) data for pattern 11 are shown. [Figure 5] An overlay of the XRPD diffractograms of patterns 11 and 3 is shown. [Figure 6] FIG. 1 shows a form diagram depicting the conditions used to obtain 11 different polymorphic forms of the free base of structure (I). [Figure 7] FIG. 1 is an X-ray powder diffraction pattern of structure (I) from lot A. [Figure 8] TGA (top) and DSC (bottom) of structure (I) from Lot A are shown. [Figure 9] 1 is an overlay of XRPD diffractograms of different patterns of a salt of structure (I) and the free form of structure (I). [Figure 10]Depicting (from bottom to top) an overlay of XRPD diffractograms of fumarate salt pattern 2 after humid, dry, and 7 days of storage at 40° C. / 75% RH. [Figure 11] Shown is an overlay of XRPD diffractograms of (from bottom to top) free form Pattern 3, sulfonate Pattern 1, sulfonate Pattern 2 before storage, and sulfonate Pattern 2 after storage. Storage conditions were 40°C / 75% RH for 7 days. [Figure 12] An overlay of XRPD diffractograms comparing pattern 1 before (top) and after (bottom) a two-cycle GVS experiment is shown. [Figure 13] Shown (from bottom to top) are overlays of XRPD diffractograms of Pattern 1 as a reference material after 8 days of storage at 25° C. / 97% RH and 8 days of storage at 40° C. / 75% RH. [Figure 14] 1 is an overlay of XRPD diffractograms of (from bottom to top) Free Form Pattern 3 (from Lot B), Free Form Pattern 2, and Free Form Pattern 1 (from Lot A). [Figure 15] 1 depicts an overlay of XRPD diffractograms of free form Pattern 3 before (bottom) and after (top) GVS. [Figure 16] An overlay of XRPD diffractograms of free form Pattern 3 (bottom), free form Pattern 3 after 7 days of storage at 25°C / 97% RH (middle), and after 7 days of storage at 40°C / 75% RH (top) is shown. [Figure 17] An overlay of XRPD diffractograms of free form Pattern 3 under various vacuum and temperature conditions is shown. From bottom to top, the conditions were: 25°C + vacuum released after 30 minutes, 50°C vacuum for 3 days, 50°C vacuum, 50°C vacuum, 50°C vacuum, 50°C no vacuum, and 25°C no vacuum. [Figure 18] An overlay of XRPD diffractograms of pattern 3 under various temperature conditions is shown, from bottom to top: 25°C, 250°C, 175°C, 50°C, and 25°C. [Figure 19]An overlay of XRPD diffractograms of five patterns obtained from salt screening using a 9:1 THF:water mixture for various salts. The solid forms, from bottom to top, are free form Pattern 1, tartrate Pattern 1, fumarate Pattern 1, citrate Pattern 1, malate Pattern 1, and succinate Pattern 1. [Figure 20] 1 depicts an overlay of XRPD diffractograms of solids obtained from phosphoric acid addition in a hot salt screen. From bottom to top, the diffractograms are: phosphate pattern 1 (reference), phosphate pattern 1 showing extra peaks, phosphate pattern 1, phosphate pattern 2, and phosphate pattern 1 with extra peaks. [Figure 21] Shown is an overlay of the XRPD diffractograms of the less crystalline free form Pattern 1 (bottom) compared to the free form Pattern 2 (top). [Figure 22] Shown is 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). [Figure 23] Shown are (from bottom to top) an overlay of XRPD diffractograms of free form Pattern 1 (bottom), HCl salt Pattern 1, HCl salt Pattern 2, HCl salt Pattern 3, a combination of HCl salt Patterns 1 and 3, and an overlay of HCl salt Pattern 4 (top). [Figure 24] 1. (From bottom to top) An overlay of XRPD diffractograms of Free Form Pattern 2 (bottom), Free Form Pattern 1, Sulfate Pattern 1, and Sulfate Pattern 1 (top). [Figure 25] Depicted is an overlay of the XRPD diffractograms of (from bottom to top) free form Pattern 2 (bottom), free form Pattern 1, para-toluenesulfonate Pattern 1, and para-toluenesulfonate Pattern 1 (top). [Figure 26] Shown is an overlay of XRPD diffractograms of (from bottom to top) free form pattern 2 (bottom), free form pattern 1, methanesulfonate salt pattern 1, and methanesulfonate salt pattern 2 (top). [Figure 27]Shown is an overlay of XRPD diffractograms of (from bottom to top) free form pattern 2, free form pattern 1, benzenefluconate salt pattern 1, and benzenesulfonate salt pattern 1 (top). [Figure 28] Shown is an overlay of the XRPD diffractograms of (from bottom to top) Free Form Pattern 2 (bottom), Free Form Pattern 1, Maleate Pattern 1, and Maleate Pattern 1 (top). [Figure 29] (From bottom to top) An overlay of XRPD diffractograms of H3PO4 salt pattern 1 (top), H3PO4 salt pattern 2, and H3PO4 salt pattern 1 (top). [Figure 30] Depicted (from bottom to top) is an overlay of the XRPD diffractograms of free form Pattern 2 (bottom), free form Pattern 1, L-tartrate salt Pattern 1, and the poorly crystalline material. [Figure 31] An overlay of XRPD diffractograms of (from bottom to top) Free Form Pattern 2, Free Form Pattern 1, Fumarate Pattern 1, and Poorly Crystalline Fumarate Pattern 1 is shown. [Figure 32] Shown is an overlay of the XRPD diffractograms of (from bottom to top) Free Form Pattern 2 (bottom), Free Form Pattern 1, Citrate Pattern 1, and Citrate Pattern 1 (top). [Figure 33] Shown is an overlay of XRPD diffractograms of (from bottom to top) free form pattern 2 (bottom), free form pattern 1, L-malate pattern 1, and L-malate pattern 2 (top). [Figure 34] Overlay of XRPD diffractograms of (from bottom to top) Free Form Pattern 2 (bottom), Free Form Pattern 1, Succinate Pattern 1 (reassigned as Free Form Pattern 2), and Succinate Pattern 2 (top—showing some extra peaks). [Figure 35] An overlay of the XRPD diffractograms of HBr salt Pattern 1 (bottom) and free form Pattern 1 (from Lot A) (top) is depicted. [Figure 36] 1 shows the DSC thermogram of HBr salt pattern 1. [Figure 37]An overlay of the XRPD diffractogram of HBr salt Pattern 1 after 7 days at 40° C. and 75% relative humidity (bottom) is shown with a reference trace of HBr salt Pattern 1 (top). [Figure 38] Shown is an overlay of XRPD diffractograms of (from bottom to top) HCl salt Pattern 1 (bottom), HCl salt Pattern 2, HCl salt Pattern 3, and free form Pattern 1 (from Lot A). These materials were obtained using a 9:1 ratio of THF:water in the screening process, as described herein below. [Figure 39] (From bottom to top) An overlay of the XRPD diffractograms of free form Pattern 1 (from Lot A), HCl salt Pattern 1 upon storage for 7 days at 40° C. and 70% relative humidity, and HCl salt Pattern 1 (top). [Figure 40] 1 depicts (from bottom to top) an overlay of the XRPD diffractograms of sulfate salt Pattern 1 (bottom) and free form Pattern 1 (from Lot A). This material was obtained using a 9:1 ratio of THF:water in the screening process, as described herein below. [Figure 41] Shown (from bottom to top) are overlays of the XRPD diffractograms of sulfate pattern 1 (bottom) and sulfate pattern 1 stored at 40° C. and 75% relative humidity for 7 days. [Figure 42] Shown is an overlay of the XRPD diffractograms of (bottom to top) tosylate salt pattern 1 and free form pattern 1 (from lot A). [Figure 43] Shown is an overlay of the XRPD diffractograms of (bottom to top) Free Form Pattern 1 and Free Form Pattern 3 (top). [Figure 44] (From bottom to top) An overlay of XRPD diffractograms of besylate salt pattern 1 and free form pattern 1 (from Lot A). [Figure 45] 1 depicts (from bottom to top) besylate pattern 1 after 7 days at 40° C. and 70% relative humidity and an overlay of the XRPD diffractogram of besylate pattern 1. [Figure 46]Shown (from bottom to top) is an XRPD overlay of maleate salt pattern 1 and free form pattern 1 (from lot A). [Figure 47] Shown (from bottom to top) are maleate pattern 1 and an overlay of the XRPD diffractogram of maleate pattern 1 after 7 days at 40° C. and 70% relative humidity. [Figure 48] Shown is an overlay of XRPD diffractograms of (bottom to top) phosphate pattern 1 and free form pattern 1 (from lot A). [Figure 49] (From bottom to top) Phosphate Pattern 1 after 7 days at 40° C. and 70% relative humidity and an overlay of the XRPD diffractogram of Phosphate Pattern 1. [Figure 50] An overlay of the XRPD diffractograms of (bottom to top) free form Pattern 1 (bottom), citrate Pattern 1, and tartrate Pattern 1 is depicted. [Figure 51] Shown (from bottom to top) are tartrate pattern 1 and an overlay of the XRPD diffractogram of tartrate pattern 1 after 7 days at 40° C. and 70% relative humidity. [Figure 52] Shown is an overlay of XRPD diffractograms of (bottom to top) fumarate salt pattern 1 and free form pattern 1 (from lot A). [Figure 53] Shown (from bottom to top) are fumarate salt pattern 1 and an overlay of the XRPD diffractogram of fumarate salt pattern 1 after 7 days at 40° C. and 70% relative humidity. [Figure 54] 1 is an overlay of XRPD diffractograms of (bottom to top) free form Pattern 1, citrate Pattern 1, and tartrate Pattern 1. [Figure 55] Depicted (from bottom to top) are Citrate Pattern 1 and an overlay of the XRPD diffractogram of Citrate Pattern 1 after 7 days at 40° C. and 70% relative humidity. [Figure 56] Shown (from bottom to top) is an overlay of the XRPD diffractograms of poorly crystalline free form Pattern 1 and free form Pattern 2. [Figure 57]Shown are (from bottom to top) an overlay of XRPD diffractograms of free form Pattern 1 (top), HCl salt Pattern 1, HCl salt Pattern 2, HCl salt Pattern 3, a combination of HCl salt Patterns 1 and 3, and HCl salt Pattern 4. [Figure 58] Shown (from bottom to top) are HCl salt Pattern 4 and an overlay of the XRPD diffractogram of HCl salt Pattern 4 after 7 days at 40° C. and 70% relative humidity. [Figure 59] 1 is an overlay of XRPD diffractograms of (from bottom to top) Free Form Pattern 2, Free Form Pattern 1, Mesylate Pattern 1, and Mesylate Pattern 2. [Figure 60] 1 depicts an overlay of the XRPD diffractograms of (from bottom to top) Free Form Pattern 2, Free Form Pattern 1, L-Malate Pattern 1, and L-Malate Pattern 2. [Figure 61] Shown is an overlay of XRPD diffractograms of (from bottom to top) free form pattern 3 (input), HCl 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). [Figure 62] Shown are (from bottom to top) an overlay of the XRPD diffractograms of Pattern 1, free form Pattern 3 (input material), free form Pattern 2, HCl salt Pattern 1, HCl salt Pattern 2, HCl salt Pattern 3, HCl salt Pattern 4, and HCl salt. [Figure 63] 1 shows the XRPD diffractogram of HCl salt pattern 1. [Figure 64] 1 is an overlay of XRPD diffractograms of (from bottom to top) Free Form Pattern 3 (input material), Free Form Pattern 2, Phosphate Pattern 1, Phosphate Pattern 2, Phosphate Pattern 1, and Phosphate Pattern 1. [Figure 65] 1 depicts the XRPD diffractogram of phosphate pattern 1. [Figure 66]Shown is an overlay of the XRPD diffractograms of (from bottom to top) Free Form Pattern 3 (input material), Free Form Pattern 2, Fumarate Pattern 1, Fumarate Pattern 2, and Fumarate Pattern 2 (top). [Figure 67] 1 shows the XRPD diffractogram of fumarate salt pattern 2. [Figure 68] Shown is an overlay of XRPD diffractograms of (from bottom to top) Free Form Pattern 3 (input material), Free Form Pattern 2, Mesylate Pattern 1, Mesylate Pattern 2, Mesylate Pattern 2, and Mesylate Pattern 2. [Figure 69] FIG. 1 is an XRPD diffractogram of mesylate pattern 2. [Figure 70] An overlay of the XRPD diffractograms of (bottom to top) the free form pattern 3, the sulfate salt pattern 1, and the HCl salt pattern 1 is depicted. [Figure 71] Shown are (from bottom to top) an overlay of XRPD diffractograms of the reference material in pattern 1, a sample treated with the inverse antisolvent of DMSO / water, a sample treated with dry grinding for 30 min, a sample treated with the inverse antisolvent of DMSO / TBME (pattern 4), and the free form pattern 3 (from lot B). [Figure 72] Shown (from bottom to top) are overlays of XRPD diffractograms of Pattern 4 after 7 days at 40° C. and 70% relative humidity, Pattern 4 before storage, and free form Pattern 3. [Figure 73] 1 shows an overlay of XRPD diffractograms of the amorphous material after 7 days at 40° C. and 70% relative humidity, the amorphous material before storage, and the free form Pattern 3. [Figure 74]1 is an overlay of XRPD diffractograms showing diffractograms from samples prepared to explore the results of polymorph screen (Polymorph Screen 1) using the low-crystalline Pattern 3 described herein: (from bottom to top) free form Pattern 1, free form Pattern 2, free form Pattern 3, input material, free form Pattern 3, Pattern 5, a mixture of Patterns 3 and 5, Pattern 6, free form Pattern 3, Pattern 7, Pattern 3 (with an extra peak at 8.3°), Pattern 8, and free form Pattern 3. [Figure 75] 1 depicts an overlay of XRPD diffractograms showing diffractograms from samples prepared to explore the results of the polymorph screening with low crystalline Pattern 3 described herein, i.e., the diffractograms are (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. [Figure 76] 1 shows an overlay of XRPD diffractograms showing diffractograms from samples prepared to explore the results of polymorph screening (Polymorph Screen 2) using the amorphous material described herein, i.e., the diffractograms are (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. [Figure 77] 1 shows an overlay of XRPD diffractograms showing diffractograms from samples prepared to explore the results of polymorph screen (Polymorph Screen 2) using the amorphous material described herein, i.e., the diffractograms are (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. [Figure 78] Shown is an overlay of XRPD diffractograms of (bottom to top) free form Pattern 3, Pattern 6 (wet), and Pattern 6 (dry). [Figure 79] (From bottom to top) An overlay of the XRPD diffractograms of free form Pattern 3, Pattern 7 (wet), and Pattern 7 (dry). [Figure 80] Depicted (from bottom to top) is an overlay of the XRPD diffractograms of free form Pattern 3, Pattern 8 (wet), and Pattern 8 (dry). [Figure 81] Shown is an overlay of XRPD diffractograms of (bottom to top) free form Pattern 3, Pattern 9 (wet), and Pattern 9 (dry). [Figure 82] 1 shows an overlay of XRPD diffractograms showing the formation of pattern 7 (top) from slurry pattern 3 (bottom) in methyl ethyl ketone. [Figure 83] An overlay of XRPD diffractograms showing the formation of pattern 11 is shown. From bottom to top, the diffractograms are pattern 11 (after drying at ambient temperature for 1 day), pattern 11 (after drying at 250°C for 1 hour), patterns 10 and 11 as references, and pattern 3 (from lot B). [Figure 84] Thermal analysis (TGA (top) and DSC (bottom)) readouts of pattern 11. [Figure 85] Depicted (from bottom to top) are overlays of the XRPD diffractograms of pattern 11 after 7 days at 40° C. and 70% relative humidity, pattern 11 after 3 days at 40° C. and 70% relative humidity, and pattern 11 before storage. [Figure 86] An overlay of XRPD diffractograms of two preparations of pattern 11 is shown. [Figure 87] Shown (from bottom to top) is an overlay of the XRPD diffractograms of pattern 11 after GVS and pattern 11 before GVS. [Figure 88] Shown is an overlay of the XRPD diffractograms of (from bottom to top) pattern 11, pattern 11 after 10 days at 40° C. and 70% relative humidity, and pattern 10 after 10 days at 25° C. and 97% relative humidity. [Figure 89] FIG. 1 is a ball-and-stick diagram of free form Pattern 3 as a hemihydrate. [Figure 90] 1 depicts a diagram of the free form Pattern 3 as a hemihydrate from the single crystal structure showing the atomic numbering scheme. Anisotropic atomic displacement ellipsoids of non-hydrogen atoms are shown at the 50% probability level. [Figure 91] The hydrogen bond network of free form Pattern 3 is shown (intermolecular hydrogen bonds are depicted as dashed lines). [Figure 92] The hydrogen bond network of free form Pattern 3 is shown (intermolecular hydrogen bonds are depicted as dashed lines). [Figure 93] The crystal packing of free form pattern 3 is shown looking down the crystallographic a-axis. For clarity, all hydrogen atoms have been removed from the packing diagram. [Figure 94] Crystal packing diagram of free form pattern 3 looking down the crystallographic b axis. For clarity, all hydrogen atoms have been removed from the packing diagram. [Figure 95] 1 depicts the crystal packing diagram of free form pattern 3 looking down the crystallographic c-axis. For clarity, all hydrogen atoms have been removed from the packing diagram. [Figure 96] 1 shows a simulated XRPD diffractogram of free form Pattern 3 at 293K. [Figure 97] A comparison of the experimental diffractogram of free form Pattern 3 (bottom) collected at room temperature with a pattern simulated from single crystal data at 293 K (top) is shown. The patterns are consistent, confirming that the single crystal used for structure determination represents the reference material. The slight differences between the simulated and experimental diffractograms are due to preferred orientation. [Figure 98] 1 is an exemplary XRPD spectrum of a material containing pattern 3 of structure (I) and additional peaks. [Figure 99] 1 is an overlay of the Pattern 3 Reference XRPD spectrum and material from Example 22, Part 2 after being slurried in water for 8 hours. DETAILED DESCRIPTION OF THE INVENTION

