Solid dispersion formulations of MNK inhibitors

Abstract

The present disclosure provides amorphous solid dispersion compositions and formulations of MNK inhibitors, as well as uses thereof for the treatment of MNK-associated diseases, disorders, and conditions.

Description

Docket No.: 408994-410WO (219446) SOLID DISPERSION FORMULATIONS OF MNK INHIBITORS CROSS REFERENCE TO RELATED APPICATIONS

[0001] This application claims the benefit of and priority to United States Provisional PatentApplication serial number 63 / 664,411, filed June 26, 2024, and United States Provisional Patent Application serial number 63 / 789,820, filed April 16, 2025, the contents of each of which are hereby incorporated by reference in their entirety. BACKGROUND

[0002] Inadequate treatment of pain is a devastating health problem in the United States. Onethird of all Americans suffer from some form of chronic pain and a third of these have pain that is resistant to current medical therapies. The economic impact of pain is equally large at approximately $100 billion annually. Opioid or narcotic analgesics, typified by morphine, are the most effective treatments for acute and chronic severe pain. However, their clinical utility is often hampered by the development of analgesic tolerance which requires escalating doses to achieve equivalent pain relief. Furthermore, opioids and narcotic analgesics are often ineffective for neuropathic pain treatment, and patients using these drugs often experience worse quality of life due to the resulting drug-induced sedation, reduced physical activity, constipation, respiratory depression, high potential for addiction, and other side effects.

[0003] Inhibitors of mitogen-activated protein kinase interacting protein kinase (MNK) are apromising alternative to opioid and narcotic analgesics for treatment of neuropathic pain and other indications. Neuropathic pain often involves abnormal nociceptor sensitivity. Nociceptor sensitization may be blocked by inhibiting activity-dependent mRNA translation through mechanistic targeting of the mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway signals to the eukaryotic translation initiation factor (eIF) 4E complex to regulate the sensitization of nociceptors. MNKs phosphorylate the eukaryotic translation initiation factor 4E (eIF4E). Inhibition of MNK has been shown to disrupt the MAPK pathway, thereby decreasing sensitization of nociceptors, which may achieve a therapeutic effect on neuropathic pain. Page 1 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) SUMMARY

[0004] The present disclosure provides compositions comprising a MNK inhibitor, as well asuses thereof for the treatment of MNK-associated diseases, disorders, and conditions, such as neuropathic pain and migraine. In some embodiments, provided compositions comprise an amorphous solid dispersion of a MNK inhibitor and one or more excipients. In some embodiments, provided compositions comprise a spray-dried dispersion composition of a MNK inhibitor and one or more excipients. In some embodiments, provided compositions are suitable for oral administration.

[0005] The present disclosure encompasses the recognition that compounds of Formula I,described herein, are challenging to formulate for pharmaceutical use. In particular, compounds of Formula I are poorly soluble in water, which impacts their bioavailability and exposure when administered to a subject. The present disclosure provides a solution to the problem of formulating amorphous solid dispersion compositions of compounds of Formula I (e.g., spray-dried dispersion compositions).

[0006] As described herein, amorphous solid dispersion (e.g., spray-dried dispersion)compositions of a MNK inhibitor (e.g., a MNK inhibitor described herein) impart certain benefits, e.g., relative to an unformulated MNK inhibitor and / or a MNK inhibitor not formulated as an amorphous solid dispersion. For example, amorphous solid dispersion compositions may exhibit greater aqueous solubility, bioavailability, and / or exposure of a MNK inhibitor relative to other types of compositions, any of which may allow for different dosing regimens, e.g., dosing regimens that are more favorable and / or convenient for patients, such as those with a lower dose and / or less frequent administration. Accordingly, amorphous solid dispersion (e.g., spray-dried dispersion compositions) compositions may be better suited for use as a pharmaceutical drug product than other types of formulations. BRIEF DESCRIPTION OF THE DRAWINGS

[0007] FIG. 1 is a graph showing concentration of Compound 2 (“API”) over time forredissolution studies of Formulations 1-5.

[0008] FIG. 2 is a graph showing concentration of Compound 2 (“API”) over time forredissolution studies of Formulations 6-10.

[0009] FIG. 3 is an X-ray powder diffraction (XRPD) spectrum of Formulation 1.Page 2 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446)

[0010] FIG. 4 is an XRPD spectrum of Formulation 9.

[0011] FIG. 5 is a graph showing concentration-time curves of Compound 2 (“API”)formulations in female rats.

[0012] FIG. 6 is a graph showing results of various spray-dried dispersion compositions in atwo-stage dissolution test.

[0013] FIG. 7 is a graph showing results of drug load screening experiments using one- andtwo-stage dissolution tests.

[0014] FIG. 8 is an XRPD spectrum of Formulation 11.

[0015] FIG. 9 is a differential scanning calorimetry (DSC) graph of Formulation 11.DETAILED DESCRIPTION Compounds and Definitions

[0016] Compounds of the present disclosure include those described generally herein, and arefurther illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0017] Unless otherwise indicated, structures depicted herein are meant to include compoundsthat differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including replacement of hydrogen by deuterium or tritium, or replacement of a carbon by13C- or14C-enriched carbon are within the scope of this disclosure.

[0018] The term “aliphatic” refers to a straight-chain (unbranched) or branched, optionallysubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation but which is not aromatic (also referred to herein as “carbocyclic” or “cycloaliphatic”), that has a single point of attachment to the rest of the molecule. Unless Page 3 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) otherwise specified, aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., C1-6). In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C1-5). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C1-4). In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C1-3), and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C1-2). Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof. In some embodiments, “aliphatic” refers to a straight-chain (unbranched) or branched, optionally substituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation that has a single point of attachment to the rest of the molecule.

[0019] The term “alkyl”, used alone or as part of a larger moiety, refers to a saturated,optionally substituted straight or branched hydrocarbon group having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C1-12, C1-10, C1-8, C1-6, C1-4, C1-3, or C1-2). Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.

[0020] The term “about” or “approximately”, when used herein in reference to a value, refersto a value that is similar, in context to the referenced value. In general, those skilled in the art, familiar with the context, will appreciate the relevant degree of variance encompassed by “about” in that context.

[0021] As used herein, the term “administering” or “administration” typically refers toadministration of a composition to a subject to achieve delivery of an active agent to a site of interest (e.g., a target site which may, in some embodiments, be a site of disease or damage, and / or a site of responsive processes, cells, tissues, etc.). As will be understood by those skilled in the art, reading the present disclosure, in some embodiments, one or more particular routes of administration may be feasible and / or useful in the practice of the present disclosure. For example, in some embodiments, administration may be parenteral. In some embodiments, administration may be oral. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve application of a fixed number of doses. In some embodiments, administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and / or periodic (e.g., individual doses separated by a common period of time) dosing. Page 4 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446)

[0022] As used herein, the term “pharmaceutically acceptable polymer” refers to a polymerthat is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and / or other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio.

[0023] As described herein, compounds of the disclosure may contain “optionally substituted”moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasiblecompounds. The term “stable,” as used herein, refers to compounds that are not substantiallyaltered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0024] Suitable monovalent substituents on a substitutable carbon atom of an “optionallysubstituted” group are independently halogen; –(CH2)0–4R^; –(CH2)0–4OR^; -O(CH2)0-4Ro, –O– (CH2)0–4C(O)OR°; –(CH2)0–4CH(OR^)2; –(CH2)0–4SR^; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R^)2; –(CH2)0–4N(R^)C(O)R^; –N(R^)C(S)R^; –(CH2)0– 4N(R^)C(O)NR^2; -N(R^)C(S)NR^2; –(CH2)0–4N(R^)C(O)OR^; – N(R^)N(R^)C(O)R^; -N(R^)N(R^)C(O)NR^2; -N(R^)N(R^)C(O)OR^; –(CH2)0–4C(O)R^; – C(S)R^; –(CH2)0–4C(O)OR^; –(CH2)0–4C(O)SR^; -(CH2)0–4C(O)OSiR^3; –(CH2)0–4OC(O)R^; – OC(O)(CH2)0–4SR°; –(CH2)0–4SC(O)R^; –(CH2)0–4C(O)NR^2; –C(S)NR^2; –C(S)SR°; – SC(S)SR°, -(CH2)0–4OC(O)NR^2; -C(O)N(OR^)R^; –C(O)C(O)R^; –C(O)CH2C(O)R^; –C(NOR^)R^; -(CH2)0–4SSR^; –(CH2)0–4S(O)2R^; –(CH2)0–4S(O)2OR^; –(CH2)0–4OS(O)2R^; –S(O)2NR^2; -(CH2)0–4S(O)R^; -N(R^)S(O)2NR^2; –N(R^)S(O)2R^; –N(OR^)R^; –C(NH)NR^2; – (CH2)0–4P(O)2R^; –(CH2)0–4P(O)R^2; –(CH2)0–4P(O)(OR^)2; –(CH2)0–4OP(O)R^2; –(CH2)0– Page 5 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446)4OP(O)(OR^)2; SiR^3; –(C1–4straight or branched alkylene)O–N(R^)2; or –(C1–4straight or branched alkylene)C(O)O–N(R^)2, wherein each R^ may be substituted as defined below and is independently hydrogen, C1–6aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5-6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^, taken together with their intervening atom(s), form a 3–12– membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0025] Suitable monovalent substituents on R^ (or the ring formed by taking two independentoccurrences of R^ together with their intervening atoms), are independently halogen, –(CH2)0–2R^, –(haloR^), –(CH2)0–2OH, –(CH2)0–2OR^, –(CH2)0–2CH(OR^)2; -O(haloR^), –CN, –N3, –(CH2)0–2C(O)R^, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR^, –(CH2)0–2SR^, –(CH2)0–2SH, –(CH2)0–2NH2, – (CH2)0–2NHR^, –(CH2)0–2NR^2, –NO2, –SiR^3, –OSiR^3, -C(O)SR^,–(C1–4straight or branched alkylene)C(O)OR^, or –SSR^wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4aliphatic, – CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0– 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R^ include =O and =S.

[0026] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted”group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–, or –S(C(R*2))2–3S–, wherein each independent occurrence of R*is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Page 6 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446)

[0027] Suitable substituents on the aliphatic group of R* include halogen, –R^, -(haloR^), -OH,–OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or –NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0028] Suitable substituents on a substitutable nitrogen of an “optionally substituted” groupinclude –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, – C(O)CH2C(O)R†, -S(O)2R†, -S(O)2NR†2, –C(S)NR†2, –C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0029] Suitable substituents on the aliphatic group of R† are independently halogen, –R^, -(haloR^), –OH, –OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or -NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0030] The term “pharmaceutically acceptable salt,” as used herein, refers to a form of arelevant compound as a salt appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and / or other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977).

[0031] As used herein, the term “subject” refers an organism, typically a mammal (e.g., ahuman). In some embodiments, a subject is suffering from a relevant disease, disorder or condition. Page 7 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) In some embodiments, a human subject is an adult, adolescent, or pediatric subject. In some embodiments, a subject is at risk of (e.g., susceptible to), e.g., at elevated risk of relative to an appropriate control individual or population thereof, a disease, disorder, or condition. In some embodiments, a subject displays one or more symptoms or characteristics of a disease, disorder or condition. In some embodiments, a subject does not display any symptom or characteristic of a disease, disorder, or condition. In some embodiments, a subject is someone with one or more features characteristic of susceptibility to or risk of a disease, disorder, or condition. In some embodiments, a subject is an individual to whom diagnosis and / or therapy and / or prophylaxis is and / or has been administered. The terms “subject” and “patient” are used interchangeably herein.

[0032] As used herein, the term “treat” (also “treatment” or “treating”) refers to anyadministration of a therapy that partially or completely alleviates, ameliorates, relieves, inhibits, delays onset of, reduces severity of, and / or reduces incidence of one or more symptoms, features, and / or causes of a particular disease, disorder, and / or condition. In some embodiments, such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and / or condition and / or of a subject who exhibits only early signs of the disease, disorder, and / or condition. Alternatively or additionally, such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and / or condition. In some embodiments, treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and / or condition. MNK Inhibitors

[0033] In some embodiments, MNK inhibitors useful in compositions described herein have astructure of Formula I:or a pharmaceutically acceptable salt thereof, wherein R is halogen or optionally substituted C1-6 aliphatic. Page 8 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446)

[0034] In some embodiments of Formula I, R is halogen or optionally substituted C1-6 alkyl.In some embodiments, R is halogen or C1-6 aliphatic. In some embodiments, R is halogen or C1-6 alkyl. In some embodiments, R is halogen. In some embodiments, R is chloro. In some embodiments, R is optionally substituted C1-6aliphatic. In some embodiments, R is C1-6aliphatic. In some embodiments, R is optionally substituted C1-6 alkyl. In some embodiments, R is C1-6 alkyl. In some embodiments, R is methyl. In some embodiments, R is -CD3.

[0035] In some embodiments, a compound of Formula I is Compound 1, i.e., 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:Compound 1 is a MNK inhibitor described in WO 2023 / 278686, which publication is herein incorporated by reference in its entirety. Compound 1 has been shown to inhibit MNK in various assays described therein. Accordingly, Compound 1 is useful for treating diseases, disorders, or conditions associated with MNK, such as neuropathic pain and migraine. Compound 1 has also been shown to have minimal blood-brain barrier penetration, making it particularly suitable for treating indications that do not require blood-brain barrier penetration for efficacy (e.g., indications where treatment of brain neurons or other brain tissues is not required) and / or for minimizing central nervous system side effects.

[0036] In some embodiments, Compound 1 is provided and / or utilized in accordance with thepresent disclosure in a free base form. In some embodiments, Compound 1 is provided and / or utilized in accordance with the present disclosure in a salt form. Pharmaceutically acceptable salts are well known in the art.

[0037] In some embodiments, Compound 1 is provided and / or utilized in accordance with thepresent disclosure in a hydrate form (e.g., a hemihydrate). Hydrate forms of Compound 1 are described in WO 2024 / 148040, along with other solid forms of Compound 1. Page 9 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446)

[0038] Unless otherwise indicated, as used herein, “Compound 1” refers to Compound 1 inany available form, such as, e.g., a free base form or salt form. It will be understood, therefore, that reference to an amount (e.g., in mg) of Compound 1 means the amount of Compound 1 in free base, unsolvated, form.

[0039] In some embodiments, a compound of Formula I is Compound 2:Compound 2 is a MNK inhibitor described in WO 2023 / 278686 and WO 2023 / 014943. Compound 2 has been shown to inhibit MNK in various assays (see, e.g., WO 2023 / 014943). Accordingly, Compound 2 is useful for treating diseases, disorders, or conditions associated with MNK, such as neuropathic pain and migraine.

[0040] In some embodiments, Compound 2 is provided and / or utilized in accordance with thepresent disclosure in a free base form. In some embodiments, Compound 2 is provided and / or utilized in accordance with the present disclosure in a salt form. Pharmaceutically acceptable salts are well known in the art.

[0041] Unless otherwise indicated, as used herein, “Compound 2” refers to Compound 2 inany available form, such as, e.g., a free base hydrated form or salt form. It will be understood, therefore, that reference to an amount (e.g., in mg) of Compound 2 means the amount of Compound 2 in free base, unsolvated, form.

[0042] In some embodiments, a compound of Formula I is Compound 3:Page 10 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) Compound 3 is a MNK inhibitor, as described in Example 4 herein. Accordingly, Compound 3 is useful for treating diseases, disorders, or conditions associated with MNK, such as neuropathic pain and migraine.

[0043] In some embodiments, Compound 3 is provided and / or utilized in accordance with thepresent disclosure in a free base form. In some embodiments, Compound 3 is provided and / or utilized in accordance with the present disclosure in a salt form. Pharmaceutically acceptable salts are well known in the art.

[0044] Unless otherwise indicated, as used herein, “Compound 3” refers to Compound 3 inany available form, such as, e.g., a free base hydrated form or salt form. It will be understood, therefore, that reference to an amount (e.g., in mg) of Compound 3 means the amount of Compound 3 in free base, unsolvated, form. Provided Compositions

[0045] The present disclosure provides compositions comprising a MNK inhibitor and one ormore pharmaceutically acceptable excipients. In some embodiments, the present disclosure provides compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable polymer; and optionally, a surfactant. In some embodiments, provided compositions are amorphous solid dispersions. In some embodiments, provided compositions are spray-dried dispersions.

[0046] In some embodiments, provided compositions comprise about 10 wt% to about 30 wt%of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 20 wt% to about 30 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 25 wt% to about 30 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 30 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 25 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 20 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 15 wt% of a compound of Formula I, or a pharmaceutically Page 11 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) acceptable salt thereof. In some embodiments, provided compositions comprise about 10 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, provided compositions comprise about 10 wt% to about 30 wt%of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 25 wt% to about 30 wt% of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 30 wt% of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 25 wt% of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 20 wt% of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 15 wt% of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 10 wt% of Compound 1, or a pharmaceutically acceptable salt thereof.

[0048] In some embodiments, provided compositions comprise about 10 wt% to about 30 wt%of Compound 1. In some embodiments, provided compositions comprise about 25 wt% to about 30 wt% of Compound 1. In some embodiments, provided compositions comprise about 30 wt% of Compound 1. In some embodiments, provided compositions comprise about 25 wt% of Compound 1. In some embodiments, provided compositions comprise about 20 wt% of Compound 1. In some embodiments, provided compositions comprise about 15 wt% of Compound 1. In some embodiments, provided compositions comprise about 10 wt% of Compound 1.

[0049] In some embodiments, provided compositions comprise about 10 wt% to about 30 wt%of Compound 2, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 25 wt% to about 30 wt% of Compound 2, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 30 wt% of Compound 2, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 25 wt% of Compound 2, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 20 wt% of Compound 2, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 15 wt% of Compound 2, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 10 wt% of Compound 2, or a pharmaceutically acceptable salt thereof. Page 12 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446)

[0050] In some embodiments, provided compositions comprise about 10 wt% to about 30 wt%of Compound 2. In some embodiments, provided compositions comprise about 25 wt% to about 30 wt% of Compound 2. In some embodiments, provided compositions comprise about 30 wt% of Compound 2. In some embodiments, provided compositions comprise about 25 wt% of Compound 2. In some embodiments, provided compositions comprise about 20 wt% of Compound 2. In some embodiments, provided compositions comprise about 15 wt% of Compound 2. In some embodiments, provided compositions comprise about 10 wt% of Compound 2.

[0051] In some embodiments, provided compositions comprise about 10 wt% to about 30 wt%of Compound 3, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 25 wt% to about 30 wt% of Compound 3, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 30 wt% of Compound 3, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 25 wt% of Compound 3, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 20 wt% of Compound 3, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 15 wt% of Compound 3, or a pharmaceutically acceptable salt thereof. In some embodiments, provided compositions comprise about 10 wt% of Compound 3, or a pharmaceutically acceptable salt thereof.

[0052] In some embodiments, provided compositions comprise about 10 wt% to about 30 wt%of Compound 3. In some embodiments, provided compositions comprise about 25 wt% to about 30 wt% of Compound 3. In some embodiments, provided compositions comprise about 30 wt% of Compound 3. In some embodiments, provided compositions comprise about 25 wt% of Compound 3. In some embodiments, provided compositions comprise about 20 wt% of Compound 3. In some embodiments, provided compositions comprise about 15 wt% of Compound 3. In some embodiments, provided compositions comprise about 10 wt% of Compound 3.

[0053] In some embodiments, provided compositions comprise a pharmaceutically acceptablepolymer, wherein the polymer is or comprises hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose ether, hydroxypropyl cellulose, an amino methacrylate copolymer, a methacrylic acid copolymer, a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer, or combinations thereof. Page 13 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446)

[0054] In some embodiments, provided compositions comprise a pharmaceutically acceptablepolymer, wherein the polymer is or comprises hydroxypropyl methylcellulose (HPMC). In some embodiments, a pharmaceutically acceptable polymer is selected from hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose ether, and combinations thereof. In some embodiments, a pharmaceutically acceptable polymer is selected from HPMC-P55, HPMCAS-H, HPMC E5, HPC SSL, HPMCAS- L, and combinations thereof.

[0055] In some embodiments, a pharmaceutically acceptable polymer is or compriseshydroxypropyl methylcellulose phthalate (HPMCP). In some embodiments, a pharmaceutically acceptable polymer is or comprises HPMC-P55. Hydroxypropyl methylcellulose phthalate is also referred to as hypromellose phthalate and is identified by CAS No. 9050-31-1. HPMCP is a cellulose in which some of the hydroxy groups are replaced with methyl ethers, 2-hydroxypropyl ethers, or phthalyl esters. Different types of HPMCP are commercially available with molecular weights in the range of 20,000-200,000, but typical average values are 80,000-130,000. Various grades of HPMCP are available with differing degrees of substitution and physical properties. The grades are usually denoted as “HP” followed by a number, wherein the number refers to the pH value x 10 at which the polymer dissolves in aqueous buffer solutions. For example, HP-55 (or “HPMC-P55”) refers to hydroxypropyl methylcellulose phthalate that dissolves in aqueous buffer at pH 5.5. HP-55 has an approximate molecular weight of 78,000 and an approximate hydroxypropoxy content of 5-9%, methoxy content of 18-22%, and phthalyl content of 27-35%.

[0056] In some embodiments, a pharmaceutically acceptable polymer is or compriseshydroxypropyl methylcellulose acetate succinate (HPMCAS or HPMC-AS). In some embodiments, a pharmaceutically acceptable polymer is or comprises HPMCAS-H, HPMCAS-L, or HPMCAS-M. In some embodiments, a pharmaceutically acceptable polymer is or comprises HPMCAS-H. In some embodiments, a pharmaceutically acceptable polymer is or comprises HPMCAS-L. In some embodiments, a pharmaceutically acceptable polymer is or comprises HPMCAS-M. HPMCAS is a cellulose in which some of the hydroxy groups are replaced with methyl ethers, 2-hydroxypropyl ethers, succinoyl esters, or acetyl esters. Different types of HPMCAS are available, each dissolving at different pH levels. Type L (HPMCAS-L) contains a high ratio of succinoyl substitution to acetyl substitution (S / A ratio), type M (HPMC-ASM) contains a middle or near equal S / A ratio, and type H (HPMCAS-H) contains a low S / A ratio. Type Page 14 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) L dissolves at a lower pH (≥ 5.5), type M dissolves around pH 6-6.5, and type H dissolves at a higher pH (≥ 6.8).

[0057] In some embodiments, a pharmaceutically acceptable polymer is or compriseshydroxypropyl methylcellulose ether (HPMC E). In some embodiments, a pharmaceutically acceptable polymer is or comprises HPMC E5. HPMC E5 is also identified by CAS No.9004-65- 3. In some embodiments, a pharmaceutically acceptable polymer is or comprises HPMC E3.

[0058] In some embodiments, a pharmaceutically acceptable polymer is or compriseshydroxypropyl cellulose. In some embodiments, a pharmaceutically acceptable polymer is or comprises HPC SSL. HPC SSL is a low-viscosity hydroxypropyl cellulose polymer.

[0059] In some embodiments, a pharmaceutically acceptable polymer is or comprises anamino methacrylate copolymer (e.g., poly(butylmethacrylate-co-(2-dimethylamino) ethyl methacrylate-co-methyl methacrylate, or a copolymer of (2-dimethylaminoethyl) methacrylate, butyl methacrylate, and methyl methacrylate). In some embodiments, a pharmaceutically acceptable polymer is or comprises Eudragit EPO.

[0060] In some embodiments, a pharmaceutically acceptable polymer is or comprises amethacrylic acid copolymer (e.g., a methacrylic acid copolymer type C). In some embodiments, a methacrylic acid copolymer is poly(methacrylic acid, ethyl acrylate) or a copolymer of methacrylic acid and ethyl acrylate. In some embodiments, the copolymer is in about a 1:1 ratio. In some embodiments, a pharmaceutically acceptable polymer is or comprises Eudragit L100-55.

[0061] In some embodiments, a pharmaceutically acceptable polymer is or comprises apolyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer (e.g., in about a 57:30:13 ratio). In some embodiments, a pharmaceutically acceptable polymer is or comprises Soluplus.

[0062] In some embodiments, provided compositions comprise about 60 wt% to about 90 wt%pharmaceutically acceptable polymer. In some embodiments, provided compositions comprise about 70 wt% to about 90 wt% pharmaceutically acceptable polymer. In some embodiments, provided compositions comprise about 70 wt% to about 80 wt% pharmaceutically acceptable polymer. In some embodiments, provided compositions comprise about 90 wt% pharmaceutically acceptable polymer. In some embodiments, provided compositions comprise about 85 wt% pharmaceutically acceptable polymer. In some embodiments, provided compositions comprise about 80 wt% pharmaceutically acceptable polymer. In some embodiments, provided Page 15 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) compositions comprise about 75 wt% pharmaceutically acceptable polymer. In some embodiments, provided compositions comprise about 70 wt% pharmaceutically acceptable polymer. In some embodiments, provided compositions comprise about 65 wt% pharmaceutically acceptable polymer. In some embodiments, provided compositions comprise about 60 wt% pharmaceutically acceptable polymer.

[0063] In some embodiments, provided compositions comprise a surfactant. In someembodiments, a surfactant is selected from TPGS, Kolliphor RH40, sodium lauryl sulfate, poloxamer 407, poloxamer 188, and combinations thereof.