[0018] The details described herein are by way of example and for purposes of illustrative discussion of embodiments of the present disclosure only. Any and all examples provided herein, or the use of exemplary language (e.g., "such as" or "for example"), are intended merely to better clarify the disclosure and do not impose limitations on the scope of the claimed disclosure. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure. Furthermore, all methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context.

[0019] The use of the alternative (e.g., "or") should be understood to mean one, both, or any combination thereof of the alternatives. The various embodiments described above can be combined to provide further embodiments. Groupings of alternative elements or embodiments of the disclosure described herein should not be construed as limitations. Members of each group may be referred to and claimed individually or in any combination with other members of the group or other elements found herein.

[0020] Each embodiment disclosed herein can comprise, consist essentially of, or consist of certain described elements, steps, ingredients, or components. As used herein, the terms "comprise" or "comprises" mean "including, but not limited to," allowing for the inclusion of unspecified elements, steps, ingredients, or components, even in greater amounts. As used herein, the phrase "consisting of" excludes any unspecified element, step, ingredient, or component. As used herein, the phrase "consisting essentially of" limits the scope of the present embodiments to the specified elements, steps, ingredients, or components, as well as those that do not materially affect the basic and novel characteristics of the claimed disclosure.

[0021] As used in the context of describing the present invention (particularly in the context of the claims that follow), the terms "a," "an," "the," and similar articles or terms should be construed to encompass both the singular and the plural (i.e., "one or more") unless otherwise indicated herein or clearly contradicted by context. Ranges of values ​​recited herein are intended to serve as shorthand for individually referring to each separate value falling within the range. As used herein, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the recited range, and, where appropriate, fractions thereof (such as integer tenths and hundredths), unless otherwise indicated. Also, any numerical range recited herein with respect to any physical characteristic, such as size or thickness, should be understood to include any integer within the recited range, unless otherwise indicated. Unless otherwise indicated herein, each separate value is incorporated herein as if it were individually recited herein.

[0022] The term "about," when used in conjunction with a stated numerical value or range, has the meaning reasonably interpreted by one of ordinary skill in the art, i.e., to indicate somewhat more or somewhat less than the stated value or range, within ±20% of the stated value, ±19% of the stated value, ±18% of the stated value, ±17% of the stated value, ±16% of the stated value, ±15% of the stated value, ±14% of the stated value, ±13% of the stated value, ±12% of the stated value, ±11% of the stated value, ±10% of the stated value, ±9% of the stated value, ±8% of the stated value, ±7% of the stated value, ±6% of the stated value, ±5% of the stated value, ±4% of the stated value, ±3% of the stated value, ±2% of the stated value, or ±1% of the stated value.

[0023] Structure (I) The 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: [ka] is an inhibitor of MNK and is further described in WO2023 / 278686. Structure (I) has demonstrated potency against MNK in various assays (see, e.g., WO2023 / 278686). Thus, structure (I) is useful for treating diseases, disorders, or conditions associated with MNK, such as neuropathic pain.

[0024] The present disclosure provides various free and salt forms of structure (I), solid forms thereof, and pharmaceutical compositions comprising them. The salt forms and solid forms (e.g., crystalline solid forms) impart or may impart characteristics such as improved water solubility, stability, hygroscopicity (e.g., a provided form may be less hygroscopic than another form), absorption, bioavailability, and ease of formulation.

[0025] It will be understood that the crystalline solid form of structure (I) or a salt thereof can exist in pure (i.e., unsolvated), hydrated, solvated, and / or heterosolvated forms. In some embodiments, the crystalline solid form of structure (I) or a salt thereof does not have water or other solvents incorporated into the crystal lattice (i.e., is "unsolvated" or "anhydrous"). In some embodiments, the crystalline solid form of structure (I) or a salt thereof includes water and / or other solvents in the crystal lattice (i.e., is a hydrate and / or solvate, respectively). It will be understood that solvates containing only certain solvents, particularly water, are suitable for development as drugs. Solvates containing other solvents may be useful, especially for manufacturing and / or testing, even if they are not acceptable for use in approved therapeutic products.

[0026] While not wishing to be bound by any particular theory, the present disclosure recognizes a particular challenge in obtaining pattern 3 of structure (I) substantially free of other forms and / or impurities in a consistent manner and provides a solution to this problem. As described in Example 22, slurry materials having 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 pattern 3 of structure (I) and one or more other forms in water surprisingly yielded pattern 3 of structure (I) free of the other forms and with lower water content (e.g., water content corresponding to the 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).

[0027] Free base pattern 3 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).

[0028] Specifically, one embodiment is a compound having the following structure (I): [ka] or a tautomer thereof, wherein the solid form has an X-ray powder diffraction pattern with at least two peaks at 2θ angles selected from the group consisting of 5.6±0.2°, 10.9±0.2°, 18.2±0.2°, and 18.6±0.2°.

[0029] In some embodiments, the solid form has an X-ray powder diffraction pattern with at least three peaks at 2θ angles 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 2θ angles 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 2θ angles selected from the group consisting of 5.6°, 10.9°, 18.2°, and 18.6°.

[0030] In certain embodiments, the solid form has an X-ray powder diffraction pattern with at least three peaks at 2θ angles 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 2θ angles of 5.6°, 10.9°, 18.2°, and 18.6°.

[0031] In some embodiments, the solid form has a tangential angle 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 and an X-ray powder diffraction pattern having peaks at 2θ angles of 0.8±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°).

[0032] 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°.

[0033] In some particular embodiments, the solid form is characterized by an XRPD pattern comprising pattern 3. In certain embodiments, the solid form is characterized by an XRPD pattern consisting essentially of pattern 3. In some embodiments, a composition comprising the solid form is substantially pure.

[0034] One embodiment is a compound having the following structure (I): [ka] or a tautomer thereof, wherein the solid form has an X-ray powder diffraction pattern substantially in accordance with that depicted in FIG.

[0035] In some embodiments, the solid form is characterized by a differential scanning calorimetry thermogram comprising an endothermic peak with an onset of about 89.5° C. In some more particular embodiments, the endothermic peak has an area under the curve greater than 60 J / g. In some embodiments, the endothermic peak has an area under the curve greater than 65 J / g.

[0036] In some particular embodiments, the solid form is characterized by a differential scanning calorimetry thermogram comprising an exothermic peak with an onset of about 213.5°C. In some embodiments, the exothermic peak has an area under the curve greater than 30 J / g. In certain embodiments, the endothermic peak has an area under the curve 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 depicted in Figure 2.

[0037] Free base pattern 11 In some embodiments, the present disclosure provides a solid form of structure (I), referred to herein as Pattern 11. In some embodiments, Pattern 11 is anhydrous and non-solvated.

[0038] One embodiment is a compound having the following structure (I): [ka] or a tautomer thereof, wherein the solid form has an X-ray powder diffraction pattern with at least two peaks at 2θ angles selected from the group consisting of 19.2±0.2°, 19.5±0.2°, and 21.2±0.2°.

[0039] In some embodiments, the solid form has an X-ray powder diffraction pattern with peaks at 2θ 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 2θ angles selected 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 2θ angles of 19.2°, 19.5°, and 21.2°.

[0040] In certain embodiments, the solid form has a temperature 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°, 20.2°, 20.3°, 20.4°, 20.5°, 20.6°, 20.7°, 20.8°, 20.9°, 21.0°, 21.1°, 21.2°, 21.3°, 21.4°, 21.5°, 21.6°, 21.7°, 21.8°, 21.9°, 22.0°, 22.1°, 22.2°, 22.3°, 22.4°, 22.5°, 22.6°, 22.7°, 22.8°, 22.9°, 23.0°, 23.1°, 23.2°, 23.3°, 23.4°, 23.5°, 23.6°, 23.8°, 23.9 having an X-ray powder diffraction pattern with peaks at 2θ angles of 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°.

[0041] 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°.

[0042] 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 embodiments, a composition comprising the solid form is substantially pure.

[0043] One embodiment is a compound having the following structure (I): [ka] or a solid form of a tautomer thereof, wherein the solid form has an X-ray powder diffraction pattern substantially in accordance with that depicted in FIG.

[0044] In some embodiments, the solid form is characterized by a differential scanning calorimetry thermogram that contains no events up to 340° C. In certain embodiments, the solid form is characterized by a differential scanning calorimetry thermogram substantially in accordance with that depicted in FIG.

[0045] Other free base forms In some embodiments, the present disclosure provides various free base forms of structure (I), including amorphous and crystalline forms.

[0046] In some embodiments, the present disclosure provides a crystalline solid form of structure (I). Exemplary crystalline solid forms of structure (I), and methods for preparing them, are described in the Examples below.

[0047] In some embodiments, the present disclosure provides Pattern 1 of Structure (I). In some embodiments, the present disclosure provides Pattern 2 of Structure (I). In some embodiments, the present disclosure provides Pattern 4 of Structure (I). In some embodiments, the present disclosure provides Pattern 5 of Structure (I). In some embodiments, the present disclosure provides Pattern 6 of Structure (I). In some embodiments, the present disclosure provides Pattern 7 of Structure (I). In some embodiments, the present disclosure provides Pattern 8 of Structure (I). In some embodiments, the present disclosure provides Pattern 9 of Structure (I). In some embodiments, the present disclosure provides Pattern 10 of Structure (I).

[0048] In some embodiments, the present disclosure provides amorphous forms of structure (I). Exemplary amorphous forms of structure (I), and methods for preparing them, are described in the Examples below.

[0049] Salt form of structure (I) In some embodiments, the present disclosure provides solid forms (i.e., salts or co-crystals) of structure (I), where structure (I) and the co-former are, for example, ionically bonded or hydrogen bonded to form the provided forms described herein. When salt forms of structure (I) are solid forms, they can be amorphous, crystalline, or mixtures thereof. Exemplary salt forms of structure (I), and methods for preparing them, are described in the examples below.

[0050] In some embodiments, the present disclosure provides a salt form of structure (I) formed between structure (I) and a co-former selected from 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.

[0051] 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 HCl Pattern 1. In some embodiments, the salt form of structure (I) is HCl Pattern 2. In some embodiments, the salt form of structure (I) is HCl Pattern 3. In some embodiments, the salt form of structure (I) is HCl Pattern 4.

[0052] 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.

[0053] 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.

[0054] 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 maleate pattern 1.

[0055] 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 fumarate pattern 1. In some embodiments, the salt form of structure (I) is fumarate pattern 2.

[0056] 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 phosphate pattern 1. In some embodiments, the salt form of structure (I) is phosphate pattern 2.

[0057] 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 citrate pattern 1.

[0058] 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 tosylate Pattern 1.

[0059] 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 mesylate pattern 2.

[0060] 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 besylate pattern 1.

[0061] 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 tartrate pattern 1.

[0062] 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., chloride, bromide, sulfate, acetate, maleate, fumarate, phosphate, citrate, tosylate, mesylate, besylate, tartrate, succinate, or malate).

[0063] 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., chloride, bromide, sulfate, acetate, maleate, fumarate, phosphate, citrate, tosylate, mesylate, besylate, tartrate, succinate, or malate).

[0064] 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., chloride, bromide, sulfate, acetate, maleate, fumarate, phosphate, citrate, tosylate, mesylate, besylate, tartrate, succinate, or malate).

[0065] 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., chloride, bromide, sulfate, acetate, maleate, fumarate, phosphate, citrate, tosylate, mesylate, besylate, tartrate, succinate, or malate).

[0066] 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., chloride, bromide, sulfate, acetate, maleate, fumarate, phosphate, citrate, tosylate, mesylate, besylate, tartrate, succinate, or malate).

[0067] 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., chloride, bromide, sulfate, acetate, maleate, fumarate, phosphate, citrate, tosylate, mesylate, besylate, tartrate, succinate, or malate).

[0068] 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., chloride, bromide, sulfate, acetate, maleate, fumarate, phosphate, citrate, tosylate, mesylate, besylate, tartrate, succinate, or malate).