[0064] In some embodiments, a surfactant is α-tocopherol polyethylene glycol succinate(TPGS).

[0065] In some embodiments, a surfactant is Kolliphor RH40 (polyoxyl 40 hydrogenatedcastor oil). Kolliphor RH40 comprises a hydrophobic portion made up of glycerol polyethylene glycol hydroxystearate and fatty acid glycerl polyglycol esters, and a hydrophilic portion made up of polyethylene glycols and glycerol ethoxylate. Kolliphor RH40 is obtained by reacting about 1 mole of hydrogenated castor oil with about 40 moles of ethylene oxide.

[0066] In some embodiments, a surfactant is sodium lauryl sulfate (SLS).

[0067] In some embodiments, a surfactant is a poloxamer. In some embodiments, a surfactantis poloxamer 407. In some embodiments, a surfactant is poloxamer 188. Poloxamers are typically block copolymers comprising a hydrophobic chain of polyoxypropylene (e.g., polypropylene glycol, PPG, and / or poly(propylene oxide), PPO) flanked by two hydrophilic chains of polyoxyethylene (e.g., polyethylene glycol, PEG, and / or poly(ethylene oxide), PEO). Poloxamers are known by the trade names Synperonic, Pluronic, and / or Kolliphor. Poloxamers are commonly named with the letter P (for poloxamer) followed by three digits: the first two digits multiplied by 100 give the approximate molecular mass of the polyoxypropylene chain, and the last digit multiplied by 10 gives the percentage polyoxyethylene content.

[0068] In some embodiments, provided compositions comprise about 0 wt% to about 10 wt%surfactant. In some embodiments, provided compositions comprise about 0 wt% to about 5 wt% surfactant. In some embodiments, provided compositions comprise about 1 wt% to about 10 wt% surfactant. In some embodiments, provided compositions comprise about 1 wt% to about 5 wt% surfactant. In some embodiments, provided compositions comprise about 10 wt% surfactant. In some embodiments, provided compositions comprise about 7.5 wt% surfactant. In some Page 16 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) embodiments, provided compositions comprise about 5 wt% surfactant. In some embodiments, provided compositions comprise about 2.5 wt% surfactant. In some embodiments, provided compositions comprise about 1 wt% surfactant. In some embodiments, provided compositions comprise no surfactant.

[0069] In some embodiments, provided compositions comprise:about 10 wt% to about 30 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof; and about 70 wt% to about 90 wt% pharmaceutically acceptable polymer.

[0070] In some embodiments, provided compositions comprise:about 10 wt% to about 30 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof; about 70 wt% to about 90 wt% pharmaceutically acceptable polymer; and about 0 wt% to about 5 wt% surfactant.

[0071] In some embodiments, provided compositions comprise:about 10 wt% to about 30 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof; and about 70 wt% to about 90 wt% hydroxypropyl methylcellulose phthalate.

[0072] In some embodiments, provided compositions comprise:about 10 wt% to about 30 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof; about 70 wt% to about 90 wt% hydroxypropyl methylcellulose phthalate; and about 0 wt% to about 5 wt% poloxamer.

[0073] In some embodiments, provided compositions comprise:about 10 wt% to about 30 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof; and about 70 wt% to about 90 wt% HPMC-P55.

[0074] In some embodiments, provided compositions comprise:about 10 wt% to about 30 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof; about 70 wt% to about 90 wt% HPMC-P55; and about 0 wt% to about 5 wt% poloxamer 407. Page 17 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446)

[0075] In some embodiments, the present disclosure provides a composition comprising:about 30 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof; and about 70 wt% hydroxypropyl methylcellulose phthalate .

[0076] In some embodiments, the present disclosure provides a composition comprising:about 30 wt% of Compound 1, or a pharmaceutically acceptable salt thereof; and about 70 wt% hydroxypropyl methylcellulose phthalate.

[0077] In some embodiments, the present disclosure provides a composition comprising:about 30 wt% of Compound 2, or a pharmaceutically acceptable salt thereof; and about 70 wt% hydroxypropyl methylcellulose phthalate.

[0078] In some embodiments, the present disclosure provides a composition comprising:about 30 wt% of Compound 3, or a pharmaceutically acceptable salt thereof; and about 70 wt% hydroxypropyl methylcellulose phthalate.

[0079] In some embodiments, the present disclosure provides a composition comprising:about 25 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof; about 70 wt% hydroxypropyl methylcellulose phthalate; and about 5 wt% poloxamer.

[0080] In some embodiments, the present disclosure provides a composition comprising:about 25 wt% of Compound 1, or a pharmaceutically acceptable salt thereof; about 70 wt% hydroxypropyl methylcellulose phthalate; and about 5 wt% poloxamer.

[0081] In some embodiments, the present disclosure provides a composition comprising:about 25 wt% of Compound 2, or a pharmaceutically acceptable salt thereof; about 70 wt% hydroxypropyl methylcellulose phthalate; and about 5 wt% poloxamer.

[0082] In some embodiments, the present disclosure provides a composition comprising:about 25 wt% of Compound 3, or a pharmaceutically acceptable salt thereof; about 70 wt% hydroxypropyl methylcellulose phthalate; and about 5 wt% poloxamer.

[0083] In some embodiments, the present disclosure provides a composition comprising:Page 18 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) about 30 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof; and about 70 wt% HPMC-P55.

[0084] In some embodiments, the present disclosure provides a composition comprising:about 30 wt% of Compound 1, or a pharmaceutically acceptable salt thereof; and about 70 wt% HPMC-P55.

[0085] In some embodiments, the present disclosure provides a composition comprising:about 30 wt% of Compound 2, or a pharmaceutically acceptable salt thereof; and about 70 wt% HPMC-P55.

[0086] In some embodiments, the present disclosure provides a composition comprising:about 30 wt% of Compound 3, or a pharmaceutically acceptable salt thereof; and about 70 wt% HPMC-P55.

[0087] In some embodiments, the present disclosure provides a composition comprising:about 25 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof; about 70 wt% HPMC-P55; and about 5 wt% poloxamer 407.

[0088] In some embodiments, the present disclosure provides a composition comprising:about 25 wt% of Compound 1, or a pharmaceutically acceptable salt thereof; about 70 wt% HPMC-P55; and about 5 wt% poloxamer 407.

[0089] In some embodiments, the present disclosure provides a composition comprising:about 25 wt% of Compound 2, or a pharmaceutically acceptable salt thereof; about 70 wt% HPMC-P55; and about 5 wt% poloxamer 407.

[0090] In some embodiments, the present disclosure provides a composition comprising:about 25 wt% of Compound 3, or a pharmaceutically acceptable salt thereof; about 70 wt% HPMC-P55; and about 5 wt% poloxamer 407.

[0091] In some embodiments, the present disclosure provides a composition comprising:about 20 wt% to about 30 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof; and Page 19 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) about 70 wt% to about 80 wt% of a pharmaceutically acceptable polymer.

[0092] In some embodiments, the present disclosure provides a composition comprising:about 20 wt% to about 30 wt% of Compound 1, or a pharmaceutically acceptable salt thereof; and about 70 wt% to about 80 wt% of a pharmaceutically acceptable polymer.

[0093] In some embodiments, the present disclosure provides a composition comprising:about 20 wt% to about 30 wt% of Compound 2, or a pharmaceutically acceptable salt thereof; and about 70 wt% to about 80 wt% of a pharmaceutically acceptable polymer.

[0094] In some embodiments, the present disclosure provides a composition comprising:about 20 wt% to about 30 wt% of Compound 3, or a pharmaceutically acceptable salt thereof; and about 70 wt% to about 80 wt% of a pharmaceutically acceptable polymer.

[0095] In some embodiments, the present disclosure provides a composition comprising:about 20 wt% to about 30 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof; and about 70 wt% to about 80 wt% of a pharmaceutically acceptable polymer that is or comprises hydroxypropyl methylcellulose acetate succinate.

[0096] In some embodiments, the present disclosure provides a composition comprising:about 20 wt% to about 30 wt% of Compound 1, or a pharmaceutically acceptable salt thereof; and about 70 wt% to about 80 wt% of a pharmaceutically acceptable polymer that is or comprises hydroxypropyl methylcellulose acetate succinate.

[0097] In some embodiments, the present disclosure provides a composition comprising:about 20 wt% to about 30 wt% of Compound 2, or a pharmaceutically acceptable salt thereof; and about 70 wt% to about 80 wt% of a pharmaceutically acceptable polymer that is or comprises hydroxypropyl methylcellulose acetate succinate.

[0098] In some embodiments, the present disclosure provides a composition comprising:about 20 wt% to about 30 wt% of Compound 3, or a pharmaceutically acceptable salt thereof; and Page 20 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) about 70 wt% to about 80 wt% of a pharmaceutically acceptable polymer that is or comprises hydroxypropyl methylcellulose acetate succinate.

[0099] In some embodiments, the present disclosure provides a composition comprising:about 20 wt% to about 30 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof; and about 70 wt% to about 80 wt% of a pharmaceutically acceptable polymer that is or comprises HPMC-ASH.

[0100] In some embodiments, the present disclosure provides a composition comprising:about 20 wt% to about 30 wt% of Compound 1, or a pharmaceutically acceptable salt thereof; and about 70 wt% to about 80 wt% of a pharmaceutically acceptable polymer that is or comprises HPMC-ASH.

[0101] In some embodiments, the present disclosure provides a composition comprising:about 20 wt% to about 30 wt% of Compound 2, or a pharmaceutically acceptable salt thereof; and about 70 wt% to about 80 wt% of a pharmaceutically acceptable polymer that is or comprises HPMC-ASH.

[0102] In some embodiments, the present disclosure provides a composition comprising:about 20 wt% to about 30 wt% of Compound 3, or a pharmaceutically acceptable salt thereof; and about 70 wt% to about 80 wt% of a pharmaceutically acceptable polymer that is or comprises HPMC-ASH.

[0103] In some embodiments, the present disclosure provides a composition comprising:about 25 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof; and about 75 wt% of a pharmaceutically acceptable polymer.

[0104] In some embodiments, the present disclosure provides a composition comprising:about 25 wt% of Compound 1, or a pharmaceutically acceptable salt thereof; and about 75 wt% of a pharmaceutically acceptable polymer.

[0105] In some embodiments, the present disclosure provides a composition comprising:about 25 wt% of Compound 2, or a pharmaceutically acceptable salt thereof; and Page 21 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) about 75 wt% of a pharmaceutically acceptable polymer.

[0106] In some embodiments, the present disclosure provides a composition comprising:about 25 wt% of Compound 3, or a pharmaceutically acceptable salt thereof; and about 75 wt% of a pharmaceutically acceptable polymer.

[0107] In some embodiments, the present disclosure provides a composition comprising:about 25 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof; and about 75 wt% of a pharmaceutically acceptable polymer that is or comprises hydroxypropyl methylcellulose acetate succinate.

[0108] In some embodiments, the present disclosure provides a composition comprising:about 25 wt% of Compound 1, or a pharmaceutically acceptable salt thereof; and about 75 wt% of a pharmaceutically acceptable polymer that is or comprises hydroxypropyl methylcellulose acetate succinate.

[0109] In some embodiments, the present disclosure provides a composition comprising:about 25 wt% of Compound 2, or a pharmaceutically acceptable salt thereof; and about 75 wt% of a pharmaceutically acceptable polymer that is or comprises hydroxypropyl methylcellulose acetate succinate.

[0110] In some embodiments, the present disclosure provides a composition comprising:about 25 wt% of Compound 3, or a pharmaceutically acceptable salt thereof; and about 75 wt% of a pharmaceutically acceptable polymer that is or comprises hydroxypropyl methylcellulose acetate succinate.

[0111] In some embodiments, the present disclosure provides a composition comprising:about 25 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof; and about 75 wt% of a pharmaceutically acceptable polymer that is or comprises HPMC-ASH.

[0112] In some embodiments, the present disclosure provides a composition comprising:about 25 wt% of Compound 1, or a pharmaceutically acceptable salt thereof; and about 75 wt% of a pharmaceutically acceptable polymer that is or comprises HPMC-ASH.

[0113] In some embodiments, the present disclosure provides a composition comprising:about 25 wt% of Compound 2, or a pharmaceutically acceptable salt thereof; and about 75 wt% of a pharmaceutically acceptable polymer that is or comprises HPMC-ASH. Page 22 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446)

[0114] In some embodiments, the present disclosure provides a composition comprising:about 25 wt% of Compound 3, or a pharmaceutically acceptable salt thereof; and about 75 wt% of a pharmaceutically acceptable polymer that is or comprises HPMC-ASH.

[0115] In some embodiments, the present disclosure provides a composition selected fromthose described in the Examples section herein.

[0116] In some embodiments, provided compositions are an amorphous solid dispersion. Insome embodiments, provided compositions are a spray-dried dispersion.

[0117] In some embodiments, provided compositions are lyophilized.

[0118] In addition to methods described in the ensuing Examples, it will be appreciated bypersons skilled in the art that other methods of obtaining amorphous solid dispersions are known and applicable to the claimed compositions. In some embodiments, provided compositions are coprecipitated amorphous dispersions (e.g., such as those described in Strotman et al., “Coprecipitated Amorphous Dispersions as Drug Substance: Opportunities and Challenges” Org. Process Res. Dev., 2022, 26, 10-13; Shah et al., “Improved Human Bioavailability of Vemurafenib, a Practically Insoluble Drug, Using an Amorphous Polymer-Stabilized Solid Dispersion Prepared by a Solvent-Controlled Coprecipitation Process” Journal of Pharmaceutical Sciences, Vol. 102, No.3, March 2013, pp.967-981). In some such embodiments, a solution containing a provided compound described herein (e.g., Compound 1, 2, or 3) and an additional agent (e.g., a polymer) is rapidly mixed with antisolvent in a high-shear environment leading to precipitation of amorphous particles. In some embodiments, the additional agent is a polymer that imparts beneficial properties to the resulting material, e.g., by stabilizing the amorphous form of a provided compound (e.g., Compound 1, 2, or 3) within the composition. One of skill in the art would be aware of the various means of achieving a coprecipitated amorphous dispersion using techniques known in the art.

[0119] In some embodiments, provided compositions are amorphous (e.g., when measured byXRPD).

[0120] In some embodiments, provide compositions are achieved via hot melt extrusion.

[0121] In some embodiments, provided compositions display one or more desirablecharacteristics, such as increased aqueous solubility, bioavailability, and / or exposure.

[0122] In some embodiments, the present disclosure provides a composition comprising acompound of Formula I, or a pharmaceutically acceptable salt thereof; a pharmaceutically Page 23 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) acceptable polymer; and optionally, a surfactant (e.g., a composition described herein), wherein when about 1 mg of the composition is reconstituted in about 1 mL phosphate buffer (pH 6.8) (e.g., as described in Example 1), the concentration of the compound of Formula I is at least 5 µg / mL. In some embodiments, when about 1 mg of a provided composition is reconstituted in about 1 mL phosphate buffer (pH 6.8) (e.g., as described in Example 1), the concentration of the compound of Formula I is at least 10 µg / mL. In some embodiments, when about 1 mg of a provided composition is reconstituted in about 1 mL phosphate buffer (pH 6.8) (e.g., as described in Example 1), the concentration of the compound of Formula I is at least 15 µg / mL. In some embodiments, when about 1 mg of a provided composition is reconstituted in about 1 mL phosphate buffer (pH 6.8) (e.g., as described in Example 1), the concentration of the compound of Formula I is at least 20 µg / mL.

[0123] In some embodiments, the present disclosure provides a composition comprising acompound of Formula I, or a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable polymer; and optionally, a surfactant (e.g., a composition described herein), wherein when the composition is orally administered to rats, it achieves an increased AUC exposure, compared to a formulation comprising the compound of Formula (I) in 0.5% HPMC / H2O and 0.1 N HCl (pH 5) (e.g., as described in Example 3). In some embodiments, when a provided composition is orally administered to rats, it achieves at least about 3 times greater AUC exposure, compared to a formulation comprising the compound of Formula (I) in 0.5% HPMC / H2O and 0.1 N HCl (pH 5). In some embodiments, when a provided composition is orally administered to rats, it achieves at least about 2 times greater AUC exposure, compared to a formulation comprising the compound of Formula (I) in 0.5% HPMC / H2O and 0.1 N HCl (pH 5).

[0124] In some embodiments, the present disclosure provides a composition comprising acompound of Formula I, or a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable polymer; and optionally, a surfactant (e.g., a composition described herein), wherein when the composition is orally administered to rats, it achieves an increased Cmax, compared to a formulation comprising the compound of Formula (I) in 0.5% HPMC / H2O and 0.1 N HCl (pH 5) (e.g., as described in Example 3). In some embodiments, when a provided composition is orally administered to rats, it achieves at least about 1.5 times greater Cmax, compared to a formulation comprising the compound of Formula (I) in 0.5% HPMC / H2O and 0.1 N HCl (pH 5). In some Page 24 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) embodiments, when a provided composition is orally administered to rats, it achieves at least about 1.2 times greater Cmax, compared to a formulation comprising the compound of Formula (I) in 0.5% HPMC / H2O and 0.1 N HCl (pH 5).

[0125] In some embodiments, the present disclosure provides a composition comprising acompound of Formula I, or a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable polymer; and optionally, a surfactant (e.g., a composition described herein), wherein when the composition is orally administered to rats, it achieves an increased oral bioavailability, compared to a formulation comprising the compound of Formula (I) in 0.5% HPMC / H2O and 0.1 N HCl (pH 5) (e.g., as described in Example 3). In some embodiments, when the composition is orally administered to rats, it achieves at least about 2.5 times greater oral bioavailability, compared to a formulation comprising the compound of Formula (I) in 0.5% HPMC / H2O and 0.1 N HCl (pH 5). In some embodiments, when the composition is orally administered to rats, it achieves at least about 2 times greater oral bioavailability, compared to a formulation comprising the compound of Formula (I) in 0.5% HPMC / H2O and 0.1 N HCl (pH 5).

[0126] In some embodiments, the present disclosure provides a composition comprising acompound of Formula I, or a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable polymer; and optionally, a surfactant (e.g., a composition described herein), wherein when the composition is orally administered to rats, it achieves an earlier Tmax, compared to a formulation comprising the compound of Formula (I) in 0.5% HPMC / H2O and 0.1 N HCl (pH 5) (e.g., as described in Example 3). In some embodiments, when the composition is orally administered to rats, it achieves at least about 3 hours earlier Tmax, compared to a formulation comprising the compound of Formula (I) in 0.5% HPMC / H2O and 0.1 N HCl (pH 5). In some embodiments, when the composition is orally administered to rats, it achieves at least about 2 hours earlier Tmax, compared to a formulation comprising the compound of Formula (I) in 0.5% HPMC / H2O and 0.1 N HCl (pH 5).

[0127] In some embodiments, the present disclosure provides a composition comprising acompound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable polymer (e.g., a composition described herein), wherein when about 9 mg of the composition is mixed in about 1.5 mL 0.01M HCl and about 3.0 mL of modified fasted simulated intestinal fluid at 37 °C (e.g., as described in Example 5), the concentration of the compound of Formula I is at least 0.015 mg / mL. In some embodiments, when about 9 mg of a provided Page 25 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) composition is mixed in about 1.5 mL 0.01M HCl and about 3.0 mL of modified fasted simulated intestinal fluid at 37 °C (e.g., as described in Example 5), the concentration of the compound of Formula I is at least 0.020 mg / mL. In some embodiments, when about 9 mg of a provided composition is mixed in about 1.5 mL 0.01M HCl and about 3.0 mL of modified fasted simulated intestinal fluid at 37 °C (e.g., as described in Example 5), the concentration of the compound of Formula I is at least 0.040 mg / mL. In some embodiments, when about 9 mg of a provided composition is mixed in about 1.5 mL 0.01M HCl and about 3.0 mL of modified fasted simulated intestinal fluid at 37 °C (e.g., as described in Example 5), the concentration of the compound of Formula I is at least 0.050 mg / mL.

[0128] In some embodiments, provided compositions are formulated for oral administration(e.g., as a tablet or a capsule). In some embodiments, the present disclosure provides a tablet comprising a provided composition. In some embodiments, the present disclosure provides a capsule (e.g., a HPMC or gelatin capsule) comprising a provided composition. In some embodiments, a tablet or capsule comprising a provided composition also comprises one or more pharmaceutically acceptable excipients, such as fillers, disintegrants, lubricants, glidants, anti- adherents, anti-statics, flow agents, and / or binders, etc. It will be appreciated that when a tablet or capsule comprises a provided composition and one or more other components, the weight percentages for the compound of Formula I, pharmaceutically acceptable polymer, and optional surfactant described herein are relative to the provided composition itself, not relative to the total weight of the tablet or capsule.

[0129] In some embodiments, provided compositions are reconstituted in phosphate-bufferedsaline (pH 6.8) before administration. Spray-dried Dispersion Compositions

[0130] In some embodiments, the present disclosure provides spray-dried dispersioncompositions comprising a MNK inhibitor and one or more pharmaceutically acceptable excipients. In some embodiments, the present disclosure provides spray-dried dispersion compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable polymer.

[0131] In some embodiments, provided spray-dried dispersion compositions comprise about10 wt% to about 30 wt% of a compound of Formula I, or a pharmaceutically acceptable salt Page 26 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) thereof. In some embodiments, provided spray-dried dispersion compositions comprise about 20 wt% to about 30 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray-dried dispersion compositions comprise about 20 wt% to about 25 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray-dried dispersion compositions comprise about 25 wt% to about 30 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray-dried dispersion compositions comprise about 30 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray-dried dispersion compositions comprise about 25 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray-dried dispersion compositions comprise about 20 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray-dried dispersion compositions comprise about 15 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray-dried dispersion compositions comprise about 10 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0132] In some embodiments, provided spray-dried dispersion compositions comprise about10 wt% to about 30 wt% of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray-dried dispersion compositions comprise about 20 wt% to about 30 wt% of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray-dried dispersion compositions comprise about 20 wt% to about 25 wt% of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray- dried dispersion compositions comprise about 25 wt% to about 30 wt% of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray-dried dispersion compositions comprise about 30 wt% of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray-dried dispersion compositions comprise about 25 wt% of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray-dried dispersion compositions comprise about 20 wt% of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray-dried dispersion compositions comprise about 15 wt% of Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray-dried dispersion compositions comprise about 10 wt% of Compound 1, or a pharmaceutically acceptable salt thereof. Page 27 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446)

[0133] In some embodiments, provided spray-dried dispersion compositions comprise about10 wt% to about 30 wt% of Compound 1. In some embodiments, provided spray-dried dispersion compositions comprise about 20 wt% to about 30 wt% of Compound 1. In some embodiments, provided spray-dried dispersion compositions comprise about 20 wt% to about 25 wt% of Compound 1. In some embodiments, provided spray-dried dispersion compositions comprise about 25 wt% to about 30 wt% of Compound 1. In some embodiments, provided spray-dried dispersion compositions comprise about 30 wt% of Compound 1. In some embodiments, provided spray-dried dispersion compositions comprise about 25 wt% of Compound 1. In some embodiments, provided spray-dried dispersion compositions comprise about 20 wt% of Compound 1. In some embodiments, provided spray-dried dispersion compositions comprise about 15 wt% of Compound 1. In some embodiments, provided spray-dried dispersion compositions comprise about 10 wt% of Compound 1.

[0134] In some embodiments, provided spray-dried dispersion compositions comprise about10 wt% to about 30 wt% of Compound 2, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray-dried dispersion compositions comprise about 20 wt% to about 30 wt% of Compound 2, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray-dried dispersion compositions comprise about 20 wt% to about 25 wt% of Compound 2, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray- dried dispersion compositions comprise about 25 wt% to about 30 wt% of Compound 2, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray-dried dispersion compositions comprise about 30 wt% of Compound 2, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray-dried dispersion compositions comprise about 25 wt% of Compound 2, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray-dried dispersion compositions comprise about 20 wt% of Compound 2, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray-dried dispersion compositions comprise about 15 wt% of Compound 2, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray-dried dispersion compositions comprise about 10 wt% of Compound 2, or a pharmaceutically acceptable salt thereof.

[0135] In some embodiments, provided spray-dried dispersion compositions comprise about10 wt% to about 30 wt% of Compound 2. In some embodiments, provided spray-dried dispersion compositions comprise about 20 wt% to about 30 wt% of Compound 2. In some embodiments, Page 28 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) provided spray-dried dispersion compositions comprise about 20 wt% to about 25 wt% of Compound 2. In some embodiments, provided spray-dried dispersion compositions comprise about 25 wt% to about 30 wt% of Compound 2. In some embodiments, provided spray-dried dispersion compositions comprise about 30 wt% of Compound 2. In some embodiments, provided spray-dried dispersion compositions comprise about 25 wt% of Compound 2. In some embodiments, provided spray-dried dispersion compositions comprise about 20 wt% of Compound 2. In some embodiments, provided spray-dried dispersion compositions comprise about 15 wt% of Compound 2. In some embodiments, provided spray-dried dispersion compositions comprise about 10 wt% of Compound 2.