[0069] 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., chloride, bromide, sulfate, acetate, maleate, fumarate, phosphate, citrate, tosylate, mesylate, besylate, tartrate, succinate, or malate).

[0070] 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., chloride, bromide, sulfate, acetate, maleate, fumarate, phosphate, citrate, tosylate, mesylate, besylate, tartrate, succinate, or malate).

[0071] 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., chloride, bromide, sulfate, acetate, maleate, fumarate, phosphate, citrate, tosylate, mesylate, besylate, tartrate, succinate, or malate).

[0072] 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., chloride, bromide, sulfate, acetate, maleate, fumarate, phosphate, citrate, tosylate, mesylate, besylate, tartrate, succinate, or malate).

[0073] In some of the foregoing 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.

[0074] Methods for preparing the provided forms Solid forms (eg, crystalline and amorphous free base and salt forms) can be prepared according to the methods described in the Examples.

[0075] In some embodiments, the present disclosure provides methods for preparing forms of structure (I) described herein, comprising one or more steps of removing solvent or adding solvent. In some embodiments, the added solvent is the same as the removed solvent. In some embodiments, the added solvent is different from the removed solvent. Means of solvent removal are known in the synthetic and chemical arts, and include, but are not limited to, any of those described herein and in the Examples.

[0076] In some embodiments, the methods for preparing the Structure (I) forms described herein include one or more steps of heating or cooling the preparation. In some embodiments, the methods for preparing the Structure (I) forms described herein include one or more steps of stirring or agitating the preparation. In some embodiments, the methods for preparing the Structure (I) forms described herein include adding a suitable co-former to a solution or slurry of Structure (I). In some embodiments, the methods for preparing the Structure (I) forms described herein include adding a suitable acid to a solution or slurry of Structure (I).

[0077] In some embodiments, the form of Structure (I) described herein precipitates from the mixture. In other embodiments, the form of Structure (I) described herein crystallizes from the mixture.

[0078] The forms of structure (I) described herein can be precipitated from the reaction mixture or produced by removing some or all of the solvent by methods such as evaporation, distillation, filtration (e.g., nanofiltration, ultrafiltration), reverse osmosis, absorption and reaction, by adding a suitable anti-solvent, by cooling, or by various combinations of these methods.

[0079] As generally described herein, the form of structure (I) is optionally isolated. It will be understood that the form of structure (I) can be isolated by any suitable physical means known to those skilled 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.

[0080] In some embodiments, the structure (I) form is optionally purified. It will be understood that the structure (I) form can be purified by any suitable physical means known to those skilled in the art. In some embodiments, the crude structure (I) form is slurried in a suitable solvent (e.g., water) to provide the structure (I) form with higher purity.

[0081] composition One embodiment provides a pharmaceutical composition comprising any one of the solid forms 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.

[0082] 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 intravenous, intramuscular, or subcutaneous routes. In some embodiments, the pharmaceutical composition is formulated for rectal or vaginal routes. In some embodiments, the pharmaceutical composition is formulated for inhalation.

[0083] In some embodiments, the present disclosure provides compositions 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 does not contain significant amounts of foreign matter. Such foreign matter may include different forms of structure (I), residual solvent, or any other impurities that may 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.

[0084] In some embodiments, the present disclosure provides compositions comprising a form of crystalline 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 compositions do not contain significant amounts 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 yet other embodiments of the present disclosure, at least about 99% by weight of the crystalline form of Structure (I) is present.

[0085] In some embodiments, the present disclosure provides compositions comprising an amorphous form of structure (I), wherein the composition is substantially free of the crystalline form of structure (I). For example, such compositions do not contain a significant amount of the crystalline form 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 yet other embodiments of the present disclosure, at least about 99% by weight of the amorphous form of structure (I) is present.

[0086] How to use Certain embodiments provide a method for treating, preventing, or alleviating the effects of migraine or symptoms associated with migraine, comprising administering a therapeutically effective amount of a solid form of any one of the embodiments disclosed herein, or a pharmaceutical composition thereof.

[0087] One embodiment provides a method for treating, preventing, or alleviating 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 the embodiments disclosed herein, or a pharmaceutical composition thereof.

[0088] One embodiment provides a method for treating, preventing, or alleviating the effects of neuropathic pain, lupus, viral infection-induced pain, COVID-19-associated acute respiratory distress syndrome (ARDS), non-alcoholic fatty liver disease (NAFLD), high-fat diet-induced obesity, 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 the embodiments disclosed herein, or a pharmaceutical composition thereof.

[0089] Illustrative Embodiments The following numbered embodiments are non-limiting examples of certain aspects of the present disclosure. 1. A compound having the following structure (I): [ka] or a solid form of a tautomer thereof, wherein the solid form has an X-ray powder diffraction pattern with at least two peaks at 2θ angles 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 embodiment 1, wherein the solid form has an X-ray powder diffraction pattern with at least three peaks at 2θ angles 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 embodiment 1, wherein the solid form has an X-ray powder diffraction pattern with peaks at 2θ angles of 5.6±0.2°, 10.9±0.2°, 18.2±0.2°, and 18.6±0.2°. 4. The solid form of embodiment 1, wherein the solid form has an X-ray powder diffraction pattern with at least two peaks at 2θ angles selected from the group consisting of 5.6°, 10.9°, 18.2°, and 18.6°. 5. The solid form of embodiment 1, wherein the solid form has an X-ray powder diffraction pattern with at least three peaks at 2θ angles selected from the group consisting of 5.6°, 10.9°, 18.2°, and 18.6°. 6. The solid form of embodiment 1, wherein the solid form has an X-ray powder diffraction pattern with peaks at 2θ angles of 5.6°, 10.9°, 18.2°, and 18.6°. 7. The solid form has the following characteristics: 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° 2. The solid form of embodiment 1, having an X-ray powder diffraction pattern with peaks at 2θ angles of 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°. 8. The solid form of embodiment 1, wherein said 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°. 9. The solid form of embodiment 1, wherein the solid form comprises pattern 3. 10. The solid form of embodiment 1, wherein the solid form consists essentially of Pattern 3. 11. The solid form of embodiment 1, wherein the solid form is substantially pure. 12. A compound having the following structure (I): [ka] or a solid form of a tautomer thereof, wherein the solid form has an X-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 13. The solid form of any one of embodiments 1-12, characterized by a differential scanning calorimetry thermogram comprising an endothermic peak with an onset of about 89.5°C. 14. The solid form of embodiment 13, wherein the endothermic peak is greater than 60 J / g. 15. The solid form of embodiment 13, wherein the endothermic peak is greater than 65 J / g. 16. The solid form of any one of embodiments 1-15, characterized by a differential scanning calorimetry thermogram comprising an exothermic peak with an onset of about 213.5 °C. 17. The solid form of embodiment 16, wherein the exotherm peak is greater than 30 J / g. 18. The solid form of embodiment 16, wherein the endothermic peak is greater than 35 J / g. 19. The solid form of any one of embodiments 1-18, characterized by a differential scanning calorimetry thermogram substantially in accordance with that depicted in FIG. 2. 20. A compound having the following structure (I): [ka] or a solid form of a tautomer thereof, wherein the solid form has an X-ray powder diffraction pattern with at least two peaks at 2θ angles selected from the group consisting of 19.2±0.2°, 19.5±0.2°, and 21.2±0.2°. 21. The solid form of embodiment 20, wherein the solid form has an X-ray powder diffraction pattern with peaks at 2θ angles of 19.2±0.2°, 19.5±0.2°, and 21.2±0.2°. 22. The solid form of embodiment 20, wherein the solid form has an X-ray powder diffraction pattern with at least two peaks at 2θ angles selected from the group consisting of 19.2°, 19.5°, and 21.2°. 23. The solid form of embodiment 20, wherein the solid form has an X-ray powder diffraction pattern with peaks at 2θ angles of 19.2°, 19.5°, and 21.2°. 24. The solid forms were 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. 21. The solid form of embodiment 20, having an X-ray powder diffraction pattern with peaks at 2θ angles of 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°. 25. The solid form of embodiment 20, wherein 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°. 26. The solid form of embodiment 20, wherein the solid form comprises pattern 11. 27. The solid form of embodiment 20, wherein the solid form consists essentially of pattern 11. 28. The solid form of embodiment 20, wherein said solid form is substantially pure. 29. A compound having the following structure (I): [ka] or a tautomer thereof, having an X-ray powder diffraction pattern substantially in accordance with that depicted in FIG. 30. The solid form of any one of embodiments 20-29, characterized by an event-free differential scanning calorimetry thermogram up to 340°C. 31. The solid form of any one of embodiments 20-29, characterized by a differential scanning calorimetry thermogram substantially in accordance with that depicted in FIG. 32. A pharmaceutical composition comprising a solid form according to any one of embodiments 1 to 31 and a pharmaceutically acceptable carrier or excipient. 33. The pharmaceutical composition of embodiment 32, formulated for oral administration. 34. The pharmaceutical composition of embodiment 32, in the form of a capsule. 35. The pharmaceutical composition according to embodiment 32, in the form of a tablet. 36. A method for treating, preventing, or alleviating the effects of migraine or symptoms associated with migraine, comprising administering a therapeutically effective amount of the solid form of any one of embodiments 1-31, or the pharmaceutical composition of any one of embodiments 32-35. 37. A method for treating, preventing, or alleviating the effects of a disease associated with abnormal MNK activity in a mammal in need thereof, comprising administering to said mammal a therapeutically effective amount of a solid form according to any one of embodiments 1 to 31, or a pharmaceutical composition according to any one of embodiments 32 to 35. 38. A method for treating, preventing, or alleviating the effects of neuropathic pain, lupus, viral infection-induced pain, COVID-19-associated acute respiratory distress syndrome (ARDS), non-alcoholic fatty liver disease (NAFLD), high-fat diet-induced obesity, Alzheimer's disease, or fragile X syndrome in a mammal in need thereof, comprising administering to said mammal a therapeutically effective amount of the solid form of any one of embodiments 1-31, or the pharmaceutical composition of any one of embodiments 32-35. [Example]

[0090] The specific conditions for preparation and data acquisition are shown below. Abbreviation / Acronym / Acronym 13 C NMR = carbon nuclear magnetic resonance 1 H NMR = proton nuclear magnetic resonance 1-PrOH = 1-propanol 2D = two-dimensional 2-Me-1-PrOH = 2-methyl-1-propanol ACN = acetonitrile ADD = additional peaks API = Active Pharmaceutical Ingredient AS = antisolvent ASR = Analysis Services Report ca. = approximately DMSO = dimethyl sulfoxide D-PAS = Dip-Probe Absorption Spectroscopy DSC = Differential Scanning Calorimetry DVS = Dynamic Vapor Sorption Eq / Eq. / Equiv.=equiv. EtOAc = ethyl acetate EtOH = ethanol FaSSGF = Fasted State Simulated Gastric Fluid FaSSIF = Fasted State Simulated Intestinal Fluid FeSSIF = fed state simulated intestinal fluid GVS = Gravimetric Vapor Sorption H2O = Water HBr = Hydrobromic Acid HCl = Hydrochloric acid HPLC = High-Performance Liquid Chromatography Hr or hr = hours HSM = Hot Stage Microscopy IC = ion chromatography ID=Identification IPA = 2-propanol iPrOAc = isopropyl acetate IR = Infrared spectroscopy ISA = ionic strength adjusted KF = Karl Fischer MALe = Maleate MALi = L-Malate MDSC = Modulated Differential Scanning Calorimetry MeCN = acetonitrile MEK = methyl ethyl ketone MeOH = methanol MIBK = methyl isobutyl ketone Min or min = minutes mol = mole MS=mass spectrometry N / A=Not Applicable NMR=nuclear magnetic resonance No. = Number P=Pattern PE = polyethylene PLM = polarized light microscopy PTFE = Polytetrafluoroethylene RH = relative humidity RRT = relative retention time RT=room temperature SCXRD = Single Crystal X-ray Diffraction SGF=simulated gastric fluid SIF=simulated intestinal fluid SUC = succinate TAR = L-tartaric acid (or its salts) TBME = tert-butyl methyl ether Temp=temperature TFA = trifluoroacetic acid Tg = glass transition temperature TGA=thermogravimetric analysis THF = tetrahydrofuran TRIS = Tris(hydroxymethyl)aminomethane USP = United States Pharmacopoeia UV=ultraviolet light v / v = volume to volume ratio vac=vacuum Vol = volume w / w = weight-to-weight ratio wt=weight wt%=weight% XRPD = X-ray powder diffraction

[0091] General method X-ray powder diffraction (XRPD) Bruker AXS D8 Advance XRPD diffractograms were collected on a Bruker D8 diffractometer using Cu Kα radiation (40 kV, 40 mA, λ = 1.540562 Å) and a θ-2θ goniometer equipped with a Ge monochromator. The incident beam passed through a 2.0 mm divergence slit, followed by a 0.2 mm anti-scatter slit and a knife edge. The diffracted beam passed through an 8.0 mm receiving slit with a 2.5° Soller slit, followed by a Lynxeye detector. The software used for data collection and analysis was Diffrac Plus XRD Commander and HighScore Plus, respectively.

[0092] Samples were run under ambient conditions as powders or flat specimens. Samples were prepared on polished, zero-background (510) silicon wafers by gently pressing them onto a flat surface or by packing them into cut cavities. The samples were rotated within their own plane.

[0093] Details of the standard Pharmorphix data collection method are as follows. Angle range: 2 to 42°2θ Step size: 0.05°2θ Acquisition time: 0.5 seconds / step (total acquisition time: 6.40 minutes)

[0094] PANalytical Empyrean XRPD diffractograms were collected on a PANalytical Empyrean diffractometer using Cu Kα radiation (45 kV, 40 mA, λ = 1.544398 Å) in transmission geometry. The incident beam used a 0.5° slit, a 4 mm mask, and a 0.04 rad Soller slit with a collecting mirror. A PIXcel3D detector positioned on the diffracted beam was fitted with an acceptance slit and a 0.04 rad Soller slit. The software used for data collection was X'Pert Data Collector with the X'Pert Operator Interface. Data were analyzed and presented using HighScore Plus.

[0095] Samples were prepared and analyzed in transmission mode in either metal or Millipore 96-well plates. X-ray transparent film was used between metal sheets on the metal well plates (approximately 1-2 mg). Millipore plates were used to separate and analyze solids from suspension by adding a small amount of suspension directly to the plate before filtering under light vacuum.

[0096] The scan mode for the metal plates used the gonioscan axis, while for the Millipore plates a 2θ scan was used.

[0097] Details of standard screening data collection methods are as follows: Angle range: 2.5 to 32.0° 2θ Step size: 0.0130°2θ Acquisition time: 12.75 seconds / step (total acquisition time 2.07 minutes)

[0098] Non-ambient conditions XRPD diffractograms were collected on a PANalytical Empyrean diffractometer using Cu Kα radiation (45 kV, 40 mA, λ = 1.544398 Å) in reflection geometry. The instrument was fitted with an Anton Paar CHC plus+ stage fitted with a graphite / Kapton window and equipped with an air-cooled or rough vacuum pumping system using an Edwards RV3 pump. The incident beam used a 10 mm fixed incident beam mask, a Ni filter, and a programmable divergence slit (automatic mode) with a 0.04 radian Soller slit. A PIXcel placed on the diffracted beam 3D The detector was fitted with a programmable anti-scatter slit (automatic mode) and a 0.04 radian Soller slit.