[0136] In some embodiments, provided spray-dried dispersion compositions comprise about10 wt% to about 30 wt% of Compound 3, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray-dried dispersion compositions comprise about 20 wt% to about 30 wt% of Compound 3, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray-dried dispersion compositions comprise about 20 wt% to about 25 wt% of Compound 3, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray- dried dispersion compositions comprise about 25 wt% to about 30 wt% of Compound 3, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray-dried dispersion compositions comprise about 30 wt% of Compound 3, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray-dried dispersion compositions comprise about 25 wt% of Compound 3, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray-dried dispersion compositions comprise about 20 wt% of Compound 3, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray-dried dispersion compositions comprise about 15 wt% of Compound 3, or a pharmaceutically acceptable salt thereof. In some embodiments, provided spray-dried dispersion compositions comprise about 10 wt% of Compound 3, or a pharmaceutically acceptable salt thereof.

[0137] In some embodiments, provided spray-dried dispersion compositions comprise about10 wt% to about 30 wt% of Compound 3. In some embodiments, provided spray-dried dispersion compositions comprise about 20 wt% to about 30 wt% of Compound 3. In some embodiments, provided spray-dried dispersion compositions comprise about 20 wt% to about 25 wt% of Compound 3. In some embodiments, provided spray-dried dispersion compositions comprise about 25 wt% to about 30 wt% of Compound 3. In some embodiments, provided spray-dried Page 29 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) dispersion compositions comprise about 30 wt% of Compound 3. In some embodiments, provided spray-dried dispersion compositions comprise about 25 wt% of Compound 3. In some embodiments, provided spray-dried dispersion compositions comprise about 20 wt% of Compound 3. In some embodiments, provided spray-dried dispersion compositions comprise about 15 wt% of Compound 3. In some embodiments, provided spray-dried dispersion compositions comprise about 10 wt% of Compound 3.

[0138] In some embodiments, provided spray-dried dispersion compositions comprise apharmaceutically acceptable polymer, wherein the polymer is or comprises hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose ether, an amino methacrylate copolymer, a methacrylic acid copolymer, a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer, or combinations thereof. In some embodiments, provided spray-dried dispersion compositions comprise a pharmaceutically acceptable polymer, wherein the polymer is or comprises hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose ether, an amino methacrylate copolymer, a methacrylic acid copolymer, a polyvinyl caprolactam- polyvinyl acetate-polyethylene glycol graft co-polymer, hydroxypropyl methylcellulose phthalate, or combinations thereof.

[0139] In some embodiments, provided spray-dried dispersion compositions comprise apharmaceutically acceptable polymer, wherein the polymer is or comprises hydroxypropyl methylcellulose (HPMC). In some embodiments, a pharmaceutically acceptable polymer is selected from hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose ether, and combinations thereof.

[0140] In some embodiments, a pharmaceutically acceptable polymer is or compriseshydroxypropyl methylcellulose acetate succinate (HPMCAS or HPMC-AS). In some embodiments, a pharmaceutically acceptable polymer is or comprises HPMC-ASH, HPMC-ASL, or HPMC-ASM. In some embodiments, a pharmaceutically acceptable polymer is or comprises HPMC-ASH. In some embodiments, a pharmaceutically acceptable polymer is or comprises HPMC-ASL. In some embodiments, a pharmaceutically acceptable polymer is or comprises HPMC-ASM. HPMC-AS is a cellulose in which some of the hydroxy groups are replaced with methyl ethers, 2-hydroxypropyl ethers, succinoyl esters, or acetyl esters. Different types of HPMC- AS are available, each dissolving at different pH levels. Type L (HPMC-ASL) contains a high ratio of succinoyl substitution to acetyl substitution (S / A ratio), type M (HPMC-ASM) contains a Page 30 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) middle or near equal S / A ratio, and type H (HPMC-ASH) contains a low S / A ratio. Type L dissolves around pH 5.5-6, type M dissolves around pH 6-6.5, and type H dissolves at pH ≥ 6.8.

[0141] In some embodiments, a pharmaceutically acceptable polymer is or compriseshydroxypropyl methylcellulose ether (HPMC E). In some embodiments, a pharmaceutically acceptable polymer is or comprises HPMC E3.

[0142] In some embodiments, a pharmaceutically acceptable polymer is or comprises anamino methacrylate copolymer (e.g., poly(butylmethacrylate-co-(2-dimethylamino) ethyl methacrylate-co-methyl methacrylate, or a copolymer of (2-dimethylaminoethyl) methacrylate, butyl methacrylate, and methyl methacrylate). In some embodiments, a pharmaceutically acceptable polymer is or comprises Eudragit EPO.

[0143] In some embodiments, a pharmaceutically acceptable polymer is or comprises amethacrylic acid copolymer (e.g., a methacrylic acid copolymer type C). In some embodiments, a methacrylic acid copolymer is poly(methacrylic acid, ethyl acrylate) or a copolymer of methacrylic acid and ethyl acrylate. In some embodiments, the copolymer is in about a 1:1 ratio. In some embodiments, a pharmaceutically acceptable polymer is or comprises Eudragit L100-55.

[0144] In some embodiments, a pharmaceutically acceptable polymer is or comprises apolyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer (e.g., in about a 57:30:13 ratio). In some embodiments, a pharmaceutically acceptable polymer is or comprises Soluplus.

[0145] In some embodiments, a pharmaceutically acceptable polymer is or compriseshydroxypropyl methylcellulose phthalate (HPMCP). In some embodiments, a pharmaceutically acceptable polymer is or comprises HPMC-P55.

[0146] In some embodiments, provided spray-dried dispersion compositions comprise about60 wt% to about 90 wt% pharmaceutically acceptable polymer. In some embodiments, provided spray-dried dispersion compositions comprise about 70 wt% to about 90 wt% pharmaceutically acceptable polymer. In some embodiments, provided spray-dried dispersion compositions comprise about 70 wt% to about 80 wt% pharmaceutically acceptable polymer. In some embodiments, provided spray-dried dispersion compositions comprise about 90 wt% pharmaceutically acceptable polymer. In some embodiments, provided spray-dried dispersion compositions comprise about 85 wt% pharmaceutically acceptable polymer. In some embodiments, provided spray-dried dispersion compositions comprise about 80 wt% Page 31 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) pharmaceutically acceptable polymer. In some embodiments, provided spray-dried dispersion compositions comprise about 75 wt% pharmaceutically acceptable polymer. In some embodiments, provided spray-dried dispersion compositions comprise about 70 wt% pharmaceutically acceptable polymer. In some embodiments, provided spray-dried dispersion compositions comprise about 65 wt% pharmaceutically acceptable polymer. In some embodiments, provided spray-dried dispersion compositions comprise about 60 wt% pharmaceutically acceptable polymer.

[0147] In some embodiments, provided spray-dried dispersion compositions comprise:about 10 wt% to about 30 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof; and about 70 wt% to about 90 wt% of a pharmaceutically acceptable polymer.

[0148] In some embodiments, provided spray-dried dispersion compositions comprise:about 10 wt% to about 30 wt% of Compound 1, or a pharmaceutically acceptable salt thereof; and about 70 wt% to about 90 wt% of a pharmaceutically acceptable polymer.

[0149] In some embodiments, provided spray-dried dispersion compositions comprise:about 10 wt% to about 30 wt% of Compound 2, or a pharmaceutically acceptable salt thereof; and about 70 wt% to about 90 wt% of a pharmaceutically acceptable polymer.

[0150] In some embodiments, provided spray-dried dispersion compositions comprise:about 10 wt% to about 30 wt% of Compound 3, or a pharmaceutically acceptable salt thereof; and about 70 wt% to about 90 wt% of a pharmaceutically acceptable polymer.

[0151] In some embodiments, provided spray-dried dispersion compositions comprise:about 20 wt% to about 30 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof; and about 70 wt% to about 80 wt % of a pharmaceutically acceptable polymer.

[0152] In some embodiments, provided spray-dried dispersion compositions comprise:about 20 wt% to about 30 wt% of Compound 1, or a pharmaceutically acceptable salt thereof; and about 70 wt% to about 80 wt% of a pharmaceutically acceptable polymer. Page 32 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446)

[0153] In some embodiments, provided spray-dried dispersion compositions comprise:about 20 wt% to about 30 wt% of Compound 2, or a pharmaceutically acceptable salt thereof; and about 70 wt% to about 80 wt% of a pharmaceutically acceptable polymer.

[0154] In some embodiments, provided spray-dried dispersion compositions comprise:about 20 wt% to about 30 wt% of Compound 3, or a pharmaceutically acceptable salt thereof; and about 70 wt% to about 80 wt% of a pharmaceutically acceptable polymer.

[0155] In some embodiments, provided spray-dried dispersion compositions comprise:about 20 wt% to about 30 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof; and about 70 wt% to about 80 wt% of a pharmaceutically acceptable polymer that is or comprises hydroxypropyl methylcellulose acetate succinate.

[0156] In some embodiments, provided spray-dried dispersion compositions comprise:about 20 wt% to about 30 wt% of Compound 1, or a pharmaceutically acceptable salt thereof; and about 70 wt% to about 80 wt% of a pharmaceutically acceptable polymer that is or comprises hydroxypropyl methylcellulose acetate succinate.

[0157] In some embodiments, provided spray-dried dispersion compositions comprise:about 20 wt% to about 30 wt% of Compound 2, or a pharmaceutically acceptable salt thereof; and about 70 wt% to about 80 wt% of a pharmaceutically acceptable polymer that is or comprises hydroxypropyl methylcellulose acetate succinate.

[0158] In some embodiments, provided spray-dried dispersion compositions comprise:about 20 wt% to about 30 wt% of Compound 3, or a pharmaceutically acceptable salt thereof; and about 70 wt% to about 80 wt% of a pharmaceutically acceptable polymer that is or comprises hydroxypropyl methylcellulose acetate succinate.

[0159] In some embodiments, provided spray-dried dispersion compositions comprise:about 20 wt% to about 30 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof; and Page 33 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) about 70 wt% to about 80 wt% of a pharmaceutically acceptable polymer that is or comprises HPMC-ASH.

[0160] In some embodiments, provided spray-dried dispersion compositions comprise:about 20 wt% to about 30 wt% of Compound 1, or a pharmaceutically acceptable salt thereof; and about 70 wt% to about 80 wt% of a pharmaceutically acceptable polymer that is or comprises HPMC-ASH.

[0161] In some embodiments, provided spray-dried dispersion compositions comprise:about 20 wt% to about 30 wt% of Compound 2, or a pharmaceutically acceptable salt thereof; and about 70 wt% to about 80 wt% of a pharmaceutically acceptable polymer that is or comprises HPMC-ASH.

[0162] In some embodiments, provided spray-dried dispersion compositions comprise:about 20 wt% to about 30 wt% of Compound 3, or a pharmaceutically acceptable salt thereof; and about 70 wt% to about 80 wt% of a pharmaceutically acceptable polymer that is or comprises HPMC-ASH.

[0163] In some embodiments, provided spray-dried dispersion compositions comprise:about 25 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof; and about 75 wt% of a pharmaceutically acceptable polymer.

[0164] In some embodiments, provided spray-dried dispersion compositions comprise:about 25 wt% of Compound 1, or a pharmaceutically acceptable salt thereof; and about 75 wt% of a pharmaceutically acceptable polymer.

[0165] In some embodiments, provided spray-dried dispersion compositions comprise:about 25 wt% of Compound 2, or a pharmaceutically acceptable salt thereof; and about 75 wt% of a pharmaceutically acceptable polymer.

[0166] In some embodiments, provided spray-dried dispersion compositions comprise:about 25 wt% of Compound 3, or a pharmaceutically acceptable salt thereof; and about 75 wt% of a pharmaceutically acceptable polymer.

[0167] In some embodiments, provided spray-dried dispersion compositions comprise:Page 34 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) about 25 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof; and about 75 wt% of a pharmaceutically acceptable polymer that is or comprises hydroxypropyl methylcellulose acetate succinate.

[0168] In some embodiments, provided spray-dried dispersion compositions comprise:about 25 wt% of Compound 1, or a pharmaceutically acceptable salt thereof; and about 75 wt% of a pharmaceutically acceptable polymer that is or comprises hydroxypropyl methylcellulose acetate succinate.

[0169] In some embodiments, provided spray-dried dispersion compositions comprise:about 25 wt% of Compound 2, or a pharmaceutically acceptable salt thereof; and about 75 wt% of a pharmaceutically acceptable polymer that is or comprises hydroxypropyl methylcellulose acetate succinate.

[0170] In some embodiments, provided spray-dried dispersion compositions comprise:about 25 wt% of Compound 3, or a pharmaceutically acceptable salt thereof; and about 75 wt% of a pharmaceutically acceptable polymer that is or comprises hydroxypropyl methylcellulose acetate succinate.

[0171] In some embodiments, provided spray-dried dispersion compositions comprise:about 25 wt% of a compound of Formula I, or a pharmaceutically acceptable salt thereof; and about 75 wt% of a pharmaceutically acceptable polymer that is or comprises HPMC-ASH.

[0172] In some embodiments, provided spray-dried dispersion compositions comprise:about 25 wt% of Compound 1, or a pharmaceutically acceptable salt thereof; and about 75 wt% of a pharmaceutically acceptable polymer that is or comprises HPMC-ASH.

[0173] In some embodiments, provided spray-dried dispersion compositions comprise:about 25 wt% of Compound 2, or a pharmaceutically acceptable salt thereof; and about 75 wt% of a pharmaceutically acceptable polymer that is or comprises HPMC-ASH.

[0174] In some embodiments, provided spray-dried dispersion compositions comprise:about 25 wt% of Compound 3, or a pharmaceutically acceptable salt thereof; and about 75 wt% of a pharmaceutically acceptable polymer that is or comprises HPMC-ASH.

[0175] In some embodiments, the present disclosure provides a spray-dried dispersioncomposition selected from those described in the Examples section herein. Page 35 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446)

[0176] In some embodiments, provided spray-dried dispersion compositions display one ormore desirable characteristics, such as increased aqueous solubility, bioavailability, and / or exposure.

[0177] In some embodiments, the present disclosure provides a spray-dried dispersioncomposition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable polymer (e.g., a spray-dried dispersion composition described herein), wherein when about 9 mg of the composition is mixed in about 1.5 mL 0.01M HCl and about 3.0 mL of modified fasted simulated intestinal fluid at 37 °C (e.g., as described in Example 5), the concentration of the compound of Formula I is at least 0.015 mg / mL. In some embodiments, when about 9 mg of a provided spray-dried dispersion composition is mixed in about 1.5 mL 0.01M HCl and about 3.0 mL of modified fasted simulated intestinal fluid at 37 °C (e.g., as described in Example 5), the concentration of the compound of Formula I is at least 0.020 mg / mL. In some embodiments, when about 9 mg of a provided spray-dried dispersion composition is mixed in about 1.5 mL 0.01M HCl and about 3.0 mL of modified fasted simulated intestinal fluid at 37 °C (e.g., as described in Example 5), the concentration of the compound of Formula I is at least 0.040 mg / mL. In some embodiments, when about 9 mg of a provided spray-dried dispersion composition is mixed in about 1.5 mL 0.01M HCl and about 3.0 mL of modified fasted simulated intestinal fluid at 37 °C (e.g., as described in Example 5), the concentration of the compound of Formula I is at least 0.050 mg / mL.

[0178] In some embodiments, provided spray-dried dispersion compositions are formulatedfor oral administration (e.g., as a tablet or a capsule). In some embodiments, the present disclosure provides a tablet comprising a provided spray-dried dispersion composition. In some embodiments, the present disclosure provides a capsule (e.g., a HPMC or gelatin capsule) comprising a provided spray-dried dispersion composition. In some embodiments, a tablet or capsule comprising a provided spray-dried dispersion composition also comprises one or more pharmaceutically acceptable excipients, such as fillers, disintegrants, lubricants, glidants, anti- adherents, anti-statics, flow agents, and / or binders, etc. It will be appreciated that when a tablet or capsule comprises a provided spray-dried dispersion composition and one or more other components, the weight percentages for the compound of Formula I and pharmaceutically acceptable polymers described herein are relative to the provided spray-dried dispersion composition itself, not relative to the total weight of the tablet or capsule. Page 36 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) Methods of Preparing Provided Compositions

[0179] The present disclosure also provides methods of preparing compositions comprising aMNK inhibitor (e.g., a compound of Formula I, or a pharmaceutically acceptable salt thereof) and one or more pharmaceutically acceptable excipients. In some embodiments, the present disclosure provides methods of preparing compositions provided herein.

[0180] In some embodiments, the present disclosure provides a method of preparing aprovided composition, the method comprising: (i) mixing a compound of Formula I (e.g., Compound 1, Compound 2, or Compound 3) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer, and optionally a surfactant in a suitable solvent; and (ii) removing the solvent, to provide the composition. In some embodiments, removing the solvent comprises heating the mixture (e.g., to about 45 °C), optionally under vacuum. In some embodiments, a suitable solvent is tetrahydrofuran (THF), ethanol, water, or a combination thereof. In some embodiments, a suitable solvent is a mixture of THF and water (e.g., in a 9:1 ratio). In some embodiments, a suitable solvent is a mixture of THF, ethanol, and water (e.g., in a 85:15:5 ratio).

[0181] In some embodiments, the present disclosure provides a composition prepared by amethod described herein.

[0182] In some embodiments, the present disclosure provides a composition prepared by: (i)mixing a compound of Formula I (e.g., Compound 1, Compound 2, or Compound 3) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer, and optionally a surfactant in a suitable solvent; and (ii) removing the solvent. In some embodiments, removing the solvent comprises heating the mixture (e.g., to about 45 °C), optionally under vacuum. In some embodiments, a suitable solvent is tetrahydrofuran (THF), ethanol, water, or a combination thereof. In some embodiments, a suitable solvent is a mixture of THF and water (e.g., in a 9:1 ratio). In some embodiments, a suitable solvent is a mixture of THF, ethanol, and water (e.g., in a 85:15:5 ratio).

[0183] In some embodiments, the present disclosure provides a method of preparing aprovided spray-dried dispersion composition, the method comprising: (i) mixing a compound of Formula I (e.g., Compound 1, Compound 2, or Compound 3) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable polymer (e.g., as described herein) in a solvent to form Page 37 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) a mixture; and (ii) spray drying the mixture, to provide the composition. In some embodiments, a suitable solvent is tetrahydrofuran (THF), water, or a combination thereof. In some embodiments, a suitable solvent is a mixture of THF and water (e.g., in a 9:1 ratio (v / v)). In some embodiments, the mixture comprises about 0.5% to about 5% solid content (w / w) (i.e., about 0.5% to about 5% solid relative to solvent). In some embodiments, the mixture comprises about 2% solid content (w / w). In some embodiments, the method further comprises a step of secondary drying (e.g., at 50 °C for, e.g., 3 days).

[0184] In some embodiments, a step of spray drying a mixture comprises atomization of themixture, e.g., by forcing the mixture through a nozzle under suitable conditions. In some embodiments, a nozzle comprises an inlet and an outlet. In some embodiments, a step of spray drying comprises applying heat to the mixture as it enters the nozzle. In some embodiments, a step of spray drying comprises heating the inlet to a temperature that is greater than the boiling point of the solvent. In some embodiments, a step of spray drying comprises heating the inlet to a temperature of about 100 °C to about 150 °C. In some embodiments, a step of spray drying comprises heating the inlet to a temperature of about 125 °C. In some embodiments, a step of spray drying comprises heating the outlet to a temperature of about 50 °C to about 70 °C. In some embodiments, a step of spray drying comprises heating the outlet to a temperature of about 60 °C. In some embodiments, a step of spray drying a mixture comprises forcing the mixture through a nozzle using pressurized gas. In some such embodiments, the gas pressure (e.g., the atomization gas pressure) is about 1.25 bar to about 1.75 bar. In some embodiments, the gas pressure (e.g., the atomization gas pressure) is about 1.5 bar. In some embodiments, a step of spray drying a mixture comprises forcing the mixture through a nozzle at a spray rate of about 6.5 kg / h.

[0185] In some embodiments, the present disclosure provides a spray-dried dispersioncomposition prepared by a method described herein.

[0186] In some embodiments, the present disclosure provides a spray-dried dispersioncomposition prepared by: (i) mixing a compound of Formula I (e.g., Compound 1, Compound 2, or Compound 3) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable polymer (e.g., as described herein) in a solvent; and (ii) spray drying the mixture, to provide the composition. In some embodiments, a suitable solvent is tetrahydrofuran (THF), water, or a combination thereof. In some embodiments, a suitable solvent is a mixture of THF and water (e.g., in a 9:1 ratio). In some embodiments, the mixture comprises about 0.5% to about 5% solid content Page 38 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) (w / w) (i.e., about 0.5% to about 5% solid relative to solvent). In some embodiments, the mixture comprises about 2% solid content (w / w). In some embodiments, the method further comprises a step of secondary drying (e.g., at 50 °C for, e.g., 3 days). In some embodiments, a step of spray drying a mixture comprises atomization of the mixture, e.g., by forcing the mixture through a nozzle under suitable conditions. In some embodiments, a nozzle comprises an inlet and an outlet. In some embodiments, a step of spray drying comprises applying heat to the mixture as it enters the nozzle. In some embodiments, a step of spray drying comprises heating the inlet to a temperature that is greater than the boiling point of the solvent. In some embodiments, a step of spray drying comprises heating the inlet to a temperature of about 100 °C to about 150 °C. In some embodiments, a step of spray drying comprises heating the inlet to a temperature of about 125 °C. In some embodiments, a step of spray drying comprises heating the outlet to a temperature of about 50 °C to about 70 °C. In some embodiments, a step of spray drying comprises heating the outlet to a temperature of about 60 °C. In some embodiments, a step of spray drying a mixture comprises forcing the mixture through a nozzle using pressurized gas. In some such embodiments, the gas pressure (e.g., the atomization gas pressure) is about 1.25 bar to about 1.75 bar. In some embodiments, the gas pressure (e.g., the atomization gas pressure) is about 1.5 bar. In some embodiments, a step of spray drying a mixture comprises forcing the mixture through a nozzle at a spray rate of about 6.5 kg / h. Uses

[0187] The present disclosure also encompasses uses of provided compositions. In someembodiments, provided compositions are useful in methods of treating MNK-associated diseases, disorders, or conditions.

[0188] In some embodiments, the present disclosure provides methods of administeringprovided compositions to a subject in need thereof. In some embodiments, the present disclosure provides methods of administering provided compositions to a subject suffering from or susceptible to a disease, disorder, or condition associated with MNK.

[0189] In some embodiments, the present disclosure provides methods of treating a disease,disorder, or condition associated with MNK, comprising administering a provided composition to a subject in need thereof. In some embodiments, the present disclosure provides methods of Page 39 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) treating a disease, disorder, or condition, comprising administering a provided composition to a subject in need thereof.

[0190] In some embodiments, the present disclosure provides a method of treating a subject inneed thereof, comprising administering to the subject a provided composition, wherein the subject is suffering from or susceptible to a disease, disorder, or condition associated with MNK. In some embodiments, the present disclosure provides a method of treating a subject in need thereof, comprising administering to the subject a provided composition, wherein the subject is suffering from or susceptible to a disease, disorder, or condition selected from migraine, rheumatoid arthritis, neuropathic pain, post-surgical pain, chronic lower back pain, pain associated with rheumatoid arthritis, and pain associated with osteoarthritis. In some embodiments, the provided composition is in the form of a tablet or capsule.

[0191] In some embodiments, the present disclosure provides a composition for use in treatinga subject suffering from or susceptible to a disease, disorder, or condition associated with MNK. In some embodiments, the present disclosure provides a composition for use in treating a subject suffering from or susceptible to a disease, disorder, or condition selected from migraine, rheumatoid arthritis, neuropathic pain, post-surgical pain, chronic lower back pain, pain associated with rheumatoid arthritis, and pain associated with osteoarthritis. In some embodiments, the provided composition is in the form of a tablet or capsule.

[0192] In some embodiments, the present disclosure provides the use of a composition in themanufacture of a medicament for treating a subject suffering from or susceptible to a disease, disorder, or condition associated with MNK. In some embodiments, the present disclosure provides the use of a composition in the manufacture of a medicament for treating a subject suffering from or susceptible to a disease, disorder, or condition selected from migraine, rheumatoid arthritis, neuropathic pain, post-surgical pain, chronic lower back pain, pain associated with rheumatoid arthritis, and pain associated with osteoarthritis. In some embodiments, the provided composition is in the form of a tablet or capsule.

[0193] Exemplary such methods and uses are described further below and herein.

[0194] In some embodiments, provided methods are for treating pain. For instance, in someembodiments, the present disclosure provides a method of treating pain selected from chronic lower back pain, pain associated with rheumatoid arthritis, pain associated with osteoarthritis, and Page 40 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) post-surgical pain, the method comprising administering a provided composition to a subject in need thereof.

[0195] In some embodiments, provided methods are for treating neuropathic pain. In someembodiments, the present disclosure provides a method of treating neuropathic pain, the method comprising administering a provided composition to a subject in need thereof.

[0196] Neuropathic pain typically develops over time and may benefit from therapies thatinterfere with pathways involved in its development and / or continuation. Disease or damage causing neuropathic pain may affect the central nervous system (CNS), the peripheral nervous system, or both (as opposed to causes of nociceptive pain, which affect the peripheral nervous system only). 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-related neuropathies, nutritional deficiencies, toxins, remote manifestations of malignancies, immune mediated disorders, physical trauma to a nerve trunk such as during surgery, peripheral ischemia, peripheral nerve lesions, nerve compression, chemotherapy or other drug-induced nerve damage, radiation injury, arthritis, autoimmune disease, and infection in an area near the affected nerves. In certain embodiments, the neuropathic pain is diabetic peripheral neuropathy. In certain embodiments, the neuropathic pain is chemotherapy-induced peripheral neuropathy.