[0099] The software used to collect the data was X'Pert Data Collector and the data was analyzed and presented using Highscore Plus.

[0100] For variable temperature (VT-XRPD) experiments, samples were prepared and analyzed in an Anton Paar chrome stain sample holder. The sample chamber was under ambient atmosphere, and a heating / cooling rate of 10 °C / min was used with a 2-minute isothermal hold before measurements began. Measurement parameters followed the standard screening data collection method (detailed above). Measurements were performed at the following temperatures: 25, 80, 170, 250, and 25 °C.

[0101] For XRPD under vacuum, samples were prepared and analyzed in an Anton Paar chrome stain sample holder. Sample temperature was kept constant throughout at 25°C. Measurement parameters followed the standard screening data collection method (detailed above). An initial measurement was taken before starting the vacuum, followed by measurements at 10-minute intervals. Data collection was stopped after three consecutive scans showing no change.

[0102] nuclear magnetic resonance (NMR) 1H NMR and / or 13 C NMR spectra were collected on a Bruker 400 MHz instrument equipped with an autosampler and controlled by a DRX400 console. Unless otherwise stated, samples were prepared in DMSO-d6 solvent. Automated experiments were performed using standard Bruker load experiments ( 1 H, 13 C{ 1 H}, DEPT135) acquired using the ICON-NMR configuration within Topspin software. Offline analysis was performed using an ACD Spectrus processor.

[0103] For non-routine spectroscopy (2D NMR and variable temperature NMR), data were acquired using Topspin alone.

[0104] Differential scanning calorimetry (DSC) TA Instruments Q2000 DSC data were collected on a TA Instruments Q2000 equipped with a 50-position autosampler. Typically, 0.5–3 mg of each sample in a pinhole aluminum pan was heated from 25°C to 300°C at 10°C / min. A 50 mL / min purge of dry nitrogen was maintained over the sample.

[0105] The instrument control software was Advantage and Thermal Advantage for Q Series, and data were analyzed using Universal Analysis or TRIOS.

[0106] TA Instruments Discovery DSC DSC data were collected on a TA Instruments Discovery DSC equipped with a 50-position autosampler. Typically, 0.5–3 mg of each sample in a pinhole aluminum pan was heated from 25°C to 300°C at 10°C / min. A 50 mL / min purge of dry nitrogen was maintained over the sample.

[0107] The instrument control software was TRIOS and data were analyzed using TRIOS or Universal Analysis.

[0108] Thermogravimetric analysis (TGA) TA Instruments Q500 TGA data were collected on a TA Instruments Q500 TGA equipped with a 16-position autosampler. Typically, 5-10 mg of each sample was loaded into pre-tared aluminum DSC pans and heated from ambient temperature to 350 °C at 10 °C / min. A 60 mL / min nitrogen purge was maintained over the sample.

[0109] The instrument control software was Advantage and Thermal Advantage for Q Series, and data were analyzed using Universal Analysis or TRIOS.

[0110] TA Instruments Discovery TGA TGA data were collected on a TA Instruments Discovery TGA equipped with a 25-position autosampler. Typically, 5–10 mg of each sample was loaded into a pre-tarred aluminum DSC pan and heated from ambient temperature to 350 °C at 10 °C / min. A 25 mL / min nitrogen purge was maintained over the sample.

[0111] The instrument control software was TRIOS and data were analyzed using TRIOS or Universal Analysis.

[0112] Polarized Light Microscope (PLM) Leica LM / DM Polarizing Microscope Samples were analyzed with a Leica LM / DM polarizing microscope using a digital video camera for image capture. A small amount of each sample was placed on a glass slide, with or without immersion oil, and covered with a glass slip. Samples were viewed at appropriate magnification and with partial polarized light coupled with a λ false color filter. Images were captured using StudioCapture or Image ProPlus software.

[0113] Hot Stage Microscopy (HSM) Hot-stage microscopy was performed using a Leica LM / DM polarizing microscope in combination with a Mettler-Toledo FP82HT hot stage and a digital video camera for image capture. A small amount of each sample was placed on a glass slide, separating individual particles as much as possible. Samples were observed at appropriate magnification and partially polarized light coupled with a λ false color filter while heating from ambient temperature, typically at 10°C / min. Data were collected using StudioCapture.

[0114] Gravimetric Vapor Sorption (GVS) SMS DVS Intrinsic Adsorption isotherms were obtained using an SMS DVS Intrinsic moisture sorption analyzer controlled by DVS Intrinsic Control software. Sample temperature was maintained at 25 °C by the instrument control. Humidity was controlled by mixing dry and humid nitrogen streams, with a total flow rate of 200 mL / min. Relative humidity was measured by a calibrated Rotronic probe (dynamic range 1.0–100% RH) located near the sample. Sample weight change (mass relaxation) as a function of % RH was constantly monitored by a microbalance (accuracy ±0.005 mg).

[0115] Typically, 5-30 mg of sample was placed in a tar-coated mesh stainless steel basket under ambient conditions. Samples were loaded and removed at 40% RH and 25°C (typical room conditions). Moisture sorption isotherms were performed as outlined below (two scans per complete cycle). Standard isotherms were run at 25°C at 10% RH intervals over a 0-90% RH range. Typically, duplicate cycles (four scans) were performed. Data analysis was performed in Microsoft Excel using the DVS Analysis Suite. [Table 1]

[0116] Hiden IGASorp Adsorption isotherms were obtained using a Hiden IGASorp moisture sorption analyzer controlled by Isochema HISorp software. Sample temperature was maintained at 25 °C by a Grant LT Ecocool 150 recirculating water bath. Humidity was controlled by mixing dry and humid nitrogen streams, with a total flow rate of 250 ml min-1. Relative humidity was measured by a calibrated Vaisala RH probe (dynamic range 0–95% RH) located near the sample. Sample weight change (mass relaxation) as a function of % RH was constantly monitored by a microbalance (accuracy ±0.001 mg).

[0117] Typically, 20-30 mg of sample was placed in a tar-coated mesh stainless steel basket under ambient conditions. Samples were loaded and removed at 40% RH and 25 °C (typical room conditions). Moisture sorption isotherms were performed as outlined below (two scans obtained one complete cycle). Standard isotherms were run at 25 °C at 10% RH intervals over a 0-90% RH range. Typically, duplicate cycles (four scans) were performed. Data analysis was performed within Isochema HISorp 2019 software and exported to Microsoft Excel and presented accordingly. [Table 2]

[0118] Chemical Purity Measurement by HPLC Purity analyses were 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. [Table 3]

[0119] Water Determination by Karl Fischer Titration (KF) The moisture content of each sample was measured at 150°C on a Metrohm 874 oven sample processor using an 851 Titrano Coulometer with Hydranal Coulomat AG oven reagent and a nitrogen purge. A weighed solid sample was introduced into a sealed sample vial. Approximately 10 mg of sample was used per titration, and duplicate measurements were performed. Unless otherwise stated, the average of these results is presented. Data collection and analysis were performed using Tiamo software.

[0120] Ion Chromatography (IC) Data were collected using IC MagicNet software on a Metrohm 930 Compact IC Flex with an 858 Professional autosampler and an 800 Dosino weighing unit monitor. Accurately weighed samples were prepared as stock solutions in suitable solvents. Quantitation was achieved by comparison with standard solutions of known concentrations of the ions being analyzed. Analyses were performed in duplicate, and the average of values ​​is given unless otherwise stated. [Table 4] [Table 5]

[0121] Experimental crystallization method The choice of crystallization method influences which form is produced; therefore, different crystallization methods and conditions may produce different polymorphs.

[0122] The crystallization methods used herein are listed in Table 6 along with the degrees of freedom available for each method. [Table 6]

[0123] Solvent-mediated technology Without wishing to be bound by theory, crystallization occurs when the concentration of a compound in a solvent is higher than its solubility product.

[0124] Solvents with a wide variety of properties (e.g., hydrogen bond donor / acceptor tendencies, dipole moments, dielectric constants, viscosities, etc.) were selected for crystallization screening. 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.

[0125] Maturation / Ripening Aging experiments (or slurry aging) were carried out in various solvents or solvent mixtures and subjected to thermal cooling cycles. Without wishing to be bound by theory, repeated heating and cooling cycles may increase crystallinity or convert a metastable state (or a non-equilibrium state in the case of amorphous materials) to a more thermodynamically stable crystalline form. The rate and extent of conversion depend on the solubility of the input materials.

[0126] Cooling crystallization Crystallization was carried out by lowering the temperature of the clear solution. Without wishing to be bound by theory, the solubility of most materials decreases with decreasing temperature, so cooling can be used to create supersaturation, thereby resulting in crystallization.

[0127] Controlled Evaporation Crystallization was carried out by controlled evaporation of a clear, particle-free solution. Without wishing to be bound by theory, controlled evaporation often works well when the solvent has a relatively high vapor pressure, as the solvent is removed from the system, thereby increasing the solute concentration.

[0128] Precipitation / crystallization by adding antisolvent Antisolvent crystallization (down-out) 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 reduces the solute's original solubility, increases saturation, and causes its precipitation. Typically, the antisolvent is selected to be miscible with the solvent in any proportion, and the solute is relatively insoluble in the antisolvent.

[0129] Example 1 Overview of salt form research This study identified salt forms of structure (I) with solid-state and physicochemical properties suitable for pharmaceutical use. In parallel, the free solid form was also investigated via polymorphic evaluation to identify forms with properties suitable for end use.

[0130] pKa measurements indicated that structure (I) has a basic pKa of 4.73 and an acidic center of 11.49; therefore, the compound was considered a suitable candidate for salt formation at both ends of the pH scale. A broad-spectrum study was conducted to identify salt forms of structure (I). The study included solubility and salt formation evaluations, as well as four salt screens. A screen with 12 acids was used, employing the following techniques: thermal cooling cycles, cooling ramps, high-temperature screens, targeted screens at 1 and 2 equivalents, and targeted screens using high-purity input materials.

[0131] During this study, 12 salt forms were identified, along with multiple free base forms, two of which were selected for further development (free form patterns 3 and 11). Some of the salts formed did not exhibit the desired properties. Some 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 approaching ambient conditions, thus limiting the potential use of these forms in pharmaceuticals. However, it will be appreciated that salts and free base forms with less desirable properties may still be useful for manufacturing processes (e.g., intermediates) and / or testing purposes, especially if not acceptable for use in approved therapeutic products.

[0132] Example 2 Salt screening Acid and base stock solutions used in screening were prepared as described in Table 7 below. [Table 7]

[0133] Structure (I) (20 mg) from Lot A (Free Form Pattern 1) was charged into solvent-treated HPLC vials, 10 volumes at a time, until the material was completely dissolved or a maximum of 50 volumes had been added. Once 50 volumes had been reached without dissolution, the temperature was increased to 50°C. To each suspension, 1.1 molar equivalents (60 μL) of HCl (1 M in THF) was added, stirred for 5 minutes, and slowly cooled to 5°C at 0.1°C / min and held at that temperature overnight. All solids were then isolated by filtration through a PTFE frit and dried under vacuum for 20 minutes. Samples were analyzed by XRPD.

[0134] Pattern 1 of structure (I) was insoluble in most solvents under each condition. After the addition of HCl, new XRPD patterns were obtained from methanol, ethanol, ethyl acetate, isopropyl acetate, acetonitrile, and THF:water (90:10). Based on the solubility and salt formation results, THF:water (90:10) was selected as the solvent for subsequent salt screening. [Table 8]

[0135] Example 3 Salt screening 1-THF:water (9:1) The poorly crystalline structure (I) (from Lot A, free form pattern 1, 30 mg) was dissolved in 50 volumes of THF:water (9:1) at 60°C in 13 vials with stirring at 500 RPM (a small amount of debris was present). The solution was then treated with 1.1 molar equivalents (90 / 180 μL) 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 suspension was filtered and dried under vacuum for 20 minutes. The gummy samples were left uncapped to promote crystallization. All resulting solids were initially analyzed by XRPD and stored in glass HPLC vials for subsequent analysis. All solids that showed new XRPD diffractograms were analyzed by DSC, HPLC, and HPLC. 1 Further characterization was performed using some or all of 1 H NMR and storage at high temperature and humidity.

[0136] Solid materials were isolated from all samples suggesting that the compound of structure (I) readily forms salts. Based on 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. [Table 9]

[0137] Example 4 Salt Screening 2 - High Temperature Solvent Screening Due to the low solubility observed in the experiments in Example 2, a second solubility evaluation of structure (I) from Lot A was performed using a higher temperature closer to the boiling point of the selected solvent system (Table 10). Once at temperature, phosphoric acid or a base was added to promote the formation of phosphate or Na / K salts.

[0138] Structure (I) (from Lot A, free form pattern 1, 30 mg) was weighed into six HPLC vials and a stir bar was added to each vial. 50 volumes of different solvents according to Table 10 were added to the samples, and the samples were heated incrementally on a Polar Bear heating block and stirred at 400 RPM. Observations were recorded as the temperature was increased, and each temperature was held for 10 minutes.

[0139] All samples were then cooled to 60 °C, and samples 10-1 through 10-5 received 90 μL of 1.1 molar equivalents of phosphoric acid (1 M in THF). These were equilibrated, cooled to 5 °C at 0.1 °C / min, and stirred (400 rpm) for 14 h. Sample 10-6 received no acid but was subjected to the same cooling profile. Vials containing samples 10-7 and 10-8 received 0.8 molar equivalents of NaOH and KOH solution (1 M in water) before being equilibrated and subjected to the same cooling profile.

[0140] The suspension was isolated using positive pressure and a filter cartridge with a PE frit. The resulting solid was dried under compressed air and analyzed by XRPD.

[0141] All solids that showed new XRPD diffractograms were analyzed by DSC, HPLC, and 1 Further characterization was performed using H NMR and is described herein.

[0142] Observations made during the solubility evaluation are presented in Table 10. Despite the increased temperature, none of the solvent systems showed complete dissolution (some debris was still present in the THF:water (9:1) sample). [Table 10]

[0143] Addition of 1.1 molar equivalents of phosphoric acid to samples 10-1 through 10-5 resulted in the isolation of phosphate salt (PHO) Pattern 1 from ethyl acetate, PHO Pattern 1 with several additional peaks from acetone:water (9:1) and ethanol:water (9:1), and a new form of PHO Pattern 2 from 1,4-dioxane. Sample 10-6, without added counterion, yielded free form Pattern 2. Samples to which base was added yielded a brown oily / sticky 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. [Table 11]

[0144] Characterization of sample 10-6 is summarized in Table 12. XRPD indicated the isolation of a new crystalline form, Free Form Pattern 2. Crystallization yielded material with 98.2% purity, however the material still contained 0.2 molar equivalents of potassium, which was also present in the input material. [Table 12]

[0145] Example 5 Salt Screening 3-2x Equivalent Salt Solution To facilitate the formation of different salt forms, another screen was performed, primarily in THF:water (9:1), using an additional equivalent of each of the selected acids.

[0146] The low crystalline structure (I) (from Lot A, free form pattern 1, 20 mg) was dissolved in 50 volumes of the solvent system at 60 °C in 13 vials (samples 13-1 to 13-13) and in DMSO at 60 °C in vial 14 (sample 13-14). The solution was then treated with 2.1 molar equivalents of a counterion selected according to Table 13. The resulting solution was then cooled to 5 °C at 0.1 °C / min and held at this temperature for 2 days. Stirring (500 rpm) was maintained throughout. The suspension was isolated using a PE frit and a filter cartridge.

[0147] Addition of 2.1 molar equivalents of acid counterion resulted in the isolation of numerous solids, three of which had not been observed previously. These were HCl Pattern 4, mesylate Pattern 2, and malate Pattern 2; further characterization of these forms can be found in the disclosure and figures herein. It was also noted that some of the suspensions filter poorly, likely a function of particle size. [Table 13]

[0148] Example 6 Characterization of individuals from screens 1-3 The materials produced in screens 1–3 were characterized to determine their solid state properties. [Table 14]

[0149] HBr pattern 1 contained several diffraction peaks consistent with the input material, and the thermal behavior included two broad endotherms and no obvious melting, making it unlikely to be suitable for use as a drug product. The sample maintained HBr pattern 1 after storage, and a slight increase in purity was observed.

[0150] HCl patterns 1 and 3 appeared to be a mixture of forms based on the XRPD patterns observed in the salt formation evaluation. Thermal analysis contained two endotherms, a smaller broad endotherm followed by a sharper endotherm that may be a melt. Ion chromatography observed only 0.8 molar equivalents of chloride. The sample was stable to storage at 40°C / 75% RH. [Table 15]

[0151] SUL pattern 1 contained 1 molar equivalent of sulfate by ion chromatography and 97.4% purity by HPLC. DSC contained two broad endotherms, and the shape of the first endotherm suggests that a second event may be occurring simultaneously. No well-defined melting behavior was observed. The solid form was stable to storage at 40°C / 75% RH, although there was a decrease in chemical purity observed.

[0152] TOS pattern 1 is 1 H NMR also showed the presence of 0.42 equivalents of THF, containing 1 molar equivalent of the tosylate salt, although this does not exclude the possibility that the solid form is solvated. DSC included a large endotherm between 40 and 140 °C (165 J / g), likely representing this solvent loss. DSC also included two exotherms at higher temperatures, with no apparent melting. After storage at 40 °C / 75% RH, there was a significant loss of crystallinity, with the possibility that some free form pattern 1 was present. [Table 16]

[0153] Sample 9-5 was originally assigned as mesylate salt (MES) Pattern 1, but after characterization and comparison with other collected data, it was determined to be free form Pattern 3. Only 0.19 molar equivalents of mesylate salt were observed by NMR, along with 0.15 equivalents of THF. The material remained unchanged by XRPD after storage at 40 °C / 75% RH, with a slight decrease in chemical purity.

[0154] Sample 9-6, designated BES pattern 1, 1 It was found to contain 1 molar equivalent of benzenesulfonate by H NMR spectroscopy. The sample contained 0.18 molar equivalents of THF. Residual solvent likely contributed to the overlapping endotherms seen in the DSC between 50 and 120 °C. The DSC also contained two exotherms at higher temperatures. The solid form was not stable to storage at 40 °C / 75% RH. [Table 17]

[0155] Maleate Pattern 1 was prepared by elution with 0.25 molar equivalents of residual THF. 1 It contained 1.2 molar equivalents of maleate salt by H NMR spectroscopy. The salt form had fairly simple thermal data with a small exotherm at 126.8 °C and a larger overlapping event starting at 226.2 °C. The XRPD after 7 days of storage at 40 °C / 75% RH had very low intensity, likely due to low sample loading, and the observed reflections were consistent with the maleate salt pattern 1.

[0156] Phosphate Pattern 1 was obtained with an HPLC purity of 98.0%; the solid contained 0.11 molar equivalents of THF. IC indicated that the solid contained 1.27 molar equivalents of phosphate. DSC showed a large, broad endotherm between 50 and 150 °C (212.5 J / g), followed by a smaller, broad endotherm with an onset at 207.6 °C (39.5 J / g). XRPD after 7 days of storage at 40 °C / 75% RH had low intensity, likely due to low sample loading; the observed reflections were consistent with PHO Pattern 1.

[0157] Tartrate salt Pattern 1 had an XRPD diffractogram that matched that of citrate salt (CIT) Pattern 1 (Table 18). 1 In the H NMR spectrum, one molar equivalent of tartaric acid with traces of THF was observed. DSC contained a broad endotherm between 40 and 150 °C with two overlapping exotherms just above 200 °C. The solid form is stable to storage under high temperature and humidity conditions. CIT Pattern 1 (Table 18 below) did not appear to be a salt, but shared an XRPD pattern with TAR Pattern 1, which may be the free form. [Table 18]

[0158] FUM pattern 1 was obtained with an HPLC purity of 98.1%. 1 The H NMR spectrum showed that the material contained 1.83 molar equivalents of fumarate, which was inconsistent with the formation of a salt according to standard stoichiometry. The material also contained 0.5 molar equivalents of THF, which may indicate that it was in a solvated form. DSC contained a single endotherm with an onset at 180.5°C, but the shape of this event suggested that this may be two overlapping events. The solid form was stable to storage at 40°C / 75% RH for 7 days, and a slight increase was observed in the HPLC of the sample. One possibility is that a cocrystal was formed, which may or may not contain any charged species.

[0159] Samples 9-11, designated CIT Pattern 1, had an XRPD pattern consistent with TAR Pattern 1 above, and were assigned to be mono-salts. 1 H NMR spectroscopy does not contain any citrate, suggesting that it may be in the free form. [Table 19]

[0160] Samples 9-12 were originally designated as MALi pattern 1, but subsequent comparison with data and 1 The lack of malate observed in H NMR led to reassignment as free form Pattern 2. The XRPD patterns of samples 9-13 matched well with free form Pattern 2 and were therefore also reassigned on this basis. Both samples had 4.1 and 0.5 molar equivalents of residual THF, respectively, suggesting that they may be in solvated forms. [Table 20]

[0161] PHO pattern 2 was obtained from 1,4-dioxane in salt screen 2. It exhibited complex thermal behavior with a broad endotherm between 30 and 120 °C, followed by a series of other endothermic events. This material, which had 1.1 equivalents of phosphate by IC, lost a significant amount of crystallinity upon storage at 40 °C and 75% RH for 7 days.

[0162] HCl Pattern 4 was poorly crystalline, with the two largest peaks being attributable to contamination from the filter frit (21.5° and 24.0° 2θ). DSC contained one sharp endotherm with an onset at 123.7°C attributed to the polyethylene filter frit. The sample also 1 It also contained a large amount of residual THF by H NMR spectroscopy. The poor crystallinity and instability to storage at high temperature and humidity indicated that this salt form was likely not suitable for pharmaceutical use. [Table 21]

[0163] MES pattern 2, obtained from a double equivalent screening, had a relatively low purity of 93.2%. It had a high residual solvent content, reflected by a large, broad endotherm at the onset of the DSC. At high temperatures >200°C, there was a complex endotherm and exotherm.

[0164] MALi pattern 2 is 1 The H NMR spectrum lacked peaks attributable to the L-malate salt, suggesting it was likely the free form obtained from a double equivalence screen. There was a large amount of residual THF (0.82 equiv.), which was also seen in DSC as a large, broad endotherm with an onset at 65.6 °C. There were numerous overlapping events between 180 and 260 °C.

[0165] Example 7 Summary of salt screening 1-3 Solubility and pre-salt formation evaluations were performed using the compound of structure (I), pattern 1 (from Lot A), as input material, along with three salt screens. Two of the screens were performed in THF:water (9:1), as this was the only solvent system identified with any significant solubility. The third screen attempted to circumvent this by increasing the temperature used for the selected solvent.

[0166] Through these screens, a total of 11 salt forms have been crystallized and characterized. In addition, two new free form patterns were identified: Free Form Pattern 2 and Free Form Pattern 3. Three additional samples were isolated where the nature of the form was inconclusive (TAR Pattern 1, CIT Pattern 1, and MALi Pattern 2).

[0167] In general, the solid form properties of salts isolated from screening using structure (I) from Lot A were not desirable for pharmaceutical development (e.g., due to complex or unfavorable thermal behavior or instability under certain storage conditions), but may nevertheless have utility as intermediates in manufacturing processes and / or for testing purposes. It was hypothesized that the 0.2 equivalents of potassium in the input material from Lot A may affect the properties of the resulting material.

[0168] Example 8 Screening 4 - Targeted Salt Screening An additional targeted salt screen was performed on compounds of structure (I) using material from Lot B, which had low residual potassium content and was characterized as free form pattern 3 (see Example 20 below). Salts were attempted using THF:water (9:1) or 1,4-dioxane with the most promising candidates from the previous screen: hydrochloric acid, methanesulfonic acid, phosphoric acid, fumaric acid, and sulfuric acid.

[0169] Compound of structure (I) (from Lot B, approximately 30 mg, free form pattern 3) was treated with increasing aliquots of THF:water (9:1) or 1,4-dioxane up to 70 volumes (2.1 mL) or until dissolution was achieved at 50°C and 500 rpm. Observations were recorded after each solvent addition. Undissolved samples were heated to 70°C and 500 rpm, and further observations were made at 70°C.

[0170] Each sample was then subjected to 1.1, 2.1, or 3.1 molar equivalents of the selected free acid, depending on the target stoichiometry (Table 22).

[0171] The sample was then cooled from 70 to 5°C at 0.1°C / min and held at 5°C overnight at 500 rpm. Further observations were made and solid material was isolated after 24 hours using an SPE syringe cartridge and frit under positive pressure.

[0172] Any solids obtained were analyzed by XRPD, 1Analyses were performed by H NMR, HPLC, TGA, DSC, XRPD after 7 days of storage at 40 °C / 75% RH, and IC as needed. Additional microscopy techniques (PLM and HSM) were used as needed to complement the above analyses. [Table 22] Results and Discussion

[0173] The results from the targeted salt screen are summarized in Table 23. [Table 23]

[0174] As can be seen from Table 23, none of the samples dissolved at 70°C and 70 volumes.

[0175] This is in contrast to the batch of material used in the previous screen where dissolution was achieved (i.e., material from Lot A was characterized as low-crystalline free form Pattern 1). The higher crystallinity and different solid form of the input material used in these experiments may have influenced the results. As a result of insolubility, complete dissolution of the API could not be achieved before counterion addition. Therefore, salt formation in this screen was a product of slurry conversion.

[0176] From previous screening, chloride patterns 1 and 3, phosphate patterns 1 and 2, fumarate patterns 1, and mesylate patterns 2 were targeted. These salts were deemed to have promising solid-state morphology properties. Therefore, the conditions used for salt formation were repeated for these systems. Several color changes from white to yellow were observed with the addition of fumaric acid, methanesulfonic acid, and sulfuric acid.

[0177] XRPD analysis of the solid material was performed after 24 hours. Targeted salt screening yielded the following patterns: HCl Pattern 1, PHO Pattern 1, MES Pattern 2, and a novel FUM form (Pattern 2).

[0178] The samples were analyzed by XRPD, 1 They were characterized by H NMR, HPLC, TGA, DSC, XRPD after 7 days of storage at 40 °C / 75% RH, and IC. Additional microscopy techniques (PLM and HSM) were used, as needed, to complement the above analyses.

[0179] The results for Chloride Pattern 1 and Phosphate Pattern 1 are summarized in Table 24. [Table 24]

[0180] From the table, sample 22-1 (chloride pattern 1) showed an XRPD pattern consistent with previous samples, but the thermal behavior was inconsistent with previous samples (sample 9-2, P1+P3), showing a larger, broader endotherm followed by an exotherm. The initial endotherm was similar to that observed from the as-supplied free form. HPLC data indicated that the purity of the material remained high.

[0181] The weight loss in TGA coincided with a large, broad endotherm in DSC, suggesting possible hydrate behavior. Insufficient material was available to correlate the mass loss in TGA with residual THF content by NMR. Chloride Pattern 1 remained stable by XRPD and HPLC after 7 days of storage at 40°C / 75% RH. IC results indicated that chloride Pattern 1 contained 0.5 molar equivalents of counterion, suggesting incomplete salt formation. Based on the available data, the sample was likely a mixture of the chloride salt and the free form.

[0182] Sample 22-2 exhibited an XRPD pattern consistent with phosphate pattern 1. The sample exhibited high purity and 1H NMR was consistent with the expected structure, with <0.1 molar equivalents of residual THF present. TGA showed a 7 wt% weight loss, corresponding to 1.9 moles of water. DSC showed a large, broad endotherm (onset 82.1 °C), followed by a second endotherm at 207 °C.

[0183] The weight loss in TGA coincided with a large, broad endotherm in DSC, suggesting possible hydrate behavior. Phosphate Pattern 1 remained stable by XRPD and HPLC after 7 days of storage at 40 °C / 75% RH. IC results indicate that PHO Pattern 1 contained 1 molar equivalent of counterion. Further analysis of PHO Pattern 1 by PLM and HSM showed that the sample consisted of thin needles that remained stable up to 260 °C, at which point it began to melt.

[0184] Based on the available data, the sample was likely the monophosphate hydrate. This salt form had reasonable properties, but had a large endotherm and mass loss at relatively low temperatures, so the hydrate occupancy may not be clear at ambient conditions.

[0185] The results of the targeted screening of FUM pattern 1 and MES pattern 2 are summarized in Table 25. [Table 25]

[0186] Sample 22-3 exhibited an XRPD pattern that did not match the previously obtained fumarate pattern 1 and was therefore designated as a new pattern (Fumarate Pattern 2). Furthermore, when the sample was dried, it was found to exhibit additional peaks (FUM P2+ADD) that were not observed when wet, suggesting that the form may be unstable. It also suggested that there may be another fumarate form that is accessed by drying fumarate Form 2.

[0187] 1Analysis by H NMR showed lower than expected stoichiometry of fumarate salt pattern 2, suggesting the formation of a half salt. A small amount (0.2 molar equivalents) of residual THF was also observed. The sample remained highly pure.

[0188] TGA showed a large weight loss of 14 wt %, corresponding to 3.5 moles of water and 0.2 moles of THF. DSC showed a large, broad endotherm (onset 41.3° C.) followed by an exotherm with an onset of 147° C. The weight loss in TGA coincided with the large, broad endotherm in DSC, suggesting a possible hydrate.

[0189] Storage of the sample at 40 °C / 75% RH for 7 days resulted in the loss of the additional peak observed after drying the material, suggesting that fumarate pattern 2 is likely a variable occupancy hydrate.