[0197] Neuropathic pain often involves abnormal nociceptor sensitivity. Nociceptors arespecialized neurons that detect pain. Nociceptor sensitivity is not fixed; it can change over time. Some causes of neuropathic pain affect nociceptor sensitivity by inducing “peripheral sensitization.” Peripheral sensitization includes spontaneous pathological activity, abnormal excitability, heightened sensitivity to chemical stimuli, heightened sensitivity to thermal stimuli, heightened sensitivity to mechanical stimuli, and any combinations of these. Disruption of peripheral sensitization, either by reducing or preventing such peripheral sensitization in the first place or by reducing the degree of already-developed peripheral sensitization, may therefore treat neuropathic pain. Although the disclosure is not limited to one mechanism of action, MNK inhibitors as disclosed herein (e.g., compounds of Formula I) may disrupt peripheral sensitization.

[0198] MNKs phosphorylate the eukaryotic translation initiation factor 4E (eIF4E). MNKsare a subfamily of Ser / Thr kinases, phylogenetically considered Ca2+ / calmodulin-dependent kinases (CaMKs). MNKs are activated through phosphorylation by the growth factor-stimulated Page 41 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) Ras / extracellular signal-regulated kinase pathway and the stress-induced p38 pathway. Nociceptor sensitization may be blocked by inhibiting activity-dependent mRNA translation through mechanistic targeting of the mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway signal to the eukaryotic translation initiation factor (eIF) 4E complex to regulate the sensitization of nociceptors.

[0199] In some embodiments, provided methods are for treating migraine. In someembodiments, the present disclosure provides a method of treating migraine, the method comprising administering a provided composition to a subject in need thereof.

[0200] In some embodiments, provided methods are for treating rheumatoid arthritis. In someembodiments, the present disclosure provides a method of treating rheumatoid arthritis, the method comprising administering a provided composition to a subject in need thereof.

[0201] In some embodiments, provided methods are for treating or preventing pain associatedwith rheumatoid arthritis. In some embodiments, the present disclosure provides a method of treating or preventing pain associated with rheumatoid arthritis, the method comprising administering a provided composition to a subject in need thereof.

[0202] In some embodiments, provided methods are for treating a disease, disorder, orcondition selected from viral infection-induced pain, lupus, COVID-19-related acute respiratory distress syndrome (ARDS), Alzheimer's disease, Huntingdon’s disease, high fat-induced obesity, non-alcoholic fatty liver disease (NAFLD), and Fragile X syndrome. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition selected from viral infection-induced pain, lupus, COVID-19-related acute respiratory distress syndrome (ARDS), Alzheimer's disease, Huntingdon’s disease, high fat-induced obesity, non-alcoholic fatty liver disease (NAFLD), and Fragile X syndrome, the method comprising administering a provided composition to a subject in need thereof.

[0203] In some embodiments, provided compositions are formulated in a unit dosage form forease of administration and uniformity of dosage. The expression “unit dosage form” as used herein refers to a physically discrete unit of an active agent (e.g., a compound of Formula I) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, a unit dosage form contains an entire single dose of the agent. In some embodiments, more than one unit dosage form is administered to achieve a total single dose. In some embodiments, administration of multiple unit dosage forms is required, or expected to be Page 42 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) required, in order to achieve an intended effect. A unit dosage form may be, for a solid pharmaceutical composition (e.g., a capsule or a tablet) containing a predetermined amount of an active agent (e.g., a compound of Formula I).

[0204] Provided compositions may be administered in accordance with a dosing regimen thatincludes a single dose or multiple doses separated from one another in time, administered via a particular route of administration that is demonstrated to be effective for treating (e.g., delaying onset of and / or decreasing incidence and / or intensity of) a disease or disorder, for example, as described herein.

[0205] In some embodiments, provided compositions are administered orally.EXAMPLES Example 1. Matrix Screening for Amorphous Solid Dispersion Formulations

[0206] Various matrix materials were screened and evaluated for use in an amorphous soliddispersion formulation of a MNK inhibitor. Briefly, Compound 2 and polymer (collectively, 1 mg) were dissolved individually in a solvent or solvent mixture and then mixed together in a centrifuge tube. Solvent was removed using a vacuum concentrator. The resulting solid was reconstituted in 1 mL phosphate buffer (pH 6.8), and the samples were mixed for 4, 10, and 30 minutes. The samples were then analyzed by UV spectrometry (absorbance at 360 nm). The formulations used in this study are summarized in Table 1.1. Table 1.1. Formulation No. API-Polymer Combination1Ratio (w / w)AS- H = hydroxypropyl methylcellulose acetate succinate grade H; HPMC E5 = hydroxypropyl methylcellulose ether; HPC SSL = hydroxypropyl cellulose SSL; HPMCAS-L = hydroxypropyl Page 43 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) methylcellulose acetate succinate grade L; TPGS = α-tocopherol polyethylene glycol succinate; SLS = sodium lauryl sulfate.

[0207] Redissolution behavior of the material obtained from Formulations 1-5 is shown inFIG. 1. HPMC-P55 (Formulation 1) displayed the best redissolution behavior with a 30% drug load. All formulations tested displayed better redissolution than Compound 2 (API) alone.

[0208] Redissolution behavior of the material obtained from Formulations 6-10 is shown inFIG.2. Formulation 9, using poloxamer 407, displayed the best redissolution behavior with a 25% drug load. All formulations tested displayed better redissolution than Compound 2 (API) alone.

[0209] The matrix compositions prepared from Formulations 1 and 9 were analyzed by XRPD.The XRPD spectra are shown in FIG. 3 and FIG. 4, respectively, and indicated that the material was amorphous.

[0210] XRPD spectra were collected using the following parameters:X-ray 40 kV, 15 mAExample 2. Preparation of Formulation 9

[0211] Formulation 9 was prepared as follows: Three stock solutions were prepared inTHF / Water (9:1) – 2 mg / mL Compound 2; 10 mg / mL HPMC-P55; and 5 mg / mL poloxamer 407. 500 µL of Compound 2 stock solution, 280 µL of HPMC-P55 stock solution, and 40 µL of poloxamer 407 stock solution were added to a 2 mL centrifuge tube. The tube was vortexed for 20 seconds. The open tube was then placed into the chamber of a Savant SpeedVac Concentrator SPD121P with a vacuum pump OFP400 and Savant Refrigerated Vapor Trap RVT5105 and dried for ~2 h at 45 °C with RC light and vacuum on.

[0212] Other formulations described herein can be prepared analogously.Page 44 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) Example 3. Rat Pharmacokinetic Studies with Amorphous Solid Dispersion Formulations

[0213] Pharmacokinetic studies of the formulation from Formulations 1 and 9 were conductedin rats. Three oral dosing groups were used, including Formulation 1 (in 50 mM PBS, pH 6.8) (Group 3), Formulation 9 (in 50 mM PBS, pH 6.8) (Group 4), and a water-based formulation (“API_PO”) comprising Compound 2 in 10% DMSO, 10% TPGS, 20% PG (propylene glycol), 30% PEG 400, and 30% sterile water with 0.01 mL 1N HCl, pH 5 (Group 2). One IV dosing group (Group 1) was also included, using a formulation comprising Compound 2 in 10% DMSO, 50% PEG 400, and 40% water. The dose volume was 5 mL / kg for IV and 10 mL / kg for PO.

[0214] Eight female Sprague-Dawley rats were used in the study. 3-4 days prior to dosing,jugular vein cannulation (JVC) surgery was performed in a laminar flow cabinet. Prior to dosing, the animals were randomly divided into 4 groups (2 rats per group). 2 animals (Group 1) were dosed by IV administration at 0.5 mg / kg with a dosing volume of 5 mL / kg, and the other 6 animals (Groups 2 - 4) were dosed by PO administration at 10 mg / kg with a dosing volume of 10 mL / kg. Plasma (~0.25 mL per time point) was collected via jugular vein into EDTA-K2 tubes at the following time-points: 0.0833 (IV), 0.25, 0.5, 1, 2, 4, 8 and 24 hr post-dose. Immediately following plasma collection, the samples were put on wet ice and then stored at -20 °C during the duration of the study (24 hr post-dose). After the last sample was collected, the samples were transferred to a -80 °C freezer for storage. Plasma concentrations of Compound 2 were then analyzed.

[0215] FIG. 5 shows concentration-time curves of Compound 2 formulations in female rats.Formulation 9 provided the best exposure in a clinically suitable oral formulation, though Formulation 1 also performed well. It will be appreciated that a “clinically suitable” formulation comprises excipients that are known to be safe and acceptable for use in humans, such as the pharmaceutically acceptable polymer and surfactant used in Formulations 1 and 9.

[0216] Table 2.1 summarizes rat PK properties of different Compound 2 formulations.Compared to a water-based vehicle (row 1), Formulation 9 (row 2) showed a 3x increase in AUC exposure (dose-normalized); a 1.5x increase in Cmax (dose-normalized); a 2.5x increase in oral bioavailability; and an earlier Tmax. Higher exposure and bioavailability, like that demonstrated by Formulation 9, are desirable PK attributes for drug development. Table 2.1. Page 45 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) Dose Level AUClasSex T mg / kg Formulation1 / 2TmaxCmaxtF h h (n / mL) (hr*ng (%) .5.4.9xamp e . yn es s an o og ca c v y o ompoun

[0217] Compound 3 was prepared according to the following scheme:,deuterated methyl boronic acid Int-1 (0.009 g, 0.147 mmol), Pd(OAc)2 (0.001 g, 0.005 mmol), tricyclohexylphosphine tetrafluoroboroate salt (0.004 g, 0.010 mmol), K3PO4 (0.031 g, 0.147 mmol), and 9:11,4-dioxane:water (3.2 mL). The mixture was degassed and then sealed under N2and irradiated (30 min, 140 °C, Anton Paar Monowave 300). Water (10 mL) and 3:1 chloroform:isopropanol (20 mL) were added to the reaction mixture. The layers were separated and the aqueous layer was extracted with additional 3:1 chloroform:isopropanol (2 x 20 mL). The organic layers were combined and concentrated in vacuo to about 10 mL. The 10 mL of solution was divided among 10 prep plates (SiO2, 20 cm x 20 cm, 1000 micron thickness) that were eluted with 19:1 chloroform:0.25M NH3in MeOH to afford Compound 3 (9.2 mg, 50%).1H NMR (400 MHz, DMSO) δ 10.05 (s, 1H), 8.63 (s, 1H), 8.40 (s, 1H), 8.18 (s, 1H), 6.51 (s, 2H), 6.15 (s, 1H), Page 46 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) 3.30 – 3.18 (m, 1H), 2.23 – 2.09 (m, 2H), 1.51 – 1.32 (m, 2H), 0.97 – 0.84 (m, 2H), 0.47 – 0.36 (m, 2H), 0.36 – 0.27 (m, 2H). HPLC-MS (ESI): m / z 370.5 [M+H]+.

[0219] Compound 3 had an IC50 value of 114 nM against MNK1 and 4.9 nM against MNK2in the following assay, measuring inhibition of MNK: Recombinant full-length human kinase MNK1 or MNK2 was expressed in insect cells. In a radiometric activity assay, the test compound was incubated with MNK1 or MNK2 kinase, substrate, cofactors, and radioisotope-labeled ATP, and % kinase activity determined based upon the extent of substrate phosphorylation.

[0220] Compound 3 had an IC50 value of 6.5 nM in the following HEK cell assay: The abilityof Compound 3 to inhibit eIF4E phosphorylation at Serine 209 in the human embryonic kidney (HEK) 293 cell line was tested by exposing the cells to compound for 2 hours and then measuring eIF4E phosphorylation with a phosphorylation-specific antibody in a fluorescent plate reader. These experiments were done with HEK-293 cells plated on 96 well plates. Following treatment, cells were fixed with ice cold methanol for 10 min and then washed in 1X phosphate buffered saline (PBS) and the permeabilized with 0.02% Triton X-100 in 10% normal goat serum made up in PBS. Primary antibody was applied overnight at a concentration dilution of 1:2000 (p-eIF4E antibody from Cell Signaling ab76256). Following washing, cells were then exposed to secondary antibody conjugated to alexa-fluor 488 and then visualized on a Syngergy HTX plate reader. Fluorescence for p-eIF4E was measured and normalized to total DAPI fluorescence to determine the percentage of eIF4E phosphorylation in each well. Data were plotted in Graphpad Prism V8 to determine concentration-response effects and calculate IC50values. Example 5. Polymer Screening for Spray-dried Dispersion Compositions

[0221] Spray-dried dispersion compositions comprising Compound 1 and variouspharmaceutically acceptable polymers in a ratio of 30:70 were prepared and tested in a two-stage dissolution test using the following protocol: Approximately 2.25 mg equivalent of Compound 1 (9.0 mg of SDD) was weighed into a vial.1.5 mL of 0.01 M HCl (pre-warmed to 37 °C) was added to the vial, and the sample was mixed in a heated shaker block at 37 °C. After about 15 minutes, an aliquot was removed and centrifuge filtered for determination of the solution concentration by HPLC. At about 20 minutes, 3.0 mL of modified fasted simulated intestinal fluid (pre-warmed to 37 °C) was added, and the sample was continued to be mixed in the heated shaker block at 37 Page 47 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) °C. Additional samples were removed and centrifuge filtered for determination of the solution concentration by HPLC over the next 2-4 hours.

[0222] Results are shown in FIG. 6. In FIG. 6, time 0 on the y-axis represents the shift fromsimulated stomach conditions to simulated intestinal conditions. Absorption is expected to occur in the intestine. As shown in FIG.6, Compound 1 alone had very low concentrations in solution (2-3 ug / mL) during the simulated intestinal conditions, and Compound 1 rapidly crystallized out of solution in the simulated intestinal fluid. Spray-dried dispersions of Compound 1 with various pharmaceutically acceptable polymers resulted in higher solubility in simulated intestinal conditions, which enables higher absorption. Example 6. Drug Load Screening for Spray-dried Dispersion Compositions

[0223] Spray-dried dispersion compositions comprising Compound 1 and HPMC-ASH indifferent ratios were tested in both one-stage and two-stage dissolution experiments. The one-stage dissolution experiments were performed as described in Example 5, but the material was dissolved only in modified fasted simulated intestinal fluid. The two-stage dissolution experiments were performed as described in Example 5.

[0224] Results of the drug load screening experiments are shown in FIG. 7. Spray-drieddispersion compositions comprising Compound 1 at both 20 wt% and 25 wt% displayed suitable dissolution profiles. Example 7. Preparation of Formulation 11

[0225] Compound 1 hemihydrate (5.01 g) was stirred with 841 g of THF and 105.11 g of waterat 30 °C. The mixture was filtered and 14.67 g of HPMC-ASH was added. The resulting hazy solution was spray dried on a Buchi S-300 with a 130 °C inlet temperature, 30 m3 / h drying gas flow rate, 1000 L / h spray gas flow rate, and 20 mL / min pump rate. The resulting solids were collected and subjected to secondary drying at 50 °C for 3 days. The resulting spray-dried solid dispersion (17.26 g, 88% yield) was isolated as a white powder (“Formulation 11”).

[0226] Formulation 11 was amorphous by XRPD (FIG. 8) and had a Tg (glass transition)temperature of 120 °C (FIG.9).

[0227] While we have described a number of embodiments of this invention, it is apparent thatour basic examples may be altered to provide other embodiments that utilize compositions and Page 48 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example. Page 49 of 60 BUSINESS.33096897.1

Claims

Docket No.: 408994-410WO (219446) CLAIMS 1. A composition comprising: a compound of Formula I or a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable polymer; and optionally a surfactant, wherein the compound of Formula I is: wherein R is halogen2. The composition of claim 1, wherein the composition comprises about 10 wt% to about 30 wt% of the compound of Formula I.

3. The composition of claim 2, wherein the composition comprises about 30 wt% of the compound of Formula I.

4. The composition of claim 2, wherein the composition comprises about 25 wt% of the compound of Formula I.

5. The composition of any one of claims 1-4, wherein the compound of Formula I is Compound 1:Page 50 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) 6. The composition of any one of claims 1-4, wherein the compound of Formula I is Compound 2:

7. The composition of any one of claims 1-4, wherein the compound of Formula I is Compound 3:

8. The composition of any one of claims 1-7, wherein the composition comprises about 70 wt% to about 90 wt% pharmaceutically acceptable polymer.

9. The composition of claim 8, wherein the composition comprises about 70 wt% pharmaceutically acceptable polymer.

10. The composition of any one of claims 1-9, wherein the pharmaceutically acceptable polymer is or comprises hydroxypropyl methylcellulose.

11. The composition of any one of claims 8-10, wherein the pharmaceutically acceptable polymer is or comprises hydroxypropyl methylcellulose phthalate. Page 51 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) 12. The composition of claim 11, wherein the polymer is or comprises HPMC-P55.

13. The composition of any one of claims 1-10, wherein the pharmaceutically acceptable polymer is at least one of HPMC-P55, HPMCAS-H, HPMC E5, HPC SSL, HPMCAS-L, or a combination of one or more thereof.

14. The composition of any one of claims 1-13, wherein the composition comprises a surfactant.

15. The composition of claim 14, wherein the composition comprises about 5 wt% surfactant.

16. The composition of claim 14 or 15, wherein the surfactant is a poloxamer.

17. The composition of claim 16, wherein the surfactant is poloxamer 407.

18. The composition of claim 14 or 15, wherein the surfactant is selected from TPGS, Kolliphor RH40, sodium lauryl sulfate, poloxamer 407, and poloxamer 188.

19. The composition of any one of claims 1-18, wherein the composition is an amorphous solid dispersion.

20. The composition of any one of claims 1-19, wherein the composition is amorphous (e.g., when measured by XRPD).

21. The composition of any one of claims 1-20, wherein the composition is formulated for oral administration (e.g., as a tablet or capsule).

22. The composition of any one of claims 1-20, wherein the composition is reconstituted in phosphate-buffered saline before administration. Page 52 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) 23. The composition of any one of claims 1-22, wherein when about 1 mg of the composition is reconstituted in about 1 mL phosphate buffer (pH 6.8) (e.g., as described in Example 1), the concentration of the compound of Formula I is at least 5 µg / mL.

24. The composition of any one of claims 1-22, wherein when about 1 mg of the composition is reconstituted in about 1 mL phosphate buffer (pH 6.8) (e.g., as described in Example 1), the concentration of the compound of Formula I is at least 20 µg / mL.

25. The composition of any one of claims 1-24, wherein the composition achieves one or more of the following: an increased AUC exposure; an increased Cmax; an increased oral bioavailability; or an earlier Tmax, when orally administered to rats, compared to a formulation comprising the compound of Formula (I) in 0.5% HPMC / H2O + 0.1 N HCl (pH 5).

26. The composition of claim 25, wherein the composition achieves one or more of the following: about 3 times greater AUC exposure; about 1.5 times greater Cmax; about 2.5 times greater oral bioavailability; or about 3 hours earlier Tmax, when orally administered to rats, compared to a formulation comprising the compound of Formula (I) in 0.5% HPMC / H2O + 0.1 N HCl (pH 5).

27. A composition prepared by a process comprising: mixing a compound of Formula I or a pharmaceutically acceptable salt thereof, the pharmaceutically acceptable polymer, and optionally the surfactant, in a solvent (e.g., 9:1 THF / water); and removing the solvent, Page 53 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) wherein the compound of Formula I is: wherein R is halogen or28. A tablet comprising the composition of any one of claims 1-27 and, optionally, one or more pharmaceutically acceptable excipients.

29. A capsule comprising the composition of any one of claims 1-27 and, optionally, one or more pharmaceutically acceptable excipients.

30. A method of preparing the composition of any one of claims 1-26, the method comprising: mixing the compound of Formula I or a pharmaceutically acceptable salt thereof, the pharmaceutically acceptable polymer, and optionally the surfactant, in a solvent (e.g., 9:1 THF / water); and removing the solvent to provide the composition.

31. A spray-dried dispersion composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable polymer, wherein the compound of Formula I is:wherein R is halogen or optionally substituted C1-6 aliphatic. Page 54 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) 32. The composition of claim 31, wherein the composition comprises about 10 wt% to about 30 wt% of the compound of Formula I.

33. The composition of claim 32, wherein the composition comprises about 25 wt% of the compound of Formula I.

34. The composition of any one of claims 31-33, wherein the compound of Formula I is Compound 1:

35. The composition of any one of claims 31-33, wherein the compound of Formula I is Compound 2:

36. The composition of any one of claims 31-33, wherein the compound of Formula I is Compound 3: Page 55 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446)37. The composition of any one of claims 31-36, wherein the composition comprises about 70 wt% to about 90 wt% pharmaceutically acceptable polymer.

38. The composition of claim 37, wherein the composition comprises about 75 wt% pharmaceutically acceptable polymer.

39. The composition of any one of claims 31-38, wherein the pharmaceutically acceptable polymer is or comprises hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose ether, an amino methacrylate copolymer, a methacrylic acid copolymer, a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer, or combinations thereof.

40. The composition of any one of claims 31-38, wherein the pharmaceutically acceptable polymer is or comprises hydroxypropyl methylcellulose.

41. The composition of any one of claims 31-40, wherein the pharmaceutically acceptable polymer is or comprises hydroxypropyl methylcellulose acetate succinate.

42. The composition of claim 41, wherein the pharmaceutically acceptable polymer is selected from HPMC-ASH, HPMC-ASM, HPMC-ASL, and combinations thereof.

43. The composition of any one of claims 31-42, wherein the pharmaceutically acceptable polymer is HPMC-ASH. Page 56 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) 44. The composition of any one of claims 31-42, wherein the pharmaceutically acceptable polymer is HPMC-ASM.

45. The composition of any one of claims 31-44, wherein the composition is formulated for oral administration (e.g., as a tablet or capsule).

46. The composition of any one of claims 31-45, wherein when about 9 mg of the composition is mixed in about 1.5 mL 0.01M HCl and about 3.0 mL of modified fasted simulated intestinal fluid at 37 °C (e.g., as described in Example 5), the concentration of the compound of Formula I is at least 0.015 mg / mL.

47. The composition of any one of claims 31-45, wherein when about 9 mg of the composition is mixed in about 1.5 mL 0.01M HCl and about 3.0 mL of modified fasted simulated intestinal fluid at 37 °C (e.g., as described in Example 5), the concentration of the compound of Formula I is at least 0.040 mg / mL.

48. A spray-dried dispersion composition prepared by a process comprising: mixing a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable polymer in a solvent (e.g., 9:1 THF:water v / v) to form a mixture; and spray-drying the mixture to provide the composition, wherein the compound of Formula I is:wherein R is halogen or optionally substituted C1-6 aliphatic.

49. A tablet comprising the composition of any one of claims 31-48 and, optionally, one or more pharmaceutically acceptable excipients. Page 57 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) 50. A capsule comprising the composition of any one of claims 31-48 and, optionally, one or more pharmaceutically acceptable excipients.

51. A method of preparing the composition of any one of claims 31-48, the method comprising: mixing the compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable polymer in a solvent (e.g., 9:1 THF:water v / v) to form a mixture; and spray-drying the mixture to provide the composition.

52. A method of treating a subject in need thereof, comprising administering to the subject the composition of any one of claims 1-27 or 31-48, the tablet of claim 28 or 49, or the capsule of claim 29 or 50, wherein the subject is suffering from or susceptible to a disease, disorder, or condition associated with MNK.

53. Use of a composition of any one of claims 1-27 or 31-48 in the manufacture of a medicament for treating a subject suffering from or susceptible to a disease, disorder, or condition associated with MNK.

54. A composition of any one of claims 1-27 or 31-48, the tablet of claim 28 or 49, or the capsule of claim 29 or 50, for use in treating a subject suffering from or susceptible to a disease, disorder, or condition associated with MNK.

55. A method of treating a subject in need thereof, comprising administering to the subject the composition of any one of claims 1-27 or 31-48, the tablet of claim 28 or 49, or the capsule of claim 29 or 50, wherein the subject is suffering from or susceptible to a disease, disorder, or condition selected from migraine, rheumatoid arthritis, neuropathic pain, post-surgical pain, chronic lower back pain, pain associated with rheumatoid arthritis, and pain associated with osteoarthritis.

56. Use of a composition of any one of claims 1-27 or 31-48 in the manufacture of a medicament for treating a subject suffering from or susceptible to a disease, disorder, or condition Page 58 of 60 BUSINESS.33096897.1Docket No.: 408994-410WO (219446) selected from migraine, rheumatoid arthritis, neuropathic pain, post-surgical pain, chronic lower back pain, pain associated with rheumatoid arthritis, and pain associated with osteoarthritis.

57. A composition of any one of claims 1-27 or 31-48, the tablet of claim 28 or 49, or the capsule of claim 29 or 50, for use in treating a subject suffering from or susceptible to a disease, disorder, or condition selected from migraine, rheumatoid arthritis, neuropathic pain, post-surgical pain, chronic lower back pain, pain associated with rheumatoid arthritis, and pain associated with osteoarthritis. Page 59 of 60 BUSINESS.33096897.1

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