[0190] Due to the combination of complex thermal behavior and apparent (partial) morphological changes, this salt form likely does not exhibit ideal properties for use in pharmaceuticals.

[0191] Sample 22-6 exhibited an XRPD pattern consistent with the previously obtained mesylate pattern 2.

[0192] 1 Analysis by H NMR showed the sample contained 1.1 molar equivalents of mesylate counterion with no detectable residual solvent. HPLC showed the sample remained highly pure.

[0193] TGA showed a weight loss of 8 wt.% before decomposition (approximately 300°C), corresponding to 2.2 moles of water. However, data quality was poor and repeat measurements may be required. The DSC thermogram showed a large, broad endotherm (onset 65.0°C) followed by a double exotherm with an onset of 196°C.

[0194] Storage of the sample at 40°C / 75% RH for 7 days showed no change in the material by XRPD or HPLC.

[0195] Based on the available data, the sample was likely the monomesylate hydrate. Because dehydration of this material occurred near ambient conditions, the solid form may not be suitable for further development as a pharmaceutical.

[0196] The results of the characterization of materials from the targeted screening of SUL Pattern 1 are summarized in Table 26. [Table 26]

[0197] Sample 22-8 exhibited an XRPD pattern that was generally consistent with the previously obtained sulfate pattern 1, although additional peaks were observed.

[0198] HPLC showed that sample purity remained above 99%, and IC analysis showed that the sample contained 0.7 molar equivalents of sulfate counterion. PLM of the sample showed that the particles were <25 μm in size and generally aggregated. 1 Analysis by H NMR showed the sample was consistent with the supplied structure, with significant residual solvent (1.9 molar equivalents of THF) detected. TGA analysis showed a 7 wt% weight loss (approximately 250 °C) before decomposition, corresponding to 1.9 moles of water or 0.5 moles of THF. The difference between the NMR and TGA data may indicate that the sample was still wet when analyzed by NMR. The DSC thermogram showed a poorly defined asymmetric endotherm (onset 36 °C) over a broad range (35-190 °C). No clear melt was observed.

[0199] Storage of the sample at 40°C / 75% RH for 7 days showed that the material was unstable and converted to a new pattern designated Sulfate Pattern 2. This new form shared many of the peaks with Sulfate Pattern 1 but appeared to be more crystalline. The purity of the sample remained high under storage.

[0200] In summary, a target salt screen was completed using lot B of structure (I). Conditions favoring the formation of chloride, mesylate, phosphate, fumarate, and sulfate salts were tested.

[0201] Screening yielded chloride Pattern 1, phosphate Pattern 1, mesylate Pattern 2, sulfate Pattern 1 (with additional peaks), and a novel fumarate Pattern 2. All resulting patterns were analyzed using a variety of techniques. From the data obtained, the samples generally appeared to be hydrated salts, with the possible exceptions of chloride Pattern 1 and sulfate Pattern 1, which appeared to be mixtures of the free and salt forms. All hydrated forms readily lost water at near ambient conditions.

[0202] Based on these results, neither salt was suitable for further development as a pharmaceutical product.

[0203] Example 9 Salt Screening Conclusion Several experiments were carried out to isolate salt forms of the compound of structure (I), taking the form of solubility and salt formation evaluations, as well as four salt screens: a standard screen involving 12 common acids, a high temperature screen, a double equivalent screen, and a targeted screen using high purity input material.

[0204] During this investigation, 12 salt forms were identified, along with two free base forms and several unspecified forms. Some of the salts formed exhibited properties undesirable for pharmaceutical use. Some of the most promising candidates (e.g., PHO Pattern 1, MES Pattern 1) were characterized as hydrates, but the water within these solids is lost at temperatures approaching ambient conditions, which may result in less stability than desired.

[0205] Additionally, some solids isolated with substoichiometric amounts of the counterion (HCl Pattern 1) were noted, and several free form patterns were observed. Finally, two new free base forms were identified: Free Form Pattern 2 and Free Form Pattern 3. An investigation of the polymorphic behavior of the free base was performed and is presented in the Examples disclosed herein.

[0206] Example 10 Polymorphic screening of the free form of structure (I) Since none of the identified salt forms were optimal, the free form of structure (I) was further investigated. This study aimed to identify polymorphs of structure (I), characterize them, and determine their suitability for use in pharmaceuticals.

[0207] To facilitate the generation and identification of a wide range of morphologies, amorphous material was used as input for screening. Several different methodologies were tested for the generation of amorphous material, as further described below.

[0208] Structure (I) (from Lot B, 30 mg, free form pattern 3) was treated with increasing aliquots of THF:water (7:3 v / v) or MeCN:water (1:2 v / v) up to 100 volumes (3 mL) at 50°C. After 100 volumes, the sample was left at 50°C for 1 hour.

[0209] Since neither sample dissolved, the freeze-drying was incomplete and no amorphous material could be produced using this method.

[0210] Reverse antisolvent addition (DMSO / TBME) Compound of structure (I) (from Lot B, 30 mg) was treated with an aliquot of DMSO (5 volumes, 150 μL) and stirred at 50° C. until dissolved (40 volumes, 1.2 mL total). TBME (12 mL, 1:10 solvent:antisolvent volume ratio) was stirred at room temperature, and the warm DMSO solution was added dropwise to the TBME. The resulting suspension was filtered (Sample 27-1).

[0211] The suspension was characterized and a summary of the data is presented in Table 27. The solid, Pattern 4, exhibited a large mass loss in TGA and 1 It was a DMSO solvate as evidenced by the solvent content in the H NMR spectrum, which converted to pattern 3 upon storage at 40 °C / 75% RH for 7 days. [Table 27]

[0212] Reverse antisolvent addition (DMSO / water) Compound of structure (I) (from Lot B, 30 mg) was dissolved in DMSO (40 volumes, 1.2 mL). Water (12 mL, 1:10 solvent:antisolvent volume ratio) was stirred at room temperature, and the warm DMSO solution was added dropwise to the water. The resulting suspension was filtered. XRPD analysis of the sample showed it to be free form pattern 1.

[0213] Ball mill grinding test Structure (I) (from Lot B, 30 mg) was added to a stainless steel grinding jar along with grinding balls. The sample was ground at 30 Hz for 60 minutes. Sample ID: 28-1

[0214] XRPD analysis of the material showed it to be amorphous except for two small peaks due to residual potassium chloride. Chemical purity did not deteriorate during amorphization. The Tg was not determined by mDSC because it appeared to be hidden under a large endotherm, indicating possible water loss. Two endothermic events at 149.9 °C and 196.8 °C, attributed to crystallization, were observed in mDSC. The amorphous material converted to free form Pattern 3 after storage at 40 °C / 75% RH for 7 days. [Table 28]

[0215] Ball mill grinding for screening 1 Structure (I) (from Lot B, 700 mg) was added to a 5 mL stainless steel grinding jar with 9 mm grinding balls. The sample was milled at 30 Hz for 60 minutes. The sample was milled for an additional 90 minutes. XRPD analysis of the material indicated that crystallinity had decreased, but complete amorphization had not been achieved. This material (Sample 28-2) was used as input for the first screening.

[0216] Ball mill grinding for screening 2 Compound of structure (I) (from Lot B, 1 g) was added to a 10 mL stainless steel grinding jar along with 9 mm grinding balls. The sample was milled at 30 Hz for 90 minutes. The sample was milled for an additional 2 x 90 minutes. Sample ID: 29-1

[0217] Extended grinding times and refined parameters allowed access to fully amorphous material. Characterization was consistent with that collected for small-scale sample 28-1 and is summarized in Table 29. This was used as input material for the second screening. [Table 29]

[0218] Example 11 Polymorphism screening 1 - Low crystalline pattern 3 input Structure (I) (sample 28-2, 30 mg, low-crystalline pattern 3) was wetted with solvent (300 μL, 10 volumes) according to Table 30 and placed on 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. Those exhibiting novel patterns were further characterized, including reanalysis by XRPD after allowing the samples to dry overnight under ambient conditions. This characterization is presented and explained in the examples detailed herein (see, e.g., Figure 75).

[0219] The use of the less crystalline Pattern 3 (Sample 28-2) as input material did not prevent the formation of four new patterns. Patterns 5-9 all have similar XRPD patterns with some shifts of certain peaks, suggesting they are structurally related forms, possibly solvates. Patterns 8 and 9 were unstable to drying under ambient conditions, and Pattern 3 peaks appeared and transformed into Pattern 8. [Table 30]

[0220] Example 12 Polymorphism Screening 2 - Amorphous Input Amorphous structure (I) (sample 29-1, 30 mg) was wetted with solvent (300 μL, 10 volumes) according to Table 31 and placed in a shaker at 50° C. for 3 days. The sample was isolated using a filter cartridge and frit, and the XRPD pattern was collected. See, for example, Figure 77.

[0221] When amorphous material was used as input for screening, less diverse results were obtained, with all but four samples yielding Pattern 3. Pattern 7 was isolated from MEK and ethanol, which in the first screening gave Patterns 7 and 8, respectively. Pattern 8 was obtained from MeOH and ACN, which in the first screening gave Pattern 9 (which converts to P8+P3 upon drying) and Pattern 8, respectively. [Table 31]

[0222] The novel forms identified in the polymorphism screen were characterized to determine the nature of the solid forms. [Table 32]

[0223] Sample 30-2 was originally isolated as Pattern 5 but began to convert to Pattern 3 upon gentle drying under ambient conditions. This transition was complete upon storage at 40°C / 75% RH for 7 days. NMR indicated that 0.2 molar equivalents of ethyl acetate were present in the sample, which was in reasonable agreement with TGA. In addition to the endotherm associated with solvent loss, DSC also contained an endotherm after mass loss beginning at approximately 180°C.

[0224] Sample 30-4 was isolated as Pattern 6, which persisted after gentle drying, but converted to Pattern 3 when stored at 40°C / 75% RH for 7 days. Both NMR and TGA indicated that 0.5 molar equivalents of MIBK were present in the sample, suggesting that the sample was an MIBK solvate. [Table 33]

[0225] Sample 30-6 was isolated from MEK and showed pattern 7 by XRPD. 1 H NMR is consistent with a solvent content of 0.4 molar equivalents. The material was not stable to static storage at 40° C. / 75% RH for 7 days, converting to pattern 3.

[0226] Sample 30-15 showed a transformation from pattern 9 to pattern 8+3 under ambient drying for 1 day. Interestingly, NMR showed no residual solvent, but TGA showed a 3.6% mass loss between 40 and 145 °C, suggesting the presence of 0.8 molar equivalents of water in the material.

[0227] Example 13 Formation of crystalline pattern 7 from pattern 3 The solvate form, Pattern 7, was obtained from MEK in both screens. The input for these screens was either amorphous or poorly crystalline structure (I). This experiment was performed to determine whether a solvate could be formed under the same conditions using crystalline Pattern 3 as the input material.

[0228] Structure (I) (from lot B, 30 mg) was wetted with MEK (300 μL, 10 volumes) and placed in a shaker at 50° C. for 3 days. A sample was aliquoted for XRPD.

[0229] XRPD of the sample showed that pattern 3 transformed into pattern 7, indicating that solvate formation was favored even when more stable crystalline material was used as input.

[0230] Example 14A Generating Pattern 11 - Method A Pattern 11 was first identified in the VT-XRPD of Pattern 3 (from Lot B) and was formed after dehydration of Pattern 3 to Pattern 10, followed by 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 whether this form could be isolated as a phase-pure material and whether it was stable under ambient conditions.

[0231] Structure (I) (from Lot 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 inside to cool. After cooling for 1 hour, the sample was removed from the oven and analyzed by XRPD (Sample 34-1).

[0232] The sample was found to be pattern 11, free of any other morphology, and was found to be stable at ambient conditions, suggesting that this may be a suitable morphology for further development. [Table 34]

[0233] Example 14B Formation of Pattern 11 - Method B Polymorphic studies of structure (I) were performed at 75°C, 100°C, 175°C, and 250°C. Approximately 500 mg of structure (I), pattern 3, was heated at 75°C for 24 hours in a vacuum tray dryer (VTD) under reduced pressure. The material obtained after heating at 75°C was analyzed for purity by HPLC and XPRD analysis. Results indicated that the sample remained as pattern 3 by XRPD, with no change in HPLC purity. Additionally, approximately 500 mg of structure (I) was heated at 75°C for 24 hours in a VTD under reduced pressure. After 24 hours, the material was cooled to 25-30°C under an inert atmosphere and analyzed for purity by HPLC and XRPD.

[0234] Approximately 500 mg of structure (I) was heated at 100°C in a VTD under reduced pressure for 24 hours. The material obtained after heating at 100°C was analyzed for purity by HPLC and XPRD. The analysis showed that the sample remained as pattern 3 by XRPD, with no change in HPLC purity. Approximately 500 mg of structure (I) was further heated at 100°C in a VTD under reduced pressure for 24 hours. After 24 hours, the material was cooled to 25-30°C under an inert atmosphere. The material obtained was analyzed for purity by HPLC and XPRD.

[0235] Approximately 500 mg of structure (I) was heated at 175°C in a VTD under reduced pressure for 24 hours. The material obtained after heating at 175°C was analyzed for purity by HPLC and XPRD. The analysis showed that the sample was converted to pattern 11 as confirmed by XRPD, and no change in HPLC purity was detected. Approximately 500 mg of structure (I) was further heated at 175°C in a VTD under reduced pressure for 24 hours. After 24 hours, the material was cooled to 25-30°C under an inert atmosphere. The material obtained was analyzed for purity by HPLC and XPRD.

[0236] Approximately 500 mg of structure (I) was heated in a VTD at 250°C for 24 hours. The material obtained after heating at 250°C was analyzed for purity by HPLC and XPRD. The analysis showed that the sample was converted to pattern 11 as confirmed by XRPD. During sample preparation for HPLC analysis, the sample exhibited turbidity in the diluent used for sample preparation (10% DMSO in MeOH).

[0237] The material was tested for DSC studies before proceeding to heating experiments at 250° C. The DSC results showed that no major safety issues were observed up to temperatures of 400° C.

[0238] Approximately 500 mg of structure (I) was heated in a VTD at 250° C. for 24 hours. After 24 hours, the sample was cooled to 25-30° C. under an inert atmosphere. The resulting material was analyzed for purity by HPLC and XPRD analysis.

[0239] Based on the results obtained from 175°C and 250°C (i.e., pattern 11 was obtained and confirmed by XPRD analysis), the polymorphism study was repeated on a 2 g scale to produce seed material of pattern 11 at 175°C.

[0240] Example 15 Pattern 1 formation - ion content analysis Pattern 1 was also observed to form during solubility analysis in pH 2 buffer and in a FaSSGF simulant fluid at pH 1.6. It was hypothesized that the formation of Pattern 1 may indicate the formation of an HCl salt. Pattern 1 was generated by slurrying Pattern 3 in pH 2 buffer.

[0241] Structure (I) (from Lot B, 30 mg) was suspended in pH 2.0 buffer (chloride buffer, 3 mL) and placed on a shaker at room temperature. After 1 day, the sample was filtered and analyzed by XRPD. The sample was resuspended in pH 2.0 buffer (2 mL) and returned to shaking at room temperature for 4 days. The sample was aliquoted and analyzed by XRPD, then filtered and dried under vacuum. After 5 days, the sample was found to be Pattern 1.

[0242] Ion chromatography indicated the presence of 0.49 molar equivalents of chloride. The substoichiometric amount of chloride suggested that only partial salt formation had occurred.

[0243] Pattern 1 was previously obtained from the inverse anti-solvent addition of DMSO to water in the absence of chloride, and was also the form of the input material from Lot A, which did not contain chloride. Therefore, if a chloride salt had been produced in the solubility measurements, it would likely have been amorphous and not detected by XRPD. In this case, it can be concluded that the resulting solid was a mixture of the free base Pattern 1 and the amorphous HCl salt.

[0244] Example 16 Summary of polymorphism evaluation Two polymorphic evaluations were performed on the free base compound of structure (I): one using the poorly crystalline pattern 3 (sample 28-2) as input material, and the second using the 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 antisolvent addition (DMSO to TBME). Finally, pattern 11, identified during VT-XRPD of pattern 3, was generated by heating pattern 3 to 250 °C in an oven.

[0245] 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 / isopropyl acetate, MIBK, and MEK, respectively, suggesting that they are most likely a family of structurally similar solvates. Pattern 8, despite having a similar diffractogram, did not appear to have any solvent present, so it is possible that the voids in these structural families may be occupied by water. Because this structure tends to contain solvent and transforms to pattern 3 under high temperature and humidity, these forms are likely not ideal for pharmaceutical development.

[0246] Pattern 11 appeared to be an anhydrous form with reasonable stability at 40°C / 75% RH, so investigations were carried out to further characterize this form.

[0247] Example 17 Formation and characterization of new crystalline forms Structure (I) (from Lot B, 750 mg) was heated in a 250° C. oven for 1.5 hours. After 1.5 hours, the oven was turned off but the sample was kept in the oven to cool. After cooling for 1 hour, the sample was removed from the oven and analyzed by XRPD.

[0248] Sample 35-1 was characterized using a range of techniques to investigate the solid morphology properties of pattern 11 of structure (I). A summary of the results is shown in Table 35. [Table 35]

[0249] After being grown in an oven at 250° C., the sample was found to be pattern 11 by XRPD. 1H NMR was consistent with the structure and showed no evidence of residual solvent. The measured purity of the material was 97.9%, suggesting that no significant decomposition occurred despite the high temperatures involved in the generation of the morphology (input material purity = 98.1%). The PLM of the material showed to consist of soft aggregates of lath-shaped crystals up to 120 μm in length. The crystals were fractured and not suitable for analysis by single crystal X-ray diffraction.

[0250] TGA showed no mass loss before the onset of decomposition at >300°C, suggesting an anhydrous form. DSC had no obvious events other than a possible change in baseline at 290°C, and no melting was observed up to 350°C. GVS indicated that Pattern 11 was slightly hygroscopic, exhibiting very little hysteresis in the isotherm. The sample remained Pattern 11 after double-cycling experiments, with an extra peak observed at 7.7° 2θ. Samples were stored at elevated temperature and / or humidity for 10 days and were found to be stable in morphology and purity.

[0251] The thermodynamic solubility of Pattern 11 was determined in three simulated media and two buffer solutions. Pattern 11 was found to be virtually insoluble in the media, with the highest solubility in low pH media.

[0252] Characterization data for pattern 11 of structure (I) suggested that it is a solid form that may be suitable for use in pharmaceuticals. It is an anhydrous form that is stable under high humidity conditions and is slightly hygroscopic.

[0253] Example 18 Competitive Slurries and Stability Relationships A solid mixture of Pattern 3 (from Lot B, 300 mg) and Pattern 11 (Sample 35-1, 300 mg) of Structure (I) was mixed for 3 hours using a turbulent mixer.

[0254] The solid mixtures (30 mg) were suspended in solvent (dried over molecular sieves, 600 μL, 20 volumes) and stirred in a refrigerator or shaken at room temperature or 55° C. After 7 days, aliquots of each suspension were analyzed by XRPD. Samples that were still in the form of mixtures were returned to the refrigerator / shaker for an additional 10 days and reanalyzed (results are shown in Table 36).

[0255] The results of the competitive slurries were inconclusive, as one form did not persist over the other in all solvent systems at any temperature. In pure THF and IPA, pattern 11 was obtained after 7 days of slurrying at all temperatures; however, in the case of IPA, additional peaks were present in the XRPD, consistent with those associated with the solvate group represented by patterns 5–9. This suggests that the conversion may have proceeded via solvated forms, and therefore may not inform the relative stability of patterns 3 and 11. When conversion was observed, pattern 3 converted to pattern 11, but conversion of pattern 11 to pattern 3 was not observed. [Table 36]

[0256] To determine that Pattern 3 was not simply dissolving in the solvent system when the solid was introduced, gravimetric solubility measurements were performed using 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 in the solid mixture introduced to each competitive slurry (0.6 mL) was 15 mg; therefore, a solubility of 25 mg / mL would be required to dissolve all of the Pattern 3. There was not enough solubility at room temperature to dissolve the Pattern 3 present in the competitive slurry experiments. [Table 37]

[0257] To minimize dissolution that may occur at temperatures other than room temperature, the competitive slurry experiment at 55°C was repeated along with that at 5°C using saturated solutions as the solvent mixture.

[0258] A saturated solution of structure (I) (from lot B) in THF / water (9:1) (5 mL) was equilibrated overnight in a shaker at 55° C. Prior to use, the solution was filtered using a 0.45 μm nylon filter.

[0259] A 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, and Sample 38-1 was pipetted onto an XRPD holder and allowed to dry prior to analysis (solids that passed through the filter).

[0260] The results of this experiment, in which a saturated solution was used as the slurry medium, are summarized in Table 38. Both experiments yielded a mixture of Pattern 3 and Pattern 11 without any significant change in intensity. This contradicts the first competitive slurry experiment, in which both of these samples yielded Pattern 11. The difference in the experimental results at 55°C may 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 conclusion, the series of competitive slurries does not clearly demonstrate that Pattern 3 and Pattern 11 interconvert or that one form is more stable than the other. [Table 38]

[0261] Example 19 Summary of conditions for obtaining solid forms of patterns 1-11 Polymorphic evaluation was performed from the free form of compound of structure (I). This evaluation involved the preparation of amorphous material followed by two screening studies. The first utilized the poorly crystalline pattern 3 of compound of structure (I) as input material, and the second used amorphous compound of structure (I).

[0262] During this investigation, 11 free form patterns of compound (I) were identified. Pattern 1 was a low-crystalline form. Pattern 2 was observed during three salt screening experiments using material with potassium impurity as input, and the high solvent content in one of the samples suggested it may be a THF solvate. Pattern 3 was a hemihydrate and was the predominant form obtained during both polymorph screening experiments. Pattern 4 was obtained by reverse antisolventization using dimethyl sulfoxide (DMSO) and tert-butyl methyl ether (TBME) and was determined to be a DMSO solvate. Patterns 5–9, isolated from the two polymorph screening experiments, were a series of structurally related solvates. Pattern 10 was a dehydrated form of pattern 3 and was observed only using in situ measurements during VT-XRPD and VAC-XRPD, reverting to pattern 3 under ambient conditions. Pattern 11 was formed by heating pattern 3 (through pattern 10) at temperatures near 250 °C. Pattern 11 was the anhydrous form and was stable at room temperature. The relationships between the observed solid forms are summarized in Figure 6, and each condition is used for the transition as shown below. 1. Cool with tetrahydrofuran (THF):water (9:1) 2. Reverse Antisolvent DMSO / Water 3. Reverse Antisolvent DMSO / TBME 4. 7 days at 40°C and 75% relative humidity 5. Ambient conditions (subject to condition 4 above) 6. Heat at 175°C under vacuum at 50°C 7. Heat at 250℃ 8. Slurry of fasted-state simulated gastric fluid (FaSSGF) and pH 2.0 buffer 9. Dry grinding 10. Slurry in various solvents at 50°C for 7 days at 40°C / 70% relative humidity 11. Slurry in ethyl acetate and isopropyl acetate at 50°C 12. Slurry in methyl isobutyl ketone (MIBK) at 50°C 13. Slurry in methanol at 50°C 14. Slurry in ethanol and acetone at 50°C 15. Slurry in methyl ethyl ketone (MEK) at 50°C 16. Slurry in methanol and acetonitrile at 50°C 17. Slurry in MEK and ethanol at 50°C 18. Ambient conditions

[0263] Of the identified forms of compound of structure (I), Pattern 3 and Pattern 11 possess solid-state properties suitable for pharmaceutical use. Pattern 3 is a hemihydrate with good stability for storage under high-temperature and high-humidity conditions. Despite being hygroscopic (8.4 wt% change from 0 to 90% RH), the solid form was retained after two cycles of GVS experiments. Pattern 11 is an anhydrous form with good stability, but unlike Pattern 3, it is only slightly hygroscopic (0.3 wt% change from 0 to 90% RH). Because Pattern 11 was formed via high-temperature form transformation, it may be necessary to investigate whether it can be obtained via a more scalable solution-based method. Thermodynamic solubility measurements of both forms in simulated media and buffer at 25 °C did not reveal any significant advantage for one form over the other. A comparison of the XRPD patterns is shown in Figure 5.

[0264] Competitive slurries were conducted using mixtures of Pattern 3 and Pattern 11 to determine the stability relationship between the two forms. The results were inconclusive, with some of the slurries remaining as mixtures. The complex relationship between these forms may be the result of both temperature and water activity dependence. Additionally, this project aimed to identify salt forms of Structure (I) with solid-state and physicochemical properties suitable for pharmaceutical use. The solid state forms of the free form were also investigated via polymorphic evaluation to identify forms with properties suitable for end-use products.

[0265] Two lots of material were used in these experiments. Lot A was determined to be free form Pattern 1, which is low crystalline, highly hygroscopic, and has a potassium content of 0.2 molar equivalents. Lot B, characterized by Pattern 3, is a hemihydrate, is hygroscopic, but was found to be crystalline and stable. A single crystal structure of Pattern 3 was collected and is shown in Figures 89-92.

[0266] Measurement of the molecule's pKa shows it to have a basic pKa of 4.73 and an acidic centre of 11.49, and therefore can suitably form salts at both ends of the pH scale.

[0267] Experiments were carried out to isolate salt forms of the compound of structure (I), taking the form of solubility and salt formation evaluations, as well as four salt screens: a standard screen involving 12 common acids, a high temperature screen, a double equivalent screen, and a targeted screen using high purity input material.

[0268] During this investigation, 12 salt forms were identified, along with two free base forms and several unspecified forms. Some of the salts formed had properties undesirable for pharmaceutical use. Some of the most promising candidates (e.g., PHO Pattern 1, MES Pattern 1) were characterized as hydrates, but in each case, water was lost at temperatures approaching ambient conditions, which may result in less stability than desired.

[0269] A polymorphic evaluation of the free form of structure (I) was performed, consisting of two screens with 18 solvents, one performed using the poorly crystalline pattern 3 as input material and the second performed using the amorphous compound of structure (I) as input material.

[0270] During the course of the Examples described herein, eleven free form patterns of compound of structure (I) were identified. Pattern 1 was the low-crystalline form initially observed in the original material. Pattern 2 was observed only during salt screening. Pattern 3 was a hemihydrate and was also the predominant form obtained during both polymorph screenings. Pattern 4 was obtained by inverse antisolventization using DMSO and TBME and was determined to be a DMSO solvate. Patterns 5–9, isolated from the two polymorph screenings, were a series of structurally related solvates. Pattern 10 was a dehydrated form of pattern 3, observed only using in situ measurements during VT-XRPD and VAC-XRPD, and converted back to pattern 3 under ambient conditions. Pattern 11 was formed by heating pattern 3 (through pattern 10) at temperatures near 250°C. Pattern 11 was the anhydrous form and was stable at room temperature.

[0271] Patterns 3 and 11 were free forms with properties suitable for scale-up and further characterization. Pattern 3 was hygroscopic, but this did not affect the solid form retained upon returning from high humidity levels to ambient conditions. Pattern 11 was slightly hygroscopic. Pattern 11 was not accessed via solution-based methods, but Pattern 3 was the product of numerous screening experiments. Thermodynamic solubility data was collected for both forms in simulated fluids and buffer solutions, and results were similar for both forms and therefore could not be used as a differentiating factor. Competitive slurry experiments were conducted in five solvents at three temperatures, but these were ultimately inconclusive. Note, however, that none of the experiments during the cross-seeding experiments yielded phase-pure Pattern 3; all resulted in either a mixture of forms or Pattern 11.

[0272] Example 20 Preparation and Characterization of Lot A and Lot B of Structure (I) Two lots of structure (I) were used in the screening experiments described herein. They were generally prepared as described in WO2023 / 278686. The final step to generate structure (I) was carried out as follows: [ka] To a suspension of Int-A (1 equivalent) in EtOH / THF / HO (2:1:1, v / v / v, 25 volumes), aqueous potassium hydroxide (7.5 equivalents in 1 volume of water) was added dropwise at 25-35°C. 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. Charcoal (20%) was added to the reaction mixture and stirred for 1 hour. The reaction mixture was then filtered through a bed of Celite® and washed with a mixture of EtOH / THF / HO (2 volumes). Siramet thiourea (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 HCl. The mixture was stirred for 1 hour at 0-5°C, and the precipitate was collected by filtration and washed with water. The isolated solid was slurried with purified water (10 volumes x 2) for 30 minutes at 25-30°C. The solid was collected by filtration and washed with water (2 volumes). The solid was collected and dried at 45-50°C for 3 hours to give structure (I).

[0273] Characterization of Lot A of Structure (I) Lot A was prepared as above with a batch size of 6.4 g.

[0274] Lot A was characterized using a variety of techniques, as summarized in Table 39. [Table 39]

[0275] Lot A was determined to be poorly crystalline, with an XRPD pattern consistent with Pattern 1. HPLC showed 97.6% purity, but IC indicated 0.2 molar equivalents of potassium were present in the sample. Lot A was highly hygroscopic, with a maximum mass change of 23.8% from 0 to 90% RH measured during the GVS experiment. The morphology by XRPD did not change during the experiment, nor did it change after 8 days of storage under high temperature and / or high humidity conditions. Pattern 1 of structure (I) is slightly soluble in SGF (0.13 mg / mL) and virtually insoluble in FaSSIF (0.006 mg / mL) and FeSSIF (0.02 mg / mL), according to USP guidance.

[0276] Characterization of Lot B of Structure (I) Lot B was prepared as above with a batch size of 11.8 g, except the pH was adjusted to 8-9 using 1.5 N aqueous HCl.

[0277] Lot B was characterized using a variety of techniques, as summarized in Table 40. [Table 40]

[0278] Two samples from Lot B were determined to be Pattern 3. IC analysis showed that fewer ions were present in these batches than in Lot A, particularly Sample 2 from Lot B, which had only 0.01 molar equivalents of chloride. The solid form and chemical purity remained unchanged when the samples were stored at elevated temperature and humidity.

[0279] Moisture content analysis by KF indicated that the material contained 3.4 wt% water (0.72 molar equivalents of water). This was consistent with the TGA data, which showed a total mass loss of 3.6 wt% from ambient to 265 °C. When the humidity was reduced to 0% during the GVS experiment, a mass loss of 0.8 wt% was observed, suggesting that at least a portion of the water (the remaining 2.6% based on the KF results) was tightly bound and likely part of the crystalline structure rather than surface-bound. Based on these data, the material was assigned to be a hemihydrate.

[0280] The nature of the hydrate was further investigated by vacuum XRPD and variable-temperature XRPD. When placed under vacuum, Lot B (Pattern 3) converted to Pattern 10, likely a dehydrated form of this material. When Pattern 10 was exposed to ambient conditions for 30 minutes, it reverted to Pattern 3. When Pattern 3 was heated to 175°C, Pattern 10 was again observed, consistent with the temperature at which the 3.0% mass loss observed by TGA occurred. When this material was further heated to 250°C, Pattern 10 partially converted to Pattern 11. Pattern 10 of this physical mixture converted to Pattern 3 upon returning to ambient conditions, while Pattern 11 remained unchanged. These experiments suggest that Pattern 3 is a hemihydrate, which can be dehydrated to yield Pattern 10, which then readily rehydrates under ambient conditions. Pattern 11 is formed by heating Pattern 10 to around 250°C, which is seen as an exotherm by DSC, and appears to be stable under ambient conditions.

[0281] 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).

[0282] Example 21 Single-crystal X-ray diffraction analysis of free form Pattern 3 Crystals of structure (I) pattern 3 were obtained by evaporation of a THF:water (9:1) solution. Crystals of structure (I) pattern 3 of sufficient size and quality for analysis by single crystal X-ray diffraction were isolated from a sample of approximate dimensions 0.15 × 0.05 × 0.02 mm.

[0283] The single crystal X-ray structure of Structure (I) Pattern 3 was determined at 293(2)K and a summary of the structural data can be found in Table 41. The crystal structure of Structure (I) Pattern 3 was solved in the triclinic space group P-1 with a final R1[I>2σ(I)]=4.36%. The structure was identified as depicted in Figures 89 and 90, and the asymmetric unit was found to contain two molecules of Structure (I).

[0284] Figures 91 and 92 show the hydrogen-bonding network of pattern 3 of structure (I), with intermolecular hydrogen bonds shown as dashed lines. Figures 93-95 show diagrams of portions of the crystal packing within the unit cell along the crystallographic a-, b-, and c-axes, respectively. For clarity, all hydrogen atoms have been removed from the packing diagrams.

[0285] A simulated XRPD pattern of pattern 3 of structure (I) at (293(2)K) is shown in Figure 96. The overlay in Figure 97 shows a comparison of the experimental diffractogram collected at room temperature with the pattern simulated from the single crystal data at 293K. The patterns were consistent, confirming that the single crystal used for structure determination represented the reference material. The slight differences between the simulated and experimental diffractograms were attributed to preferred orientation. [Table 41]

[0286] Example 22 Water slurry experiments with free form pattern 3 In certain batches of Structure (I) Pattern 3, additional peaks were observed in the XRPD spectrum (see, e.g., Figure 98), and a greater amount of water was measured than expected for a hemihydrate. For consistency, a study was conducted to determine the conditions under which the mixture of forms would convert to only Structure (I) Pattern 3.

[0287] Approximately 10 g of material with additional peaks and increased water content, including Structure (I) Pattern 3 (e.g., as shown in Figure 98), was tested under reprocessing conditions to isolate the initial solid after pH adjustment as follows: An approximately 10 g aliquot of material was dissolved in a mixture of EtOH / THF / HO (2:1:1 / V:V:V, 25 V) and KOH (7.0 equiv.). The reaction 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, after which the solid was collected by filtration and washed with purified water.

[0288] The isolated solid was then divided into two parts (Part 1 and Part 2). The material from Part 1 was dried under vacuum in a VTD at 50°C for 48 hours. The material from Part 2 was subjected to a water slurry at 25-30°C for 1 hour, followed by drying under vacuum in a VTD at 50°C for 48 hours. Samples from Parts 1 and 2 were analyzed for moisture content using XPRD. The material from Part 1 partially conformed to Pattern 3, with a moisture content of 3.1% w / w, while the material from Part 2 was similar to the material before reprocessing, with a moisture content of 4.8% w / w.

[0289] Approximately 2 g of the Part 2 material was subjected to further water slurry using a stir bar at 25-30° C. for 8 hours, followed by drying in a VTD under reduced pressure at 50° C. for 48 hours. The resulting material was analyzed for water content using XRPD and found to have a water content of 2.3% (w / w), consistent with Pattern 3 (Figure 99).

[0290] To confirm the reproducibility of these results, additional experiments were performed on the same material containing Pattern 3 of Structure (I), which had additional peaks and increased water content. The material was not reprocessed as above, but was slurried in water at 25–30°C for 8 hours. One aliquot (5 g) was slurried in water with a stir bar, and another aliquot (5 g) was slurried in water with an overhead stirrer. After slurrying, 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 slurrying with a stir bar was consistent with Pattern 3 and had a water content of 2.8% w / w. The material obtained by slurrying with an overhead stirrer was partially consistent with Pattern 3 and had a water content of 3.6% w / w. When this material was re-slurried in water using an overhead stirrer at 25-30°C for a further 16 hours, a material was obtained that was in perfect agreement with Pattern 3 and had a moisture content of 2.6% w / w.

[0291] Example 23 Characterization study of free form pattern 3 For example, a batch of pattern 3 of structure (I) with additional peaks, as described in Example 22, was further characterized.

[0292] The material containing pattern 3 of structure (I) with additional peaks (e.g., as in Figure 98) was micronized using an air jet mirror targeting D90<20 microns under the following conditions: 6 kg / cm 2 Primary nitrogen pressure of 6 kg / cm 2 A secondary nitrogen pressure of 0.05 wt. sq. m., nitrogen atmosphere, room temperature, a 75 g input weight, and a 62 g output weight after micronization were used. The micronized material was analyzed using XRPD. Only slight changes in the XRPD spectrum were observed; additional peaks were still present. After micronization, a particle size target of D90<20 microns was achieved. Attempts to dry the sample after micronization at 50°C for 24 hours did not result in a change in moisture content.

[0293] The feed material and the jet milled batch from Example 22 were analyzed using variable temperature XRPD. [Table 42]

[0294] The various embodiments described above can be combined to provide further embodiments. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and / or non-patent publications mentioned in this application and / or listed in this application data sheet are incorporated herein by reference in their entirety. If necessary, aspects of the embodiments can be modified to provide still further embodiments using concepts from the various patents, applications, and publications.

[0295] These and other changes can be made to the embodiments in light of the above detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments, along with the full range of equivalents to which such claims are entitled. Accordingly, the claims are not limited by this disclosure.

Claims

1. A compound having the following structure (I): 【Chemistry 12】 or a solid form of a tautomer thereof, wherein said solid form has an X-ray powder diffraction pattern with at least two peaks at 2θ angles selected from the group consisting of 5.6±0.2°, 10.9±0.2°, 18.2±0.2°, and 18.6±0.2°.

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

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

4. The solid form has a refractive index 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° 2. The solid form of claim 1, having an X-ray powder diffraction pattern with peaks at 2θ angles of 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 compound having the following structure (I): 【Chemistry 13】 or a solid form of a tautomer thereof, wherein the solid form has an X-ray powder diffraction pattern substantially in accordance with that depicted in FIG.

6. 6. The solid form of any one of claims 1 to 5, characterized by a differential scanning calorimetry thermogram comprising an endothermic peak with an onset of about 89.5°C.

7. 7. The solid form of any one of claims 1 to 6, characterized by a differential scanning calorimetry thermogram comprising an exothermic peak with an onset of about 213.5°C.

8. 8. The solid form of any one of claims 1 to 7, characterized by a differential scanning calorimetry thermogram substantially in accordance with that depicted in Figure 2.

9. A compound having the following structure (I): 【Chemistry 14】 or a solid form of a tautomer thereof, said solid form being (i) providing N-(6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-imidazo[1,5-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); (iii) isolating said solid form of the compound having structure (I).

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

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

12. A compound having the following structure (I): 【Chemistry 15】 or a solid form of its tautomer, wherein said solid form has an X-ray powder diffraction pattern with at least two peaks at 2θ angles selected from the group consisting of 19.2±0.2°, 19.5±0.2°, and 21.2±0.2°.

13. 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 has the following refractive indices: 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°, 23.7±0.2°, 24.7±0.2°, 25.7±0.2°, 26.7±0.2°, 27.7±0.2°, 28.7±0.2°, 29.7±0.2°, 30.7±0.2°, 31.7±0.2°, 32.7±0.2°, 33.7±0.2°, 34.7±0.2°, 35.7±0.2°, 36.7±0.2°, 37.7±0.2°, 38.7±0.2°, 39.7±0.2°, 40.7±0.2°, 41.7±0.2°, 42.7±0.2°, 43.7±0.2°, 44.7±0.2°, 45.7±0.2°, 46.7±0.2°, 47.7±0.2°, 48.7±0.2°, 49.7±0.2°, 50.7±0.2°, 51.7±0.2°, 52.7±0.2°, 53.7±0 13. The solid form of claim 12, having an X-ray powder diffraction pattern with peaks at 2θ angles of 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 compound having the following structure (I): 【Chemistry 16】 or a solid form of a tautomer thereof, wherein the solid form has an X-ray powder diffraction pattern substantially in accordance with that depicted in FIG.

16. 16. The solid form of any one of claims 12 to 15, characterized by an event-free differential scanning calorimetry thermogram up to about 340°C.

17. 16. The solid form of any one of claims 12 to 15, characterized by a differential scanning calorimetry thermogram substantially in accordance with that depicted in Figure 4.

18. A compound having the following structure (I): 【Chemistry 17】 or a solid form of a tautomer thereof, said solid form being (i) providing a pattern 3 of structure (I); (ii) heating the pattern 3 of structure (I) to about 250° C. under vacuum; (iii) isolating said 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 not solvated.

20. A compound having the following structure (I): [Chemistry 18] or a tautomer thereof, in an amorphous solid form.

21. A compound having the following structure (I): 【Chemistry 19】 or an amorphous solid form of a tautomer thereof, said amorphous form being (i) providing a pattern 3 of structure (I); (ii) ball milling the pattern 3 of structure (I) at a suitable frequency (e.g., 30 Hz) and for a suitable time (e.g., 3 sessions of 90 minutes each); (iii) isolating said amorphous form of the compound having structure (I).

22. A compound having the following structure (I): 【Chemistry 20】 or a crystalline solid form of a tautomer thereof, said crystalline solid form being described in the Examples herein.

23. A compound having the following structure (I): 【Chemistry 21】 or a crystalline solid form of a tautomer thereof, said crystalline solid form being: (i) providing a 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, methyl ethyl ketone, acetone, ethanol, tert-butyl methyl ether, 2-methyl-1-propanol, cyclohexane, methanol, toluene, tetrahydrofuran, acetonitrile, water, dimethyl sulfoxide, or combinations thereof); (iii) isolating said crystalline solid form; A crystalline solid form wherein said process optionally comprises heating or cooling said mixture of structure (I) in a suitable solvent or a solid precipitate isolated therefrom.

24. A compound having the following structure (I): 【Chemistry 22】 or a salt form of a tautomer thereof, said salt form being formed between structure (I) and a co-former selected from 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. 25. The salt form of claim 24, wherein the salt form is described in the Examples herein.

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

27. A compound having the following structure (I): 【Chemistry 23】 or a salt form of its tautomer, said salt form being (i) providing a structure (I); (ii) contacting structure (I) with a co-former selected from 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; (iii) isolating said salt form.

28. A compound having the following structure (I): 【Chemistry 24】 or a solid form of its tautomer (e.g., a crystalline or amorphous form of the free base or a salt form), wherein said solid form is prepared by the process described in the Examples herein.

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

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

31. 30. The pharmaceutical composition of claim 29 in the form of a capsule.

32. 30. The pharmaceutical composition of claim 29 in the form of a tablet.

33. A compound having the following structure (I): 【Chemistry 25】 or a solid form of its tautomer, comprising: (i) providing N-(6-((8″-methyl-1″,5″-dioxo-1″,5″-dihydro-2″H-dispiro[cyclopropane-1,1′-cyclohexane-4′,3″-imidazo[1,5-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); (iii) isolating said solid form of the compound having structure (I).

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

35. A compound having the following structure (I): 【Chemistry 26】 or a solid form of its tautomer, comprising: (i) providing a pattern 3 of structure (I); (ii) heating the pattern 3 of structure (I) to about 250° C. under vacuum; (iii) isolating said solid form of the compound having structure (I).

36. A compound having the following structure (I): 【Chemistry 27】 or a tautomer thereof, comprising: (i) providing a pattern 3 of structure (I); (ii) ball milling the pattern 3 of structure (I) at a suitable frequency (e.g., 30 Hz) and for a suitable time (e.g., 3 sessions of 90 minutes each); (iii) isolating said amorphous form of the compound having structure (I).

37. A compound having the following structure (I): 【Chemistry 28】 or a crystalline form of its tautomer, comprising: (i) providing a 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, methyl ethyl ketone, acetone, ethanol, tert-butyl methyl ether, 2-methyl-1-propanol, cyclohexane, methanol, toluene, tetrahydrofuran, acetonitrile, water, dimethyl sulfoxide, or combinations thereof); (iii) isolating said crystalline solid form; The method optionally comprises the step of heating or cooling said mixture of structure (I) in a suitable solvent or a solid precipitate isolated therefrom.

38. A compound having the following structure (I): 【Chemistry 29】 or a salt form of its tautomer, comprising the steps of: (i) providing a structure (I); (ii) contacting structure (I) with a co-former selected from 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; (iii) isolating said salt form.

39. 32. A method for treating, preventing or alleviating the effects of migraine or symptoms associated with migraine, 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. 32. A method for treating, preventing or alleviating the effects of a disease associated with abnormal MNK activity in a mammal in need thereof, comprising administering to said mammal 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.

41. 32. Treating, preventing, or alleviating the effects of neuropathic pain, lupus, viral infection-induced pain, COVID-19 associated acute respiratory distress syndrome (ARDS), non-alcoholic fatty liver disease (NAFLD), high-fat diet-induced obesity, Alzheimer's disease, or Fragile X syndrome.

33. A method for treating, preventing, or alleviating the effects of neuropathic pain, lupus, viral infection-induced pain, COVID-19 associated acute respiratory distress syndrome (ARDS), non-alcoholic fatty liver disease (NAFLD), high-fat diet-induced obesity, Alzheimer's disease, or Fragile X syndrome in a mammal in need thereof, comprising administering to said mammal 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.

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